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<table styleCode="Noautorules" width="96.56%"><col width="84%"/><col width="16%"/><tbody><tr><td valign="top"><paragraph>Boxed Warning</paragraph><paragraph>Dosage and Administration (<linkHtml href="#s2">2</linkHtml>)</paragraph><paragraph>Warnings and Precautions (<linkHtml href="#s5p1">5.1</linkHtml>)</paragraph></td><td valign="top"><paragraph>6/2025</paragraph><paragraph>6/2025</paragraph><paragraph>6/2025</paragraph></td></tr><tr><td valign="top"><paragraph>Warnings and Precautions (<linkHtml href="#s5p6">5.5</linkHtml>)</paragraph></td><td valign="top"><paragraph>1/2025</paragraph></td></tr></tbody></table>

WARNING: SEVERE NEUTROPENIA; ORTHOSTATIC HYPOTENSION, BRADYCARDIA, AND SYNCOPE; SEIZURE; MYOCARDITIS, PERICARDITIS AND CARDIOMYOPATHY; INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS Severe Neutropenia CLOZARIL has caused severe neutropenia which is associated with an increased risk of serious and potentially fatal infections. Prior to initiating CLOZARIL treatment, obtain baseline ANC(s). CLOZARIL initiation is not recommended in patients with a baseline ANC less than 1500/μL (less than 1000/μL for those with Benign Ethnic Neutropenia (also known as Duffy-null associated neutrophil count)). See recommendations for dosage modifications based on ANC levels during CLOZARIL treatment [see Dosage and Administration ( 2.3 , 2.4 )] . Consider a hematology consultation before initiating CLOZARIL or during CLOZARIL treatment [see Warnings and Precautions ( 5.1 )] . Orthostatic Hypotension, Bradycardia, Syncope Orthostatic hypotension, bradycardia, syncope, and cardiac arrest have occurred with CLOZARIL treatment. The risk is highest during the initial titration period, particularly with rapid dose escalation. These reactions can occur with the first dose, with doses as low as 12.5 mg per day, or when restarting patients who have had even a brief interruption in treatment with CLOZARIL. Initiate treatment at 12.5 mg once or twice daily; titrate slowly; and use divided dosages to minimize risk. Use CLOZARIL cautiously in patients with cardiovascular or cerebrovascular disease or conditions predisposing to hypotension (e.g., dehydration, use of antihypertensive medications) [see Dosage and Administration ( 2.2 , 2.6 ), Warnings and Precautions ( 5.2 )]. Seizures Seizures have occurred with CLOZARIL treatment. The risk is dose-related. Initiate treatment at 12.5 mg, titrate gradually, and use divided dosing. Use caution when administering CLOZARIL to patients with a history of seizures or other predisposing risk factors for seizure (CNS pathology, medications that lower the seizure threshold, alcohol abuse). Caution patients about engaging in any activity where sudden loss of consciousness could cause serious risk to themselves or others [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.4 )]. Myocarditis, Pericarditis, Cardiomyopathy and Mitral Valve Incompetence Fatal myocarditis and cardiomyopathy have occurred with CLOZARIL treatment. Discontinue CLOZARIL and obtain a cardiac evaluation upon suspicion of these reactions. Generally, patients with CLOZARIL-related myocarditis or cardiomyopathy should not be rechallenged with CLOZARIL. Consider the possibility of myocarditis, pericarditis, or cardiomyopathy if chest pain, tachycardia, palpitations, dyspnea, fever, flu-like symptoms, hypotension, or ECG changes occur [see Warnings and Precautions( 5.5 )] . Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. CLOZARIL is not approved for use in patients with dementia-related psychosis [see Warnings and Precautions ( 5.6 )]. WARNING: SEVERE NEUTROPENIA; ORTHOSTATIC HYPOTENSION, BRADYCARDIA, AND SYNCOPE; SEIZURE; MYOCARDITIS, PERICARDITIS AND CARDIOMYOPATHY; INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS See full prescribing information for complete boxed warning.

ed psychosis [see Warnings and Precautions ( 5.6 )]. WARNING: SEVERE NEUTROPENIA; ORTHOSTATIC HYPOTENSION, BRADYCARDIA, AND SYNCOPE; SEIZURE; MYOCARDITIS, PERICARDITIS AND CARDIOMYOPATHY; INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS See full prescribing information for complete boxed warning. • Severe Neutropenia: CLOZARIL has caused severe neutropenia, which is associated with an increased risk of serious and fatal infections. Prior to initiating CLOZARIL treatment, obtain baseline ANC(s). CLOZARIL initiation is not recommended in patients with a baseline ANC less than 1500/ μ L (less than 1000 μ L for those with Benign Ethnic Neutropenia (also known as Duffy-null associated neutrophil count)). See recommendations for dosage modifications based on ANC levels during CLOZARIL treatment ( 2.3 , 2.4 , 5.1 ) • Orthostatic Hypotension, Bradycardia, and Syncope: Risk is dose-related. Starting dose is 12.5 mg. Titrate gradually and use divided dosages. ( 2.2 , 2.6 , 5.2 ) • Seizure: Risk is dose-related. Titrate gradually and use divided doses. Use with caution in patients with history of seizure or risk factors for seizure. ( 2.2 , 5.4 ) • Myocarditis, Pericarditis, Cardiomyopathy and Mitral Valve Incompetence: Can be fatal. Discontinue and obtain cardiac evaluation if findings suggest these cardiac reactions. ( 5.5 ) • Increased Mortality in Elderly Patients with Dementia-Related Psychosis: CLOZARIL is not approved for this condition. ( 5.6 )

1 INDICATIONS AND USAGE CLOZARIL is an atypical antipsychotic indicated for: • Treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment. Because of the risks of severe neutropenia and of seizure associated with its use, CLOZARIL should be used only in patients who have failed to respond adequately to standard antipsychotic treatment ( 1.1 ) • Reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for re-experiencing suicidal behavior. ( 1.2 ) 1.1 Treatment-Resistant Schizophrenia CLOZARIL is indicated for the treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment. Because of the risks of severe neutropenia and of seizure associated with its use, CLOZARIL should be used only in patients who have failed to respond adequately to standard antipsychotic treatment [see Warnings and Precautions ( 5.1 , 5.4 )]. The effectiveness of CLOZARIL in treatment-resistant schizophrenia was demonstrated in a 6-week, randomized, double-blind, active-controlled study comparing CLOZARIL and chlorpromazine in patients who had failed other antipsychotics [see Clinical Studies ( 14.1 )] . 1.2 Reduction in the Risk of Recurrent Suicidal Behavior in Schizophrenia or Schizoaffective Disorder CLOZARIL is indicated for reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for re-experiencing suicidal behavior, based on history and recent clinical state. Suicidal behavior refers to actions by a patient that put him/herself at risk for death. The effectiveness of CLOZARIL in reducing the risk of recurrent suicidal behavior was demonstrated over a two-year treatment period in the InterSePT™ trial [see Clinical Studies ( 14.2 )] .

sed on history and recent clinical state. Suicidal behavior refers to actions by a patient that put him/herself at risk for death. The effectiveness of CLOZARIL in reducing the risk of recurrent suicidal behavior was demonstrated over a two-year treatment period in the InterSePT™ trial [see Clinical Studies ( 14.2 )] . 1.1 Treatment-Resistant Schizophrenia CLOZARIL is indicated for the treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment. Because of the risks of severe neutropenia and of seizure associated with its use, CLOZARIL should be used only in patients who have failed to respond adequately to standard antipsychotic treatment [see Warnings and Precautions ( 5.1 , 5.4 )]. The effectiveness of CLOZARIL in treatment-resistant schizophrenia was demonstrated in a 6-week, randomized, double-blind, active-controlled study comparing CLOZARIL and chlorpromazine in patients who had failed other antipsychotics [see Clinical Studies ( 14.1 )] . 1.2 Reduction in the Risk of Recurrent Suicidal Behavior in Schizophrenia or Schizoaffective Disorder CLOZARIL is indicated for reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for re-experiencing suicidal behavior, based on history and recent clinical state. Suicidal behavior refers to actions by a patient that put him/herself at risk for death. The effectiveness of CLOZARIL in reducing the risk of recurrent suicidal behavior was demonstrated over a two-year treatment period in the InterSePT™ trial [see Clinical Studies ( 14.2 )] .

2 DOSAGE AND ADMINISTRATION • Recommended starting oral dosage is 12.5 mg once daily or twice daily. ( 2.2 ) • If well-tolerated, increase the total daily dosage in increments of 25 mg to 50 mg per day to achieve a target dosage of 150 mg to 225 mg twice per day by the end of two weeks. ( 2.2 ) • Subsequently may increase the dosage in increments up to 100 mg once or twice weekly ( 2.2 ) • Maximum daily dosage is 450 mg twice daily. ( 2.2 ) • Administer with or without food. ( 2.2 ) • See the dosage modifications based on ANC results and recommended frequency of ANC testing in the full prescribing information. ( 2.3 , 2.4 ) • See recommendations for discontinuing CLOZARIL treatment ( 2.5 ), restarting CLOZARIL after interrupting dosing ( 2.6 ), dosage modifications for drug interactions( 2.7 ), dosage recommendations in patients with renal or hepatic impairment and CYP2D6 poor metabolizers ( 2.8 ) in the full prescribing information. 2.1 Absolute Neutrophil Count Testing Prior to CLOZARIL Initiation Prior to initiating CLOZARIL treatment, obtain a baseline absolute neutrophil count (ANC). CLOZARIL initiation is not recommended in patients with an ANC less than 1500/μL [see Warnings and Precautions ( 5.1 )] . For patients with documented Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count), obtain at least two baseline ANC levels. CLOZARIL initiation is not recommended in patients with BEN with an ANC less than 1000/μL [see Warnings and Precautions ( 5.1 )] . For dosage modifications based on ANC results, see Dosage and Administration ( 2.3 , 2.4 ). 2.2 Recommended Dosage and Administration To reduce the risk of orthostatic hypotension, bradycardia, and syncope, the recommended starting dosage is much lower than the target dosage [see Warnings and Precautions ( 5.2 )] . CLOZARIL can be taken with or without food [see Clinical Pharmacology ( 12.3 )]. The recommended starting oral dosage of CLOZARIL is 12.5 mg once or twice daily. If well-tolerated, increase the total daily dose in increments of 25 mg to 50 mg per day to achieve a target dosage of 150 mg to 225 mg twice per day by the end of two weeks. Subsequently, may increase the dosage in increments of up to 100 mg once weekly or twice weekly. The maximum recommended CLOZARIL oral dosage is 450 mg twice daily. 2.3 Dosage Modifications Based on ANC Results Table 1 provides recommended CLOZARIL dosage modifications based on ANC results [see Warnings and Precautions ( 5.1 )]. For dosage modifications based on ANC results for patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count), see Table 2 [see Dosage and Administration ( 2.4 )]. Table 1.

des recommended CLOZARIL dosage modifications based on ANC results [see Warnings and Precautions ( 5.1 )]. For dosage modifications based on ANC results for patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count), see Table 2 [see Dosage and Administration ( 2.4 )]. Table 1. CLOZARIL Dosage Modifications Based on ANC Results and Frequency of ANC Testing Recommended Dosage Modification Recommended Frequency of ANC Testing During CLOZARIL Treatment ANC Within Normal Range (≥ 1500/μL) No dosage modification; continue treatment • Day 1 to Month 6: Weekly • Month 7 to Month 12: Every 2 weeks • Month 13 and thereafter: Every month If CLOZARIL treatment is reinitiated after a dosage interruption (e.g., patient had neutropenia which required dosage interruption and now has a normal ANC level) for: • < 30 days, continue the previous ANC testing frequency • ≥ 30 days, obtain ANC tests according to the frequency for patients who initiate treatment Mild Neutropenia (ANC between 1000 to 1499/μL) Confirm all initial reports of ANC less than 1500/μL with a repeat ANC measurement within 24 hours. No dosage modification; continue treatment • Three times weekly • Once ANC ≥ 1500/μL, recommend returning to the patient’s last Normal Range ANC testing frequency Moderate Neutropenia (ANC between 500 to 999/μL) • Interrupt treatment and recommend hematology consultation • Resume treatment once ANC ≥1000/μL • Daily • Once ANC ≥ 1000/μL, three times weekly • Once ANC ≥ 1500/μL, test weekly for 4 weeks. If ANC ≥ 1500/μL after monitoring weekly for 4 weeks, return to the patient’s last Normal Range ANC testing frequency Severe Neutropenia (ANC less than 500/μL) Discontinue treatment and recommend hematology consultation • Daily • Once ANC ≥ 1000/μL, three times weekly • Once ANC ≥ 1500/μL, if the benefits outweigh the risks of restarting treatment, resume treatment and obtain ANC tests according to the frequency for patients who initiate treatment 2.4 Dosage Modifications Based on ANC Results for Patients with Benign Ethnic Neutropenia Table 2 provides recommended CLOZARIL dosage modifications based on ANC results for patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count) [see Warnings and Precautions ( 5.1 )] . For dosage modifications based on ANC results for patients without BEN, see Table 1 [see Dosage and Administration ( 2.3 )]. Table 2. CLOZARIL Dosage Modifications Based on ANC Results and Frequency of ANC Testing in Patients with Benign Ethnic Neutropenia Benign Ethnic Neutropenia (BEN) is also known as Duffy-null associated neutrophil count. Recommended Dosage Modification Recommended Frequency of ANC Testing During CLOZARIL Treatment in Patients with BEN ANC Within the Normal Range for Patients with BEN (≥ 1000/μL ) No dosage modification; continue treatment • Day 1 to Month 6: Weekly • Month 7 to Month 12: Every 2 weeks • Month 13 and thereafter: Monthly If CLOZARIL treatment is reinitiated after a dosage interruption (e.g., patient had neutropenia which required dosage interruption and now their ANC (≥ 1000/μL and ≥ the patient’s ANC baseline prior to treatment) for: • < 30 days, continue previous ANC testing frequency • ≥ 30 days, obtain ANC tests according to the frequency for patients with BEN who initiate treatment Neutropenia in Patients with BEN (ANC level between 500 to 999/μL) Confirm all initial reports of ANC less than 1500/μL with a repeat ANC measurement within 24 hours.

< 30 days, continue previous ANC testing frequency • ≥ 30 days, obtain ANC tests according to the frequency for patients with BEN who initiate treatment Neutropenia in Patients with BEN (ANC level between 500 to 999/μL) Confirm all initial reports of ANC less than 1500/μL with a repeat ANC measurement within 24 hours. • Recommend hematology consultation • No dosage modification; continue treatment • Three times weekly • Once ANC ≥ 1000/μL and ≥ the patient’s ANC baseline, obtain ANC tests weekly for 4 weeks • If ANC ≥1000/μL and ≥ the patient’s baseline after monitoring for 4 weeks, return to the patient’s last Normal ANC Range testing frequency for patients with BEN Severe Neutropenia in Patients with BEN (ANC level less than 500/μL) Discontinue treatment and recommend hematology consultation • Daily • Once ANC ≥ 500/μL, obtain ANC three times weekly • Once ANC ≥ 1000/μL and ≥ the patient’s baseline, if the benefits outweigh the risks of restarting treatment, resume treatment and obtain ANC tests according to the frequency for patients with BEN who initiate treatment 2.5 Discontinuation of CLOZARIL Treatment If discontinuing CLOZARIL in patients with: • Moderate or severe neutropenia, see Table 1 [see Dosage and Administration ( 2.3 )]. • Normal or mild neutropenia, reduce the dosage gradually over a period of 1 to 2 weeks, and continue monitoring ANC levels until their ANC is ≥1500/μL. If discontinuing CLOZARIL in patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count) with: • Neutropenia, see Table 2 [see Dosage and Administration ( 2.4 )]. • ANC within their normal range of ANC reduce the dosage gradually over a period of 1 to 2 weeks. When discontinuing CLOZARIL, monitor patients for the symptoms related to psychotic recurrence and cholinergic rebound (e.g., profuse sweating, headache, nausea, vomiting, diarrhea). 2.6 Restarting CLOZARIL Treatment After Interrupting CLOZARIL When restarting CLOZARIL in patients who have interrupted CLOZARIL treatment, use a lower dosage to minimize the risk of hypotension, bradycardia, and syncope [see Warnings and Precautions ( 5.2 )] . • If one day’s dosage is missed, resume CLOZARIL treatment at 40% to 50% of the previous dosage. • If two days of dosing is missed, resume CLOZARIL treatment at approximately 25% of the previous dosage. • For longer interruptions, restart CLOZARIL treatment with a dosage of 12.5 mg once or twice daily. If this dosage is well-tolerated, may increase the dosage to the previous dosage more quickly than recommended than for initial CLOZARIL treatment. 2.7 Dosage Modifications for Drug Interactions See Table 3 for recommended dosage modifications to reduce the risk of CLOZARIL-associated adverse reactions or reduce the risk of lower effectiveness [see Drug Interactions ( 7 )]. Table 3. CLOZARIL Dosage Modifications for Drug Interactions Strong CYP1A2 Inhibitors Administer one third of the CLOZARIL dosage. Moderate or Weak CYP1A2 Inhibitors Consider reducing the CLOZARIL dosage if necessary. CYP2D6 or CYP3A4 Inhibitors Strong CYP3A4 Inducers Concomitant use is not recommended. However, if concomitant use is necessary, it may be necessary to increase the CLOZARIL dosage. Monitor for decreased effectiveness. Moderate or weak CYP1A2 or CYP3A4 Inducers Consider increasing the CLOZARIL dosage if necessary. 2.8 Dosage Recommendations in Patients with Renal or Hepatic Impairment, or CYP2D6 Poor Metabolizers It may be necessary to reduce the CLOZARIL dosage in patients with significant renal impairment or hepatic impairment, or in CYP2D6 poor metabolizers [see Use in Specific Populations ( 8.6 , 8.7 )].

dosage if necessary. 2.8 Dosage Recommendations in Patients with Renal or Hepatic Impairment, or CYP2D6 Poor Metabolizers It may be necessary to reduce the CLOZARIL dosage in patients with significant renal impairment or hepatic impairment, or in CYP2D6 poor metabolizers [see Use in Specific Populations ( 8.6 , 8.7 )]. 2.1 Absolute Neutrophil Count Testing Prior to CLOZARIL Initiation Prior to initiating CLOZARIL treatment, obtain a baseline absolute neutrophil count (ANC). CLOZARIL initiation is not recommended in patients with an ANC less than 1500/μL [see Warnings and Precautions ( 5.1 )] . For patients with documented Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count), obtain at least two baseline ANC levels. CLOZARIL initiation is not recommended in patients with BEN with an ANC less than 1000/μL [see Warnings and Precautions ( 5.1 )] . For dosage modifications based on ANC results, see Dosage and Administration ( 2.3 , 2.4 ). 2.2 Recommended Dosage and Administration To reduce the risk of orthostatic hypotension, bradycardia, and syncope, the recommended starting dosage is much lower than the target dosage [see Warnings and Precautions ( 5.2 )] . CLOZARIL can be taken with or without food [see Clinical Pharmacology ( 12.3 )]. The recommended starting oral dosage of CLOZARIL is 12.5 mg once or twice daily. If well-tolerated, increase the total daily dose in increments of 25 mg to 50 mg per day to achieve a target dosage of 150 mg to 225 mg twice per day by the end of two weeks. Subsequently, may increase the dosage in increments of up to 100 mg once weekly or twice weekly. The maximum recommended CLOZARIL oral dosage is 450 mg twice daily.

increase the total daily dose in increments of 25 mg to 50 mg per day to achieve a target dosage of 150 mg to 225 mg twice per day by the end of two weeks. Subsequently, may increase the dosage in increments of up to 100 mg once weekly or twice weekly. The maximum recommended CLOZARIL oral dosage is 450 mg twice daily. 2.3 Dosage Modifications Based on ANC Results Table 1 provides recommended CLOZARIL dosage modifications based on ANC results [see Warnings and Precautions ( 5.1 )]. For dosage modifications based on ANC results for patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count), see Table 2 [see Dosage and Administration ( 2.4 )]. Table 1. CLOZARIL Dosage Modifications Based on ANC Results and Frequency of ANC Testing Recommended Dosage Modification Recommended Frequency of ANC Testing During CLOZARIL Treatment ANC Within Normal Range (≥ 1500/μL) No dosage modification; continue treatment • Day 1 to Month 6: Weekly • Month 7 to Month 12: Every 2 weeks • Month 13 and thereafter: Every month If CLOZARIL treatment is reinitiated after a dosage interruption (e.g., patient had neutropenia which required dosage interruption and now has a normal ANC level) for: • < 30 days, continue the previous ANC testing frequency • ≥ 30 days, obtain ANC tests according to the frequency for patients who initiate treatment Mild Neutropenia (ANC between 1000 to 1499/μL) Confirm all initial reports of ANC less than 1500/μL with a repeat ANC measurement within 24 hours. No dosage modification; continue treatment • Three times weekly • Once ANC ≥ 1500/μL, recommend returning to the patient’s last Normal Range ANC testing frequency Moderate Neutropenia (ANC between 500 to 999/μL) • Interrupt treatment and recommend hematology consultation • Resume treatment once ANC ≥1000/μL • Daily • Once ANC ≥ 1000/μL, three times weekly • Once ANC ≥ 1500/μL, test weekly for 4 weeks. If ANC ≥ 1500/μL after monitoring weekly for 4 weeks, return to the patient’s last Normal Range ANC testing frequency Severe Neutropenia (ANC less than 500/μL) Discontinue treatment and recommend hematology consultation • Daily • Once ANC ≥ 1000/μL, three times weekly • Once ANC ≥ 1500/μL, if the benefits outweigh the risks of restarting treatment, resume treatment and obtain ANC tests according to the frequency for patients who initiate treatment

penia (ANC less than 500/μL) Discontinue treatment and recommend hematology consultation • Daily • Once ANC ≥ 1000/μL, three times weekly • Once ANC ≥ 1500/μL, if the benefits outweigh the risks of restarting treatment, resume treatment and obtain ANC tests according to the frequency for patients who initiate treatment 2.4 Dosage Modifications Based on ANC Results for Patients with Benign Ethnic Neutropenia Table 2 provides recommended CLOZARIL dosage modifications based on ANC results for patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count) [see Warnings and Precautions ( 5.1 )] . For dosage modifications based on ANC results for patients without BEN, see Table 1 [see Dosage and Administration ( 2.3 )]. Table 2. CLOZARIL Dosage Modifications Based on ANC Results and Frequency of ANC Testing in Patients with Benign Ethnic Neutropenia Benign Ethnic Neutropenia (BEN) is also known as Duffy-null associated neutrophil count. Recommended Dosage Modification Recommended Frequency of ANC Testing During CLOZARIL Treatment in Patients with BEN ANC Within the Normal Range for Patients with BEN (≥ 1000/μL ) No dosage modification; continue treatment • Day 1 to Month 6: Weekly • Month 7 to Month 12: Every 2 weeks • Month 13 and thereafter: Monthly If CLOZARIL treatment is reinitiated after a dosage interruption (e.g., patient had neutropenia which required dosage interruption and now their ANC (≥ 1000/μL and ≥ the patient’s ANC baseline prior to treatment) for: • < 30 days, continue previous ANC testing frequency • ≥ 30 days, obtain ANC tests according to the frequency for patients with BEN who initiate treatment Neutropenia in Patients with BEN (ANC level between 500 to 999/μL) Confirm all initial reports of ANC less than 1500/μL with a repeat ANC measurement within 24 hours. • Recommend hematology consultation • No dosage modification; continue treatment • Three times weekly • Once ANC ≥ 1000/μL and ≥ the patient’s ANC baseline, obtain ANC tests weekly for 4 weeks • If ANC ≥1000/μL and ≥ the patient’s baseline after monitoring for 4 weeks, return to the patient’s last Normal ANC Range testing frequency for patients with BEN Severe Neutropenia in Patients with BEN (ANC level less than 500/μL) Discontinue treatment and recommend hematology consultation • Daily • Once ANC ≥ 500/μL, obtain ANC three times weekly • Once ANC ≥ 1000/μL and ≥ the patient’s baseline, if the benefits outweigh the risks of restarting treatment, resume treatment and obtain ANC tests according to the frequency for patients with BEN who initiate treatment

nt and recommend hematology consultation • Daily • Once ANC ≥ 500/μL, obtain ANC three times weekly • Once ANC ≥ 1000/μL and ≥ the patient’s baseline, if the benefits outweigh the risks of restarting treatment, resume treatment and obtain ANC tests according to the frequency for patients with BEN who initiate treatment 2.5 Discontinuation of CLOZARIL Treatment If discontinuing CLOZARIL in patients with: • Moderate or severe neutropenia, see Table 1 [see Dosage and Administration ( 2.3 )]. • Normal or mild neutropenia, reduce the dosage gradually over a period of 1 to 2 weeks, and continue monitoring ANC levels until their ANC is ≥1500/μL. If discontinuing CLOZARIL in patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count) with: • Neutropenia, see Table 2 [see Dosage and Administration ( 2.4 )]. • ANC within their normal range of ANC reduce the dosage gradually over a period of 1 to 2 weeks. When discontinuing CLOZARIL, monitor patients for the symptoms related to psychotic recurrence and cholinergic rebound (e.g., profuse sweating, headache, nausea, vomiting, diarrhea). 2.6 Restarting CLOZARIL Treatment After Interrupting CLOZARIL When restarting CLOZARIL in patients who have interrupted CLOZARIL treatment, use a lower dosage to minimize the risk of hypotension, bradycardia, and syncope [see Warnings and Precautions ( 5.2 )] . • If one day’s dosage is missed, resume CLOZARIL treatment at 40% to 50% of the previous dosage. • If two days of dosing is missed, resume CLOZARIL treatment at approximately 25% of the previous dosage. • For longer interruptions, restart CLOZARIL treatment with a dosage of 12.5 mg once or twice daily. If this dosage is well-tolerated, may increase the dosage to the previous dosage more quickly than recommended than for initial CLOZARIL treatment.

resume CLOZARIL treatment at approximately 25% of the previous dosage. • For longer interruptions, restart CLOZARIL treatment with a dosage of 12.5 mg once or twice daily. If this dosage is well-tolerated, may increase the dosage to the previous dosage more quickly than recommended than for initial CLOZARIL treatment. 2.7 Dosage Modifications for Drug Interactions See Table 3 for recommended dosage modifications to reduce the risk of CLOZARIL-associated adverse reactions or reduce the risk of lower effectiveness [see Drug Interactions ( 7 )]. Table 3. CLOZARIL Dosage Modifications for Drug Interactions Strong CYP1A2 Inhibitors Administer one third of the CLOZARIL dosage. Moderate or Weak CYP1A2 Inhibitors Consider reducing the CLOZARIL dosage if necessary. CYP2D6 or CYP3A4 Inhibitors Strong CYP3A4 Inducers Concomitant use is not recommended. However, if concomitant use is necessary, it may be necessary to increase the CLOZARIL dosage. Monitor for decreased effectiveness. Moderate or weak CYP1A2 or CYP3A4 Inducers Consider increasing the CLOZARIL dosage if necessary. 2.8 Dosage Recommendations in Patients with Renal or Hepatic Impairment, or CYP2D6 Poor Metabolizers It may be necessary to reduce the CLOZARIL dosage in patients with significant renal impairment or hepatic impairment, or in CYP2D6 poor metabolizers [see Use in Specific Populations ( 8.6 , 8.7 )].

4 CONTRAINDICATIONS CLOZARIL is contraindicated in patients with a history of hypersensitivity to clozapine (e.g., photosensitivity, vasculitis, erythema multiforme, or Stevens-Johnson syndrome) or any other component of CLOZARIL [see Adverse Reactions ( 6.2 )]. Known hypersensitivity to clozapine or any other component of CLOZARIL. ( 4 )

5 WARNINGS AND PRECAUTIONS • Severe neutropenia : See Boxed Warnings ( 5.1 ) • Gastrointestinal Hypomotility with Severe Complications : Severe gastrointestinal adverse reactions have occurred with the use of CLOZARIL. If constipation is identified, close monitoring and prompt treatment is advised. ( 5.7 ) • Eosinophilia : Assess for organ involvement (e.g., myocarditis, pancreatitis, hepatitis, colitis, nephritis). Discontinue if these occur. ( 5.8 ) • QT Interval Prolongation : Can be fatal. Consider additional risk factors for prolonged QT interval (disorders and drugs). ( 5.9 ) • Metabolic Changes : Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include: 1. Hyperglycemia and Diabetes Mellitus : Monitor for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Monitor glucose regularly in patients with diabetes or at risk for diabetes. ( 5.10 ) 2. Dyslipidemia : Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics. ( 5.10 ) 3. Weight Gain : Significant weight gain has occurred. Monitor weight gain. ( 5.10 ) • Neuroleptic Malignant Syndrome (NMS) : Immediately discontinue and monitor closely. Assess for co-morbid conditions. ( 5.11 ) • Hepatotoxicity : Can be fatal. Monitor for hepatotoxicity. Discontinue treatment if hepatitis or transaminase elevations combined with other symptoms occur ( 5.12 ). • Fever : Evaluate for infection and for neutropenia, NMS. ( 5.13 ) • Pulmonary Embolism (PE) : Consider PE if respiratory distress, chest pain, or deep-vein thrombosis occur. ( 5.14 ) • Anticholinergic Toxicity : When possible, avoid use with other anticholinergic drugs and use with caution in patients with a current diagnosis or prior history of constipation, urinary retention, clinically significant prostatic hypertrophy, or other conditions in which anticholinergic effects can lead to significant adverse reactions. ( 5.15 , 7.1 ) • Interference with Cognitive and Motor Performance : Advise caution when operating machinery, including automobiles. ( 5.16 ) 5.1 Severe Neutropenia CLOZARIL has caused severe neutropenia (absolute neutrophil count (ANC) less than 500/μL) [see Adverse Reactions ( 6.1 , 6.2 )] and is associated with an increased risk of serious and potentially fatal infections. Severe neutropenia occurred in a small percentage of CLOZARIL-treated patients. The risk of severe neutropenia appears greatest during the first 18 weeks of CLOZARIL treatment. The mechanism by which CLOZARIL causes neutropenia is unknown. Neutropenia is not dose dependent. Consider a hematology consultation before initiating CLOZARIL treatment or during treatment. ANC Monitoring and Dosage Modifications Prior to initiating CLOZARIL treatment, obtain a baseline ANC. CLOZARIL initiation is not recommended in patients with a baseline ANC less than 1500/μL. Throughout CLOZARIL treatment, regularly monitor ANC. Table 1 provides recommendations for dosage modifications (dosage interruption and treatment discontinuation), based on ANC levels, during CLOZARIL treatment and frequency of ANC monitoring [see Dosage and Administration ( 2.3 )].

h a baseline ANC less than 1500/μL. Throughout CLOZARIL treatment, regularly monitor ANC. Table 1 provides recommendations for dosage modifications (dosage interruption and treatment discontinuation), based on ANC levels, during CLOZARIL treatment and frequency of ANC monitoring [see Dosage and Administration ( 2.3 )]. ANC Monitoring and Dosage Modification in Patients with Benign Ethnic Neutropenia Patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count) generally have lower baseline neutrophil counts but they are not at higher risk for developing infections, and they are not at increased risk for developing CLOZARIL-induced neutropenia. For patients with documented BEN, obtain at least two baseline ANC levels prior to CLOZARIL initiation. CLOZARIL initiation is not recommended in patients with BEN with an ANC less than 1000/μL. There are different ANC dosage modification recommendations in CLOZARIL-treated patients with BEN due to their lower baseline ANC levels. Table 2 provides recommendations on dosage modifications (dosage interruption and treatment discontinuation), based on ANC monitoring, during CLOZARIL treatment in patients with BEN and recommended frequency of ANC testing [see Dosage and Administration ( 2.4 )]. Management of CLOZARIL-Treated Patients Who Develop a Fever For patients who develop a fever during CLOZARIL treatment: • Interrupt CLOZARIL in those who develop a temperature of 101.3 °F (38.5 °C) or greater and obtain an ANC level. • If the ANC is less than 1000/μL in patients without BEN, initiate appropriate workup and treatment for infection. Refer to Table 1 or Table 2 for dosage modifications based on ANC monitoring [see Dosage and Administration ( 2.3 , 2.4 )]. In patients with fever and a normal neutrophil count, see Warnings and Precautions ( 5.11 ) for neuroleptic malignant syndrome and Warnings and Precautions ( 5.13 ) for fever. Restarting CLOZARIL in Patients Who Recovered from Severe Neutropenia Generally, do not rechallenge patients with CLOZARIL in those who experienced severe neutropenia. However, for some patients who had resolution of their CLOZARIL-related severe neutropenia after stopping CLOZARIL, the risk of schizophrenia exacerbation from not restarting CLOZARIL treatment may be greater than the risk of neutropenia reoccurrence from restarting CLOZARIL (e.g., patients who have no treatment options other than CLOZARIL). Concomitant Use of CLOZARIL with Other Drugs Known to Cause Neutropenia If CLOZARIL is used concomitantly with another drug known to cause neutropenia, consider more frequently ANC monitoring than the recommendations provided in Table 1 and Table 2 . 5.2 Orthostatic Hypotension, Bradycardia, and Syncope Hypotension, bradycardia, syncope, and cardiac arrest have occurred with clozapine treatment. The risk is highest during the initial titration period, particularly with rapid dose-escalation. These reactions can occur with the first dose, at doses as low as 12.5 mg. These reactions can be fatal. The syndrome is consistent with neurally mediated reflex bradycardia (NMRB). Treatment must begin at a maximum dose of 12.5 mg once daily or twice daily. The total daily dose can be increased in increments of 25 mg to 50 mg per day, if well-tolerated, to a target dose of 300 mg to 450 mg per day (administered in divided doses) by the end of 2 weeks. Subsequently, the dose can be increased weekly or twice weekly, in increments of up to 100 mg. The maximum dose is 900 mg per day. Use cautious titration and a divided dosage schedule to minimize the risk of serious cardiovascular reactions [see Dosage and Administration ( 2.2 )] . Consider reducing the dose if hypotension occurs.

, the dose can be increased weekly or twice weekly, in increments of up to 100 mg. The maximum dose is 900 mg per day. Use cautious titration and a divided dosage schedule to minimize the risk of serious cardiovascular reactions [see Dosage and Administration ( 2.2 )] . Consider reducing the dose if hypotension occurs. When restarting CLOZARIL in patients who have had even a brief interruption in treatment with CLOZARIL, the dosage must be reduced. This is necessary to minimize the risk of hypotension, bradycardia, and syncope [see Dosage and Administration (2.6 )]. Use CLOZARIL cautiously in patients with cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension (e.g., concomitant use of antihypertensives, dehydration and hypovolemia). 5.3 Falls CLOZARIL may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long‑term antipsychotic therapy. 5.4 Seizures Seizure has been estimated to occur in association with clozapine use at a cumulative incidence at one year of approximately 5%, based on the occurrence of one or more seizures in 61 of 1743 patients exposed to clozapine during its clinical testing prior to domestic marketing (i.e., a crude rate of 3.5%). The risk of seizure is dose-related. Initiate treatment with a low dose (12.5 mg), titrate slowly, and use divided dosing. Use caution when administering CLOZARIL to patients with a history of seizures or other predisposing risk factors for seizure (e.g., head trauma or other CNS pathology, use of medications that lower the seizure threshold, or alcohol abuse). Because of the substantial risk of seizure associated with CLOZARIL use, caution patients about engaging in any activity where sudden loss of consciousness could cause serious risk to themselves or others (e.g., driving an automobile, operating complex machinery, swimming, climbing). 5.5 Myocarditis, Pericarditis, Cardiomyopathy and Mitral Valve Incompetence Myocarditis, pericarditis and cardiomyopathy have occurred with the use of CLOZARIL. These reactions can be fatal. Discontinue CLOZARIL and obtain a cardiac evaluation upon suspicion of myocarditis, pericarditis, or cardiomyopathy. Generally, patients with a history of clozapine-associated myocarditis or cardiomyopathy should not be rechallenged with CLOZARIL. However, if the benefit of CLOZARIL treatment is judged to outweigh the potential risks of recurrence, the clinician may consider rechallenge with CLOZARIL in consultation with a cardiologist. Myocarditis and pericarditis most frequently presents within the first 2 months of clozapine treatment. Symptoms of cardiomyopathy generally occur later than clozapine-associated myocarditis or pericarditis and usually after 8 weeks of treatment. However, myocarditis, pericarditis and cardiomyopathy can occur at any period during treatment with CLOZARIL. In patients who are diagnosed with cardiomyopathy while taking CLOZARIL mitral valve incompetence has been reported. 5.6 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients.

treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality in this population. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. CLOZARIL is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning ] . 5.7 Gastrointestinal Hypomotility with Severe Complications Severe gastrointestinal adverse reactions have occurred with the use of CLOZARIL, primarily due to its potent anticholinergic effects and resulting gastrointestinal hypomotility. In post marketing experience, reported effects range from constipation to paralytic ileus. Increased frequency of constipation and delayed diagnosis and treatment increased the risk of severe complications of gastrointestinal hypomotility, which can result in fecal impaction, megacolon, and intestinal obstruction, ischemia, infarction, perforation, ulceration, or necrosis [see Adverse Reaction ( 6.2 )]. These reactions have resulted in hospitalization, surgery, and death. The risk of severe adverse reactions is further increased with anticholinergic medications (and other medications that decrease gastrointestinal peristalsis); therefore, concomitant use should be avoided when possible [see Warnings and Precautions ( 5.15 ), Drug Interactions ( 7.1 )]. Prior to initiating CLOZARIL, screen for constipation and treat as necessary. Subjective symptoms of constipation may not accurately reflect the degree of gastrointestinal hypomotility in CLOZARIL treated patients. Therefore, reassess bowel function frequently with careful attention to any changes in the frequency or character of bowel movements, as well as signs and symptoms of complications of hypomotility (e.g., nausea, vomiting, abdominal distension, abdominal pain). If constipation or gastrointestinal hypomotility are identified, monitor closely and treat promptly with appropriate laxatives, as necessary, to prevent severe complications. Consider prophylactic laxatives in high risk patients. 5.8 Eosinophilia Eosinophilia, defined as a blood eosinophil count of greater than 700/µL, has occurred with CLOZARIL treatment. In clinical trials, approximately 1% of patients developed eosinophilia. Clozapine-related eosinophilia usually occurs during the first month of treatment. In some patients, it has been associated with myocarditis, pancreatitis, hepatitis, colitis, and nephritis. Such organ involvement could be consistent with a drug reaction with eosinophilia and systemic symptoms syndrome (DRESS), also known as drug induced hypersensitivity syndrome (DIHS). If eosinophilia develops during CLOZARIL treatment, evaluate promptly for signs and symptoms of systemic reactions, such as rash or other allergic symptoms, myocarditis, or other organ-specific disease associated with eosinophilia. If CLOZARIL-related systemic disease is suspected, discontinue CLOZARIL immediately.

S). If eosinophilia develops during CLOZARIL treatment, evaluate promptly for signs and symptoms of systemic reactions, such as rash or other allergic symptoms, myocarditis, or other organ-specific disease associated with eosinophilia. If CLOZARIL-related systemic disease is suspected, discontinue CLOZARIL immediately. If a cause of eosinophilia unrelated to CLOZARIL is identified (e.g., asthma, allergies, collagen vascular disease, parasitic infections, and specific neoplasms), treat the underlying cause and continue CLOZARIL. Clozapine-related eosinophilia has also occurred in the absence of organ involvement and can resolve without intervention. There are reports of successful rechallenge after discontinuation of clozapine, without recurrence of eosinophilia. In the absence of organ involvement, continue CLOZARIL under careful monitoring. If the total eosinophil count continues to increase over several weeks in the absence of systemic disease, the decision to interrupt CLOZARIL therapy and rechallenge after the eosinophil count decreases should be based on the overall clinical assessment, in consultation with an internist or hematologist. 5.9 QT Interval Prolongation QT prolongation, Torsade de Pointes and other life-threatening ventricular arrhythmias, cardiac arrest, and sudden death have occurred with CLOZARIL treatment. When prescribing CLOZARIL, consider the presence of additional risk factors for QT prolongation and serious cardiovascular reactions. Conditions that increase these risks include the following: history of QT prolongation, long QT syndrome, family history of long QT syndrome or sudden cardiac death, significant cardiac arrhythmia, recent myocardial infarction, uncompensated heart failure, treatment with other medications that cause QT prolongation, treatment with medications that inhibit the metabolism of clozapine, and electrolyte abnormalities. Prior to initiating treatment with CLOZARIL, perform a careful physical examination, medical history, and concomitant medication history. Consider obtaining a baseline ECG and serum chemistry panel. Correct electrolyte abnormalities. Discontinue CLOZARIL if the QTc interval exceeds 500 msec. If patients experience symptoms consistent with Torsades de Pointes, or other arrhythmias (e.g., syncope, presyncope, dizziness, or palpitations), obtain a cardiac evaluation and discontinue CLOZARIL. Use caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of CLOZARIL. Drugs that cause QT prolongation include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, thioridazine, mesoridazine, droperidol, pimozide), specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin), Class 1A antiarrhythmic medications (e.g., quinidine, procainamide) or Class III antiarrhythmics (e.g., amiodarone, sotalol), and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus). Clozapine is primarily metabolized by CYP isoenzymes 1A2, 2D6, and 3A4. Concomitant treatment with inhibitors of these enzymes can increase the concentration of CLOZARIL [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 )] . Hypokalemia and hypomagnesemia increase the risk of QT prolongation. Hypokalemia can result from diuretic therapy, diarrhea, and other causes. Use caution when treating patients at risk for significant electrolyte disturbance, particularly hypokalemia. Obtain baseline measurements of serum potassium and magnesium levels, and periodically monitor electrolytes. Correct electrolyte abnormalities before initiating treatment with CLOZARIL.

rrhea, and other causes. Use caution when treating patients at risk for significant electrolyte disturbance, particularly hypokalemia. Obtain baseline measurements of serum potassium and magnesium levels, and periodically monitor electrolytes. Correct electrolyte abnormalities before initiating treatment with CLOZARIL. 5.10 Metabolic Changes Atypical antipsychotic drugs, including CLOZARIL have been associated with metabolic changes that can increase cardiovascular and cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While atypical antipsychotic drugs may produce some metabolic changes, each drug in the class has its own specific risk profile. Hyperglycemia and Diabetes Mellitus Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including CLOZARIL. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse reactions is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent, hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics are not available. Patients with an established diagnosis of diabetes mellitus who are started on CLOZARIL should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug. In a pooled data analysis of 8 studies in adult subjects with schizophrenia, the mean changes in fasting glucose concentration in the CLOZARIL and chlorpromazine groups were +11 mg/dL and +4 mg/dL respectively. A higher proportion of the CLOZARIL group demonstrated categorical increases from baseline in fasting glucose concentrations, compared to the chlorpromazine group ( Table 4 ). The CLOZARIL doses were 100–900 mg per day (mean modal dose: 512 mg per day). The maximum chlorpromazine dose was 1800 mg per day (mean modal dose: 1029 mg per day). The median duration of exposure was 42 days for CLOZARIL and chlorpromazine. Table 4.Categorical Changes in Fasting Glucose Level in Studies in Adult Subjects with Schizophrenia Laboratory Parameter Category Change (at least once) from baseline Treatment Arm N n (%) Fasting Glucose Normal (<100 mg/dL) to High (≥126 mg/dL) CLOZARIL 198 53 (27) Chlorpromazine 135 14 (10) Borderline (100 to 125 mg/dL) to High (≥126 mg/dL) CLOZARIL 57 24 (42) Chlorpromazine 43 12 (28) Dyslipidemia Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics, including CLOZARIL.

ose Normal (<100 mg/dL) to High (≥126 mg/dL) CLOZARIL 198 53 (27) Chlorpromazine 135 14 (10) Borderline (100 to 125 mg/dL) to High (≥126 mg/dL) CLOZARIL 57 24 (42) Chlorpromazine 43 12 (28) Dyslipidemia Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics, including CLOZARIL. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using CLOZARIL, is recommended. In a pooled data analysis of 10 studies in adult subjects with schizophrenia, CLOZARIL treatment was associated with increases in serum total cholesterol. No data were collected on LDL and HDL cholesterol. The mean increase in total cholesterol was 13 mg/dL in the CLOZARIL group and 15 mg/dL in the chlorpromazine group. In a pooled data analysis of 2 studies in adult subjects with schizophrenia, CLOZARIL treatment was associated with increases in fasting serum triglyceride. The mean increase in fasting triglyceride was 71 mg/dL (54%) in the CLOZARIL group and 39 mg/dL (35%) in the chlorpromazine group ( Table 5 ). In addition, CLOZARIL treatment was associated with categorical increases in serum total cholesterol and triglyceride, as illustrated in Table 6 . The proportion of patients with categorical increases in total cholesterol or fasting triglyceride increased with the duration of exposure. The median duration of CLOZARIL and chlorpromazine exposure was 45 days and 38 days, respectively. The CLOZARIL dose range was 100 mg to 900 mg daily; the maximum chlorpromazine dose was 1800 mg daily. Table 5. Mean Changes in Total Cholesterol and Triglyceride Concentration in Studies in Adult Subjects with Schizophrenia Treatment Arm Baseline total cholesterol concentration (mg/dL) Change from baseline mg/dL (%) CLOZARIL (N=334) 184 +13 (7) Chlorpromazine (N=185) 182 +15 (8) Baseline triglyceride concentration (mg/dL) Change from baseline mg/dL (%) CLOZARIL (N=6) 130 +71 (54) Chlorpromazine (N=7) 110 +39 (35) Table 6. Categorical Changes in Lipid Concentrations in Studies in Adult Subjects with Schizophrenia Laboratory Parameter Category Change (at least once) from baseline Treatment Arm N n (%) Total Cholesterol (random or fasting) Increase by ≥40 mg/dL CLOZARIL 334 111 (33) Chlorpromazine 185 46 (25) Normal (<200 mg/dL) to High (≥240 mg/dL) CLOZARIL 222 18 (8) Chlorpromazine 132 3 (2) Borderline (200 – 239 mg/dL) to High (≥240 mg/dL) CLOZARIL 79 30 (38) Chlorpromazine 34 14 (41) Triglycerides (fasting) Increase by ≥50 mg/dL CLOZARIL 6 3 (50) Chlorpromazine 7 3 (43) Normal (<150 mg/dL) to High (≥200 mg/dL) CLOZARIL 4 0 (0) Chlorpromazine 6 2 (33) Borderline (≥150 mg/dL and <200 mg/dL) to High (≥200 mg/dL) CLOZARIL 1 1 (100) Chlorpromazine 1 0 (0) Weight Gain Weight gain has occurred with the use of antipsychotics, including CLOZARIL. Monitor weight during treatment with CLOZARIL. Table 7 summarizes the data on weight gain by the duration of exposure pooled from 11 studies with CLOZARIL and active comparators. The median duration of exposure was 609, 728, and 42 days, in the CLOZARIL, olanzapine, and chlorpromazine group, respectively. Table 7. Mean Change in Body Weight (kg) by Duration of Exposure from Studies in Adult Subjects with Schizophrenia Metabolic parameter Exposure duration CLOZARIL (N=669) Olanzapine (N=442) Chlorpromazine (N=155) n Mean n Mean n Mean Weight change from baseline 2 weeks (Day 11–17) 6 +0.9 3 +0.7 2 -0.5 4 weeks (Day 21–35) 23 +0.7 8 +0.8 17 +0.6 8 weeks (Day 49–63) 12 +1.9 13 +1.8 16 +0.9 12 weeks (Day 70–98) 17 +2.8 5 +3.1 0 0 24 weeks (Day 154–182) 42 -0.6 12 +5.7 0 0 48 weeks (Day 322–350) 3 +3.7 3 +13.7 0 0 Table 8 summarizes pooled data from 11 studies in adult subjects with schizophrenia demonstrating weight gain ≥7% of body weight relative to baseline.

8 weeks (Day 49–63) 12 +1.9 13 +1.8 16 +0.9 12 weeks (Day 70–98) 17 +2.8 5 +3.1 0 0 24 weeks (Day 154–182) 42 -0.6 12 +5.7 0 0 48 weeks (Day 322–350) 3 +3.7 3 +13.7 0 0 Table 8 summarizes pooled data from 11 studies in adult subjects with schizophrenia demonstrating weight gain ≥7% of body weight relative to baseline. The median duration of exposure was 609, 728, and 42 days, in the CLOZARIL, olanzapine, and chlorpromazine group, respectively. Table 8. Proportion of Adult Subjects in Schizophrenia Studies with Weight Gain ≥7% Relative to Baseline Body Weight Weight change CLOZARIL Olanzapine Chlorpromazine N 669 442 155 ≥7% (inclusive) 236 (35%) 203 (46%) 13 (8%) 5.11 Neuroleptic Malignant Syndrome Antipsychotic drugs including CLOZARIL can cause a potentially fatal symptom complex referred to as Neuroleptic Malignant Syndrome (NMS). Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Associated findings can include elevated creatine phosphokinase (CPK), myoglobinuria, rhabdomyolysis, and acute renal failure. The diagnostic evaluation of patients with this syndrome is complicated. It is important to consider the presence of other serious medical conditions (e.g., severe neutropenia, infection, heat stroke, primary CNS pathology, central anticholinergic toxicity, extrapyramidal symptoms, and drug fever). The management of NMS should include (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, (2) intensive symptomatic treatment and medical monitoring, and (3) treatment of comorbid medical conditions. There is no general agreement about specific pharmacological treatments for NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. NMS can recur. Monitor closely if restarting treatment with antipsychotics. NMS has occurred with CLOZARIL monotherapy and with concomitant CNS-active medications, including lithium. 5.12 Hepatotoxicity Severe, life threatening, and in some cases fatal hepatotoxicity including hepatic failure, hepatic necrosis, and hepatitis have been reported in post marketing studies in patients treated with clozapine [see Adverse Reactions ( 6.2 )] . Monitor for the appearance of signs and symptoms of hepatotoxicity such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinemia, coagulopathy, and hepatic encephalopathy. Perform serum tests for liver injury and consider permanently discontinuing treatment if hepatitis or transaminase elevations combined with other systemic symptoms are due to clozapine. 5.13 Fever During clozapine therapy, patients have experienced transient, clozapine-related fever. The peak incidence is within the first 3 weeks of treatment. While this fever is generally benign and self-limited, it may necessitate discontinuing treatment. The fever can be associated with an increase or decrease in WBC count. Carefully evaluate patients with fever to rule out severe neutropenia or infection. Consider the possibility of NMS [see Warnings and Precautions ( 5.11 )] . 5.14 Pulmonary Embolism Pulmonary embolism and deep-vein thrombosis have occurred in patients treated with CLOZARIL. Consider the possibility of pulmonary embolism in patients who present with deep-vein thrombosis, acute dyspnea, chest pain, or with other respiratory signs and symptoms. Whether pulmonary embolus and deep-vein thrombosis can be attributed to clozapine or some characteristic(s) of patients is not clear. 5.15 Anticholinergic Toxicity CLOZARIL has potent anticholinergic effects.

who present with deep-vein thrombosis, acute dyspnea, chest pain, or with other respiratory signs and symptoms. Whether pulmonary embolus and deep-vein thrombosis can be attributed to clozapine or some characteristic(s) of patients is not clear. 5.15 Anticholinergic Toxicity CLOZARIL has potent anticholinergic effects. Treatment with CLOZARIL can result in CNS and peripheral anticholinergic toxicity, especially at higher dosages, or in overdose situations [see Overdosage ( 10 )] . Use with caution in patients with a current diagnosis or prior history of constipation, urinary retention, clinically significant prostatic hypertrophy, or other conditions in which anticholinergic effects can lead to significant adverse reactions. When possible, avoid concomitant use, with other anticholinergic medications because the risk for anticholinergic toxicity or severe gastrointestinal adverse reactions is increased [see Warnings and Precautions ( 5.7 ), Drug Interactions ( 7.1 )]. 5.16 Interference with Cognitive and Motor Performance CLOZARIL can cause sedation and impairment of cognitive and motor performance. Caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that CLOZARIL does not affect them adversely. These reactions may be dose-related. Consider reducing the dose if they occur. 5.17 Tardive Dyskinesia Tardive dyskinesia (TD) has occurred in patients treated with antipsychotic drugs, including CLOZARIL. The syndrome consists of potentially irreversible, involuntary, dyskinetic movements. The risk of TD and the likelihood that it will become irreversible are believed to increase with greater durations of treatment and higher total cumulative doses. However, the syndrome can develop after relatively brief treatment periods at low doses. Prescribe CLOZARIL in a manner that is most likely to minimize the risk of developing TD. Use the lowest effective dose and the shortest duration necessary to control symptoms. Periodically assess the need for continued treatment. Consider discontinuing treatment if TD occurs. However, some patients may require treatment with CLOZARIL despite the presence of the syndrome. TD may remit partially or completely if treatment is discontinued. Antipsychotic treatment, itself, may suppress (or partially suppress) the signs and symptoms, and it has the potential to mask the underlying process. The effect of symptom suppression on the long-term course of TD is unknown. 5.18 Cerebrovascular Adverse Reactions In controlled trials, elderly patients with dementia-related psychosis treated with some atypical antipsychotics had an increased risk (compared to placebo) of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities. The mechanism for this increased risk is not known. An increased risk cannot be excluded for CLOZARIL or other antipsychotics or other patient populations. CLOZARIL should be used with caution in patients with risk factors for cerebrovascular adverse reactions. 5.19 Recurrence of Psychosis and Cholinergic Rebound after Abrupt Discontinuation of CLOZARIL If abrupt discontinuation of CLOZARIL is necessary (because of severe neutropenia or another medical condition, for example) [see Dosage and Administration ( 2.5 ), Warnings and Precautions ( 5.1 )] , monitor carefully for the recurrence of psychotic symptoms and adverse reactions related to cholinergic rebound, such as profuse sweating, headache, nausea, vomiting and diarrhea.

of severe neutropenia or another medical condition, for example) [see Dosage and Administration ( 2.5 ), Warnings and Precautions ( 5.1 )] , monitor carefully for the recurrence of psychotic symptoms and adverse reactions related to cholinergic rebound, such as profuse sweating, headache, nausea, vomiting and diarrhea. 5.1 Severe Neutropenia CLOZARIL has caused severe neutropenia (absolute neutrophil count (ANC) less than 500/μL) [see Adverse Reactions ( 6.1 , 6.2 )] and is associated with an increased risk of serious and potentially fatal infections. Severe neutropenia occurred in a small percentage of CLOZARIL-treated patients. The risk of severe neutropenia appears greatest during the first 18 weeks of CLOZARIL treatment. The mechanism by which CLOZARIL causes neutropenia is unknown. Neutropenia is not dose dependent. Consider a hematology consultation before initiating CLOZARIL treatment or during treatment. ANC Monitoring and Dosage Modifications Prior to initiating CLOZARIL treatment, obtain a baseline ANC. CLOZARIL initiation is not recommended in patients with a baseline ANC less than 1500/μL. Throughout CLOZARIL treatment, regularly monitor ANC. Table 1 provides recommendations for dosage modifications (dosage interruption and treatment discontinuation), based on ANC levels, during CLOZARIL treatment and frequency of ANC monitoring [see Dosage and Administration ( 2.3 )]. ANC Monitoring and Dosage Modification in Patients with Benign Ethnic Neutropenia Patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count) generally have lower baseline neutrophil counts but they are not at higher risk for developing infections, and they are not at increased risk for developing CLOZARIL-induced neutropenia. For patients with documented BEN, obtain at least two baseline ANC levels prior to CLOZARIL initiation. CLOZARIL initiation is not recommended in patients with BEN with an ANC less than 1000/μL. There are different ANC dosage modification recommendations in CLOZARIL-treated patients with BEN due to their lower baseline ANC levels. Table 2 provides recommendations on dosage modifications (dosage interruption and treatment discontinuation), based on ANC monitoring, during CLOZARIL treatment in patients with BEN and recommended frequency of ANC testing [see Dosage and Administration ( 2.4 )]. Management of CLOZARIL-Treated Patients Who Develop a Fever For patients who develop a fever during CLOZARIL treatment: • Interrupt CLOZARIL in those who develop a temperature of 101.3 °F (38.5 °C) or greater and obtain an ANC level. • If the ANC is less than 1000/μL in patients without BEN, initiate appropriate workup and treatment for infection. Refer to Table 1 or Table 2 for dosage modifications based on ANC monitoring [see Dosage and Administration ( 2.3 , 2.4 )]. In patients with fever and a normal neutrophil count, see Warnings and Precautions ( 5.11 ) for neuroleptic malignant syndrome and Warnings and Precautions ( 5.13 ) for fever. Restarting CLOZARIL in Patients Who Recovered from Severe Neutropenia Generally, do not rechallenge patients with CLOZARIL in those who experienced severe neutropenia. However, for some patients who had resolution of their CLOZARIL-related severe neutropenia after stopping CLOZARIL, the risk of schizophrenia exacerbation from not restarting CLOZARIL treatment may be greater than the risk of neutropenia reoccurrence from restarting CLOZARIL (e.g., patients who have no treatment options other than CLOZARIL). Concomitant Use of CLOZARIL with Other Drugs Known to Cause Neutropenia If CLOZARIL is used concomitantly with another drug known to cause neutropenia, consider more frequently ANC monitoring than the recommendations provided in Table 1 and Table 2 .

L (e.g., patients who have no treatment options other than CLOZARIL). Concomitant Use of CLOZARIL with Other Drugs Known to Cause Neutropenia If CLOZARIL is used concomitantly with another drug known to cause neutropenia, consider more frequently ANC monitoring than the recommendations provided in Table 1 and Table 2 . 5.2 Orthostatic Hypotension, Bradycardia, and Syncope Hypotension, bradycardia, syncope, and cardiac arrest have occurred with clozapine treatment. The risk is highest during the initial titration period, particularly with rapid dose-escalation. These reactions can occur with the first dose, at doses as low as 12.5 mg. These reactions can be fatal. The syndrome is consistent with neurally mediated reflex bradycardia (NMRB). Treatment must begin at a maximum dose of 12.5 mg once daily or twice daily. The total daily dose can be increased in increments of 25 mg to 50 mg per day, if well-tolerated, to a target dose of 300 mg to 450 mg per day (administered in divided doses) by the end of 2 weeks. Subsequently, the dose can be increased weekly or twice weekly, in increments of up to 100 mg. The maximum dose is 900 mg per day. Use cautious titration and a divided dosage schedule to minimize the risk of serious cardiovascular reactions [see Dosage and Administration ( 2.2 )] . Consider reducing the dose if hypotension occurs. When restarting CLOZARIL in patients who have had even a brief interruption in treatment with CLOZARIL, the dosage must be reduced. This is necessary to minimize the risk of hypotension, bradycardia, and syncope [see Dosage and Administration (2.6 )]. Use CLOZARIL cautiously in patients with cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension (e.g., concomitant use of antihypertensives, dehydration and hypovolemia). 5.3 Falls CLOZARIL may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long‑term antipsychotic therapy.

sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long‑term antipsychotic therapy. 5.4 Seizures Seizure has been estimated to occur in association with clozapine use at a cumulative incidence at one year of approximately 5%, based on the occurrence of one or more seizures in 61 of 1743 patients exposed to clozapine during its clinical testing prior to domestic marketing (i.e., a crude rate of 3.5%). The risk of seizure is dose-related. Initiate treatment with a low dose (12.5 mg), titrate slowly, and use divided dosing. Use caution when administering CLOZARIL to patients with a history of seizures or other predisposing risk factors for seizure (e.g., head trauma or other CNS pathology, use of medications that lower the seizure threshold, or alcohol abuse). Because of the substantial risk of seizure associated with CLOZARIL use, caution patients about engaging in any activity where sudden loss of consciousness could cause serious risk to themselves or others (e.g., driving an automobile, operating complex machinery, swimming, climbing). 5.5 Myocarditis, Pericarditis, Cardiomyopathy and Mitral Valve Incompetence Myocarditis, pericarditis and cardiomyopathy have occurred with the use of CLOZARIL. These reactions can be fatal. Discontinue CLOZARIL and obtain a cardiac evaluation upon suspicion of myocarditis, pericarditis, or cardiomyopathy. Generally, patients with a history of clozapine-associated myocarditis or cardiomyopathy should not be rechallenged with CLOZARIL. However, if the benefit of CLOZARIL treatment is judged to outweigh the potential risks of recurrence, the clinician may consider rechallenge with CLOZARIL in consultation with a cardiologist. Myocarditis and pericarditis most frequently presents within the first 2 months of clozapine treatment. Symptoms of cardiomyopathy generally occur later than clozapine-associated myocarditis or pericarditis and usually after 8 weeks of treatment. However, myocarditis, pericarditis and cardiomyopathy can occur at any period during treatment with CLOZARIL. In patients who are diagnosed with cardiomyopathy while taking CLOZARIL mitral valve incompetence has been reported.

than clozapine-associated myocarditis or pericarditis and usually after 8 weeks of treatment. However, myocarditis, pericarditis and cardiomyopathy can occur at any period during treatment with CLOZARIL. In patients who are diagnosed with cardiomyopathy while taking CLOZARIL mitral valve incompetence has been reported. 5.6 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality in this population. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. CLOZARIL is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning ] .

n this population. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. CLOZARIL is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning ] . 5.7 Gastrointestinal Hypomotility with Severe Complications Severe gastrointestinal adverse reactions have occurred with the use of CLOZARIL, primarily due to its potent anticholinergic effects and resulting gastrointestinal hypomotility. In post marketing experience, reported effects range from constipation to paralytic ileus. Increased frequency of constipation and delayed diagnosis and treatment increased the risk of severe complications of gastrointestinal hypomotility, which can result in fecal impaction, megacolon, and intestinal obstruction, ischemia, infarction, perforation, ulceration, or necrosis [see Adverse Reaction ( 6.2 )]. These reactions have resulted in hospitalization, surgery, and death. The risk of severe adverse reactions is further increased with anticholinergic medications (and other medications that decrease gastrointestinal peristalsis); therefore, concomitant use should be avoided when possible [see Warnings and Precautions ( 5.15 ), Drug Interactions ( 7.1 )]. Prior to initiating CLOZARIL, screen for constipation and treat as necessary. Subjective symptoms of constipation may not accurately reflect the degree of gastrointestinal hypomotility in CLOZARIL treated patients. Therefore, reassess bowel function frequently with careful attention to any changes in the frequency or character of bowel movements, as well as signs and symptoms of complications of hypomotility (e.g., nausea, vomiting, abdominal distension, abdominal pain). If constipation or gastrointestinal hypomotility are identified, monitor closely and treat promptly with appropriate laxatives, as necessary, to prevent severe complications. Consider prophylactic laxatives in high risk patients.

plications of hypomotility (e.g., nausea, vomiting, abdominal distension, abdominal pain). If constipation or gastrointestinal hypomotility are identified, monitor closely and treat promptly with appropriate laxatives, as necessary, to prevent severe complications. Consider prophylactic laxatives in high risk patients. 5.8 Eosinophilia Eosinophilia, defined as a blood eosinophil count of greater than 700/µL, has occurred with CLOZARIL treatment. In clinical trials, approximately 1% of patients developed eosinophilia. Clozapine-related eosinophilia usually occurs during the first month of treatment. In some patients, it has been associated with myocarditis, pancreatitis, hepatitis, colitis, and nephritis. Such organ involvement could be consistent with a drug reaction with eosinophilia and systemic symptoms syndrome (DRESS), also known as drug induced hypersensitivity syndrome (DIHS). If eosinophilia develops during CLOZARIL treatment, evaluate promptly for signs and symptoms of systemic reactions, such as rash or other allergic symptoms, myocarditis, or other organ-specific disease associated with eosinophilia. If CLOZARIL-related systemic disease is suspected, discontinue CLOZARIL immediately. If a cause of eosinophilia unrelated to CLOZARIL is identified (e.g., asthma, allergies, collagen vascular disease, parasitic infections, and specific neoplasms), treat the underlying cause and continue CLOZARIL. Clozapine-related eosinophilia has also occurred in the absence of organ involvement and can resolve without intervention. There are reports of successful rechallenge after discontinuation of clozapine, without recurrence of eosinophilia. In the absence of organ involvement, continue CLOZARIL under careful monitoring. If the total eosinophil count continues to increase over several weeks in the absence of systemic disease, the decision to interrupt CLOZARIL therapy and rechallenge after the eosinophil count decreases should be based on the overall clinical assessment, in consultation with an internist or hematologist.

ul monitoring. If the total eosinophil count continues to increase over several weeks in the absence of systemic disease, the decision to interrupt CLOZARIL therapy and rechallenge after the eosinophil count decreases should be based on the overall clinical assessment, in consultation with an internist or hematologist. 5.9 QT Interval Prolongation QT prolongation, Torsade de Pointes and other life-threatening ventricular arrhythmias, cardiac arrest, and sudden death have occurred with CLOZARIL treatment. When prescribing CLOZARIL, consider the presence of additional risk factors for QT prolongation and serious cardiovascular reactions. Conditions that increase these risks include the following: history of QT prolongation, long QT syndrome, family history of long QT syndrome or sudden cardiac death, significant cardiac arrhythmia, recent myocardial infarction, uncompensated heart failure, treatment with other medications that cause QT prolongation, treatment with medications that inhibit the metabolism of clozapine, and electrolyte abnormalities. Prior to initiating treatment with CLOZARIL, perform a careful physical examination, medical history, and concomitant medication history. Consider obtaining a baseline ECG and serum chemistry panel. Correct electrolyte abnormalities. Discontinue CLOZARIL if the QTc interval exceeds 500 msec. If patients experience symptoms consistent with Torsades de Pointes, or other arrhythmias (e.g., syncope, presyncope, dizziness, or palpitations), obtain a cardiac evaluation and discontinue CLOZARIL. Use caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of CLOZARIL. Drugs that cause QT prolongation include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, thioridazine, mesoridazine, droperidol, pimozide), specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin), Class 1A antiarrhythmic medications (e.g., quinidine, procainamide) or Class III antiarrhythmics (e.g., amiodarone, sotalol), and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus). Clozapine is primarily metabolized by CYP isoenzymes 1A2, 2D6, and 3A4. Concomitant treatment with inhibitors of these enzymes can increase the concentration of CLOZARIL [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 )] . Hypokalemia and hypomagnesemia increase the risk of QT prolongation. Hypokalemia can result from diuretic therapy, diarrhea, and other causes. Use caution when treating patients at risk for significant electrolyte disturbance, particularly hypokalemia. Obtain baseline measurements of serum potassium and magnesium levels, and periodically monitor electrolytes. Correct electrolyte abnormalities before initiating treatment with CLOZARIL.

8 weeks (Day 49–63) 12 +1.9 13 +1.8 16 +0.9 12 weeks (Day 70–98) 17 +2.8 5 +3.1 0 0 24 weeks (Day 154–182) 42 -0.6 12 +5.7 0 0 48 weeks (Day 322–350) 3 +3.7 3 +13.7 0 0 Table 8 summarizes pooled data from 11 studies in adult subjects with schizophrenia demonstrating weight gain ≥7% of body weight relative to baseline. The median duration of exposure was 609, 728, and 42 days, in the CLOZARIL, olanzapine, and chlorpromazine group, respectively. Table 8. Proportion of Adult Subjects in Schizophrenia Studies with Weight Gain ≥7% Relative to Baseline Body Weight Weight change CLOZARIL Olanzapine Chlorpromazine N 669 442 155 ≥7% (inclusive) 236 (35%) 203 (46%) 13 (8%) 5.11 Neuroleptic Malignant Syndrome Antipsychotic drugs including CLOZARIL can cause a potentially fatal symptom complex referred to as Neuroleptic Malignant Syndrome (NMS). Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Associated findings can include elevated creatine phosphokinase (CPK), myoglobinuria, rhabdomyolysis, and acute renal failure. The diagnostic evaluation of patients with this syndrome is complicated. It is important to consider the presence of other serious medical conditions (e.g., severe neutropenia, infection, heat stroke, primary CNS pathology, central anticholinergic toxicity, extrapyramidal symptoms, and drug fever). The management of NMS should include (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, (2) intensive symptomatic treatment and medical monitoring, and (3) treatment of comorbid medical conditions. There is no general agreement about specific pharmacological treatments for NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. NMS can recur. Monitor closely if restarting treatment with antipsychotics. NMS has occurred with CLOZARIL monotherapy and with concomitant CNS-active medications, including lithium.

quires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. NMS can recur. Monitor closely if restarting treatment with antipsychotics. NMS has occurred with CLOZARIL monotherapy and with concomitant CNS-active medications, including lithium. 5.12 Hepatotoxicity Severe, life threatening, and in some cases fatal hepatotoxicity including hepatic failure, hepatic necrosis, and hepatitis have been reported in post marketing studies in patients treated with clozapine [see Adverse Reactions ( 6.2 )] . Monitor for the appearance of signs and symptoms of hepatotoxicity such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinemia, coagulopathy, and hepatic encephalopathy. Perform serum tests for liver injury and consider permanently discontinuing treatment if hepatitis or transaminase elevations combined with other systemic symptoms are due to clozapine. 5.13 Fever During clozapine therapy, patients have experienced transient, clozapine-related fever. The peak incidence is within the first 3 weeks of treatment. While this fever is generally benign and self-limited, it may necessitate discontinuing treatment. The fever can be associated with an increase or decrease in WBC count. Carefully evaluate patients with fever to rule out severe neutropenia or infection. Consider the possibility of NMS [see Warnings and Precautions ( 5.11 )] . 5.14 Pulmonary Embolism Pulmonary embolism and deep-vein thrombosis have occurred in patients treated with CLOZARIL. Consider the possibility of pulmonary embolism in patients who present with deep-vein thrombosis, acute dyspnea, chest pain, or with other respiratory signs and symptoms. Whether pulmonary embolus and deep-vein thrombosis can be attributed to clozapine or some characteristic(s) of patients is not clear.

with CLOZARIL. Consider the possibility of pulmonary embolism in patients who present with deep-vein thrombosis, acute dyspnea, chest pain, or with other respiratory signs and symptoms. Whether pulmonary embolus and deep-vein thrombosis can be attributed to clozapine or some characteristic(s) of patients is not clear. 5.15 Anticholinergic Toxicity CLOZARIL has potent anticholinergic effects. Treatment with CLOZARIL can result in CNS and peripheral anticholinergic toxicity, especially at higher dosages, or in overdose situations [see Overdosage ( 10 )] . Use with caution in patients with a current diagnosis or prior history of constipation, urinary retention, clinically significant prostatic hypertrophy, or other conditions in which anticholinergic effects can lead to significant adverse reactions. When possible, avoid concomitant use, with other anticholinergic medications because the risk for anticholinergic toxicity or severe gastrointestinal adverse reactions is increased [see Warnings and Precautions ( 5.7 ), Drug Interactions ( 7.1 )]. 5.16 Interference with Cognitive and Motor Performance CLOZARIL can cause sedation and impairment of cognitive and motor performance. Caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that CLOZARIL does not affect them adversely. These reactions may be dose-related. Consider reducing the dose if they occur.

mance CLOZARIL can cause sedation and impairment of cognitive and motor performance. Caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that CLOZARIL does not affect them adversely. These reactions may be dose-related. Consider reducing the dose if they occur. 5.17 Tardive Dyskinesia Tardive dyskinesia (TD) has occurred in patients treated with antipsychotic drugs, including CLOZARIL. The syndrome consists of potentially irreversible, involuntary, dyskinetic movements. The risk of TD and the likelihood that it will become irreversible are believed to increase with greater durations of treatment and higher total cumulative doses. However, the syndrome can develop after relatively brief treatment periods at low doses. Prescribe CLOZARIL in a manner that is most likely to minimize the risk of developing TD. Use the lowest effective dose and the shortest duration necessary to control symptoms. Periodically assess the need for continued treatment. Consider discontinuing treatment if TD occurs. However, some patients may require treatment with CLOZARIL despite the presence of the syndrome. TD may remit partially or completely if treatment is discontinued. Antipsychotic treatment, itself, may suppress (or partially suppress) the signs and symptoms, and it has the potential to mask the underlying process. The effect of symptom suppression on the long-term course of TD is unknown. 5.18 Cerebrovascular Adverse Reactions In controlled trials, elderly patients with dementia-related psychosis treated with some atypical antipsychotics had an increased risk (compared to placebo) of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities. The mechanism for this increased risk is not known. An increased risk cannot be excluded for CLOZARIL or other antipsychotics or other patient populations. CLOZARIL should be used with caution in patients with risk factors for cerebrovascular adverse reactions.

stroke, transient ischemic attack), including fatalities. The mechanism for this increased risk is not known. An increased risk cannot be excluded for CLOZARIL or other antipsychotics or other patient populations. CLOZARIL should be used with caution in patients with risk factors for cerebrovascular adverse reactions. 5.19 Recurrence of Psychosis and Cholinergic Rebound after Abrupt Discontinuation of CLOZARIL If abrupt discontinuation of CLOZARIL is necessary (because of severe neutropenia or another medical condition, for example) [see Dosage and Administration ( 2.5 ), Warnings and Precautions ( 5.1 )] , monitor carefully for the recurrence of psychotic symptoms and adverse reactions related to cholinergic rebound, such as profuse sweating, headache, nausea, vomiting and diarrhea.

<table ID="_Reftable4" cellpadding="0.1pt" width="100%"><caption>Table 4.Categorical Changes in Fasting Glucose Level in Studies in Adult Subjects with Schizophrenia</caption><col width="14%"/><col width="17%"/><col width="23%"/><col width="23%"/><col width="23%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Laboratory Parameter</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Category Change (at least once) from baseline</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Treatment Arm</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">N</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">n (%)</content></paragraph></td></tr><tr><td align="center" rowspan="4" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Fasting Glucose</paragraph></td><td align="center" rowspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Normal (&lt;100 mg/dL) to High (&#x2265;126 mg/dL)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>CLOZARIL</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>198</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>53 (27)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Chlorpromazine</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>135</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>14 (10)</paragraph></td></tr><tr><td align="center" rowspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Borderline (100 to 125 mg/dL) to High (&#x2265;126 mg/dL)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>CLOZARIL</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>57</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>24 (42)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>Chlorpromazine</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>43</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>12 (28)</paragraph></td></tr></tbody></table>

Botrule Lrule Toprule " valign="middle"><paragraph>Chlorpromazine</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>43</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>12 (28)</paragraph></td></tr></tbody></table> <table ID="_Reftable5" cellpadding="0.1pt" width="100%"><caption>Table 5. Mean Changes in Total Cholesterol and Triglyceride Concentration in Studies in Adult Subjects with Schizophrenia</caption><col width="33%"/><col width="33%"/><col width="33%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Treatment Arm</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Baseline total cholesterol concentration (mg/dL)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Change from baseline mg/dL (%)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>CLOZARIL (N=334)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>184</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>+13 (7)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Chlorpromazine (N=185)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>182</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>+15 (8)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"/><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Baseline triglyceride concentration (mg/dL)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Change from baseline mg/dL (%)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>CLOZARIL (N=6)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>130</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>+71 (54)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>Chlorpromazine (N=7)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>110</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>+39 (35)</paragraph></td></tr></tbody></table>

tyleCode="Rrule Botrule Lrule " valign="middle"><paragraph>Chlorpromazine (N=7)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>110</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>+39 (35)</paragraph></td></tr></tbody></table> <table ID="_RefTable6" cellpadding="0.2pt" width="100%"><caption>Table 6.

tyleCode="Rrule Botrule Lrule " valign="middle"><paragraph>Chlorpromazine (N=7)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>110</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>+39 (35)</paragraph></td></tr></tbody></table> <table ID="_RefTable6" cellpadding="0.2pt" width="100%"><caption>Table 6. Categorical Changes in Lipid Concentrations in Studies in Adult Subjects with Schizophrenia</caption><col width="14%"/><col width="21%"/><col width="21%"/><col width="21%"/><col width="21%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Laboratory Parameter</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Category Change (at least once) from baseline</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Treatment Arm</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">N</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">n (%)</content></paragraph></td></tr><tr><td rowspan="6" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Total Cholesterol (random or fasting)</paragraph></td><td align="center" rowspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Increase by &#x2265;40 mg/dL</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>CLOZARIL</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>334</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>111 (33)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Chlorpromazine</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>185</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>46 (25)</paragraph></td></tr><tr><td align="center" rowspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Normal (&lt;200 mg/dL) to High (&#x2265;240 mg/dL)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>CLOZARIL</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>222</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>18 (8)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Chlorpromazine</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>132</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>3 (2)</paragraph></td></tr><tr><td align="center" rowspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Borderline (200 &#x2013; 239 mg/dL) to High (&#x2265;240 mg/dL)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>CLOZARIL</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>79</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>30 (38)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Chlorpromazine</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><pa

td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>30 (38)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Chlorpromazine</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><pa ragraph>34</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>14 (41)</paragraph></td></tr><tr><td rowspan="6" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Triglycerides (fasting)</paragraph></td><td align="center" rowspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Increase by &#x2265;50 mg/dL</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>CLOZARIL</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>3 (50)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Chlorpromazine</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>7</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>3 (43)</paragraph></td></tr><tr><td align="center" rowspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Normal (&lt;150 mg/dL) to High (&#x2265;200 mg/dL)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>CLOZARIL</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>0 (0)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Chlorpromazine</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>2 (33)</paragraph></td></tr><tr><td align="center" rowspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Borderline (&#x2265;150 mg/dL and &lt;200 mg/dL) to High (&#x2265;200 mg/dL)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>CLOZARIL</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>1 (100)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>Chlorpromazine</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>0 (0)</paragraph></td></tr></tbody></table>

le Botrule Lrule Toprule " valign="middle"><paragraph>Chlorpromazine</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>0 (0)</paragraph></td></tr></tbody></table> <table ID="_Reftable7" cellpadding="0.2pt" width="100%"><caption>Table 7.

le Botrule Lrule Toprule " valign="middle"><paragraph>Chlorpromazine</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>0 (0)</paragraph></td></tr></tbody></table> <table ID="_Reftable7" cellpadding="0.2pt" width="100%"><caption>Table 7. Mean Change in Body Weight (kg) by Duration of Exposure from Studies in Adult Subjects with Schizophrenia</caption><col width="10%"/><col width="13%"/><col width="13%"/><col width="13%"/><col width="13%"/><col width="13%"/><col width="13%"/><col width="13%"/><tbody><tr><td rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Metabolic parameter</content></paragraph></td><td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Exposure duration</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">CLOZARIL</content> <content styleCode="bold">(N=669)</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Olanzapine</content> <content styleCode="bold">(N=442)</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Chlorpromazine</content> <content styleCode="bold">(N=155)</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph><content styleCode="bold">n</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph><content styleCode="bold">Mean</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph><content styleCode="bold">n</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph><content styleCode="bold">Mean</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph><content styleCode="bold">n</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph><content styleCode="bold">Mean</content></paragraph></td></tr><tr><td rowspan="6" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Weight change from baseline</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>2 weeks (Day 11&#x2013;17)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>+0.9</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>+0.7</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>-0.5</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>4 weeks (Day 21&#x2013;35)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>23</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>+0.7</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>8</paragraph></td><td align="center" styleCode=

="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>23</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>+0.7</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>8</paragraph></td><td align="center" styleCode= "Rrule Lrule Toprule Botrule " valign="middle"><paragraph>+0.8</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>17</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>+0.6</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>8 weeks (Day 49&#x2013;63)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>12</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>+1.9</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>13</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>+1.8</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>16</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>+0.9</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>12 weeks (Day 70&#x2013;98)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>17</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>+2.8</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>+3.1</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>24 weeks (Day 154&#x2013;182)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>42</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>-0.6</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>12</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>+5.7</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>48 weeks (Day 322&#x2013;350)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>+3.7</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>+13.7</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>0</paragraph></td></tr></tbody></table>

tyleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>+13.7</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>0</paragraph></td></tr></tbody></table> <table ID="_Reftable8" cellpadding="0.2pt" width="100%"><caption>Table 8. Proportion of Adult Subjects in Schizophrenia Studies with Weight Gain &#x2265;7% Relative to Baseline Body Weight</caption><col width="25%"/><col width="25%"/><col width="25%"/><col width="25%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Weight change</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">CLOZARIL</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Olanzapine</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Chlorpromazine</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">N</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>669</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>442</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>155</paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph><content styleCode="bold">&#x2265;7% (inclusive)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>236 (35%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>203 (46%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>13 (8%)</paragraph></td></tr></tbody></table>

lign="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>236 (35%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>203 (46%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>13 (8%)</paragraph></td></tr></tbody></table> <table ID="_Reftable4" cellpadding="0.1pt" width="100%"><caption>Table 4.Categorical Changes in Fasting Glucose Level in Studies in Adult Subjects with Schizophrenia</caption><col width="14%"/><col width="17%"/><col width="23%"/><col width="23%"/><col width="23%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Laboratory Parameter</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Category Change (at least once) from baseline</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Treatment Arm</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">N</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">n (%)</content></paragraph></td></tr><tr><td align="center" rowspan="4" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Fasting Glucose</paragraph></td><td align="center" rowspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Normal (&lt;100 mg/dL) to High (&#x2265;126 mg/dL)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>CLOZARIL</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>198</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>53 (27)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Chlorpromazine</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>135</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>14 (10)</paragraph></td></tr><tr><td align="center" rowspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Borderline (100 to 125 mg/dL) to High (&#x2265;126 mg/dL)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>CLOZARIL</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>57</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>24 (42)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>Chlorpromazine</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>43</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>12 (28)</paragraph></td></tr></tbody></table>

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: • Severe Neutropenia [see Warnings and Precautions ( 5.1 )] • Orthostatic Hypotension, Bradycardia, and Syncope [see Warnings and Precautions ( 5.2 )] • Falls [see Warnings and Precautions ( 5.3 )] • Seizures [see Warnings and Precautions ( 5.4 )] • Myocarditis, Pericarditis, Cardiomyopathy, and Mitral Valve Incompetence [see Warnings and Precautions ( 5.5 )] • Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Warnings and Precautions ( 5.6 )] • Gastrointestinal Hypomotility with Severe Complications [See Warnings and Precautions ( 5.7) ] • Eosinophilia [see Warnings and Precautions ( 5.8 )] • QT Interval Prolongation [see Warnings and Precautions ( 5.9 )] • Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain) [see Warnings and Precautions ( 5.10 )] • Neuroleptic Malignant Syndrome [see Warnings and Precautions ( 5.11 )] • Hepatotoxicity [see Warnings and Precautions ( 5.12 )] • Fever [see Warnings and Precautions ( 5.13 )] • Pulmonary Embolism [see Warnings and Precautions ( 5.14 )] • Anticholinergic Toxicity [see Warnings and Precautions ( 5.15 )] • Interference with Cognitive and Motor Performance [see Warnings and Precautions ( 5.16 )] • Tardive Dyskinesia [see Warnings and Precautions ( 5.17 )] • Cerebrovascular Adverse Reactions [see Warnings and Precautions ( 5.18 )] • Recurrence of Psychosis and Cholinergic Rebound after Abrupt Discontinuation [see Warnings and Precautions ( 5.19 )] Most common adverse reactions (≥5%) were: CNS reactions (sedation, dizziness/vertigo, headache, and tremor); cardiovascular reactions (tachycardia, hypotension, and syncope); autonomic nervous system reactions (hypersalivation, sweating, dry mouth, and visual disturbances); gastrointestinal reactions (constipation and nausea); and fever. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact HLS Therapeutics (USA), Inc. at (844) 457-8721 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The most commonly reported adverse reactions (≥5%) across CLOZARIL clinical trials were: CNS reactions, including sedation, dizziness/vertigo, headache, and tremor; cardiovascular reactions, including tachycardia, hypotension, and syncope; autonomic nervous system reactions, including hypersalivation, sweating, dry mouth, and visual disturbances; gastrointestinal reactions, including constipation and nausea; and fever. Table 9 summarizes the most commonly reported adverse reactions (≥5%) in CLOZARIL-treated patients (compared to chlorpromazine-treated patients) in the pivotal, 6-week, controlled trial in treatment-resistant schizophrenia. Table 9.

disturbances; gastrointestinal reactions, including constipation and nausea; and fever. Table 9 summarizes the most commonly reported adverse reactions (≥5%) in CLOZARIL-treated patients (compared to chlorpromazine-treated patients) in the pivotal, 6-week, controlled trial in treatment-resistant schizophrenia. Table 9. Common Adverse Reactions (≥5%) in the 6-Week, Randomized, Chlorpromazine-controlled Trial in Treatment-Resistant Schizophrenia Adverse Reaction CLOZARIL (N=126) (%) Chlorpromazine (N=142) (%) Sedation 21 13 Tachycardia 17 11 Constipation 16 12 Dizziness 14 16 Hypotension 13 38 Fever (hyperthermia) 13 4 Hypersalivation 13 1 Hypertension 12 5 Headache 10 10 Nausea/vomiting 10 12 Dry mouth 5 20 Table 10 summarizes the adverse reactions reported in CLOZARIL-treated patients at a frequency of 2% or greater across all CLOZARIL studies (excluding the 2-year InterSePT™ Study). These rates are not adjusted for duration of exposure. Table 10. Adverse Reactions (≥2%) Reported in CLOZARIL-treated Patients (N=842) Across all CLOZARIL Studies (excluding the 2-year InterSePT™ Study) †Rate based on population of approximately 1700 exposed during premarket clinical evaluation of CLOZARIL. Body System Adverse Reaction * CLOZARIL N=842 Percentage of Patients Central Nervous System Drowsiness/Sedation 39 Dizziness/Vertigo 19 Headache 7 Tremor 6 Syncope 6 Disturbed Sleep/Nightmares 4 Restlessness 4 Hypokinesia/Akinesia 4 Agitation 4 Seizures (convulsions) 3† Rigidity 3 Akathisia 3 Confusion 3 Fatigue 2 Insomnia 2 Cardiovascular Tachycardia 25† Hypotension 9 Hypertension 4 Gastrointestinal Constipation 14 Nausea 5 Abdominal Discomfort/Heartburn 4 Nausea/Vomiting 3 Vomiting 3 Diarrhea 2 Urogenital Urinary Abnormalities 2 Autonomic Nervous System Salivation 31 Sweating 6 Dry Mouth 6 Visual Disturbances 5 Skin Rash 2 Hemic/Lymphatic Leukopenia/Decreased WBC/Neutropenia 3 Miscellaneous Fever 5 Weight Gain 4 Table 11 summarizes the most commonly reported adverse reactions (≥10% of the CLOZARIL or olanzapine group) in the InterSePT™ Study. This was an adequate and well-controlled, two-year study evaluating the efficacy of CLOZARIL relative to olanzapine in reducing the risk of suicidal behavior in patients with schizophrenia or schizoaffective disorder. The rates are not adjusted for duration of exposure. Table 11. Incidence of Adverse Reactions in Patients Treated with CLOZARIL or Olanzapine in the InterSePT™ Study (≥10% in the CLOZARIL or olanzapine group) Adverse Reactions CLOZARIL N=479 % Reporting Olanzapine N=477 % Reporting Salivary hypersecretion 48 6 Somnolence 46 25 Weight increased 31 56 Dizziness (excluding vertigo) 27 12 Constipation 25 10 Insomnia 20 33 Nausea 17 10 Vomiting 17 9 Dyspepsia 14 8 Dystonia Class effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of clozapine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of clozapine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Central Nervous System Delirium, EEG abnormal, myoclonus, paresthesia, possible cataplexy, status epilepticus, obsessive compulsive symptoms, restless leg syndrome and post-discontinuation cholinergic rebound adverse reactions. Cardiovascular System Atrial or ventricular fibrillation, ventricular tachycardia, palpitations, QT interval prolongation, Torsades de Pointes, mitral valve incompetence associated with clozapine-related cardiomyopathy, myocardial infarction, cardiac arrest, myocarditis, pericarditis and periorbital edema. Endocrine System Pseudopheochromocytoma Gastrointestinal System Acute pancreatitis, dysphagia, salivary gland swelling, colitis, megacolon, fecal incontinence, and intestinal ischemia, infarction, perforation, ulceration or necrosis. Hepatobiliary System Cholestasis, hepatitis, jaundice, hepatotoxicity, hepatic steatosis, hepatic necrosis, hepatic fibrosis, hepatic cirrhosis, liver injury (hepatic, cholestatic, and mixed), and liver failure. Immune System Disorders Angioedema, leukocytoclastic vasculitis. Urogenital System Acute interstitial nephritis, nocturnal enuresis, priapism, renal failure, and retrograde ejaculation. Skin and Subcutaneous Tissue Disorders Hypersensitivity reactions: photosensitivity, vasculitis, erythema multiforme, skin pigmentation disorder, and Stevens-Johnson Syndrome. Musculoskeletal System and Connective Tissue Disorders Myasthenic syndrome, rhabdomyolysis, and systemic lupus erythematosus. Respiratory System Aspiration, pleural effusion, pneumonia, lower respiratory tract infection, sleep apnea. Hemic and Lymphatic System Mild, moderate, or severe leukopenia, agranulocytosis, granulocytopenia, WBC decreased, deep-vein thrombosis, elevated hemoglobin/hematocrit, erythrocyte sedimentation rate (ESR) increased, sepsis, thrombocytosis, and thrombocytopenia. Vision Disorders Narrow-angle glaucoma. Miscellaneous Creatine phosphokinase elevation, hyperuricemia, hyponatremia, polyserositis, and weight loss.

topenia, WBC decreased, deep-vein thrombosis, elevated hemoglobin/hematocrit, erythrocyte sedimentation rate (ESR) increased, sepsis, thrombocytosis, and thrombocytopenia. Vision Disorders Narrow-angle glaucoma. Miscellaneous Creatine phosphokinase elevation, hyperuricemia, hyponatremia, polyserositis, and weight loss. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The most commonly reported adverse reactions (≥5%) across CLOZARIL clinical trials were: CNS reactions, including sedation, dizziness/vertigo, headache, and tremor; cardiovascular reactions, including tachycardia, hypotension, and syncope; autonomic nervous system reactions, including hypersalivation, sweating, dry mouth, and visual disturbances; gastrointestinal reactions, including constipation and nausea; and fever. Table 9 summarizes the most commonly reported adverse reactions (≥5%) in CLOZARIL-treated patients (compared to chlorpromazine-treated patients) in the pivotal, 6-week, controlled trial in treatment-resistant schizophrenia. Table 9. Common Adverse Reactions (≥5%) in the 6-Week, Randomized, Chlorpromazine-controlled Trial in Treatment-Resistant Schizophrenia Adverse Reaction CLOZARIL (N=126) (%) Chlorpromazine (N=142) (%) Sedation 21 13 Tachycardia 17 11 Constipation 16 12 Dizziness 14 16 Hypotension 13 38 Fever (hyperthermia) 13 4 Hypersalivation 13 1 Hypertension 12 5 Headache 10 10 Nausea/vomiting 10 12 Dry mouth 5 20 Table 10 summarizes the adverse reactions reported in CLOZARIL-treated patients at a frequency of 2% or greater across all CLOZARIL studies (excluding the 2-year InterSePT™ Study). These rates are not adjusted for duration of exposure. Table 10. Adverse Reactions (≥2%) Reported in CLOZARIL-treated Patients (N=842) Across all CLOZARIL Studies (excluding the 2-year InterSePT™ Study) †Rate based on population of approximately 1700 exposed during premarket clinical evaluation of CLOZARIL. Body System Adverse Reaction * CLOZARIL N=842 Percentage of Patients Central Nervous System Drowsiness/Sedation 39 Dizziness/Vertigo 19 Headache 7 Tremor 6 Syncope 6 Disturbed Sleep/Nightmares 4 Restlessness 4 Hypokinesia/Akinesia 4 Agitation 4 Seizures (convulsions) 3† Rigidity 3 Akathisia 3 Confusion 3 Fatigue 2 Insomnia 2 Cardiovascular Tachycardia 25† Hypotension 9 Hypertension 4 Gastrointestinal Constipation 14 Nausea 5 Abdominal Discomfort/Heartburn 4 Nausea/Vomiting 3 Vomiting 3 Diarrhea 2 Urogenital Urinary Abnormalities 2 Autonomic Nervous System Salivation 31 Sweating 6 Dry Mouth 6 Visual Disturbances 5 Skin Rash 2 Hemic/Lymphatic Leukopenia/Decreased WBC/Neutropenia 3 Miscellaneous Fever 5 Weight Gain 4 Table 11 summarizes the most commonly reported adverse reactions (≥10% of the CLOZARIL or olanzapine group) in the InterSePT™ Study. This was an adequate and well-controlled, two-year study evaluating the efficacy of CLOZARIL relative to olanzapine in reducing the risk of suicidal behavior in patients with schizophrenia or schizoaffective disorder. The rates are not adjusted for duration of exposure. Table 11.

nzapine group) in the InterSePT™ Study. This was an adequate and well-controlled, two-year study evaluating the efficacy of CLOZARIL relative to olanzapine in reducing the risk of suicidal behavior in patients with schizophrenia or schizoaffective disorder. The rates are not adjusted for duration of exposure. Table 11. Incidence of Adverse Reactions in Patients Treated with CLOZARIL or Olanzapine in the InterSePT™ Study (≥10% in the CLOZARIL or olanzapine group) Adverse Reactions CLOZARIL N=479 % Reporting Olanzapine N=477 % Reporting Salivary hypersecretion 48 6 Somnolence 46 25 Weight increased 31 56 Dizziness (excluding vertigo) 27 12 Constipation 25 10 Insomnia 20 33 Nausea 17 10 Vomiting 17 9 Dyspepsia 14 8 Dystonia Class effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

ficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of clozapine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Central Nervous System Delirium, EEG abnormal, myoclonus, paresthesia, possible cataplexy, status epilepticus, obsessive compulsive symptoms, restless leg syndrome and post-discontinuation cholinergic rebound adverse reactions. Cardiovascular System Atrial or ventricular fibrillation, ventricular tachycardia, palpitations, QT interval prolongation, Torsades de Pointes, mitral valve incompetence associated with clozapine-related cardiomyopathy, myocardial infarction, cardiac arrest, myocarditis, pericarditis and periorbital edema. Endocrine System Pseudopheochromocytoma Gastrointestinal System Acute pancreatitis, dysphagia, salivary gland swelling, colitis, megacolon, fecal incontinence, and intestinal ischemia, infarction, perforation, ulceration or necrosis. Hepatobiliary System Cholestasis, hepatitis, jaundice, hepatotoxicity, hepatic steatosis, hepatic necrosis, hepatic fibrosis, hepatic cirrhosis, liver injury (hepatic, cholestatic, and mixed), and liver failure. Immune System Disorders Angioedema, leukocytoclastic vasculitis. Urogenital System Acute interstitial nephritis, nocturnal enuresis, priapism, renal failure, and retrograde ejaculation. Skin and Subcutaneous Tissue Disorders Hypersensitivity reactions: photosensitivity, vasculitis, erythema multiforme, skin pigmentation disorder, and Stevens-Johnson Syndrome. Musculoskeletal System and Connective Tissue Disorders Myasthenic syndrome, rhabdomyolysis, and systemic lupus erythematosus. Respiratory System Aspiration, pleural effusion, pneumonia, lower respiratory tract infection, sleep apnea. Hemic and Lymphatic System Mild, moderate, or severe leukopenia, agranulocytosis, granulocytopenia, WBC decreased, deep-vein thrombosis, elevated hemoglobin/hematocrit, erythrocyte sedimentation rate (ESR) increased, sepsis, thrombocytosis, and thrombocytopenia. Vision Disorders Narrow-angle glaucoma. Miscellaneous Creatine phosphokinase elevation, hyperuricemia, hyponatremia, polyserositis, and weight loss.

<table ID="_Reftable9" width="100%"><caption>Table 9. Common Adverse Reactions (&#x2265;5%) in the 6-Week, Randomized, Chlorpromazine-controlled Trial in Treatment-Resistant Schizophrenia</caption><col width="34%"/><col width="32%"/><col width="34%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">CLOZARIL</content> <content styleCode="bold">(N=126)</content> <content styleCode="bold">(%)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Chlorpromazine</content> <content styleCode="bold">(N=142)</content> <content styleCode="bold">(%)</content></paragraph></td></tr><tr><td styleCode="Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Sedation</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>21</paragraph></td><td align="center" styleCode="Rrule Toprule " valign="top"><paragraph>13</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><paragraph><content styleCode="bold">Tachycardia</content></paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>17</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>11</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><paragraph><content styleCode="bold">Constipation</content></paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>16</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>12</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><paragraph><content styleCode="bold">Dizziness</content></paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>14</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>16</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><paragraph><content styleCode="bold">Hypotension</content></paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>13</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>38</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><paragraph><content styleCode="bold">Fever (hyperthermia)</content></paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>13</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>4</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><paragraph><content styleCode="bold">Hypersalivation</content></paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>13</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><paragraph><content styleCode="bold">Hypertension</content></paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>12</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>5</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><paragraph><content styleCode="bold">Headache</content></paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>10</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>10</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><paragraph><content style

ign="top"><paragraph><content styleCode="bold">Headache</content></paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>10</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>10</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><paragraph><content style Code="bold">Nausea/vomiting</content></paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>10</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>12</paragraph></td></tr><tr><td styleCode="Botrule Lrule " valign="top"><paragraph><content styleCode="bold">Dry mouth</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>20</paragraph></td></tr></tbody></table> <table ID="_Reftable10" width="100%"><caption>Table 10.

Code="bold">Nausea/vomiting</content></paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>10</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>12</paragraph></td></tr><tr><td styleCode="Botrule Lrule " valign="top"><paragraph><content styleCode="bold">Dry mouth</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>20</paragraph></td></tr></tbody></table> <table ID="_Reftable10" width="100%"><caption>Table 10. Adverse Reactions (&#x2265;2%) Reported in CLOZARIL-treated Patients (N=842) Across all CLOZARIL Studies (excluding the 2-year InterSePT&#x2122; Study) </caption><col width="62%"/><col width="38%"/><tfoot><tr><td align="left" colspan="2" valign="top">&#x2020;Rate based on population of approximately 1700 exposed during premarket clinical evaluation of CLOZARIL.</td></tr></tfoot><tbody><tr><td styleCode="Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Body System</content></paragraph><paragraph><content styleCode="bold">Adverse Reaction *</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">CLOZARIL</content> <content styleCode="bold">N=842</content> <content styleCode="bold">Percentage of Patients</content></paragraph></td></tr><tr><td styleCode="Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Central Nervous System</content></paragraph></td><td styleCode="Rrule Toprule " valign="top"/></tr><tr><td styleCode="Lrule " valign="top"><list listType="unordered"><item><caption> </caption>Drowsiness/Sedation</item></list></td><td align="center" styleCode="Rrule " valign="top"><paragraph>39</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><list listType="unordered"><item><caption> </caption>Dizziness/Vertigo</item></list></td><td align="center" styleCode="Rrule " valign="top"><paragraph>19</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><list listType="unordered"><item><caption> </caption>Headache</item></list></td><td align="center" styleCode="Rrule " valign="top"><paragraph>7</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><list listType="unordered"><item><caption> </caption>Tremor</item></list></td><td align="center" styleCode="Rrule " valign="top"><paragraph>6</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><list listType="unordered"><item><caption> </caption>Syncope</item></list></td><td align="center" styleCode="Rrule " valign="top"><paragraph>6</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><list listType="unordered"><item><caption> </caption>Disturbed Sleep/Nightmares</item></list></td><td align="center" styleCode="Rrule " valign="top"><paragraph>4</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><list listType="unordered"><item><caption> </caption>Restlessness</item></list></td><td align="center" styleCode="Rrule " valign="top"><paragraph>4</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><list listType="unordered"><item><caption> </caption>Hypokinesia/Akinesia</item></list></td><td align="center" styleCode="Rrule " valign="top"><paragraph>4</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><list listType="unordered"><item><caption> </caption>Agitation</item></list></td><td align="center" styleCode="Rrule " valign="top"><paragraph>4</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><list listType="unordered"><item><caption> </caption>Seizures (convulsions)</item></list></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3&#x2020;</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><list listType="unordered"><item><caption> </caption>Rigidity</item></list></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><list listType="unordered"><item><caption> </caption>Akathisia</item></list></td><td align="center" styl

lign="top"><list listType="unordered"><item><caption> </caption>Rigidity</item></list></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><list listType="unordered"><item><caption> </caption>Akathisia</item></list></td><td align="center" styl eCode="Rrule " valign="top"><paragraph>3</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><list listType="unordered"><item><caption> </caption>Confusion</item></list></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><list listType="unordered"><item><caption> </caption>Fatigue</item></list></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><list listType="unordered"><item><caption> </caption>Insomnia</item></list></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Cardiovascular</content></paragraph></td><td styleCode="Rrule Toprule " valign="top"/></tr><tr><td styleCode="Lrule " valign="top"><list listType="unordered"><item><caption> </caption>Tachycardia</item></list></td><td align="center" styleCode="Rrule " valign="top"><paragraph>25&#x2020;</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><list listType="unordered"><item><caption> </caption>Hypotension</item></list></td><td align="center" styleCode="Rrule " valign="top"><paragraph>9</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><list listType="unordered"><item><caption> </caption>Hypertension</item></list></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4</paragraph></td></tr><tr><td styleCode="Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Gastrointestinal</content></paragraph></td><td styleCode="Rrule Toprule " valign="top"/></tr><tr><td styleCode="Lrule " valign="top"><list listType="unordered"><item><caption> </caption>Constipation</item></list></td><td align="center" styleCode="Rrule " valign="top"><paragraph>14</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><list listType="unordered"><item><caption> </caption>Nausea</item></list></td><td align="center" styleCode="Rrule " valign="top"><paragraph>5</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><list listType="unordered"><item><caption> </caption>Abdominal Discomfort/Heartburn</item></list></td><td align="center" styleCode="Rrule " valign="top"><paragraph>4</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><list listType="unordered"><item><caption> </caption>Nausea/Vomiting</item></list></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><list listType="unordered"><item><caption> </caption>Vomiting</item></list></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><list listType="unordered"><item><caption> </caption>Diarrhea</item></list></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Urogenital</content></paragraph></td><td styleCode="Rrule Toprule " valign="top"/></tr><tr><td styleCode="Lrule Botrule " valign="top"><list listType="unordered"><item><caption> </caption>Urinary Abnormalities</item></list></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Autonomic Nervous System</content>

" valign="top"><list listType="unordered"><item><caption> </caption>Urinary Abnormalities</item></list></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Autonomic Nervous System</content> </paragraph></td><td styleCode="Rrule Toprule " valign="top"/></tr><tr><td styleCode="Lrule " valign="top"><list listType="unordered"><item><caption> </caption>Salivation</item></list></td><td align="center" styleCode="Rrule " valign="top"><paragraph>31</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><list listType="unordered"><item><caption> </caption>Sweating</item></list></td><td align="center" styleCode="Rrule " valign="top"><paragraph>6</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><list listType="unordered"><item><caption> </caption>Dry Mouth</item></list></td><td align="center" styleCode="Rrule " valign="top"><paragraph>6</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><list listType="unordered"><item><caption> </caption>Visual Disturbances</item></list></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5</paragraph></td></tr><tr><td styleCode="Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Skin</content></paragraph></td><td styleCode="Rrule Toprule " valign="top"/></tr><tr><td styleCode="Lrule Botrule " valign="top"><list listType="unordered"><item><caption> </caption>Rash</item></list></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Hemic/Lymphatic</content></paragraph></td><td styleCode="Rrule Toprule " valign="top"/></tr><tr><td styleCode="Lrule Botrule " valign="top"><list listType="unordered"><item><caption> </caption>Leukopenia/Decreased WBC/Neutropenia</item></list></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3</paragraph></td></tr><tr><td styleCode="Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Miscellaneous</content></paragraph></td><td styleCode="Rrule Toprule " valign="top"/></tr><tr><td styleCode="Lrule " valign="top"><list listType="unordered"><item><caption> </caption>Fever</item></list></td><td align="center" styleCode="Rrule " valign="top"><paragraph>5</paragraph></td></tr><tr><td styleCode="Botrule Lrule " valign="top"><list listType="unordered"><item><caption> </caption>Weight Gain</item></list></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4</paragraph></td></tr></tbody></table>

lign="center" styleCode="Rrule " valign="top"><paragraph>5</paragraph></td></tr><tr><td styleCode="Botrule Lrule " valign="top"><list listType="unordered"><item><caption> </caption>Weight Gain</item></list></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4</paragraph></td></tr></tbody></table> <table ID="_Reftable11" width="100%"><caption>Table 11. Incidence of Adverse Reactions in Patients Treated with CLOZARIL or Olanzapine in the InterSePT&#x2122; Study (&#x2265;10% in the CLOZARIL or olanzapine group) </caption><col width="42%"/><col width="30%"/><col width="29%"/><tbody><tr><td styleCode="Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Adverse Reactions</content></paragraph></td><td align="center" styleCode="Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">CLOZARIL</content> <content styleCode="bold">N=479 </content> <content styleCode="bold">% Reporting </content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Olanzapine</content> <content styleCode="bold">N=477 </content> <content styleCode="bold">% Reporting </content></paragraph></td></tr><tr><td styleCode="Lrule Toprule " valign="bottom"><paragraph>Salivary hypersecretion</paragraph></td><td align="center" styleCode="Toprule " valign="bottom"><paragraph>48</paragraph></td><td align="center" styleCode="Rrule Toprule " valign="bottom"><paragraph>6</paragraph></td></tr><tr><td styleCode="Lrule " valign="bottom"><paragraph>Somnolence</paragraph></td><td align="center" valign="bottom"><paragraph>46</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>25</paragraph></td></tr><tr><td styleCode="Lrule " valign="bottom"><paragraph>Weight increased</paragraph></td><td align="center" valign="bottom"><paragraph>31</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>56</paragraph></td></tr><tr><td styleCode="Lrule " valign="bottom"><paragraph>Dizziness (excluding vertigo)</paragraph></td><td align="center" valign="bottom"><paragraph>27</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>12</paragraph></td></tr><tr><td styleCode="Lrule " valign="bottom"><paragraph>Constipation</paragraph></td><td align="center" valign="bottom"><paragraph>25</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>10</paragraph></td></tr><tr><td styleCode="Lrule " valign="bottom"><paragraph>Insomnia</paragraph></td><td align="center" valign="bottom"><paragraph>20</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>33</paragraph></td></tr><tr><td styleCode="Lrule " valign="bottom"><paragraph>Nausea</paragraph></td><td align="center" valign="bottom"><paragraph>17</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>10</paragraph></td></tr><tr><td styleCode="Lrule " valign="bottom"><paragraph>Vomiting</paragraph></td><td align="center" valign="bottom"><paragraph>17</paragraph></td><td align="center" styleCode="Rrule " valign="bottom"><paragraph>9</paragraph></td></tr><tr><td styleCode="Botrule Lrule " valign="bottom"><paragraph>Dyspepsia</paragraph></td><td align="center" styleCode="Botrule " valign="bottom"><paragraph>14</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="bottom"><paragraph>8</paragraph></td></tr></tbody></table>

<paragraph>9</paragraph></td></tr><tr><td styleCode="Botrule Lrule " valign="bottom"><paragraph>Dyspepsia</paragraph></td><td align="center" styleCode="Botrule " valign="bottom"><paragraph>14</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="bottom"><paragraph>8</paragraph></td></tr></tbody></table> <table ID="_Reftable9" width="100%"><caption>Table 9.

<paragraph>9</paragraph></td></tr><tr><td styleCode="Botrule Lrule " valign="bottom"><paragraph>Dyspepsia</paragraph></td><td align="center" styleCode="Botrule " valign="bottom"><paragraph>14</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="bottom"><paragraph>8</paragraph></td></tr></tbody></table> <table ID="_Reftable9" width="100%"><caption>Table 9. Common Adverse Reactions (&#x2265;5%) in the 6-Week, Randomized, Chlorpromazine-controlled Trial in Treatment-Resistant Schizophrenia</caption><col width="34%"/><col width="32%"/><col width="34%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">CLOZARIL</content> <content styleCode="bold">(N=126)</content> <content styleCode="bold">(%)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Chlorpromazine</content> <content styleCode="bold">(N=142)</content> <content styleCode="bold">(%)</content></paragraph></td></tr><tr><td styleCode="Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Sedation</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>21</paragraph></td><td align="center" styleCode="Rrule Toprule " valign="top"><paragraph>13</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><paragraph><content styleCode="bold">Tachycardia</content></paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>17</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>11</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><paragraph><content styleCode="bold">Constipation</content></paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>16</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>12</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><paragraph><content styleCode="bold">Dizziness</content></paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>14</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>16</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><paragraph><content styleCode="bold">Hypotension</content></paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>13</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>38</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><paragraph><content styleCode="bold">Fever (hyperthermia)</content></paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>13</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>4</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><paragraph><content styleCode="bold">Hypersalivation</content></paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>13</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><paragraph><content styleCode="bold">Hypertension</content></paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>12</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>5</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><paragraph><content styleCode="bold">Headache</content></paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>10</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>10</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><paragraph><content style

7 DRUG INTERACTIONS • Concomitant use of Strong CYP1A2 Inhibitors: Reduce CLOZARIL dose to one-third when coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, enoxacin). ( 2.7 , 7.1 ) • Concomitant use of Strong CYP3A4 Inducers is not recommended. ( 2.7 , 7.1 ) • Discontinuation of CYP1A2 or CYP3A4 Inducers: Consider reducing CLOZARIL dose when CYP1A2 inducers (e.g., tobacco smoke) or CYP3A4 inducers (e.g., carbamazepine) are discontinued. ( 2.7 , 7.1 ) • Anticholinergic drugs: Concomitant use may increase the risk for anticholinergic toxicity. ( 5.7 , 5.15 , 7.1 ) 7.1 Potential for Other Drugs to Affect CLOZARIL Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP3A4, and CYP2D6. Use caution when administering CLOZARIL concomitantly with drugs that are inducers or inhibitors of these enzymes. CYP1A2 Inhibitors Concomitant use of CLOZARIL and CYP1A2 inhibitors can increase plasma levels of clozapine, potentially resulting in adverse reactions. Reduce the CLOZARIL dose to one-third of the original dose when CLOZARIL is coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin). The CLOZARIL dose should be increased to the original dose when coadministration of strong CYP1A2 inhibitors is discontinued [see Dosage and Administration ( 2.7 ), Clinical Pharmacology ( 12.3 )] . Moderate or weak CYP1A2 inhibitors include oral contraceptives and caffeine. Monitor patients closely when CLOZARIL is coadministered with these inhibitors. Consider reducing the CLOZARIL dosage if necessary [see Dosage and Administration ( 2.7 )] . CYP2D6 and CYP3A4 Inhibitors Concomitant treatment with CLOZARIL and CYP2D6 or CYP3A4 inhibitors (e.g., cimetidine, escitalopram, erythromycin, paroxetine, bupropion, fluoxetine, quinidine, duloxetine, terbinafine, or sertraline) can increase clozapine levels and lead to adverse reactions [see Clinical Pharmacology ( 12.3 )] . Use caution and monitor patients closely when using such inhibitors. Consider reducing the CLOZARIL dose [see Dosage and Administration ( 2.7 )] . CYP1A2 and CYP3A4 Inducers Concomitant treatment with drugs that induce CYP1A2 or CYP3A4 can decrease the plasma concentration of clozapine, resulting in decreased effectiveness of CLOZARIL. Tobacco smoke is a moderate inducer of CYP1A2. Strong CYP3A4 inducers include carbamazepine, phenytoin, St. John’s wort, and rifampin. It may be necessary to increase the CLOZARIL dose if used concomitantly with inducers of these enzymes. However, concomitant use of CLOZARIL and strong CYP3A4 inducers is not recommended [see Dosage and Administration ( 2.7 )] . Consider reducing the CLOZARIL dosage when discontinuing coadministered enzyme inducers; because discontinuation of inducers can result in increased clozapine plasma levels and an increased risk of adverse reactions [see Dosage and Administration ( 2.7 )] . Anticholinergic Drugs Concomitant treatment with clozapine and other drugs with anticholinergic activity (e.g., benztropine, cyclobenzaprine, diphenhydramine) can increase the risk for anticholinergic toxicity and severe gastrointestinal adverse reactions related to hypomotility. Avoid concomitant use of CLOZARIL with anticholinergic drugs when possible [see Warnings and Precautions ( 5.7 , 5.15 )] . Drugs that Cause QT Interval Prolongation Use caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of clozapine.

ctions related to hypomotility. Avoid concomitant use of CLOZARIL with anticholinergic drugs when possible [see Warnings and Precautions ( 5.7 , 5.15 )] . Drugs that Cause QT Interval Prolongation Use caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of clozapine. Drugs that cause QT prolongation include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, thioridazine, mesoridazine, droperidol, and pimozide), specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin), Class 1A antiarrhythmics (e.g., quinidine, procainamide) or Class III antiarrhythmics (e.g., amiodarone, sotalol), and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus) [see Warnings and Precautions ( 5.9 )] . 7.2 Potential for CLOZARIL to Affect Other Drugs Concomitant use of CLOZARIL with other drugs metabolized by CYP2D6 can increase levels of these CYP2D6 substrates. Use caution when coadministering CLOZARIL with other drugs that are metabolized by CYP2D6. It may be necessary to use lower doses of such drugs than usually prescribed. Such drugs include specific antidepressants, phenothiazines, carbamazepine, and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide).

Use caution when coadministering CLOZARIL with other drugs that are metabolized by CYP2D6. It may be necessary to use lower doses of such drugs than usually prescribed. Such drugs include specific antidepressants, phenothiazines, carbamazepine, and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide). 7.1 Potential for Other Drugs to Affect CLOZARIL Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP3A4, and CYP2D6. Use caution when administering CLOZARIL concomitantly with drugs that are inducers or inhibitors of these enzymes. CYP1A2 Inhibitors Concomitant use of CLOZARIL and CYP1A2 inhibitors can increase plasma levels of clozapine, potentially resulting in adverse reactions. Reduce the CLOZARIL dose to one-third of the original dose when CLOZARIL is coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin). The CLOZARIL dose should be increased to the original dose when coadministration of strong CYP1A2 inhibitors is discontinued [see Dosage and Administration ( 2.7 ), Clinical Pharmacology ( 12.3 )] . Moderate or weak CYP1A2 inhibitors include oral contraceptives and caffeine. Monitor patients closely when CLOZARIL is coadministered with these inhibitors. Consider reducing the CLOZARIL dosage if necessary [see Dosage and Administration ( 2.7 )] . CYP2D6 and CYP3A4 Inhibitors Concomitant treatment with CLOZARIL and CYP2D6 or CYP3A4 inhibitors (e.g., cimetidine, escitalopram, erythromycin, paroxetine, bupropion, fluoxetine, quinidine, duloxetine, terbinafine, or sertraline) can increase clozapine levels and lead to adverse reactions [see Clinical Pharmacology ( 12.3 )] . Use caution and monitor patients closely when using such inhibitors. Consider reducing the CLOZARIL dose [see Dosage and Administration ( 2.7 )] . CYP1A2 and CYP3A4 Inducers Concomitant treatment with drugs that induce CYP1A2 or CYP3A4 can decrease the plasma concentration of clozapine, resulting in decreased effectiveness of CLOZARIL. Tobacco smoke is a moderate inducer of CYP1A2. Strong CYP3A4 inducers include carbamazepine, phenytoin, St. John’s wort, and rifampin. It may be necessary to increase the CLOZARIL dose if used concomitantly with inducers of these enzymes. However, concomitant use of CLOZARIL and strong CYP3A4 inducers is not recommended [see Dosage and Administration ( 2.7 )] . Consider reducing the CLOZARIL dosage when discontinuing coadministered enzyme inducers; because discontinuation of inducers can result in increased clozapine plasma levels and an increased risk of adverse reactions [see Dosage and Administration ( 2.7 )] . Anticholinergic Drugs Concomitant treatment with clozapine and other drugs with anticholinergic activity (e.g., benztropine, cyclobenzaprine, diphenhydramine) can increase the risk for anticholinergic toxicity and severe gastrointestinal adverse reactions related to hypomotility. Avoid concomitant use of CLOZARIL with anticholinergic drugs when possible [see Warnings and Precautions ( 5.7 , 5.15 )] . Drugs that Cause QT Interval Prolongation Use caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of clozapine. Drugs that cause QT prolongation include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, thioridazine, mesoridazine, droperidol, and pimozide), specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin), Class 1A antiarrhythmics (e.g., quinidine, procainamide) or Class III antiarrhythmics (e.g., amiodarone, sotalol), and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus) [see Warnings and Precautions ( 5.9 )] .

moxifloxacin, sparfloxacin), Class 1A antiarrhythmics (e.g., quinidine, procainamide) or Class III antiarrhythmics (e.g., amiodarone, sotalol), and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus) [see Warnings and Precautions ( 5.9 )] . 7.2 Potential for CLOZARIL to Affect Other Drugs Concomitant use of CLOZARIL with other drugs metabolized by CYP2D6 can increase levels of these CYP2D6 substrates. Use caution when coadministering CLOZARIL with other drugs that are metabolized by CYP2D6. It may be necessary to use lower doses of such drugs than usually prescribed. Such drugs include specific antidepressants, phenothiazines, carbamazepine, and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide).

8 USE IN SPECIFIC POPULATIONS • Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure ( 8.1 ). 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including CLOZARIL, during pregnancy. Healthcare providers are encouraged to advise patients to register by calling the National Pregnancy Registry for Atypical Antipsychotics at1-866-961-2388 or visiting http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/ . Risk Summary Neonates exposed to antipsychotic drugs, including CLOZARIL, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery ( see Clinical Considerations ). Available data from published epidemiologic studies over decades of use with clozapine during pregnancy have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes ( see Data ). There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, including CLOZARIL, during pregnancy ( see Clinical Considerations ). In animal reproduction studies, no adverse developmental effects were observed when clozapine was administered orally to pregnant rats or rabbits during the period of organogenesis, or to pregnant rats during pregnancy and lactation, at doses up to approximately 0.4 and 0.9 times the maximum recommended human dose (MRHD) of 900 mg/day, for rats and rabbits respectively, based on mg/m2 body surface area ( see Data ). The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk There is a risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide. Schizophrenia is associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. Fetal/Neonatal adverse reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who have been exposed to antipsychotic drugs, including CLOZARIL, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Data Animal Data In embryofetal developmental studies, clozapine had no effects on maternal parameters, litter sizes, or fetal parameters when administered orally to pregnant rats and rabbits during the period of organogenesis at doses up to 0.4 and 0.9 times, respectively, the MRHD of 900 mg/day on a mg/m 2 body surface area basis. In peri/postnatal developmental studies, pregnant female rats were administered clozapine over the last third of pregnancy and until day 21 postpartum.

pregnant rats and rabbits during the period of organogenesis at doses up to 0.4 and 0.9 times, respectively, the MRHD of 900 mg/day on a mg/m 2 body surface area basis. In peri/postnatal developmental studies, pregnant female rats were administered clozapine over the last third of pregnancy and until day 21 postpartum. Observations were made on fetuses at birth and during the postnatal period; the offspring were allowed to reach sexual maturity and mated. Clozapine caused a decrease in maternal body weight but had no effects on litter size or body weights of either F1 or F2 generations at doses up to 0.4 times the MRHD of 900 mg/day on a mg/m 2 body surface area basis. 8.2 Lactation Risk Summary Clozapine is present in human milk. There is one case report of sedation and a report of agranulocytosis in an infant exposed to clozapine through human milk ( see Clinical Considerations ). There is no information on the effects of clozapine on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CLOZARIL and any potential adverse effects on the breastfed child from CLOZARIL or from the underlying maternal condition. Clinical Considerations Infants exposed to CLOZARIL should be monitored for excess sedation and neutropenia. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use There have not been sufficient numbers of geriatric patients in clinical studies utilizing CLOZARIL to determine whether those over 65 years of age differ from younger subjects in their response to CLOZARIL. Orthostatic hypotension and tachycardia can occur with CLOZARIL treatment [see Boxed Warning and Warnings and Precautions ( 5.2 )] . Elderly patients, particularly those with compromised cardiovascular functioning, may be more susceptible to these effects. Elderly patients may be particularly susceptible to the anticholinergic effects of CLOZARIL, such as urinary retention and constipation [see Warnings and Precautions ( 5.15 )] . Carefully select CLOZARIL doses in elderly patients, taking into consideration their greater frequency of decreased hepatic, renal, or cardiac function, as well as other concomitant disease and other drug therapy. Clinical experience suggests that the prevalence of tardive dyskinesia appears to be highest among the elderly; especially elderly women [see Warnings and Precautions ( 5.17 )] . 8.6 Patients with Renal or Hepatic Impairment Dose reduction may be necessary in patients with significant impairment of renal or hepatic function. Clozapine concentrations may be increased in these patients, because clozapine is almost completely metabolized and then excreted [see Dosage and Administration ( 2.8 ), Clinical Pharmacology ( 12.3 )] . 8.7 CYP2D6 Poor Metabolizers Dose reduction may be necessary in patients who are CYP2D6 poor metabolizers. Clozapine concentrations may be increased in these patients, because clozapine is almost completely metabolized and then excreted [see Dosage and Administration ( 2.8 ), Clinical Pharmacology ( 12.3 )] .

12.3 )] . 8.7 CYP2D6 Poor Metabolizers Dose reduction may be necessary in patients who are CYP2D6 poor metabolizers. Clozapine concentrations may be increased in these patients, because clozapine is almost completely metabolized and then excreted [see Dosage and Administration ( 2.8 ), Clinical Pharmacology ( 12.3 )] . 8.6 Patients with Renal or Hepatic Impairment Dose reduction may be necessary in patients with significant impairment of renal or hepatic function. Clozapine concentrations may be increased in these patients, because clozapine is almost completely metabolized and then excreted [see Dosage and Administration ( 2.8 ), Clinical Pharmacology ( 12.3 )] . 8.7 CYP2D6 Poor Metabolizers Dose reduction may be necessary in patients who are CYP2D6 poor metabolizers. Clozapine concentrations may be increased in these patients, because clozapine is almost completely metabolized and then excreted [see Dosage and Administration ( 2.8 ), Clinical Pharmacology ( 12.3 )] .

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including CLOZARIL, during pregnancy. Healthcare providers are encouraged to advise patients to register by calling the National Pregnancy Registry for Atypical Antipsychotics at1-866-961-2388 or visiting http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/ . Risk Summary Neonates exposed to antipsychotic drugs, including CLOZARIL, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery ( see Clinical Considerations ). Available data from published epidemiologic studies over decades of use with clozapine during pregnancy have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes ( see Data ). There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, including CLOZARIL, during pregnancy ( see Clinical Considerations ). In animal reproduction studies, no adverse developmental effects were observed when clozapine was administered orally to pregnant rats or rabbits during the period of organogenesis, or to pregnant rats during pregnancy and lactation, at doses up to approximately 0.4 and 0.9 times the maximum recommended human dose (MRHD) of 900 mg/day, for rats and rabbits respectively, based on mg/m2 body surface area ( see Data ). The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk There is a risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide. Schizophrenia is associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. Fetal/Neonatal adverse reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who have been exposed to antipsychotic drugs, including CLOZARIL, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Data Animal Data In embryofetal developmental studies, clozapine had no effects on maternal parameters, litter sizes, or fetal parameters when administered orally to pregnant rats and rabbits during the period of organogenesis at doses up to 0.4 and 0.9 times, respectively, the MRHD of 900 mg/day on a mg/m 2 body surface area basis. In peri/postnatal developmental studies, pregnant female rats were administered clozapine over the last third of pregnancy and until day 21 postpartum. Observations were made on fetuses at birth and during the postnatal period; the offspring were allowed to reach sexual maturity and mated.

/m 2 body surface area basis. In peri/postnatal developmental studies, pregnant female rats were administered clozapine over the last third of pregnancy and until day 21 postpartum. Observations were made on fetuses at birth and during the postnatal period; the offspring were allowed to reach sexual maturity and mated. Clozapine caused a decrease in maternal body weight but had no effects on litter size or body weights of either F1 or F2 generations at doses up to 0.4 times the MRHD of 900 mg/day on a mg/m 2 body surface area basis.

8.5 Geriatric Use There have not been sufficient numbers of geriatric patients in clinical studies utilizing CLOZARIL to determine whether those over 65 years of age differ from younger subjects in their response to CLOZARIL. Orthostatic hypotension and tachycardia can occur with CLOZARIL treatment [see Boxed Warning and Warnings and Precautions ( 5.2 )] . Elderly patients, particularly those with compromised cardiovascular functioning, may be more susceptible to these effects. Elderly patients may be particularly susceptible to the anticholinergic effects of CLOZARIL, such as urinary retention and constipation [see Warnings and Precautions ( 5.15 )] . Carefully select CLOZARIL doses in elderly patients, taking into consideration their greater frequency of decreased hepatic, renal, or cardiac function, as well as other concomitant disease and other drug therapy. Clinical experience suggests that the prevalence of tardive dyskinesia appears to be highest among the elderly; especially elderly women [see Warnings and Precautions ( 5.17 )] .

10 OVERDOSAGE 10.1 Overdosage Experience The most commonly reported signs and symptoms associated with clozapine overdose are: sedation, delirium, coma, tachycardia, hypotension, respiratory depression or failure; and hypersalivation. There are reports of aspiration pneumonia, cardiac arrhythmias, and seizure. Fatal overdoses have been reported with clozapine, generally at doses above 2500 mg. There have also been reports of patients recovering from overdoses well in excess of 4 g. 10.2 Management of Overdosage There is no available specific antidote to an overdose of CLOZARIL. Establish and maintain an airway; ensure adequate oxygenation and ventilation. Monitor cardiac status and vital signs. Use general symptomatic and supportive measures. Consider the possibility of multiple-drug involvement. Contact a Certified Poison Control Center for the most up to date information on the management of overdosage (1-800-222-1222). 10.1 Overdosage Experience The most commonly reported signs and symptoms associated with clozapine overdose are: sedation, delirium, coma, tachycardia, hypotension, respiratory depression or failure; and hypersalivation. There are reports of aspiration pneumonia, cardiac arrhythmias, and seizure. Fatal overdoses have been reported with clozapine, generally at doses above 2500 mg. There have also been reports of patients recovering from overdoses well in excess of 4 g. 10.2 Management of Overdosage There is no available specific antidote to an overdose of CLOZARIL. Establish and maintain an airway; ensure adequate oxygenation and ventilation. Monitor cardiac status and vital signs. Use general symptomatic and supportive measures. Consider the possibility of multiple-drug involvement. Contact a Certified Poison Control Center for the most up to date information on the management of overdosage (1-800-222-1222).

11 DESCRIPTION CLOZARIL ® (clozapine), an atypical antipsychotic drug, is a tricyclic dibenzodiazepine derivative, 8-chloro-11-(4-methyl-1-piperazinyl)-5 H -dibenzo [ b,e ] [1,4] diazepine. The structural formula is: CLOZARIL is available in pale yellow tablets of 25 mg and 100 mg for oral administration. Active Ingredient: clozapine Inactive Ingredients are colloidal silicon dioxide, lactose, magnesium stearate, povidone, starch (corn), and talc. structural formula

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of clozapine is unknown. However, it has been proposed that the therapeutic efficacy of clozapine in schizophrenia is mediated through antagonism of the dopamine type 2 (D 2 ) and the serotonin type 2A (5-HT 2A ) receptors. CLOZARIL also acts as an antagonist at adrenergic, cholinergic, histaminergic and other dopaminergic and serotonergic receptors. 12.2 Pharmacodynamics Clozapine demonstrated binding affinity to the following receptors: histamine H 1 (K i 1.1 nM), adrenergic α 1A (K i 1.6 nM), serotonin 5-HT 6 (K i 4 nM), serotonin 5-HT 2A (K i 5.4 nM), muscarinic M 1 (K i 6.2 nM), serotonin 5-HT 7 (K i 6.3 nM), serotonin 5-HT 2C (K i 9.4 nM), dopamine D 4 (K i 24 nM), adrenergic α 2A (K i 90 nM), serotonin 5-HT 3 (K i 95 nM), serotonin 5-HT 1A (K i 120 nM), dopamine D 2 (K i 160 nM), dopamine D 1 (K i 270 nM), dopamine D 5 (K i 454 nM), and dopamine D 3 (K i 555 nM). Clozapine causes little or no prolactin elevation. Clinical electroencephalogram (EEG) studies demonstrated that clozapine increases delta and theta activity and slows dominant alpha frequencies. Enhanced synchronization occurs. Sharp wave activity and spike and wave complexes may also develop. Patients have reported an intensification of dream activity during clozapine therapy. REM sleep was found to be increased to 85% of the total sleep time. In these patients, the onset of REM sleep occurred almost immediately after falling asleep. 12.3 Pharmacokinetics Absorption In humans, CLOZARIL tablets (25 mg and 100 mg) are equally bioavailable relative to a CLOZARIL solution. Following oral administration of CLOZARIL 100 mg twice daily, the average steady-state peak plasma concentration was 319 ng/mL (range: 102 to 771 ng/mL), occurring at the average of 2.5 hours (range: 1 to 6 hours) after dosing. The average minimum concentration at steady state was 122 ng/mL (range: 41 to 343 ng/mL), after 100 mg twice daily dosing. Food does not appear to affect the systemic bioavailability of CLOZARIL. Thus, CLOZARIL may be administered with or without food. Distribution Clozapine is approximately 97% bound to serum proteins. The interaction between clozapine and other highly protein-bound drugs has not been fully evaluated but may be important [see Drug Interactions ( 7 )] . Metabolism and Excretion Clozapine is almost completely metabolized prior to excretion, and only trace amounts of unchanged drug are detected in the urine and feces. Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP2D6, and CYP3A4. Approximately 50% of the administered dose is excreted in the urine and 30% in the feces. The demethylated, hydroxylated, and N -oxide derivatives are components in both urine and feces. Pharmacological testing has shown the desmethyl metabolite (norclozapine) to have only limited activity, while the hydroxylated and N- oxide derivatives were inactive. The mean elimination half-life of clozapine after a single 75 mg dose was 8 hours (range: 4 to 12 hours), compared to a mean elimination half-life of 12 hours (range: 4 to 66 hours), after achieving steady state with 100 mg twice daily dosing. A comparison of single-dose and multiple-dose administration of clozapine demonstrated that the elimination half-life increased significantly after multiple dosing relative to that after single-dose administration, suggesting the possibility of concentration-dependent pharmacokinetics.

e with 100 mg twice daily dosing. A comparison of single-dose and multiple-dose administration of clozapine demonstrated that the elimination half-life increased significantly after multiple dosing relative to that after single-dose administration, suggesting the possibility of concentration-dependent pharmacokinetics. However, at steady state, approximately dose-proportional changes with respect to AUC (area under the curve), peak, and minimum clozapine plasma concentrations were observed after administration of 37.5, 75, and 150 mg twice daily. Drug-Drug Interaction Studies Fluvoxamine A pharmacokinetic study was conducted in 16 patients with schizophrenia who received clozapine under steady-state conditions. After coadministration of fluvoxamine for 14 days, mean trough concentrations of clozapine and its metabolites, N -desmethylclozapine and clozapine N -oxide, were elevated about three-fold compared to baseline steady-state concentrations. Paroxetine, Fluoxetine, and Sertraline In a study of patients with schizophrenia (n=14) who received clozapine under steady-state conditions, coadministration of paroxetine produced only minor changes in the levels of clozapine and its metabolites. However, other published reports describe modest elevations (less than two-fold) of clozapine and metabolite concentrations when clozapine was taken with paroxetine, fluoxetine, and sertraline. Specific Population Studies Renal or Hepatic Impairment No specific pharmacokinetic studies were conducted to investigate the effects of renal or hepatic impairment on the pharmacokinetics of clozapine. Higher clozapine plasma concentrations are likely in patients with significant renal or hepatic impairment when given usual doses. CYP2D6 Poor Metabolizers A subset (3%–10%) of the population has reduced activity of CYP2D6 (CYP2D6 poor metabolizers). These individuals may develop higher than expected plasma concentrations of clozapine when given usual doses. Patients with Pneumonia and other Inflammatory Conditions Published case reports describe examples where pneumonia or other inflammatory conditions may increase clozapine concentrations. The clinical significance, the impact of treatments to modulate this inflammation, and mechanism of this potential increase in clozapine concentrations have not been fully characterized but may involve reduced cytochrome P450 1A2 activity.

12.1 Mechanism of Action The mechanism of action of clozapine is unknown. However, it has been proposed that the therapeutic efficacy of clozapine in schizophrenia is mediated through antagonism of the dopamine type 2 (D 2 ) and the serotonin type 2A (5-HT 2A ) receptors. CLOZARIL also acts as an antagonist at adrenergic, cholinergic, histaminergic and other dopaminergic and serotonergic receptors.

12.2 Pharmacodynamics Clozapine demonstrated binding affinity to the following receptors: histamine H 1 (K i 1.1 nM), adrenergic α 1A (K i 1.6 nM), serotonin 5-HT 6 (K i 4 nM), serotonin 5-HT 2A (K i 5.4 nM), muscarinic M 1 (K i 6.2 nM), serotonin 5-HT 7 (K i 6.3 nM), serotonin 5-HT 2C (K i 9.4 nM), dopamine D 4 (K i 24 nM), adrenergic α 2A (K i 90 nM), serotonin 5-HT 3 (K i 95 nM), serotonin 5-HT 1A (K i 120 nM), dopamine D 2 (K i 160 nM), dopamine D 1 (K i 270 nM), dopamine D 5 (K i 454 nM), and dopamine D 3 (K i 555 nM). Clozapine causes little or no prolactin elevation. Clinical electroencephalogram (EEG) studies demonstrated that clozapine increases delta and theta activity and slows dominant alpha frequencies. Enhanced synchronization occurs. Sharp wave activity and spike and wave complexes may also develop. Patients have reported an intensification of dream activity during clozapine therapy. REM sleep was found to be increased to 85% of the total sleep time. In these patients, the onset of REM sleep occurred almost immediately after falling asleep.

12.3 Pharmacokinetics Absorption In humans, CLOZARIL tablets (25 mg and 100 mg) are equally bioavailable relative to a CLOZARIL solution. Following oral administration of CLOZARIL 100 mg twice daily, the average steady-state peak plasma concentration was 319 ng/mL (range: 102 to 771 ng/mL), occurring at the average of 2.5 hours (range: 1 to 6 hours) after dosing. The average minimum concentration at steady state was 122 ng/mL (range: 41 to 343 ng/mL), after 100 mg twice daily dosing. Food does not appear to affect the systemic bioavailability of CLOZARIL. Thus, CLOZARIL may be administered with or without food. Distribution Clozapine is approximately 97% bound to serum proteins. The interaction between clozapine and other highly protein-bound drugs has not been fully evaluated but may be important [see Drug Interactions ( 7 )] . Metabolism and Excretion Clozapine is almost completely metabolized prior to excretion, and only trace amounts of unchanged drug are detected in the urine and feces. Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP2D6, and CYP3A4. Approximately 50% of the administered dose is excreted in the urine and 30% in the feces. The demethylated, hydroxylated, and N -oxide derivatives are components in both urine and feces. Pharmacological testing has shown the desmethyl metabolite (norclozapine) to have only limited activity, while the hydroxylated and N- oxide derivatives were inactive. The mean elimination half-life of clozapine after a single 75 mg dose was 8 hours (range: 4 to 12 hours), compared to a mean elimination half-life of 12 hours (range: 4 to 66 hours), after achieving steady state with 100 mg twice daily dosing. A comparison of single-dose and multiple-dose administration of clozapine demonstrated that the elimination half-life increased significantly after multiple dosing relative to that after single-dose administration, suggesting the possibility of concentration-dependent pharmacokinetics. However, at steady state, approximately dose-proportional changes with respect to AUC (area under the curve), peak, and minimum clozapine plasma concentrations were observed after administration of 37.5, 75, and 150 mg twice daily. Drug-Drug Interaction Studies Fluvoxamine A pharmacokinetic study was conducted in 16 patients with schizophrenia who received clozapine under steady-state conditions. After coadministration of fluvoxamine for 14 days, mean trough concentrations of clozapine and its metabolites, N -desmethylclozapine and clozapine N -oxide, were elevated about three-fold compared to baseline steady-state concentrations. Paroxetine, Fluoxetine, and Sertraline In a study of patients with schizophrenia (n=14) who received clozapine under steady-state conditions, coadministration of paroxetine produced only minor changes in the levels of clozapine and its metabolites. However, other published reports describe modest elevations (less than two-fold) of clozapine and metabolite concentrations when clozapine was taken with paroxetine, fluoxetine, and sertraline. Specific Population Studies Renal or Hepatic Impairment No specific pharmacokinetic studies were conducted to investigate the effects of renal or hepatic impairment on the pharmacokinetics of clozapine. Higher clozapine plasma concentrations are likely in patients with significant renal or hepatic impairment when given usual doses.

lation Studies Renal or Hepatic Impairment No specific pharmacokinetic studies were conducted to investigate the effects of renal or hepatic impairment on the pharmacokinetics of clozapine. Higher clozapine plasma concentrations are likely in patients with significant renal or hepatic impairment when given usual doses. CYP2D6 Poor Metabolizers A subset (3%–10%) of the population has reduced activity of CYP2D6 (CYP2D6 poor metabolizers). These individuals may develop higher than expected plasma concentrations of clozapine when given usual doses. Patients with Pneumonia and other Inflammatory Conditions Published case reports describe examples where pneumonia or other inflammatory conditions may increase clozapine concentrations. The clinical significance, the impact of treatments to modulate this inflammation, and mechanism of this potential increase in clozapine concentrations have not been fully characterized but may involve reduced cytochrome P450 1A2 activity.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No carcinogenic potential was demonstrated in long-term studies in mice and rats at doses up to 0.3 times and 0.4 times, respectively, the maximum recommended human dose (MRHD) of 900 mg/day on a mg/m 2 body surface area basis. Mutagenesis Clozapine was not genotoxic when tested in the following gene mutation and chromosomal aberration tests: the bacterial Ames test, the in vitro mammalian V79 in Chinese hamster cells, the in vitro unscheduled DNA synthesis in rat hepatocytes or the in vivo micronucleus assay in mice. Impairment of Fertility Clozapine had no effect on any parameters of fertility, pregnancy, fetal weight or postnatal development when administered orally to male rats 70 days before mating and to female rats for 14 days before mating at doses up to 0.4 times the MRHD of 900 mg/day on a mg/m 2 body surface area basis.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No carcinogenic potential was demonstrated in long-term studies in mice and rats at doses up to 0.3 times and 0.4 times, respectively, the maximum recommended human dose (MRHD) of 900 mg/day on a mg/m 2 body surface area basis. Mutagenesis Clozapine was not genotoxic when tested in the following gene mutation and chromosomal aberration tests: the bacterial Ames test, the in vitro mammalian V79 in Chinese hamster cells, the in vitro unscheduled DNA synthesis in rat hepatocytes or the in vivo micronucleus assay in mice. Impairment of Fertility Clozapine had no effect on any parameters of fertility, pregnancy, fetal weight or postnatal development when administered orally to male rats 70 days before mating and to female rats for 14 days before mating at doses up to 0.4 times the MRHD of 900 mg/day on a mg/m 2 body surface area basis.

14 CLINICAL STUDIES 14.1 Treatment-Resistant Schizophrenia The efficacy of CLOZARIL in treatment-resistant schizophrenia was established in a multicenter, randomized, double-blind, active-controlled (chlorpromazine) study in patients with a DSM-III diagnosis of schizophrenia who had inadequate responses to at least 3 different antipsychotics (from at least 2 different chemical classes) during the preceding 5 years. The antipsychotic trials must have been judged adequate; the antipsychotic dosages must have been equivalent to or greater than 1000 mg per day of chlorpromazine for a period of at least 6 weeks, each without significant reduction of symptoms. There must have been no period of good functioning within the preceding 5 years. Patients must have had a baseline score of at least 45 on the investigator-rated Brief Psychiatric Rating Scale (BPRS). On the 18-item BPRS, 1 indicates the absence of symptoms, and 7 indicates severe symptoms; the maximum potential total BPRS score is 126. At baseline, the mean BPRS score was 61. In addition, patients must have had a score of at least 4 on at least two of the following four individual BPRS items: conceptual disorganization, suspiciousness, hallucinatory behavior, and unusual thought content. Patients must have had a Clinical Global Impressions–Severity Scale score of at least 4 (moderately ill). In the prospective, lead-in phase of the trial, all patients (N=305) initially received single-blind treatment with haloperidol (the mean dose was 61 mg per day) for 6 weeks. More than 80% of patients completed the 6-week trial. Patients with an inadequate response to haloperidol (n=268) were randomized to double-blind treatment with CLOZARIL (N=126) or chlorpromazine (N=142). The maximum daily CLOZARIL dose was 900 mg; the mean daily dose was >600 mg. The maximum daily chlorpromazine dose was 1800 mg; the mean daily dose was >1200 mg. The primary endpoint was treatment response, predefined as a decrease in BPRS score of at least 20% and either (1) a CGI-S score of ≤3 (mildly ill), or (2) a BPRS score of ≤35, at the end of 6 weeks of treatment. Approximately 88% of patients from the CLOZARIL and chlorpromazine groups completed the 6-week trial. At the end of 6 weeks, 30% of the CLOZARIL group responded to treatment, and 4% of the chlorpromazine group responded to treatment. The difference was statistically significant (p <0.001). The mean change in total BPRS score was -16 and -5 in the CLOZARIL and chlorpromazine group, respectively; the mean change in the 4 key BPRS item scores was -5 and -2 in the CLOZARIL and chlorpromazine group, respectively; and the mean change in CGI-S score was -1.2 and -0.4, in the CLOZARIL and chlorpromazine group, respectively. These changes in the CLOZARIL group were statistically significantly greater than in the chlorpromazine group (p<0.001 in each analysis). 14.2 Recurrent Suicidal Behavior in Schizophrenia or Schizoaffective Disorder The effectiveness of CLOZARIL in reducing the risk of recurrent suicidal behavior was assessed in the International Suicide Prevention Trial (InterSePT™, a trademark of Novartis Pharmaceuticals Corporation).

group (p<0.001 in each analysis). 14.2 Recurrent Suicidal Behavior in Schizophrenia or Schizoaffective Disorder The effectiveness of CLOZARIL in reducing the risk of recurrent suicidal behavior was assessed in the International Suicide Prevention Trial (InterSePT™, a trademark of Novartis Pharmaceuticals Corporation). This was a prospective, randomized, open-label, active-controlled, multicenter, international, parallel-group comparison of CLOZARIL versus olanzapine (*Zyprexa ® , a registered trademark of Eli Lilly and Company) in 956 patients with schizophrenia or schizoaffective disorder (DSM-IV) who were judged to be at risk for recurrent suicidal behavior. Only about one-fourth of these patients (27%) were considered resistant to standard antipsychotic drug treatment. To enter the trial, patients must have met 1 of the following criteria: • They had attempted suicide within the three years prior to their baseline evaluation. • They had been hospitalized to prevent a suicide attempt within the three years prior to their baseline evaluation. • They demonstrated moderate-to-severe suicidal ideation with a depressive component within one week prior to their baseline evaluation. • They demonstrated moderate-to-severe suicidal ideation accompanied by command hallucinations to do self-harm within one week prior to their baseline evaluation. Dosing regimens for each treatment group were determined by individual investigators and were individualized by patient. Dosing was flexible, with a dose range of 200–900 mg/day for CLOZARIL and 5–20 mg/day for olanzapine. For the 956 patients who received CLOZARIL or olanzapine in this study, there was extensive use of concomitant psychotropics: 84% with antipsychotics, 65% with anxiolytics, 53% with antidepressants, and 28% with mood stabilizers. There was significantly greater use of concomitant psychotropic medications among the patients in the olanzapine group. The primary efficacy measure was time to (1) a significant suicide attempt, including a completed suicide; (2) hospitalization due to imminent suicide risk, including increased level of surveillance for suicidality for patients already hospitalized; or (3) worsening of suicidality severity as demonstrated by “much worsening” or “very much worsening” from baseline in the Clinical Global Impression of Severity of Suicidality as assessed by the Blinded Psychiatrist (CGI-SS-BP) scale. A determination of whether or not a reported event met criterion 1 or 2 above was made by the Suicide Monitoring Board (SMB), a group of experts blinded to patient data. A total of 980 patients were randomized to the study and 956 received study medication. Sixty-two percent of the patients were diagnosed with schizophrenia, and the remainder (38%) were diagnosed with schizoaffective disorder. Only about one-fourth of the total patient population (27%) was identified as “treatment-resistant” at baseline. There were more males than females in the study (61% of all patients were male). The mean age of patients entering the study was 37 years of age (range 18–69). Most patients were Caucasian (71%), 15% were Black, 1% were Asian, and 13% were classified as being of “other” races. Patients treated with CLOZARIL had a statistically significant longer delay in the time to recurrent suicidal behavior in comparison with olanzapine. This result should be interpreted only as evidence of the effectiveness of CLOZARIL in delaying time to recurrent suicidal behavior and not a demonstration of the superior efficacy of CLOZARIL over olanzapine.

atistically significant longer delay in the time to recurrent suicidal behavior in comparison with olanzapine. This result should be interpreted only as evidence of the effectiveness of CLOZARIL in delaying time to recurrent suicidal behavior and not a demonstration of the superior efficacy of CLOZARIL over olanzapine. The probability of experiencing (1) a significant suicide attempt, including a completed suicide, or (2) hospitalization because of imminent suicide risk, including increased level of surveillance for suicidality for patients already hospitalized, was lower for CLOZARIL patients than for olanzapine patients at Week 104: CLOZARIL 24% versus olanzapine 32%; 95% CI of the difference: 2%, 14% ( Figure 1 ). Figure 1. Cumulative Probability of a Significant Suicide Attempt or Hospitalization to Prevent Suicide in Patients with Schizophrenia or Schizoaffective Disorder at High Risk of Suicidality Figure 1

for olanzapine patients at Week 104: CLOZARIL 24% versus olanzapine 32%; 95% CI of the difference: 2%, 14% ( Figure 1 ). Figure 1. Cumulative Probability of a Significant Suicide Attempt or Hospitalization to Prevent Suicide in Patients with Schizophrenia or Schizoaffective Disorder at High Risk of Suicidality Figure 1 14.1 Treatment-Resistant Schizophrenia The efficacy of CLOZARIL in treatment-resistant schizophrenia was established in a multicenter, randomized, double-blind, active-controlled (chlorpromazine) study in patients with a DSM-III diagnosis of schizophrenia who had inadequate responses to at least 3 different antipsychotics (from at least 2 different chemical classes) during the preceding 5 years. The antipsychotic trials must have been judged adequate; the antipsychotic dosages must have been equivalent to or greater than 1000 mg per day of chlorpromazine for a period of at least 6 weeks, each without significant reduction of symptoms. There must have been no period of good functioning within the preceding 5 years. Patients must have had a baseline score of at least 45 on the investigator-rated Brief Psychiatric Rating Scale (BPRS). On the 18-item BPRS, 1 indicates the absence of symptoms, and 7 indicates severe symptoms; the maximum potential total BPRS score is 126. At baseline, the mean BPRS score was 61. In addition, patients must have had a score of at least 4 on at least two of the following four individual BPRS items: conceptual disorganization, suspiciousness, hallucinatory behavior, and unusual thought content. Patients must have had a Clinical Global Impressions–Severity Scale score of at least 4 (moderately ill). In the prospective, lead-in phase of the trial, all patients (N=305) initially received single-blind treatment with haloperidol (the mean dose was 61 mg per day) for 6 weeks. More than 80% of patients completed the 6-week trial. Patients with an inadequate response to haloperidol (n=268) were randomized to double-blind treatment with CLOZARIL (N=126) or chlorpromazine (N=142). The maximum daily CLOZARIL dose was 900 mg; the mean daily dose was >600 mg. The maximum daily chlorpromazine dose was 1800 mg; the mean daily dose was >1200 mg. The primary endpoint was treatment response, predefined as a decrease in BPRS score of at least 20% and either (1) a CGI-S score of ≤3 (mildly ill), or (2) a BPRS score of ≤35, at the end of 6 weeks of treatment. Approximately 88% of patients from the CLOZARIL and chlorpromazine groups completed the 6-week trial. At the end of 6 weeks, 30% of the CLOZARIL group responded to treatment, and 4% of the chlorpromazine group responded to treatment. The difference was statistically significant (p <0.001). The mean change in total BPRS score was -16 and -5 in the CLOZARIL and chlorpromazine group, respectively; the mean change in the 4 key BPRS item scores was -5 and -2 in the CLOZARIL and chlorpromazine group, respectively; and the mean change in CGI-S score was -1.2 and -0.4, in the CLOZARIL and chlorpromazine group, respectively. These changes in the CLOZARIL group were statistically significantly greater than in the chlorpromazine group (p<0.001 in each analysis).

es was -5 and -2 in the CLOZARIL and chlorpromazine group, respectively; and the mean change in CGI-S score was -1.2 and -0.4, in the CLOZARIL and chlorpromazine group, respectively. These changes in the CLOZARIL group were statistically significantly greater than in the chlorpromazine group (p<0.001 in each analysis). 14.2 Recurrent Suicidal Behavior in Schizophrenia or Schizoaffective Disorder The effectiveness of CLOZARIL in reducing the risk of recurrent suicidal behavior was assessed in the International Suicide Prevention Trial (InterSePT™, a trademark of Novartis Pharmaceuticals Corporation). This was a prospective, randomized, open-label, active-controlled, multicenter, international, parallel-group comparison of CLOZARIL versus olanzapine (*Zyprexa ® , a registered trademark of Eli Lilly and Company) in 956 patients with schizophrenia or schizoaffective disorder (DSM-IV) who were judged to be at risk for recurrent suicidal behavior. Only about one-fourth of these patients (27%) were considered resistant to standard antipsychotic drug treatment. To enter the trial, patients must have met 1 of the following criteria: • They had attempted suicide within the three years prior to their baseline evaluation. • They had been hospitalized to prevent a suicide attempt within the three years prior to their baseline evaluation. • They demonstrated moderate-to-severe suicidal ideation with a depressive component within one week prior to their baseline evaluation. • They demonstrated moderate-to-severe suicidal ideation accompanied by command hallucinations to do self-harm within one week prior to their baseline evaluation. Dosing regimens for each treatment group were determined by individual investigators and were individualized by patient. Dosing was flexible, with a dose range of 200–900 mg/day for CLOZARIL and 5–20 mg/day for olanzapine. For the 956 patients who received CLOZARIL or olanzapine in this study, there was extensive use of concomitant psychotropics: 84% with antipsychotics, 65% with anxiolytics, 53% with antidepressants, and 28% with mood stabilizers. There was significantly greater use of concomitant psychotropic medications among the patients in the olanzapine group. The primary efficacy measure was time to (1) a significant suicide attempt, including a completed suicide; (2) hospitalization due to imminent suicide risk, including increased level of surveillance for suicidality for patients already hospitalized; or (3) worsening of suicidality severity as demonstrated by “much worsening” or “very much worsening” from baseline in the Clinical Global Impression of Severity of Suicidality as assessed by the Blinded Psychiatrist (CGI-SS-BP) scale. A determination of whether or not a reported event met criterion 1 or 2 above was made by the Suicide Monitoring Board (SMB), a group of experts blinded to patient data. A total of 980 patients were randomized to the study and 956 received study medication. Sixty-two percent of the patients were diagnosed with schizophrenia, and the remainder (38%) were diagnosed with schizoaffective disorder. Only about one-fourth of the total patient population (27%) was identified as “treatment-resistant” at baseline. There were more males than females in the study (61% of all patients were male). The mean age of patients entering the study was 37 years of age (range 18–69). Most patients were Caucasian (71%), 15% were Black, 1% were Asian, and 13% were classified as being of “other” races. Patients treated with CLOZARIL had a statistically significant longer delay in the time to recurrent suicidal behavior in comparison with olanzapine.

ntering the study was 37 years of age (range 18–69). Most patients were Caucasian (71%), 15% were Black, 1% were Asian, and 13% were classified as being of “other” races. Patients treated with CLOZARIL had a statistically significant longer delay in the time to recurrent suicidal behavior in comparison with olanzapine. This result should be interpreted only as evidence of the effectiveness of CLOZARIL in delaying time to recurrent suicidal behavior and not a demonstration of the superior efficacy of CLOZARIL over olanzapine. The probability of experiencing (1) a significant suicide attempt, including a completed suicide, or (2) hospitalization because of imminent suicide risk, including increased level of surveillance for suicidality for patients already hospitalized, was lower for CLOZARIL patients than for olanzapine patients at Week 104: CLOZARIL 24% versus olanzapine 32%; 95% CI of the difference: 2%, 14% ( Figure 1 ). Figure 1. Cumulative Probability of a Significant Suicide Attempt or Hospitalization to Prevent Suicide in Patients with Schizophrenia or Schizoaffective Disorder at High Risk of Suicidality Figure 1

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied CLOZARIL ® (clozapine) Tablets 25 mg Round, pale-yellow, uncoated tablet. Debossed with “CLOZARIL” once on the periphery of one side. Debossed with a facilitated score and “25” once on the other side. Bottle of 100 NDC 69809-0126-05 100 mg Round, pale-yellow, uncoated tablet. Debossed with “CLOZARIL” once on the periphery of one side. Debossed with a facilitated score and “100” once on the other side. Bottle of 100 NDC 69809-0127-05 16.2 Storage and Handling Store CLOZARIL at room temperature between 20°C to 25°C (68°F to 77°F); excursion permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. 16.1 How Supplied CLOZARIL ® (clozapine) Tablets 25 mg Round, pale-yellow, uncoated tablet. Debossed with “CLOZARIL” once on the periphery of one side. Debossed with a facilitated score and “25” once on the other side. Bottle of 100 NDC 69809-0126-05 100 mg Round, pale-yellow, uncoated tablet. Debossed with “CLOZARIL” once on the periphery of one side. Debossed with a facilitated score and “100” once on the other side. Bottle of 100 NDC 69809-0127-05

<table width="100%"><col width="71%"/><col width="29%"/><tbody><tr><td styleCode="Toprule " valign="top"><paragraph><content styleCode="bold"><content styleCode="italics">CLOZARIL ^&#xAE; (clozapine) Tablets </content></content></paragraph></td><td styleCode="Toprule " valign="top"/></tr><tr><td valign="top"><paragraph><content styleCode="bold"><content styleCode="italics">25 mg</content></content></paragraph></td><td valign="top"/></tr><tr><td valign="top"><paragraph>Round, pale-yellow, uncoated tablet. Debossed with &#x201C;CLOZARIL&#x201D; once on the periphery of one side. Debossed with a facilitated score and &#x201C;25&#x201D; once on the other side.</paragraph></td><td valign="top"/></tr><tr><td styleCode="Botrule " valign="top"><paragraph>Bottle of 100</paragraph></td><td styleCode="Botrule " valign="top"><paragraph>NDC 69809-0126-05</paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold"><content styleCode="italics">100 mg</content></content></paragraph></td><td valign="top"/></tr><tr><td valign="top"><paragraph>Round, pale-yellow, uncoated tablet. Debossed with &#x201C;CLOZARIL&#x201D; once on the periphery of one side. Debossed with a facilitated score and &#x201C;100&#x201D; once on the other side.</paragraph></td><td valign="top"/></tr><tr><td styleCode="Botrule " valign="top"><paragraph>Bottle of 100</paragraph></td><td styleCode="Botrule " valign="top"><paragraph>NDC 69809-0127-05</paragraph></td></tr></tbody></table>

f one side. Debossed with a facilitated score and &#x201C;100&#x201D; once on the other side.</paragraph></td><td valign="top"/></tr><tr><td styleCode="Botrule " valign="top"><paragraph>Bottle of 100</paragraph></td><td styleCode="Botrule " valign="top"><paragraph>NDC 69809-0127-05</paragraph></td></tr></tbody></table> <table width="100%"><col width="71%"/><col width="29%"/><tbody><tr><td styleCode="Toprule " valign="top"><paragraph><content styleCode="bold"><content styleCode="italics">CLOZARIL ^&#xAE; (clozapine) Tablets </content></content></paragraph></td><td styleCode="Toprule " valign="top"/></tr><tr><td valign="top"><paragraph><content styleCode="bold"><content styleCode="italics">25 mg</content></content></paragraph></td><td valign="top"/></tr><tr><td valign="top"><paragraph>Round, pale-yellow, uncoated tablet. Debossed with &#x201C;CLOZARIL&#x201D; once on the periphery of one side. Debossed with a facilitated score and &#x201C;25&#x201D; once on the other side.</paragraph></td><td valign="top"/></tr><tr><td styleCode="Botrule " valign="top"><paragraph>Bottle of 100</paragraph></td><td styleCode="Botrule " valign="top"><paragraph>NDC 69809-0126-05</paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold"><content styleCode="italics">100 mg</content></content></paragraph></td><td valign="top"/></tr><tr><td valign="top"><paragraph>Round, pale-yellow, uncoated tablet. Debossed with &#x201C;CLOZARIL&#x201D; once on the periphery of one side. Debossed with a facilitated score and &#x201C;100&#x201D; once on the other side.</paragraph></td><td valign="top"/></tr><tr><td styleCode="Botrule " valign="top"><paragraph>Bottle of 100</paragraph></td><td styleCode="Botrule " valign="top"><paragraph>NDC 69809-0127-05</paragraph></td></tr></tbody></table>

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Discuss the following issues with patients and caregivers: • Severe Neutropenia : Instruct patients (and caregivers) [see Warnings and Precautions ( 5.1 )]: ▪ About the risk of developing severe neutropenia and infection with CLOZARIL treatment. ▪ Instruct patients to immediately report to their health care provider any symptom or sign of during CLOZARIL treatment. ▪ About the importance of having frequent ANC testing. • Orthostatic Hypotension, Bradycardia, and Syncope: Inform patients and caregivers about the risk of orthostatic hypotension and syncope, especially during the period of initial dose titration. Instruct them to strictly follow the clinician’s instructions for dosage and administration [see Dosage and Administration ( 2.2 , 2.6 )]. Advise patients to consult their clinician immediately if they feel faint, lose consciousness or have signs or symptoms suggestive of bradycardia or arrhythmia [Warnings and Precautions ( 5.2 )] . • Seizures: Inform patients and caregivers about the significant risk of seizure during CLOZARIL treatment. Caution them about driving and any other potentially hazardous activity while taking CLOZARIL [see Warnings and Precautions ( 5.4 )] . • Gastrointestinal Hypomotility with Severe Complications: Educate patients and caregivers on the risks, prevention and treatment of clozapine-induced constipation, including medications to avoid when possible (e.g., drugs with anticholinergic activity). Encourage appropriate hydration, physical activity, and fiber intake and emphasize that prompt attention and treatment to the development of constipation or other gastrointestinal symptoms is critical in preventing severe complications. Advise patients and caregivers to contact their health care provider if they experience symptoms of constipation (e.g., difficulty passing stools, incomplete passage of stool, decreased bowel movement frequency) or other symptoms associated with gastrointestinal hypomotility (e.g., nausea, abdominal distension or pain, vomiting) [see Warnings and Precautions ( 5.7 ), Drug Interactions ( 7.1 )] . • QT Interval Prolongation: Advise patients to consult their clinician immediately if they feel faint, lose consciousness or have signs or symptoms suggestive of arrhythmia. Instruct patients to not take CLOZARIL with other drugs that cause QT interval prolongation. Instruct patients to inform their clinicians that they are taking CLOZARIL before any new drug [see Warnings and Precautions ( 5.9 ), Drug Interactions ( 7.1 )] . • Metabolic Changes (hyperglycemia and diabetes mellitus, dyslipidemia, weight gain): Educate patients and caregivers about the risk of metabolic changes and the need for specific monitoring. The risks include hyperglycemia and diabetes mellitus, dyslipidemia, weight gain, and cardiovascular reactions. Educate patients and caregivers about the symptoms of hyperglycemia (high blood sugar) and diabetes mellitus (e.g., polydipsia, polyuria, polyphagia, and weakness). Monitor all patients for these symptoms. Patients who are diagnosed with diabetes or have risk factors for diabetes (obesity, family history of diabetes) should have their fasting blood glucose monitored before beginning treatment and periodically during treatment. Patients who develop symptoms of hyperglycemia should have assessments of fasting glucose.

oms. Patients who are diagnosed with diabetes or have risk factors for diabetes (obesity, family history of diabetes) should have their fasting blood glucose monitored before beginning treatment and periodically during treatment. Patients who develop symptoms of hyperglycemia should have assessments of fasting glucose. Clinical monitoring of weight is recommended [see Warnings and Precautions ( 5.10 )] . • Interference with Cognitive and Motor Performance: Because CLOZARIL may have the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that CLOZARIL therapy does not affect them adversely [see Warnings and Precautions ( 5.16 )] . • Missed Doses and Re-initiating Treatment: Inform patients and caregivers that if the patient misses taking CLOZARIL for 1 day or more, they should not restart their medication at the same dosage but should contact their physician for dosing instructions [see Dosage and Administration ( 2.6 ), Warnings and Precautions ( 5.1 , 5.2 )] . • Pregnancy: Advise pregnant women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with CLOZARIL. Advise patients that CLOZARIL may cause extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) in a neonate. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to CLOZARIL during pregnancy [see Use in Specific Populations ( 8.1 )] . • Lactation: Advise breastfeeding women using CLOZARIL to monitor infants for excess sedation and to seek medical care if they notice this sign. Inform breastfeeding women using CLOZARIL that their healthcare provider will monitor infants for neutropenia [see Use in Specific Populations ( 8.2 )]. • Concomitant Medication: Advise patients to inform their healthcare provider if they are taking, or plan to take, any prescription or over-the-counter drugs; there is a potential for significant drug-drug interactions [see Dosage and Administration ( 2.7 ), Drug Interactions ( 7.1 )] .

Distributed by: HLS Therapeutics (USA), Inc. Rosemont, PA 19010 (844) 457-8721 © HLS Therapeutics MLRUSA: 20250603 2025HER001 June 2025 *Zyprexa ® (olanzapine) is a registered trademark of Eli Lilly and Company. **Trademark of Thomson Healthcare, Inc. CLOZARIL ® is a registered trademark of Novartis Pharmaceuticals Corporation.

MEDICATION GUIDE CLOZARIL (klow-zr-uhl) (clozapine) tablets, for oral use What is the most important information I should know about CLOZARIL? CLOZARIL can cause serious side effects including: • Severe neutropenia (low white blood cell (WBC) counts) that can lead to serious infections and death. Your healthcare provider will do WBC blood tests before starting treatment with CLOZARIL and weekly for the first 6 months. After your first 6 months of treatment, your healthcare provider will determine how frequent you will have blood tests. If you have symptoms of severe neutropenia or an infection, your healthcare provider will do more frequent WBC blood test(s) to check if CLOZARIL is causing your symptoms and may send you to see a blood specialist (hematologist). Tell your health care provider right away if you have any of the following symptoms or signs of neutropenia or infection: o feel like you have the flu • wounds that take a long time to heal o fever or chills • skin, throat, vaginal, urinary tract, or lung infection o feel extremely tired or weak • pain or burning while peeing o sores or ulcers inside your mouth, gums, or on your skin • unusual vaginal discharge or itching o sores or pain in or around your rectal area • abdominal pain or bloating • Orthostatic hypotension (decreased blood pressure), bradycardia (slow heart rate), or syncope (fainting) that can lead to death . You may feel lightheaded or faint when you rise too quickly from a sitting or lying position. Tell your healthcare provider right away if you feel dizzy or pass out. • Seizures. See “What should I avoid while taking CLOZARIL?” • Myocarditis (heart muscle inflammation), pericarditis (inflammation of outer layer of the heart) and cardiomyopathy (heart muscle weakness) that can lead to death. Symptoms of myocarditis, pericarditis, and cardiomyopathy include: o chest pain • flu-like symptoms o fast heartbeat or palpitations • feel tired or faint o shortness of breath • swollen legs, ankles, or feet o fever • Increased risk of death in elderly people with dementia-related psychosis. Medicines like CLOZARIL can increase the risk of death in elderly people who have lost touch with reality (psychosis) due to confusion and dementia. CLOZARIL is not for treatment of elderly people with dementia-related psychosis. What is CLOZARIL? CLOZARIL is a prescription antipsychotic medicine used to treat people: • Who are severely ill with schizophrenia not helped by other schizophrenia medicines • With schizophrenia or schizoaffective disorder who have been suicidal and may be at risk of suicidal behavior again It is not known if CLOZARIL is safe and effective in children. Who should not take CLOZARIL? Do not take CLOZARIL if you: • are allergic to clozapine or any of the ingredients in CLOZARIL. See the end of this Medication Guide for a complete list of ingredients in CLOZARIL.

and may be at risk of suicidal behavior again It is not known if CLOZARIL is safe and effective in children. Who should not take CLOZARIL? Do not take CLOZARIL if you: • are allergic to clozapine or any of the ingredients in CLOZARIL. See the end of this Medication Guide for a complete list of ingredients in CLOZARIL. Before taking CLOZARIL, tell your healthcare provider about all your medical conditions, including if you: • have or have had heart problems or a family history of heart problems including heart attack, heart failure, abnormal heart rhythm or long QT syndrome, or stroke • have or have had low or high blood pressure • have or have had kidney or liver problems • have or have had seizures (convulsions) • have or have had stomach or intestinal problems including constipation, slow emptying of your stomach, or diarrhea • have or have had low levels of potassium or magnesium in your blood • have or have had diabetes or high blood sugar in you or your family • have or have had high levels of total cholesterol, “bad” cholesterol (LDL-C), or triglycerides, or low levels of “good” cholesterol (HDL-C) • have increased pressure in your eyes (glaucoma), an enlarged prostate, or problems passing urine • have or have had uncontrolled movements of your tongue, face, mouth, or jaw (tardive dyskinesia) • smoke tobacco • plan to stop smoking tobacco while taking CLOZARIL • use products containing caffeine • are pregnant or plan to become pregnant. Talk to your healthcare provider if you become pregnant while taking CLOZARIL. o If you become pregnant while receiving CLOZARIL, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or go to http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/ • are breast feeding or plan to breast feed. CLOZARIL can pass into your breast milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take CLOZARIL. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. • CLOZARIL and other medicines may affect each other causing side effects. • Your healthcare provider can tell you if it is safe to take CLOZARIL with your other medicines. Do not start or stop any medicines while taking CLOZARIL without talking to your healthcare provider first. • Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I take CLOZARIL? • Take CLOZARIL exactly as your healthcare provider tells you to take it. Do not change your dose or stop taking CLOZARIL unless your healthcare provider tells you to. Talk to your healthcare provider or pharmacist if you are not sure how to take CLOZARIL. • Take CLOZARIL with or without food. • If you miss taking CLOZARIL for 1 day or more, call your healthcare provider right away. Do not take 2 doses at the same time unless your healthcare provider tells you to. • If you take too much (overdose) CLOZARIL, call your healthcare provider or the Poison Help line at 1-800-222-1222 or go to the nearest hospital emergency room right away. Symptoms of CLOZARIL overdose can include: • feeling sleepy • fast or irregular heartbeat • having a lot of saliva in your mouth • confusion • low blood pressure • seizures • coma • shallow or difficult breathing What should I avoid while taking CLOZARIL? • You should not drink alcohol while taking CLOZARIL because it can increase your chances of getting serious side effects. • Do not drive, operate machinery, swim, climb, or do dangerous activities until you know how CLOZARIL affects you.

coma • shallow or difficult breathing What should I avoid while taking CLOZARIL? • You should not drink alcohol while taking CLOZARIL because it can increase your chances of getting serious side effects. • Do not drive, operate machinery, swim, climb, or do dangerous activities until you know how CLOZARIL affects you. What are the possible side effects of CLOZARIL? CLOZARIL can cause serious side effects, including: • See "What is the most important information I should know about CLOZARIL?" • falls. CLOZARIL may make you sleepy, dizzy, may cause a decrease in your blood pressure when changing positions, and can slow your thinking and motor skills which may lead to falls that can cause fractures or other injuries. • slow emptying of your stomach and intestines (decreased gastric motility). Severe constipation and bowel problems can happen and can lead to hospitalization, surgery, and death . You may not feel or be aware of constipation symptoms. Your healthcare provider will examine you for possible bowel problems. Tell your healthcare provider if you get any signs and symptoms of decreased gastrointestinal motility during treatment with CLOZARIL, including: • having bowel movements less than normal • stomach bloating or pain • hard or dry stools • nausea or vomiting • difficulty passing gas Staying well hydrated, increasing physical activity, and taking fiber during treatment with CLOZARIL can help prevent constipation and other bowel problems. Your healthcare provider may prescribe medicines to prevent severe problems. • high count of a certain white blood cell (eosinophilia). CLOZARIL can cause a high count of eosinophils in some people and can be serious. This is a different risk than the risk of CLOZARIL causing an abnormally low white blood cell count (neutropenia). Your health care provider may send you to see an internal medicine specialist (internist) or blood specialist (hematologist). Tell your healthcare provider right away if you have any of these symptoms: • feeling very tired or weak • coughing and wheezing • fever • nausea, vomiting, or diarrhea • rash • night sweats • swelling • confusion • joint pain • difficulty swallowing • serious heart rhythm problems (QTc Interval Prolongation) that can cause death . Your healthcare provider will do a physical exam and may obtain blood tests and an electrocardiogram before starting you on treatment with CLOZARIL. Tell your healthcare provider right away if you have any of these symptoms: o passing out or feeling like you will pass out o dizziness o feeling as if your heart is pounding or missing beats • problems with your metabolism such as: o high blood sugar (hyperglycemia) or diabetes. Increases in blood sugar can happen in some people who take CLOZARIL. Extremely high blood sugar can lead to coma and death. If you have diabetes or risk factors for diabetes (such as being overweight), your health care provider should check your blood sugar before you start CLOZARIL and during treatment. Tell your healthcare provider if you have any of these symptoms of high blood sugar while taking CLOZARIL: • feel very thirsty • feel very hungry • feel sick to your stomach • need to urinate more than usual • feel weak or tired • feel confused, or your breath smells fruity o increased fat levels (cholesterol and triglycerides) in your blood (dyslipidemia). Your healthcare provider should check the fat levels in your blood before you start and during treatment with CLOZARIL. o weight gain. You and your healthcare provider should check your weight regularly. • neuroleptic malignant syndrome (NMS). NMS is a rare but serious condition that can lead to death and must be treated in a hospital.

rovider should check the fat levels in your blood before you start and during treatment with CLOZARIL. o weight gain. You and your healthcare provider should check your weight regularly. • neuroleptic malignant syndrome (NMS). NMS is a rare but serious condition that can lead to death and must be treated in a hospital. Tell your healthcare provider right away if you become severely ill and have any of these symptoms: • high fever • confusion • increased sweating • stiff muscles • changes in breathing, heartbeat, and blood pressure • liver problems . CLOZARIL can cause serious life-threatening liver problems that can lead to death. Tell your healthcare provider right away if you have any of these symptoms: • feeling tired • nausea and vomiting • pain on the right side of your stomach (abdomen) • loss of appetite • yellowing of your skin or whites of your eyes • elevated bilirubin levels • fever. Some people may have a fever while they take CLOZARIL. If you have a fever, your healthcare provider will do blood tests to check for neutropenia or an infection. Your healthcare provider may also send you to see a blood specialist (hematologist). Tell your healthcare provider if you have a fever. • blood clot in your lung (pulmonary embolism) or in the veins of your legs (deep vein thrombosis). Get emergency help right away if you have symptoms of a blood clot including: o chest pain and shortness of breath o swelling or pain in your leg, ankle or foot o warm feeling in the skin of your affected leg o changes in your skin color such as turning pale or blue • a problem that includes dry mouth, increased sweating, increased pulse rate, constipation, and urinary retention (anticholinergic toxicity). • problems thinking clearly and moving your body. See “What should I avoid while taking CLOZARIL?” • uncontrolled movements of your tongue, face, mouth, or jaw (tardive dyskinesia). Tardive dyskinesia may not go away, even if you stop CLOZARIL. Tardive dyskinesia may also start after you stop taking CLOZARIL. • stroke (cerebrovascular problems) in elderly people with dementia-related psychosis that can lead to death. The most common side effects of CLOZARIL include: • sleepiness or drowsiness • headache • dizziness • shaking movements (tremors) • heart and blood vessel problems • low blood pressure • fast heartbeat • having a lot of saliva in your mouth • passing out (syncope) • dry mouth • increased sweating • constipation and nausea • vision problems • fever • These are not all the possible side effects of CLOZARIL. • Your healthcare provider may lower your dose or temporarily or permanently stop treatment with CLOZARIL if you have certain symptoms or if your WBC count is low. • Tell your healthcare provider if you have any side effect that bothers you or that does not go away. • You may report side effects to FDA at 1-800-FDA-1088. How should I store CLOZARIL? • Store CLOZARIL at room temperature between 68°F to 77°F (20°C to 25°C). Keep CLOZARIL and all medicines out of the reach of children. General information about the safe and effective use of CLOZARIL. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use CLOZARIL for a condition for which it was not prescribed. Do not give CLOZARIL to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider (including pharmacist) for information about CLOZARIL that is written for health professionals. What are the ingredients in CLOZARIL? Active ingredients: clozapine Inactive ingredients: colloidal silicon dioxide, lactose, magnesium stearate, povidone, starch (corn), and talc Distributed by: HLS Therapeutics (USA), Inc., Rosemont, PA 19010, (844) 457-8721 This Medication Guide has been approved by the U.S.

ionals. What are the ingredients in CLOZARIL? Active ingredients: clozapine Inactive ingredients: colloidal silicon dioxide, lactose, magnesium stearate, povidone, starch (corn), and talc Distributed by: HLS Therapeutics (USA), Inc., Rosemont, PA 19010, (844) 457-8721 This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued: 06/2025 MLR USA: 20250601 associated with 2025HER001

<table styleCode="Noautorules" width="100%"><col width="12%"/><col width="51%"/><col width="37%"/><tbody><tr><td valign="top"/><td valign="top"><list listType="unordered"><item><caption> </caption><list listType="unordered"><item><caption>o</caption>feel like you have the flu</item></list></item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>wounds that take a long time to heal</item></list></td></tr><tr><td valign="top"/><td valign="top"><list listType="unordered"><item><caption> </caption><list listType="unordered"><item><caption>o</caption>fever or chills</item></list></item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>skin, throat, vaginal, urinary tract, or lung infection</item></list></td></tr><tr><td valign="top"/><td valign="top"><list listType="unordered"><item><caption> </caption><list listType="unordered"><item><caption>o</caption>feel extremely tired or weak</item></list></item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>pain or burning while peeing</item></list></td></tr><tr><td valign="top"/><td valign="top"><list listType="unordered"><item><caption> </caption><list listType="unordered"><item><caption>o</caption>sores or ulcers inside your mouth, gums, or on your skin</item></list></item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>unusual vaginal discharge or itching</item></list></td></tr><tr><td valign="top"/><td valign="top"><list listType="unordered"><item><caption> </caption><list listType="unordered"><item><caption>o</caption>sores or pain in or around your rectal area</item></list></item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>abdominal pain or bloating</item></list></td></tr></tbody></table>

listType="unordered"><item><caption> </caption><list listType="unordered"><item><caption>o</caption>sores or pain in or around your rectal area</item></list></item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>abdominal pain or bloating</item></list></td></tr></tbody></table> <table styleCode="Noautorules" width="100%"><col width="12%"/><col width="50%"/><col width="38%"/><tbody><tr><td valign="top"/><td valign="top"><list listType="unordered"><item><caption> </caption><list listType="unordered"><item><caption>o</caption>chest pain</item></list></item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>flu-like symptoms</item></list></td></tr><tr><td valign="top"/><td valign="top"><list listType="unordered"><item><caption> </caption><list listType="unordered"><item><caption>o</caption>fast heartbeat or palpitations</item></list></item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>feel tired or faint</item></list></td></tr><tr><td valign="top"/><td valign="top"><list listType="unordered"><item><caption> </caption><list listType="unordered"><item><caption>o</caption>shortness of breath</item></list></item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>swollen legs, ankles, or feet</item></list></td></tr><tr><td valign="top"/><td valign="top"><list listType="unordered"><item><caption> </caption><list listType="unordered"><item><caption>o</caption>fever</item></list></item></list></td><td valign="top"/></tr></tbody></table>

"unordered"><item><caption>&#x2022;</caption>swollen legs, ankles, or feet</item></list></td></tr><tr><td valign="top"/><td valign="top"><list listType="unordered"><item><caption> </caption><list listType="unordered"><item><caption>o</caption>fever</item></list></item></list></td><td valign="top"/></tr></tbody></table> <table styleCode="Noautorules" width="100%"><col width="8%"/><col width="23%"/><col width="38%"/><col width="31%"/><tbody><tr><td valign="top"/><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>feeling sleepy</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>fast or irregular heartbeat</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>having a lot of saliva in your mouth</item></list></td></tr><tr><td valign="top"/><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>confusion</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>low blood pressure</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>seizures</item></list></td></tr><tr><td valign="top"/><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>coma</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>shallow or difficult breathing</item></list></td><td valign="top"/></tr></tbody></table> <table styleCode="Noautorules" width="100%"><col width="11%"/><col width="41%"/><col width="48%"/><tbody><tr><td valign="top"/><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>having bowel movements less than normal</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>stomach bloating or pain</item></list></td></tr><tr><td valign="top"/><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>hard or dry stools</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>nausea or vomiting</item></list></td></tr><tr><td valign="top"/><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>difficulty passing gas</item></list></td><td valign="top"/></tr></tbody></table>

ols</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>nausea or vomiting</item></list></td></tr><tr><td valign="top"/><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>difficulty passing gas</item></list></td><td valign="top"/></tr></tbody></table> <table styleCode="Noautorules" width="100%"><col width="11%"/><col width="32%"/><col width="57%"/><tbody><tr><td valign="top"/><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>feeling very tired or weak</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>coughing and wheezing</item></list></td></tr><tr><td valign="top"/><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>fever</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>nausea, vomiting, or diarrhea</item></list></td></tr><tr><td valign="top"/><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>rash</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>night sweats</item></list></td></tr><tr><td valign="top"/><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>swelling</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>confusion</item></list></td></tr><tr><td valign="top"/><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>joint pain</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>difficulty swallowing</item></list></td></tr></tbody></table>

on>&#x2022;</caption>confusion</item></list></td></tr><tr><td valign="top"/><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>joint pain</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>difficulty swallowing</item></list></td></tr></tbody></table> <table styleCode="Noautorules" width="100%"><col width="10%"/><col width="30%"/><col width="28%"/><col width="32%"/><tbody><tr><td valign="top"/><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>feel very thirsty</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>feel very hungry</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>feel sick to your stomach</item></list></td></tr><tr><td valign="top"/><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>need to urinate more than usual</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>feel weak or tired</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>feel confused, or your breath smells fruity</item></list></td></tr></tbody></table> <table styleCode="Noautorules" width="100%"><col width="12%"/><col width="28%"/><col width="32%"/><col width="27%"/><tbody><tr><td valign="top"/><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>high fever</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>confusion</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>increased sweating</item></list></td></tr><tr><td valign="top"/><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>stiff muscles</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>changes in breathing, heartbeat, and blood pressure</item></list></td><td valign="top"/></tr></tbody></table>

tr><tr><td valign="top"/><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>stiff muscles</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>changes in breathing, heartbeat, and blood pressure</item></list></td><td valign="top"/></tr></tbody></table> <table styleCode="Noautorules" width="100%"><col width="12%"/><col width="28%"/><col width="33%"/><col width="27%"/><tbody><tr><td valign="top"/><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>feeling tired</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>nausea and vomiting</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>pain on the right side of your stomach (abdomen)</item></list></td></tr><tr><td valign="top"/><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>loss of appetite</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>yellowing of your skin or whites of your eyes</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>elevated bilirubin levels</item></list></td></tr></tbody></table>

n>loss of appetite</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>yellowing of your skin or whites of your eyes</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>elevated bilirubin levels</item></list></td></tr></tbody></table> <table styleCode="Noautorules" width="100%"><col width="8%"/><col width="41%"/><col width="51%"/><tbody><tr><td valign="top"/><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>sleepiness or drowsiness</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>headache</item></list></td></tr><tr><td valign="top"/><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>dizziness</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>shaking movements (tremors)</item></list></td></tr><tr><td valign="top"/><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>heart and blood vessel problems</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>low blood pressure</item></list></td></tr><tr><td valign="top"/><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>fast heartbeat</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>having a lot of saliva in your mouth</item></list></td></tr><tr><td valign="top"/><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>passing out (syncope)</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>dry mouth</item></list></td></tr><tr><td valign="top"/><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>increased sweating</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>constipation and nausea</item></list></td></tr><tr><td valign="top"/><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>vision problems</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>fever</item></list></td></tr></tbody></table>

WARNING: SEVERE NEUTROPENIA; ORTHOSTATIC HYPOTENSION, BRADYCARDIA, AND SYNCOPE; SEIZURE; MYOCARDITIS, PERICARDITIS, AND CARDIOMYOPATHY; INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS WARNING: SEVERE NEUTROPENIA; ORTHOSTATIC HYPOTENSION, BRADYCARDIA, AND SYNCOPE; SEIZURE; MYOCARDITIS, PERICARDITIS, AND CARDIOMYOPATHY; INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS Severe Neutropenia VERSACLOZ has caused severe neutropenia which is associated with an increased risk of serious and potentially fatal infections. Prior to initiating VERSACLOZ treatment, obtain baseline ANC(s). VERSACLOZ initiation is not recommended in patients with a baseline ANC less than 1500/µL (less than 1000/µL for those with Benign Ethnic Neutropenia (also known as Duffy-null associated neutrophil count)). See recommendations for dosage modifications based on ANC levels during VERSACLOZ treatment [see Dosage and Administration (2.4, 2.5)] . Consider a hematology consultation before initiating VERSACLOZ or during VERSACLOZ treatment [see Warnings ad Precautions (5.1)] . Orthostatic Hypotension, Bradycardia, Syncope Orthostatic hypotension, bradycardia, syncope, and cardiac arrest have occurred with clozapine treatment. The risk is highest during the initial titration period, particularly with rapid dose escalation. These reactions can occur with the first dose, with doses as low as 12.5 mg per day, or when restarting patients who have had even a brief interruption in treatment with Versacloz. Initiate treatment at 12.5 mg once or twice daily; titrate slowly; and use divided dosages to minimize risk. Use VERSACLOZ cautiously in patients with cardiovascular or cerebrovascular disease or conditions predisposing to hypotension (e.g., dehydration, use of antihypertensive medications) [see Dosage and Administration (2.2, 2.7), Warnings and Precautions (5.2)]. Seizures Seizures have occurred with clozapine treatment. The risk is dose-related. Initiate treatment at 12.5 mg, titrate gradually, and use divided dosing. Use caution when administering VERSACLOZ to patients with a history of seizures or other predisposing risk factors for seizure (CNS pathology, medications that lower the seizure threshold, alcohol abuse). Caution patients about engaging in any activity where sudden loss of consciousness could cause serious risk to themselves or others [see Dosage and Administration (2.2) and Warnings and Precautions (5.4)]. Myocarditis, Pericarditis, Cardiomyopathy and Mitral Valve Incompetence Fatal myocarditis and cardiomyopathy have occurred with clozapine treatment. Discontinue VERSACLOZ and obtain a cardiac evaluation upon suspicion of these reactions. Generally, patients with VERSACLOZ-related myocarditis or cardiomyopathy should not be rechallenged with VERSACLOZ. Consider the possibility of myocarditis, pericarditis, or cardiomyopathy if chest pain, tachycardia, palpitations, dyspnea, fever, flu-like symptoms, hypotension, or ECG changes occur. [ see Warnings and Precautions (5.5)] . Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. VERSACLOZ is not approved for use in patients with dementia- related psychosis [see Warnings and Precautions (5.6 )].

ions (5.5)] . Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. VERSACLOZ is not approved for use in patients with dementia- related psychosis [see Warnings and Precautions (5.6 )]. WARNING: SEVERE NEUTROPENIA; ORTHOSTATIC HYPOTENSION, BRADYCARDIA, AND SYNCOPE; SEIZURE; MYOCARDITIS, PERICARDITIS AND CARDIOMYOPATHY; INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS See full prescribing information for complete boxed warning. Severe Neutropenia: Clozapine can cause severe neutropenia, which can lead to serious and fatal infections. Patients initiating and continuing treatment with VERSACLOZ must have a baseline blood absolute neutrophil count (ANC) measured before treatment initiation and regular ANC monitoring during treatment ( 2.1 , 5.1 ). VERSACLOZ is available only through a restricted program called the Clozapine REMS ( 5.2 ). Orthostatic Hypotension, Bradycardia, and Syncope: Risk is dose-related. Starting dose is 12.5 mg. Titrate gradually and use divided dosages ( 2.2 , 2.6 , 5.3 ). Seizure: Risk is dose-related. Titrate gradually and use divided doses. Use with caution in patients with history of seizure or risk factors for seizure ( 2.2 , 5.5 ). Myocarditis, Pericarditis, Cardiomyopathy and Mitral Valve Incompetence : Can be fatal. Discontinue and obtain cardiac evaluation if findings suggest these cardiac reactions ( 5.6 ). Increased Mortality in Elderly Patients with Dementia-Related Psychosis: VERSACLOZ is not approved for this condition ( 5.7 ).

1 INDICATIONS AND USAGE VERSACLOZ is an atypical antipsychotic indicated for: Treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment. Because of the risks of severe neutropenia and of seizure associated with its use, VERSACLOZ should be used only in patients who have failed to respond adequately to standard antipsychotic treatment (1.1). Reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for re-experiencing suicidal behavior (1.2). 1.1 Treatment-Resistant Schizophrenia VERSACLOZ is indicated for the treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment. Because of the risks of severe neutropenia and of seizure associated with its use, VERSACLOZ should be used only in patients who have failed to respond adequately to standard antipsychotic treatment [see Warnings and Precautions (5.1 , 5.4) ] . The effectiveness of clozapine in treatment-resistant schizophrenia was demonstrated in a 6-week, randomized, double-blind, active-controlled study comparing clozapine and chlorpromazine in patients who had failed other antipsychotics [see Clinical Studies (14.1) ] . 1.2 Reduction in the Risk of Recurrent Suicidal Behavior in Schizophrenia or Schizoaffective Disorders VERSACLOZ is indicated for reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for re-experiencing suicidal behavior, based on history and recent clinical state. Suicidal behavior refers to actions by a patient that put him/herself at risk for death. The effectiveness of clozapine in reducing the risk of recurrent suicidal behavior was demonstrated over a two-year treatment period in the InterSePT™ trial [see Clinical Studies (14.2) ] .

2 DOSAGE AND ADMINISTRATION Recommended starting oral dosage is 12.5 mg once daily or twice daily (2.2). If well-tolerated, increase the total daily dosage in increments of 25 mg to 50 mg per day to achieve a target dosage of 150 mg to 225 mg twice per day by the end of two weeks (2.2). Subsequently may increase the dosage in increments up to 100 mg once or twice weekly (2.2). Maximum daily dosage is 450 mg twice daily (2.2). Administer with or without food. See important administration instructions in the full prescribing information (2.3). See the dosage modifications based on ANC results and recommended frequency of ANC testing in the full prescribing information (2.4, 2.5). See recommendations for discontinuing VERSACLOZ treatment (2.6), restarting VERSACLOZ after interrupting dosing (2.7), dosage modifications for drug interactions (2.8), dosage recommendations in patients with renal or hepatic impairment and CYP2D6 poor metabolizers (2.9) in the full prescribing information. 2.1 Absolute Neutrophil Count Testing Prior to VERSACLOZ Initiation Prior to initiating VERSACLOZ treatment, obtain a baseline absolute neutrophil count (ANC). VERSACLOZ initiation is not recommended in patients with an ANC less than 1500/µL [see Warnings and Precautions (5.1)] . For patients with documented Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count)), obtain at least two baseline ANC levels. VERSACLOZ initiation is not recommended in patients with BEN with an ANC less than 1000/µL [see Warnings and Precautions (5.1)] . For dosage modifications based on ANC results, see Dosage and Administration (2.4, 2.5) . 2.2 Recommended Dosage To reduce the risk of orthostatic hypotension, bradycardia, and syncope, the recommended starting dosage is much lower than the target dosage [see Warnings and Precautions (5.2)] . The recommended starting oral dosage of VERSACLOZ is 12.5 mg once or twice daily. If well-tolerated, increase the total daily dose in increments of 25 mg to 50 mg per day to achieve a target dosage of 150 mg to 225 mg twice per day by the end of two weeks. Subsequently, may increase the dosage in increments of up to 100 mg once weekly or twice weekly. The maximum recommended VERSACLOZ oral dosage is 450 mg twice daily. 2.3 Important Administration Instructions Educate patients and caregivers on how to administer VERSACLOZ ( see the Instructions for Use ). VERSACLOZ can be taken with or without food [ see Clinical Pharmacology (12.3) ]. The following are important administration instructions: Administer VERSACLOZ orally using the provided oral syringes (1 mL or 9 mL). After shaking the VERSACLOZ bottle for 10 seconds, press the syringe adaptor on top of the bottle. Insert the oral syringe (1 mL or 9 mL) filled with air into the adapter, dispel the air into the bottle, and then turn the bottle upside down. Draw the prescribed amount of the oral suspension from the bottle and immediately dispense directly to the mouth after preparation. Do not store a dose in the syringe for later use. After use, may wash the oral syringe with warm water and then dry the oral syringe for the next use. The bottle may be closed with the same cap without removing the bottle adapter. 2.4 Dosage Modification Based on ANC Results Table 1 provides recommended VERSACLOZ dosage modifications based on ANC results [see Warnings and Precautions (5.1)] .

ral syringe with warm water and then dry the oral syringe for the next use. The bottle may be closed with the same cap without removing the bottle adapter. 2.4 Dosage Modification Based on ANC Results Table 1 provides recommended VERSACLOZ dosage modifications based on ANC results [see Warnings and Precautions (5.1)] . For dosage modifications based on ANC results for patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count), see Table 2 [see Dosage and Administration (2.5)] . Table 1: VERSACLOZ Dosage Modifications Based on ANC Results and Frequency of ANC Testing Recommended Dosage Modification Recommended Frequency of ANC Teting During VERSACLOZ Treatment ANC Within Normal Range (≥1500/µL) No dosage modification: continue treatment Day 1 to Month 6: Weekly Month 7 to Month 12: Every 2 weeks Month 13 and thereafter: Every month If VERSACLOZ treatment is reinitiated after a dosage interruption (e.g., patient had neutropenia which required dosage interruption and now has a normal ANC level) for: < 30 days, continue the previous ANC testing frequency ≥ 30 days, obtain ANC tests according to the frequency for patients who initiate treatment Mild Neutropenia (ANC between 1000 to 1499/µL) 1 No dosage modification: continue treatment Three times weekly Once ANC ≥ 1500/µL, recommend returning to the patient’s last Normal Range ANC testing frequency Moderate Neutropenia (ANC between 500 to 999/µL) 1 Interrupt treatment and recommend hematology consultation Resume treatment once ANC ≥1000/µL Daily Once ANC ≥ 1000/µL, three times weekly Once ANC ≥ 1500/µL, test weekly for 4 weeks. If ANC ≥ 1500/µL after monitoring weekly for 4 weeks, return to the patient’s last Normal Range ANC testing frequency Severe Neutropenia (ANC less than 500/µL) 1 Discontinue treatment and recommend hematology consultation Daily Once ANC ≥ 1000/µL, three times weekly Once ANC ≥ 1500/µL, if the benefits outweigh the risks of restarting treatment, resume treatment and obtain ANC tests according to the frequency for patients who initiate treatment 1 Confirm all initial reports of ANC less than 1500/μL with a repeat ANC measurement within 24 hours 2.5 Dosage Modifications Based on ANC Results for Patients with Benign Ethnic Neutropenia Table 2 provides recommended VERSACLOZ dosage modifications based on ANC results for patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count). [see Warnings and Precautions (5.1)] . For dosage modifications based on ANC results for patients without BEN, see Table 1 [see Dosage and Administration (2.4)] .

VERSACLOZ dosage modifications based on ANC results for patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count). [see Warnings and Precautions (5.1)] . For dosage modifications based on ANC results for patients without BEN, see Table 1 [see Dosage and Administration (2.4)] . Table 2: Dosage Modifications Based on ANC Results and Frequency of ANC Testing in Patients with Benign Ethnic Neutropenia 1 Recommended Dosage Modification Recommended Frequency of ANC Teting During VERSACLOZ Treatment in Patients with BEN 1 ANC Within the Normal Range for Patients with BEN (≥ 1000/µL) No dosage modification: continue treatment Day 1 to Month 6: Weekly Month 7 to Month 12: Every 2 weeks Month 13 and thereafter: Monthly If VERSACLOZ treatment is reinitiated after a dosage interruption (e.g., patient had neutropenia which required dosage interruption and now their ANC (≥ 1000/µL and ≥ the patient’s ANC baseline prior to treatment) for: < 30 days, continue the previous ANC testing frequency ≥ 30 days, obtain ANC tests according to the frequency for patients with BEN who initiate treatment Neutropenia in Patients with BEN (ANC level between 500 to 999/μL) 2 Recommend hematology consultation No dosage modification: continue treatment Three times weekly Once ANC ≥ 1000/μL and ≥ the patient’s ANC baseline, obtain ANC tests weekly for 4 weeks If ANC ≥1000/μL and ≥ the patient’s baseline after monitoring for 4 weeks, return to the patient’s last Normal ANC Range testing frequency for patients with BEN. Severe Neutropenia in Patients with BEN (ANC level less than 500/μL) 2 Discontinue treatment and recommend hematology consultation Daily Once ANC ≥ 500/µL, obtain ANC three times weekly Once ANC ≥ 1000/µL and ≥ the patient’s baseline, if the benefits outweigh the risks of restarting treatment, resume treatment and obtain ANC tests according to the frequency for patients with BEN who initiate treatment 1 Benign Ethnic Neutropenia (BEN) is also known as Duffy-null associated neutrophil count. 2 Confirm all initial reports of ANC less than 1500/μL with a repeat ANC measurement within 24 hours 2.6 Discontinuation of VERSACLOZ Treatment If discontinuing VERSACLOZ in patients with: Moderate or severe neutropenia, see Table 1 [see Dosage and Administration (2.4)] . Normal or mild neutropenia, reduce the dosage gradually over a period of 1 to 2 weeks, and continue monitoring ANC levels until their ANC is ≥1500/μL. If discontinuing VERSACLOZ in patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count) with: Neutropenia, see Table 2 [see Dosage and Administration (2.5)] . ANC within their normal range of ANC reduce the dosage gradually over a period of 1 to 2 weeks. When discontinuing VERSACLOZ, monitor patients for the symptoms related to psychotic recurrence and cholinergic rebound (e.g., profuse sweating, headache, nausea, vomiting, diarrhea). 2.7 Restarting VERSACLOZ Treatment After Interrupting VERSACLOZ When restarting VERSACLOZ in patients who have interrupted VERSACLOZ treatment, use a lower dosage to minimize the risk of hypotension, bradycardia, and syncope [see Warnings and Precautions (5.2)] . If one day’s dosage is missed, resume VERSACLOZ treatment at 40% to 50% of the previous dosage. If two days of dosing is missed, resume VERSACLOZ treatment at approximately 25% of the previous dosage. For longer interruptions, restart VERSACLOZ treatment with a dosage of 12.5 mg once or twice daily. If this dosage is well-tolerated, may increase the dosage to the previous dosage more quickly than recommended than for initial VERSACLOZ treatment.

resume VERSACLOZ treatment at approximately 25% of the previous dosage. For longer interruptions, restart VERSACLOZ treatment with a dosage of 12.5 mg once or twice daily. If this dosage is well-tolerated, may increase the dosage to the previous dosage more quickly than recommended than for initial VERSACLOZ treatment. 2.8 Dosage Modifications for Drug Interactions See Table 3 for recommended dosage modifications to reduce the risk of VERSACLOZ associated adverse reactions or reduce the risk of lower effectiveness [see Drug Interactions (7)] . Table 3: VERSACLOZ Dosage Modifications for Drug Interactions Strong CYP1A2 Inhibitors Administer one third of the VERSACLOZ dosage. Moderate or Weak CYP1A2 Inhibitors Consider reducing the VERSACLOZ dosage if necessary. CYP2D6 or CYP3A4 Inhibitors Strong CYP3A4 Inducers Concomitant use is not recommended. However, if concomitant use is necessary, it may be necessary to increase the VERSACLOZ dosage. Monitor for decreased effectiveness. Moderate or weak CYP1A2 or CYP3A4 Inducers Consider increasing the VERSACLOZ dosage if necessary. 2.9 Dosage Recommendations in Patients with Renal or Hepatic Impairment, or CYP2D6 Poor Metabolizers It may be necessary to reduce the VERSACLOZ dosage in patients with significant renal impairment or hepatic impairment, or in CYP2D6 poor metabolizers [see Use in Specific Populations (8.6, 8.7)] .

4 CONTRAINDICATIONS VERSACLOZ is contraindicated in patients with a history of hypersensitivity to clozapine (e.g., photosensitivity, vasculitis, erythema multiforme, or Stevens-Johnson Syndrome) or any other component of VERSACLOZ [see Adverse Reactions (6.2) ] . Known hypersensitivity to clozapine or any other component of VERSACLOZ ( 4 ).

5 WARNINGS AND PRECAUTIONS Severe neutropenia: See Boxed Warning (5.1) Gastrointestinal Hypomotility with Severe Complications: Severe gastrointestinal adverse reactions have occurred with the use of VERSACLOZ. If constipation is identified, close monitoring and prompt treatment is advised ( 5.8 ). Eosinophilia: Assess for organ involvement (e.g., myocarditis, pancreatitis, hepatitis, colitis, nephritis). Discontinue if these occur ( 5.9 ). QT Interval Prolongation: Can be fatal. Consider additional risk factors for prolonged QT interval (disorders and drugs) ( 5.10 ). Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include: Hyperglycemia and Diabetes Mellitus: Monitor for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Monitor glucose regularly in patients with diabetes or at risk for diabetes ( 5.11 ). Dyslipidemia: Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics ( 5.11 ). Weight Gain: Significant weight gain has occurred. Monitor weight gain ( 5.11 ). Neuroleptic Malignant Syndrome (NMS): Immediately discontinue and monitor closely. Assess for co-morbid conditions ( 5.12 ). Hepatotoxicity: Can be fatal. Monitor for hepatotoxicity. Discontinue treatment if hepatitis or transaminase elevations combined with other symptoms occur ( 5.13 ). Fever: Evaluate for infection, and for neutropenia, NMS ( 5.14 ). Pulmonary Embolism (PE): Consider PE if respiratory distress, chest, pain, or deep vein thrombosis occurs ( 5.15 ). Anticholinergic Toxicity: When possible, avoid use with other anticholinergic drugs and use with caution in patients with a current diagnosis or prior history of constipation, urinary retention, clinically significant prostatic hypertrophy, or other conditions in which anticholinergic effects can lead to significant adverse reactions ( 5.16 , 7.1 ). Interference with Cognitive and Motor Performance: Advise caution when operating machinery, including automobiles ( 5.17 ). 5.1 Severe Neutropenia VERSACLOZ has caused severe neutropenia (absolute neutrophil count (ANC) less than 500/μL) [see Adverse Reactions (6.1, 6.2)] and is associated with an increased risk of serious and potentially fatal infections. Severe neutropenia occurred in a small percentage of VERSACLOZ-treated patients. The risk of severe neutropenia appears greatest during the first 18 weeks of VERSACLOZ treatment. The mechanism by which VERSACLOZ causes neutropenia is unknown. Neutropenia is not dose dependent. Consider a hematology consultation before initiating VERSACLOZ treatment or during treatment. ANC Monitoring and Dosage Modifications Prior to initiating VERSACLOZ treatment, obtain a baseline ANC. VERSACLOZ initiation is not recommended in patients with a baseline ANC less than 1500/μL. Throughout VERSACLOZ treatment, regularly monitor ANC. Table 1 provides recommendations for dosage modifications (dosage interruption and treatment discontinuation), based on ANC levels, during VERSACLOZ treatment and frequency of ANC monitoring [see Dosage and Administration (2.4)] .

a baseline ANC less than 1500/μL. Throughout VERSACLOZ treatment, regularly monitor ANC. Table 1 provides recommendations for dosage modifications (dosage interruption and treatment discontinuation), based on ANC levels, during VERSACLOZ treatment and frequency of ANC monitoring [see Dosage and Administration (2.4)] . ANC Monitoring and Dosage Modification in Patients with Benign Ethnic Neutropenia Patients with with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count) generally have lower baseline neutrophil counts but they are not at higher risk for developing infections, and they are not at increased risk for developing VERSACLOZ-induced neutropenia. For patients with documented BEN, obtain at least two baseline ANC levels prior to VERSACLOZ initiation. VERSACLOZ initiation is not recommended in patients with BEN with an ANC less than 1000/μL. There are different ANC dosage modification recommendations in VERSACLOZ-treated patients with BEN due to their lower baseline ANC levels. Table 2 provides recommendations on dosage modifications (dosage interruption and treatment discontinuation), based on ANC monitoring, during VERSACLOZ treatment in patients with BEN and recommended frequency of ANC testing [see Dosage and Administration (2.5)] . Management of VERSACLOZ-Treated Patients Who Develop a Fever For patients who develop a fever during VERSACLOZ treatment: Interrupt VERSACLOZ in those who develop a temperature of 101.3 °F (38.5 °C) or greater and obtain an ANC level. If the ANC is less than 1000/μL in patients without BEN, initiate appropriate workup and treatment for infection. Refer to Table 1 for dosage modifications based on ANC monitoring [see Dosage and Administration (2.4)] . In patients with fever and a normal neutrophil count, see Warnings and Precautions (5.11) for neuroleptic malignant syndrome and Warnings and Precautions (5.13) for fever. Restarting VERSACLOZ in Patients Who Recovered from Severe Neutropenia Generally, do not rechallenge patients with VERSACLOZ in those who experienced severe neutropenia. However, for some patients who had resolution of their VERSACLOZ-related severe neutropenia after stopping VERSACLOZ, the risk of schizophrenia exacerbation from not restarting VERSACLOZ treatment may be greater than the risk of neutropenia reoccurrence from restarting VERSACLOZ (e.g., patients who have no treatment options other than VERSACLOZ). Concomitant Use of VERSACLOZ with Other Drugs Known to Cause Neutropenia If VERSACLOZ is used concomitantly with another drug known to cause neutropenia, consider more frequently ANC monitoring than the recommendations provided in Table 1 and Table 2. 5.2 Orthostatic Hypotension, Bradycardia, and Syncope Hypotension, bradycardia, syncope, and cardiac arrest have occurred with clozapine treatment. The risk is highest during the initial titration period, particularly with rapid dose-escalation. These reactions can occur with the first dose, at doses as low as 12.5 mg. These reactions can be fatal. The syndrome is consistent with neurally mediated reflex bradycardia (NMRB). Treatment must begin at a maximum dose of 12.5 mg once daily or twice daily. The total daily dose can be increased in increments of 25 mg to 50 mg per day, if well-tolerated, to a target dose of 300 mg to 450 mg per day (administered in divided doses) by the end of 2 weeks. Subsequently, the dose can be increased weekly or twice weekly, in increments of up to 100 mg. The maximum dose is 900 mg per day. Use cautious titration and a divided dosage schedule to minimize the risk of serious cardiovascular reactions [see Dosage and Administration (2.2) ] . Consider reducing the dose if hypotension occurs.

y, the dose can be increased weekly or twice weekly, in increments of up to 100 mg. The maximum dose is 900 mg per day. Use cautious titration and a divided dosage schedule to minimize the risk of serious cardiovascular reactions [see Dosage and Administration (2.2) ] . Consider reducing the dose if hypotension occurs. When restarting VERSACLOZ in patients who have had even a brief interruption in treatment with VERSACLOZ, the dosage must be reduced. This is necessary to minimize the risk of hypotension, bradycardia, and syncope [see Dosage and Administration (2.6) ]. Use VERSACLOZ cautiously in patients with cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension (e.g., concomitant use of antihypertensives, dehydration and hypovolemia). 5.3 Falls VERSACLOZ may cause somnolence, postural hypotension, and motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic treatment. 5.4 Seizures Seizure has been estimated to occur in association with clozapine use at a cumulative incidence at one year of approximately 5%, based on the occurrence of one or more seizures in 61 of 1743 patients exposed to clozapine during its clinical testing prior to domestic marketing (i.e., a crude rate of 3.5%). The risk of seizure is dose-related. Initiate treatment with a low dose (12.5 mg), titrate slowly, and use divided dosing. Use caution when administering VERSACLOZ to patients with a history of seizures or other predisposing risk factors for seizure (e.g., head trauma or other CNS pathology, use of medications that lower the seizure threshold, or alcohol abuse). Because of the substantial risk of seizure associated with VERSACLOZ use, caution patients about engaging in any activity where sudden loss of consciousness could cause serious risk to themselves or others (e.g., driving an automobile, operating complex machinery, swimming, climbing). 5.5 Myocarditis, Pericarditis, Cardiomyopathy and Mitral Valve Incompetence Myocarditis, pericarditis, and cardiomyopathy have occurred with the use of clozapine. These reactions can be fatal. Discontinue VERSACLOZ and obtain a cardiac evaluation upon suspicion of myocarditis, pericarditis, or cardiomyopathy. Generally, patients with a history of clozapine-associated myocarditis, pericarditis, or cardiomyopathy should not be rechallenged with VERSACLOZ. However, if the benefit of VERSACLOZ treatment is judged to outweigh the potential risks of recurrence, the clinician may consider rechallenge with VERSACLOZ in consultation with a cardiologist. Myocarditis and pericarditis most frequently present within the first two months of clozapine treatment. Symptoms of cardiomyopathy generally occur later than clozapine-associated myocarditis or pericarditis and usually after 8 weeks of treatment. However, myocarditis, pericarditis, and cardiomyopathy can occur at any period during treatment with VERSACLOZ. In patients who are diagnosed with cardiomyopathy while taking clozapine mitral valve incompetence has been reported. 5.6 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.

ERSACLOZ. In patients who are diagnosed with cardiomyopathy while taking clozapine mitral valve incompetence has been reported. 5.6 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality in this population. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. VERSACLOZ is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning]. 5.7 Gastrointestinal Hypomotility and Severe Complications Severe gastrointestinal adverse reactions have occurred with the use of VERSACLOZ, primarily due to its potent anticholinergic effects and resulting gastrointestinal hypomotility. In post marketing experience, reported effects range from constipation to paralytic ileus. Increased frequency of constipation and delayed diagnosis and treatment increased the risk of severe complications of gastrointestinal hypomotility, which can result in fecal impaction, megacolon, and intestinal obstruction, ischemia, infarction, perforation, ulceration, or necrosis [see Adverse Reaction (6.2 )]. These reactions have resulted in hospitalization, surgery, and death. The risk for severe adverse reactions is further increased with anticholinergic medications (and other medications that decrease gastrointestinal peristalsis); therefore, concomitant use should be avoided when possible [see Warnings and Precautions (5.15), Drug Interactions (7.1) ]. Prior to initiating VERSACLOZ, screen for constipation and treat as necessary. Subjective symptoms of constipation may not accurately reflect the degree of gastrointestinal hypomotility in VERSACLOZ treated patients. Therefore, reassess bowel function frequently with careful attention to any changes in the frequency or character of bowel movements, as well as signs and symptoms of complications of hypomotility (e.g., nausea, vomiting, abdominal distension, abdominal pain). If constipation or gastrointestinal hypomotility are identified, monitor closely and treat promptly with appropriate laxatives, as necessary, to prevent severe complications. Consider prophylactic laxatives in high risk patients. 5.8 Eosinophilia Eosinophilia, defined as a blood eosinophil count of greater than 700/μL, has occurred with clozapine treatment. In clinical trials, approximately 1% of patients developed eosinophilia. Clozapine-related eosinophilia usually occurs during the first month of treatment. In some patients, it has been associated with myocarditis, pancreatitis, hepatitis, colitis, and nephritis. Such organ involvement could be consistent with a drug reaction with eosinophilia and systemic symptoms syndrome (DRESS), also known as drug induced hypersensitivity syndrome (DIHS).

the first month of treatment. In some patients, it has been associated with myocarditis, pancreatitis, hepatitis, colitis, and nephritis. Such organ involvement could be consistent with a drug reaction with eosinophilia and systemic symptoms syndrome (DRESS), also known as drug induced hypersensitivity syndrome (DIHS). If eosinophilia develops during VERSACLOZ treatment, evaluate promptly for signs and symptoms of systemic reactions, such as rash or other allergic symptoms, myocarditis, or other organ-specific disease associated with eosinophilia. If clozapine-related systemic disease is suspected, discontinue VERSACLOZ immediately. If a cause of eosinophilia unrelated to clozapine is identified (e.g., asthma, allergies, collagen vascular disease, parasitic infections, and specific neoplasms), treat the underlying cause and continue VERSACLOZ. Clozapine-related eosinophilia has also occurred in the absence of organ involvement and can resolve without intervention. There are reports of successful rechallenge after discontinuation of clozapine, without recurrence of eosinophilia. In the absence of organ involvement, continue VERSACLOZ under careful monitoring. If the total eosinophil count continues to increase over several weeks in the absence of systemic disease, the decision to interrupt VERSACLOZ therapy and rechallenge after the eosinophil count decreases should be based on the overall clinical assessment, in consultation with an internist or hematologist. 5.9 QT Interval Prolongation QT prolongation, Torsades de Pointes and other life-threatening ventricular arrhythmias, cardiac arrest, and sudden death have occurred with clozapine treatment. When prescribing VERSACLOZ, consider the presence of additional risk factors for QT prolongation and serious cardiovascular reactions. Conditions that increase these risks include the following: history of QT prolongation, long QT syndrome, family history of long QT syndrome or sudden cardiac death, significant cardiac arrhythmia, recent myocardial infarction, uncompensated heart failure, treatment with other medications that cause QT prolongation, treatment with medications that inhibit the metabolism of VERSACLOZ, and electrolyte abnormalities. Prior to initiating treatment with VERSACLOZ, perform a careful physical examination, medical history, and concomitant medication history. Consider obtaining a baseline ECG and serum chemistry panel. Correct electrolyte abnormalities. Discontinue VERSACLOZ if the QTc interval exceeds 500 msec. If patients experience symptoms consistent with Torsades de Pointes or other arrhythmias, (e.g., syncope, presyncope, dizziness, or palpitations), obtain a cardiac evaluation and discontinue VERSACLOZ. Use caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of VERSACLOZ. Drugs that cause QT prolongation include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, thioridazine, mesoridazine, droperidol, pimozide), specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin), Class 1A antiarrhythmic medications (e.g., quinidine, procainamide) or Class III antiarrhythmic (e.g., amiodarone, sotalol), and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus). VERSACLOZ is primarily metabolized by CYP isoenzymes 1A2, 2D6, and 3A4. Concomitant treatment with inhibitors of these enzymes can increase the concentration of VERSACLOZ [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ]. Hypokalemia and hypomagnesemia increase the risk of QT prolongation. Hypokalemia can result from diuretic therapy, diarrhea, and other causes.

2D6, and 3A4. Concomitant treatment with inhibitors of these enzymes can increase the concentration of VERSACLOZ [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ]. Hypokalemia and hypomagnesemia increase the risk of QT prolongation. Hypokalemia can result from diuretic therapy, diarrhea, and other causes. Use caution when treating patients at risk for significant electrolyte disturbance, particularly hypokalemia. Obtain baseline measurements of serum potassium and magnesium levels, and periodically monitor electrolytes. Correct electrolyte abnormalities before initiating treatment with VERSACLOZ. 5.10 Metabolic Changes Atypical antipsychotic drugs, including VERSACLOZ, have been associated with metabolic changes that can increase cardiovascular and cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While atypical antipsychotic drugs may produce some metabolic changes, each drug in the class has its own specific risk profile. Hyperglycemia and Diabetes Mellitus Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including VERSACLOZ. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse reactions is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent, hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics are not available. Patients with an established diagnosis of diabetes mellitus who are started on VERSACLOZ should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug. In a pooled data analysis of 8 studies in adult subjects with schizophrenia, the mean changes in fasting glucose concentration in the clozapine and chlorpromazine groups were +11 mg/dL and +4 mg/dL respectively. A higher proportion of the clozapine group demonstrated categorical increases from baseline in fasting glucose concentrations, compared to the chlorpromazine group (Table 4). The clozapine doses were 100-900 mg per day (mean modal dose: 512 mg per day). The maximum chlorpromazine dose was 1800 mg per day (mean modal dose: 1029 mg per day). The median duration of exposure was 42 days for clozapine and chlorpromazine.

ing glucose concentrations, compared to the chlorpromazine group (Table 4). The clozapine doses were 100-900 mg per day (mean modal dose: 512 mg per day). The maximum chlorpromazine dose was 1800 mg per day (mean modal dose: 1029 mg per day). The median duration of exposure was 42 days for clozapine and chlorpromazine. Table 4: Categorical Changes in Fasting Glucose Level in Studies in Adult Subjects with Schizophrenia Laboratory Parameter Category Change (at least once) from baseline Treatment Arm N n (%) Fasting Glucose Normal (<100 mg/dL) to High (≥126 mg/dL) Clozapine 198 53 (27) Chlorpromazine 135 14 (10) Borderline (100 to 125 mg/dL) to High (≥126 mg/dL) Clozapine 57 24 (42) Chlorpromazine 43 12 (28) Dyslipidemia Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics, including VERSACLOZ. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using VERSACLOZ, is recommended. In a pooled data analysis of 10 studies in adult subjects with schizophrenia, clozapine treatment was associated with increases in serum total cholesterol. No data were collected on LDL and HDL cholesterol. The mean increase in total cholesterol was 13 mg/dL in the clozapine group and 15 mg/dL in the chlorpromazine group. In a pooled data analysis of 2 studies in adult subjects with schizophrenia, clozapine treatment was associated with increases in fasting serum triglyceride. The mean increase in fasting triglyceride was 71 mg/dL (54%) in the clozapine group and 39 mg/dL (35%) in the chlorpromazine group (Table 5). In addition, clozapine treatment was associated with categorical increases in serum total cholesterol and triglyceride, as illustrated in Table 6. The proportion of patients with categorical increases in total cholesterol or fasting triglyceride increased with the duration of exposure. The median duration of clozapine and chlorpromazine exposure was 45 days and 38 days, respectively. The clozapine dose range was 100 mg to 900 mg daily; the maximum chlorpromazine dose was 1800 mg daily. Table 5: Mean Changes in Total Cholesterol and Triglyceride Concentration in Studies in Adult Subjects with Schizophrenia Treatment Arm Baseline total cholesterol concentration (mg/dL) Change from baseline mg/dL (%) Clozapine (N=334) 184 +13 (7) Chlorpromazine (N=185) 182 +15 (8) Baseline triglyceride concentration (mg/dL) Change from baseline mg/dL (%) Clozapine (N=6) 130 +71 (54) Chlorpromazine (N=7) 110 +39 (35) Table 6: Categorical Changes in Lipid Concentrations in Studies in Adult Subjects with Schizophrenia Laboratory Parameter Category Change (at least once) from Baseline Treatment Arm N n (%) Total Cholesterol (random or fasting) Increase by ≥ 40 mg/dL Clozapine 334 111 (33) Chlorpromazine 185 46 (25) Normal (<200 mg/dL) to High (≥240 mg/dL) Clozapine 222 18 (8) Chlorpromazine 132 3 (2) Borderline (200 - 239 mg/dL) to High (≥240 mg/dL) Clozapine 79 30 (38) Chlorpromazine 34 14 (41) Triglycerides (fasting) Increase by ≥50 mg/dL Clozapine 6 3 (50) Chlorpromazine 7 3 (43) Normal (<150 mg/dL) to High (≥200 mg/dL) Clozapine 4 0 (0) Chlorpromazine 6 2 (33) Borderline (≥150 mg/dL and <200 mg/dL) to High (≥200 mg/dL) Clozapine 1 1 (100) Chlorpromazine 1 0 (0) Weight Gain Weight gain has occurred with the use of antipsychotics, including VERSACLOZ. Monitor weight during treatment with VERSACLOZ. Table 7 summarizes the data on weight gain by the duration of exposure pooled from 11 studies with clozapine and active comparators. The median duration of exposure was 609, 728, and 42 days, in the clozapine, olanzapine, and chlorpromazine group, respectively.

VERSACLOZ. Monitor weight during treatment with VERSACLOZ. Table 7 summarizes the data on weight gain by the duration of exposure pooled from 11 studies with clozapine and active comparators. The median duration of exposure was 609, 728, and 42 days, in the clozapine, olanzapine, and chlorpromazine group, respectively. Table 7: Mean Change in Body Weight (kg) by duration of exposure from studies in adult subjects with schizophrenia Metabolic parameter Exposure duration Clozapine (N=669) Olanzapine (N=442) Chlorpromazine (N=155) n Mean n Mean n Mean Weight change from baseline 2 weeks (Day 11 – 17) 6 +0.9 3 +0.7 2 -0.5 4 weeks (Day 21 – 35) 23 +0.7 8 +0.8 17 +0.6 8 weeks (Day 49 – 63) 12 +1.9 13 +1.8 16 +0.9 12 weeks (Day 70 – 98) 17 +2.8 5 +3.1 0 0 24 weeks (154 – 182) 42 -0.6 12 +5.7 0 0 48 weeks (Day 322 – 350) 3 +3.7 3 +13.7 0 0 Table 8 summarizes pooled data from 11 studies in adult subjects with schizophrenia demonstrating weight gain ≥7% of body weight relative to baseline. The median duration of exposure was 609, 728, and 42 days, in the clozapine, olanzapine, and chlorpromazine group, respectively. Table 8: Proportion of adult subjects in schizophrenia studies with weight gain ≥7% relative to baseline body weight Weight change Clozapine Olanzapine Chlorpromazine N 669 442 155 ≥7% (inclusive) 236 (35%) 203 (46%) 13 (8%) 5.11 Neuroleptic Malignant Syndrome Antipsychotic drugs including VERSACLOZ can cause a potentially fatal symptom complex referred to as Neuroleptic Malignant Syndrome (NMS). Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Associated findings can include elevated creatine phosphokinase (CPK), myoglobinuria, rhabdomyolysis, and acute renal failure. The diagnostic evaluation of patients with this syndrome is complicated. It is important to consider the presence of other serious medical conditions (e.g., severe neutropenia, infection, heat stroke, primary CNS pathology, central anticholinergic toxicity, extrapyramidal symptoms, and drug fever). The management of NMS should include (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, (2) intensive symptomatic treatment and medical monitoring, and (3) treatment of co-morbid medical conditions. There is no general agreement about specific pharmacological treatments for NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. NMS can recur. Monitor closely if restarting treatment with antipsychotics. NMS has occurred with clozapine monotherapy and with concomitant CNS-active medications, including lithium. 5.12 Hepatotoxicity Severe, life threatening, and in some cases fatal hepatotoxicity including hepatic failure, hepatic necrosis, and hepatitis have been reported in patients treated with clozapine [see Adverse Reactions (6.2) ]. Monitor for the appearance of signs and symptoms of hepatotoxicity such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinemia, coagulopathy, and hepatic encephalopathy. Perform serum tests for liver injury and consider permanently discontinuing treatment if hepatitis or transaminase elevations combined with other systemic symptoms are due to clozapine. 5.13 Fever During clozapine therapy, patients have experienced transient, clozapine-related fever. The peak incidence is within the first 3 weeks of treatment. While this fever is generally benign and self-limited, it may necessitate discontinuing treatment. The fever can be associated with an increase or decrease in WBC count.

r During clozapine therapy, patients have experienced transient, clozapine-related fever. The peak incidence is within the first 3 weeks of treatment. While this fever is generally benign and self-limited, it may necessitate discontinuing treatment. The fever can be associated with an increase or decrease in WBC count. Carefully evaluate patients with fever to rule out severe neutropenia or infection[see Warnings and Precautions (5.1) ]. Consider the possibility of NMS [see Warnings and Precautions (5.11) ]. 5.14 Pulmonary Embolism Pulmonary embolism and deep vein thrombosis have occurred in patients treated with clozapine. Consider the possibility of pulmonary embolism in patients who present with deep vein thrombosis, acute dyspnea, chest pain, or with other respiratory signs and symptoms. Whether pulmonary embolus and deep vein thrombosis can be attributed to clozapine or some characteristic(s) of patients is not clear. 5.15 Anticholinergic Toxicity VERSACLOZ has potent anticholinergic effects. Treatment with VERSACLOZ can result in CNS and peripheral anticholinergic toxicity, especially at higher dosages or in overdose situations [see Overdosage (10)]. Use with caution in patients with a current diagnosis or prior history of constipation, urinary retention, clinically significant prostatic hypertrophy, or other conditions in which anticholinergic effects can lead to significant adverse reactions. When possible, avoid concomitant use with other anticholinergic medications because the risk for anticholinergic toxicity or severe gastrointestinal adverse reactions is increased [see Warnings and Precautions (5. 7 ), Drug Interactions (7.1)]. 5.16 Interference with Cognitive and Motor Performance VERSACLOZ can cause sedation and impairment of cognitive and motor performance. Caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that VERSACLOZ does not affect them adversely. These reactions may be dose-related. Consider reducing the dose if they occur. 5.17 Tardive Dyskinesia Tardive dyskinesia (TD) has occurred in patients treated with antipsychotic drugs, including VERSACLOZ. The syndrome consists of potentially irreversible, involuntary, dyskinetic movements. The risk of TD and the likelihood that it will become irreversible are believed to increase with greater durations of treatment and higher total cumulative doses. However, the syndrome can develop after relatively brief treatment periods at low doses. Prescribe VERSACLOZ in a manner that is most likely to minimize the risk of developing TD. Use the lowest effective dose and the shortest duration necessary to control symptoms. Periodically assess the need for continued treatment. Consider discontinuing treatment if TD occurs. However, some patients may require treatment with VERSACLOZ despite the presence of the syndrome. TD may remit partially or completely if treatment is discontinued. Antipsychotic treatment, itself, may suppress (or partially suppress) the signs and symptoms, and it has the potential to mask the underlying process. The effect of symptom suppression on the long-term course of TD is unknown. 5.18 Cerebrovascular Adverse Reactions In controlled trials, elderly patients with dementia-related psychosis treated with some atypical antipsychotics had an increased risk (compared to placebo) of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities. The mechanism for this increased risk is not known. An increased risk cannot be excluded for VERSACLOZ or other antipsychotics or other patient populations. VERSACLOZ should be used with caution in patients with risk factors for cerebrovascular adverse reactions.

troke, transient ischemic attack), including fatalities. The mechanism for this increased risk is not known. An increased risk cannot be excluded for VERSACLOZ or other antipsychotics or other patient populations. VERSACLOZ should be used with caution in patients with risk factors for cerebrovascular adverse reactions. 5.19 Recurrence of Psychosis and Cholinergic Rebound after Abrupt Discontinuation of VERSACLOZ If abrupt discontinuation of VERSACLOZ is necessary (because of severe neutropenia or another medical condition, for example) [see Dosage and Administration (2.6) , Warnings and Precautions (5.1) ] , monitor carefully for the recurrence of psychotic symptoms and adverse reactions related to cholinergic rebound, such as profuse sweating, headache, nausea, vomiting and diarrhea.

<table width="100%" cellspacing="0" cellpadding="0"><tbody><tr styleCode="Botrule First"><td align="center" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Laboratory Parameter</content></td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Category Change (at least once) from baseline</content></td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Treatment Arm</content></td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">N</content></td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">n (%)</content></td></tr><tr styleCode="Botrule"><td rowspan="4" align="center" styleCode="Lrule Rrule" valign="top">Fasting Glucose</td><td rowspan="2" align="center" styleCode="Rrule" valign="top">Normal (&lt;100 mg/dL) to High (&#x2265;126 mg/dL) </td><td styleCode="Rrule" valign="top">Clozapine</td><td align="center" styleCode="Rrule" valign="top">198</td><td align="center" styleCode="Rrule" valign="top">53 (27)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Chlorpromazine</td><td align="center" styleCode="Rrule" valign="top">135</td><td align="center" styleCode="Rrule" valign="top">14 (10)</td></tr><tr styleCode="Botrule"><td rowspan="2" align="center" styleCode="Lrule Rrule" valign="top">Borderline (100 to 125 mg/dL) to High (&#x2265;126 mg/dL) </td><td styleCode="Rrule" valign="top">Clozapine</td><td align="center" styleCode="Rrule" valign="top">57</td><td align="center" styleCode="Rrule" valign="top">24 (42)</td></tr><tr><td styleCode="Lrule Rrule" valign="top">Chlorpromazine</td><td align="center" styleCode="Rrule" valign="top">43</td><td align="center" styleCode="Rrule" valign="top">12 (28)</td></tr></tbody></table>

n="center" styleCode="Rrule" valign="top">57</td><td align="center" styleCode="Rrule" valign="top">24 (42)</td></tr><tr><td styleCode="Lrule Rrule" valign="top">Chlorpromazine</td><td align="center" styleCode="Rrule" valign="top">43</td><td align="center" styleCode="Rrule" valign="top">12 (28)</td></tr></tbody></table> <table width="100%" cellspacing="0" cellpadding="0"><tbody><tr styleCode="Botrule First"><td align="center" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Treatment Arm</content></td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Baseline total cholesterol concentration (mg/dL)</content></td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Change from baseline mg/dL (%)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Clozapine (N=334)</td><td align="center" styleCode="Rrule" valign="top">184</td><td align="center" styleCode="Rrule" valign="top">+13 (7)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Chlorpromazine (N=185)</td><td align="center" styleCode="Rrule" valign="top">182</td><td align="center" styleCode="Rrule" valign="top">+15 (8)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"/><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Baseline triglyceride concentration (mg/dL)</content></td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Change from baseline mg/dL (%)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Clozapine (N=6)</td><td align="center" styleCode="Rrule" valign="top">130</td><td align="center" styleCode="Rrule" valign="top">+71 (54)</td></tr><tr><td styleCode="Lrule Rrule" valign="top">Chlorpromazine (N=7)</td><td align="center" styleCode="Rrule" valign="top">110</td><td align="center" styleCode="Rrule" valign="top">+39 (35)</td></tr></tbody></table>

styleCode="Rrule" valign="top">130</td><td align="center" styleCode="Rrule" valign="top">+71 (54)</td></tr><tr><td styleCode="Lrule Rrule" valign="top">Chlorpromazine (N=7)</td><td align="center" styleCode="Rrule" valign="top">110</td><td align="center" styleCode="Rrule" valign="top">+39 (35)</td></tr></tbody></table> <table width="100%" cellspacing="0" cellpadding="0"><tbody><tr styleCode="Botrule First"><td align="center" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Laboratory Parameter</content></td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Category Change (at least once) from Baseline</content></td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Treatment Arm</content></td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">N</content></td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">n (%)</content></td></tr><tr styleCode="Botrule"><td rowspan="6" align="center" styleCode="Lrule Rrule" valign="top">Total Cholesterol (random or fasting) </td><td rowspan="2" align="center" styleCode="Rrule" valign="top">Increase by &#x2265; 40 mg/dL</td><td styleCode="Rrule" valign="top">Clozapine</td><td align="center" styleCode="Rrule" valign="top">334</td><td align="center" styleCode="Rrule" valign="top">111 (33)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Chlorpromazine</td><td align="center" styleCode="Rrule" valign="top">185</td><td align="center" styleCode="Rrule" valign="top">46 (25)</td></tr><tr styleCode="Botrule"><td rowspan="2" align="center" styleCode="Lrule Rrule" valign="top">Normal (&lt;200 mg/dL) to High (&#x2265;240 mg/dL) </td><td styleCode="Rrule" valign="top">Clozapine</td><td align="center" styleCode="Rrule" valign="top">222</td><td align="center" styleCode="Rrule" valign="top">18 (8)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Chlorpromazine</td><td align="center" styleCode="Rrule" valign="top">132</td><td align="center" styleCode="Rrule" valign="top">3 (2)</td></tr><tr styleCode="Botrule"><td rowspan="2" align="center" styleCode="Lrule Rrule" valign="top">Borderline (200 - 239 mg/dL) to High (&#x2265;240 mg/dL) </td><td styleCode="Rrule" valign="top">Clozapine</td><td align="center" styleCode="Rrule" valign="top">79</td><td align="center" styleCode="Rrule" valign="top">30 (38)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Chlorpromazine</td><td align="center" styleCode="Rrule" valign="top">34</td><td align="center" styleCode="Rrule" valign="top">14 (41)</td></tr><tr styleCode="Botrule"><td rowspan="6" align="center" styleCode="Lrule Rrule" valign="top">Triglycerides (fasting) </td><td rowspan="2" align="center" styleCode="Rrule" valign="top">Increase by &#x2265;50 mg/dL</td><td styleCode="Rrule" valign="top">Clozapine</td><td align="center" styleCode="Rrule" valign="top">6</td><td align="center" styleCode="Rrule" valign="top">3 (50)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Chlorpromazine</td><td align="center" styleCode="Rrule" valign="top">7</td><td align="center" styleCode="Rrule" valign="top">3 (43)</td></tr><tr styleCode="Botrule"><td rowspan="2" align="center" styleCode="Lrule Rrule" valign="top">Normal (&lt;150 mg/dL) to High (&#x2265;200 mg/dL) </td><td styleCode="Rrule" valign="top">Clozapine</td><td align="center" styleCode="Rrule" valign="top">4</td><td align="center" styleCode="Rrule" valign="top">0 (0)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Chlorpromazine</td><td align="center" styleCode="Rrule" valign="top">6</td><td align="center" styleCode="Rrule" valign="top">2 (33)</td></tr><tr styleCode="Botrule"><td rowspan="2" align="center" styleCode="

" styleCode="Rrule" valign="top">0 (0)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Chlorpromazine</td><td align="center" styleCode="Rrule" valign="top">6</td><td align="center" styleCode="Rrule" valign="top">2 (33)</td></tr><tr styleCode="Botrule"><td rowspan="2" align="center" styleCode=" Lrule Rrule" valign="top">Borderline (&#x2265;150 mg/dL and &lt;200 mg/dL) to High (&#x2265;200 mg/dL) </td><td styleCode="Rrule" valign="top">Clozapine</td><td align="center" styleCode="Rrule" valign="top">1</td><td align="center" styleCode="Rrule" valign="top">1 (100)</td></tr><tr><td styleCode="Lrule Rrule" valign="top">Chlorpromazine</td><td align="center" styleCode="Rrule" valign="top">1</td><td align="center" styleCode="Rrule" valign="top">0 (0)</td></tr></tbody></table>

align="center" styleCode="Rrule" valign="top">1</td><td align="center" styleCode="Rrule" valign="top">1 (100)</td></tr><tr><td styleCode="Lrule Rrule" valign="top">Chlorpromazine</td><td align="center" styleCode="Rrule" valign="top">1</td><td align="center" styleCode="Rrule" valign="top">0 (0)</td></tr></tbody></table> <table width="100%" cellspacing="0" cellpadding="0"><tbody><tr styleCode="Botrule First"><td rowspan="2" align="center" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Metabolic parameter</content></td><td rowspan="2" align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Exposure duration</content></td><td colspan="2" align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Clozapine</content> <content styleCode="bold">(N=669)</content></td><td colspan="2" align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Olanzapine</content> <content styleCode="bold">(N=442)</content></td><td colspan="2" align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Chlorpromazine</content> <content styleCode="bold">(N=155)</content></td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">n</content></td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Mean</content></td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">n</content></td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Mean</content></td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">n</content></td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Mean</content></td></tr><tr styleCode="Botrule"><td rowspan="6" align="center" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Weight change from baseline</content></td><td align="center" styleCode="Rrule" valign="top">2 weeks (Day 11 &#x2013; 17)</td><td align="center" styleCode="Rrule" valign="top">6</td><td align="center" styleCode="Rrule" valign="top">+0.9</td><td align="center" styleCode="Rrule" valign="top">3</td><td align="center" styleCode="Rrule" valign="top">+0.7</td><td align="center" styleCode="Rrule" valign="top">2</td><td align="center" styleCode="Rrule" valign="top">-0.5</td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="top">4 weeks (Day 21 &#x2013; 35)</td><td align="center" styleCode="Rrule" valign="top">23</td><td align="center" styleCode="Rrule" valign="top">+0.7</td><td align="center" styleCode="Rrule" valign="top">8</td><td align="center" styleCode="Rrule" valign="top">+0.8</td><td align="center" styleCode="Rrule" valign="top">17</td><td align="center" styleCode="Rrule" valign="top">+0.6</td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="top">8 weeks (Day 49 &#x2013; 63)</td><td align="center" styleCode="Rrule" valign="top">12</td><td align="center" styleCode="Rrule" valign="top">+1.9</td><td align="center" styleCode="Rrule" valign="top">13</td><td align="center" styleCode="Rrule" valign="top">+1.8</td><td align="center" styleCode="Rrule" valign="top">16</td><td align="center" styleCode="Rrule" valign="top">+0.9</td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="top">12 weeks (Day 70 &#x2013; 98)</td><td align="center" styleCode="Rrule" valign="top">17</td><td align="center" styleCode="Rrule" valign="top">+2.8</td><td align="center" styleCode="Rrule" valign="top">5</td><td align="center" styleCode="Rrule" valign="top">+3.1</td><td align="center" styleCode="Rrule" valign="top">0</td><td align="center" styleCode="Rrule" valign="top">0</td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="top">24 weeks (154 &#x2013;

ter" styleCode="Rrule" valign="top">5</td><td align="center" styleCode="Rrule" valign="top">+3.1</td><td align="center" styleCode="Rrule" valign="top">0</td><td align="center" styleCode="Rrule" valign="top">0</td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="top">24 weeks (154 &#x2013; 182)</td><td align="center" styleCode="Rrule" valign="top">42</td><td align="center" styleCode="Rrule" valign="top">-0.6</td><td align="center" styleCode="Rrule" valign="top">12</td><td align="center" styleCode="Rrule" valign="top">+5.7</td><td align="center" styleCode="Rrule" valign="top">0</td><td align="center" styleCode="Rrule" valign="top">0</td></tr><tr><td align="center" styleCode="Lrule Rrule" valign="top">48 weeks (Day 322 &#x2013; 350)</td><td align="center" styleCode="Rrule" valign="top">3</td><td align="center" styleCode="Rrule" valign="top">+3.7</td><td align="center" styleCode="Rrule" valign="top">3</td><td align="center" styleCode="Rrule" valign="top">+13.7</td><td align="center" styleCode="Rrule" valign="top">0</td><td align="center" styleCode="Rrule" valign="top">0</td></tr></tbody></table> <table width="100%" cellspacing="0" cellpadding="0"><tbody><tr styleCode="Botrule First"><td align="center" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Weight change</content></td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Clozapine</content></td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Olanzapine</content></td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Chlorpromazine</content></td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">N</content></td><td align="center" styleCode="Rrule" valign="top">669</td><td align="center" styleCode="Rrule" valign="top">442</td><td align="center" styleCode="Rrule" valign="top">155</td></tr><tr><td align="center" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">&#x2265;7% (inclusive)</content></td><td align="center" styleCode="Rrule" valign="top">236 (35%)</td><td align="center" styleCode="Rrule" valign="top">203 (46%)</td><td align="center" styleCode="Rrule" valign="top">13 (8%)</td></tr></tbody></table>

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: Severe Neutropenia [see Warnings and Precautions (5.1) ]. Orthostatic Hypotension, Bradycardia, and Syncope [see Warnings and Precautions (5.2) ]. Falls [see Warnings and Precautions (5.3) ] Seizures [see Warnings and Precautions (5.4) ]. Myocarditis, Pericarditis, Cardiomyopathy and Mitral Valve Incompetence [see Warnings and Precautions (5.5) ]. Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Warnings and Precautions (5.6) ]. Gastrointestinal Hypomotility and Severe Complications [see Warnings and Precautions (5.7)]. Eosinophilia [see Warnings and Precautions (5.8) ]. QT Interval Prolongation [see Warnings and Precautions (5.9) ]. Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain) [see Warnings and Precautions (5.10) ]. Neuroleptic Malignant Syndrome [see Warnings and Precautions (5.11) ]. Hepatotoxicity [see Warnings and Precautions (5.12) ]. Fever [see Warnings and Precautions (5.13) ]. Pulmonary Embolism [see Warnings and Precautions (5.14) ]. Anticholinergic Toxicity [see Warnings and Precautions (5.15) ]. Interference with Cognitive and Motor Performance [see Warnings and Precautions (5.16) ]. Tardive Dyskinesia [see Warnings and Precautions (5.17) ]. Cerebrovascular Adverse Reactions [see Warnings and Precautions (5.18) ]. Recurrence of Psychosis and Cholinergic Rebound after Abrupt Discontinuation [see Warnings and Precautions (5.19) ]. Most common adverse reactions (≥5%) were: CNS reactions (sedation, dizziness/vertigo, headache, and tremor); cardiovascular reactions (tachycardia, hypotension, and syncope); autonomic nervous system reactions (hypersalivation, sweating, dry mouth, and visual disturbances); gastrointestinal reactions (constipation and nausea); and fever ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact TruPharma, LLC, at 1-877-541-5504 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.The most commonly reported adverse reactions (>5%) across clozapine clinical trials were: CNS reactions, including sedation, dizziness/vertigo, headache, and tremor; cardiovascular reactions, including tachycardia, hypotension, and syncope; autonomic nervous system reactions, including hypersalivation, sweating, dry mouth, and visual disturbances; gastrointestinal reactions, including constipation and nausea; and fever. Table 9 summarizes the most commonly reported adverse reactions (>5%) in clozapine-treated patients (compared to chlorpromazine-treated patients) in the pivotal, 6-week, controlled trial in treatment-resistant schizophrenia.

visual disturbances; gastrointestinal reactions, including constipation and nausea; and fever. Table 9 summarizes the most commonly reported adverse reactions (>5%) in clozapine-treated patients (compared to chlorpromazine-treated patients) in the pivotal, 6-week, controlled trial in treatment-resistant schizophrenia. Table 9: Common Adverse Reactions (≥5%) in the 6-Week, Randomized, Chlorpromazine-controlled Trial in Treatment-Resistant Schizophrenia Adverse Reaction Clozapine (N=126) (%) Chlorpromazine (N=142) (%) Sedation Tachycardia Constipation Dizziness Hypotension Fever (hyperthermia) Hypersalivation Hypertension Headache Nausea/vomiting Dry mouth 21 17 16 14 13 13 13 12 10 10 5 13 11 12 16 38 4 1 5 10 12 20 Table 10 summarizes the adverse reactions reported in clozapine-treated patients at a frequency of 2% or greater across all clozapine studies (excluding the 2-year InterSePT ™ Study). These rates are not adjusted for duration of exposure. Table 10: Adverse Reactions (≥2%) Reported in Clozapine-treated Patients (N=842) across all Clozapine Studies (excluding the 2-year InterSePT™ Study) Body System Adverse Reaction Clozapine N=842 Percentage of Patients Central Nervous System Drowsiness/Sedation Dizziness/Vertigo Headache Tremor Syncope Disturbed Sleep/Nightmares Restlessness Hypokinesia/Akinesia Agitation Seizures (convulsions) Rigidity Akathisia Confusion Fatigue Insomnia 39 19 7 6 6 4 4 4 4 3† 3 3 3 2 2 Cardiovascular Tachycardia Hypotension Hypertension 25† 9 4 Gastrointestinal Constipation Nausea Abdominal Discomfort/Heartburn Nausea/Vomiting Vomiting Diarrhea 14 5 4 3 3 2 Urogenital Urinary Abnormalities 2 Autonomic Nervous System Salivation Sweating Dry Mouth Visual Disturbances 31 6 6 5 Skin Rash 2 Hemic/Lymphatic Leukopenia/Decreased WBC/Neutropenia 3 Miscellaneous Fever Weight Gain 5 4 † Rate based on population of approximately 1700 exposed during premarket clinical evaluation of clozapine. Table 11 summarizes the most commonly reported adverse reactions (>10% of the clozapine or olanzapine group) in the InterSePT ™ Study. This was an adequate and well-controlled, two-year study evaluating the efficacy of clozapine relative to olanzapine in reducing the risk of suicidal behavior in patients with schizophrenia or schizoaffective disorder. The rates are not adjusted for duration of exposure. Table 11: Incidence of Adverse Reactions in Patients Treated with Clozapine or Olanzapine in the InterSePT™ Study (≥10% in the clozapine or olanzapine group) Adverse Reactions Clozapine N=479 % Reporting Olanzapine N=477 % Reporting Salivary hypersecretion 48% 6% Somnolence 46% 25% Weight increased 31% 56% Dizziness (excluding vertigo) 27% 12% Constipation 25% 10% Insomnia 20% 33% Nausea 17% 10% Vomiting 17% 9% Dyspepsia 14% 8% Dystonia Class effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of clozapine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of clozapine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Central Nervous System Delirium, EEG abnormal, myoclonus, paresthesia, possible cataplexy, status epilepticus, obsessive compulsive symptoms, and post-discontinuation cholinergic rebound adverse reactions. Cardiovascular System Atrial or ventricular fibrillation, ventricular tachycardia, palpitations, QT interval prolongation, Torsades de Pointes, mitral valve incompetence associated with clozapine-related cardiomyopathy, myocardial infarction, cardiac arrest, myocarditis, pericarditis, and periorbital edema. Endocrine System Pseudopheochromocytoma. Gastrointestinal System Acute pancreatitis, dysphagia, salivary gland swelling, megacolon, fecal incontinence, and intestinal ischemia, infarction, perforation, ulceration or necrosis. Hepatobiliary System Cholestasis, hepatitis, jaundice, hepatotoxicity, hepatic steatosis, hepatic necrosis, hepatic fibrosis, hepatic cirrhosis, liver injury (hepatic, cholestatic, and mixed), and liver failure. Immune System Disorders Angioedema, leukocytoclastic vasculitis. Urogenital System Acute interstitial nephritis, nocturnal enuresis, priapism, renal failure and retrograde ejaculation. Skin and Subcutaneous Tissue Disorders Hypersensitivity reactions: photosensitivity, vasculitis, erythema multiforme, skin pigmentation disorder, and Stevens-Johnson Syndrome. Musculoskeletal System and Connective Tissue Disorders Myasthenic syndrome, rhabdomyolysis, and systemic lupus erythematosus. Respiratory System Aspiration, pleural effusion, pneumonia, lower respiratory tract infection, sleep apnea. Hemic and Lymphatic System Mild, moderate, or severe leukopenia, agranulocytosis, granulocytopenia, WBC decreased, deep vein thrombosis, elevated hemoglobin/hematocrit, erythrocyte sedimentation rate (ESR) increased, sepsis, thrombocytosis, and thrombocytopenia. Vision Disorders Narrow-angle glaucoma. Miscellaneous Creatine phosphokinase elevation, hyperuricemia, hyponatremia, and weight loss.

<table width="100%" cellspacing="0" cellpadding="0"><tbody><tr><td valign="top">Adverse Reaction</td><td align="center" valign="top"> Clozapine (N=126) (%) </td><td align="center" valign="top"> Chlorpromazine (N=142) (%) </td></tr><tr><td valign="top">Sedation Tachycardia Constipation Dizziness Hypotension Fever (hyperthermia) Hypersalivation Hypertension Headache Nausea/vomiting Dry mouth </td><td valign="top">21 17 16 14 13 13 13 12 10 10 5 </td><td valign="top">13 11 12 16 38 4 1 5 10 12 20 </td></tr></tbody></table>

ine (N=142) (%) </td></tr><tr><td valign="top">Sedation Tachycardia Constipation Dizziness Hypotension Fever (hyperthermia) Hypersalivation Hypertension Headache Nausea/vomiting Dry mouth </td><td valign="top">21 17 16 14 13 13 13 12 10 10 5 </td><td valign="top">13 11 12 16 38 4 1 5 10 12 20 </td></tr></tbody></table> <table width="100%" cellspacing="0" cellpadding="0"><tbody><tr><td valign="top"><content styleCode="bold">Body System </content><content styleCode="bold">Adverse Reaction</content></td><td align="center" valign="top"> <content styleCode="bold">Clozapine</content> <content styleCode="bold">N=842</content> <content styleCode="bold">Percentage of Patients</content></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Central Nervous System</content> Drowsiness/Sedation Dizziness/Vertigo Headache Tremor </paragraph><paragraph> Syncope Disturbed Sleep/Nightmares Restlessness Hypokinesia/Akinesia </paragraph><paragraph> Agitation Seizures (convulsions) Rigidity Akathisia Confusion Fatigue Insomnia </paragraph></td><td align="center" valign="top"><paragraph> 39 19 7 6 </paragraph><paragraph>6</paragraph><paragraph>4</paragraph><paragraph>4</paragraph><paragraph>4</paragraph><paragraph>4</paragraph><paragraph>3&#x2020; 3 3 3 2 2 </paragraph></td></tr><tr><td valign="top"><content styleCode="bold">Cardiovascular</content> Tachycardia Hypotension Hypertension </td><td align="center" valign="top"> 25&#x2020; 9 4 </td></tr><tr><td valign="top"><content styleCode="bold">Gastrointestinal</content> Constipation Nausea Abdominal Discomfort/Heartburn Nausea/Vomiting Vomiting Diarrhea </td><td align="center" valign="top"> 14 5 4 3 3 2 </td></tr><tr><td valign="top"><content styleCode="bold">Urogenital</content> Urinary Abnormalities </td><td align="center" valign="top"> 2 </td></tr><tr><td valign="top"><content styleCode="bold">Autonomic Nervous System</content> Salivation Sweating Dry Mouth Visual Disturbances </td><td align="center" valign="top"> 31 6 6 5 </td></tr><tr><td valign="top"><content styleCode="bold">Skin</content> Rash </td><td align="center" valign="top"> 2 </td></tr><tr><td valign="top"><content styleCode="bold">Hemic/Lymphatic</content> Leukopenia/Decreased WBC/Neutropenia </td><td align="center" valign="top"> 3 </td></tr><tr><td valign="top"><content styleCode="bold">Miscellaneous</content> Fever Weight Gain </td><td align="center" valign="top"> 5 4 </td></tr><tr><td colspan="2" valign="top">&#x2020; Rate based on population of approximately 1700 exposed during premarket clinical evaluation of clozapine.</td></tr></tbody></table>

></tr><tr><td valign="top"><content styleCode="bold">Miscellaneous</content> Fever Weight Gain </td><td align="center" valign="top"> 5 4 </td></tr><tr><td colspan="2" valign="top">&#x2020; Rate based on population of approximately 1700 exposed during premarket clinical evaluation of clozapine.</td></tr></tbody></table> <table width="100%" cellspacing="0" cellpadding="0"><tbody><tr><td valign="top"><content styleCode="bold">Adverse Reactions</content></td><td align="center" valign="top"> <content styleCode="bold">Clozapine</content> <content styleCode="bold">N=479</content> <content styleCode="bold">% Reporting</content></td><td align="center" valign="top"> <content styleCode="bold">Olanzapine</content> <content styleCode="bold">N=477</content> <content styleCode="bold">% Reporting</content></td></tr><tr><td valign="top">Salivary hypersecretion</td><td align="center" valign="top"> 48%</td><td align="center" valign="top"> 6%</td></tr><tr><td valign="top">Somnolence</td><td align="center" valign="top"> 46%</td><td align="center" valign="top"> 25%</td></tr><tr><td valign="top">Weight increased</td><td align="center" valign="top"> 31%</td><td align="center" valign="top"> 56%</td></tr><tr><td valign="top">Dizziness (excluding vertigo)</td><td align="center" valign="top"> 27%</td><td align="center" valign="top"> 12%</td></tr><tr><td valign="top">Constipation</td><td align="center" valign="top"> 25%</td><td align="center" valign="top"> 10%</td></tr><tr><td valign="top">Insomnia</td><td align="center" valign="top"> 20%</td><td align="center" valign="top"> 33%</td></tr><tr><td valign="top">Nausea</td><td align="center" valign="top"> 17%</td><td align="center" valign="top"> 10%</td></tr><tr><td valign="top">Vomiting</td><td align="center" valign="top"> 17%</td><td align="center" valign="top"> 9%</td></tr><tr><td valign="top">Dyspepsia</td><td align="center" valign="top">14%</td><td align="center" valign="top"> 8%</td></tr></tbody></table>

7 DRUG INTERACTIONS Concomitant use of Strong CYP1A2 Inhibitors : Reduce VERSACLOZ dose to one third when coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, enoxacin) ( 2.7 , 7.1 ). Concomitant use of Strong CYP3A4 Inducers is not recommended ( 2.7 , 7.1 ). Discontinuation of CYP1A2 or CYP3A4 Inducers : Consider reducing VERSACLOZ dose when CYP1A2 (e.g., tobacco smoke) or CYP3A4 inducers (e.g., carbamazepine) are discontinued ( 2.7 , 7.1 ). Anticholinergic drugs: Concomitant use may increase the risk for anticholinergic toxicity ( 5.8 , 5.16 , 7.1 ). 7.1 Potential for Other Drugs to Affect VERSACLOZ Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP3A4, and CYP2D6. Use caution when administering VERSACLOZ concomitantly with drugs that are inducers or inhibitors of these enzymes. CYP1A2 Inhibitors Concomitant use of VERSACLOZ and CYP1A2 inhibitors can increase plasma levels of clozapine, potentially resulting in adverse reactions. Reduce the VERSACLOZ dose to one third of the original dose when VERSACLOZ is coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin). The VERSACLOZ dose should be increased to the original dose when coadministration of strong CYP1A2 inhibitors is discontinued [see Dosage and Administration (2.8) , Clinical Pharmacology (12.3) ]. Moderate or weak CYP1A2 inhibitors include oral contraceptives and caffeine. Monitor patients closely when VERSACLOZ is coadministered with these inhibitors. Consider reducing the VERSACLOZ dosage if necessary [see Dosage and Administration (2.8) ] . CYP2D6 and CYP3A4 Inhibitors Concomitant treatment with VERSACLOZ and CYP2D6 or CYP3A4 inhibitors (e.g., cimetidine, escitalopram, erythromycin, paroxetine, bupropion, fluoxetine, quinidine, duloxetine, terbinafine, or sertraline) can increase clozapine levels and lead to adverse reactions [see Clinical Pharmacology (12.3) ] . Use caution and monitor patients closely when using such inhibitors. Consider reducing the VERSACLOZ dose [see Dosage and Administration (2.8) ] . CYP1A2 and CYP3A4 Inducers Concomitant treatment with drugs that induce CYP1A2 or CYP3A4 can decrease the plasma concentration of clozapine, resulting in decreased effectiveness of VERSACLOZ. Tobacco smoke is a moderate inducer of CYP1A2. Strong CYP3A4 inducers include carbamazepine, phenytoin, St. John’s wort, and rifampin. It may be necessary to increase the VERSACLOZ dose if used concomitantly with inducers of these enzymes. However, concomitant use of VERSACLOZ and strong CYP3A4 inducers is not recommended [see Dosage and Administration (2.8) ]. Consider reducing the VERSACLOZ dosage when discontinuing coadministered enzyme inducers, because discontinuation of inducers can result in increased clozapine plasma levels and an increased risk of adverse reactions [see Dosage and Administration (2.8) ]. Anticholinergic Drugs Concomitant treatment with clozapine and other drugs with anticholinergic activity (e.g., benztropine, cyclobenzaprine, diphenhydramine) can increase the risk for anticholinergic toxicity and severe gastrointestinal adverse reactions related to hypomotility. Avoid concomitant use of VERSACLOZ with anticholinergic drugs when possible [see Warnings and Precautions ( 5.7 , 5.15 )]. Drugs that Cause QT Interval Prolongation Use caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of VERSACLOZ.

ctions related to hypomotility. Avoid concomitant use of VERSACLOZ with anticholinergic drugs when possible [see Warnings and Precautions ( 5.7 , 5.15 )]. Drugs that Cause QT Interval Prolongation Use caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of VERSACLOZ. Drugs that cause QT prolongation include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, thioridazine, mesoridazine, droperidol, and pimozide), specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin), Class 1A antiarrhythmics (e.g., quinidine, procainamide) or Class III antiarrhythmics (e.g., amiodarone, sotalol), and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus) [see Warnings and Precautions (5.9) ] . 7.2 Potential for VERSACLOZ to Affect Other Drugs Concomitant use of VERSACLOZ with other drugs metabolized by CYP2D6 can increase levels of these CYP2D6 substrates. Use caution when coadministering VERSACLOZ with other drugs that are metabolized by CYP2D6. It may be necessary to use lower doses of such drugs than usually prescribed. Such drugs include specific antidepressants, phenothiazines, carbamazepine, and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide).

8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure ( 8.1 ). 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including VERSACLOZ, during pregnancy. Health care providers are encouraged to advise patients to register by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visiting http://womensmental health.org/clinical-and-research-programs/pregnancyregistry/. Risk Summary Neonates exposed to antipsychotic drugs, including VERSACLOZ, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations ). Available data from published epidemiologic studies over decades of use with clozapine during pregnancy have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. (see Data ) . There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, including VERSACLOZ, during pregnancy (see Clinical Considerations ). In animal reproduction studies, no adverse developmental effects were observed when clozapine was administered orally to pregnant rats or rabbits during the period of organogenesis, or to pregnant rats during pregnancy and lactation, at doses up to approximately 0.4 and 0.9 times the maximum recommended human dose (MRHD) of 900 mg/day, for rats and rabbits respectively, based on mg/m 2 body surface area (see Data ) . The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk There is a risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide. Schizophrenia is associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. Fetal/Neonatal adverse reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who have been exposed to antipsychotic drugs, including VERSACLOZ, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Data Human Data Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics do not report a clear association with antipsychotics and major birth defects. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects.

stries, and case reports on the use of atypical antipsychotics do not report a clear association with antipsychotics and major birth defects. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. Animal Data In embryofetal developmental studies, clozapine had no effects on maternal parameters, litter sizes, or fetal parameters when administered orally to pregnant rats and rabbits during the period of organogenesis at doses up to 0.4 and 0.9 times, respectively, the MRHD of 900 mg/day on a mg/m 2 body surface area basis. In peri/postnatal developmental studies, pregnant female rats were administered clozapine over the last third of pregnancy and until day 21 postpartum. Observations were made on fetuses at birth and during the postnatal period; the offspring were allowed to reach sexual maturity and mated. Clozapine caused a decrease in maternal body weight but had no effects on litter size or body weights of either F1 or F2 generations at doses up to 0.4 times the MRHD of 900 mg/day on a mg/m 2 body surface area basis. 8.2 Lactation Risk Summary Clozapine is present in human milk. There are reports of sedation and a report of agranulocytosis in an infant exposed to clozapine through human milk ( see Clinical Considerations ). There is no information on the effects of clozapine on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for VERSACLOZ and any potential adverse effects on the breastfed-child from VERSACLOZ or from the underlying maternal condition. Clinical Considerations Infants exposed to VERSACLOZ should be monitored for excess sedation and neutropenia. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use There have not been sufficient numbers of geriatric patients in clinical studies utilizing VERSACLOZ to determine whether those over 65 years of age differ from younger subjects in their response to VERSACLOZ. Orthostatic hypotension and tachycardia can occur with clozapine treatment [see Boxed Warning and Warnings and Precautions (5. 2 ) ]. Elderly patients, particularly those with compromised cardiovascular functioning, may be more susceptible to these effects. Elderly patients may be particularly susceptible to the anticholinergic effects of clozapine, such as urinary retention and constipation [see Warnings and Precautions (5.15) ]. Carefully select VERSACLOZ doses in elderly patients, taking into consideration their greater frequency of decreased hepatic, renal, or cardiac function, as well as other concomitant disease and other drug therapy. Clinical experience suggests that the prevalence of tardive dyskinesia appears to be highest among the elderly; especially elderly women [see Warnings and Precautions (5.17) ]. 8.6 Patients with Renal or Hepatic Impairment Dose reduction may be necessary in patients with significant impairment of renal or hepatic function. Clozapine concentrations may be increased in these patients, because clozapine is almost completely metabolized and then excreted [see Dosage and Administration (2.9) , Clinical Pharmacology (12.3) ]. 8.7 CYP2D6 Poor Metabolizers Dose reduction may be necessary in patients who are CYP2D6 poor metabolizers. Clozapine concentrations may be increased in these patients, because clozapine is almost completely metabolized and then excreted [see Dosage and Administration (2.8) , Clinical Pharmacology (12.3) ].

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including VERSACLOZ, during pregnancy. Health care providers are encouraged to advise patients to register by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visiting http://womensmental health.org/clinical-and-research-programs/pregnancyregistry/. Risk Summary Neonates exposed to antipsychotic drugs, including VERSACLOZ, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations ). Available data from published epidemiologic studies over decades of use with clozapine during pregnancy have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. (see Data ) . There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, including VERSACLOZ, during pregnancy (see Clinical Considerations ). In animal reproduction studies, no adverse developmental effects were observed when clozapine was administered orally to pregnant rats or rabbits during the period of organogenesis, or to pregnant rats during pregnancy and lactation, at doses up to approximately 0.4 and 0.9 times the maximum recommended human dose (MRHD) of 900 mg/day, for rats and rabbits respectively, based on mg/m 2 body surface area (see Data ) . The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk There is a risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide. Schizophrenia is associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. Fetal/Neonatal adverse reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who have been exposed to antipsychotic drugs, including VERSACLOZ, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Data Human Data Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics do not report a clear association with antipsychotics and major birth defects. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects.

stries, and case reports on the use of atypical antipsychotics do not report a clear association with antipsychotics and major birth defects. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. Animal Data In embryofetal developmental studies, clozapine had no effects on maternal parameters, litter sizes, or fetal parameters when administered orally to pregnant rats and rabbits during the period of organogenesis at doses up to 0.4 and 0.9 times, respectively, the MRHD of 900 mg/day on a mg/m 2 body surface area basis. In peri/postnatal developmental studies, pregnant female rats were administered clozapine over the last third of pregnancy and until day 21 postpartum. Observations were made on fetuses at birth and during the postnatal period; the offspring were allowed to reach sexual maturity and mated. Clozapine caused a decrease in maternal body weight but had no effects on litter size or body weights of either F1 or F2 generations at doses up to 0.4 times the MRHD of 900 mg/day on a mg/m 2 body surface area basis.

8.5 Geriatric Use There have not been sufficient numbers of geriatric patients in clinical studies utilizing VERSACLOZ to determine whether those over 65 years of age differ from younger subjects in their response to VERSACLOZ. Orthostatic hypotension and tachycardia can occur with clozapine treatment [see Boxed Warning and Warnings and Precautions (5. 2 ) ]. Elderly patients, particularly those with compromised cardiovascular functioning, may be more susceptible to these effects. Elderly patients may be particularly susceptible to the anticholinergic effects of clozapine, such as urinary retention and constipation [see Warnings and Precautions (5.15) ]. Carefully select VERSACLOZ doses in elderly patients, taking into consideration their greater frequency of decreased hepatic, renal, or cardiac function, as well as other concomitant disease and other drug therapy. Clinical experience suggests that the prevalence of tardive dyskinesia appears to be highest among the elderly; especially elderly women [see Warnings and Precautions (5.17) ].

10 OVERDOSAGE 10.1 Overdosage Experience The most commonly reported signs and symptoms associated with clozapine overdose are: sedation, delirium, coma, tachycardia, hypotension, respiratory depression or failure, and hypersalivation. There are reports of aspiration pneumonia, cardiac arrhythmias, and seizure. Fatal overdoses have been reported with clozapine, generally at doses above 2500 mg. There have also been reports of patients recovering from overdoses well in excess of 4 g. 10.2 Management of Overdosage There are no specific antidotes for VERSACLOZ. Establish and maintain an airway; ensure adequate oxygenation and ventilation. Monitor cardiac status and vital signs. Use general symptomatic and supportive measures. Consider the possibility of multiple-drug involvement. Contact a Certified Poison Control Center for the most up to date information on the management of overdosage (1-800-222-1222).

11 DESCRIPTION VERSACLOZ, an atypical antipsychotic drug, is a tricyclic dibenzodiazepine derivative, 8-chloro-11-(4-methyl-1-piperazinyl)-5 H -dibenzo[ b,e ][1,4]diazepine. The is: VERSACLOZ is available as a free-flowing yellow suspension. Each mL contains 50 mg of clozapine. The active component of VERSACLOZ is clozapine. The remaining components are glycerin, sorbitol (crystallizing), sodium dihydrogen phosphate dihydrate, xanthan gum, sodium methylparaben, sodium propylparaben, povidone, water, and sodium hydroxide to adjust to a pH range of 6.5 – 7.0. structure

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of clozapine is unknown. However, it has been proposed that the therapeutic efficacy of clozapine in schizophrenia is mediated through antagonism of the dopamine type 2 (D 2 ) and the serotonin type 2A (5-HT 2A ) receptors. VERSACLOZ also acts as an antagonist at adrenergic, cholinergic, histaminergic and other dopaminergic and serotonergic receptors. 12.2 Pharmacodynamics Clozapine demonstrated binding affinity to the following receptors: histamine H 1 (K i 1.1 nM), adrenergic α 1A (K i 1.6 nM), serotonin 5-HT 6 (K i 4 nM ) , serotonin 5-HT 2A (K i 5.4 nM), muscarinic M 1 (K i 6.2 nM), serotonin 5-HT 7 (K i 6.3 nM), serotonin 5-HT 2C (K i 9.4 nM), dopamine D 4 (K i 24 nM), adrenergic α 2A (K i 90 nM), serotonin 5-HT 3 (K i 95 nM), serotonin 5-HT 1A (K i 120 nM), dopamine D 2 (K i 160 nM), dopamine D 1 (K i 270 nM), dopamine D 5 (K i 454 nM), and dopamine D 3 (K i 555 nM). Clozapine causes little or no prolactin elevation. Clinical electroencephalogram (EEG) studies demonstrated that clozapine increases delta and theta activity and slows dominant alpha frequencies. Enhanced synchronization occurs. Sharp wave activity and spike and wave complexes may also develop. Patients have reported an intensification of dream activity during clozapine therapy. REM sleep was found to be increased to 85% of the total sleep time. In these patients, the onset of REM sleep occurred almost immediately after falling asleep. 12.3 Pharmacokinetics Absorption In man, clozapine tablets (25 mg and 100 mg) are equally bioavailable relative to a clozapine solution. VERSACLOZ Oral Suspension is bioequivalent to clozapine marketed tablets. Following oral administration of 100 mg to 800 mg VERSACLOZ, once daily, the average steady-state peak plasma concentration was 275 ng/mL (range: 105 - 723 ng/mL), occurring at the average of 2.2 hours (range: 1 - 3.5 hours) after dosing. The average minimum concentration at steady-state was 75 ng/mL (range: 11 - 198 ng/mL). When VERSACLOZ was administered after a high fat meal there was no effect on the AUC ss or C min, ss , however C max was reduced about 20%, and there was a slight delay in T max of 0.5 hour from a median T max of 2.0 hours under fasted conditions to 2.5 hours under fed conditions. The decrease in C max is not considered clinically relevant. Therefore VERSACLOZ may be taken without regard to meals. Distribution Clozapine is approximately 97% bound to serum proteins. The interaction between clozapine and other highly protein-bound drugs has not been fully evaluated but may be important [see Drug Interactions (7) ]. Metabolism and Excretion VERSACLOZ is almost completely metabolized prior to excretion, and only trace amounts of unchanged drug are detected in the urine and feces. VERSACLOZ is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP2D6, and CYP3A4. Approximately 50% of the administered dose is excreted in the urine and 30% in the feces. The demethylated, hydroxylated, and N -oxide derivatives are components in both urine and feces. Pharmacological testing has shown the desmethyl metabolite (norclozapine) to have only limited activity, while the hydroxylated and N -oxide derivatives were inactive.

red dose is excreted in the urine and 30% in the feces. The demethylated, hydroxylated, and N -oxide derivatives are components in both urine and feces. Pharmacological testing has shown the desmethyl metabolite (norclozapine) to have only limited activity, while the hydroxylated and N -oxide derivatives were inactive. The mean elimination half-life of clozapine after a single 75 mg dose was 8 hours (range: 4-12 hours), compared to a mean elimination half-life of 12 hours (range: 4-66 hours), after achieving steady-state with 100 mg twice daily dosing. A comparison of single-dose and multiple-dose administration of clozapine demonstrated that the elimination half-life increased significantly after multiple dosing relative to that after single-dose administration, suggesting the possibility of concentration-dependent pharmacokinetics. However, at steady-state, approximately dose-proportional changes with respect to AUC (area under the curve), peak, and minimum clozapine plasma concentrations were observed after administration of 37.5, 75, and 150 mg twice daily. Drug-Drug Interaction Studies Fluvoxamine A pharmacokinetic study was conducted in 16 patients with schizophrenia who received clozapine under steady-state conditions. After coadministration of fluvoxamine for 14 days, mean trough concentrations of clozapine and its metabolites, N -desmethylclozapine and clozapine N -oxide, were elevated about three-fold compared to baseline steady-state concentrations. Paroxetine, Fluoxetine, and Sertraline In a study of patients with schizophrenia (n=14) who received clozapine under steady-state conditions, coadministration of paroxetine produced only minor changes in the levels of clozapine and its metabolites. However, other published reports describe modest elevations (less than two-fold) of clozapine and metabolite concentrations when clozapine was taken with paroxetine, fluoxetine, and sertraline. Specific Populations Renal or Hepatic Impairment No specific pharmacokinetic studies were conducted to investigate the effects of renal or hepatic impairment on the pharmacokinetics of clozapine. Higher clozapine plasma concentrations are likely in patients with significant renal or hepatic impairment when given usual doses. CYP2D6 Poor Metabolizers A subset (3%–10%) of the population has reduced activity of CYP2D6 (CYP2D6 poor metabolizers). These individuals may develop higher than expected plasma concentrations of clozapine when given usual doses. Patients with Pneumonia and other Inflammatory Conditions Published case reports describe examples where pneumonia or other inflammatory- conditions may increase clozapine concentrations. The clinical significance, the impact of treatments to modulate this inflammation, and mechanism of this potential increase in clozapine concentrations have not been fully characterized but may involve reduced cytochrome P450 1A2 activity.

12.1 Mechanism of Action The mechanism of action of clozapine is unknown. However, it has been proposed that the therapeutic efficacy of clozapine in schizophrenia is mediated through antagonism of the dopamine type 2 (D 2 ) and the serotonin type 2A (5-HT 2A ) receptors. VERSACLOZ also acts as an antagonist at adrenergic, cholinergic, histaminergic and other dopaminergic and serotonergic receptors.

12.2 Pharmacodynamics Clozapine demonstrated binding affinity to the following receptors: histamine H 1 (K i 1.1 nM), adrenergic α 1A (K i 1.6 nM), serotonin 5-HT 6 (K i 4 nM ) , serotonin 5-HT 2A (K i 5.4 nM), muscarinic M 1 (K i 6.2 nM), serotonin 5-HT 7 (K i 6.3 nM), serotonin 5-HT 2C (K i 9.4 nM), dopamine D 4 (K i 24 nM), adrenergic α 2A (K i 90 nM), serotonin 5-HT 3 (K i 95 nM), serotonin 5-HT 1A (K i 120 nM), dopamine D 2 (K i 160 nM), dopamine D 1 (K i 270 nM), dopamine D 5 (K i 454 nM), and dopamine D 3 (K i 555 nM). Clozapine causes little or no prolactin elevation. Clinical electroencephalogram (EEG) studies demonstrated that clozapine increases delta and theta activity and slows dominant alpha frequencies. Enhanced synchronization occurs. Sharp wave activity and spike and wave complexes may also develop. Patients have reported an intensification of dream activity during clozapine therapy. REM sleep was found to be increased to 85% of the total sleep time. In these patients, the onset of REM sleep occurred almost immediately after falling asleep.

12.3 Pharmacokinetics Absorption In man, clozapine tablets (25 mg and 100 mg) are equally bioavailable relative to a clozapine solution. VERSACLOZ Oral Suspension is bioequivalent to clozapine marketed tablets. Following oral administration of 100 mg to 800 mg VERSACLOZ, once daily, the average steady-state peak plasma concentration was 275 ng/mL (range: 105 - 723 ng/mL), occurring at the average of 2.2 hours (range: 1 - 3.5 hours) after dosing. The average minimum concentration at steady-state was 75 ng/mL (range: 11 - 198 ng/mL). When VERSACLOZ was administered after a high fat meal there was no effect on the AUC ss or C min, ss , however C max was reduced about 20%, and there was a slight delay in T max of 0.5 hour from a median T max of 2.0 hours under fasted conditions to 2.5 hours under fed conditions. The decrease in C max is not considered clinically relevant. Therefore VERSACLOZ may be taken without regard to meals. Distribution Clozapine is approximately 97% bound to serum proteins. The interaction between clozapine and other highly protein-bound drugs has not been fully evaluated but may be important [see Drug Interactions (7) ]. Metabolism and Excretion VERSACLOZ is almost completely metabolized prior to excretion, and only trace amounts of unchanged drug are detected in the urine and feces. VERSACLOZ is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP2D6, and CYP3A4. Approximately 50% of the administered dose is excreted in the urine and 30% in the feces. The demethylated, hydroxylated, and N -oxide derivatives are components in both urine and feces. Pharmacological testing has shown the desmethyl metabolite (norclozapine) to have only limited activity, while the hydroxylated and N -oxide derivatives were inactive. The mean elimination half-life of clozapine after a single 75 mg dose was 8 hours (range: 4-12 hours), compared to a mean elimination half-life of 12 hours (range: 4-66 hours), after achieving steady-state with 100 mg twice daily dosing. A comparison of single-dose and multiple-dose administration of clozapine demonstrated that the elimination half-life increased significantly after multiple dosing relative to that after single-dose administration, suggesting the possibility of concentration-dependent pharmacokinetics. However, at steady-state, approximately dose-proportional changes with respect to AUC (area under the curve), peak, and minimum clozapine plasma concentrations were observed after administration of 37.5, 75, and 150 mg twice daily. Drug-Drug Interaction Studies Fluvoxamine A pharmacokinetic study was conducted in 16 patients with schizophrenia who received clozapine under steady-state conditions. After coadministration of fluvoxamine for 14 days, mean trough concentrations of clozapine and its metabolites, N -desmethylclozapine and clozapine N -oxide, were elevated about three-fold compared to baseline steady-state concentrations. Paroxetine, Fluoxetine, and Sertraline In a study of patients with schizophrenia (n=14) who received clozapine under steady-state conditions, coadministration of paroxetine produced only minor changes in the levels of clozapine and its metabolites. However, other published reports describe modest elevations (less than two-fold) of clozapine and metabolite concentrations when clozapine was taken with paroxetine, fluoxetine, and sertraline.

y-state conditions, coadministration of paroxetine produced only minor changes in the levels of clozapine and its metabolites. However, other published reports describe modest elevations (less than two-fold) of clozapine and metabolite concentrations when clozapine was taken with paroxetine, fluoxetine, and sertraline. Specific Populations Renal or Hepatic Impairment No specific pharmacokinetic studies were conducted to investigate the effects of renal or hepatic impairment on the pharmacokinetics of clozapine. Higher clozapine plasma concentrations are likely in patients with significant renal or hepatic impairment when given usual doses. CYP2D6 Poor Metabolizers A subset (3%–10%) of the population has reduced activity of CYP2D6 (CYP2D6 poor metabolizers). These individuals may develop higher than expected plasma concentrations of clozapine when given usual doses. Patients with Pneumonia and other Inflammatory Conditions Published case reports describe examples where pneumonia or other inflammatory- conditions may increase clozapine concentrations. The clinical significance, the impact of treatments to modulate this inflammation, and mechanism of this potential increase in clozapine concentrations have not been fully characterized but may involve reduced cytochrome P450 1A2 activity.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No carcinogenic potential was demonstrated in long-term studies in mice and rats at doses up to 0.3 times and 0.4 times, respectively, the maximum recommended human dose (MRHD) of 900 mg/day on a mg/m 2 body surface area basis. Mutagenesis Clozapine was not genotoxic when tested in the following gene mutation and chromosomal aberration tests: the bacterial Ames test, the in vitro mammalian V79 in Chinese hamster cells, the in vitro unscheduled DNA synthesis in rat hepatocytes, or the in vivo micronucleus assay in mice. Impairment of Fertility Clozapine had no effect on any parameters of fertility, pregnancy, fetal weight, or postnatal development when administered orally to male rats 70 days before mating and to female rats for 14 days before mating at doses up to 0.4 times the MRHD of 900 mg/day on a mg/m 2 body surface area basis.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No carcinogenic potential was demonstrated in long-term studies in mice and rats at doses up to 0.3 times and 0.4 times, respectively, the maximum recommended human dose (MRHD) of 900 mg/day on a mg/m 2 body surface area basis. Mutagenesis Clozapine was not genotoxic when tested in the following gene mutation and chromosomal aberration tests: the bacterial Ames test, the in vitro mammalian V79 in Chinese hamster cells, the in vitro unscheduled DNA synthesis in rat hepatocytes, or the in vivo micronucleus assay in mice. Impairment of Fertility Clozapine had no effect on any parameters of fertility, pregnancy, fetal weight, or postnatal development when administered orally to male rats 70 days before mating and to female rats for 14 days before mating at doses up to 0.4 times the MRHD of 900 mg/day on a mg/m 2 body surface area basis.

14 CLINICAL STUDIES 14.1 Treatment-Resistant Schizophrenia The efficacy of clozapine in treatment-resistant schizophrenia was established in a multicenter, randomized, double-blind, active-controlled (chlorpromazine) study in patients with a DSM-III diagnosis of schizophrenia who had inadequate responses to at least 3 different antipsychotics (from at least 2 different chemical classes) during the preceding 5 years. The antipsychotic trials must have been judged adequate; the antipsychotic dosages must have been equivalent to or greater than 1000 mg per day of chlorpromazine for a period of at least 6 weeks, each without significant reduction of symptoms. There must have been no period of good functioning within the preceding 5 years. Patients must have had a baseline score of at least 45 on the investigator-rated Brief Psychiatric Rating Scale (BPRS). On the 18-item BPRS, 1 indicates the absence of symptoms, and 7 indicates severe symptoms; the maximum potential total BPRS score is 126. At baseline, the mean BPRS score was 61. In addition, patients must have had a score of at least 4 on at least two of the following four individual BPRS items: conceptual disorganization, suspiciousness, hallucinatory behavior, and unusual thought content. Patients must have had a Clinical Global Impressions – Severity Scale score of at least 4 (moderately ill). In the prospective, lead-in phase of the trial, all patients (N=305) initially received single-blind treatment with haloperidol (the mean dose was 61 mg per day) for 6 weeks. More than 80% of patients completed the 6-week trial. Patients with an inadequate response to haloperidol (n=268) were randomized to double-blind treatment with clozapine (N=126) or chlorpromazine (N=142). The maximum daily clozapine dose was 900 mg; the mean daily dose was >600 mg). The maximum daily chlorpromazine dose was 1800 mg; the mean daily dose was >1200 mg. The primary endpoint was treatment response, predefined as a decrease in BPRS score of at least 20% and either (1) a CGI-S score of < 3 (mildly ill), or (2) a BPRS score of < 35, at the end of 6 weeks of treatment. Approximately 88% of patients from the clozapine and chlorpromazine groups completed the 6-week trial. At the end of six weeks, 30% of the clozapine group responded to treatment, and 4% of the chlorpromazine group responded to treatment. The difference was statistically significant (p<0.001). The mean change in total BPRS score was -16 and -5 in the clozapine and chlorpromazine group, respectively; the mean change in the 4 key BPRS item scores was -5 and -2 in the clozapine and chlorpromazine group, respectively; and the mean change in CGI-S score was -1.2 and -0.4, in the clozapine and chlorpromazine group, respectively. These changes in the clozapine group were statistically significantly greater than in the chlorpromazine group (p<0.001 in each analysis). 14.2 Recurrent Suicidal Behavior in Schizophrenia or Schizoaffective Disorder he effectiveness of clozapine in reducing the risk of recurrent suicidal behavior was assessed in the International Suicide Prevention Trial (InterSePT™, a trademark of Novartis Pharmaceuticals Corporation).

group (p<0.001 in each analysis). 14.2 Recurrent Suicidal Behavior in Schizophrenia or Schizoaffective Disorder he effectiveness of clozapine in reducing the risk of recurrent suicidal behavior was assessed in the International Suicide Prevention Trial (InterSePT™, a trademark of Novartis Pharmaceuticals Corporation). This was a prospective, randomized, open-label, active-controlled, multicenter, international, parallel-group comparison of clozapine (Clozaril ® ) versus olanzapine (Zyprexa ® , a registered trademark of Eli Lilly and Company) in 956 patients with schizophrenia or schizoaffective disorder (DSM-IV) who were judged to be at risk for recurrent suicidal behavior. Only about one-fourth of these patients (27%) were considered resistant to standard antipsychotic drug treatment. To enter the trial, patients must have met one of the following criteria: They had attempted suicide within the three years prior to their baseline evaluation. They had been hospitalized to prevent a suicide attempt within the three years prior to their baseline evaluation. They demonstrated moderate-to-severe suicidal ideation with a depressive component within one week prior to their baseline evaluation. They demonstrated moderate-to-severe suicidal ideation accompanied by command hallucinations to do self-harm within one week prior to their baseline evaluation. Dosing regimens for each treatment group were determined by individual investigators and were individualized by patient. Dosing was flexible, with a dose range of 200–900 mg/day for clozapine and 5–20 mg/day for olanzapine. For the 956 patients who received clozapine or olanzapine in this study, there was extensive use of concomitant psychotropics: 84% with antipsychotics, 65% with anxiolytics, 53% with antidepressants, and 28% with mood stabilizers. There was significantly greater use of concomitant psychotropic medications among the patients in the olanzapine group. The primary efficacy measure was time to (1) a significant suicide attempt, including a completed suicide; (2) hospitalization due to imminent suicide risk, including increased level of surveillance for suicidality for patients already hospitalized; or (3) worsening of suicidality severity as demonstrated by “much worsening” or “very much worsening” from baseline in the Clinical Global Impression of Severity of Suicidality as assessed by the Blinded Psychiatrist (CGI-SS-BP) scale. A determination of whether or not a reported event met criterion 1 or 2 above was made by the Suicide Monitoring Board (SMB), a group of experts blinded to patient data. A total of 980 patients were randomized to the study and 956 received study medication. Sixty-two percent of the patients were diagnosed with schizophrenia, and the remainder (38%) were diagnosed with schizoaffective disorder. Only about one-fourth of the total patient population (27%) was identified as “treatment-resistant” at baseline. There were more males than females in the study (61% of all patients were male). The mean age of patients entering the study was 37 years of age (range: 18–69). Most patients were Caucasian (71%), 15% were Black, 1% were Asian, and 13% were classified as being of “other” races. Patients treated with clozapine had a statistically significant longer delay in the time to recurrent suicidal behavior in comparison with olanzapine. This result should be interpreted only as evidence of the effectiveness of clozapine in delaying time to recurrent suicidal behavior and not a demonstration of the superior efficacy of clozapine over olanzapine.

istically significant longer delay in the time to recurrent suicidal behavior in comparison with olanzapine. This result should be interpreted only as evidence of the effectiveness of clozapine in delaying time to recurrent suicidal behavior and not a demonstration of the superior efficacy of clozapine over olanzapine. The probability of experiencing (1) a significant suicide attempt, including a completed suicide, or (2) hospitalization because of imminent suicide risk, including increased level of surveillance for suicidality for patients already hospitalized, was lower for clozapine patients than for olanzapine patients at Week 104: clozapine 24% versus olanzapine 32%; 95% CI of the difference: 2%, 14% (Figure 1). Figure 1. Cumulative Probability of a Significant Suicide Attempt or Hospitalization to Prevent Suicide in Patients with Schizophrenia or Schizoaffective Disorder at High Risk of Suicidality figure-02 cumulative

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Oral Suspension Free-flowing, yellow suspension (50 mg/mL) in amber bottle containing 100 mL. Each box contains 1 x 1 mL oral syringe, 1 x 9 mL oral syringe and 1 bottle adaptor. NDC No. 52817-601-38 16.2 Storage and Handling Store VERSACLOZ at room temperature between 20°C to 25°C (68°F to 77°F); excursion permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Do not refrigerate or freeze. Protect from light. Shake well for 10 seconds before use. The suspension is stable for 100 days after initial bottle opening. Keep out of reach of children

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). • Severe Neutropenia: Instruct patients (and caregivers) [see Warnings and Precautions (5.1)]: - About the risk of developing severe neutropenia and infection with VERSACLOZ treatment. - To immediately report to their health care provider any symptom or sign of infection during VERSACLOZ treatment. - About the importance of having frequent ANC testing. • Orthostatic Hypotension, Bradycardia, and Syncope: Inform patients and caregivers about the risk of orthostatic hypotension and syncope, especially during the period of initial dose titration. Instruct them to strictly follow the clinician’s instructions for dosage and administration [see Dosage and Administration (2.2., 2.7)]. Advise patients to consult their clinician immediately if they feel faint, lose consciousness or have signs or symptoms suggestive of bradycardia or arrhythmia [see Warnings and Precautions (5.2)]. • Falls: Inform patients of the risk of falls, which may lead to fractures or other injuries [see Warnings and Precautions (5.3)]. • Seizures: Inform patients and caregivers about the significant risk of seizure during VERSACLOZ treatment. Caution them about driving and any other potentially hazardous activity while taking VERSACLOZ [see Warnings and Precautions (5.4)]. • Gastrointestinal Hypomotility with Severe Complications: Educate patients and caregivers on the risks, prevention, and treatment of clozapine-induced constipation, including medications to avoid when possible (e.g., drugs with anticholinergic activity). Encourage appropriate hydration, physical activity, and fiber intake and emphasize that prompt attention and treatment to the development of constipation or other gastrointestinal symptoms is critical in preventing severe complications. Advise patients and caregivers to contact their health care provider if they experience symptoms of constipation (e.g., difficulty passing stools, incomplete passage of stool, decreased bowel movement frequency) or other symptoms associated with gastrointestinal hypomotility (e.g., nausea, abdominal distension or pain, vomiting) [see Warnings and Precautions (5.7), Drug Interactions (7.1)]. • QT Interval Prolongation: Advise patients to consult their clinician immediately if they feel faint, lose consciousness, or have signs or symptoms suggestive of arrhythmia. Instruct patients to not take VERSACLOZ with other drugs that cause QT interval prolongation. Instruct patients to inform their clinicians that they are taking VERSACLOZ before any new drug [see Warnings and Precautions (5.9) and Drug Interactions (7.1)]. • Metabolic Changes (hyperglycemia and diabetes mellitus, dyslipidemia, weight gain): Educate patients and caregivers about the risk of metabolic changes and the need for specific monitoring. The risks include hyperglycemia and diabetes mellitus, dyslipidemia, weight gain, and cardiovascular reactions. Educate patients and caregivers about the symptoms of hyperglycemia (high blood sugar) and diabetes mellitus (e.g., polydipsia, polyuria, polyphagia, and weakness). Monitor all patients for these symptoms. Patients who are diagnosed with diabetes or have risk factors for diabetes (obesity, family history of diabetes) should have their fasting blood glucose monitored before beginning treatment and periodically during treatment.

e.g., polydipsia, polyuria, polyphagia, and weakness). Monitor all patients for these symptoms. Patients who are diagnosed with diabetes or have risk factors for diabetes (obesity, family history of diabetes) should have their fasting blood glucose monitored before beginning treatment and periodically during treatment. Patients who develop symptoms of hyperglycemia should have assessments of fasting glucose. Clinical monitoring of weight is recommended [see Warnings and Precautions (5.10)]. • Interference with Cognitive and Motor Performance: Because VERSACLOZ may have the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that VERSACLOZ therapy does not affect them adversely [see Warnings and Precautions (5.16)]. • Hepatotoxicity: Instruct patients to immediately report to their physician any symptoms or signs of potential liver injury (e.g. fatigue, malaise, anorexia, nausea, jaundice, bilirubinemia, coagulopathy, and hepatic encephalopathy). [see Warnings and Precautions (5.12)]. • Missed Doses and Re-Initiating Treatment: Inform patients and caregivers that if the patient misses taking VERSACLOZ for 1 day or more, they should not restart their medication at the same dosage but should contact their physician for dosing instructions [see Dosage and Administration (2.7) and Warnings and Precautions (5.1, 5.2)]. • Pregnancy: Advise pregnant women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with VERSACLOZ. Advise patients that VERSACLOZ may cause extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) in a neonate. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to VERSACLOZ during pregnancy [see Use in Specific Populations (8.1)]. • Lactation: Advise breastfeeding women using VERSACLOZ to monitor infants for excess sedation and to seek medical care if they notice this sign. Inform breastfeeding women using VERSACLOZ that their healthcare provider will monitor infants for neutropenia [see Use in Specific Populations (8.2)]. • Concomitant Medication: Advise patients to inform their healthcare provider if they are taking, or plan to take, any prescription or over-the-counter drugs; there is a potential for significant drug-drug interactions [see Dosage and Administration (2.8), Drug Interactions (7.1)]. • Patient Instructions for Use: Educate the patient and caregiver about the Patient Instructions for Use if VERSACLOZ will be administered at home. Discuss the specific steps for administering the prescribed dose using the oral syringe. [see Dosage and Administration (2.3)]. Distributed by: TruPharma, LLC Tampa, FL 33609 U.S. Patent No. 8057811 VERSACLOZ is a registered trademark of Douglas Pharmaceuticals Limited in New Zealand and other countries. 311653 Revised: June 2025

Patient Information MEDICATION GUIDE VERSACLOZ (VER sa kloz) (clozapine) oral suspension What is the most important information I should know about VERSACLOZ? VERSACLOZ can cause serious side effects, including: Severe neutropenia (low white blood cell (WBC) counts) that can lead to serious infections and death. Your healthcare provider will do WBC blood tests before starting treatment with VERSACLOZ and weekly for the first 6 months. After your first 6 months of treatment, your healthcare provider will determine how frequent you will have blood tests. If you have symptoms of severe neutropenia or an infection, your healthcare provider will do more frequent WBC blood test(s) to check if VERSACLOZ is causing your symptoms and may send you to see a blood specialist (hematologist). Tell your health care provider right away if you have any of the following symptoms or signs of neutropenia or infection: feel like you have the flu wounds that take a long time heal fever or chills skin, throat, vaginal, urinary tract, or lung infection feel extremely tired or weak pain or burning while peeing sores or ulcers inside your mouth, gums, or on your skin unusual vaginal discharge or itching sores or pain in or around your rectal area abdominal pain or bloating Orthostatic hypotension (decreased blood pressure), bradycardia (slow heart rate), or syncope (fainting) that can lead to death. You feel lightheaded or faint when you rise too quickly from a sitting or lying position. Tell your healthcare provider right away if you feel dizzy or pass out. Seizures. See “What should I avoid while taking VERSACLOZ? ” Myocarditis (heart muscle inflammation), pericarditis (inflammation of outer layer of the heart) and cardiomyopathy (heart muscle weakness) that can lead to death. Symptoms of myocarditis, pericarditis, and cardiomyopathy include: chest pain flu-like symptoms fast heartbeat or palpitations feel tired or faint shortness of breath swollen legs, ankles, or fee fever Increased risk of death in elderly people with dementia-related psychosis. Medicines likeVERSACLOZ can increase the risk of death in elderly people who have lost touch with reality (psychosis) due to confusion and dementia. VERSACLOZ is not for treatment of elderly people with dementia-related psychosis. What is VERSACLOZ? VERSACLOZ is a prescription antipsychotic medicine used to treat people: Who are severely ill with schizophrenia not helped by other schizophrenia medicines With schizophrenia or schizoaffective disorder who have been suicidal and may be at risk of suicidal behavior again It is not known if VERSACLOZ is safe and effective in children. Who should not take VERSACLOZ? Do not take VERSACLOZ if you: are allergic to clozapine or any of the ingredients in VERSACLOZ. See the end of this Medication Guide for a complete list of ingredients in VERSACLOZ.

d may be at risk of suicidal behavior again It is not known if VERSACLOZ is safe and effective in children. Who should not take VERSACLOZ? Do not take VERSACLOZ if you: are allergic to clozapine or any of the ingredients in VERSACLOZ. See the end of this Medication Guide for a complete list of ingredients in VERSACLOZ. Before taking VERSACLOZ, tell your healthcare provider about all your medical conditions, including if you : have or have had heart problems or a family history of heart problems including heart attack, heart failure, abnormal heart rhythm or long QT syndrome, or stroke have or have had low or high blood pressure have or have had kidney or liver problems have or have had seizures (convulsions) have or have had stomach or intestinal problems including constipation, slow emptying of your stomach, or diarrhea have or have had low levels of potassium or magnesium in your blood have or have had diabetes or high blood sugar in you or your family have or have had high levels of total cholesterol, “bad” cholesterol (LDL-C), or triglycerides, or low levels of “good” cholesterol (HDL-C) have increased pressure in your eyes (glaucoma), an enlarged prostate, or problems passing urine have or have had uncontrolled movements of your tongue, face, mouth, or jaw (tardive dyskinesia) smoke tobacco plan to stop smoking tobacco while taking VERSACLOZ use products containing caffeine are pregnant or plan to become pregnant. Talk to your healthcare provider if you become pregnant while taking VERSACLOZ. If you become pregnant while receiving VERSACLOZ, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or go to http://womensmentalhealth.org/clinical-and-research- programs/pregnancyregistry/ are breast feeding or plan to breast feed. VERSACLOZ can pass into your breast milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take VERSACLOZ. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. VERSACLOZ and other medicines may affect each other causing side effects. Your healthcare provider can tell you if it is safe to take VERSACLOZ with your other medicines. Do not start or stop any medicines while taking VERSACLOZ without talking to your healthcare provider first. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I take VERSACLOZ? Take VERSACLOZ exactly as your healthcare provider tells you to take it. Do not change your dose or stop taking VERSACLOZ unless your healthcare provider tells you to. Talk to your healthcare provider or pharmacist if you are not sure how to take VERSACLOZ. Take VERSACLOZ with or without food. If your healthcare provider decides that you can take VERSACLOZ at home, you should receive training on the correct way to take VERSACLOZ. Do not try to take VERSACLOZ yourself until you have been shown how to take VERSACLOZ. See the detailed Instructions for Use at the end of this Medication Guide for information on how to take VERSACLOZ. If you miss taking VERSACLOZ for 1 day or more, call your healthcare provider right away. Do not take 2 doses at the same time unless your healthcare provider tells you to. If you take too much (overdose) VERSACLOZ, call your healthcare provider or the Poison Help line at 1-800-222-1222 or go to the nearest hospital emergency room right away.

CLOZ for 1 day or more, call your healthcare provider right away. Do not take 2 doses at the same time unless your healthcare provider tells you to. If you take too much (overdose) VERSACLOZ, call your healthcare provider or the Poison Help line at 1-800-222-1222 or go to the nearest hospital emergency room right away. Symptoms of VERSACLOZ overdose can include: feeling sleepy fast or irregular heartbeat having a lot of saliva in your mouth confusion low blood pressure seizures coma shallow or difficult breathing What should I avoid while taking VERSACLOZ? You should not drink alcohol while taking VERSACLOZ because it can increase your chances of getting serious side effects. Do not drive, operate machinery, swim, climb, or do dangerous activities until you know how VERSACLOZ affects you. What are the possible side effects of VERSACLOZ? VERSACLOZ may cause serious side effects, including: See "What is the most important information I should know about VERSACLOZ?" falls. VERSACLOZ may make you sleepy, dizzy, may cause a decrease in your blood pressure when changing positions, and can slow your thinking and motor skills which may lead to falls that can cause fractures or other injuries. slow emptying of your stomach and intestines (decreased gastric motility). Severe constipation and bowel problems can happen and can lead to hospitalization, surgery, and death. You may not feel or be aware of constipation symptoms. Your healthcare provider will examine you for possible bowel problems. Tell your healthcare provider if you get any signs and symptoms of decreased gastrointestinal motility during treatment during treatment with VERSACLOZ, including: having bowel movements less than normal stomach bloating or pain hard or dry stools nausea or vomiting difficulty in passing gas Staying well hydrated, increasing physical activity, and taking fiber during treatment with VERSACLOZ can help prevent constipation and other bowel problems. Your healthcare provider may prescribe medicines to prevent severe problems. high count of a certain white blood cell (eosinophilia). VERSACLOZ can cause a high count of eosinophils in some people and can be serious. This is a different risk than the risk of VERSACLOZ causing an abnormally low white blood cell count (neutropenia). Your health care provider may send you to see an internal medicine specialist (internist) or blood specialist (hematologist). Tell your healthcare provider right away if you have any of these symptoms: feeling very tired or weak coughing and wheezing fever nausea, vomiting, or diarrhea rash night sweats swelling confusion joint pain difficulty swallowing serious heart rhythm problems (QTc Interval Prolongation) that can cause death. Your healthcare provider will do a physical exam and may obtain blood tests and an electrocardiogram before starting you on treatment with VERSACLOZ. Tell your healthcare provider right away if you have any of these symptoms: passing out or feeling like you will pass out dizziness feeling as if your heart is pounding or missing beats problems with your metabolism such as: high blood sugar (hyperglycemia) or diabetes . Increases in blood sugar can happen in some people who take VERSACLOZ. Extremely high blood sugar can lead to coma and death. If you have diabetes or risk factors for diabetes (such as being overweight), your health care provider should check your blood sugar before you start VERSACLOZ and during treatment. Tell your healthcare provider if you have any of these symptoms of high blood sugar while taking VERSACLOZ: feel very thirsty feel very hungry feel sick to your stomach need to urinate more than usual feel weak or tired feel confused, or your breath smells fruity increased fat levels (cholesterol and triglycerides) in your blood (dyslipidemia).

der if you have any of these symptoms of high blood sugar while taking VERSACLOZ: feel very thirsty feel very hungry feel sick to your stomach need to urinate more than usual feel weak or tired feel confused, or your breath smells fruity increased fat levels (cholesterol and triglycerides) in your blood (dyslipidemia). Your healthcare provider should check the fat levels in your blood before you start and during treatment with VERSACLOZ. weight gain. You and your healthcare provider should check your weight regularly. neuroleptic malignant syndrome (NMS). NMS is a rare but serious condition that can lead to death and must be treated in a hospital. Tell your healthcare provider right away if you become severely ill and have any of these symptoms: high fever confusion increased sweating stiff muscles changes in breathing, heartbeat, and blood pressure liver problems. VERSACLOZ can cause serious life-threatening liver problems that can lead to death. Tell your healthcare provider right away if you have any of these symptoms: feeling tired nausea and vomiting pain on the right side of your stomach (abdomen) loss of appetite yellowing of your skin or whites of your eyes elevated bilirubin levels fever. Some people may have a fever while they take VERSACLOZ. If you have a fever, your healthcare provider will do blood tests to check for neutropenia or an infection. Your healthcare provider may also send you to see a blood specialist (hematologist). Tell your healthcare provider if you have a fever. blood clot in your lung (pulmonary embolism) or in the veins of your legs (deep vein thrombosis). Get emergency help right away if you have symptoms of a blood clot including: chest pain and shortness of breath swelling or pain in your leg, ankle or foot warm feeling in the skin of your affected leg changes in your skin color such as turning pale or blue a problem that includes dry mouth, increased sweating, increased pulse rate, constipation, and urinary retention (anticholinergic toxicity). problems thinking clearly and moving your body. See “What should I avoid while taking VERSACLOZ?” uncontrolled movements of your tongue, face, mouth, or jaw (tardive dyskinesia ) . Tardive dyskinesia may not go away, even if you stop VERSACLOZ. Tardive dyskinesia may also start after you stop taking VERSACLOZ. stroke (cerebrovascular problems) in elderly people with dementia-related psychosis that can lead to death. The most common side effects of VERSACLOZ include: sleepiness or drowsiness headache dizziness shaking movements (tremors) heart and blood vessel problems low blood pressure fast heartbeat having a lot of saliva in your mouth passing out (syncope) dry mouth increased sweating constipation and nausea vision problems fever These are not all the possible side effects of VERSACLOZ. Your healthcare provider may lower your dose or temporarily or permanently stop treatment with VERSACLOZ if you have certain symptoms or if your WBC count is low. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. You may report side effects to FDA at 1-800-FDA-1088. How should I store VERSACLOZ? Store VERSACLOZ at room temperature between 68°F to 77°F (20°C to 25°C). Do not refrigerate VERSACLOZ. Do not freeze VERSACLOZ. Keep the VERSACLOZ bottle in the carton to protect it from light. Throw away (discard) any unused VERSACLOZ oral suspension remaining after 100 days of first opening the bottle. Keep VERSACLOZ and all medicines out of the reach of children. General information about the safe and effective use of VERSACLOZ Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use VERSACLOZ for a condition for which it was not prescribed.

first opening the bottle. Keep VERSACLOZ and all medicines out of the reach of children. General information about the safe and effective use of VERSACLOZ Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use VERSACLOZ for a condition for which it was not prescribed. Do not give VERSACLOZ to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider (including pharmacist) for information about VERSACLOZ that is written for healthcare professionals. What are the ingredients in VERSACLOZ? Active ingredient: clozapine Inactive ingredients: glycerin, sorbitol (crystallizing), sodium dihydrogen phosphate dihydrate, xanthan gum, sodium methylparaben, sodium propylparaben, povidone, water, and sodium hydroxide Distributed by: TruPharma, LLC Tampa, FL 33609 For optional information, go to www.VERSACLOZ.com or call 1-800-520-5538. This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued: June 2025 Instructions for Use VERSACLOZ ® (VER sa kloz) (clozapine) oral suspension Supplies you will need to take your VERSACLOZ dose: VERSACLOZ ® oral Suspension bottle a bottle neck adaptor the correct oral syringe to measure your dose ο If your dose is 1 mL (50 mg) or less , use the smaller 1 mL oral syringe. ο If your dose is more than 1 mL (50 mg), use the larger 9 mL oral syringe. Disposal of your or al syringe, empty VER SACLOZ bottle and bottle neck adaptor: Place the cap back on the empty VERSACLOZ bottle before you throw it away. The oral syringe, empty bottle and bottle neck adaptor should be placed in your household trash when you finish your bottle of VERSACLOZ. The oral syringe should not be shared with other people or used for medicines other than VERSACLOZ. Distributed by: TruPharma, LLC Tampa, FL 33609 This Patient Information and the Instructions for Use have been approved by the U.S. Food and Drug Administration. 311653 Revised: June 2025 patient-use-instruction figure-a-step-1 figure-b-step-2 figure-c-step-3 step-4 figure-d figure-e-step-5 figure-f-step-6 figure-g-step-7 figure-h-step-8 figure-i-step-9 figure-j-step-10 figure-k-step-11 figure-l-step-12 figure-m-step-13 figure-n-step-14

<table width="576px" cellspacing="0" cellpadding="0"><tbody><tr><td valign="top"><list listType="unordered"><item> feel like you have the flu</item></list></td><td valign="top"><list listType="unordered"><item> wounds that take a long time heal</item></list></td></tr><tr><td valign="top"><list listType="unordered"><item> fever or chills</item></list></td><td valign="top"><list listType="unordered"><item> skin, throat, vaginal, urinary tract, or lung infection</item></list></td></tr><tr><td valign="top"><list listType="unordered"><item> feel extremely tired or weak</item></list></td><td valign="top"><list listType="unordered"><item> pain or burning while peeing</item></list></td></tr><tr><td valign="top"><list listType="unordered"><item> sores or ulcers inside your mouth, gums, or on your skin</item></list></td><td valign="top"><list listType="unordered"><item> unusual vaginal discharge or itching</item></list></td></tr><tr><td valign="top"><list listType="unordered"><item> sores or pain in or around your rectal area</item></list></td><td valign="top"><list listType="unordered"><item> abdominal pain or bloating</item></list></td></tr></tbody></table> <table cellspacing="0" cellpadding="0"><tbody><tr><td valign="top"><list listType="unordered"><item>chest pain</item></list></td><td valign="top"><list listType="unordered"><item> flu-like symptoms</item></list></td></tr><tr><td valign="top"><list listType="unordered"><item> fast heartbeat or palpitations </item></list></td><td valign="top"><list listType="unordered"><item> feel tired or faint</item></list></td></tr><tr><td valign="top"><list listType="unordered"><item> shortness of breath</item></list></td><td valign="top"><list listType="unordered"><item> swollen legs, ankles, or fee</item></list></td></tr><tr><td valign="top"><list listType="unordered"><item> fever</item></list></td><td valign="top"/></tr></tbody></table>

></tr><tr><td valign="top"><list listType="unordered"><item> shortness of breath</item></list></td><td valign="top"><list listType="unordered"><item> swollen legs, ankles, or fee</item></list></td></tr><tr><td valign="top"><list listType="unordered"><item> fever</item></list></td><td valign="top"/></tr></tbody></table> <table width="605px" cellspacing="0" cellpadding="0"><tbody><tr><td valign="top"><list listType="unordered"><item>feeling sleepy</item></list></td><td valign="top"><list listType="unordered"><item> fast or irregular heartbeat</item></list></td><td valign="top"><list listType="unordered"><item> having a lot of saliva in your mouth</item></list></td></tr><tr><td valign="top"><list listType="unordered"><item> confusion</item></list></td><td valign="top"><list listType="unordered"><item> low blood pressure</item></list></td><td valign="top"><list listType="unordered"><item> seizures</item></list></td></tr><tr><td valign="top"><list listType="unordered"><item> coma</item></list></td><td valign="top"><list listType="unordered"><item> shallow or difficult breathing</item></list></td><td valign="top"/></tr></tbody></table> <table width="614px" cellspacing="0" cellpadding="0"><tbody><tr><td valign="top"><list listType="unordered"><item>having bowel movements less than normal</item></list></td><td valign="top"><list listType="unordered"><item> stomach bloating or pain</item></list></td></tr><tr><td valign="top"><list listType="unordered"><item> hard or dry stools</item></list></td><td valign="top"><list listType="unordered"><item> nausea or vomiting</item></list></td></tr><tr><td valign="top"><list listType="unordered"><item> difficulty in passing gas</item></list></td><td valign="top"/></tr></tbody></table>

><td valign="top"><list listType="unordered"><item> hard or dry stools</item></list></td><td valign="top"><list listType="unordered"><item> nausea or vomiting</item></list></td></tr><tr><td valign="top"><list listType="unordered"><item> difficulty in passing gas</item></list></td><td valign="top"/></tr></tbody></table> <table width="520px" cellspacing="0" cellpadding="0"><tbody><tr><td valign="top"><list listType="unordered"><item>feeling very tired or weak</item></list></td><td valign="top"><list listType="unordered"><item>coughing and wheezing</item></list></td></tr><tr><td valign="top"><list listType="unordered"><item>fever</item></list></td><td valign="top"><list listType="unordered"><item>nausea, vomiting, or diarrhea</item></list></td></tr><tr><td valign="top"><list listType="unordered"><item>rash</item></list></td><td valign="top"><list listType="unordered"><item>night sweats</item></list></td></tr><tr><td valign="top"><list listType="unordered"><item>swelling </item></list></td><td valign="top"><list listType="unordered"><item>confusion</item></list></td></tr><tr><td valign="top"><list listType="unordered"><item>joint pain</item></list></td><td valign="top"><list listType="unordered"><item>difficulty swallowing</item></list></td></tr></tbody></table> <table width="539px" cellspacing="0" cellpadding="0"><tbody><tr><td valign="top"><list listType="unordered"><item>feel very thirsty</item></list></td><td valign="top"><list listType="unordered"><item> feel very hungry</item></list></td><td valign="top"><list listType="unordered"><item> feel sick to your stomach</item></list></td></tr><tr><td valign="top"><list listType="unordered"><item> need to urinate more than usual</item></list></td><td valign="top"><list listType="unordered"><item> feel weak or tired</item></list></td><td valign="top"><list listType="unordered"><item> feel confused, or your breath smells fruity</item></list></td></tr></tbody></table>

valign="top"><list listType="unordered"><item> need to urinate more than usual</item></list></td><td valign="top"><list listType="unordered"><item> feel weak or tired</item></list></td><td valign="top"><list listType="unordered"><item> feel confused, or your breath smells fruity</item></list></td></tr></tbody></table> <table width="583px" cellspacing="0" cellpadding="0"><tbody><tr><td valign="top"><list listType="unordered"><item> high fever</item></list></td><td valign="top"><list listType="unordered"><item> confusion</item></list></td><td valign="top"><list listType="unordered"><item> increased sweating</item></list></td></tr><tr><td valign="top"><list listType="unordered"><item> stiff muscles</item></list></td><td valign="top"><list listType="unordered"><item> changes in breathing, heartbeat, and blood pressure</item></list></td><td valign="top"/></tr></tbody></table> <table width="576px" cellspacing="0" cellpadding="0"><tbody><tr><td valign="top"><list listType="unordered"><item>feeling tired</item></list></td><td valign="top"><list listType="unordered"><item> nausea and vomiting</item></list></td><td valign="top"><list listType="unordered"><item> pain on the right side of your stomach (abdomen)</item></list></td></tr><tr><td valign="top"><list listType="unordered"><item> loss of appetite</item></list></td><td valign="top"><list listType="unordered"><item> yellowing of your skin or whites of your eyes</item></list></td><td valign="top"><list listType="unordered"><item> elevated bilirubin levels</item></list></td></tr></tbody></table>

tr><td valign="top"><list listType="unordered"><item> loss of appetite</item></list></td><td valign="top"><list listType="unordered"><item> yellowing of your skin or whites of your eyes</item></list></td><td valign="top"><list listType="unordered"><item> elevated bilirubin levels</item></list></td></tr></tbody></table> <table cellspacing="0" cellpadding="0"><tbody><tr><td valign="top"><list listType="unordered"><item>sleepiness or drowsiness</item></list></td><td valign="top"><list listType="unordered"><item> headache</item></list></td></tr><tr><td valign="top"><list listType="unordered"><item> dizziness</item></list></td><td valign="top"><list listType="unordered"><item> shaking movements (tremors)</item></list></td></tr><tr><td valign="top"><list listType="unordered"><item> heart and blood vessel problems</item></list></td><td valign="top"><list listType="unordered"><item> low blood pressure</item></list></td></tr><tr><td valign="top"><list listType="unordered"><item> fast heartbeat</item></list></td><td valign="top"><list listType="unordered"><item> having a lot of saliva in your mouth</item></list></td></tr><tr><td valign="top"><list listType="unordered"><item> passing out (syncope)</item></list></td><td valign="top"><list listType="unordered"><item> dry mouth</item></list></td></tr><tr><td valign="top"><list listType="unordered"><item> increased sweating</item></list></td><td valign="top"><list listType="unordered"><item> constipation and nausea</item></list></td></tr><tr><td valign="top"><list listType="unordered"><item> vision problems</item></list></td><td valign="top"><list listType="unordered"><item> fever</item></list></td></tr></tbody></table>

WARNING: SEVERE NEUTROPENIA; ORTHOSTATIC HYPOTENSION, BRADYCARDIA, AND SYNCOPE; SEIZURE; MYOCARDITIS, PERICARDITIS, AND CARDIOMYOPATHY; INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS Severe Neutropenia Clozapine has caused severe neutropenia which is associated with an increased risk of serious and potentially fatal infections. Prior to initiating clozapine treatment, obtain baseline ANC(s). Clozapine initiation is not recommended in patients with a baseline ANC less than 1500/μL (less than 1000/μL for those with Benign Ethnic Neutropenia (also known as Duffy-null associated neutrophil count)). See recommendations for dosage modifications based on ANC levels during clozapine treatment [see Dosage and Administration (2.3 , 2.4) ]. Consider a hematology consultation before initiating clozapine or during clozapine treatment [see Warnings and Precautions (5.1) ]. Orthostatic Hypotension, Bradycardia, Syncope Orthostatic hypotension, bradycardia, syncope, and cardiac arrest have occurred with clozapine treatment. The risk is highest during the initial titration period, particularly with rapid dose escalation. These reactions can occur with the first dose, with doses as low as 12.5 mg per day, or when restarting patients who have had even a brief interruption in treatment with clozapine. Initiate treatment at 12.5 mg once or twice daily; titrate slowly; and use divided dosages to minimize risk. Use clozapine cautiously in patients with cardiovascular or cerebrovascular disease or conditions predisposing to hypotension (e.g., dehydration, use of antihypertensive medications) [see Dosage and Administration (2.2 , 2.6) , Warnings and Precautions (5.2) ]. Seizures Seizures have occurred with clozapine treatment. The risk is dose-related. Initiate treatment at 12.5 mg, titrate gradually, and use divided dosing. Use caution when administering clozapine to patients with a history of seizures or other predisposing risk factors for seizure (CNS pathology, medications that lower the seizure threshold, alcohol abuse). Caution patients about engaging in any activity where sudden loss of consciousness could cause serious risk to themselves or others [see Dosage and Administration (2.2) , Warnings and Precautions (5.4) ]. Myocarditis, Pericarditis, Cardiomyopathy and Mitral Valve Incompetence Fatal myocarditis and cardiomyopathy have occurred with clozapine treatment. Discontinue clozapine and obtain a cardiac evaluation upon suspicion of these reactions. Generally, patients with clozapine-related myocarditis or cardiomyopathy should not be rechallenged with clozapine. Consider the possibility of myocarditis, pericarditis, or cardiomyopathy if chest pain, tachycardia, palpitations, dyspnea, fever, flu-like symptoms, hypotension, or ECG changes occur [see Warnings and Precautions (5.5) ] . Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Clozapine is not approved for use in patients with dementia-related psychosis [see Warnings and Precautions (5.6) ]. WARNING: SEVERE NEUTROPENIA; ORTHOSTATIC HYPOTENSION, BRADYCARDIA, AND SYNCOPE; SEIZURE; MYOCARDITIS, PERICARDITIS, AND CARDIOMYOPATHY; INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS See full prescribing information for complete boxed warning .

d psychosis [see Warnings and Precautions (5.6) ]. WARNING: SEVERE NEUTROPENIA; ORTHOSTATIC HYPOTENSION, BRADYCARDIA, AND SYNCOPE; SEIZURE; MYOCARDITIS, PERICARDITIS, AND CARDIOMYOPATHY; INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS See full prescribing information for complete boxed warning . • Severe Neutropenia: Clozapine has caused severe neutropenia, which is associated with an increased risk of serious and fatal infections. Prior to initiating clozapine treatment, obtain baseline ANC(s). Clozapine initiation is not recommended in patients with a baseline ANC less than 1500/μL (less than 1000/μL for those with Benign Ethnic Neutropenia (also known as Duffy-null associated neutrophil count)). See recommendations for dosage modifications based on ANC levels during clozapine treatment ( 2.3 , 2.4 , 5.1 ). • Orthostatic Hypotension, Bradycardia, and Syncope: Risk is dose-related. Starting dose is 12.5 mg. Titrate gradually and use divided dosages. ( 2.2 , 2.6 , 5.2 ) • Seizure: Risk is dose-related. Titrate gradually and use divided doses. Use with caution in patients with history of seizure or risk factors for seizure. ( 2.2 , 5.4 ) • Myocarditis, Pericarditis, Cardiomyopathy and Mitral Valve Incompetence: Can be fatal. Discontinue and obtain cardiac evaluation if findings suggest these cardiac reactions. ( 5.5 ) • Increased Mortality in Elderly Patients with Dementia-Related Psychosis: Clozapine is not approved for this condition. ( 5.6 )

1 INDICATIONS AND USAGE Clozapine tablets are an atypical antipsychotic indicated for: • Treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment. Because of the risks of severe neutropenia and of seizure associated with its use, clozapine tablets should be used only in patients who have failed to respond adequately to standard antipsychotic treatment. ( 1.1 ) • Reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for re-experiencing suicidal behavior. ( 1.2 ) 1.1 Treatment-Resistant Schizophrenia Clozapine tablets are indicated for the treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment. Because of the risks of severe neutropenia and of seizure associated with its use, clozapine tablets should be used only in patients who have failed to respond adequately to standard antipsychotic treatment [see Warnings and Precautions (5.1 , 5.4) ]. The effectiveness of clozapine tablets in treatment-resistant schizophrenia was demonstrated in a 6-week, randomized, double-blind, active-controlled study comparing clozapine tablets and chlorpromazine in patients who had failed other antipsychotics [see Clinical Studies (14.1) ]. 1.2 Reduction in the Risk of Recurrent Suicidal Behavior in Schizophrenia or Schizoaffective Disorder Clozapine tablets are indicated for reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for re-experiencing suicidal behavior, based on history and recent clinical state. Suicidal behavior refers to actions by a patient that put him/herself at risk for death. The effectiveness of clozapine tablets in reducing the risk of recurrent suicidal behavior was demonstrated over a two-year treatment period in the InterSePT™ trial [see Clinical Studies (14.2) ] .

2 DOSAGE AND ADMINISTRATION • Recommended starting oral dosage is 12.5 mg once daily or twice daily. ( 2.2 ) • If well-tolerated, increase the total daily dosage in increments of 25 mg to 50 mg per day to achieve a target dosage of 150 mg to 225 mg twice per day by the end of two weeks ( 2.2 ). • Subsequently may increase the dosage in increments up to 100 mg once or twice weekly ( 2.2 ). • Maximum daily dosage is 450 mg twice daily ( 2.2 ). • Administer with or without food ( 2.2 ). • See the dosage modifications based on ANC results and recommended frequency of ANC testing in the full prescribing information ( 2.3 , 2.4 ). • See recommendations for discontinuing clozapine tablets treatment (2.5), restarting clozapine tablets after interrupting dosing ( 2.6 ), dosage modifications for drug interactions (2.7), dosage recommendations in patients with renal or hepatic impairment and CYP2D6 poor metabolizers ( 2.8 ) in the full prescribing information. 2.1 Absolute Neutrophil Count Testing Prior to Clozapine Tablets Initiation Prior to initiating clozapine tablets treatment, obtain a baseline absolute neutrophil count (ANC). Clozapine tablets initiation is not recommended in patients with an ANC less than 1500/μL [see Warnings and Precautions (5.1) ] . For patients with documented Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count), obtain at least two baseline ANC levels. Clozapine tablets initiation is not recommended in patients with BEN with an ANC less than 1000/μL [see Warnings and Precautions (5.1) ] . For dosage modifications based on ANC results, see Dosage and Administration (2.3 , 2.4) . 2.2 Recommended Dosage and Administration To reduce the risk of orthostatic hypotension, bradycardia, and syncope, the recommended starting dosage is much lower than the target dosage [see Warnings and Precautions (5.2) ] . Clozapine tablets can be taken with or without food [see Clinical Pharmacology (12.3) ] . The recommended starting oral dosage of clozapine tablets is 12.5 mg once or twice daily. If well-tolerated, increase the total daily dose in increments of 25 mg to 50 mg per day to achieve a target dosage of 150 mg to 225 mg twice per day by the end of two weeks. Subsequently, may increase the dosage in increments of up to 100 mg once weekly or twice weekly. The maximum recommended clozapine tablets oral dosage is 450 mg twice daily. 2.3 Dosage Modifications Based on ANC Results Table 1 provides recommended clozapine tablets dosage modifications based on ANC results [see Warnings and Precautions (5.1) ]. For dosage modifications based on ANC results for patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count), see Table 2 [see Dosage and Administration (2.4) ]. Table 1.

ommended clozapine tablets dosage modifications based on ANC results [see Warnings and Precautions (5.1) ]. For dosage modifications based on ANC results for patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count), see Table 2 [see Dosage and Administration (2.4) ]. Table 1. Clozapine Tablets Dosage Modifications Based on ANC Results and Frequency of ANC Testing 1 Confirm all initial reports of ANC less than 1500/μL with a repeat ANC measurement within 24 hours Recommended Dosage Modification Recommended Frequency of ANC Testing During Clozapine Tablets Treatment ANC Within Normal Range (≥ 1500/μL) No dosage modification; continue treatment • Day 1 to Month 6: Weekly • Month 7 to Month 12: Every 2 weeks • Month 13 and thereafter: Every month If clozapine tablets treatment is reinitiated after a dosage interruption (e.g., patient had neutropenia which required dosage interruption and now has a normal ANC level) for: • < 30 days, continue the previous ANC testing frequency • ≥ 30 days, obtain ANC tests according to the frequency for patients who initiate treatment Mild Neutropenia (ANC between 1000 to 1499/μL) 1 No dosage modification; continue treatment • Three times weekly • Once ANC ≥ 1500/μL, recommend returning to the patient’s last Normal Range ANC testing frequency Moderate Neutropenia (ANC between 500 to 999/μL) 1 • Interrupt treatment and recommend hematology consultation • Resume treatment once ANC ≥1000/μL • Daily • Once ANC ≥ 1000/μL, three times weekly • Once ANC ≥ 1500/μL, test weekly for 4 weeks. If ANC ≥ 1500/μL after monitoring weekly for 4 weeks, return to the patient’s last Normal Range ANC testing frequency Severe Neutropenia (ANC less than 500/μL) 1 Discontinue treatment and recommend hematology consultation • Daily • Once ANC ≥ 1000/μL, three times weekly • Once ANC ≥ 1500/μL, if the benefits outweigh the risks of restarting treatment, resume treatment and obtain ANC tests according to the frequency for patients who initiate treatment 2.4 Dosage Modifications Based on ANC Results for Patients with Benign Ethnic Neutropenia Table 2 provides recommended clozapine tablets dosage modifications based on ANC results for patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count) [see Warnings and Precautions (5.1) ] . For dosage modifications based on ANC results for patients without BEN, see Table 1 [see Dosage and Administration (2.3) ]. Table 2. Clozapine Tablets Dosage Modifications Based on ANC Results and Frequency of ANC Testing in Patients with Benign Ethnic Neutropenia 1 1 Benign Ethnic Neutropenia (BEN) is also known as Duffy-null associated neutrophil count. 2 Confirm all initial reports of ANC less than 1500/μL with a repeat ANC measurement within 24 hours.

ine Tablets Dosage Modifications Based on ANC Results and Frequency of ANC Testing in Patients with Benign Ethnic Neutropenia 1 1 Benign Ethnic Neutropenia (BEN) is also known as Duffy-null associated neutrophil count. 2 Confirm all initial reports of ANC less than 1500/μL with a repeat ANC measurement within 24 hours. Recommended Dosage Modification Recommended Frequency of ANC Testing During Clozapine Tablets Treatment in Patients with BEN ANC Within the Normal Range for Patients with BEN (≥ 1000/μL ) No dosage modification; continue treatment • Day 1 to Month 6: Weekly • Month 7 to Month 12: Every 2 weeks • Month 13 and thereafter: Monthly If clozapine tablets treatment is reinitiated after a dosage interruption (e.g., patient had neutropenia which required dosage interruption and now their ANC (≥ 1000/μL and ≥ the patient’s ANC baseline prior to treatment) for: • < 30 days, continue previous ANC testing frequency • ≥ 30 days, obtain ANC tests according to the frequency for patients with BEN who initiate treatment Neutropenia in Patients with BEN (ANC level between 500 to 999/μL) 2 • Recommend hematology consultation • No dosage modification; continue treatment • Three times weekly • Once ANC ≥ 1000/μL and ≥ the patient’s ANC baseline, obtain ANC tests weekly for 4 weeks • If ANC ≥1000/μL and ≥ the patient’s baseline after monitoring for 4 weeks, return to the patient’s last Normal ANC Range testing frequency for patients with BEN Severe Neutropenia in Patients with BEN (ANC level less than 500/μL) 2 Discontinue treatment and recommend hematology consultation • Daily • Once ANC ≥ 500/μL, obtain ANC three times weekly • Once ANC ≥ 1000/μL and ≥ the patient’s baseline, if the benefits outweigh the risks of restarting treatment, resume treatment and obtain ANC tests according to the frequency for patients with BEN who initiate treatment 2.5 Discontinuation of Clozapine Tablets Treatment If discontinuing clozapine tablets in patients with: • Moderate or severe neutropenia, see Table 1 [see Dosage and Administration (2.3) ]. • Normal or mild neutropenia, reduce the dosage gradually over a period of 1 to 2 weeks, and continue monitoring ANC levels until their ANC is ≥1500/μL. If discontinuing clozapine tablets in patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count) with: • Neutropenia, see Table 2 [see Dosage and Administration (2.4) ]. • ANC within their normal range of ANC reduce the dosage gradually over a period of 1 to 2 weeks. When discontinuing clozapine tablets, monitor patients for the symptoms related to psychotic recurrence and cholinergic rebound (e.g., profuse sweating, headache, nausea, vomiting, diarrhea). 2.6 Restarting Clozapine Tablets Treatment After Interrupting Clozapine Tablets When restarting clozapine tablets in patients who have interrupted clozapine tablets treatment, use a lower dosage to minimize the risk of hypotension, bradycardia, and syncope [see Warnings and Precautions (5.2) ] . • If one day’s dosage is missed, resume clozapine tablets treatment at 40% to 50% of the previous dosage. • If two days of dosing is missed, resume clozapine tablets treatment at approximately 25% of the previous dosage. • For longer interruptions, restart clozapine tablets treatment with a dosage of 12.5 mg once or twice daily. If this dosage is well-tolerated, may increase the dosage to the previous dosage more quickly than recommended than for initial clozapine tablets treatment. 2.7 Dosage Modifications for Drug Interactions See Table 3 for recommended dosage modifications to reduce the risk of clozapine tablets-associated adverse reactions or reduce the risk of lower effectiveness [see Drug Interactions (7) ]. Table 3.

ore quickly than recommended than for initial clozapine tablets treatment. 2.7 Dosage Modifications for Drug Interactions See Table 3 for recommended dosage modifications to reduce the risk of clozapine tablets-associated adverse reactions or reduce the risk of lower effectiveness [see Drug Interactions (7) ]. Table 3. Clozapine Tablets Dosage Modifications for Drug Interactions Strong CYP1A2 Inhibitors Administer one third of the clozapine tablets dosage. Moderate or Weak CYP1A2 Inhibitors Consider reducing the clozapine tablets dosage if necessary. CYP2D6 or CYP3A4 Inhibitors Strong CYP3A4 Inducers Concomitant use is not recommended. However, if concomitant use is necessary, it may be necessary to increase the clozapine tablets dosage. Monitor for decreased effectiveness. Moderate or weak CYP1A2 or CYP3A4 Inducers Consider increasing the clozapine tablets dosage if necessary. 2.8 Dosage Recommendations in Patients with Renal or Hepatic Impairment, or CYP2D6 Poor Metabolizers It may be necessary to reduce the clozapine tablets dosage in patients with significant renal impairment or hepatic impairment, or in CYP2D6 poor metabolizers [see Use in Specific Populations (8.6 , 8.7) ] .

3 DOSAGE FORMS AND STRENGTHS Clozapine Tablets USP, 25 mg are pale yellow colored, round, flat faced, bevel edged uncoated tablets debossed with ‘C facilitated scoreline (functional) C’ on one side and ‘54’ on the other side. Clozapine Tablets USP, 50 mg are pale yellow colored, round, flat faced, bevel edged uncoated tablets debossed with ‘C facilitated scoreline (functional) C’ on one side and ‘55’ on the other side. Clozapine Tablets USP, 100 mg are pale yellow colored, round, flat faced, bevel edged uncoated tablets debossed with ‘C facilitated scoreline (functional) C’ on one side and ‘57’ on the other side. Clozapine Tablets USP, 200 mg are pale yellow colored, oval shaped, uncoated tablets debossed with ‘C scoreline (functional) C’ on one side and ‘71’ on the other side. 25 mg, 50 mg, 100 mg and 200 mg tablets with score on one side (3)

4 CONTRAINDICATIONS Clozapine tablets are contraindicated in patients with a history of hypersensitivity to clozapine (e.g., photosensitivity, vasculitis, erythema multiforme, or Stevens-Johnson syndrome) or any other component of clozapine tablets [see Adverse Reactions (6.2) ] . Known hypersensitivity to clozapine or any other component of clozapine tablets. ( 4 )

5 WARNINGS AND PRECAUTIONS • Severe neutropenia: See Boxed Warning ( 5.1 ) • Gastrointestinal Hypomotility with Severe Complications : Severe gastrointestinal adverse reactions have occurred with the use of clozapine. If constipation is identified, close monitoring and prompt treatment is advised. ( 5.7 ) • Eosinophilia : Assess for organ involvement (e.g., myocarditis, pancreatitis, hepatitis, colitis, nephritis). Discontinue if these occur. ( 5.8 ) • QT Interval Prolongation : Can be fatal. Consider additional risk factors for prolonged QT interval (disorders and drugs). ( 5.9 ) • Metabolic Changes : Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include: • Hyperglycemia and Diabetes Mellitus: Monitor for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Monitor glucose regularly in patients with diabetes or at risk for diabetes. ( 5.10 ) • Dyslipidemia: Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics. ( 5.10 ) • Weight Gain: Significant weight gain has occurred. Monitor weight gain. ( 5.10 ) • Neuroleptic Malignant Syndrome (NMS) : Immediately discontinue and monitor closely. Assess for co-morbid conditions. ( 5.11 ) • Hepatotoxicity : Can be fatal. Monitor for hepatotoxicity. Discontinue treatment if hepatitis or transaminase elevations combined with other symptoms occur ( 5.12 ). • Fever : Evaluate for infection and for neutropenia, NMS. ( 5.13 ) • Pulmonary Embolism (PE) : Consider PE if respiratory distress, chest pain, or deep-vein thrombosis occur. ( 5.14 ) • Anticholinergic Toxicity : When possible, avoid use with other anticholinergic drugs and use with caution in patients with a current diagnosis or prior history of constipation, urinary retention, clinically significant prostatic hypertrophy, or other conditions in which anticholinergic effects can lead to significant adverse reactions. ( 5.15 , 7.1 ) • Interference with Cognitive and Motor Performance : Advise caution when operating machinery, including automobiles. ( 5.16 ) 5.1 Severe Neutropenia Clozapine has caused severe neutropenia (absolute neutrophil count (ANC) less than 500/μL) [see Adverse Reactions (6.1 , 6.2) ] and is associated with an increased risk of serious and potentially fatal infections. Severe neutropenia occurred in a small percentage of clozapine-treated patients. The risk of severe neutropenia appears greatest during the first 18 weeks of clozapine treatment. The mechanism by which clozapine causes neutropenia is unknown. Neutropenia is not dose dependent. Consider a hematology consultation before initiating clozapine treatment or during treatment. ANC Monitoring and Dosage Modifications Prior to initiating clozapine treatment, obtain a baseline ANC. Clozapine initiation is not recommended in patients with a baseline ANC less than 1500/μL. Throughout clozapine treatment, regularly monitor ANC. Table 1 provides recommendations for dosage modifications (dosage interruption and treatment discontinuation), based on ANC levels, during clozapine treatment and frequency of ANC monitoring [see Dosage and Administration (2.3) ].

a baseline ANC less than 1500/μL. Throughout clozapine treatment, regularly monitor ANC. Table 1 provides recommendations for dosage modifications (dosage interruption and treatment discontinuation), based on ANC levels, during clozapine treatment and frequency of ANC monitoring [see Dosage and Administration (2.3) ]. ANC Monitoring and Dosage Modification in Patients with Benign Ethnic Neutropenia Patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count) generally have lower baseline neutrophil counts but they are not at higher risk for developing infections, and they are not at increased risk for developing clozapine-induced neutropenia. For patients with documented BEN, obtain at least two baseline ANC levels prior to clozapine initiation. Clozapine initiation is not recommended in patients with BEN with an ANC less than 1000/μL. There are different ANC dosage modification recommendations in clozapine-treated patients with BEN due to their lower baseline ANC levels. Table 2 provides recommendations on dosage modifications (dosage interruption and treatment discontinuation), based on ANC monitoring, during clozapine treatment in patients with BEN and recommended frequency of ANC testing [see Dosage and Administration (2.4) ]. Management of Clozapine-Treated Patients Who Develop a Fever For patients who develop a fever during clozapine treatment: • Interrupt clozapine in those who develop a temperature of 101.3°F (38.5°C) or greater and obtain an ANC level. • If the ANC is less than 1000/μL in patients without BEN, initiate appropriate workup and treatment for infection. Refer to Table 1 or Table 2 for dosage modifications based on ANC monitoring [see Dosage and Administration (2.3 , 2.4) ]. In patients with fever and a normal neutrophil count, see Warnings and Precautions (5.11) for neuroleptic malignant syndrome and Warnings and Precautions (5.13) for fever. Restarting Clozapine in Patients Who Recovered from Severe Neutropenia Generally, do not rechallenge patients with clozapine in those who experienced severe neutropenia. However, for some patients who had resolution of their clozapine-related severe neutropenia after stopping clozapine, the risk of schizophrenia exacerbation from not restarting clozapine treatment may be greater than the risk of neutropenia reoccurrence from restarting clozapine (e.g., patients who have no treatment options other than clozapine). Concomitant Use of Clozapine with Other Drugs Known to Cause Neutropenia If clozapine is used concomitantly with another drug known to cause neutropenia, consider more frequently ANC monitoring than the recommendations provided in Table 1 and Table 2. 5.2 Orthostatic Hypotension, Bradycardia, and Syncope Hypotension, bradycardia, syncope, and cardiac arrest have occurred with clozapine treatment. The risk is highest during the initial titration period, particularly with rapid dose-escalation. These reactions can occur with the first dose, at doses as low as 12.5 mg. These reactions can be fatal. The syndrome is consistent with neurally mediated reflex bradycardia (NMRB). Treatment must begin at a maximum dose of 12.5 mg once daily or twice daily. The total daily dose can be increased in increments of 25 mg to 50 mg per day, if well-tolerated, to a target dose of 300 mg to 450 mg per day (administered in divided doses) by the end of 2 weeks. Subsequently, the dose can be increased weekly or twice weekly, in increments of up to 100 mg. The maximum dose is 900 mg per day. Use cautious titration and a divided dosage schedule to minimize the risk of serious cardiovascular reactions [see Dosage and Administration (2.2) ]. Consider reducing the dose if hypotension occurs.

ly, the dose can be increased weekly or twice weekly, in increments of up to 100 mg. The maximum dose is 900 mg per day. Use cautious titration and a divided dosage schedule to minimize the risk of serious cardiovascular reactions [see Dosage and Administration (2.2) ]. Consider reducing the dose if hypotension occurs. When restarting clozapine in patients who have had even a brief interruption in treatment with clozapine, the dosage must be reduced. This is necessary to minimize the risk of hypotension, bradycardia, and syncope [see Dosage and Administration (2.6) ]. Use clozapine cautiously in patients with cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension (e.g., concomitant use of antihypertensives, dehydration and hypovolemia). 5.3 Falls Clozapine may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy. 5.4 Seizures Seizure has been estimated to occur in association with clozapine use at a cumulative incidence at one year of approximately 5%, based on the occurrence of one or more seizures in 61 of 1743 patients exposed to clozapine during its clinical testing prior to domestic marketing (i.e., a crude rate of 3.5%). The risk of seizure is dose-related. Initiate treatment with a low dose (12.5 mg), titrate slowly, and use divided dosing. Use caution when administering clozapine to patients with a history of seizures or other predisposing risk factors for seizure (e.g., head trauma or other CNS pathology, use of medications that lower the seizure threshold, or alcohol abuse). Because of the substantial risk of seizure associated with clozapine use, caution patients about engaging in any activity where sudden loss of consciousness could cause serious risk to themselves or others (e.g., driving an automobile, operating complex machinery, swimming, climbing). 5.5 Myocarditis, Pericarditis, Cardiomyopathy and Mitral Valve Incompetence Myocarditis, pericarditis, and cardiomyopathy have occurred with the use of clozapine. These reactions can be fatal. Discontinue clozapine and obtain a cardiac evaluation upon suspicion of myocarditis, pericarditis, or cardiomyopathy. Generally, patients with a history of clozapine-associated myocarditis or cardiomyopathy should not be rechallenged with clozapine. However, if the benefit of clozapine treatment is judged to outweigh the potential risks of recurrence, the clinician may consider rechallenge with clozapine in consultation with a cardiologist. Myocarditis and pericarditis most frequently present within the first 2 months of clozapine treatment. Symptoms of cardiomyopathy generally occur later than clozapine-associated myocarditis or pericarditis and usually after 8 weeks of treatment. However, myocarditis, pericarditis, and cardiomyopathy can occur at any period during treatment with clozapine. In patients who are diagnosed with cardiomyopathy while taking clozapine mitral valve incompetence has been reported. 5.6 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients.

treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality in this population. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Clozapine is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning ] . 5.7 Gastrointestinal Hypomotility with Severe Complications Severe gastrointestinal adverse reactions have occurred with the use of clozapine, primarily due to its potent anticholinergic effects and resulting gastrointestinal hypomotility. In post marketing experience, reported effects range from constipation to paralytic ileus. Increased frequency of constipation and delayed diagnosis and treatment increased the risk of severe complications of gastrointestinal hypomotility, which can result in fecal impaction, megacolon, and intestinal obstruction, ischemia, infarction, perforation, ulceration, or necrosis [see Adverse Reaction (6.2) ]. These reactions have resulted in hospitalization, surgery, and death. The risk of severe adverse reactions is further increased with anticholinergic medications (and other medications that decrease gastrointestinal peristalsis); therefore, concomitant use should be avoided when possible [see Warnings and Precautions (5.15) , Drug Interactions (7.1) ]. Prior to initiating clozapine, screen for constipation and treat as necessary. Subjective symptoms of constipation may not accurately reflect the degree of gastrointestinal hypomotility in clozapine treated patients. Therefore, reassess bowel function frequently with careful attention to any changes in the frequency or character of bowel movements, as well as signs and symptoms of complications of hypomotility (e.g., nausea, vomiting, abdominal distension, abdominal pain). If constipation or gastrointestinal hypomotility are identified, monitor closely and treat promptly with appropriate laxatives, as necessary, to prevent severe complications. Consider prophylactic laxatives in high risk patients. 5.8 Eosinophilia Eosinophilia, defined as a blood eosinophil count of greater than 700/µL, has occurred with clozapine treatment. In clinical trials, approximately 1% of patients developed eosinophilia. Clozapine-related eosinophilia usually occurs during the first month of treatment. In some patients, it has been associated with myocarditis, pancreatitis, hepatitis, colitis, and nephritis. Such organ involvement could be consistent with a drug reaction with eosinophilia and systemic symptoms syndrome (DRESS), also known as drug induced hypersensitivity syndrome (DIHS). If eosinophilia develops during clozapine treatment, evaluate promptly for signs and symptoms of systemic reactions, such as rash or other allergic symptoms, myocarditis, or other organ-specific disease associated with eosinophilia. If clozapine-related systemic disease is suspected, discontinue clozapine immediately.

If eosinophilia develops during clozapine treatment, evaluate promptly for signs and symptoms of systemic reactions, such as rash or other allergic symptoms, myocarditis, or other organ-specific disease associated with eosinophilia. If clozapine-related systemic disease is suspected, discontinue clozapine immediately. If a cause of eosinophilia unrelated to clozapine is identified (e.g., asthma, allergies, collagen vascular disease, parasitic infections, and specific neoplasms), treat the underlying cause and continue clozapine. Clozapine-related eosinophilia has also occurred in the absence of organ involvement and can resolve without intervention. There are reports of successful rechallenge after discontinuation of clozapine, without recurrence of eosinophilia. In the absence of organ involvement, continue clozapine under careful monitoring. If the total eosinophil count continues to increase over several weeks in the absence of systemic disease, the decision to interrupt clozapine therapy and rechallenge after the eosinophil count decreases should be based on the overall clinical assessment, in consultation with an internist or hematologist. 5.9 QT Interval Prolongation QT prolongation, Torsade de Pointes and other life-threatening ventricular arrhythmias, cardiac arrest, and sudden death have occurred with clozapine treatment. When prescribing clozapine, consider the presence of additional risk factors for QT prolongation and serious cardiovascular reactions. Conditions that increase these risks include the following: history of QT prolongation, long QT syndrome, family history of long QT syndrome or sudden cardiac death, significant cardiac arrhythmia, recent myocardial infarction, uncompensated heart failure, treatment with other medications that cause QT prolongation, treatment with medications that inhibit the metabolism of clozapine, and electrolyte abnormalities. Prior to initiating treatment with clozapine, perform a careful physical examination, medical history, and concomitant medication history. Consider obtaining a baseline ECG and serum chemistry panel. Correct electrolyte abnormalities. Discontinue clozapine if the QTc interval exceeds 500 msec. If patients experience symptoms consistent with Torsades de Pointes, or other arrhythmias (e.g., syncope, presyncope, dizziness, or palpitations), obtain a cardiac evaluation and discontinue clozapine. Use caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of clozapine. Drugs that cause QT prolongation include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, thioridazine, mesoridazine, droperidol, pimozide), specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin), Class 1A antiarrhythmic medications (e.g., quinidine, procainamide) or Class III antiarrhythmics (e.g., amiodarone, sotalol), and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus). Clozapine is primarily metabolized by CYP isoenzymes 1A2, 2D6, and 3A4. Concomitant treatment with inhibitors of these enzymes can increase the concentration of clozapine [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] . Hypokalemia and hypomagnesemia increase the risk of QT prolongation. Hypokalemia can result from diuretic therapy, diarrhea, and other causes. Use caution when treating patients at risk for significant electrolyte disturbance, particularly hypokalemia. Obtain baseline measurements of serum potassium and magnesium levels, and periodically monitor electrolytes. Correct electrolyte abnormalities before initiating treatment with clozapine.

rhea, and other causes. Use caution when treating patients at risk for significant electrolyte disturbance, particularly hypokalemia. Obtain baseline measurements of serum potassium and magnesium levels, and periodically monitor electrolytes. Correct electrolyte abnormalities before initiating treatment with clozapine. 5.10 Metabolic Changes Atypical antipsychotic drugs, including clozapine have been associated with metabolic changes that can increase cardiovascular and cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While atypical antipsychotic drugs may produce some metabolic changes, each drug in the class has its own specific risk profile. Hyperglycemia and Diabetes Mellitus Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including clozapine. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse reactions is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent, hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics are not available. Patients with an established diagnosis of diabetes mellitus who are started on clozapine should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug. In a pooled data analysis of 8 studies in adult subjects with schizophrenia, the mean changes in fasting glucose concentration in the clozapine and chlorpromazine groups were +11 mg/dL and +4 mg/dL respectively. A higher proportion of the clozapine group demonstrated categorical increases from baseline in fasting glucose concentrations, compared to the chlorpromazine group (Table 4). The clozapine doses were 100 to 900 mg per day (mean modal dose: 512 mg per day). The maximum chlorpromazine dose was 1800 mg per day (mean modal dose: 1029 mg per day). The median duration of exposure was 42 days for clozapine and chlorpromazine. Table 4. Categorical Changes in Fasting Glucose Level in Studies in Adult Subjects with Schizophrenia Laboratory Parameter Category Change (at least once) from baseline Treatment Arm N n (%) Fasting Glucose Normal (<100 mg/dL) to High (≥126 mg/dL) Clozapine 198 53 (27) Chlorpromazine 135 14 (10) Borderline (100 to 125 mg/dL) to High (≥126 mg/dL) Clozapine 57 24 (42) Chlorpromazine 43 12 (28) Dyslipidemia Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics, including clozapine.

Normal (<100 mg/dL) to High (≥126 mg/dL) Clozapine 198 53 (27) Chlorpromazine 135 14 (10) Borderline (100 to 125 mg/dL) to High (≥126 mg/dL) Clozapine 57 24 (42) Chlorpromazine 43 12 (28) Dyslipidemia Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics, including clozapine. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using clozapine, is recommended. In a pooled data analysis of 10 studies in adult subjects with schizophrenia, clozapine treatment was associated with increases in serum total cholesterol. No data were collected on LDL and HDL cholesterol. The mean increase in total cholesterol was 13 mg/dL in the clozapine group and 15 mg/dL in the chlorpromazine group. In a pooled data analysis of 2 studies in adult subjects with schizophrenia, clozapine treatment was associated with increases in fasting serum triglyceride. The mean increase in fasting triglyceride was 71 mg/dL (54%) in the clozapine group and 39 mg/dL (35%) in the chlorpromazine group (Table 5). In addition, clozapine treatment was associated with categorical increases in serum total cholesterol and triglyceride, as illustrated in Table 6. The proportion of patients with categorical increases in total cholesterol or fasting triglyceride increased with the duration of exposure. The median duration of clozapine and chlorpromazine exposure was 45 days and 38 days, respectively. The clozapine dose range was 100 mg to 900 mg daily; the maximum chlorpromazine dose was 1800 mg daily. Table 5. Mean Changes in Total Cholesterol and Triglyceride Concentration in Studies in Adult Subjects with Schizophrenia Treatment Arm Baseline total cholesterol concentration (mg/dL) Change from baseline mg/dL (%) Clozapine (N=334) 184 +13 (7) Chlorpromazine (N=185) 182 +15 (8) Baseline triglyceride concentration (mg/dL) Change from baseline mg/dL (%) Clozapine (N=6) 130 +71 (54) Chlorpromazine (N=7) 110 +39 (35) Table 6. Categorical Changes in Lipid Concentrations in Studies in Adult Subjects with Schizophrenia Laboratory Parameter Category Change (at least once) from baseline Treatment Arm N n (%) Total Cholesterol (random or fasting) Increase by ≥40 mg/dL Clozapine 334 111 (33) Chlorpromazine 185 46 (25) Normal (<200 mg/dL) to High (≥240 mg/dL) Clozapine 222 18 (8) Chlorpromazine 132 3 (2) Borderline (200 to 239 mg/dL) to High (≥240 mg/dL) Clozapine 79 30 (38) Chlorpromazine 34 14 (41) Triglycerides (fasting) Increase by ≥50 mg/dL Clozapine 6 3 (50) Chlorpromazine 7 3 (43) Normal (<150 mg/dL) to High (≥200 mg/dL) Clozapine 4 0 (0) Chlorpromazine 6 2 (33) Borderline (≥150 mg/dL and <200 mg/dL) to High (≥200 mg/dL) Clozapine 1 1 (100) Chlorpromazine 1 0 (0) Weight Gain Weight gain has occurred with the use of antipsychotics, including clozapine. Monitor weight during treatment with clozapine. Table 7 summarizes the data on weight gain by the duration of exposure pooled from 11 studies with clozapine and active comparators. The median duration of exposure was 609, 728, and 42 days, in the clozapine, olanzapine, and chlorpromazine group, respectively. Table 7.

. Monitor weight during treatment with clozapine. Table 7 summarizes the data on weight gain by the duration of exposure pooled from 11 studies with clozapine and active comparators. The median duration of exposure was 609, 728, and 42 days, in the clozapine, olanzapine, and chlorpromazine group, respectively. Table 7. Mean Change in Body Weight (kg) by Duration of Exposure from Studies in Adult Subjects with Schizophrenia Metabolic parameter Exposure duration Clozapine (N=669) Olanzapine (N=442) Chlorpromazine (N=155) n Mean n Mean n Mean Weight change from baseline 2 weeks (Day 11 to 17) 6 +0.9 3 +0.7 2 -0.5 4 weeks (Day 21 to 35) 23 +0.7 8 +0.8 17 +0.6 8 weeks (Day 49 to 63) 12 +1.9 13 +1.8 16 +0.9 12 weeks (Day 70 to 98) 17 +2.8 5 +3.1 0 0 24 weeks (Day 154 to 182) 42 -0.6 12 +5.7 0 0 48 weeks (Day 322 to 350) 3 +3.7 3 +13.7 0 0 Table 8 summarizes pooled data from 11 studies in adult subjects with schizophrenia demonstrating weight gain ≥7% of body weight relative to baseline. The median duration of exposure was 609, 728, and 42 days, in the clozapine, olanzapine, and chlorpromazine group, respectively. Table 8. Proportion of Adult Subjects in Schizophrenia Studies with Weight Gain ≥7% Relative to Baseline Body Weight Weight change Clozapine Olanzapine Chlorpromazine N 669 442 155 ≥7% (inclusive) 236 (35%) 203 (46%) 13 (8%) 5.11 Neuroleptic Malignant Syndrome Antipsychotic drugs including clozapine can cause a potentially fatal symptom complex referred to as Neuroleptic Malignant Syndrome (NMS). Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Associated findings can include elevated creatine phosphokinase (CPK), myoglobinuria, rhabdomyolysis, and acute renal failure. The diagnostic evaluation of patients with this syndrome is complicated. It is important to consider the presence of other serious medical conditions (e.g., severe neutropenia, infection, heat stroke, primary CNS pathology, central anticholinergic toxicity, extrapyramidal symptoms, and drug fever). The management of NMS should include (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, (2) intensive symptomatic treatment and medical monitoring, and (3) treatment of comorbid medical conditions. There is no general agreement about specific pharmacological treatments for NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. NMS can recur. Monitor closely if restarting treatment with antipsychotics. NMS has occurred with clozapine monotherapy and with concomitant CNS-active medications, including lithium. 5.12 Hepatotoxicity Severe, life threatening, and in some cases fatal hepatotoxicity including hepatic failure, hepatic necrosis, and hepatitis have been reported in post marketing studies in patients treated with clozapine [see Adverse Reactions (6.2) ] . Monitor for the appearance of signs and symptoms of hepatotoxicity such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinemia, coagulopathy, and hepatic encephalopathy. Perform serum tests for liver injury and consider permanently discontinuing treatment if hepatitis or transaminase elevations combined with other systemic symptoms are due to clozapine. 5.13 Fever During clozapine therapy, patients have experienced transient, clozapine-related fever. The peak incidence is within the first 3 weeks of treatment. While this fever is generally benign and self-limited, it may necessitate discontinuing treatment. The fever can be associated with an increase or decrease in WBC count.

r During clozapine therapy, patients have experienced transient, clozapine-related fever. The peak incidence is within the first 3 weeks of treatment. While this fever is generally benign and self-limited, it may necessitate discontinuing treatment. The fever can be associated with an increase or decrease in WBC count. Carefully evaluate patients with fever to rule out severe neutropenia or infection. Consider the possibility of NMS [see Warnings and Precautions (5.11) ] . 5.14 Pulmonary Embolism Pulmonary embolism and deep-vein thrombosis have occurred in patients treated with clozapine. Consider the possibility of pulmonary embolism in patients who present with deep-vein thrombosis, acute dyspnea, chest pain, or with other respiratory signs and symptoms. Whether pulmonary embolus and deep-vein thrombosis can be attributed to clozapine or some characteristic(s) of patients is not clear. 5.15 Anticholinergic Toxicity Clozapine has potent anticholinergic effects. Treatment with clozapine can result in CNS and peripheral anticholinergic toxicity, especially at higher dosages, or in overdose situations [see Overdosage (10) ]. Use with caution in patients with a current diagnosis or prior history of constipation, urinary retention, clinically significant prostatic hypertrophy, or other conditions in which anticholinergic effects can lead to significant adverse reactions. When possible, avoid concomitant use, with other anticholinergic medications because the risk for anticholinergic toxicity or severe gastrointestinal adverse reactions is increased [see Warnings and Precautions (5.7) , Drug Interactions (7.1) ]. 5.16 Interference with Cognitive and Motor Performance Clozapine can cause sedation and impairment of cognitive and motor performance. Caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that clozapine does not affect them adversely. These reactions may be dose-related. Consider reducing the dose if they occur. 5.17 Tardive Dyskinesia Tardive dyskinesia (TD) has occurred in patients treated with antipsychotic drugs, including clozapine. The syndrome consists of potentially irreversible, involuntary, dyskinetic movements. The risk of TD and the likelihood that it will become irreversible are believed to increase with greater durations of treatment and higher total cumulative doses. However, the syndrome can develop after relatively brief treatment periods at low doses. Prescribe clozapine in a manner that is most likely to minimize the risk of developing TD. Use the lowest effective dose and the shortest duration necessary to control symptoms. Periodically assess the need for continued treatment. Consider discontinuing treatment if TD occurs. However, some patients may require treatment with clozapine despite the presence of the syndrome. TD may remit partially or completely if treatment is discontinued. Antipsychotic treatment, itself, may suppress (or partially suppress) the signs and symptoms, and it has the potential to mask the underlying process. The effect of symptom suppression on the long-term course of TD is unknown. 5.18 Cerebrovascular Adverse Reactions In controlled trials, elderly patients with dementia-related psychosis treated with some atypical antipsychotics had an increased risk (compared to placebo) of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities. The mechanism for this increased risk is not known. An increased risk cannot be excluded for clozapine or other antipsychotics or other patient populations. Clozapine should be used with caution in patients with risk factors for cerebrovascular adverse reactions.

troke, transient ischemic attack), including fatalities. The mechanism for this increased risk is not known. An increased risk cannot be excluded for clozapine or other antipsychotics or other patient populations. Clozapine should be used with caution in patients with risk factors for cerebrovascular adverse reactions. 5.19 Recurrence of Psychosis and Cholinergic Rebound after Abrupt Discontinuation of Clozapine If abrupt discontinuation of clozapine is necessary (because of severe neutropenia or another medical condition, for example) [see Dosage and Administration (2.5) , Warnings and Precautions (5.1) ] , monitor carefully for the recurrence of psychotic symptoms and adverse reactions related to cholinergic rebound, such as profuse sweating, headache, nausea, vomiting and diarrhea.

<table ID="_RefID0EKPBG" cellpadding="0pt" cellspacing="0pt" width="100%"><caption>Table 4. Categorical Changes in Fasting Glucose Level in Studies in Adult Subjects with Schizophrenia</caption><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><thead><tr><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Laboratory</content> <content styleCode="bold">Parameter</content> </th><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Category Change</content> <content styleCode="bold">(at least once) from</content> <content styleCode="bold">baseline</content> </th><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Treatment Arm</content> </th><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">N</content> </th><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">n (%)</content> </th></tr></thead><tbody><tr><td align="center" rowspan="4" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Fasting Glucose </paragraph></td><td align="center" rowspan="2" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>Normal (&lt;100 mg/dL) to High (&#x2265;126 mg/dL) </paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>Clozapine </paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>198 </paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>53 (27) </paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Chlorpromazine </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>135 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>14 (10) </paragraph></td></tr><tr><td align="center" rowspan="2" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Borderline (100 to 125 mg/dL) to High (&#x2265;126 mg/dL) </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>Clozapine </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>57 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>24 (42) </paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>Chlorpromazine </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>43 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>12 (28) </paragraph></td></tr></tbody></table>

align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>Chlorpromazine </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>43 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>12 (28) </paragraph></td></tr></tbody></table> <table ID="_RefID0EBVBG" cellpadding="0pt" cellspacing="0pt" width="100%"><caption>Table 5. Mean Changes in Total Cholesterol and Triglyceride Concentration in Studies in Adult Subjects with Schizophrenia</caption><col width="34%"/><col width="33%"/><col width="34%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Treatment Arm</content> </paragraph></td><td styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Baseline total cholesterol concentration (mg/dL)</content> </paragraph></td><td styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Change from baseline mg/dL (%)</content> </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Clozapine (N=334) </paragraph></td><td styleCode="Rrule Botrule " valign="middle"><paragraph>184 </paragraph></td><td styleCode="Rrule Botrule " valign="middle"><paragraph>+13 (7) </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Chlorpromazine (N=185) </paragraph></td><td styleCode="Rrule Botrule " valign="middle"><paragraph>182 </paragraph></td><td styleCode="Rrule Botrule " valign="middle"><paragraph>+15 (8) </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> </paragraph></td><td styleCode="Rrule Botrule " valign="middle"><paragraph><content styleCode="bold">Baseline triglyceride concentration (mg/dL)</content> </paragraph></td><td styleCode="Rrule Botrule " valign="middle"><paragraph><content styleCode="bold">Change from baseline mg/dL (%)</content> </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Clozapine (N=6) </paragraph></td><td styleCode="Rrule Botrule " valign="middle"><paragraph>130 </paragraph></td><td styleCode="Rrule Botrule " valign="middle"><paragraph>+71 (54) </paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>Chlorpromazine (N=7) </paragraph></td><td styleCode="Rrule Botrule " valign="middle"><paragraph>110 </paragraph></td><td styleCode="Rrule Botrule " valign="middle"><paragraph>+39 (35) </paragraph></td></tr></tbody></table>

71 (54) </paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>Chlorpromazine (N=7) </paragraph></td><td styleCode="Rrule Botrule " valign="middle"><paragraph>110 </paragraph></td><td styleCode="Rrule Botrule " valign="middle"><paragraph>+39 (35) </paragraph></td></tr></tbody></table> <table ID="_RefID0E1YBG" cellpadding="0pt" cellspacing="0pt" width="100%"><caption>Table 6.

71 (54) </paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>Chlorpromazine (N=7) </paragraph></td><td styleCode="Rrule Botrule " valign="middle"><paragraph>110 </paragraph></td><td styleCode="Rrule Botrule " valign="middle"><paragraph>+39 (35) </paragraph></td></tr></tbody></table> <table ID="_RefID0E1YBG" cellpadding="0pt" cellspacing="0pt" width="100%"><caption>Table 6. Categorical Changes in Lipid Concentrations in Studies in Adult Subjects with Schizophrenia</caption><col width="14%"/><col width="20%"/><col width="22%"/><col width="22%"/><col width="22%"/><thead><tr><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Laboratory</content> <content styleCode="bold">Parameter</content> </th><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Category Change (at least once) from baseline</content> </th><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Treatment Arm</content> </th><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">N</content> </th><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">n (%)</content> </th></tr></thead><tbody><tr><td rowspan="6" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Total Cholesterol (random or fasting) </paragraph></td><td align="center" rowspan="2" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>Increase by &#x2265;40 mg/dL </paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>Clozapine </paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>334 </paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>111 (33) </paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Chlorpromazine </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>185 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>46 (25) </paragraph></td></tr><tr><td align="center" rowspan="2" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Normal (&lt;200 mg/dL) to High (&#x2265;240 mg/dL) </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>Clozapine </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>222 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>18 (8) </paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Chlorpromazine </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>132 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>3 (2) </paragraph></td></tr><tr><td align="center" rowspan="2" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Borderline (200 to 239 mg/dL) to High (&#x2265;240 mg/dL) </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>Clozapine </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>79 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>30 (38) </paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Chlorpromazine </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>34 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>14 (41) </paragraph></td></tr><tr><td rowspan="6" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Triglycerides (fasting) </paragraph></td>

td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>34 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>14 (41) </paragraph></td></tr><tr><td rowspan="6" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Triglycerides (fasting) </paragraph></td> <td align="center" rowspan="2" styleCode="Rrule Botrule " valign="middle"><paragraph>Increase by &#x2265;50 mg/dL </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>Clozapine </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>6 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>3 (50) </paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Chlorpromazine </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>7 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>3 (43) </paragraph></td></tr><tr><td align="center" rowspan="2" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Normal (&lt;150 mg/dL) to High (&#x2265;200 mg/dL) </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>Clozapine </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>4 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0 (0) </paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Chlorpromazine </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>6 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>2 (33) </paragraph></td></tr><tr><td align="center" rowspan="2" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Borderline (&#x2265;150 mg/dL and &lt;200 mg/dL) to High (&#x2265;200 mg/dL) </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>Clozapine </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>1 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>1 (100) </paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>Chlorpromazine </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>1 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0 (0) </paragraph></td></tr></tbody></table>

<td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>Chlorpromazine </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>1 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0 (0) </paragraph></td></tr></tbody></table> <table ID="_RefID0EUEAI" cellpadding="0pt" cellspacing="0pt" width="100%"><caption>Table 7.

<td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>Chlorpromazine </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>1 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0 (0) </paragraph></td></tr></tbody></table> <table ID="_RefID0EUEAI" cellpadding="0pt" cellspacing="0pt" width="100%"><caption>Table 7. Mean Change in Body Weight (kg) by Duration of Exposure from Studies in Adult Subjects with Schizophrenia</caption><col width="10%"/><col width="13%"/><col width="13%"/><col width="13%"/><col width="13%"/><col width="13%"/><col width="13%"/><col width="13%"/><tbody><tr><td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Metabolic parameter</content> </paragraph></td><td align="center" rowspan="2" styleCode="Rrule Botrule Toprule " valign="middle"><paragraph><content styleCode="bold">Exposure duration</content> </paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="middle"><paragraph><content styleCode="bold">Clozapine </content> <content styleCode="bold">(N=669)</content> </paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="middle"><paragraph><content styleCode="bold">Olanzapine</content> <content styleCode="bold">(N=442)</content> </paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="middle"><paragraph><content styleCode="bold">Chlorpromazine</content> <content styleCode="bold"> (N=155)</content> </paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">n</content> </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph><content styleCode="bold">Mean</content> </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph><content styleCode="bold">n</content> </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph><content styleCode="bold">Mean</content> </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph><content styleCode="bold">n</content> </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph><content styleCode="bold">Mean</content> </paragraph></td></tr><tr><td align="center" rowspan="6" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Weight change from baseline</content> </paragraph></td><td styleCode="Rrule Botrule " valign="middle"><paragraph>2 weeks (Day 11 to 17) </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>6 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>+0.9 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>3 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>+0.7 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>2 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>-0.5 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>4 weeks (Day 21 to 35) </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>23 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>+0.7 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>8 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>+0.8 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>17 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>

le Botrule " valign="middle"><paragraph>8 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>+0.8 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>17 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph> +0.6 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>8 weeks (Day 49 to 63) </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>12 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>+1.9 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>13 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>+1.8 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>16 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>+0.9 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>12 weeks (Day 70 to 98) </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>17 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>+2.8 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>5 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>+3.1 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>24 weeks (Day 154 to 182) </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>42 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>-0.6 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>12 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>+5.7 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0 </paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>48 weeks (Day 322 to 350) </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>3 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>+3.7 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>3 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>+13.7 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0 </paragraph></td></tr></tbody></table>

3 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>+13.7 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0 </paragraph></td></tr></tbody></table> <table ID="_RefID0EDRAI" cellpadding="0pt" cellspacing="0pt" width="100%"><caption>Table 8. Proportion of Adult Subjects in Schizophrenia Studies with Weight Gain &#x2265;7% Relative to Baseline Body Weight</caption><col width="25%"/><col width="25%"/><col width="25%"/><col width="24%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Weight change</content> </paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="middle"><paragraph><content styleCode="bold">Clozapine</content> </paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="middle"><paragraph><content styleCode="bold">Olanzapine</content> </paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="middle"><paragraph><content styleCode="bold">Chlorpromazine</content> </paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">N</content> </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>669 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>442 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>155 </paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph><content styleCode="bold">&#x2265;7% (inclusive)</content> </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>236 (35%) </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>203 (46%) </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>13 (8%) </paragraph></td></tr></tbody></table>

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: • Severe Neutropenia [see Warnings and Precautions (5.1) ] • Orthostatic Hypotension, Bradycardia, and Syncope [see Warnings and Precautions (5.2) ] • Falls [see Warnings and Precautions (5.3) ] • Seizures [see Warnings and Precautions (5.4) ] • Myocarditis, Pericarditis, Cardiomyopathy, and Mitral Valve Incompetence [see Warnings and Precautions (5.5) ] • Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Warnings and Precautions (5.6) ] • Gastrointestinal Hypomotility with Severe Complications [See Warnings and Precautions (5.7) ] • Eosinophilia [see Warnings and Precautions (5.8) ] • QT Interval Prolongation [see Warnings and Precautions (5.9) ] • Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain) [see Warnings and Precautions (5.10) ] • Neuroleptic Malignant Syndrome [see Warnings and Precautions (5.11) ] • Hepatotoxicity [see Warnings and Precautions (5.12) ] • Fever [see Warnings and Precautions (5.13) ] • Pulmonary Embolism [see Warnings and Precautions (5.14) ] • Anticholinergic Toxicity [see Warnings and Precautions (5.15) ] • Interference with Cognitive and Motor Performance [see Warnings and Precautions (5.16) ] • Tardive Dyskinesia [see Warnings and Precautions (5.17) ] • Cerebrovascular Adverse Reactions [see Warnings and Precautions (5.18) ] • Recurrence of Psychosis and Cholinergic Rebound after Abrupt Discontinuation [see Warnings and Precautions (5.19) ] Most common adverse reactions (≥5%) were: CNS reactions (sedation, dizziness/vertigo, headache, and tremor); cardiovascular reactions (tachycardia, hypotension, and syncope); autonomic nervous system reactions (hypersalivation, sweating, dry mouth, and visual disturbances); gastrointestinal reactions (constipation and nausea); and fever. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The most commonly reported adverse reactions (≥5%) across clozapine clinical trials were: CNS reactions, including sedation, dizziness/vertigo, headache, and tremor; cardiovascular reactions, including tachycardia, hypotension, and syncope; autonomic nervous system reactions, including hypersalivation, sweating, dry mouth, and visual disturbances; gastrointestinal reactions, including constipation and nausea; and fever. Table 9 summarizes the most commonly reported adverse reactions (≥5%) in clozapine-treated patients (compared to chlorpromazine-treated patients) in the pivotal, 6-week, controlled trial in treatment-resistant schizophrenia. Table 9.

isturbances; gastrointestinal reactions, including constipation and nausea; and fever. Table 9 summarizes the most commonly reported adverse reactions (≥5%) in clozapine-treated patients (compared to chlorpromazine-treated patients) in the pivotal, 6-week, controlled trial in treatment-resistant schizophrenia. Table 9. Common Adverse Reactions (≥5%) in the 6-Week, Randomized, Chlorpromazine-controlled Trial in Treatment-Resistant Schizophrenia Adverse Reaction Clozapine (N=126) (%) Chlorpromazine (N=142) (%) Sedation 21 13 Tachycardia 17 11 Constipation 16 12 Dizziness 14 16 Hypotension 13 38 Fever (hyperthermia) 13 4 Hypersalivation 13 1 Hypertension 12 5 Headache 10 10 Nausea/vomiting 10 12 Dry mouth 5 20 Table 10 summarizes the adverse reactions reported in clozapine-treated patients at a frequency of 2% or greater across all clozapine studies (excluding the 2-year InterSePT™ Study). These rates are not adjusted for duration of exposure. Table 10. Adverse Reactions (≥2%) Reported in Clozapine-treated Patients (N=842) Across all Clozapine Studies (excluding the 2-year InterSePT TM Study) Body System Adverse Reaction* Clozapine N=842 Percentage of Patients Central Nervous System Drowsiness/Sedation 39 Dizziness/Vertigo 19 Headache 7 Tremor 6 Syncope 6 Disturbed Sleep/Nightmares 4 Restlessness 4 Hypokinesia/Akinesia 4 Agitation 4 Seizures (convulsions) 3 † Rigidity 3 Akathisia 3 Confusion 3 Fatigue 2 Insomnia 2 Cardiovascular Tachycardia 25 † Hypotension 9 Hypertension 4 Gastrointestinal Constipation 14 Nausea 5 Abdominal Discomfort/Heartburn 4 Nausea/Vomiting 3 Vomiting 3 Diarrhea 2 Urogenital Urinary Abnormalities 2 Autonomic Nervous System Salivation 31 Sweating 6 Dry Mouth 6 Visual Disturbances 5 Skin Rash 2 Hemic/Lymphatic Leukopenia/Decreased WBC/Neutropenia 3 Miscellaneous Fever 5 Weight Gain 4 † Rate based on population of approximately 1700 exposed during premarket clinical evaluation of clozapine. Table 11 summarizes the most commonly reported adverse reactions (≥10% of the clozapine or olanzapine group) in the InterSePT™ Study. This was an adequate and well-controlled, two-year study evaluating the efficacy of clozapine relative to olanzapine in reducing the risk of suicidal behavior in patients with schizophrenia or schizoaffective disorder. The rates are not adjusted for duration of exposure. Table 11. Incidence of Adverse Reactions in Patients Treated with Clozapine or Olanzapine in the InterSePT TM Study (≥10% in the Clozapine or olanzapine group) Adverse Reactions Clozapine N=479 % Reporting Olanzapine N=477 % Reporting Salivary hypersecretion 48 6 Somnolence 46 25 Weight increased 31 56 Dizziness (excluding vertigo) 27 12 Constipation 25 10 Insomnia 20 33 Nausea 17 10 Vomiting 17 9 Dyspepsia 14 8 Dystonia Class effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of clozapine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of clozapine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Central Nervous System Delirium, EEG abnormal, myoclonus, paresthesia, possible cataplexy, status epilepticus, obsessive compulsive symptoms, restless leg syndrome and post-discontinuation cholinergic rebound adverse reactions. Cardiovascular System Atrial or ventricular fibrillation, ventricular tachycardia, palpitations, QT interval prolongation, Torsades de Pointes, mitral valve incompetence associated with clozapine-related cardiomyopathy, myocardial infarction, cardiac arrest, myocarditis, pericarditis, and periorbital edema. Endocrine System Pseudopheochromocytoma Gastrointestinal System Acute pancreatitis, dysphagia, salivary gland swelling, colitis, megacolon, fecal incontinence, and intestinal ischemia, infarction, perforation, ulceration or necrosis. Hepatobiliary System Cholestasis, hepatitis, jaundice, hepatotoxicity, hepatic steatosis, hepatic necrosis, hepatic fibrosis, hepatic cirrhosis, liver injury (hepatic, cholestatic, and mixed), and liver failure. Immune System Disorders Angioedema, leukocytoclastic vasculitis. Urogenital System Acute interstitial nephritis, nocturnal enuresis, priapism, renal failure, and retrograde ejaculation. Skin and Subcutaneous Tissue Disorders Hypersensitivity reactions: photosensitivity, vasculitis, erythema multiforme, skin pigmentation disorder, and Stevens-Johnson Syndrome. Musculoskeletal System and Connective Tissue Disorders Myasthenic syndrome, rhabdomyolysis, and systemic lupus erythematosus. Respiratory System Aspiration, pleural effusion, pneumonia, lower respiratory tract infection, sleep apnea. Hemic and Lymphatic System Mild, moderate, or severe leukopenia, agranulocytosis, granulocytopenia, WBC decreased, deep-vein thrombosis, elevated hemoglobin/hematocrit, erythrocyte sedimentation rate (ESR) increased, sepsis, thrombocytosis, and thrombocytopenia. Vision Disorders Narrow-angle glaucoma. Miscellaneous Creatine phosphokinase elevation, hyperuricemia, hyponatremia, polyserositis, and weight loss.

<table ID="_RefID0EYABI" cellpadding="0pt" cellspacing="0pt" width="100%"><caption>Table 9. Common Adverse Reactions (&#x2265;5%) in the 6-Week, Randomized, Chlorpromazine-controlled Trial in Treatment-Resistant Schizophrenia</caption><col width="34%"/><col width="32%"/><col width="34%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Adverse Reaction </content> </paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="middle"><paragraph><content styleCode="bold">Clozapine</content> <content styleCode="bold">(N=126)</content> <content styleCode="bold">(%)</content> </paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="middle"><paragraph><content styleCode="bold">Chlorpromazine</content> <content styleCode="bold">(N=142)</content> <content styleCode="bold">(%)</content> </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Sedation </content> </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>21 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>13 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Tachycardia </content> </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>17 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>11 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Constipation </content> </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>16 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>12 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Dizziness </content> </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>14 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>16 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Hypotension </content> </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>13 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>38 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Fever (hyperthermia) </content> </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>13 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>4 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Hypersalivation </content> </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>13 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>1 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Hypertension </content> </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>12 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>5 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content st

de="bold">Hypertension </content> </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>12 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>5 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content st yleCode="bold">Headache </content> </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>10 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>10 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Nausea/vomiting </content> </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>10 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>12 </paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="middle"><paragraph><content styleCode="bold">Dry mouth </content> </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>5 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>20 </paragraph></td></tr></tbody></table> <table ID="_RefID0EVJBI" cellpadding="0pt" cellspacing="0pt" width="100%"><caption>Table 10.

yleCode="bold">Headache </content> </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>10 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>10 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Nausea/vomiting </content> </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>10 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>12 </paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="middle"><paragraph><content styleCode="bold">Dry mouth </content> </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>5 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>20 </paragraph></td></tr></tbody></table> <table ID="_RefID0EVJBI" cellpadding="0pt" cellspacing="0pt" width="100%"><caption>Table 10. Adverse Reactions (&#x2265;2%) Reported in Clozapine-treated Patients (N=842) Across all Clozapine Studies (excluding the 2-year InterSePT^TM Study)</caption><col width="51%"/><col width="49%"/><thead><tr><th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Body System</content> <content styleCode="bold">Adverse Reaction*</content> </th><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Clozapine</content> <content styleCode="bold">N=842</content> <content styleCode="bold">Percentage of Patients</content> </th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph><content styleCode="bold">Central Nervous System</content> </paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph> </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Drowsiness/Sedation </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>39 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Dizziness/Vertigo </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>19 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Headache </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>7 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Tremor </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>6 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Syncope </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>6 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Disturbed Sleep/Nightmares </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>4 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Restlessness </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>4 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Hypokinesia/Akinesia </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>4 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Agitation </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>4 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Seizures (convulsions) </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>3^&#x2020; </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Rigidity </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>3 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Akathisia </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>3 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Confusion </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>3 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Bot

align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>3 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Confusion </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>3 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Bot rule " valign="middle"><paragraph>Fatigue </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>2 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Insomnia </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>2 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Cardiovascular</content> </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph> </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Tachycardia </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>25^&#x2020; </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Hypotension </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>9 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Hypertension </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>4 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Gastrointestinal</content> </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph> </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Constipation </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>14 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Nausea </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>5 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Abdominal Discomfort/Heartburn </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>4 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Nausea/Vomiting </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>3 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Vomiting </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>3 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Diarrhea </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>2 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Urogenital</content> </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph> </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Urinary Abnormalities </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>2 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Autonomic Nervous System</content> </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph> </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Salivation </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>31 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule

n="center" styleCode="Rrule Botrule " valign="middle"><paragraph> </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Salivation </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>31 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Sweating </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>6 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Dry Mouth </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>6 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Visual Disturbances </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>5 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Skin</content> </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph> </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Rash </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>2 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Hemic/Lymphatic</content> </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph> </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Leukopenia/Decreased WBC/Neutropenia </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>3 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Miscellaneous</content> </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph> </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Fever </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>5 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Weight Gain </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>4 </paragraph></td></tr><tr><td colspan="2" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>^&#x2020;Rate based on population of approximately 1700 exposed during premarket clinical evaluation of clozapine.

Gain </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>4 </paragraph></td></tr><tr><td colspan="2" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>^&#x2020;Rate based on population of approximately 1700 exposed during premarket clinical evaluation of clozapine. </paragraph></td></tr></tbody></table> <table ID="_RefID0EK3BI" cellpadding="0pt" cellspacing="0pt" width="100%"><caption>Table 11.

Gain </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>4 </paragraph></td></tr><tr><td colspan="2" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>^&#x2020;Rate based on population of approximately 1700 exposed during premarket clinical evaluation of clozapine. </paragraph></td></tr></tbody></table> <table ID="_RefID0EK3BI" cellpadding="0pt" cellspacing="0pt" width="100%"><caption>Table 11. Incidence of Adverse Reactions in Patients Treated with Clozapine or Olanzapine in the InterSePT^TM Study (&#x2265;10% in the Clozapine or olanzapine group)</caption><col width="34%"/><col width="34%"/><col width="32%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Adverse Reactions</content> </paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="middle"><paragraph><content styleCode="bold">Clozapine</content> <content styleCode="bold">N=479 </content> <content styleCode="bold"> % Reporting</content> </paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="middle"><paragraph><content styleCode="bold">Olanzapine</content> <content styleCode="bold">N=477 </content> <content styleCode="bold"> % Reporting</content> </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Salivary hypersecretion </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>48 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>6 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Somnolence </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>46 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>25 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Weight increased </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>31 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>56 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Dizziness (excluding vertigo) </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>27 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>12 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Constipation </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>25 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>10 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Insomnia </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>20 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>33 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Nausea </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>17 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>10 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Vomiting </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>17 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>9 </paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>Dyspepsia </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>14 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>8 </paragraph></td></tr></tbody></table>

7 DRUG INTERACTIONS • Concomitant use of Strong CYP1A2 Inhibitors : Reduce clozapine dose to one-third when coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, enoxacin). ( 2.7 , 7.1 ) • Concomitant use of Strong CYP3A4 Inducers is not recommended. ( 2.7 , 7.1 ) • Discontinuation of CYP1A2 or CYP3A4 Inducers : Consider reducing clozapine dose when CYP1A2 inducers (e.g., tobacco smoke) or CYP3A4 inducers (e.g., carbamazepine) are discontinued. ( 2.7 , 7.1 ) • Anticholinergic drugs: Concomitant use may increase the risk for anticholinergic toxicity. ( 5.7 , 5.15 , 7.1 ) 7.1 Potential for Other Drugs to Affect Clozapine Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP3A4, and CYP2D6. Use caution when administering clozapine concomitantly with drugs that are inducers or inhibitors of these enzymes. CYP1A2 Inhibitors Concomitant use of clozapine and CYP1A2 inhibitors can increase plasma levels of clozapine, potentially resulting in adverse reactions. Reduce the clozapine dose to one-third of the original dose when clozapine is coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin). The clozapine dose should be increased to the original dose when coadministration of strong CYP1A2 inhibitors is discontinued [see Dosage and Administration (2.7) , Clinical Pharmacology (12.3) ]. Moderate or weak CYP1A2 inhibitors include oral contraceptives and caffeine. Monitor patients closely when clozapine is coadministered with these inhibitors. Consider reducing the clozapine dosage if necessary [see Dosage and Administration (2.7) ]. CYP2D6 and CYP3A4 Inhibitors Concomitant treatment with clozapine and CYP2D6 or CYP3A4 inhibitors (e.g., cimetidine, escitalopram, erythromycin, paroxetine, bupropion, fluoxetine, quinidine, duloxetine, terbinafine, or sertraline) can increase clozapine levels and lead to adverse reactions [see Clinical Pharmacology (12.3) ] . Use caution and monitor patients closely when using such inhibitors. Consider reducing the clozapine dose [see Dosage and Administration (2.7) ]. CYP1A2 and CYP3A4 Inducers Concomitant treatment with drugs that induce CYP1A2 or CYP3A4 can decrease the plasma concentration of clozapine, resulting in decreased effectiveness of clozapine. Tobacco smoke is a moderate inducer of CYP1A2. Strong CYP3A4 inducers include carbamazepine, phenytoin, St. John’s wort, and rifampin. It may be necessary to increase the clozapine dose if used concomitantly with inducers of these enzymes. However, concomitant use of clozapine and strong CYP3A4 inducers is not recommended [see Dosage and Administration (2.7) ] . Consider reducing the clozapine dosage when discontinuing coadministered enzyme inducers; because discontinuation of inducers can result in increased clozapine plasma levels and an increased risk of adverse reactions [see Dosage and Administration (2.7) ] . Anticholinergic Drugs Concomitant treatment with clozapine and other drugs with anticholinergic activity (e.g., benztropine, cyclobenzaprine, diphenhydramine) can increase the risk for anticholinergic toxicity and severe gastrointestinal adverse reactions related to hypomotility. Avoid concomitant use of clozapine with anticholinergic drugs when possible [see Warnings and Precautions (5.7 , 5.15) ].

ticholinergic activity (e.g., benztropine, cyclobenzaprine, diphenhydramine) can increase the risk for anticholinergic toxicity and severe gastrointestinal adverse reactions related to hypomotility. Avoid concomitant use of clozapine with anticholinergic drugs when possible [see Warnings and Precautions (5.7 , 5.15) ]. Drugs that Cause QT Interval Prolongation Use caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of clozapine. Drugs that cause QT prolongation include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, thioridazine, mesoridazine, droperidol, and pimozide), specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin), Class 1A antiarrhythmics (e.g., quinidine, procainamide) or Class III antiarrhythmics (e.g., amiodarone, sotalol), and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus) [see Warnings and Precautions (5.9) ] . 7.2 Potential for Clozapine to Affect Other Drugs Concomitant use of clozapine with other drugs metabolized by CYP2D6 can increase levels of these CYP2D6 substrates. Use caution when coadministering clozapine with other drugs that are metabolized by CYP2D6. It may be necessary to use lower doses of such drugs than usually prescribed. Such drugs include specific antidepressants, phenothiazines, carbamazepine, and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide).

8 USE IN SPECIFIC POPULATIONS • Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure ( 8.1 ). 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including clozapine, during pregnancy. Healthcare providers are encouraged to advise patients to register by calling the National Pregnancy Registry for Atypical Antipsychotics at1-866-961-2388 or visiting http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. Risk Summary Neonates exposed to antipsychotic drugs, including clozapine, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery ( see Clinical Considerations ). Available data from published epidemiologic studies over decades of use with clozapine during pregnancy have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes ( see Data ). There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, including clozapine, during pregnancy ( see Clinical Considerations ). In animal reproduction studies, no adverse developmental effects were observed when clozapine was administered orally to pregnant rats or rabbits during the period of organogenesis, or to pregnant rats during pregnancy and lactation, at doses up to approximately 0.4 and 0.9 times the maximum recommended human dose (MRHD) of 900 mg/day, for rats and rabbits respectively, based on mg/m 2 body surface area ( see Data ). The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk There is a risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide. Schizophrenia is associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. Fetal/Neonatal adverse reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who have been exposed to antipsychotic drugs, including clozapine, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Data Animal Data In embryofetal developmental studies, clozapine had no effects on maternal parameters, litter sizes, or fetal parameters when administered orally to pregnant rats and rabbits during the period of organogenesis at doses up to 0.4 and 0.9 times, respectively, the MRHD of 900 mg/day on a mg/m 2 body surface area basis. In peri/postnatal developmental studies, pregnant female rats were administered clozapine over the last third of pregnancy and until day 21 postpartum.

pregnant rats and rabbits during the period of organogenesis at doses up to 0.4 and 0.9 times, respectively, the MRHD of 900 mg/day on a mg/m 2 body surface area basis. In peri/postnatal developmental studies, pregnant female rats were administered clozapine over the last third of pregnancy and until day 21 postpartum. Observations were made on fetuses at birth and during the postnatal period; the offspring were allowed to reach sexual maturity and mated. Clozapine caused a decrease in maternal body weight but had no effects on litter size or body weights of either F1 or F2 generations at doses up to 0.4 times the MRHD of 900 mg/day on a mg/m 2 body surface area basis. 8.2 Lactation Risk Summary Clozapine is present in human milk. There is one case report of sedation and a report of agranulocytosis in an infant exposed to clozapine through human milk ( see Clinical Considerations ). There is no information on the effects of clozapine on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for clozapine and any potential adverse effects on the breastfed child from clozapine or from the underlying maternal condition. Clinical Considerations Infants exposed to clozapine should be monitored for excess sedation and neutropenia. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use There have not been sufficient numbers of geriatric patients in clinical studies utilizing clozapine to determine whether those over 65 years of age differ from younger subjects in their response to clozapine. Orthostatic hypotension and tachycardia can occur with clozapine treatment [see Boxed Warning and Warnings and Precautions (5.2) ] . Elderly patients, particularly those with compromised cardiovascular functioning, may be more susceptible to these effects. Elderly patients may be particularly susceptible to the anticholinergic effects of clozapine, such as urinary retention and constipation [see Warnings and Precautions (5.15) ] . Carefully select clozapine doses in elderly patients, taking into consideration their greater frequency of decreased hepatic, renal, or cardiac function, as well as other concomitant disease and other drug therapy. Clinical experience suggests that the prevalence of tardive dyskinesia appears to be highest among the elderly; especially elderly women [see Warnings and Precautions (5.17) ] . 8.6 Patients with Renal or Hepatic Impairment Dose reduction may be necessary in patients with significant impairment of renal or hepatic function. Clozapine concentrations may be increased in these patients, because clozapine is almost completely metabolized and then excreted [see Dosage and Administration (2.8) , Clinical Pharmacology (12.3) ]. 8.7 CYP2D6 Poor Metabolizers Dose reduction may be necessary in patients who are CYP2D6 poor metabolizers. Clozapine concentrations may be increased in these patients, because clozapine is almost completely metabolized and then excreted [see Dosage and Administration (2.8) , Clinical Pharmacology (12.3) ] .

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including clozapine, during pregnancy. Healthcare providers are encouraged to advise patients to register by calling the National Pregnancy Registry for Atypical Antipsychotics at1-866-961-2388 or visiting http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. Risk Summary Neonates exposed to antipsychotic drugs, including clozapine, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery ( see Clinical Considerations ). Available data from published epidemiologic studies over decades of use with clozapine during pregnancy have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes ( see Data ). There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, including clozapine, during pregnancy ( see Clinical Considerations ). In animal reproduction studies, no adverse developmental effects were observed when clozapine was administered orally to pregnant rats or rabbits during the period of organogenesis, or to pregnant rats during pregnancy and lactation, at doses up to approximately 0.4 and 0.9 times the maximum recommended human dose (MRHD) of 900 mg/day, for rats and rabbits respectively, based on mg/m 2 body surface area ( see Data ). The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk There is a risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide. Schizophrenia is associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. Fetal/Neonatal adverse reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who have been exposed to antipsychotic drugs, including clozapine, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Data Animal Data In embryofetal developmental studies, clozapine had no effects on maternal parameters, litter sizes, or fetal parameters when administered orally to pregnant rats and rabbits during the period of organogenesis at doses up to 0.4 and 0.9 times, respectively, the MRHD of 900 mg/day on a mg/m 2 body surface area basis. In peri/postnatal developmental studies, pregnant female rats were administered clozapine over the last third of pregnancy and until day 21 postpartum. Observations were made on fetuses at birth and during the postnatal period; the offspring were allowed to reach sexual maturity and mated.

8.2 Lactation Risk Summary Clozapine is present in human milk. There is one case report of sedation and a report of agranulocytosis in an infant exposed to clozapine through human milk ( see Clinical Considerations ). There is no information on the effects of clozapine on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for clozapine and any potential adverse effects on the breastfed child from clozapine or from the underlying maternal condition. Clinical Considerations Infants exposed to clozapine should be monitored for excess sedation and neutropenia.

8.5 Geriatric Use There have not been sufficient numbers of geriatric patients in clinical studies utilizing clozapine to determine whether those over 65 years of age differ from younger subjects in their response to clozapine. Orthostatic hypotension and tachycardia can occur with clozapine treatment [see Boxed Warning and Warnings and Precautions (5.2) ] . Elderly patients, particularly those with compromised cardiovascular functioning, may be more susceptible to these effects. Elderly patients may be particularly susceptible to the anticholinergic effects of clozapine, such as urinary retention and constipation [see Warnings and Precautions (5.15) ] . Carefully select clozapine doses in elderly patients, taking into consideration their greater frequency of decreased hepatic, renal, or cardiac function, as well as other concomitant disease and other drug therapy. Clinical experience suggests that the prevalence of tardive dyskinesia appears to be highest among the elderly; especially elderly women [see Warnings and Precautions (5.17) ] .

10 OVERDOSAGE 10.1 Overdosage Experience The most commonly reported signs and symptoms associated with clozapine overdose are: sedation, delirium, coma, tachycardia, hypotension, respiratory depression or failure; and hypersalivation. There are reports of aspiration pneumonia, cardiac arrhythmias, and seizure. Fatal overdoses have been reported with clozapine, generally at doses above 2500 mg. There have also been reports of patients recovering from overdoses well in excess of 4 g. 10.2 Management of Overdosage There is no available specific antidote to an overdose of clozapine. Establish and maintain an airway; ensure adequate oxygenation and ventilation. Monitor cardiac status and vital signs. Use general symptomatic and supportive measures. Consider the possibility of multiple-drug involvement. Contact a Certified Poison Control Center for the most up to date information on the management of overdosage (1-800‑-222-1222).

11 DESCRIPTION Clozapine, an atypical antipsychotic drug, is a tricyclic dibenzodiazepine derivative, 8-chloro-11-(4-methyl-1-piperazinyl)-5 H -dibenzo [ b,e ] [1,4] diazepine. The structural formula is: Clozapine USP is available in pale yellow colored tablets of 25 mg, 50 mg, 100 mg, and 200 mg for oral administration. Active Ingredient: clozapine Inactive Ingredients are colloidal silicon dioxide, corn starch, lactose monohydrate, magnesium stearate, povidone, and talc. Chemical Structure

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of clozapine is unknown. However, it has been proposed that the therapeutic efficacy of clozapine in schizophrenia is mediated through antagonism of the dopamine type 2 (D 2 ) and the serotonin type 2A (5-HT 2A ) receptors. Clozapine also acts as an antagonist at adrenergic, cholinergic, histaminergic and other dopaminergic and serotonergic receptors. 12.2 Pharmacodynamics Clozapine demonstrated binding affinity to the following receptors: histamine H 1 (K i 1.1 nM), adrenergic α 1A (K i 1.6 nM), serotonin 5-HT 6 (K i 4 nM ) , serotonin 5-HT 2A (K i 5.4 nM), muscarinic M 1 (K i 6.2 nM), serotonin 5-HT 7 (K i 6.3 nM), serotonin 5-HT 2C (K i 9.4 nM), dopamine D 4 (K i 24 nM), adrenergic α 2A (K i 90 nM), serotonin 5-HT 3 (K i 95 nM), serotonin 5-HT 1A (K i 120 nM), dopamine D 2 (K i 160 nM), dopamine D 1 (K i 270 nM), dopamine D 5 (K i 454 nM), and dopamine D 3 (K i 555 nM). Clozapine causes little or no prolactin elevation. Clinical electroencephalogram (EEG) studies demonstrated that clozapine increases delta and theta activity and slows dominant alpha frequencies. Enhanced synchronization occurs. Sharp wave activity and spike and wave complexes may also develop. Patients have reported an intensification of dream activity during clozapine therapy. REM sleep was found to be increased to 85% of the total sleep time. In these patients, the onset of REM sleep occurred almost immediately after falling asleep. 12.3 Pharmacokinetics Absorption In humans, clozapine tablets (25 mg and 100 mg) are equally bioavailable relative to a clozapine solution. Following oral administration of clozapine 100 mg twice daily, the average steady-state peak plasma concentration was 319 ng/mL (range: 102 to 771 ng/mL), occurring at the average of 2.5 hours (range: 1 to 6 hours) after dosing. The average minimum concentration at steady state was 122 ng/mL (range: 41 to 343 ng/mL), after 100 mg twice daily dosing. Food does not appear to affect the systemic bioavailability of clozapine. Thus, clozapine may be administered with or without food. Distribution Clozapine is approximately 97% bound to serum proteins. The interaction between clozapine and other highly protein-bound drugs has not been fully evaluated but may be important [see Drug Interactions (7) ]. Metabolism and Excretion Clozapine is almost completely metabolized prior to excretion, and only trace amounts of unchanged drug are detected in the urine and feces. Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP2D6, and CYP3A4. Approximately 50% of the administered dose is excreted in the urine and 30% in the feces. The demethylated, hydroxylated, and N -oxide derivatives are components in both urine and feces. Pharmacological testing has shown the desmethyl metabolite (norclozapine) to have only limited activity, while the hydroxylated and N -oxide derivatives were inactive. The mean elimination half-life of clozapine after a single 75 mg dose was 8 hours (range: 4 to 12 hours), compared to a mean elimination half-life of 12 hours (range: 4 to 66 hours), after achieving steady state with 100 mg twice daily dosing. A comparison of single-dose and multiple-dose administration of clozapine demonstrated that the elimination half-life increased significantly after multiple dosing relative to that after single-dose administration, suggesting the possibility of concentration-dependent pharmacokinetics.

e with 100 mg twice daily dosing. A comparison of single-dose and multiple-dose administration of clozapine demonstrated that the elimination half-life increased significantly after multiple dosing relative to that after single-dose administration, suggesting the possibility of concentration-dependent pharmacokinetics. However, at steady state, approximately dose-proportional changes with respect to AUC (area under the curve), peak, and minimum clozapine plasma concentrations were observed after administration of 37.5, 75, and 150 mg twice daily. Drug-Drug Interaction Studies Fluvoxamine A pharmacokinetic study was conducted in 16 patients with schizophrenia who received clozapine under steady-state conditions. After coadministration of fluvoxamine for 14 days, mean trough concentrations of clozapine and its metabolites, N -desmethylclozapine and clozapine N -oxide, were elevated about three-fold compared to baseline steady-state concentrations. Paroxetine, Fluoxetine, and Sertraline In a study of patients with schizophrenia (n=14) who received clozapine under steady-state conditions, coadministration of paroxetine produced only minor changes in the levels of clozapine and its metabolites. However, other published reports describe modest elevations (less than two-fold) of clozapine and metabolite concentrations when clozapine was taken with paroxetine, fluoxetine, and sertraline. Specific Population Studies Renal or Hepatic Impairment No specific pharmacokinetic studies were conducted to investigate the effects of renal or hepatic impairment on the pharmacokinetics of clozapine. Higher clozapine plasma concentrations are likely in patients with significant renal or hepatic impairment when given usual doses. CYP2D6 Poor Metabolizers A subset (3% to 10%) of the population has reduced activity of CYP2D6 (CYP2D6 poor metabolizers). These individuals may develop higher than expected plasma concentrations of clozapine when given usual doses. Patients with Pneumonia and other Inflammatory Conditions Published case reports describe examples where pneumonia or other inflammatory conditions may increase clozapine concentrations. The clinical significance, the impact of treatments to modulate this inflammation, and mechanism of this potential increase in clozapine concentrations have not been fully characterized but may involve reduced cytochrome P450 1A2 activity.

12.1 Mechanism of Action The mechanism of action of clozapine is unknown. However, it has been proposed that the therapeutic efficacy of clozapine in schizophrenia is mediated through antagonism of the dopamine type 2 (D 2 ) and the serotonin type 2A (5-HT 2A ) receptors. Clozapine also acts as an antagonist at adrenergic, cholinergic, histaminergic and other dopaminergic and serotonergic receptors.

12.3 Pharmacokinetics Absorption In humans, clozapine tablets (25 mg and 100 mg) are equally bioavailable relative to a clozapine solution. Following oral administration of clozapine 100 mg twice daily, the average steady-state peak plasma concentration was 319 ng/mL (range: 102 to 771 ng/mL), occurring at the average of 2.5 hours (range: 1 to 6 hours) after dosing. The average minimum concentration at steady state was 122 ng/mL (range: 41 to 343 ng/mL), after 100 mg twice daily dosing. Food does not appear to affect the systemic bioavailability of clozapine. Thus, clozapine may be administered with or without food. Distribution Clozapine is approximately 97% bound to serum proteins. The interaction between clozapine and other highly protein-bound drugs has not been fully evaluated but may be important [see Drug Interactions (7) ]. Metabolism and Excretion Clozapine is almost completely metabolized prior to excretion, and only trace amounts of unchanged drug are detected in the urine and feces. Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP2D6, and CYP3A4. Approximately 50% of the administered dose is excreted in the urine and 30% in the feces. The demethylated, hydroxylated, and N -oxide derivatives are components in both urine and feces. Pharmacological testing has shown the desmethyl metabolite (norclozapine) to have only limited activity, while the hydroxylated and N -oxide derivatives were inactive. The mean elimination half-life of clozapine after a single 75 mg dose was 8 hours (range: 4 to 12 hours), compared to a mean elimination half-life of 12 hours (range: 4 to 66 hours), after achieving steady state with 100 mg twice daily dosing. A comparison of single-dose and multiple-dose administration of clozapine demonstrated that the elimination half-life increased significantly after multiple dosing relative to that after single-dose administration, suggesting the possibility of concentration-dependent pharmacokinetics. However, at steady state, approximately dose-proportional changes with respect to AUC (area under the curve), peak, and minimum clozapine plasma concentrations were observed after administration of 37.5, 75, and 150 mg twice daily. Drug-Drug Interaction Studies Fluvoxamine A pharmacokinetic study was conducted in 16 patients with schizophrenia who received clozapine under steady-state conditions. After coadministration of fluvoxamine for 14 days, mean trough concentrations of clozapine and its metabolites, N -desmethylclozapine and clozapine N -oxide, were elevated about three-fold compared to baseline steady-state concentrations. Paroxetine, Fluoxetine, and Sertraline In a study of patients with schizophrenia (n=14) who received clozapine under steady-state conditions, coadministration of paroxetine produced only minor changes in the levels of clozapine and its metabolites. However, other published reports describe modest elevations (less than two-fold) of clozapine and metabolite concentrations when clozapine was taken with paroxetine, fluoxetine, and sertraline. Specific Population Studies Renal or Hepatic Impairment No specific pharmacokinetic studies were conducted to investigate the effects of renal or hepatic impairment on the pharmacokinetics of clozapine. Higher clozapine plasma concentrations are likely in patients with significant renal or hepatic impairment when given usual doses.

lation Studies Renal or Hepatic Impairment No specific pharmacokinetic studies were conducted to investigate the effects of renal or hepatic impairment on the pharmacokinetics of clozapine. Higher clozapine plasma concentrations are likely in patients with significant renal or hepatic impairment when given usual doses. CYP2D6 Poor Metabolizers A subset (3% to 10%) of the population has reduced activity of CYP2D6 (CYP2D6 poor metabolizers). These individuals may develop higher than expected plasma concentrations of clozapine when given usual doses. Patients with Pneumonia and other Inflammatory Conditions Published case reports describe examples where pneumonia or other inflammatory conditions may increase clozapine concentrations. The clinical significance, the impact of treatments to modulate this inflammation, and mechanism of this potential increase in clozapine concentrations have not been fully characterized but may involve reduced cytochrome P450 1A2 activity.

14 CLINICAL STUDIES 14.1 Treatment-Resistant Schizophrenia The efficacy of clozapine in treatment-resistant schizophrenia was established in a multicenter, randomized, double-blind, active-controlled (chlorpromazine) study in patients with a DSM-III diagnosis of schizophrenia who had inadequate responses to at least 3 different antipsychotics (from at least 2 different chemical classes) during the preceding 5 years. The antipsychotic trials must have been judged adequate; the antipsychotic dosages must have been equivalent to or greater than 1000 mg per day of chlorpromazine for a period of at least 6 weeks, each without significant reduction of symptoms. There must have been no period of good functioning within the preceding 5 years. Patients must have had a baseline score of at least 45 on the investigator-rated Brief Psychiatric Rating Scale (BPRS). On the 18-item BPRS, 1 indicates the absence of symptoms, and 7 indicates severe symptoms; the maximum potential total BPRS score is 126. At baseline, the mean BPRS score was 61. In addition, patients must have had a score of at least 4 on at least two of the following four individual BPRS items: conceptual disorganization, suspiciousness, hallucinatory behavior, and unusual thought content. Patients must have had a Clinical Global Impressions–Severity Scale score of at least 4 (moderately ill). In the prospective, lead-in phase of the trial, all patients (N=305) initially received single-blind treatment with haloperidol (the mean dose was 61 mg per day) for 6 weeks. More than 80% of patients completed the 6-week trial. Patients with an inadequate response to haloperidol (n=268) were randomized to double-blind treatment with clozapine (N=126) or chlorpromazine (N=142). The maximum daily clozapine dose was 900 mg; the mean daily dose was >600 mg. The maximum daily chlorpromazine dose was 1800 mg; the mean daily dose was >1200 mg. The primary endpoint was treatment response, predefined as a decrease in BPRS score of at least 20% and either (1) a CGI-S score of ≤3 (mildly ill), or (2) a BPRS score of ≤35, at the end of 6 weeks of treatment. Approximately 88% of patients from the clozapine and chlorpromazine groups completed the 6-week trial. At the end of 6 weeks, 30% of the clozapine group responded to treatment, and 4% of the chlorpromazine group responded to treatment. The difference was statistically significant (p <0.001). The mean change in total BPRS score was -16 and -5 in the clozapine and chlorpromazine group, respectively; the mean change in the 4 key BPRS item scores was -5 and -2 in the clozapine and chlorpromazine group, respectively; and the mean change in CGI-S score was -1.2 and -0.4, in the clozapine and chlorpromazine group, respectively. These changes in the clozapine group were statistically significantly greater than in the chlorpromazine group (p<0.001 in each analysis). 14.2 Recurrent Suicidal Behavior in Schizophrenia or Schizoaffective Disorder The effectiveness of clozapine in reducing the risk of recurrent suicidal behavior was assessed in the International Suicide Prevention Trial (InterSePT™, a trademark of Novartis Pharmaceuticals Corporation).

group (p<0.001 in each analysis). 14.2 Recurrent Suicidal Behavior in Schizophrenia or Schizoaffective Disorder The effectiveness of clozapine in reducing the risk of recurrent suicidal behavior was assessed in the International Suicide Prevention Trial (InterSePT™, a trademark of Novartis Pharmaceuticals Corporation). This was a prospective, randomized, open-label, active-controlled, multicenter, international, parallel-group comparison of clozapine versus olanzapine (*Zyprexa ® , a registered trademark of Eli Lilly and Company) in 956 patients with schizophrenia or schizoaffective disorder (DSM-IV) who were judged to be at risk for recurrent suicidal behavior. Only about one-fourth of these patients (27%) were considered resistant to standard antipsychotic drug treatment. To enter the trial, patients must have met 1 of the following criteria: • They had attempted suicide within the three years prior to their baseline evaluation. • They had been hospitalized to prevent a suicide attempt within the three years prior to their baseline evaluation. • They demonstrated moderate-to-severe suicidal ideation with a depressive component within one week prior to their baseline evaluation. • They demonstrated moderate-to-severe suicidal ideation accompanied by command hallucinations to do self-harm within one week prior to their baseline evaluation. Dosing regimens for each treatment group were determined by individual investigators and were individualized by patient. Dosing was flexible, with a dose range of 200 to 900 mg/day for clozapine and 5 to 20 mg/day for olanzapine. For the 956 patients who received clozapine or olanzapine in this study, there was extensive use of concomitant psychotropics: 84% with antipsychotics, 65% with anxiolytics, 53% with antidepressants, and 28% with mood stabilizers. There was significantly greater use of concomitant psychotropic medications among the patients in the olanzapine group. The primary efficacy measure was time to (1) a significant suicide attempt, including a completed suicide; (2) hospitalization due to imminent suicide risk, including increased level of surveillance for suicidality for patients already hospitalized; or (3) worsening of suicidality severity as demonstrated by “much worsening” or “very much worsening” from baseline in the Clinical Global Impression of Severity of Suicidality as assessed by the Blinded Psychiatrist (CGI-SS-BP) scale. A determination of whether or not a reported event met criterion 1 or 2 above was made by the Suicide Monitoring Board (SMB), a group of experts blinded to patient data. A total of 980 patients were randomized to the study and 956 received study medication. Sixty-two percent of the patients were diagnosed with schizophrenia, and the remainder (38%) were diagnosed with schizoaffective disorder. Only about one-fourth of the total patient population (27%) was identified as “treatment-resistant” at baseline. There were more males than females in the study (61% of all patients were male). The mean age of patients entering the study was 37 years of age (range 18 to 69). Most patients were Caucasian (71%), 15% were Black, 1% were Asian, and 13% were classified as being of “other” races. Patients treated with clozapine had a statistically significant longer delay in the time to recurrent suicidal behavior in comparison with olanzapine. This result should be interpreted only as evidence of the effectiveness of clozapine in delaying time to recurrent suicidal behavior and not a demonstration of the superior efficacy of clozapine over olanzapine.

istically significant longer delay in the time to recurrent suicidal behavior in comparison with olanzapine. This result should be interpreted only as evidence of the effectiveness of clozapine in delaying time to recurrent suicidal behavior and not a demonstration of the superior efficacy of clozapine over olanzapine. The probability of experiencing (1) a significant suicide attempt, including a completed suicide, or (2) hospitalization because of imminent suicide risk, including increased level of surveillance for suicidality for patients already hospitalized, was lower for clozapine patients than for olanzapine patients at Week 104: clozapine 24% versus olanzapine 32%; 95% CI of the difference: 2%, 14% (Figure 1). Figure 1. Cumulative Probability of a Significant Suicide Attempt or Hospitalization to Prevent Suicide in Patients with Schizophrenia or Schizoaffective Disorder at High Risk of Suicidality Figure 1. Cumulative Probability of a Significant Suicide Attempt or Hospitalization to Prevent Suicide in Patients with Schizophrenia or Schizoaffective Disorder at High Risk of Suicidality

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Clozapine Tablets USP, 100 mg are pale yellow colored, round, flat faced, bevel edged uncoated tablets debossed with ‘C facilitated scoreline (functional) C’ on one side and ‘57’ on the other side. Overbagged with 10 tablets per bag, NDC 55154-3568-0 WARNING: This Unit Dose package is not child resistant and is Intended for Institutional Use Only. Keep this and all drugs out of the reach of children. 16.2 Storage and Handling Store clozapine tablets, USP at room temperature between 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Keep out of reach of children.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Medication Guide ). Discuss the following issues with patients and caregivers: • Severe Neutropenia: Instruct patients (and caregivers) [see Warnings and Precautions (5.1) ]: - About the risk of developing severe neutropenia and infection with clozapine tablets treatment. - Instruct patients to immediately report to their health care provider any symptom or sign of during clozapine tablets treatment. - About the importance of having frequent ANC testing. • Orthostatic Hypotension, Bradycardia, and Syncope : Inform patients and caregivers about the risk of orthostatic hypotension and syncope, especially during the period of initial dose titration. Instruct them to strictly follow the clinician’s instructions for dosage and administration [see Dosage and Administration (2.2 , 2.6) ]. Advise patients to consult their clinician immediately if they feel faint, lose consciousness or have signs or symptoms suggestive of bradycardia or arrhythmia [ Warnings and Precautions (5.2) ]. • Seizures: Inform patients and caregivers about the significant risk of seizure during clozapine treatment. Caution them about driving and any other potentially hazardous activity while taking clozapine tablets [see Warnings and Precautions (5.4) ]. • Gastrointestinal Hypomotility with Severe Complications: Educate patients and caregivers on the risks, prevention and treatment of clozapine-induced constipation, including medications to avoid when possible (e.g., drugs with anticholinergic activity). Encourage appropriate hydration, physical activity, and fiber intake and emphasize that prompt attention and treatment to the development of constipation or other gastrointestinal symptoms is critical in preventing severe complications. Advise patients and caregivers to contact their health care provider if they experience symptoms of constipation (e.g., difficulty passing stools, incomplete passage of stool, decreased bowel movement frequency) or other symptoms associated with gastrointestinal hypomotility (e.g., nausea, abdominal distension or pain, vomiting) [see Warnings and Precautions (5.7) , Drug Interactions (7.1) ]. • QT Interval Prolongation: Advise patients to consult their clinician immediately if they feel faint, lose consciousness or have signs or symptoms suggestive of arrhythmia. Instruct patients to not take clozapine tablets with other drugs that cause QT interval prolongation. Instruct patients to inform their clinicians that they are taking clozapine tablets before any new drug [see Warnings and Precautions (5.9) , Drug Interactions (7.1) ]. • Metabolic Changes (hyperglycemia and diabetes mellitus, dyslipidemia, weight gain) : Educate patients and caregivers about the risk of metabolic changes and the need for specific monitoring. The risks include hyperglycemia and diabetes mellitus, dyslipidemia, weight gain, and cardiovascular reactions. Educate patients and caregivers about the symptoms of hyperglycemia (high blood sugar) and diabetes mellitus (e.g., polydipsia, polyuria, polyphagia, and weakness). Monitor all patients for these symptoms. Patients who are diagnosed with diabetes or have risk factors for diabetes (obesity, family history of diabetes) should have their fasting blood glucose monitored before beginning treatment and periodically during treatment. Patients who develop symptoms of hyperglycemia should have assessments of fasting glucose.

oms. Patients who are diagnosed with diabetes or have risk factors for diabetes (obesity, family history of diabetes) should have their fasting blood glucose monitored before beginning treatment and periodically during treatment. Patients who develop symptoms of hyperglycemia should have assessments of fasting glucose. Clinical monitoring of weight is recommended [see Warnings and Precautions (5.10) ] . • Interference with Cognitive and Motor Performance: Because clozapine tablets may have the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that clozapine therapy does not affect them adversely [see Warnings and Precautions (5.16) ] . • Missed Doses and Re-initiating Treatment: Inform patients and caregivers that if the patient misses taking clozapine tablets for 1 day or more, they should not restart their medication at the same dosage but should contact their physician for dosing instructions [see Dosage and Administration (2.6) , Warnings and Precautions (5.1 , 5.2) ]. • Pregnancy: Advise pregnant women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with clozapine. Advise patients that clozapine tablets may cause extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) in a neonate. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to clozapine tablets during pregnancy [see Use in Specific Populations (8.1) ]. • Lactation: Advise breastfeeding women using clozapine to monitor infants for excess sedation and to seek medical care if they notice this sign. Inform breastfeeding women using clozapine that their healthcare provider will monitor infants for neutropenia [see Use in Specific Populations (8.2) ]. • Concomitant Medication: Advise patients to inform their healthcare provider if they are taking, or plan to take, any prescription or over-the-counter drugs; there is a potential for significant drug-drug interactions [see Dosage and Administration (2.7) , Drug Interactions (7.1) ] . Distributed by: Aurobindo Pharma USA, Inc. 279 Princeton-Hightstown Road East Windsor, NJ 08520 Manufactured by: Aurobindo Pharma Limited Hyderabad-500 032, India Packaged and Distributed by: MAJOR® PHARMACEUTICALS Indianapolis, IN 46268 USA Refer to package label for Distributor's NDC Number Distributed By: Cardinal Health Dublin, OH 43017 L57473990324 Revised: 07/2025 *Zyprexa ® (olanzapine) is a registered trademark of Eli Lilly and Company.

MEDICATION GUIDE Clozapine ( kloe′ za peen ) Tablets, USP for oral use What is the most important information I should know about clozapine tablets? Clozapine tablets can cause serious side effects including: • Severe neutropenia (low white blood cell (WBC) counts) that can lead to serious infections and death . Your healthcare provider will do WBC blood tests before starting treatment with clozapine tablets and weekly for the first 6 months. After your first 6 months of treatment, your healthcare provider will determine how frequent you will have blood tests. If you have symptoms of severe neutropenia or an infection, your healthcare provider will do more frequent WBC blood test(s) to check if clozapine tablets are causing your symptoms and may send you to see a blood specialist (hematologist). Tell your health care provider right away if you have any of the following symptoms or signs of neutropenia or infection: o feel like you have the flu o wounds that take a long time to heal o fever or chills o skin, throat, vaginal, urinary tract, or lung infection o feel extremely tired or weak o pain or burning while peeing o sores or ulcers inside your mouth, gums, or on your skin o unusual vaginal discharge or itching o sores or pain in or around your rectal area o abdominal pain or bloating • Orthostatic hypotension (decreased blood pressure), bradycardia (slow heart rate), or syncope (fainting) that can lead to death . You may feel lightheaded or faint when you rise too quickly from a sitting or lying position. Tell your healthcare provider right away if you feel dizzy or pass out. • Seizures. See “What should I avoid while taking clozapine tablets?” • Myocarditis (heart muscle inflammation), pericarditis (inflammation of outer layer of the heart) and cardiomyopathy (heart muscle weakness) that can lead to death. Symptoms of myocarditis, pericarditis, and cardiomyopathy include: o chest pain o flu-like symptoms o fast heartbeat or palpitations o feel tired or faint o shortness of breath o swollen legs, ankles, or feet o fever • Increased risk of death in elderly people with dementia-related psychosis. Medicines like clozapine tablets can increase the risk of death in elderly people who have lost touch with reality (psychosis) due to confusion and dementia. Clozapine tablets are not for treatment of elderly people with dementia-related psychosis. What are clozapine tablets? Clozapine tablets are a prescription antipsychotic medicine used to treat people: • Who are severely ill with schizophrenia not helped by other schizophrenia medicines • With schizophrenia or schizoaffective disorder who have been suicidal and may be at risk of suicidal behavior again It is not known if clozapine tablets are safe and effective in children. Who should not take clozapine tablets? Do not take clozapine tablets if you: • are allergic to clozapine or any of the ingredients in clozapine tablets. See the end of this Medication Guide for a complete list of ingredients in clozapine tablets.

It is not known if clozapine tablets are safe and effective in children. Who should not take clozapine tablets? Do not take clozapine tablets if you: • are allergic to clozapine or any of the ingredients in clozapine tablets. See the end of this Medication Guide for a complete list of ingredients in clozapine tablets. Before taking clozapine tablets, tell your healthcare provider about all your medical conditions, including if you: • have or have had heart problems or a family history of heart problems including heart attack, heart failure, abnormal heart rhythm or long QT syndrome, or stroke • have or have had low or high blood pressure • have or have had kidney or liver problems • have or have had seizures (convulsions) • have or have had stomach or intestinal problems including constipation, slow emptying of your stomach, or diarrhea • have or have had low levels of potassium or magnesium in your blood • have or have had diabetes or high blood sugar in you or your family • have or have had high levels of total cholesterol, “bad” cholesterol (LDL-C), or triglycerides, or low levels of “good” cholesterol (HDL-C) • have increased pressure in your eyes (glaucoma), an enlarged prostate, or problems passing urine • have or have had uncontrolled movements of your tongue, face, mouth, or jaw (tardive dyskinesia) • smoke tobacco • plan to stop smoking tobacco while taking clozapine tablets • use products containing caffeine • are pregnant or plan to become pregnant. Talk to your healthcare provider if you become pregnant while taking clozapine tablets. o If you become pregnant while receiving clozapine tablets, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or go to http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/ • are breast feeding or plan to breast feed. Clozapine can pass into your breast milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take clozapine tablets. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. • Clozapine tablets and other medicines may affect each other causing side effects. • Your healthcare provider can tell you if it is safe to take clozapine tablets with your other medicines. Do not start or stop any medicines while taking clozapine tablets without talking to your healthcare provider first. • Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I take clozapine tablets? • Take clozapine tablets exactly as your healthcare provider tells you to take it. Do not change your dose or stop taking clozapine tablets unless your healthcare provider tells you to. Talk to your healthcare provider or pharmacist if you are not sure how to take clozapine tablets. • Take clozapine tablets with or without food. • If you miss taking clozapine tablets for 1 day or more, call your healthcare provider right away. Do not take 2 doses at the same time unless your healthcare provider tells you to. • If you take too much (overdose) clozapine, call your healthcare provider or the Poison Help line at 1-800-222-1222 or go to the nearest hospital emergency room right away. Symptoms of clozapine tablets overdose can include: • feeling sleepy • fast or irregular heartbeat • having a lot of saliva in your mouth • confusion • low blood pressure • seizures • coma • shallow or difficult breathing What should I avoid while taking clozapine tablets? • You should not drink alcohol while taking clozapine tablets because it can increase your chances of getting serious side effects.

lar heartbeat • having a lot of saliva in your mouth • confusion • low blood pressure • seizures • coma • shallow or difficult breathing What should I avoid while taking clozapine tablets? • You should not drink alcohol while taking clozapine tablets because it can increase your chances of getting serious side effects. • Do not drive, operate machinery, swim, climb, or do dangerous activities until you know how clozapine tablets affect you. What are the possible side effects of clozapine tablets? Clozapine tablets can cause serious side effects, including: • See "What is the most important information I should know about clozapine tablets?" • falls. Clozapine tablets may make you sleepy, dizzy, may cause a decrease in your blood pressure when changing positions, and can slow your thinking and motor skills which may lead to falls that can cause fractures or other injuries. • slow emptying of your stomach and intestines (decreased gastric motility). Severe constipation and bowel problems can happen and can lead to hospitalization, surgery, and death. You may not feel or be aware of constipation symptoms. Your healthcare provider will examine you for possible bowel problems. Tell your healthcare provider if you get any signs and symptoms of decreased gastrointestinal motility during treatment with clozapine tablets, including: o having bowel movements less than normal o stomach bloating or pain o hard or dry stools o nausea or vomiting o difficulty passing gas Staying well hydrated, increasing physical activity, and taking fiber during treatment with clozapine tablets can help prevent constipation and other bowel problems. Your healthcare provider may prescribe medicines to prevent severe problems. • high count of a certain white blood cell (eosinophilia). Clozapine tablets can cause a high count of eosinophils in some people and can be serious. This is a different risk than the risk of clozapine tablets causing an abnormally low white blood cell count (neutropenia). Your health care provider may send you to see an internal medicine specialist (internist) or blood specialist (hematologist). Tell your healthcare provider right away if you have any of these symptoms: o feeling very tired or weak o coughing and wheezing o fever o nausea, vomiting, or diarrhea o rash o night sweats o swelling o confusion o joint pain o difficulty swallowing • serious heart rhythm problems (QTc Interval Prolongation) that can cause death . Your healthcare provider will do a physical exam and may obtain blood tests and an electrocardiogram before starting you on treatment with clozapine tablets. Tell your healthcare provider right away if you have any of these symptoms: o passing out or feeling like you will pass out o dizziness o feeling as if your heart is pounding or missing beats • problems with your metabolism such as: o high blood sugar (hyperglycemia) or diabetes. Increases in blood sugar can happen in some people who take clozapine tablets. Extremely high blood sugar can lead to coma and death. If you have diabetes or risk factors for diabetes (such as being overweight), your health care provider should check your blood sugar before you start clozapine tablets and during treatment. Tell your healthcare provider if you have any of these symptoms of high blood sugar while taking clozapine tablets: o feel very thirsty o feel very hungry o feel sick to your stomach o need to urinate more than usual o feel weak or tired o feel confused, or your breath smells fruity o increased fat levels (cholesterol and triglycerides) in your blood (dyslipidemia). Your healthcare provider should check the fat levels in your blood before you start and during treatment with clozapine tablets. o weight gain. You and your healthcare provider should check your weight regularly.

r breath smells fruity o increased fat levels (cholesterol and triglycerides) in your blood (dyslipidemia). Your healthcare provider should check the fat levels in your blood before you start and during treatment with clozapine tablets. o weight gain. You and your healthcare provider should check your weight regularly. • neuroleptic malignant syndrome (NMS). NMS is a rare but serious condition that can lead to death and must be treated in a hospital. Tell your healthcare provider right away if you become severely ill and have any of these symptoms: o high fever o confusion o increased sweating o stiff muscles o changes in breathing, heartbeat, and blood pressure • liver problems . Clozapine tablets can cause serious life-threatening liver problems that can lead to death. Tell your healthcare provider right away if you have any of these symptoms: o feeling tired o nausea and vomiting o pain on the right side of your stomach (abdomen) o loss of appetite o yellowing of your skin or whites of your eyes o elevated bilirubin levels • fever. Some people may have a fever while they take clozapine tablets. If you have a fever, your healthcare provider will do blood tests to check for neutropenia or an infection. Your healthcare provider may also send you to see a blood specialist (hematologist). Tell your healthcare provider if you have a fever. • blood clot in your lung (pulmonary embolism) or in the veins of your legs (deep vein thrombosis). Get emergency help right away if you have symptoms of a blood clot including: o chest pain and shortness of breath o swelling or pain in your leg, ankle or foot o warm feeling in the skin of your affected leg o changes in your skin color such as turning pale or blue • a problem that includes dry mouth, increased sweating, increased pulse rate, constipation, and urinary retention (anticholinergic toxicity). • problems thinking clearly and moving your body. See “What should I avoid while taking clozapine tablets?” • uncontrolled movements of your tongue, face, mouth, or jaw (tardive dyskinesia). Tardive dyskinesia may not go away, even if you stop clozapine tablets. Tardive dyskinesia may also start after you stop taking clozapine tablets. • stroke (cerebrovascular problems) in elderly people with dementia-related psychosis that can lead to death. The most common side effects of clozapine tablets include: o sleepiness or drowsiness o headache o dizziness o shaking movements (tremors) o heart and blood vessel problems o low blood pressure o fast heartbeat o having a lot of saliva in your mouth o passing out (syncope) o dry mouth o increased sweating o constipation and nausea o vision problems o fever • These are not all the possible side effects of clozapine tablets. • Your healthcare provider may lower your dose or temporarily or permanently stop treatment with clozapine tablets if you have certain symptoms or if your WBC count is low. • Tell your healthcare provider if you have any side effect that bothers you or that does not go away. • You may report side effects to FDA at 1-800-FDA-1088. How should I store clozapine tablets? • Store clozapine tablets at room temperature between 68°F to 77°F (20°C to 25°C). Keep clozapine tablets and all medicines out of the reach of children. General information about the safe and effective use of clozapine tablets. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use clozapine tablets for a condition for which it was not prescribed. Do not give clozapine tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider (including pharmacist) for information about clozapine tablets that is written for health professionals. What are the ingredients in clozapine tablets?

not prescribed. Do not give clozapine tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider (including pharmacist) for information about clozapine tablets that is written for health professionals. What are the ingredients in clozapine tablets? Active ingredients: clozapine Inactive ingredients: colloidal silicon dioxide, corn starch, lactose monohydrate, magnesium stearate, povidone, and talc. Distributed by: Aurobindo Pharma USA, Inc. 279 Princeton-Hightstown Road East Windsor, NJ 08520 Manufactured by: Aurobindo Pharma Limited Hyderabad-500 032, India Packaged and Distributed by: MAJOR® PHARMACEUTICALS Indianapolis, IN 46268 USA Refer to package label for Distributor's NDC Number Distributed By: Cardinal Health Dublin, OH 43017 L57473990324 This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 07/2025

<table cellpadding="0pt" cellspacing="0pt" width="100%"><col width="100%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph> <content styleCode="bold">MEDICATION GUIDE</content> <content styleCode="bold">Clozapine (<content styleCode="italics">kloe&#x2032; za peen</content>) Tablets, USP</content> <content styleCode="bold">for oral use</content> </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> <content styleCode="bold">What is the most important information I should know about clozapine tablets?</content> <content styleCode="bold">Clozapine tablets can cause serious side effects including:</content> </paragraph><list listType="unordered"><item><caption>&#x2022;</caption><content styleCode="bold">Severe neutropenia (low white blood cell (WBC) counts) that can lead to serious infections and death</content>. Your healthcare provider will do WBC blood tests before starting treatment with clozapine tablets and weekly for the first 6 months. After your first 6 months of treatment, your healthcare provider will determine how frequent you will have blood tests. If you have symptoms of severe neutropenia or an infection, your healthcare provider will do more frequent WBC blood test(s) to check if clozapine tablets are causing your symptoms and may send you to see a blood specialist (hematologist). Tell your health care provider right away if you have any of the following symptoms or signs of neutropenia or infection: <list listType="unordered"><item><caption>o</caption>feel like you have the flu</item><item><caption>o</caption>wounds that take a long time to heal</item><item><caption>o</caption>fever or chills</item><item><caption>o</caption>skin, throat, vaginal, urinary tract, or lung infection</item><item><caption>o</caption>feel extremely tired or weak</item><item><caption>o</caption>pain or burning while peeing</item><item><caption>o</caption>sores or ulcers inside your mouth, gums, or on your skin</item><item><caption>o</caption>unusual vaginal discharge or itching</item><item><caption>o</caption>sores or pain in or around your rectal area</item><item><caption>o</caption>abdominal pain or bloating</item></list></item><item><caption>&#x2022;</caption><content styleCode="bold">Orthostatic hypotension (decreased blood pressure), bradycardia (slow heart rate), or syncope (fainting) that can lead to death</content>. You may feel lightheaded or faint when you rise too quickly from a sitting or lying position. Tell your healthcare provider right away if you feel dizzy or pass out. </item><item><caption>&#x2022;</caption><content styleCode="bold">Seizures. </content>See<content styleCode="bold"> &#x201C;What should I avoid while taking clozapine tablets?&#x201D;</content> </item><item><caption>&#x2022;</caption><content styleCode="bold">Myocarditis (heart muscle inflammation), pericarditis (inflammation of outer layer of the heart) and cardiomyopathy (heart muscle weakness) that can lead to death.

Code="bold"> &#x201C;What should I avoid while taking clozapine tablets?&#x201D;</content> </item><item><caption>&#x2022;</caption><content styleCode="bold">Myocarditis (heart muscle inflammation), pericarditis (inflammation of outer layer of the heart) and cardiomyopathy (heart muscle weakness) that can lead to death. </content>Symptoms of myocarditis, pericarditis, and cardiomyopathy include: <list listType="unordered"><item><caption>o</caption>chest pain</item><item><caption>o</caption>flu-like symptoms</item><item><caption>o</caption>fast heartbeat or palpitations</item><item><caption>o</caption>feel tired or faint</item><item><caption>o</caption>shortness of breath</item><item><caption>o</caption>swollen legs, ankles, or feet</item><item><caption>o</caption>fever</item></list></item><item><caption>&#x2022;</caption><content styleCode="bold">Increased risk of death in elderly people with dementia-related psychosis. </content>Medicines like clozapine tablets can increase the risk of death in elderly people who have lost touch with reality (psychosis) due to confusion and dementia. Clozapine tablets are not for treatment of elderly people with dementia-related psychosis.</item></list><paragraph> </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> <content styleCode="bold">What are clozapine tablets?</content> Clozapine tablets are a prescription antipsychotic medicine used to treat people: </paragraph><list listType="unordered"><item><caption>&#x2022;</caption>Who are severely ill with schizophrenia not helped by other schizophrenia medicines </item><item><caption>&#x2022;</caption>With schizophrenia or schizoaffective disorder who have been suicidal and may be at risk of suicidal behavior again</item></list><paragraph> It is not known if clozapine tablets are safe and effective in children. </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> <content styleCode="bold">Who should not take clozapine tablets?</content> <content styleCode="bold">Do not take clozapine tablets if you:</content> </paragraph><list listType="unordered"><item><caption>&#x2022;</caption>are allergic to clozapine or any of the ingredients in clozapine tablets.

valign="top"><paragraph> <content styleCode="bold">Who should not take clozapine tablets?</content> <content styleCode="bold">Do not take clozapine tablets if you:</content> </paragraph><list listType="unordered"><item><caption>&#x2022;</caption>are allergic to clozapine or any of the ingredients in clozapine tablets. See the end of this Medication Guide for a complete list of ingredients in clozapine tablets.</item></list><paragraph> </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> <content styleCode="bold">Before taking clozapine tablets, tell your healthcare provider about all your medical conditions, including if you:</content> </paragraph><list listType="unordered"><item><caption>&#x2022;</caption>have or have had heart problems or a family history of heart problems including heart attack, heart failure, abnormal heart rhythm or long QT syndrome, or stroke </item><item><caption>&#x2022;</caption>have or have had low or high blood pressure </item><item><caption>&#x2022;</caption>have or have had kidney or liver problems </item><item><caption>&#x2022;</caption>have or have had seizures (convulsions) </item><item><caption>&#x2022;</caption>have or have had stomach or intestinal problems including constipation, slow emptying of your stomach, or diarrhea </item><item><caption>&#x2022;</caption>have or have had low levels of potassium or magnesium in your blood </item><item><caption>&#x2022;</caption>have or have had diabetes or high blood sugar in you or your family </item><item><caption>&#x2022;</caption>have or have had high levels of total cholesterol, &#x201C;bad&#x201D; cholesterol (LDL-C), or triglycerides, or low levels of &#x201C;good&#x201D; cholesterol (HDL-C) </item><item><caption>&#x2022;</caption>have increased pressure in your eyes (glaucoma), an enlarged prostate, or problems passing urine </item><item><caption>&#x2022;</caption>have or have had uncontrolled movements of your tongue, face, mouth, or jaw (tardive dyskinesia) </item><item><caption>&#x2022;</caption>smoke tobacco </item><item><caption>&#x2022;</caption>plan to stop smoking tobacco while taking clozapine tablets </item><item><caption>&#x2022;</caption>use products containing caffeine </item><item><caption>&#x2022;</caption>are pregnant or plan to become pregnant. Talk to your healthcare provider if you become pregnant while taking clozapine tablets. <list listType="unordered"><item><caption>o</caption>If you become pregnant while receiving clozapine tablets, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or go to http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/</item></list></item><item><caption>&#x2022;</caption>are breast feeding or plan to breast feed. Clozapine can pass into your breast milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take clozapine tablets.</item></list><paragraph><content styleCode="bold">Tell your healthcare provider about all the medicines you take,</content> including prescription and over-the-counter medicines, vitamins, and herbal supplements. </paragraph><list listType="unordered"><item><caption>&#x2022;</caption>Clozapine tablets and other medicines may affect each other causing side effects. </item><item><caption>&#x2022;</caption>Your healthcare provider can tell you if it is safe to take clozapine tablets with your other medicines. Do not start or stop any medicines while taking clozapine tablets without talking to your healthcare provider first. </item><item><caption>&#x2022;</caption>Know the medicines you take.

em><caption>&#x2022;</caption>Your healthcare provider can tell you if it is safe to take clozapine tablets with your other medicines. Do not start or stop any medicines while taking clozapine tablets without talking to your healthcare provider first. </item><item><caption>&#x2022;</caption>Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.</item></list><paragraph> </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> <content styleCode="bold">How should I take clozapine tablets?</content> </paragraph><list listType="unordered"><item><caption>&#x2022;</caption>Take clozapine tablets exactly as your healthcare provider tells you to take it. <content styleCode="bold">Do not</content> change your dose or stop taking clozapine tablets unless your healthcare provider tells you to. Talk to your healthcare provider or pharmacist if you are not sure how to take clozapine tablets. </item><item><caption>&#x2022;</caption>Take clozapine tablets with or without food. </item><item><caption>&#x2022;</caption>If you miss taking clozapine tablets for 1 day or more, call your healthcare provider right away. Do not take 2 doses at the same time unless your healthcare provider tells you to. </item><item><caption>&#x2022;</caption>If you take too much (overdose) clozapine, call your healthcare provider or the Poison Help line at 1-800-222-1222 or go to the nearest hospital emergency room right away. <content styleCode="bold"> Symptoms of clozapine tablets overdose can include:</content> </item><item><caption>&#x2022;</caption>feeling sleepy </item><item><caption>&#x2022;</caption>fast or irregular heartbeat </item><item><caption>&#x2022;</caption>having a lot of saliva in your mouth </item><item><caption>&#x2022;</caption>confusion </item><item><caption>&#x2022;</caption>low blood pressure </item><item><caption>&#x2022;</caption>seizures </item><item><caption>&#x2022;</caption>coma </item><item><caption>&#x2022;</caption>shallow or difficult breathing</item></list><paragraph> </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> <content styleCode="bold">What should I avoid while taking clozapine tablets?</content> </paragraph><list listType="unordered"><item><caption>&#x2022;</caption>You should not drink alcohol while taking clozapine tablets because it can increase your chances of getting serious side effects. </item><item><caption>&#x2022;</caption>Do not drive, operate machinery, swim, climb, or do dangerous activities until you know how clozapine tablets affect you.</item></list><paragraph> </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> <content styleCode="bold">What are the possible side effects of clozapine tablets?</content> <content styleCode="bold">Clozapine tablets can cause serious side effects, including:</content> </paragraph><list listType="unordered"><item><caption>&#x2022;</caption>See <content styleCode="bold">&quot;What is the most important information I should know about clozapine tablets?&quot;</content> </item><item><caption>&#x2022;</caption><content styleCode="bold">falls.</content> Clozapine tablets may make you sleepy, dizzy, may cause a decrease in your blood pressure when changing positions, and can slow your thinking and motor skills which may lead to falls that can cause fractures or other injuries. </item><item><caption>&#x2022;</caption><content styleCode="bold">slow emptying of your stomach and intestines (decreased gastric motility). Severe constipation and bowel problems can happen and can lead to hospitalization, surgery, and death.</content> You may not feel or be aware of constipation symptoms.

r injuries. </item><item><caption>&#x2022;</caption><content styleCode="bold">slow emptying of your stomach and intestines (decreased gastric motility). Severe constipation and bowel problems can happen and can lead to hospitalization, surgery, and death.</content> You may not feel or be aware of constipation symptoms. Your healthcare provider will examine you for possible bowel problems. Tell your healthcare provider if you get any signs and symptoms of decreased gastrointestinal motility during treatment with clozapine tablets, including: <list listType="unordered"><item><caption>o</caption>having bowel movements less than normal</item><item><caption>o</caption>stomach bloating or pain</item><item><caption>o</caption>hard or dry stools</item><item><caption>o</caption>nausea or vomiting</item><item><caption>o</caption>difficulty passing gas</item><item><caption> </caption>Staying well hydrated, increasing physical activity, and taking fiber during treatment with clozapine tablets can help prevent constipation and other bowel problems. Your healthcare provider may prescribe medicines to prevent severe problems.</item></list></item><item><caption>&#x2022;</caption><content styleCode="bold">high count of a certain white blood cell (eosinophilia).</content> Clozapine tablets can cause a high count of eosinophils in some people and can be serious. This is a different risk than the risk of clozapine tablets causing an abnormally low white blood cell count (neutropenia). Your health care provider may send you to see an internal medicine specialist (internist) or blood specialist (hematologist). Tell your healthcare provider right away if you have any of these symptoms: <list listType="unordered"><item><caption>o</caption>feeling very tired or weak</item><item><caption>o</caption>coughing and wheezing</item><item><caption>o</caption>fever </item><item><caption>o</caption>nausea, vomiting, or diarrhea</item><item><caption>o</caption>rash </item><item><caption>o</caption>night sweats</item><item><caption>o</caption>swelling </item><item><caption>o</caption>confusion</item><item><caption>o</caption>joint pain </item><item><caption>o</caption>difficulty swallowing</item></list></item><item><caption>&#x2022;</caption><content styleCode="bold">serious heart rhythm problems (QTc Interval Prolongation) that can cause death</content>. Your healthcare provider will do a physical exam and may obtain blood tests and an electrocardiogram before starting you on treatment with clozapine tablets. Tell your healthcare provider right away if you have any of these symptoms: <list listType="unordered"><item><caption>o</caption>passing out or feeling like you will pass out</item><item><caption>o</caption>dizziness</item><item><caption>o</caption>feeling as if your heart is pounding or missing beats</item></list></item><item><caption>&#x2022;</caption><content styleCode="bold">problems with your metabolism such as:</content> <list listType="unordered"><item><caption>o</caption><content styleCode="bold">high blood sugar (hyperglycemia) or diabetes.</content> Increases in blood sugar can happen in some people who take clozapine tablets. Extremely high blood sugar can lead to coma and death. If you have diabetes or risk factors for diabetes (such as being overweight), your health care provider should check your blood sugar before you start clozapine tablets and during treatment.

eases in blood sugar can happen in some people who take clozapine tablets. Extremely high blood sugar can lead to coma and death. If you have diabetes or risk factors for diabetes (such as being overweight), your health care provider should check your blood sugar before you start clozapine tablets and during treatment. Tell your healthcare provider if you have any of these symptoms of high blood sugar while taking clozapine tablets:</item><item><caption>o</caption>feel very thirsty</item><item><caption>o</caption>feel very hungry</item><item><caption>o</caption>feel sick to your stomach</item><item><caption>o</caption>need to urinate more than usual</item><item><caption>o</caption>feel weak or tired</item><item><caption>o</caption>feel confused, or your breath smells fruity</item><item><caption>o</caption><content styleCode="bold">increased fat levels (cholesterol and triglycerides) in your blood (dyslipidemia). </content>Your healthcare provider should check the fat levels in your blood before you start and during treatment with clozapine tablets.</item><item><caption>o</caption><content styleCode="bold">weight gain. </content>You and your healthcare provider should check your weight regularly.</item></list></item><item><caption>&#x2022;</caption><content styleCode="bold">neuroleptic malignant syndrome (NMS). </content>NMS is a rare but serious condition that can lead to death and must be treated in a hospital. Tell your healthcare provider right away if you become severely ill and have any of these symptoms: <list listType="unordered"><item><caption>o</caption>high fever </item><item><caption>o</caption>confusion </item><item><caption>o</caption>increased sweating</item><item><caption>o</caption>stiff muscles </item><item><caption>o</caption>changes in breathing, heartbeat, and blood pressure</item></list></item><item><caption>&#x2022;</caption><content styleCode="bold">liver problems</content>. Clozapine tablets can cause serious life-threatening liver problems that can lead to death. Tell your healthcare provider right away if you have any of these symptoms: <list listType="unordered"><item><caption>o</caption>feeling tired</item><item><caption>o</caption>nausea and vomiting</item><item><caption>o</caption>pain on the right side of your stomach (abdomen)</item><item><caption>o</caption>loss of appetite</item><item><caption>o</caption>yellowing of your skin or whites of your eyes</item><item><caption>o</caption>elevated bilirubin levels</item></list></item><item><caption>&#x2022;</caption><content styleCode="bold">fever. </content>Some people may have a fever while they take clozapine tablets. If you have a fever, your healthcare provider will do blood tests to check for neutropenia or an infection. Your healthcare provider may also send you to see a blood specialist (hematologist). Tell your healthcare provider if you have a fever. </item><item><caption>&#x2022;</caption><content styleCode="bold">blood clot in your lung (pulmonary embolism) or in the veins of your legs (deep vein thrombosis). </content>Get emergency help right away if you have symptoms of a blood clot including: <list listType="unordered"><item><caption>o</caption>chest pain and shortness of breath</item><item><caption>o</caption>swelling or pain in your leg, ankle or foot</item><item><caption>o</caption>warm feeling in the skin of your affected leg</item><item><caption>o</caption>changes in your skin color such as turning pale or blue</item></list></item><item><caption>&#x2022;</caption><content styleCode="bold">a problem that includes dry mouth, increased sweating, increased pulse rate, constipation, and urinary retention (anticholinergic toxicity).</content> </item><item><caption>&#x2022;</caption><content styleCode="bold">problems thinking clearly and moving your body.

em><caption>&#x2022;</caption><content styleCode="bold">a problem that includes dry mouth, increased sweating, increased pulse rate, constipation, and urinary retention (anticholinergic toxicity).</content> </item><item><caption>&#x2022;</caption><content styleCode="bold">problems thinking clearly and moving your body. </content>See<content styleCode="bold"> &#x201C;What should I avoid while taking clozapine tablets?&#x201D;</content> </item><item><caption>&#x2022;</caption><content styleCode="bold">uncontrolled movements of your tongue, face, mouth, or jaw (tardive dyskinesia).</content> Tardive dyskinesia may not go away, even if you stop clozapine tablets. Tardive dyskinesia may also start after you stop taking clozapine tablets. </item><item><caption>&#x2022;</caption><content styleCode="bold">stroke (cerebrovascular problems) in elderly people with dementia-related psychosis that can lead to death.</content> <content styleCode="bold">The most common side effects of clozapine tablets include:</content> <list listType="unordered"><item><caption>o</caption>sleepiness or drowsiness</item><item><caption>o</caption>headache</item><item><caption>o</caption>dizziness</item><item><caption>o</caption>shaking movements (tremors)</item><item><caption>o</caption>heart and blood vessel problems</item><item><caption>o</caption>low blood pressure</item><item><caption>o</caption>fast heartbeat</item><item><caption>o</caption>having a lot of saliva in your mouth</item><item><caption>o</caption>passing out (syncope)</item><item><caption>o</caption>dry mouth</item><item><caption>o</caption>increased sweating </item><item><caption>o</caption>constipation and nausea </item><item><caption>o</caption>vision problems</item><item><caption>o</caption>fever</item></list></item><item><caption>&#x2022;</caption>These are not all the possible side effects of clozapine tablets. </item><item><caption>&#x2022;</caption>Your healthcare provider may lower your dose or temporarily or permanently stop treatment with clozapine tablets if you have certain symptoms or if your WBC count is low. </item><item><caption>&#x2022;</caption>Tell your healthcare provider if you have any side effect that bothers you or that does not go away. </item><item><caption>&#x2022;</caption>You may report side effects to FDA at 1-800-FDA-1088.</item></list><paragraph> </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> <content styleCode="bold">How should I store clozapine tablets?</content> </paragraph><list listType="unordered"><item><caption>&#x2022;</caption>Store clozapine tablets at room temperature between 68&#xB0;F to 77&#xB0;F (20&#xB0;C to 25&#xB0;C).</item></list><paragraph> <content styleCode="bold">Keep clozapine tablets and all medicines out of the reach of children.</content> </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> <content styleCode="bold">General information about the safe and effective use of clozapine tablets.</content> Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use clozapine tablets for a condition for which it was not prescribed. Do not give clozapine tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider (including pharmacist) for information about clozapine tablets that is written for health professionals.

apine tablets for a condition for which it was not prescribed. Do not give clozapine tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider (including pharmacist) for information about clozapine tablets that is written for health professionals. </paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> <content styleCode="bold">What are the ingredients in clozapine tablets?</content> <content styleCode="bold">Active ingredients: </content>clozapine <content styleCode="bold">Inactive ingredients: </content>colloidal silicon dioxide, corn starch, lactose monohydrate, magnesium stearate, povidone, and talc. Distributed by: <content styleCode="bold">Aurobindo Pharma USA, Inc.</content> 279 Princeton-Hightstown Road East Windsor, NJ 08520 Manufactured by: <content styleCode="bold">Aurobindo Pharma Limited </content> Hyderabad-500 032, India</paragraph><paragraph><content styleCode="bold">Packaged and Distributed by:</content></paragraph><paragraph><content styleCode="bold">MAJOR&#xAE; PHARMACEUTICALS</content></paragraph><paragraph>Indianapolis, IN 46268 USA</paragraph><paragraph>Refer to package label for Distributor&apos;s NDC Number</paragraph><paragraph><content styleCode="bold">Distributed By:</content></paragraph><paragraph><content styleCode="bold">Cardinal Health </content></paragraph><paragraph>Dublin, OH 43017</paragraph><paragraph>L57473990324 </paragraph></td></tr></tbody></table>