Browse the corpus

WARNING: SEVERE TOXIC REACTIONS, INCLUDING EMBRYO-FETAL TOXICITY AND DEATH Otrexup should be used only by physicians whose knowledge and experience include the use of antimetabolite therapy. Because of the possibility of serious toxic reactions (which can be fatal), Otrexup should be used only in patients with psoriasis or rheumatoid arthritis with severe, recalcitrant, disabling disease which is not adequately responsive to other forms of therapy. Deaths have been reported with the use of methotrexate in the treatment of malignancy, psoriasis, and rheumatoid arthritis. Patients should be closely monitored for bone marrow, liver, lung, skin, and kidney toxicities. Patients should be informed by their physician of the risks involved and be under a physician’s care throughout therapy [see Warnings and Precautions ( 5.1 )]. 1. Methotrexate can cause embryo-fetal toxicity, including fetal death. Use is contraindicated during pregnancy. Verify the pregnancy status of females of reproductive potential prior to initiating therapy. Advise females and males of reproductive potential to use effective contraception during and after treatment with Otrexup [see Contraindications ( 4 ), Warnings and Precautions ( 5.2 ), and Use in Specific Populations ( 8.1 , 8.3 )]. 2. Methotrexate elimination is reduced in patients with impaired renal functions, ascites, or pleural effusions. Such patients require especially careful monitoring for toxicity, and require dose reduction or, in some cases, discontinuation of Otrexup administration [see Warnings and Precautions ( 5.6 )] . 3. Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and gastrointestinal toxicity have been reported with concomitant administration of methotrexate (usually in high dosage) along with some nonsteroidal anti-inflammatory drugs (NSAIDs) [see Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7.1 )]. 4. Methotrexate causes hepatotoxicity, fibrosis and cirrhosis, but generally only after prolonged use. Acutely, liver enzyme elevations are frequently seen. These are usually transient and asymptomatic, and also do not appear predictive of subsequent hepatic disease. Liver biopsy after sustained use often shows histologic changes, and fibrosis and cirrhosis have been reported; these latter lesions may not be preceded by symptoms or abnormal liver function tests in the psoriasis population. For this reason, periodic liver biopsies are usually recommended for psoriatic patients who are under long-term treatment. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid arthritis population [see Warnings and Precautions ( 5.1 )]. 5. Methotrexate-induced lung disease, including acute or chronic interstitial pneumonitis, is a potentially dangerous lesion, which may occur acutely at any time during therapy and has been reported at low doses. It is not always fully reversible and fatalities have been reported. Pulmonary symptoms (especially a dry, nonproductive cough) may require interruption of treatment and careful investigation [see Warnings and Precautions ( 5.1 )]. 6. Diarrhea and ulcerative stomatitis require interruption of therapy: otherwise, hemorrhagic enteritis and death from intestinal perforation may occur [see Warnings and Precautions ( 5.1 )]. 7.

nonproductive cough) may require interruption of treatment and careful investigation [see Warnings and Precautions ( 5.1 )]. 6. Diarrhea and ulcerative stomatitis require interruption of therapy: otherwise, hemorrhagic enteritis and death from intestinal perforation may occur [see Warnings and Precautions ( 5.1 )]. 7. Malignant lymphomas, which may regress following withdrawal of methotrexate, may occur in patients receiving low-dose methotrexate and, thus, may not require cytotoxic treatment. Discontinue Otrexup first and, if the lymphoma does not regress, appropriate treatment should be instituted [see Warnings and Precautions ( 5.8 )] . 8. Like other cytotoxic drugs, methotrexate may induce “tumor lysis syndrome” in patients with rapidly growing tumors [see Warnings and Precautions ( 5.9 )] . 9. Severe, occasionally fatal, skin reactions have been reported following single or multiple doses of methotrexate. Reactions have occurred within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Recovery has been reported with discontinuation of therapy [see Warnings and Precautions ( 5.1 )] . 10. Potentially fatal opportunistic infections, especially Pneumocystis jiroveci pneumonia, may occur with methotrexate therapy [see Warnings and Precautions ( 5.1 )] . 11. Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis [see Warnings and Precautions ( 5.10 )] . WARNING: SEVERE TOXIC REACTIONS, INCLUDING EMBRYO-FETAL TOXICITY AND DEATH See full prescribing information for complete boxed warning. • Serious toxic reactions and death have been reported with the use of methotrexate. Patients should be closely monitored for bone marrow, liver, lung, skin, and kidney toxicities ( 5.1 ). • Methotrexate can cause embryo-fetal toxicity, including fetal death. Use is contraindicated during pregnancy ( 4 ). Advise females and males of reproductive potential to use effective contraception during and after treatment with methotrexate ( 5.2 , 8.1 , 8.3 ). • Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and gastrointestinal toxicity have been reported with concomitant administration of methotrexate (usually in high dosage) along with some nonsteroidal anti-inflammatory drugs (NSAIDs) ( 5.1 ). • Hepatotoxicity, fibrosis, and cirrhosis may occur after prolonged use ( 5.1 ). • Methotrexate may cause interstitial pneumonitis at any time during therapy and has been reported at low doses. Pulmonary symptoms (especially a dry, nonproductive cough) may require interruption of treatment and careful investigation ( 5.1 ). • Diarrhea, ulcerative stomatitis, hemorrhagic enteritis, and death from intestinal perforation may occur ( 5.1 ). • Severe, occasionally fatal, skin reactions have been reported ( 5.1 ). • Potentially fatal opportunistic infections may occur ( 5.1 ).

1 INDICATIONS AND USAGE Otrexup is a folate analog metabolic inhibitor indicated for the: • Management of patients with severe, active rheumatoid arthritis (RA) and polyarticular juvenile idiopathic arthritis (pJIA), who are intolerant of or had an inadequate response to first-line therapy ( 1.1 ). • Symptomatic control of severe, recalcitrant, disabling psoriasis in adults who are not adequately responsive to other forms of therapy ( 1.2 ). Limitation of Use Otrexup is not indicated for the treatment of neoplastic diseases ( 1.3 ). 1.1 Rheumatoid Arthritis including Polyarticular Juvenile Idiopathic Arthritis Otrexup is indicated in the management of selected adults with severe, active rheumatoid arthritis (RA) (ACR criteria), or children with active polyarticular juvenile idiopathic arthritis (pJIA), who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy including full dose non-steroidal anti-inflammatory agents (NSAIDs). 1.2 Psoriasis Otrexup is indicated in adults for the symptomatic control of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy, but only when the diagnosis has been established, as by biopsy and/or after dermatologic consultation. It is important to ensure that a psoriasis “flare” is not due to an undiagnosed concomitant disease affecting immune responses. 1.3 Limitation of Use Otrexup is not indicated for the treatment of neoplastic diseases.

2 DOSAGE AND ADMINISTRATION Otrexup is for once weekly subcutaneous use only. Administer Otrexup in the abdomen or thigh. ( 2.1 ). Use another formulation of methotrexate for patients requiring oral, intramuscular, intravenous, intra-arterial, or intrathecal dosing, doses less than 10 mg per week, doses above 25 mg per week, high-dose regimens, or dose adjustments of less than 5 mg increments ( 2.1 ). Starting doses of methotrexate: RA: 7.5 mg once weekly ( 2.2 ). pJIA: 10 mg/m 2 once weekly ( 2.2 ). Psoriasis: 10 to 25 mg once weekly of an oral, intramuscular, subcutaneous, or intravenous formulation ( 2.3 ). Adjust dose gradually to achieve an optimal response ( 2.2 , 2.3 ). 2.1 Important Dosing Information Otrexup is a single-dose auto-injector for once-weekly subcutaneous use only [see Warnings and Precautions ( 5.5 )] . Administer Otrexup in the abdomen or the thigh. Otrexup is available in the following dosage strengths: 10, 12.5, 15, 17.5, 20, 22.5 and 25 mg. Use another formulation of methotrexate for alternative dosing in patients who require oral, intramuscular, intravenous, intra-arterial, or intrathecal dosing, doses less than 10 mg per week, doses more than 25 mg per week, high-dose regimens, or dose adjustments between the available doses. 2.2 Rheumatoid Arthritis including Polyarticular Juvenile Idiopathic Arthritis Recommended starting dose of methotrexate: Adult RA: 7.5 mg once weekly. pJIA : 10 mg/m 2 once weekly. For patients switching from oral methotrexate to Otrexup, consider any differences in bioavailability between oral and subcutaneously administered methotrexate [see Clinical Pharmacology ( 12.3 )] . Dosages may be adjusted gradually to achieve an optimal response. Limited experience shows a significant increase in the incidence and severity of serious toxic reactions, especially bone marrow suppression, at doses greater than 20 mg/wk in adults. Although there is experience with doses up to 30 mg/m 2 /wk in children, there are too few published data to assess how doses over 20 mg/m 2 /wk might affect the risk of serious toxicity in children. Experience does suggest, however, that children receiving 20 to 30 mg/m 2 /wk (0.65 to 1.0 mg/kg/wk) may have better absorption and fewer gastrointestinal side effects if methotrexate is administered either intramuscularly or subcutaneously. Therapeutic response usually begins within 3 to 6 weeks and the patient may continue to improve for another 12 weeks or more. The optimal duration of therapy is unknown. Limited data available from long-term studies in adults indicate that the initial clinical improvement is maintained for at least two years with continued therapy. When methotrexate is discontinued, the arthritis usually worsens within 3 to 6 weeks. The patient should be fully informed of the risks involved and should be under constant supervision of the physician. Assessment of hematologic, hepatic, renal, and pulmonary function should be made by history, physical examination, and laboratory tests before beginning, periodically during, and before reinstituting Otrexup therapy [see Warnings and Precautions ( 5.4 )] . Females of childbearing potential should not be started on Otrexup until pregnancy is excluded [see Contraindications ( 4 ) and Warnings and Precautions ( 5.2 )] All schedules should be continually tailored to the individual patient. An initial test dose may be given prior to the regular dosing schedule to detect any extreme sensitivity to adverse effects.

ld not be started on Otrexup until pregnancy is excluded [see Contraindications ( 4 ) and Warnings and Precautions ( 5.2 )] All schedules should be continually tailored to the individual patient. An initial test dose may be given prior to the regular dosing schedule to detect any extreme sensitivity to adverse effects. Maximal myelosuppression usually occurs in seven to ten days. 2.3 Psoriasis Recommended starting dose of methotrexate: Psoriasis: single weekly oral, intramuscular, subcutaneous, or intravenous doses of 10-25 mg. For patients switching from oral methotrexate to Otrexup, consider any differences in bioavailability between oral and subcutaneously administered methotrexate [see Clinical Pharmacology ( 12.3 )] . Dosage may be gradually adjusted to achieve optimal clinical response; 30 mg/week should not ordinarily be exceeded. Once optimal clinical response has been achieved, the dosage should be reduced to the lowest possible amount of drug and to the longest possible rest period. The use of Otrexup may permit the return to conventional topical therapy, which should be encouraged. 2.4 Administration and Handling Otrexup is an auto-injector intended for subcutaneous use under the guidance and supervision of a physician. Patients may self-inject with Otrexup if a physician determines that it is appropriate, if they have received proper training in how to prepare and administer the correct dose, and if they receive medical follow-up, as necessary. A trainer device is available for training purposes. Visually inspect Otrexup for particulate matter and discoloration prior to administration. Do not use Otrexup if the seal is broken. Handle and dispose of Otrexup consistent with recommendations for handling and disposal of cytotoxic drugs 1 . 2.5 Pregnancy testing Verify the pregnancy status of females of reproductive potential prior to initiating treatment with Otrexup [see Use in Specific Populations ( 8.1 , 8.3 )] .

3 DOSAGE FORMS AND STRENGTHS Otrexup is an injection available as an autoinjector that administers a single 0.4 mL dose of methotrexate solution in the following dosage strengths: 10 mg/0.4 mL methotrexate 12.5 mg/0.4 mL methotrexate 15 mg/0.4 mL methotrexate 17.5 mg/0.4 mL methotrexate 20 mg/0.4 mL methotrexate 22.5 mg/0.4 mL methotrexate 25 mg/0.4 mL methotrexate Injection: Single-dose auto-injector delivering 0.4 mL of methotrexate in the following dosage strengths: 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg and 25 mg ( 3 ).

4 CONTRAINDICATIONS Otrexup is contraindicated in the following: • Pregnancy Otrexup can cause embryo-fetal toxicity and fetal death when administered during pregnancy [see Warnings and Precautions ( 5.2 ) and Use in Specific Populations ( 8.1 )]. • Alcoholism or Liver Disease Patients with alcoholism, alcoholic liver disease or other chronic liver disease [see Warnings and Precautions ( 5.1 ) ]. • Immunodeficiency Syndromes Patients who have overt or laboratory evidence of immunodeficiency syndromes [ see Warnings and Precautions ( 5.1 ) ]. • Preexisting Blood Dyscrasias Patients who have preexisting blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia [see Warnings and Precautions ( 5.1 )]. • Hypersensitivity Patients with a known hypersensitivity to methotrexate. Severe hypersensitivity reactions have been observed with methotrexate use [see Warnings and Precautions ( 5.1 ) and Adverse Reactions ( 6.1 and 6.2 )]. Pregnancy ( 4 ) Alcoholism or liver disease ( 4 ) Immunodeficiency syndromes ( 4 ) Preexisting blood dyscrasias ( 4 ) Hypersensitivity to methotrexate ( 4 )

5 WARNINGS AND PRECAUTIONS Organ system toxicity: Potential for serious toxicity. Only for use by physicians experienced in antimetabolite therapy ( 5.1 ). Effects on reproduction: May cause impairment of fertility, oligospermia and menstrual dysfunction ( 5.3 , 8.3 ). Laboratory tests: Monitor complete blood counts, renal function and liver function tests ( 5.4 ). Risks from improper dosing: Mistaken daily use has led to fatal toxicity ( 5.5 ). Patients with impaired renal function, ascites, or pleural effusions: Elimination is reduced ( 5.6 ). Dizziness and fatigue: May impair ability to drive or operate machinery ( 5.7 ). 5.1 Organ System Toxicity Otrexup should be used only by physicians whose knowledge and experience include the use of antimetabolite therapy. Because of the possibility of serious toxic reactions (which can be fatal), Otrexup should be used only in patients with psoriasis or rheumatoid arthritis with severe, recalcitrant, disabling disease which is not adequately responsive to other forms of therapy. Deaths have been reported with the use of methotrexate in the treatment of malignancy, psoriasis, and rheumatoid arthritis. Patients should be closely monitored for bone marrow, liver, lung and kidney toxicities. Otrexup has the potential for serious toxicity. Toxic effects may be related in frequency and severity to dose or frequency of administration but have been seen at all doses. Because they can occur at any time during therapy, it is necessary to follow patients on Otrexup closely. Most adverse reactions are reversible if detected early. When such reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken. If necessary, this could include the use of leucovorin calcium and/or acute, intermittent hemodialysis with a high-flux dialyzer [see Overdosage ( 10 )] . If Otrexup therapy is reinstituted, it should be carried out with caution, with adequate consideration of further need for the drug and increased alertness as to possible recurrence of toxicity. The clinical pharmacology of methotrexate has not been well studied in older individuals. Due to diminished hepatic and renal function as well as decreased folate stores in this population, relatively low doses should be considered, and these patients should be closely monitored for early signs of toxicity [see Use in Specific Populations ( 8.5 )]. Gastrointestinal: Diarrhea and ulcerative stomatitis require interruption of therapy: otherwise, hemorrhagic enteritis and death from intestinal perforation may occur. If vomiting, diarrhea, or stomatitis occur, which may result in dehydration, Otrexup should be discontinued until recovery occurs. Otrexup should be used with extreme caution in the presence of peptic ulcer disease or ulcerative colitis. Unexpectedly severe (sometimes fatal) gastrointestinal toxicity has been reported with concomitant administration of methotrexate (usually in high dosage) along with some nonsteroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions ( 7.1 )]. Hematologic: Otrexup can suppress hematopoiesis and cause anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia. In patients with preexisting hematopoietic impairment, Otrexup should be used with caution, if at all.

idal anti-inflammatory drugs (NSAIDs) [see Drug Interactions ( 7.1 )]. Hematologic: Otrexup can suppress hematopoiesis and cause anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia. In patients with preexisting hematopoietic impairment, Otrexup should be used with caution, if at all. In controlled clinical trials conducted with another formulation of methotrexate in rheumatoid arthritis (n=128), leukopenia (WBC <3000/mm 3 ) was seen in 2 patients, thrombocytopenia (platelets <100,000/mm 3 ) in 6 patients, and pancytopenia in 2 patients. Otrexup should be stopped immediately if there is a significant drop in blood counts. Patients with profound granulocytopenia and fever should be evaluated immediately and usually require parenteral broad-spectrum antibiotic therapy. Unexpectedly severe (sometimes fatal) bone marrow suppression and aplastic anemia have been reported with concomitant administration of methotrexate (usually in high dosage) along with some nonsteroidal anti-inflammatory drugs (NSAIDs ) [see Drug Interactions ( 7.1 )]. Hepatic: Otrexup has the potential for acute (elevated transaminases) and chronic (fibrosis and cirrhosis) hepatotoxicity. Chronic toxicity is potentially fatal; it generally has occurred after prolonged use (generally two years or more) and after a total dose of at least 1.5 grams. In studies in psoriatic patients, hepatotoxicity appeared to be a function of total cumulative dose and appeared to be enhanced by alcoholism, obesity, diabetes and advanced age. An accurate incidence rate has not been determined; the rate of progression and reversibility of lesions is not known. Special caution is indicated in the presence of preexisting liver damage or impaired hepatic function. In psoriasis, liver function tests, including serum albumin, should be performed periodically prior to dosing but are often normal in the face of developing fibrosis or cirrhosis. These lesions may be detectable only by biopsy. The usual recommendation is to obtain a liver biopsy at 1) pretherapy or shortly after initiation of therapy (2 to 4 months), 2) a total cumulative dose of 1.5 grams, and 3) after each additional 1.0 to 1.5 grams. Moderate fibrosis or any cirrhosis normally leads to discontinuation of the drug; mild fibrosis normally suggests a repeat biopsy in 6 months. Milder histologic findings such as fatty change and low grade portal inflammation, are relatively common pretherapy. Although these mild changes are usually not a reason to avoid or discontinue Otrexup therapy, the drug should be used with caution. In rheumatoid arthritis, age at first use of methotrexate and duration of therapy have been reported as risk factors for hepatotoxicity; other risk factors, similar to those observed in psoriasis, may be present in rheumatoid arthritis but have not been confirmed to date. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in this population. There is a combined reported experience in 217 rheumatoid arthritis patients with liver biopsies both before and during treatment (after a cumulative dose of at least 1.5 g) and in 714 patients with a biopsy only during treatment. There are 64 (7%) cases of fibrosis and 1 (0.1%) case of cirrhosis. Of the 64 cases of fibrosis, 60 were deemed mild. The reticulin stain is more sensitive for early fibrosis and its use may increase these figures. It is unknown whether even longer use will increase these risks. Liver function tests should be performed at baseline at 4 to 8 week intervals in patients receiving Otrexup for rheumatoid arthritis.

is, 60 were deemed mild. The reticulin stain is more sensitive for early fibrosis and its use may increase these figures. It is unknown whether even longer use will increase these risks. Liver function tests should be performed at baseline at 4 to 8 week intervals in patients receiving Otrexup for rheumatoid arthritis. Pretreatment liver biopsy should be performed for patients with a history of excessive alcohol consumption, persistently abnormal baseline liver function test values or chronic hepatitis B or C infection. During therapy, liver biopsy should be performed if there are persistent liver function test abnormalities or there is a decrease in serum albumin below the normal range (in the setting of well controlled rheumatoid arthritis). If the results of a liver biopsy show mild changes (Roenigk, grades I, II, IIIa), Otrexup may be continued and the patient monitored as per recommendations listed above. Otrexup should be discontinued in any patient who displays persistently abnormal liver function tests and refuses liver biopsy or in any patient whose liver biopsy shows moderate to severe changes (Roenigk grade IIIb or IV). Infection or Immunologic States: Otrexup should be used with extreme caution in the presence of active infection, and is contraindicated in patients with overt or laboratory evidence of immunodeficiency syndromes. Immunization may be ineffective when given during Otrexup therapy. Immunization with live virus vaccines is generally not recommended. There have been reports of disseminated vaccinia infections after smallpox immunizations in patients receiving methotrexate therapy. Hypogammaglobulinemia has been reported rarely. Potentially fatal opportunistic infections, especially Pneumocystis jiroveci pneumonia, may occur with Otrexup therapy. When a patient presents with pulmonary symptoms, the possibility of Pneumocystis jiroveci pneumonia should be considered. Neurologic: There have been reports of leukoencephalopathy following intravenous administration of methotrexate to patients who have had craniospinal irradiation. Serious neurotoxicity, frequently manifested as generalized or focal seizures, has been reported with unexpectedly increased frequency among pediatric patients with acute lymphoblastic leukemia who were treated with intermediate-dose intravenous methotrexate (1 gm/m 2 ). Symptomatic patients were commonly noted to have leukoencephalopathy and/or microangiopathic calcifications on diagnostic imaging studies. Chronic leukoencephalopathy has also been reported in patients who received repeated doses of high-dose methotrexate with leucovorin rescue even without cranial irradiation. Discontinuation of methotrexate does not always result in complete recovery. A transient acute neurologic syndrome has been observed in patients treated with high dose regimens. Manifestations of this stroke-like encephalopathy may include confusion, hemiparesis, transient blindness, seizures and coma. The exact cause is unknown. After the intrathecal use of methotrexate, the central nervous system toxicity which may occur can be classified as follows: acute chemical arachnoiditis manifested by such symptoms as headache, back pain, nuchal rigidity, and fever; sub-acute myelopathy characterized by paraparesis/paraplegia associated with involvement with one or more spinal nerve roots; chronic leukoencephalopathy manifested by confusion, irritability, somnolence, ataxia, dementia, seizures and coma. This condition can be progressive and even fatal. Pulmonary: Methotrexate-induced lung disease, including acute or chronic interstitial pneumonitis, is a potentially dangerous lesion, which may occur acutely at any time during therapy and has been reported at low doses. It is not always fully reversible and fatalities have been reported.

be progressive and even fatal. Pulmonary: Methotrexate-induced lung disease, including acute or chronic interstitial pneumonitis, is a potentially dangerous lesion, which may occur acutely at any time during therapy and has been reported at low doses. It is not always fully reversible and fatalities have been reported. Pulmonary symptoms (especially a dry nonproductive cough) or a non-specific pneumonitis occurring during Otrexup therapy may be indicative of a potentially dangerous lesion and require interruption of treatment and careful investigation. Although clinically variable, the typical patient with methotrexate induced lung disease presents with fever, cough, dyspnea, hypoxemia, and an infiltrate on chest X-ray; infection (including pneumonia) needs to be excluded. This lesion can occur at all dosages. Renal: Otrexup may cause renal damage that may lead to acute renal failure. High doses of methotrexate used in the treatment of osteosarcoma may cause renal damage leading to acute renal failure. Nephrotoxicity is due primarily to the precipitation of methotrexate and 7- hydroxymethotrexate in the renal tubules. Close attention to renal function including adequate hydration, urine alkalinization and measurement of serum methotrexate and creatinine levels are essential for safe administration. Skin: Severe, occasionally fatal, dermatologic reactions, including toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, have been reported in children and adults, within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Reactions were noted after single or multiple low, intermediate, or high doses of methotrexate in patients with neoplastic and non-neoplastic diseases. Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation. Radiation dermatitis and sunburn may be “recalled” by the use of methotrexate. Other precautions: Otrexup should be used with extreme caution in the presence of debility. Methotrexate exits slowly from third space compartments (e.g., pleural effusions or ascites). This results in a prolonged terminal plasma half-life and unexpected toxicity. In patients with significant third space accumulations, it is advisable to evacuate the fluid before treatment and to monitor plasma methotrexate levels. 5.2 Embryo-Fetal Toxicity Based on published reports and methotrexate’s mechanism of action, methotrexate can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman. In pregnant women Otrexup is contraindicated. Verify pregnancy status in females of reproductive potential prior to initiating Otrexup. Advise females of reproductive potential to use effective contraception during treatment with Otrexup and for 6 months after the final dose. Advise males of reproductive potential to use effective contraception during Otrexup treatment and for at least 3 months after the final dose [see Contraindications ( 4 ), Use in Specific Populations ( 8.1 , 8.3 ), Clinical Pharmacology ( 12.1 )]. 5.3 Effects on Reproduction Based on published reports, methotrexate can cause impairment of fertility, oligospermia, and menstrual dysfunction. It is not known if the infertility is reversible in affected patients. Discuss the risk of effects on reproduction with female and male patients of reproductive potential. [see Use in Specific Populations ( 8.3 )]. 5.4 Laboratory Tests Patients undergoing Otrexup therapy should be closely monitored so that toxic effects are detected promptly. Baseline assessment should include a complete blood count with differential and platelet counts, hepatic enzymes, renal function tests and a chest X-ray.

se in Specific Populations ( 8.3 )]. 5.4 Laboratory Tests Patients undergoing Otrexup therapy should be closely monitored so that toxic effects are detected promptly. Baseline assessment should include a complete blood count with differential and platelet counts, hepatic enzymes, renal function tests and a chest X-ray. During therapy, monitoring of these parameters is recommended: hematology at least monthly, renal function and liver function every 1 to 2 months [see Warnings and Precautions ( 5.1 )]. During initial or changing doses , or during periods of increased risk of elevated methotrexate blood levels (e.g., dehydration), more frequent monitoring may also be indicated. Liver Function Tests Transient liver function test abnormalities are observed frequently after methotrexate administration and are usually not cause for modification of methotrexate therapy. Persistent liver function test abnormalities, and/or depression of serum albumin may be indicators of serious liver toxicity and require evaluation [see Warnings and Precautions ( 5.1 )]. A relationship between abnormal liver function tests and fibrosis or cirrhosis of the liver has not been established for patients with psoriasis. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid arthritis population. Pulmonary Function Tests Pulmonary function tests may be useful if methotrexate-induced lung disease is suspected, especially if baseline measurements are available [see Warnings and Precautions ( 5.1 )]. 5.5 Risks from Improper Dosing Both the physician and pharmacist should emphasize to the patient that Otrexup is administered weekly and that mistaken daily use has led to fatal toxicity [see Dosage and Administration ( 2 )]. 5.6 Patients with Impaired Renal Function, Ascites, or Pleural Effusions Methotrexate elimination is reduced in patients with impaired renal function, ascites, or pleural effusions. Such patients require especially careful monitoring for toxicity and require dose reduction or, in some cases, discontinuation of Otrexup administration. 5.7 Dizziness and Fatigue Adverse reactions, such as dizziness and fatigue, may affect the ability to drive or operate machinery. 5.8 Malignant Lymphomas Non-Hodgkin’s lymphoma and other tumors have been reported in patients receiving low-dose oral methotrexate. However, there have been instances of malignant lymphoma arising during treatment with low-dose oral methotrexate, which have regressed completely following withdrawal of methotrexate, without requiring active anti-lymphoma treatment. Discontinue Otrexup first and, if the lymphoma does not regress, appropriate treatment should be instituted. 5.9 Tumor Lysis Syndrome Like other cytotoxic drugs, methotrexate may induce "tumor lysis syndrome" in patients with rapidly growing tumors. 5.10 Concomitant Radiation Therapy Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling. Organ System Toxicity [see Warnings and Precautions ( 5.1 )] Embryo-Fetal Toxicity [see Warnings and Precautions ( 5.2 )] Effects on Reproduction [see Warnings and Precautions ( 5.3 )] Malignant Lymphomas [see Warnings and Precautions ( 5.8 )] The most frequently reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse reactions are malaise, undue fatigue, chills and fever, dizziness and decreased resistance to infection. Common adverse reactions are: nausea, abdominal pain, dyspepsia, stomatitis/mouth sores, rash, nasopharyngitis, diarrhea, liver function test abnormalities, vomiting, headache, bronchitis, thrombocytopenia, alopecia, leucopenia, pancytopenia, dizziness, photosensitivity, and “burning of skin lesions” ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Antares at 1-855-Otrexup (1-855-687-3987) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience This section provides a summary of adverse reactions reported in subjects in clinical studies conducted with Otrexup as well as with methotrexate injection and oral methotrexate. 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 practice. Rheumatoid Arthritis The approximate incidences of methotrexate-attributed (i.e. placebo rate subtracted) adverse reactions in 12 to 18 week double-blind studies of patients (n=128) with rheumatoid arthritis treated with low-dose oral (7.5 to 15 mg/week) pulse methotrexate, are listed below. Virtually all of these patients were on concomitant nonsteroidal anti-inflammatory drugs and some were also taking low dosages of corticosteroids. Hepatic histology was not examined in these short-term studies. Incidence greater than 10%: Elevated liver function tests 15%, nausea/vomiting 10%. Incidence 3% to 10%: Stomatitis, thrombocytopenia (platelet count less than 100,000/mm 3 ). Incidence 1% to 3%: Rash/pruritis/dermatitis, diarrhea, alopecia, leukopenia (WBC less than 3000/mm 3 ), pancytopenia, dizziness. Two other controlled trials of patients (n=680) with Rheumatoid Arthritis on 7.5 mg to 15 mg/wk oral doses showed an incidence of interstitial pneumonitis of 1%. Other less common reactions included decreased hematocrit, headache, upper respiratory infection, anorexia, arthralgias, chest pain, coughing, dysuria, eye discomfort, epistaxis, fever, infection, sweating, tinnitus, and vaginal discharge. Polyarticular Juvenile Idiopathic Arthritis The approximate incidences of adverse reactions reported in pediatric patients with pJIA treated with oral, weekly doses of methotrexate (5 to 20 mg/m 2 /wk or 0.1 to 0.65 mg/kg/wk) were as follows (virtually all patients were receiving concomitant nonsteroidal anti-inflammatory drugs, and some also were taking low doses of corticosteroids): elevated liver function tests, 14%; gastrointestinal reactions (e.g., nausea, vomiting, diarrhea), 11%; stomatitis, 2%; leukopenia, 2%; headache, 1.2%; alopecia, 0.5%; dizziness, 0.2%; and rash, 0.2%.

re receiving concomitant nonsteroidal anti-inflammatory drugs, and some also were taking low doses of corticosteroids): elevated liver function tests, 14%; gastrointestinal reactions (e.g., nausea, vomiting, diarrhea), 11%; stomatitis, 2%; leukopenia, 2%; headache, 1.2%; alopecia, 0.5%; dizziness, 0.2%; and rash, 0.2%. Although there is experience with dosing up to 30 mg/m 2 /wk in pJIA, the published data for doses above 20 mg/m 2 /wk are too limited to provide reliable estimates of adverse reaction rates. Psoriasis There are two literature reports (Roenigk, 1969, and Nyfors, 1978) describing large series (n=204, 248) of psoriasis patients treated with methotrexate. Dosages ranged up to 25 mg per week and treatment was administered for up to four years. With the exception of alopecia, photosensitivity, and “burning of skin lesions” (each 3% to 10%), the adverse reaction rates in these reports were very similar to those in the rheumatoid arthritis studies. Rarely, painful plaque erosions may appear (Pearce, HP and Wilson, BB: Am Acad Dermatol 35: 835-838, 1996). 6.2 Other Adverse Reactions Other adverse reactions that have been reported with methotrexate in oncology, RA, pJIA, and psoriasis patients are listed below by organ system. Alimentary System: gingivitis, pharyngitis, stomatitis, anorexia, nausea, vomiting, diarrhea, hematemesis, melena, gastrointestinal ulceration and bleeding, enteritis, pancreatitis. Blood and Lymphatic System Disorders: suppressed hematopoiesis, anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, thrombocytopenia, agranulocytosis, eosinophilia, lymphadenopathy and lymphoproliferative disorders (including reversible). Hypogammaglobulinemia has been reported rarely. Cardiovascular: pericarditis, pericardial effusion, hypotension, and thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus). Central Nervous System: headaches, drowsiness, blurred vision, transient blindness, speech impairment including dysarthria and aphasia, hemiparesis, paresis and convulsions have also occurred following administration of methotrexate. Following low doses, there have been occasional reports of transient subtle cognitive dysfunction, mood alteration or unusual cranial sensations, leukoencephalopathy, or encephalopathy. Hepatobiliary Disorders: hepatotoxicity, acute hepatitis, chronic fibrosis and cirrhosis, hepatic failure, decrease in serum albumin, liver enzyme elevations. Infection: There have been case reports of sometimes fatal opportunistic infections in patients receiving methotrexate therapy for neoplastic and non-neoplastic diseases. Pneumocystis jiroveci pneumonia was the most common opportunistic infection. There have also been reports of infections, pneumonia, Cytomegalovirus infection, including cytomegaloviral pneumonia, sepsis, fatal sepsis, nocardiosis; histoplasmosis, cryptococcosis, Herpes zoster , Herpes simplex hepatitis, and disseminated Herpes simplex . Musculoskeletal System: stress fracture. Ophthalmic: conjunctivitis, serious visual changes of unknown etiology. Pulmonary System: respiratory fibrosis, respiratory failure, alveolitis, interstitial pneumonitis deaths have been reported, and chronic interstitial obstructive pulmonary disease has occasionally occurred. Skin: erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, skin necrosis, skin ulceration and exfoliative dermatitis.

lmonary disease has occasionally occurred. Skin: erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, skin necrosis, skin ulceration and exfoliative dermatitis. Urogenital System: severe nephropathy or renal failure, azotemia, cystitis, hematuria, proteinuria; defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, vaginal discharge, and gynecomastia; infertility, abortion, fetal death, fetal defects. Other rarer reactions related to or attributed to the use of methotrexate such as nodulosis, vasculitis, arthralgia/myalgia, loss of libido/ impotence, diabetes, osteoporosis, sudden death, lymphoma, including reversible lymphomas, tumor lysis syndrome, soft tissue necrosis and osteonecrosis. Anaphylactoid reactions have been reported.

7 DRUG INTERACTIONS Aspirin, NSAIDs, and steroids: concomitant use may elevate and prolong serum methotrexate levels and cause increased toxicity ( 7.1 ). Proton pump inhibitors : concomitant use may elevate and prolong serum methotrexate levels and cause increased toxicity ( 7.2 ). 7.1 Aspirin, Nonsteroidal Anti-Inflammatory Drugs, and Steroids Nonsteroidal anti-inflammatory drugs (NSAIDs) should not be administered prior to or concomitantly with the high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate levels, resulting in deaths from severe hematologic and gastrointestinal toxicity [see Warnings and Precautions ( 5.1 )]. Caution should be used when NSAIDs and salicylates are administered concomitantly with lower doses of methotrexate, including Otrexup. These drugs have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite the potential interactions, studies of methotrexate in patients with rheumatoid arthritis have usually included concurrent use of constant dosage regimens of NSAIDs, without apparent problems. It should be appreciated, however, that the doses used in rheumatoid arthritis (7.5 to 15 mg/week) are somewhat lower than those used in psoriasis and that larger doses could lead to unexpected toxicity. Aspirin, NSAIDs, and/or low dose steroids may be continued, although the possibility of increased toxicity with concomitant use of NSAIDs including salicylates has not been fully explored. Steroids may be reduced gradually in patients who respond to methotrexate. 7.2 Proton Pump Inhibitors (PPIs) Use caution if high-dose methotrexate is administered to patients receiving proton pump inhibitor (PPI) therapy. Case reports and published population pharmacokinetic studies suggest that concomitant use of some PPIs, such as omeprazole, esomeprazole, and pantoprazole, with methotrexate (primarily at high dose), may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. In two of these cases, delayed methotrexate elimination was observed when high-dose methotrexate was co-administered with PPIs, but was not observed when methotrexate was co-administered with ranitidine. However, no formal drug interaction studies of methotrexate with ranitidine have been conducted. 7.3 Oral Antibiotics Oral antibiotics such as tetracycline, chloramphenicol, and nonabsorbable broad spectrum antibiotics, may decrease intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of the drug by bacteria. Penicillins may reduce the renal clearance of methotrexate; increased serum concentrations of methotrexate with concomitant hematologic and gastrointestinal toxicity have been observed with high and low dose methotrexate. Use of Otrexup with penicillins should be carefully monitored. Trimethoprim/sulfamethoxazole has been reported rarely to increase bone marrow suppression in patients receiving methotrexate, probably by decreased tubular secretion and/or an additive antifolate effect. 7.4 Hepatotoxins The potential for increased hepatotoxicity when methotrexate is administered with other hepatotoxic agents has not been evaluated.

s been reported rarely to increase bone marrow suppression in patients receiving methotrexate, probably by decreased tubular secretion and/or an additive antifolate effect. 7.4 Hepatotoxins The potential for increased hepatotoxicity when methotrexate is administered with other hepatotoxic agents has not been evaluated. However, hepatotoxicity has been reported in such cases. Therefore, patients receiving concomitant therapy with Otrexup and other potential hepatotoxins (e.g., azathioprine, retinoids, and sulfasalazine) should be closely monitored for possible increased risk of hepatotoxicity. 7.5 Theophylline Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with Otrexup. 7.6 Folic Acid and Antifolates Vitamin preparations containing folic acid or its derivatives may decrease responses to systemically administered methotrexate. Preliminary animal and human studies have shown that small quantities of intravenously administered leucovorin enter the CSF primarily as 5-methyltetrahydrofolate and, in humans, remain 1 to 3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration. However, high doses of leucovorin may reduce the efficacy of intrathecally administered methotrexate. Folate deficiency states may increase methotrexate toxicity. Trimethoprim/sulfamethoxazole has been reported rarely to increase bone marrow suppression in patients receiving methotrexate, probably by decreased tubular secretion and/or an additive antifolate effect. 7.7 Mercaptopurine Methotrexate increases the plasma levels of mercaptopurine. The combination of Otrexup and mercaptopurine may therefore require dose adjustment. 7.8 Nitrous Oxide The use of nitrous oxide anesthesia potentiates the effect of methotrexate on folate dependent metabolic pathways, resulting in the potential for increased toxicity. Avoid concomitant nitrous oxide anesthesia in patients receiving methotrexate. 7.9 Other Drugs Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by certain drugs, such as salicylates, phenylbutazone, phenytoin, and sulfonamides. Renal tubular transport is also diminished by probenecid; use of Otrexup with this drug should be carefully monitored. Combined use of methotrexate with gold, penicillamine, hydroxychloroquine, sulfasalazine, or cytotoxic agents, has not been studied and may increase the incidence of adverse effects.

8 USE IN SPECIFIC POPULATIONS Pediatric use: Safety and efficacy of methotrexate, including Otrexup, have not been established in pediatric patients with psoriasis. Safety and efficacy of Otrexup have not been established in pediatric patients with malignancy ( 8.4 ). Geriatric use: Use caution in dose selection ( 8.5 ). Lactation: Advise women not to breastfeed ( 8.2 ). 8.1 Pregnancy Risk Summary Based on published reports and methotrexate’s mechanism of action, methotrexate can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman [see Data and Clinical Pharmacology ( 12.1 )] . In pregnant women with non-malignant disease, Otrexup is contraindicated. Consider the benefits and risks of Otrexup and risks to the fetus when prescribing Otrexup to a pregnant patient. There are no animal data that meet current standards for nonclinical developmental toxicity studies. The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, 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 2-4% and 15-20%, respectively. Data Human Data Published data from cases, literature reviews, and observational studies report that methotrexate exposure during pregnancy is associated with an increased risk of embryo-fetal toxicity and fetal death. Methotrexate exposure during the first trimester of pregnancy is associated with an increased incidence of spontaneous abortions and multiple adverse developmental outcomes, including skull anomalies, facial dysmorphism, central nervous system abnormalities, limb abnormalities, and sometimes cardiac anomalies and intellectual impairment. Adverse outcomes associated with exposure during second and third trimesters of pregnancy include intrauterine growth restriction and functional abnormalities. Because methotrexate is widely distributed and persists in the body for a prolonged period, there is a potential risk to the fetus from preconception methotrexate exposure. A prospective multicenter study evaluated pregnancy outcomes in women taking methotrexate less than or equal to 30 mg/week after conception. The rate of miscarriage in pregnant women exposed to methotrexate was 42.5% (95% confidence interval [95% CI] 29.2-58.7), which was higher than in unexposed patients with autoimmune disease (22.5%, 95% CI 16.8-29.7) and unexposed patients with non-autoimmune disease (17.3%, 95% CI 13-22.8). Of the live births, the rate of major birth defects in pregnant women exposed to methotrexate after conception was higher than in unexposed patients with autoimmune disease (adjusted odds ratio (OR) 1.8 [95% CI 0.6-5.7]) and unexposed patients with non-autoimmune disease (adjusted OR 3.1 [95% CI 1.03-9.5]). Major birth defects associated with pregnancies exposed to methotrexate after conception were not always consistent with methotrexate-associated adverse developmental outcomes. 8.2 Lactation Risk Summary Limited published literature report the presence of methotrexate in human milk in low amounts following oral methotrexate administration, with the highest breast milk to plasma concentration ratio reported to be 0.08:1. No information is available on the effects of methotrexate on a breastfed infant or on milk production.

ited published literature report the presence of methotrexate in human milk in low amounts following oral methotrexate administration, with the highest breast milk to plasma concentration ratio reported to be 0.08:1. No information is available on the effects of methotrexate on a breastfed infant or on milk production. Because of the potential for serious adverse reactions including myelosuppression, from methotrexate in breastfed infants, advise women not to breastfeed during treatment with Otrexup and for one week after the final dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating Otrexup. Contraception Females Otrexup can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )] . Advise females of reproductive potential to use effective contraception during and for 6 months after the final dose of Otrexup. Males Methotrexate can cause chromosomal damage to sperm cells. Advise males with female partners of reproductive potential to use effective contraception during and for at least 3 months after the final dose of Otrexup. Infertility Females Based on published reports of female infertility after treatment with methotrexate, advise females of reproductive potential that Otrexup can cause impairment of fertility and menstrual dysfunction during and after cessation of therapy. It is not known if the infertility may be reversed in all affected females. Males Based on published reports of male infertility after treatment with methotrexate, advise males of reproductive potential that Otrexup can cause oligospermia or infertility during and after cessation of therapy. It is not known if the infertility may be reversed in all affected males. 8.4 Pediatric Use The safety and effectiveness of methotrexate, including Otrexup, have not been established in pediatric patients with psoriasis. The safety and effectiveness of Otrexup have not been established in pediatric patients with neoplastic diseases. The safety and effectiveness of methotrexate have been established in pediatric patients with polyarticular juvenile idiopathic arthritis [see Clinical Studies ( 14.2 )] . Published clinical studies evaluating the use of methotrexate in children and adolescents (i.e., patients 2 to 16 years of age) with pJIA demonstrated safety comparable to that observed in adults with rheumatoid arthritis [ see Adverse Reactions ( 6.1 ) ]. Otrexup does not contain a preservative. However, methotrexate injectable formulations containing the preservative benzyl alcohol are not recommended for use in neonates. There have been reports of fatal ‘gasping syndrome’ in neonates (children less than one month of age) following the administrations of intravenous solutions containing the preservative benzyl alcohol. Symptoms include a striking onset of gasping respiration, hypotension, bradycardia, and cardiovascular collapse. Serious neurotoxicity, frequently manifested as generalized or focal seizures, has been reported with unexpectedly increased frequency among pediatric patients with acute lymphoblastic leukemia who were treated with intermediate-dose intravenous methotrexate (1 gm/m 2 ) [see Warnings and Precautions ( 5.1 )] . 8.5 Geriatric Use Clinical studies of methotrexate did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects.

phoblastic leukemia who were treated with intermediate-dose intravenous methotrexate (1 gm/m 2 ) [see Warnings and Precautions ( 5.1 )] . 8.5 Geriatric Use Clinical studies of methotrexate did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious reflecting the greater frequency of decreased hepatic and renal function, decreased folate stores, concomitant disease or other drug therapy (i.e., that interfere with renal function, methotrexate or folate metabolism) in this population [see Warnings and Precautions ( 5.1 ), Drug Interactions ( 7.7 ) and Use in Specific Populations ( 8.6 )]. Since decline in renal function may be associated with increases in adverse reactions and serum creatinine measurements may over estimate renal function in the elderly, more accurate methods (i.e., creatinine clearance) should be considered. Serum methotrexate levels may also be helpful. Elderly patients should be closely monitored for early signs of hepatic, bone marrow and renal toxicity. In chronic use situations, certain toxicities may be reduced by folate supplementation. Post-marketing experience suggests that the occurrence of bone marrow suppression, thrombocytopenia, and pneumonitis may increase with age [see Warnings and Precautions ( 5.1 )]. 8.6 Renal Impairment Methotrexate elimination is reduced in patients with impaired renal function. Such patients require especially careful monitoring for toxicity and require dose reduction or, in some cases, discontinuation of Otrexup administration. 8.7 Hepatic Impairment The effect of hepatic impairment on methotrexate pharmacokinetics has not been studied. Otrexup is contraindicated in patients with alcoholic liver disease or other chronic liver disease. Patients with obesity, diabetes, hepatic fibrosis or steatohepatitis are at increased risk for hepatic injury and fibrosis secondary to methotrexate, and should be monitored closely [see Warnings and Precautions ( 5.1 )] .

8.1 Pregnancy Risk Summary Based on published reports and methotrexate’s mechanism of action, methotrexate can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman [see Data and Clinical Pharmacology ( 12.1 )] . In pregnant women with non-malignant disease, Otrexup is contraindicated. Consider the benefits and risks of Otrexup and risks to the fetus when prescribing Otrexup to a pregnant patient. There are no animal data that meet current standards for nonclinical developmental toxicity studies. The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, 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 2-4% and 15-20%, respectively. Data Human Data Published data from cases, literature reviews, and observational studies report that methotrexate exposure during pregnancy is associated with an increased risk of embryo-fetal toxicity and fetal death. Methotrexate exposure during the first trimester of pregnancy is associated with an increased incidence of spontaneous abortions and multiple adverse developmental outcomes, including skull anomalies, facial dysmorphism, central nervous system abnormalities, limb abnormalities, and sometimes cardiac anomalies and intellectual impairment. Adverse outcomes associated with exposure during second and third trimesters of pregnancy include intrauterine growth restriction and functional abnormalities. Because methotrexate is widely distributed and persists in the body for a prolonged period, there is a potential risk to the fetus from preconception methotrexate exposure. A prospective multicenter study evaluated pregnancy outcomes in women taking methotrexate less than or equal to 30 mg/week after conception. The rate of miscarriage in pregnant women exposed to methotrexate was 42.5% (95% confidence interval [95% CI] 29.2-58.7), which was higher than in unexposed patients with autoimmune disease (22.5%, 95% CI 16.8-29.7) and unexposed patients with non-autoimmune disease (17.3%, 95% CI 13-22.8). Of the live births, the rate of major birth defects in pregnant women exposed to methotrexate after conception was higher than in unexposed patients with autoimmune disease (adjusted odds ratio (OR) 1.8 [95% CI 0.6-5.7]) and unexposed patients with non-autoimmune disease (adjusted OR 3.1 [95% CI 1.03-9.5]). Major birth defects associated with pregnancies exposed to methotrexate after conception were not always consistent with methotrexate-associated adverse developmental outcomes.

8.4 Pediatric Use The safety and effectiveness of methotrexate, including Otrexup, have not been established in pediatric patients with psoriasis. The safety and effectiveness of Otrexup have not been established in pediatric patients with neoplastic diseases. The safety and effectiveness of methotrexate have been established in pediatric patients with polyarticular juvenile idiopathic arthritis [see Clinical Studies ( 14.2 )] . Published clinical studies evaluating the use of methotrexate in children and adolescents (i.e., patients 2 to 16 years of age) with pJIA demonstrated safety comparable to that observed in adults with rheumatoid arthritis [ see Adverse Reactions ( 6.1 ) ]. Otrexup does not contain a preservative. However, methotrexate injectable formulations containing the preservative benzyl alcohol are not recommended for use in neonates. There have been reports of fatal ‘gasping syndrome’ in neonates (children less than one month of age) following the administrations of intravenous solutions containing the preservative benzyl alcohol. Symptoms include a striking onset of gasping respiration, hypotension, bradycardia, and cardiovascular collapse. Serious neurotoxicity, frequently manifested as generalized or focal seizures, has been reported with unexpectedly increased frequency among pediatric patients with acute lymphoblastic leukemia who were treated with intermediate-dose intravenous methotrexate (1 gm/m 2 ) [see Warnings and Precautions ( 5.1 )] .

8.5 Geriatric Use Clinical studies of methotrexate did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious reflecting the greater frequency of decreased hepatic and renal function, decreased folate stores, concomitant disease or other drug therapy (i.e., that interfere with renal function, methotrexate or folate metabolism) in this population [see Warnings and Precautions ( 5.1 ), Drug Interactions ( 7.7 ) and Use in Specific Populations ( 8.6 )]. Since decline in renal function may be associated with increases in adverse reactions and serum creatinine measurements may over estimate renal function in the elderly, more accurate methods (i.e., creatinine clearance) should be considered. Serum methotrexate levels may also be helpful. Elderly patients should be closely monitored for early signs of hepatic, bone marrow and renal toxicity. In chronic use situations, certain toxicities may be reduced by folate supplementation. Post-marketing experience suggests that the occurrence of bone marrow suppression, thrombocytopenia, and pneumonitis may increase with age [see Warnings and Precautions ( 5.1 )].

10 OVERDOSAGE Leucovorin is indicated to diminish the toxicity and counteract the effect of inadvertently administered overdosages of methotrexate. Leucovorin administration should begin as promptly as possible. As the time interval between methotrexate administration and leucovorin initiation increases, the effectiveness of leucovorin in counteracting toxicity decreases. Monitoring of the serum methotrexate concentration is essential in determining the optimal dose and duration of treatment with leucovorin. In cases of massive overdosage, hydration and urinary alkalinization may be necessary to prevent the precipitation of methotrexate and/or its metabolites in the renal tubules. Generally speaking, neither hemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination. However, effective clearance of methotrexate has been reported with acute, intermittent hemodialysis using a high-flux dialyzer (Wall, SM et al: Am J Kidney Dis 28 (6): 846-854, 1996). Accidental intrathecal overdosage may require intensive systemic support, high-dose systemic leucovorin, alkaline diuresis and rapid CSF drainage and ventriculolumbar perfusion. In postmarketing experience, overdose with methotrexate has generally occurred with oral and intrathecal administration, although intravenous and intramuscular overdose have also been reported. Reports of oral overdose often indicate accidental daily administration instead of weekly (single or divided doses). Symptoms commonly reported following oral overdose include those symptoms and signs reported at pharmacologic doses, particularly hematologic and gastrointestinal reaction. For example, leukopenia, thrombocytopenia, anemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, gastrointestinal bleeding. In some cases, no symptoms were reported. There have been reports of death following overdose. In these cases, events such as sepsis or septic shock, renal failure, and aplastic anemia were also reported. Symptoms of intrathecal overdose are generally central nervous system (CNS) symptoms, including headache, nausea and vomiting, seizure or convulsion, and acute toxic encephalopathy. In some cases, no symptoms were reported. There have been reports of death following intrathecal overdose. In these cases, cerebellar herniation associated with increased intracranial pressure, and acute toxic encephalopathy have also been reported. There are published case reports of intravenous and intrathecal carboxypeptidase G2 treatment to hasten clearance of methotrexate in cases of overdose.

11 DESCRIPTION Otrexup contains methotrexate, a folate analog metabolic inhibitor. Chemically, methotrexate is [N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-Lglutamic acid. The structural formula is: C 20 H 22 N 8 O 5 M.W.= 454.45 Otrexup contains methotrexate in a sterile, preservative-free, unbuffered solution with a 27 gauge ½ inch needle for a single subcutaneous injection. Otrexup solution is yellow in color. Inactive ingredients include sodium chloride and water for injection, USP. The amounts of sodium chloride vary with the amount of methotrexate. Amount of methotrexate (mg) per 0.4 mL 10 12.5 15 17.5 20 22.5 25 Amount of sodium chloride (mg) per 0.4 mL 1.96 2.04 1.60 1.48 1.28 0.92 0.56 Hydrochloric acid and additional sodium hydroxide may have been added, if necessary, to adjust the pH to 8.0. Structure

<table><col width="36%"/><col width="8%"/><col width="8%"/><col width="8%"/><col width="8%"/><col width="8%"/><col width="8%"/><col width="8%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule "><paragraph>Amount of methotrexate (mg) per 0.4 mL</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule "><paragraph>10</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule "><paragraph>12.5</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule "><paragraph>15</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule "><paragraph>17.5</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule "><paragraph>20</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule "><paragraph>22.5</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule "><paragraph>25</paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule "><paragraph>Amount of sodium chloride (mg) per 0.4 mL</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule "><paragraph>1.96</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule "><paragraph>2.04</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule "><paragraph>1.60</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule "><paragraph>1.48</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule "><paragraph>1.28</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule "><paragraph>0.92</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule "><paragraph>0.56</paragraph></td></tr></tbody></table>

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Methotrexate inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be utilized as carriers of one-carbon groups in the synthesis of purine nucleotides and thymidylate. Therefore, methotrexate interferes with DNA synthesis, repair, and cellular replication. Actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary bladder are in general more sensitive to this effect of methotrexate. The mechanism of action in rheumatoid arthritis is unknown; it may affect immune function. 12.2 Pharmacodynamics Two reports describe in vitro methotrexate inhibition of DNA precursor uptake by stimulated mononuclear cells, and another describes in animal polyarthritis partial correction by methotrexate of spleen cell hyporesponsiveness and suppressed IL 2 production. Other laboratories, however, have been unable to demonstrate similar effects. Clarification of methotrexate’s effect on immune activity and its relation to rheumatoid immunopathogenesis await further studies. In psoriasis, the rate of production of epithelial cells in the skin is greatly increased over normal skin. This differential in proliferation rates is the basis for the use of methotrexate to control the psoriatic process. Methotrexate in high doses, followed by leucovorin rescue, is used as a part of the treatment of patients with non-metastatic osteosarcoma. The original rationale for high dose methotrexate therapy was based on the concept of selective rescue of normal tissues by leucovorin. More recent evidence suggests that high dose methotrexate may also overcome methotrexate resistance caused by impaired active transport, decreased affinity of dihydrofolic acid reductase for methotrexate, increased levels of dihydrofolic acid reductase resulting from gene amplification, or decreased polyglutamation of methotrexate. The actual mechanism of action is unknown. 12.3 Pharmacokinetics Absorption In adults, oral absorption appears to be dose dependent. Peak serum levels are reached within one to two hours. At doses of 30 mg/m 2 or less, methotrexate is generally well absorbed with a mean bioavailability of about 60%. The absorption of doses greater than 80 mg/m 2 is significantly less, possibly due to a saturation effect. In relative bioavailability studies in rheumatoid arthritis patients, systemic exposure of methotrexate was found to be similar between Otrexup and intramuscular or subcutaneous administration of methotrexate injection at the same doses, however systemic exposure of methotrexate was higher with Otrexup as compared to oral administration of methotrexate at the same dose. Bioavailability following oral dosing showed a plateau effect at doses of 15 mg and greater. The systemic exposure of methotrexate from Otrexup at doses of 10, 15, 20, and 25 mg was higher than that of oral methotrexate by 17, 13, 31, and 36%, respectively. Methotrexate systemic absorption from Otrexup was similar when administered into the abdomen or thigh. In leukemic pediatric patients, oral absorption of methotrexate also appears to be dose dependent and has been reported to vary widely (23% to 95%). A twenty fold difference between highest and lowest peak levels (Cmax: 0.11 to 2.3 micromolar after a 20 mg/m 2 dose) has been reported.

istered into the abdomen or thigh. In leukemic pediatric patients, oral absorption of methotrexate also appears to be dose dependent and has been reported to vary widely (23% to 95%). A twenty fold difference between highest and lowest peak levels (Cmax: 0.11 to 2.3 micromolar after a 20 mg/m 2 dose) has been reported. Significant interindividual variability has also been noted in time to peak concentration (Tmax: 0.67 to 4 hrs after a 15 mg/m 2 dose) and fraction of dose absorbed. The absorption of doses greater than 40 mg/m 2 has been reported to be significantly less than that of lower doses. Food has been shown to delay absorption and reduce peak concentration. Methotrexate is generally completely absorbed from parenteral routes of injection. After intramuscular injection, peak serum concentrations occur in 30 to 60 minutes. As in leukemic pediatric patients, a wide interindividual variability in the plasma concentrations of methotrexate has been reported in pediatric patients with JIA. Following oral administration of methotrexate in doses of 6.4 to 11.2 mg/m 2 /week in pediatric patients with JIA, mean serum concentrations were 0.59 micromolar (range, 0.03 to 1.40) at 1 hour, 0.44 micromolar (range, 0.01 to 1.00) at 2 hours, and 0.29 micromolar (range, 0.06 to 0.58) at 3 hours. Distribution After intravenous administration, the initial volume of distribution is approximately 0.18 L/kg (18% of body weight) and steady-state volume of distribution is approximately 0.4 to 0.8 L/kg (40 to 80% of body weight). Methotrexate competes with reduced folates for active transport across cell membranes by means of a single carrier-mediated active transport process. At serum concentrations greater than 100 micromolar, passive diffusion becomes a major pathway by which effective intracellular concentrations can be achieved. Methotrexate in serum is approximately 50% protein bound. Laboratory studies demonstrate that it may be displaced from plasma albumin by various compounds including sulfonamides, salicylates, tetracyclines, chloramphenicol, and phenytoin. Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given orally or parenterally. High CSF concentrations of the drug may be attained by intrathecal administration of other parenteral forms of methotrexate. In dogs, synovial fluid concentrations after oral dosing were higher in inflamed than uninflamed joints. Although salicylates did not interfere with this penetration, prior prednisone treatment reduced penetration into inflamed joints to the level of normal joints. Metabolism After absorption, methotrexate undergoes hepatic and intracellular metabolism to polyglutamated forms which can be converted back to methotrexate by hydrolase enzymes. These polyglutamates act as inhibitors of dihydrofolate reductase and thymidylate synthetase. Small amounts of methotrexate polyglutamates may remain in tissues for extended periods. The retention and prolonged drug action of these active metabolites vary among different cells, tissues and tumors. A small amount of metabolism to 7-hydroxymethotrexate may occur at doses commonly prescribed. Accumulation of this metabolite may become significant at the high doses used in osteogenic sarcoma. The aqueous solubility of 7-hydroxymethotrexate is 3 to 5 fold lower than the parent compound. Methotrexate is partially metabolized by intestinal flora after oral administration. Half-Life The terminal half-life reported for methotrexate is approximately three to ten hours for patients receiving treatment for psoriasis, or rheumatoid arthritis or low dose antineoplastic therapy (less than 30 mg/m 2 ). For patients receiving high doses of methotrexate, the terminal half-life is eight to 15 hours.

alf-Life The terminal half-life reported for methotrexate is approximately three to ten hours for patients receiving treatment for psoriasis, or rheumatoid arthritis or low dose antineoplastic therapy (less than 30 mg/m 2 ). For patients receiving high doses of methotrexate, the terminal half-life is eight to 15 hours. In pediatric patients receiving methotrexate for acute lymphocytic leukemia (6.3 to 30 mg/m 2 ), or for JIA (3.75 to 26.2 mg/m 2 ), the terminal half-life has been reported to range from 0.7 to 5.8 hours or 0.9 to 2.3 hours, respectively. Excretion Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration. With IV administration, 80% to 90% of the administered dose is excreted unchanged in the urine within 24 hours. There is limited biliary excretion amounting to 10% or less of the administered dose. Enterohepatic recirculation of methotrexate has been proposed. Renal excretion occurs by glomerular filtration and active tubular secretion. Nonlinear elimination due to saturation of renal tubular reabsorption has been observed in psoriatic patients at doses between 7.5 and 30 mg. Impaired renal function, as well as concurrent use of drugs such as weak organic acids that also undergo tubular secretion, can markedly increase methotrexate serum levels. Excellent correlation has been reported between methotrexate clearance and endogenous creatinine clearance. Methotrexate clearance rates vary widely and are generally decreased at higher doses. Delayed drug clearance has been identified as one of the major factors responsible for methotrexate toxicity. It has been postulated that the toxicity of methotrexate for normal tissues is more dependent upon the duration of exposure to the drug rather than the peak level achieved. When a patient has delayed drug elimination due to compromised renal function, a third space effusion, or other causes, methotrexate serum concentrations may remain elevated for prolonged periods. When other forms of parenteral methotrexate are administered during cancer chemotherapy, the potential for toxicity from high dose regimens or delayed excretion is reduced by the administration of leucovorin calcium during the final phase of methotrexate plasma elimination. Pharmacokinetic monitoring of methotrexate serum concentrations may help identify those patients at high risk for methotrexate toxicity and aid in proper adjustments of leucovorin dosing.

12.1 Mechanism of Action Methotrexate inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be utilized as carriers of one-carbon groups in the synthesis of purine nucleotides and thymidylate. Therefore, methotrexate interferes with DNA synthesis, repair, and cellular replication. Actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary bladder are in general more sensitive to this effect of methotrexate. The mechanism of action in rheumatoid arthritis is unknown; it may affect immune function.

12.2 Pharmacodynamics Two reports describe in vitro methotrexate inhibition of DNA precursor uptake by stimulated mononuclear cells, and another describes in animal polyarthritis partial correction by methotrexate of spleen cell hyporesponsiveness and suppressed IL 2 production. Other laboratories, however, have been unable to demonstrate similar effects. Clarification of methotrexate’s effect on immune activity and its relation to rheumatoid immunopathogenesis await further studies. In psoriasis, the rate of production of epithelial cells in the skin is greatly increased over normal skin. This differential in proliferation rates is the basis for the use of methotrexate to control the psoriatic process. Methotrexate in high doses, followed by leucovorin rescue, is used as a part of the treatment of patients with non-metastatic osteosarcoma. The original rationale for high dose methotrexate therapy was based on the concept of selective rescue of normal tissues by leucovorin. More recent evidence suggests that high dose methotrexate may also overcome methotrexate resistance caused by impaired active transport, decreased affinity of dihydrofolic acid reductase for methotrexate, increased levels of dihydrofolic acid reductase resulting from gene amplification, or decreased polyglutamation of methotrexate. The actual mechanism of action is unknown.

12.3 Pharmacokinetics Absorption In adults, oral absorption appears to be dose dependent. Peak serum levels are reached within one to two hours. At doses of 30 mg/m 2 or less, methotrexate is generally well absorbed with a mean bioavailability of about 60%. The absorption of doses greater than 80 mg/m 2 is significantly less, possibly due to a saturation effect. In relative bioavailability studies in rheumatoid arthritis patients, systemic exposure of methotrexate was found to be similar between Otrexup and intramuscular or subcutaneous administration of methotrexate injection at the same doses, however systemic exposure of methotrexate was higher with Otrexup as compared to oral administration of methotrexate at the same dose. Bioavailability following oral dosing showed a plateau effect at doses of 15 mg and greater. The systemic exposure of methotrexate from Otrexup at doses of 10, 15, 20, and 25 mg was higher than that of oral methotrexate by 17, 13, 31, and 36%, respectively. Methotrexate systemic absorption from Otrexup was similar when administered into the abdomen or thigh. In leukemic pediatric patients, oral absorption of methotrexate also appears to be dose dependent and has been reported to vary widely (23% to 95%). A twenty fold difference between highest and lowest peak levels (Cmax: 0.11 to 2.3 micromolar after a 20 mg/m 2 dose) has been reported. Significant interindividual variability has also been noted in time to peak concentration (Tmax: 0.67 to 4 hrs after a 15 mg/m 2 dose) and fraction of dose absorbed. The absorption of doses greater than 40 mg/m 2 has been reported to be significantly less than that of lower doses. Food has been shown to delay absorption and reduce peak concentration. Methotrexate is generally completely absorbed from parenteral routes of injection. After intramuscular injection, peak serum concentrations occur in 30 to 60 minutes. As in leukemic pediatric patients, a wide interindividual variability in the plasma concentrations of methotrexate has been reported in pediatric patients with JIA. Following oral administration of methotrexate in doses of 6.4 to 11.2 mg/m 2 /week in pediatric patients with JIA, mean serum concentrations were 0.59 micromolar (range, 0.03 to 1.40) at 1 hour, 0.44 micromolar (range, 0.01 to 1.00) at 2 hours, and 0.29 micromolar (range, 0.06 to 0.58) at 3 hours. Distribution After intravenous administration, the initial volume of distribution is approximately 0.18 L/kg (18% of body weight) and steady-state volume of distribution is approximately 0.4 to 0.8 L/kg (40 to 80% of body weight). Methotrexate competes with reduced folates for active transport across cell membranes by means of a single carrier-mediated active transport process. At serum concentrations greater than 100 micromolar, passive diffusion becomes a major pathway by which effective intracellular concentrations can be achieved. Methotrexate in serum is approximately 50% protein bound. Laboratory studies demonstrate that it may be displaced from plasma albumin by various compounds including sulfonamides, salicylates, tetracyclines, chloramphenicol, and phenytoin. Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given orally or parenterally. High CSF concentrations of the drug may be attained by intrathecal administration of other parenteral forms of methotrexate.

amides, salicylates, tetracyclines, chloramphenicol, and phenytoin. Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given orally or parenterally. High CSF concentrations of the drug may be attained by intrathecal administration of other parenteral forms of methotrexate. In dogs, synovial fluid concentrations after oral dosing were higher in inflamed than uninflamed joints. Although salicylates did not interfere with this penetration, prior prednisone treatment reduced penetration into inflamed joints to the level of normal joints. Metabolism After absorption, methotrexate undergoes hepatic and intracellular metabolism to polyglutamated forms which can be converted back to methotrexate by hydrolase enzymes. These polyglutamates act as inhibitors of dihydrofolate reductase and thymidylate synthetase. Small amounts of methotrexate polyglutamates may remain in tissues for extended periods. The retention and prolonged drug action of these active metabolites vary among different cells, tissues and tumors. A small amount of metabolism to 7-hydroxymethotrexate may occur at doses commonly prescribed. Accumulation of this metabolite may become significant at the high doses used in osteogenic sarcoma. The aqueous solubility of 7-hydroxymethotrexate is 3 to 5 fold lower than the parent compound. Methotrexate is partially metabolized by intestinal flora after oral administration. Half-Life The terminal half-life reported for methotrexate is approximately three to ten hours for patients receiving treatment for psoriasis, or rheumatoid arthritis or low dose antineoplastic therapy (less than 30 mg/m 2 ). For patients receiving high doses of methotrexate, the terminal half-life is eight to 15 hours. In pediatric patients receiving methotrexate for acute lymphocytic leukemia (6.3 to 30 mg/m 2 ), or for JIA (3.75 to 26.2 mg/m 2 ), the terminal half-life has been reported to range from 0.7 to 5.8 hours or 0.9 to 2.3 hours, respectively. Excretion Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration. With IV administration, 80% to 90% of the administered dose is excreted unchanged in the urine within 24 hours. There is limited biliary excretion amounting to 10% or less of the administered dose. Enterohepatic recirculation of methotrexate has been proposed. Renal excretion occurs by glomerular filtration and active tubular secretion. Nonlinear elimination due to saturation of renal tubular reabsorption has been observed in psoriatic patients at doses between 7.5 and 30 mg. Impaired renal function, as well as concurrent use of drugs such as weak organic acids that also undergo tubular secretion, can markedly increase methotrexate serum levels. Excellent correlation has been reported between methotrexate clearance and endogenous creatinine clearance. Methotrexate clearance rates vary widely and are generally decreased at higher doses. Delayed drug clearance has been identified as one of the major factors responsible for methotrexate toxicity. It has been postulated that the toxicity of methotrexate for normal tissues is more dependent upon the duration of exposure to the drug rather than the peak level achieved. When a patient has delayed drug elimination due to compromised renal function, a third space effusion, or other causes, methotrexate serum concentrations may remain elevated for prolonged periods. When other forms of parenteral methotrexate are administered during cancer chemotherapy, the potential for toxicity from high dose regimens or delayed excretion is reduced by the administration of leucovorin calcium during the final phase of methotrexate plasma elimination.

ns may remain elevated for prolonged periods. When other forms of parenteral methotrexate are administered during cancer chemotherapy, the potential for toxicity from high dose regimens or delayed excretion is reduced by the administration of leucovorin calcium during the final phase of methotrexate plasma elimination. Pharmacokinetic monitoring of methotrexate serum concentrations may help identify those patients at high risk for methotrexate toxicity and aid in proper adjustments of leucovorin dosing.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Methotrexate has been evaluated in a number of animal studies for carcinogenic potential with inconclusive results. Although there is evidence that methotrexate causes chromosomal damage to animal somatic cells and human bone marrow cells, the clinical significance remains uncertain. Data are available regarding the risks for pregnancy and for fertility in humans [see Use in Specific Populations ( 8.1 and 8.3 )].

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Methotrexate has been evaluated in a number of animal studies for carcinogenic potential with inconclusive results. Although there is evidence that methotrexate causes chromosomal damage to animal somatic cells and human bone marrow cells, the clinical significance remains uncertain. Data are available regarding the risks for pregnancy and for fertility in humans [see Use in Specific Populations ( 8.1 and 8.3 )].

14 CLINICAL STUDIES 14.1 Rheumatoid Arthritis Clinical trials in patients with rheumatoid arthritis were performed using other formulations of methotrexate. In patients with rheumatoid arthritis, effects of methotrexate on articular swelling and tenderness can be seen as early as 3 to 6 weeks. Most studies of methotrexate in patients with rheumatoid arthritis are relatively short term (3 to 6 months). Limited data from long-term studies indicate that an initial clinical improvement is maintained for at least two years with continued therapy. 14.2 Polyarticular Juvenile Idiopathic Arthritis Clinical trials in patients with polyarticular juvenile idiopathic arthritis were performed using other formulations of methotrexate. In a 6-month double-blind, placebo-controlled trial of 127 pediatric patients with pJIA (mean age, 10.1 years; age range, 2.5 to 18 years; mean duration of disease, 5.1 years) on background nonsteroidal anti-inflammatory drugs and/or prednisone, methotrexate given weekly at an oral dose of 10 mg/m 2 provided significant clinical improvement compared to placebo as measured by either the physician’s global assessment, or by a patient composite (25% reduction in the articular-severity score plus improvement in parent and physician global assessments of disease activity). Over two-thirds of the patients in this trial had polyarticular-course JIA, and the numerically greatest response was seen in this subgroup treated with 10 mg/m 2 /wk methotrexate. The overwhelming majority of the remaining patients had systemic-course JIA. All patients were unresponsive to NSAIDs; approximately one-third were using low dose corticosteroids. Weekly methotrexate at a dose of 5 mg/m 2 was not significantly more effective than placebo in this trial.

16 HOW SUPPLIED/STORAGE AND HANDLING Otrexup contains methotrexate in a preservative-free sterile solution for a single subcutaneous injection. Otrexup is available in the following strengths and configurations. Otrexup (methotrexate) injection 10 mg/0.4 mL Carton of 1 NDC 54436-010-01 Carton of 4 NDC 54436-010-04 Otrexup NDC 54436-010-02 Otrexup (methotrexate) injection 12.5 mg/0.4 mL Carton of 1 NDC 54436-012-01 Carton of 4 NDC 54436-012-04 Otrexup NDC 54436-012-02 Otrexup (methotrexate) injection 15 mg/0.4 mL Carton of 1 NDC 54436-015-01 Carton of 4 NDC 54436-015-04 Otrexup NDC 54436-015-02 Otrexup (methotrexate) injection 17.5 mg/0.4 mL Carton of 1 NDC 54436-017-01 Carton of 4 NDC 54436-017-04 Otrexup NDC 54436-017-02 Otrexup (methotrexate) injection 20 mg/0.4 mL Carton of 1 NDC 54436-020-01 Carton of 4 NDC 54436-020-04 Otrexup NDC 54436-020-02 Otrexup (methotrexate) injection 22.5 mg/0.4 mL Carton of 1 NDC 54436-022-01 Carton of 4 NDC 54436-022-04 Otrexup NDC 54436-022-02 Otrexup (methotrexate) injection 25 mg/0.4 mL Carton of 1 NDC 54436-025-01 Carton of 4 NDC 54436-025-04 Otrexup NDC 54436-025-02 Store at controlled room temperature, 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). PROTECT FROM LIGHT. Handling and Disposal Handle and dispose of Otrexup consistent with recommendations for handling and disposal of cytotoxic drugs. 1

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling ( Patient Information and Instructions for Use ) Risk of Organ Toxicity Inform patients of the risks of organ toxicity, including gastrointestinal, hematologic, hepatic, infections, neurologic, pulmonary, renal and skin as well as possible signs and symptoms for which they should contact their healthcare provider. Advise patients of the need for close follow-up, including periodic laboratory tests to monitor toxicity [see Warnings and Precautions ( 5.1 and 5.4 )] . Importance of Proper Dosing and Administration Both the physician and pharmacist should emphasize to the patient that the recommended dose is taken weekly and that mistaken daily use of the recommended dose has led to fatal toxicity [see Dosing and Administration ( 2 )] . Otrexup is intended for use under the guidance and supervision of a physician. Patients should not self-administer until they receive training from a healthcare professional. The patient’s or caregiver’s ability to administer Otrexup should be assessed. A trainer device is available for training purposes. Patients should be instructed to use administration sites on the abdomen or the thigh. Administration should not be made within 2 inches of the navel. Instruct patients not to administer Otrexup to the arms or any other areas of the body, as delineated in the Otrexup Instructions for Use [see Instructions for Use ] . Embryo-Fetal Toxicity Advise females of reproductive potential that Otrexup can cause fetal harm and is contraindicated in pregnancy. Advise women of childbearing potential that Otrexup should not be started until pregnancy is excluded. Women should be fully counseled on the serious risk to the fetus should they become pregnant while undergoing treatment. Inform patients to contact their physician if they suspect that they are pregnant [see Boxed Warning , Contraindications ( 4 ), Warnings and Precautions ( 5.2 ), Use in Specific Populations ( 8.1 )] . Advise females of reproductive potential to use effective contraception during Otrexup therapy and for 6 months after the final dose [see Use in Specific Populations ( 8.3 )] . Advise males of reproductive potential to use effective contraception during Otrexup therapy and for 3 months after the final dose [see Use in Specific Populations ( 8.3 )] . Infertility Advise patients of reproductive potential that Otrexup may cause impairment of fertility, oligospermia, and menstrual dysfunction [see Warnings and Precautions ( 5.2 ), Use in Specific Populations ( 8.3 )] . Lactation Advise females not to breastfeed during treatment with Otrexup and for one week after the final dose [see Use in Specific Populations ( 8.3 )] . Ability to Drive or Operate Machinery Inform patients that adverse reactions such as dizziness and fatigue may affect their ability to drive or operate machinery. Proper Storage and Disposal Advise patients to store Otrexup at room temperature (68 to 77°F or 20 to 25°C). Inform patients and caregivers of the need for proper disposal after use, including the use of a sharps disposal container. Address Medical Inquiries to: Antares Pharma, Inc. Medical Communications 100 Princeton South, Suite 300 Ewing, NJ 08628 1-855-Otrexup (1-855-687-3987) Manufactured for: Antares Pharma, Inc. 100 Princeton South, Suite 300 Ewing, NJ 08628 USA Otrexup™ is the subject of US Patent Nos. 8,021,335, 6,746,429, 8,480,631, 8,562,564, 8,579,865, and 8,945,063.

ares Pharma, Inc. Medical Communications 100 Princeton South, Suite 300 Ewing, NJ 08628 1-855-Otrexup (1-855-687-3987) Manufactured for: Antares Pharma, Inc. 100 Princeton South, Suite 300 Ewing, NJ 08628 USA Otrexup™ is the subject of US Patent Nos. 8,021,335, 6,746,429, 8,480,631, 8,562,564, 8,579,865, and 8,945,063. ©2019 Antares Pharma, Inc., Ewing, NJ 08628 Antares Pharma Logo

Patient Package Insert PATIENT INFORMATION Otrexup™ (oh-TREKS-up) (methotrexate) injection, for subcutaneous use What is Otrexup? Otrexup is a single-dose auto-injector containing a prescription medicine, methotrexate. Methotrexate is used to: treat certain adults with severe, active rheumatoid arthritis (RA), and children with active polyarticular juvenile idiopathic arthritis (pJIA), after treatment with other medicines including non-steroidal anti-inflammatory (NSAIDS) have been used and did not work well. control the symptoms of severe, resistant, disabling psoriasis in adults when other types of treatment have been used and did not work well. Otrexup is available in doses of 10, 12.5, 15, 17.5, 20, 22.5 and 25 mg. Your doctor will prescribe a different way to take methotrexate if you need to take methotrexate by mouth or in some other way. Your doctor may also change your prescription if your dose does not match the available Otrexup doses, such as doses of less than 10 mg, more than 25 mg, or doses in between the available Otrexup doses. Otrexup should not be used for the treatment of cancer. Otrexup should not be used for the treatment of children with psoriasis. What is the most important information I should know about Otrexup ? Otrexup can cause serious side effects that can lead to death, including: 1. Organ system toxicity. People who use methotrexate for the treatment of cancer, psoriasis, or rheumatoid arthritis, have an increased risk of death from organ toxicity. Types of organ toxicity can include: o gastrointestinal o bone marrow o liver o immune system o nerve o lung o kidneys o skin Your doctor will do blood tests and other types of tests before you take and while you are taking Otrexup to check for signs and symptoms of organ toxicity. Call your doctor right away if you have any of the following symptoms of organ toxicity: o vomiting o diarrhea o mouth sores o fever o confusion o weakness o temporary blindness o seizures o headache o back pain o neck stiffness o paralysis o irritability o sleepiness o problems with coordination o dry cough o trouble breathing o severe skin rash 2. Women who are pregnant are at increased risk for death of the baby and birth defects. Women who are pregnant or who plan to become pregnant must not take Otrexup. A pregnancy test should be performed before starting Otrexup. Contraception should be used by both females and males while taking Otrexup. Pregnancy should be avoided if either partner is receiving Otrexup: for a minimum of 3 months after treatment with Otrexup for males. during and for 6 months after treatment with Otrexup for females. Who should not take Otrexup? Do not take Otrexup if you: are pregnant or planning to become pregnant. See “What is the most important information I should know about Otrexup?" are breastfeeding. Otrexup can pass into your breast milk and may harm your baby. Do not breastfeed while taking Otrexup. Talk to your doctor about the best way to feed your baby if you take Otrexup. have alcohol problems (alcoholism). have liver problems. have problems fighting infection (immunodeficiency syndrome). have been told you have (or think you have) a blood disorder such as low levels of white blood cells, red blood cells (anemia), or platelets. have had an allergy to methotrexate or any of the ingredients in Otrexup. See the end of this leaflet for a complete list of ingredients in Otrexup.

(immunodeficiency syndrome). have been told you have (or think you have) a blood disorder such as low levels of white blood cells, red blood cells (anemia), or platelets. have had an allergy to methotrexate or any of the ingredients in Otrexup. See the end of this leaflet for a complete list of ingredients in Otrexup. Talk to your doctor before taking this medicine if you have any of these conditions. What should I tell my doctor before taking Otrexup? Before you take Otrexup , tell your doctor if you have any other medical conditions. Tell your doctor about all of the medicines you take , including prescription, over-the-counter medicines, vitamins, and herbal supplements. Otrexup may affect how other medicines work, and other medicines may affect how Otrexup works causing side effects. Ask your doctor or pharmacist for a list of medicines if you are not sure. Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine. How should I take Otrexup? Read the Instructions for Use that come with Otrexup. Take Otrexup exactly as your doctor tells you to take it. Inject Otrexup only 1 time each week . Do not take Otrexup every day. Taking Otrexup every day may cause death from toxicity. Your doctor will show you or your caregiver how to inject Otrexup. You should not inject Otrexup until you have been trained on the right way to use it. Check Otrexup before you inject it. Otrexup should be yellow in color and should not have any lumps or particles in it. Otrexup should be injected in the stomach (abdomen) or thigh. Do not inject Otrexup within 2 inches of the belly button (navel). Do not inject Otrexup in the arms or any other areas of the body. Do not inject Otrexup in areas where the skin is tender, bruised, red, scaly, hard, or has scars or stretch marks. If you are not sure if Otrexup was injected, or if you have hard time giving the injection, do not inject another dose. Call your pharmacist or doctor right away. If you inject too much Otrexup, call your doctor or go to the nearest hospital emergency room right away. What should I avoid while taking Otrexup? Do not drink alcohol while taking Otrexup. Drinking alcohol can increase your chances of getting serious side effects. Otrexup can cause dizziness and tiredness. Do not drive a car, operate machinery, or do anything that needs you to be alert until you know how Otrexup affects you. Certain vaccinations should be avoided while taking Otrexup. Talk to your doctor before you or members of your household receive any vaccines. What are the possible side effects of Otrexup? Otrexup may cause serious side effects, including: See “What is the most important information I should know about Otrexup?" fertility problems. Methotrexate, the active ingredient in Otrexup, may affect your ability to have a baby. Males may have a decreased sperm count, and females may have changes to their menstrual cycle. This can happen while taking Otrexup and for a short period of time after you stop. certain cancers. Some people who have taken methotrexate have had a certain type of cancer called Non-Hodgkin’s lymphoma and other tumors. Your doctor may tell you to stop taking Otrexup if this happens. tissue and bone problems. Taking Methotrexate while having radiation therapy may increase the risk of your tissue or bone not receiving enough blood. This may lead to death of the tissue or bone.

e of cancer called Non-Hodgkin’s lymphoma and other tumors. Your doctor may tell you to stop taking Otrexup if this happens. tissue and bone problems. Taking Methotrexate while having radiation therapy may increase the risk of your tissue or bone not receiving enough blood. This may lead to death of the tissue or bone. Common side effects of Otrexup include: • nausea • stomach pain • indigestion (dyspepsia) • mouth sores • rash • stuffy or runny nose and sore throat • diarrhea • abnormal liver function tests • vomiting • headache • bronchitis • low red, white, and platelet blood cell count • hair loss • dizziness • sensitivity to light • burning skin lesions • lung problems Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Otrexup. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I dispose of Otrexup? Do not throw away in the household trash. Put used Otrexup in a FDA-cleared sharps disposal container right away after use. If you do not have a FDA-cleared sharps disposal container, you may use a household container that is: made of a heavy-duty plastic can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out upright stable during use leak-resistant properly labeled to warn of hazardous waste inside the container When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about the safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal . Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. Safely dispose of Otrexup that is out of date or is no longer needed. How should I store Otrexup? Store Otrexup at room temperature between 68°F to 77°F (20°C to 25°C). Do not freeze Keep Otrexup out of the light. Keep Otrexup and all medicines out of the reach of children. General information about the safe and effective use of Otrexup. Methotrexate is sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use Otrexup for a condition for which it was not prescribed. Do not give Otrexup to other people, even if they have the same symptoms that you have. It may harm them. This Patient Information leaflet summarizes the most important information about Otrexup. If you would like more information, talk to your doctor. You can ask your doctor or pharmacist for information about Otrexup that is written for health professionals. For more information, go to www.Otrexup.com or call 1-855-Otrexup (1-855-687-3987). What are the ingredients in Otrexup? Active ingredient: methotrexate Inactive ingredients: hydrochloric acid, sodium chloride, sodium hydroxide and water for injection, USP. This Patient Information has been approved by the U.S. Food and Drug Administration. Manufactured for: Antares Pharma, Inc. 100 Princeton South, Suite 300 Ewing, NJ 08628 USA ©2019 Antares Pharma, Inc., Ewing, NJ 08628 Issued: 12/2019 Antares Pharma Logo

<table><col width="44%"/><col width="34%"/><tbody><tr styleCode="First Last"><td valign="top"><paragraph>o gastrointestinal</paragraph><paragraph>o bone marrow</paragraph><paragraph>o liver</paragraph><paragraph>o immune system</paragraph></td><td valign="top"><paragraph>o nerve</paragraph><paragraph>o lung</paragraph><paragraph>o kidneys</paragraph><paragraph>o skin</paragraph></td></tr></tbody></table> <table><col width="44%"/><col width="34%"/><tbody><tr styleCode="First Last"><td valign="top"><paragraph>o vomiting</paragraph><paragraph>o diarrhea</paragraph><paragraph>o mouth sores</paragraph><paragraph>o fever</paragraph><paragraph>o confusion</paragraph><paragraph>o weakness</paragraph><paragraph>o temporary blindness</paragraph><paragraph>o seizures</paragraph><paragraph>o headache</paragraph><paragraph>o back pain</paragraph></td><td valign="top"><paragraph>o neck stiffness</paragraph><paragraph>o paralysis</paragraph><paragraph>o irritability</paragraph><paragraph>o sleepiness</paragraph><paragraph>o problems with coordination</paragraph><paragraph>o dry cough</paragraph><paragraph>o trouble breathing</paragraph><paragraph>o severe skin rash</paragraph></td></tr></tbody></table> <table><col width="42%"/><col width="39%"/><tbody><tr styleCode="First Last"><td valign="top"><paragraph>&#x2022; nausea</paragraph><paragraph>&#x2022; stomach pain</paragraph><paragraph>&#x2022; indigestion (dyspepsia)</paragraph><paragraph>&#x2022; mouth sores</paragraph><paragraph>&#x2022; rash</paragraph><paragraph>&#x2022; stuffy or runny nose and sore throat</paragraph><paragraph>&#x2022; diarrhea</paragraph><paragraph>&#x2022; abnormal liver function tests</paragraph><paragraph>&#x2022; vomiting</paragraph></td><td valign="top"><paragraph>&#x2022; headache</paragraph><paragraph>&#x2022; bronchitis</paragraph><paragraph>&#x2022; low red, white, and platelet blood cell count</paragraph><paragraph>&#x2022; hair loss</paragraph><paragraph>&#x2022; dizziness</paragraph><paragraph>&#x2022; sensitivity to light</paragraph><paragraph>&#x2022; burning skin lesions</paragraph><paragraph>&#x2022; lung problems</paragraph></td></tr></tbody></table>

Instructions for Use Read this Instructions for Use before using Otrexup™ (oh-TREKS-up) (methotrexate) injection, for subcutaneous use Prepare to Use Otrexup Do not remove cap (marked 1) or safety clip (marked 2) until you are ready to inject Otrexup. Wash your hands well with soap and warm water. Check the expiration date on the label. Do not use if expired. Check the seal. Do not use Otrexup if the seal is broken ( See Figure B ). In addition to Otrexup, you will need the following items: 1 alcohol swab and 1 cotton ball or gauze. Check the Liquid Look at the viewing window ( See Figure C ). The liquid should be yellow in color and should not have any lumps or particles in it. You may see an air bubble. This is normal. Choose an Injection Site Otrexup should be injected into the stomach (abdomen) or thigh. Do not inject Otrexup within 2 inches of the belly button (navel) ( See Figure D ). Do not inject Otrexup in the arms or any other areas of the body. Do not inject Otrexup in areas where the skin is tender, bruised, red, scaly, hard, or has scars or stretch marks. Wipe the area with an alcohol swab. Allow the skin to dry and do not touch this area again before giving Otrexup. Do not fan or blow on the clean area. Give your Injection Step 1: Remove Cap (marked 1) Twist cap marked 1 to remove ( See Figure E ). This will break the seal. You may notice 1 or 2 drops of medicine. This is normal. Do not touch the needle end with your hands or fingers. This could inject the medicine into your hand. Do not replace the cap after it has been removed. After the cap is removed Otrexup must be used or disposed of safely (See step 5). STEP 2: Remove the Safety Clip (marked 2) Flip the Safety Clip marked 2 ( See Figure F ). STEP 3: Inject Otrexup Place needle end of Otrexup flat against thigh or stomach (abdomen) at a 90° and firmly push device against the injection site until fully depressed. You will hear a click, hold for 3 seconds (slowly count 1,2,3) ( See Figure G ). After counting to 3, remove Otrexup from the injection site. You may notice a small amount of blood or liquid at the administration site, which is normal. Press a cotton ball or gauze on the area for 10 seconds. Do not rub the area. Step 4: Check the Viewing Window Check the viewing window ( See Figure H ). The viewing window will be half blocked with a red flag to show that the full dose was delivered. ( See Figure H ). Dispose of Otrexup in a puncture-proof disposable container (See Step 5) . If the viewing window is not half blocked with a red flag , call your doctor or pharmacist, or call 1-855-Otrexup (1-855-687-3987) for help. Do not use another Otrexup without talking to your doctor. Step 5: Dispose of Otrexup Do not throw away in the household trash . Put used Otrexup in a FDA-cleared sharps disposal container right away after use. If you do not have a FDA-cleared sharps disposal container, you may use a household container that is: made of a heavy-duty plastic can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out upright and stable during use leak-resistant properly labeled to warn of hazardous waste inside the container When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes.

operly labeled to warn of hazardous waste inside the container When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about the safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal. Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. Safely dispose of Otrexup that is out of date or no longer needed. How should I store Otrexup? Store Otrexup at room temperature between 68°F to 77°F (20°C to 25°C). Do not freeze. Keep Otrexup out of the light. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Mfd. For Antares Pharma, Inc. Ewing, NJ 08628 12/2019 PII-13-001 V11 IFU Figure A IFU Figure B IFU Figure C IFU Figure D IFU Figure E IFU Figure F IFU Figure G IFU Figure H

WARNING: EMBRYO-FETAL TOXICITY, HYPERSENSITIVITY REACTIONS, BENZYL ALCOHOL TOXICITY, andOTHER SERIOUS ADVERSE REACTIONS Methotrexate Injection can cause embryo-fetal toxicity, including fetal death. For non-neoplastic diseases, Methotrexate Injection is contraindicated in pregnancy. Advise females and males of reproductive potential to use effective contraception [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 ), and Use in Specific Populations ( 8.1 , 8.3 )] . Methotrexate Injection is contraindicated in patients with a history of severe hypersensitivity reactions to methotrexate, including anaphylaxis [see Contraindications ( 4 ) and Warnings and Precautions ( 5.2 )]. Formulations with benzyl alcohol can cause severe central nervous toxicity or metabolic acidosis. Use only preservative-free Methotrexate Injection for treatment of neonates or low birth weight infants and for intrathecal use. Do not use benzyl alcohol-containing formulations for high-dose regimens unless immediate treatment is required and preservative-free formulations are not available [see Dosage and Administration ( 2.1 ) and Warnings and Precautions ( 5.3 )]. Other serious adverse reactions, including death, have been reported with methotrexate. Closely monitor for infections and adverse reactions of the bone marrow, kidneys, liver, nervous system, gastrointestinal tract, lungs, and skin. Withhold or discontinue Methotrexate Injection as appropriate [see Warnings and Precautions ( 5.4 , 5.5 , 5.6 , 5.7 , 5.8 , 5.9 , 5.10 , 5.11 )]. WARNING: EMBRYO-FETAL TOXICITY, HYPERSENSITIVITY REACTIONS, BENZYL ALCOHOL TOXICITY, and OTHER SERIOUS ADVERSE REACTIONS See full prescribing information for complete boxed warning . Methotrexate Injection can cause embryo-fetal toxicity, including fetal death. Use in non-neoplastic diseases is contraindicated during pregnancy. Advise females and males of reproductive potential to use effective contraception during and after treatment with Methotrexate Injection. ( 4 , 5.1 , 8.1 , 8.3 ) Methotrexate Injection is contraindicated in patients with a history of severe hypersensitivity reactions to methotrexate, including anaphylaxis. ( 4 , 5.2 ) Formulations with benzyl alcohol can cause severe central nervous toxicity or metabolic acidosis. Use only preservative-free Methotrexate Injection for treatment of neonates or low birth weight infants, and for intrathecal use. Do not use benzyl alcohol-containing formulations for high-dose regimens unless immediate treatment is required and preservative-free formulations are not available. ( 2.1 , 5.3 ) Other serious adverse reactions, including death, have been reported with methotrexate. Closely monitor for infections and adverse reactions of the bone marrow, kidneys, liver, nervous system, gastrointestinal tract, lungs, and skin. Withhold or discontinue Methotrexate Injection as appropriate. ( 5.4 , 5.5 , 5.6 , 5.7 , 5.8 , 5.9 , 5.10 , 5.11)

1 INDICATIONS AND USAGE Methotrexate Injection is a folate analog metabolic inhibitor indicated for: The following neoplastic diseases for the: Treatment of adult and pediatric patients with acute lymphoblastic leukemia as part of a combination chemotherapy regimen. ( 1.1 ) Prophylaxis and treatment of adult and pediatric patients with meningeal leukemia. ( 1.2 ) Treatment of adult and pediatric patients with non-Hodgkin lymphoma. ( 1.3 ) Treatment of adult and pediatric patients with osteosarcoma as part of a combination chemotherapy regimen. ( 1.4 ) Treatment of adults with breast cancer as part of a combination chemotherapy regimen. ( 1.5 ) Treatment of adults with squamous cell carcinoma of the head and neck as a single agent. ( 1.6 ) Treatment of adults with gestational trophoblastic neoplasia as part of a combination chemotherapy regimen. ( 1.7 ) Treatment of adults with rheumatoid arthritis (RA). ( 1.8 ) Treatment of pediatric patients with polyarticular juvenile idiopathic arthritis (pJIA). ( 1.9 ) Treatment of adults with severe psoriasis. ( 1.10 ) 1.1 Acute Lymphoblastic Leukemia Methotrexate Injection is indicated for the treatment of adult and pediatric patients with acute lymphoblastic leukemia (ALL) as part of a combination chemotherapy regimen. 1.2 Meningeal Leukemia: Prophylaxis and Treatment Methotrexate Injection is indicated for the prophylaxis and treatment of meningeal leukemia in adult and pediatric patients. 1.3 Non-Hodgkin Lymphoma Methotrexate Injection is indicated for the treatment of adults and pediatric patients with non-Hodgkin lymphoma. 1.4 Osteosarcoma Methotrexate Injection is indicated for the treatment of adults and pediatric patients with osteosarcoma as part of a combination chemotherapy regimen. 1.5 Breast Cancer Methotrexate Injection is indicated for the treatment of adults with breast cancer as part of a combination chemotherapy regimen. 1.6 Squamous Cell Carcinoma of the Head and Neck Methotrexate Injection is indicated for the treatment of adults with squamous cell carcinoma of the head and neck as a single agent. 1.7 Gestational Trophoblastic Neoplasia Methotrexate Injection is indicated for the treatment of adults with gestational trophoblastic neoplasia (GTN) as part of a combination chemotherapy regimen. 1.8 Rheumatoid Arthritis Methotrexate Injection is indicated for the treatment of adults with rheumatoid arthritis (RA). 1.9 Polyarticular Juvenile Idiopathic Arthritis Methotrexate Injection is indicated for the treatment of pediatric patients with polyarticular Juvenile Idiopathic Arthritis (pJIA). 1.10 Psoriasis Methotrexate Injection is indicated for the treatment of adults with severe psoriasis.

2 DOSAGE AND ADMINISTRATION Verify pregnancy status in females of reproductive potential before starting Methotrexate Injection. ( 2.1 , 4 , 5.1 ) Neoplastic diseases: Refer to the prescribing information for disease specific dosing recommendations. Follow guidelines for high-dose regimens. ( 2.2 , 2.3 , 2.4 , 2.5 , 2.6 , 2.7 , 2.8 , 2.9 ) RA: Recommended starting dosage of 7.5 mg once weekly intramuscularly; adjust dose to achieve an optimal response. ( 2.10 ) pJIA: Recommended starting dosage of 10 mg/m 2 once weekly subcutaneously or intramuscularly; adjust dose to achieve an optimal response. ( 2.11 ) Psoriasis: Recommended dosage of 10 mg to 25 mg once weekly intramuscularly or intravenously; adjust dose to achieve optimal response. Once achieved, reduce to lowest possible dosage. ( 2.12 ) 2.1 Important Dosage and Safety Information Use only preservative-free Methotrexate Injection for treatment of neonates or low birth weight infants and for intrathecal use. Do not use benzyl alcohol-containing formulations for high-dose regimens unless immediate treatment is required and preservative-free formulations are not available [see Warnings and Precautions (5.3) and Use in Specific Populations (8.4) ]. Verify pregnancy status in females of reproductive potential before starting Methotrexate Injection [see Contraindications (4) and Warnings and Precautions (5.1) ]. For patients switching between a methotrexate product administered orally and Methotrexate Injection, consider potential differences in bioavailability . 2.2 Recommended Monitoring and Concomitant Therapies for Intermediate- and High-Dose Regimens To decrease the risk of severe adverse reactions [see Warnings and Precautions (5) ] : Administer leucovorin rescue in patients receiving Methotrexate Injection doses of 500 mg/m 2 or greater (e.g., high-dose) . Consider leucovorin rescue for patients receiving Methotrexate Injection doses between 100 mg/m 2 to less than 500 mg/m 2 (e.g., intermediate-dose). Refer to the leucovorin prescribing information for additional information. For high-dose Methotrexate Injection regimens, follow the supportive care and monitoring instructions below. Also consider for patients receiving intermediate-dose Methotrexate Injection regimens. - Monitor serum creatinine, electrolytes, at baseline and at least daily during therapy - Administer intravenous fluids starting before the first dose and continuing throughout treatment to maintain adequate hydration and urine output - Alkalinize urine starting before the first dose and continuing throughout treatment to maintain a urinary pH of 7 or higher - Monitor methotrexate concentrations at least daily and adjust hydration and leucovorin dosing as needed Administer glucarpidase in patients who have toxic plasma methotrexate concentrations (>1 micromole per liter) and delayed methotrexate clearance due to impaired renal function (refer to the glucarpidase prescribing information for additional information). 2.3 Recommended Dosage for Acute Lymphoblastic Leukemia Methotrexate Injection is used as part of a multi-drug regimen. The recommended dosage varies from 10 to 5000 mg/m 2 intravenously. For high-dose Methotrexate Injection regimens, use leucovorin rescue in accordance with high-dose methotrexate regimen guidelines [see Dosage and Administration (2.2)] . Lower doses (e.g., 20 to 30 mg/m 2 per week) may be used intramuscularly.

regimen. The recommended dosage varies from 10 to 5000 mg/m 2 intravenously. For high-dose Methotrexate Injection regimens, use leucovorin rescue in accordance with high-dose methotrexate regimen guidelines [see Dosage and Administration (2.2)] . Lower doses (e.g., 20 to 30 mg/m 2 per week) may be used intramuscularly. Individualize the dose and schedule of Methotrexate Injection based on disease state, patient risk category, concurrent drugs used, phase of treatment, and response to treatment. 2.4 Recommended Dosage for Meningeal Leukemia: Prophylaxis and Treatment Use only preservative-free Methotrexate Injection for intrathecal use. Prior to administration, dilute preservative-free Methotrexate Injection to a concentration of 1 mg/mL in preservative-free 0.9% Sodium Chloride Injection, USP. The recommended intrathecal dose of Methotrexate Injection (preservative-free) is based on age: less than 1 year: 6 mg 1 to less than 2 years: 8 mg 2 to less than 3 years: 10 mg 3 to less than 9 years: 12 mg greater than or equal to 9 years: 12 to 15 mg For treatment of meningeal leukemia, intrathecal methotrexate may be given at intervals of 2 or more days up to twice weekly; however, administration at intervals of less than 1 week may result in increased subacute toxicity. For meningeal leukemia prophylaxis, Methotrexate Injection is administered no more than once weekly. For patients with Down Syndrome, administer leucovorin rescue with intrathecal Methotrexate Injection. 2.5 Recommended Dosage for Non-Hodgkin Lymphoma The recommended dosage of Methotrexate Injection varies. When used in combination, recommended dosages range from 10 mg/m 2 to 8000 mg/m 2 intravenously. When used as a single agent, recommended dosages include 8000 mg/m 2 intravenously for central nervous system-directed therapy or 5 to 75 mg intravenously for cutaneous forms of non-Hodgkin lymphoma. As part of a combination chemotherapy regimen, a recommended dosage of Methotrexate Injection is 1000 mg/m 2 or 3000 mg/m 2 as an intravenous infusion over 24 hours followed by leucovorin rescue in accordance with high-dose methotrexate regimen guidelines [see Dosage and Administration (2.2) ] . For central nervous system-directed therapy, a recommended dosage of Methotrexate Injection is 8000 mg/m 2 as an intravenous infusion over 4 hours as a single agent or in combination with immunochemotherapy at doses ranging from 3000 mg/m 2 to 8000 mg/m 2 followed by leucovorin rescue in accordance with high-dose methotrexate regimen guidelines [see Dosage and Administration (2.2) ] . For intrathecal Methotrexate Injection (preservative-free), the recommended dose is based on age [see Dosage and Administration (2.4) ] . The frequency of administration varies based on whether it is being used for treatment or prophylaxis, and other factors. 2.6 Recommended Dosage for Osteosarcoma The recommended dosage of Methotrexate Injection is typically 12 g/m 2 (maximum 20 g/dose) as an intravenous infusion over 4 hours administered as a component of a combination chemotherapy regimen. Administer leucovorin rescue in accordance with high-dose methotrexate regimen guidelines [see Dosage and Administration (2.2) ]. Subsequent doses may need to be adjusted based on observed peak serum methotrexate concentrations. Dosage and schedule may vary based upon factors such as patient comorbidities, disease state, and prior treatments. 2.7 Recommended Dosage for Breast Cancer A recommended dosage of Methotrexate Injection is 40 mg/m 2 intravenously as a component of a cyclophosphamide- and fluorouracil-based multi-drug regimen. 2.8 Recommended Dosage for Squamous Cell Carcinoma of Head and Neck The recommended dosage of Methotrexate Injection ranges from 40 to 60 mg/m 2 intravenously once weekly.

mmended dosage of Methotrexate Injection is 40 mg/m 2 intravenously as a component of a cyclophosphamide- and fluorouracil-based multi-drug regimen. 2.8 Recommended Dosage for Squamous Cell Carcinoma of Head and Neck The recommended dosage of Methotrexate Injection ranges from 40 to 60 mg/m 2 intravenously once weekly. 2.9 Recommended Dosage for Gestational Trophoblastic Neoplasia For patients with low-risk gestational trophoblastic neoplasia (GTN) a recommended dosage for Methotrexate Injection is 30 mg/m 2 to 200 mg/m 2 or 0.4 mg/kg to 1 mg/kg intravenously or intramuscularly. For patients with high-risk GTN, a recommended dosage for Methotrexate Injection is 300 mg/m 2 over 12 hours as an intravenous infusion as a component of a multi-drug regimen. 2.10 Recommended Dosage for Rheumatoid Arthritis The recommended starting dosage of Methotrexate Injection is 7.5 mg once weekly, administered intramuscularly with escalation to achieve optimal response. Dosages of more than 20 mg once weekly result in an increased risk of serious adverse reactions, including myelosuppression. When responses are observed, the majority occurred between 3 and 6 weeks from initiation of treatment; however, responses have occurred up to 12 weeks after treatment initiation. Administer folic acid or folinic acid to reduce the risk of methotrexate adverse reactions [see Warnings and Precautions (5.12 )]. 2.11 Recommended Dosage for Polyarticular Juvenile Idiopathic Arthritis The recommended starting dosage of Methotrexate Injection is 10 mg/m 2 once weekly administered subcutaneously or intramuscularly, with escalation to achieve optimal response. Dosages over 30 mg/m 2 per week may result in an increased risk of serious adverse reactions, including myelosuppression. When responses are observed, the majority occurred between 3 and 6 weeks from initiation of treatment; however, responses have occurred up to 12 weeks after treatment initiation. Administer folic acid or folinic acid to reduce the risk of methotrexate adverse reactions [see Warnings and Precautions (5.12) ]. 2.12 Recommended Dosage for Psoriasis The recommended dosage of Methotrexate Injection is 10 mg to 25 mg intramuscularly or intravenously once weekly until adequate response is achieved. Adjust the dose gradually to achieve optimal clinical response; do not exceed 25 mg per week. Once optimal clinical response has been achieved, reduce the dosage to the lowest possible dosing regimen. Administer folic acid or folinic acid to reduce the risk of methotrexate adverse reactions [see Warnings and Precautions (5.12) ]. 2.13 Dosage Modifications for Adverse Reactions Discontinue Methotrexate Injection for: Anaphylaxis or other severe hypersensitivity reactions [see Warnings and Precautions (5.2) ] Lymphoproliferative disease [see Warnings and Precautions (5.13) ] Withhold, dose reduce or discontinue Methotrexate Injection as appropriate for: Myelosuppression [see Warnings and Precautions (5.4 )] Withhold or discontinue Methotrexate Injection as appropriate for: Serious infections [see Warnings and Precautions (5.5) ] Renal toxicity [see Warnings and Precautions (5.6) ] Hepatotoxicity [see Warnings and Precautions (5.7) ] Neurotoxicity [see Warnings and Precautions (5.8 )] Gastrointestinal toxicity [see Warnings and Precautions (5.9) ] Pulmonary toxicity [see Warnings and Precautions (5.10) ] Dermatologic reactions [see Warnings and Precautions (5.11) ] 2.14 Administration and Handling Information Methotrexate Injection is a hazardous drug. Follow applicable special handling and disposable procedures.

al toxicity [see Warnings and Precautions (5.9) ] Pulmonary toxicity [see Warnings and Precautions (5.10) ] Dermatologic reactions [see Warnings and Precautions (5.11) ] 2.14 Administration and Handling Information Methotrexate Injection is a hazardous drug. Follow applicable special handling and disposable procedures. 1 With Preservative (Multiple-Dose Vial) Methotrexate Injection formulation containing benzyl alcohol as a preservative may be administered by intramuscular, intravenous, or subcutaneous injection [see Dosage and Administration (2.1) ] . Methotrexate Injection with preservative may be further diluted with 0.9% Sodium Chloride Injection, USP. Diluted product should be used within 4 hours when stored at room temperature (20°C to 25°C) or 24 hours under refrigeration (2°C to 8°C). Visually inspect product for particulate matter and discoloration prior to administration. Discard if particulate matter or discoloration is observed. Preservative-Free (Single -Dose Vial) Methotrexate Injection preservative-free may be administered by intramuscular, intravenous, subcutaneous, or intrathecal injection. Use only preservative-free Methotrexate Injection for treatment of neonates or low birth weight infants and for intrathecal use [see Warning and Precautions (5.3) and Use in Specific Populations (8.4) ] . Use preservative-free Methotrexate Injection for high-dose regimens unless immediate treatment is required, and preservative-free formulations are not available [see Warning and Precautions (5.3) and Use in Specific Populations (8.4) ] . Preservative-free Methotrexate Injection may be further diluted before use with preservative-free 0.9% Sodium Chloride Injection, USP. Diluted product should be used within 4 hours when stored at room temperature (20°C to 25°C) or 24 hours when stored under refrigeration (2°C to 8°C). Discard unused portion. Visually inspect for particulate matter and discoloration prior to administration. Discard if particulate matter or discoloration is observed.

3 DOSAGE FORMS AND STRENGTHS Injection: Methotrexate Injection, USP is a clear, yellow solution and is supplied in single-dose vials (preservative-free) and multiple-dose vials (with preservative) in the following strengths: With Preservative (Multiple-Dose Vial) 50 mg/2 mL (25 mg/mL) Preservative-Free (Single-Dose Vial) 1 g/40 mL (25 mg/mL) Injection: ( 3 ) With preservative (multiple-dose vials): 50 mg/2 mL (25mg/mL) Preservative-free (single-dose vials): 1 g/40 mL (25 mg/mL)

4 CONTRAINDICATIONS Methotrexate Injection is contraindicated in: Patients with history of severe hypersensitivity to methotrexate [see Warnings and Precautions (5.2) ] . Pregnancy in patients with non-neoplastic diseases [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1) ] . History of severe hypersensitivity to methotrexate. (4 ) Pregnancy: in patients with non-neoplastic diseases. (4 )

5 WARNINGS AND PRECAUTIONS Secondary malignancies can occur. ( 5.13 ) Tumor lysis syndrome can occur in patients with rapidly growing tumors. (5.14) Immunizations and Risks associated with Live Vaccines: Immunizations may be ineffective. Live vaccines are not recommended due to risk of disseminated infection. (5.15 ) Infertility: Can cause impairment of fertility, oligospermia, and menstrual dysfunction. ( 5.16, 8.3 ) 5.1 Embryo-Fetal Toxicity Based on published reports and its mechanism of action, methotrexate can cause embryo-fetal toxicity, including fetal death when administered to a pregnant woman. Methotrexate Injection is contraindicated for use in pregnant women with non-neoplastic diseases. Advise pregnant women with neoplastic diseases of the potential risk to a fetus. The preservative benzyl alcohol can cross the placenta; when possible, use the preservative-free formulation when Methotrexate Injection is needed during pregnancy to treat a neoplastic disease [see Warnings and Precautions (5.3 )] . Advise females of reproductive potential to use effective contraception during Methotrexate Injection treatment and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during Methotrexate Injection treatment and for 3 months after the last dose [see Contraindications (4) and Use in Specific Populations ( 8.1 , 8.3 , 8.4 )] . 5.2 Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis, can occur with methotrexate [see Adverse Reactions (6.1) ]. If signs or symptoms of anaphylaxis or any other serious hypersensitivity reaction occurs, immediately discontinue Methotrexate Injection and institute appropriate therapy [see Contraindications (4) ] . 5.3 Risks of Serious Adverse Reactions due to Benzyl Alcohol-Preservative Formulations with benzyl alcohol can cause severe central nervous toxicity or metabolic acidosis, if used in neonates or low birth weight infants, intrathecally, or in high-dose regimens. Use only preservative-free Methotrexate Injection for treatment of neonates or low birth weight infants and for intrathecal use. Do not use benzyl alcohol-containing formulations for high-dose regimens unless immediate treatment is required, and preservative-free formulations are not available. The preservative benzyl alcohol can cross the placenta; when possible, use the preservative-free formulation when Methotrexate Injection is needed during pregnancy to treat a neoplastic disease [see Use in Specific Populations (8.1) ] . Serious and Fatal Adverse Reactions Including Gasping Syndrome in Neonates and Low Birth Weight Infants Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low birth weight infants treated with drugs containing benzyl alcohol, including Methotrexate Injection with preservative. The “gasping syndrome” is characterized by central nervous system (CNS) depression, metabolic acidosis, and gasping respirations. When prescribing in infants (non-neonate, non-low birth weight), if a preservative-free formulation of Methotrexate Injection is not available and use of a benzyl alcohol-containing formulation is necessary, consider the combined daily metabolic load of benzyl alcohol from all sources including Methotrexate Injection (Methotrexate Injection contains 9.4 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol.

otrexate Injection is not available and use of a benzyl alcohol-containing formulation is necessary, consider the combined daily metabolic load of benzyl alcohol from all sources including Methotrexate Injection (Methotrexate Injection contains 9.4 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known [see Use in Specific Populations (8.4) ]. Neurotoxicity Due to Intrathecal Administration Serious neurotoxicity can occur following the intrathecal administration of Methotrexate Injection containing the preservative benzyl alcohol. Metabolic Acidosis with High-Dose Therapy Severe metabolic acidosis can occur with Methotrexate Injection that contains the preservative benzyl alcohol. 5.4 Myelosuppression Methotrexate suppresses hematopoiesis and can cause severe and life-threatening pancytopenia, anemia, aplastic anemia, leukopenia, neutropenia, and thrombocytopenia [see Adverse Reactions (6.1) ]. Obtain blood counts at baseline and periodically during treatment. Monitor patients for possible clinical complications of myelosuppression. Provide supportive care and withhold, reduce dose, or discontinue Methotrexate Injection as needed. 5.5 Serious Infections Patients treated with methotrexate are at increased risk for developing life-threatening or fatal bacterial, fungal, or viral infections including opportunistic infections such as Pneumocystis jiroveci pneumonia, invasive fungal infections, hepatitis B reactivation, tuberculosis primary infection or reactivation, and disseminated Herpes zoster and cytomegalovirus infections. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with Methotrexate Injection. Withhold or discontinue Methotrexate Injection in patients who develop serious infections . 5.6 Renal Toxicity Methotrexate can cause renal toxicity including irreversible acute renal failure. Monitor renal function and withhold or discontinue Methotrexate Injection as needed for severe renal toxicity. For patients receiving high-dose regimens, follow recommendations to decrease the risk of renal injury and mitigate renal toxicity [see Dosage and Administration (2.2) ]. Patients with impaired renal function are at increased risk for methotrexate toxicity [see Use in Specific Populations (8.6) ]. Consider administration of glucarpidase in patients with toxic plasma methotrexate concentrations (>1 micromole per liter) and delayed clearance due to impaired renal function. [see Dosage and Administration (2.2) ] . 5.7 Hepatotoxicity Methotrexate can cause severe and potentially irreversible hepatotoxicity including fibrosis, cirrhosis, and fatal liver failure [see Adverse Reactions ( 6.1 , 6.2 )]. In patients with psoriasis, fibrosis or cirrhosis may occur in the absence of symptoms or abnormal liver function tests. In patients with psoriasis, the risk of hepatotoxicity appears to increase with total cumulative dose and generally occurs after receipt of a total cumulative dose of 1.5 g or more. The safety of Methotrexate Injection in patients with liver disease is unknown. Avoid use of Methotrexate Injection in patients with chronic liver disease, unless benefits clearly outweigh the risks. The risk of hepatotoxicity is increased with heavy alcohol consumption. Assess liver function prior to initiating Methotrexate Injection and monitor liver function tests during treatment. Withhold or discontinue Methotrexate Injection as appropriate. 5.8 Neurotoxicity Methotrexate can cause severe acute and chronic neurotoxicity which can be progressive, irreversible, and fatal.

nsumption. Assess liver function prior to initiating Methotrexate Injection and monitor liver function tests during treatment. Withhold or discontinue Methotrexate Injection as appropriate. 5.8 Neurotoxicity Methotrexate can cause severe acute and chronic neurotoxicity which can be progressive, irreversible, and fatal. Serious neurotoxicity, including generalized and focal seizures, have occurred in pediatric patients [see Use in Specific Populations (8.4) ] . Monitor patients for signs of neurotoxicity and withhold or discontinue Methotrexate Injection when appropriate. Leukoencephalopathy Leukoencephalopathy can occur with intermediate and high-dose intravenous regimens, intrathecal methotrexate, and low-dose methotrexate therapy. The risk of leukoencephalopathy is increased with prior cranial radiation. Transient Acute Neurologic Syndrome A transient acute stroke-like syndrome can occur with high-dose methotrexate. Clinical manifestations include confusion, hemiparesis, transient blindness, seizures, and coma. Neurologic Adverse Reactions Associated with Intrathecal Administration Intrathecal methotrexate can cause the following additional neurologic adverse reactions: Acute chemical arachnoiditis manifested by symptoms such as headache, back pain, nuchal rigidity, and fever. Subacute myelopathy characterized by paraparesis or paraplegia. Avoid the intrathecal use of Methotrexate Injection that contains the preservative benzyl alcohol because of the risk of serious neurotoxicity [see Warnings and Precautions (5.3) ]. 5.9 Gastrointestinal Toxicity Methotrexate can cause diarrhea, vomiting, stomatitis, hemorrhagic enteritis and fatal intestinal perforation [see Adverse Reactions (6.1) ] . Patients with peptic ulcer disease or ulcerative colitis are at a greater risk of developing severe gastrointestinal adverse reactions. Withhold or discontinue Methotrexate Injection for severe gastrointestinal toxicity, and institute appropriate supportive care as needed. 5.10 Pulmonary Toxicity Methotrexate-induced pulmonary toxicity including acute or chronic interstitial pneumonitis and irreversible or fatal cases can occur at all dose levels. Monitor patients for signs of pulmonary toxicity and withhold or discontinue Methotrexate Injection as appropriate. 5.11 Dermatologic Reactions Severe, including fatal, dermatologic reactions, such as toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, can occur with methotrexate [see Adverse Reactions ( 6.1 , 6.2 )]. Psoriasis may be aggravated by concomitant exposure to ultraviolet radiation. Methotrexate can cause radiation recall, photodermatitis (sunburn) reactivation, photosensitivity, and severe sunburn reactions. Advise patients to limit sun exposure while taking Methotrexate Injection. Advise patients when outdoors to wear a hat and protective clothing and use a broad-spectrum Ultraviolet A (UVA)/Ultraviolet B (UVB) sunscreen and lip balm (SPF ≥30) to help protect against sunburn. Monitor patients for signs of dermatologic toxicity and withhold or permanently discontinue Methotrexate Injection for severe dermatologic adverse reactions. 5.12 Folic Acid Supplementation Neoplastic Diseases Products containing folic acid or its derivatives may decrease the clinical effectiveness of methotrexate. Avoid use of products containing folic acid or folinic acid unless clinically indicated [see Drug Interactions (7.1) ] . Non-neoplastic Diseases Folate deficiency may increase methotrexate adverse reactions. Administer folic acid or folinic acid to patients with rheumatoid arthritis, pJIA, and psoriasis [see Dosage and Administration ( 2.10 , 2.11 , 2.12 )] . 5.13 Secondary Malignancies Secondary malignancies can occur at all dose levels of methotrexate.

seases Folate deficiency may increase methotrexate adverse reactions. Administer folic acid or folinic acid to patients with rheumatoid arthritis, pJIA, and psoriasis [see Dosage and Administration ( 2.10 , 2.11 , 2.12 )] . 5.13 Secondary Malignancies Secondary malignancies can occur at all dose levels of methotrexate. In some cases, lymphoproliferative disease that occurred during therapy with low-dose methotrexate regressed completely following withdrawal of methotrexate. If lymphoproliferative disease occurs, discontinue Methotrexate Injection and institute appropriate treatment if lymphoma does not regress. 5.14 Tumor Lysis Syndrome Methotrexate can induce tumor lysis syndrome in patients with rapidly growing tumors. Institute appropriate treatment for prevention and management of tumor lysis syndrome. 5.15 Immunization and Risks Associated with Live Vaccines Immunization during Methotrexate Injection treatment may be ineffective. Disseminated infections following administration of live vaccines have been reported. Update immunizations according to immunization guidelines prior to initiating Methotrexate Injection. Immunization with live vaccines is not recommended during treatment. The interval between live vaccinations and initiation of Methotrexate Injection should be in accordance with current vaccination guidelines for patients on immunosuppressive therapies. 5.16 Infertility Based on published reports, methotrexate can cause impairment of fertility, oligospermia, and menstrual dysfunction. It is not known if the infertility may be reversible in affected patients. Discuss the risk of effects on reproduction with female and male patients of reproductive potential [see Use in Specific Populations (8.3 )]. 5.17 Increased Risk of Adverse Reactions Due to Third-Space Accumulation Methotrexate can exit slowly from third-space accumulations resulting in prolonged terminal plasma half-life and toxicity. Evacuate significant third-space accumulations prior to Methotrexate Injection administration [see Clinical Pharmacology (12.3 )]. 5.18 Increased Risk of Soft Tissue and Bone Toxicity with Concomitant Radiotherapy Concomitant radiation therapy increases the risk of soft tissue necrosis and osteonecrosis associated with methotrexate. 5.19 Risk of Serious Adverse Reactions with Medication Errors Serious adverse reactions, including death, have occurred due to medication errors. Most commonly, these errors occurred in patients who were taking methotrexate daily when a weekly dosing regimen was prescribed. Ensure that patients receive the recommended dosage, because medication errors have led to death.

6 ADVERSE REACTIONS The following adverse reactions are described, or described in greater detail, in other sections: Hypersensitivity Reactions [see Warnings and Precautions (5.2 )] Myelosuppression [see Warnings and Precautions (5.4 )] Serious Infections [see Warnings and Precautions (5.5) ] Renal Toxicity [see Warnings and Precautions (5.6) ] Hepatotoxicity [see Warnings and Precautions (5.7) ] Neurotoxicity [see Warnings and Precautions (5.8) ] Gastrointestinal Toxicity [see Warnings and Precautions (5.9) ] Pulmonary Toxicity [see Warnings and Precautions (5.10) ] Dermatologic Reactions [see Warnings and Precautions (5.11) ] Secondary Malignancies [see Warnings and Precautions (5.13) ] Tumor Lysis Syndrome [see Warnings and Precautions (5.14) ] Increased Risk of Adverse Reactions due to Third-Space Accumulation [see Warnings and Precautions (5.17) ] Common adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Alembic Pharmaceuticals, Inc. at 1-866-210-9797 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials and other studies 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 practice. Commonly reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse reactions are infection, malaise, fatigue, chills, fever, and dizziness. Rheumatoid Arthritis The approximate incidences of methotrexate-attributed (i.e., placebo rate subtracted) adverse reactions in 12- to 18-week double-blind studies in patients (n = 128) with RA treated with low-dose oral (7.5 mg per week to 15 mg per week) pulse methotrexate are listed below. Most patients were on concomitant NSAIDs and some received corticosteroids. Hepatic histology was not examined in these short-term studies. Incidence ≥10%: Elevated liver function tests 15%, nausea/vomiting 10%. Incidence 3% to <10%: Stomatitis, thrombocytopenia (platelet count less than 100,000/mm3). Incidence 1% to <3%: Rash/pruritus/dermatitis, diarrhea, alopecia, leukopenia (white blood cell count less than 3000/mm3), pancytopenia, dizziness. Two other controlled trials of patients (n = 680) with RA on 7.5 mg per week to 15 mg per week oral doses showed the following adverse reactions: Incidence 1%: Interstitial pneumonitis. Other less common adverse reactions: Decreased hematocrit, headache, upper respiratory infection, anorexia, arthralgias, chest pain, coughing, dysuria, eye discomfort, epistaxis, fever, infection, sweating, tinnitus, vaginal discharge. Polyarticular Juvenile Idiopathic Arthritis (pJIA) The approximate incidences of adverse reactions reported in patients 2 to 18 years of age with pJIA treated with oral, weekly doses of methotrexate (5 mg/m 2 per week to 20 mg/m 2 per week or 0.1 mg/kg per week to 0.65 mg/kg per week) were as follows (most patients were receiving concomitant NSAIDs, and some received corticosteroids): elevated liver function tests, 14%; gastrointestinal reactions (e.g., nausea, vomiting, diarrhea), 11%; stomatitis, 2%; leukopenia, 2%; headache, 1.2%; alopecia, 0.5%; dizziness, 0.2%; rash, 0.2%.

0.65 mg/kg per week) were as follows (most patients were receiving concomitant NSAIDs, and some received corticosteroids): elevated liver function tests, 14%; gastrointestinal reactions (e.g., nausea, vomiting, diarrhea), 11%; stomatitis, 2%; leukopenia, 2%; headache, 1.2%; alopecia, 0.5%; dizziness, 0.2%; rash, 0.2%. Psoriasis In two published series of adult psoriasis patients (n = 204, 248) treated with methotrexate doses up to 25 mg per week for up to 4 years, adverse reaction rates were similar to those in patients with RA, except for alopecia, photosensitivity, and “burning of skin lesions” (each 3% to 10%). Painful plaque erosions have been reported. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of methotrexate. 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. Blood and lymphatic system disorders: Aplastic anemia, lymphadenopathy, hypogammaglobulinemia Cardiovascular disorders: Thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus), pericarditis, pericardial effusion, hypotension, sudden death Endocrine: Diabetes Eye disorders: Optic neuropathy, blurred vision, ocular irritation, conjunctivitis, xerophthalmia Gastrointestinal disorders: Hemorrhagic enteritis, intestinal perforation, gingivitis, pancreatitis, pharyngitis, hematemesis, melena, gastrointestinal ulceration and bleeding Hepatobiliary disorders: Acute hepatitis, decreased serum albumin, fibrosis, cirrhosis, liver failure Immune system disorders: Anaphylaxis, anaphylactoid reactions, vasculitis Metabolism: Hyperglycemia Musculoskeletal disorders: Stress fracture, soft tissue necrosis, arthralgia, myalgia, osteoporosis Nervous system disorders: Headaches, drowsiness, blurred vision, speech impairment (including dysarthria and aphasia), transient cognitive dysfunction, mood alteration, unusual cranial sensations, paresis, encephalopathy, leukoencephalopathy, and convulsions. Also, spinal radiculopathy with intrathecal use Renal disorders: Severe renal toxicity including renal failure, azotemia, hematuria, proteinuria, cystitis Reproductive disorders: Defective oogenesis or spermatogenesis, loss of libido, impotence, gynecomastia, menstrual dysfunction Respiratory disorders: Pulmonary fibrosis, respiratory failure, chronic interstitial obstructive pulmonary disease, pleuritic pain and thickening, alveolitis Skin disorders: Toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, erythematous rashes, pruritus, alopecia, skin ulceration, accelerated nodulosis, urticaria, pigmentary changes, ecchymosis, telangiectasia, photosensitivity, acne, furunculosis General disorders and administration site conditions: Injection site necrosis, injection site reaction

7 DRUG INTERACTIONS Refer to full prescribing information for drug interactions with Methotrexate Injection. ( 7 ) 7.1 Effects of Other Drugs on Methotrexate Drugs that Increase Methotrexate Exposure Coadministration of methotrexate with the following products may increase methotrexate plasma concentrations, which may increase the risk of methotrexate severe adverse reactions. Increased organ specific adverse reactions may also occur when methotrexate is coadministered with hepatotoxic or nephrotoxic products. If coadministration cannot be avoided, monitor closely for methotrexate adverse reactions when coadministered with: Penicillin or sulfonamide antibiotics Highly protein bound drugs (e.g., oral anticoagulants, phenytoin, salicylates, sulfonamides, sulfonylureas, and tetracyclines) Proton pump inhibitors Probenecid Antifolate drugs (e.g., dapsone, pemetrexed, pyrimethamine and sulfonamides) Aspirin and other nonsteroidal anti-inflammatory drugs Unexpectedly severe and fatal gastrointestinal toxicity can occur with concomitant administration of methotrexate (primarily at high dose) and nonsteroidal anti-inflammatory drugs (NSAIDs). Mercaptopurine Hepatotoxic products Weak acids (e.g., salicylates) Nephrotoxic products Hematotoxic agents Nitrous Oxide Coadministration of methotrexate with nitrous oxide anesthesia potentiates the effect of methotrexate on folate-dependent metabolic pathways, which may increase the risk of severe methotrexate adverse reactions. Avoid nitrous oxide anesthesia in patients receiving methotrexate. Consider alternative therapies in patients who have received prior nitrous oxide anesthesia. Folic Acid Coadministration of methotrexate with folic acid or its derivatives decreases the clinical effectiveness of methotrexate in patients with neoplastic diseases. Methotrexate competes with reduced folates for active transport across cell membranes. Instruct patients to take folic or folinic acid only as directed by their healthcare provider [see Warnings and Precautions (5.12) ]. 7.2 Effects of Methotrexate on Other Drugs Theophylline Coadministration of methotrexate with theophylline increases theophylline plasma concentrations which may increase the risk of theophylline adverse reactions. Monitor theophylline levels and adjust the theophylline dosage in accordance with approved product labeling.

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2 ) Pediatric use: Intermediate-dose methotrexate can cause serious neurotoxicity in patients with acute lymphoblastic leukemia. ( 8.4 ) 8.1 Pregnancy Risk Summary Methotrexate Injection is contraindicated in pregnant women with non-neoplastic diseases. Based on published reports and its mechanism of action, methotrexate can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman [see Data and Clinical Pharmacology (12.1) ]. There are no animal data that meet current standards for nonclinical developmental toxicity studies. Advise pregnant women with neoplastic diseases of the potential risk to a fetus. The preservative benzyl alcohol can cross the placenta; when possible, use the preservative-free formulation when Methotrexate Injection is needed during pregnancy to treat a neoplastic disease [see Warnings and Precautions (5.3) and Use in Specific Populations (8.4) ] . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Human Data Published data from case reports, literature reviews, and observational studies report that methotrexate exposure during pregnancy is associated with an increased risk of embryo-fetal toxicity and fetal death. Methotrexate exposure during the first trimester of pregnancy is associated with an increased incidence of spontaneous abortions and multiple adverse developmental outcomes, including skull anomalies, facial dysmorphism, CNS abnormalities, limb abnormalities, and sometimes cardiac anomalies and intellectual impairment. Adverse outcomes associated with exposure during second and third trimesters of pregnancy include intrauterine growth restriction and functional abnormalities. Because methotrexate is widely distributed and persists in the body for a prolonged period, there is a potential risk to the fetus from preconception methotrexate exposure. A prospective multicenter study evaluated pregnancy outcomes in women taking methotrexate less than or equal to 30 mg per week after conception. The rate of spontaneous abortion/miscarriage in pregnant women exposed to methotrexate was 42.5% (95% confidence interval [95% CI] 29.2–58.7), which was higher than in unexposed patients with autoimmune disease (22.5%, 95% CI 16.8–29.7) and unexposed patients with non-autoimmune disease (17.3%, 95% CI 13–22.8). Of the live births, the rate of major birth defects in pregnant women exposed to methotrexate after conception was higher than in unexposed patients with autoimmune disease (adjusted odds ratio (OR) 1.8 [95% CI 0.6–5.7]) and unexposed patients with non-autoimmune disease (adjusted OR 3.1 [95% CI 1.03–9.5]) (2.9%). Major birth defects associated with pregnancies exposed to methotrexate after conception were not always consistent with methotrexate-associated adverse developmental outcomes. 8.2 Lactation Risk Summary Limited published literature reports the presence of methotrexate in human milk in low amounts, with the highest breast milk to plasma concentration ration reported to be 0.08:1. No information is available on the effects of methotrexate on a breastfed infant or on milk production. Because of the potential for serious adverse reactions from methotrexate in breastfed infants, advise women not to breastfeed during treatment with Methotrexate Injection and for 1 week after the last dose.

e 0.08:1. No information is available on the effects of methotrexate on a breastfed infant or on milk production. Because of the potential for serious adverse reactions from methotrexate in breastfed infants, advise women not to breastfeed during treatment with Methotrexate Injection and for 1 week after the last dose. 8.3 Females and Males of Reproductive Potential Methotrexate can cause malformations and fetal death at doses less than or equal to the recommended clinical doses [see Use in Specific Populations (8.1) ] . Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating Methotrexate Injection [see Contraindications (4) and Use in Specific Populations (8.1) ]. Contraception Females Advise females of reproductive potential to use effective contraception during and for 6 months after the last dose of Methotrexate Injection therapy. Males Methotrexate can cause chromosomal damage to sperm cells. Advise males with female partners of reproductive potential to use effective contraception during and for 3 months after the last dose of Methotrexate Injection therapy. Infertility Females Based on published reports of female infertility after therapy with methotrexate, advise females of reproductive potential that Methotrexate Injection can cause impairment of fertility and menstrual dysfunction during and after cessation of therapy. It is not known if the infertility may be reversed in all affected females. Males Based on published reports of male infertility after therapy with methotrexate, advise males that Methotrexate Injection can cause oligospermia or infertility during and after cessation of therapy. It is not known if the infertility may be reversed in all affected males. 8.4 Pediatric Use The safety and effectiveness of Methotrexate Injection in pediatric patients have been established for ALL, meningeal leukemia prophylaxis and treatment, non-Hodgkin lymphoma, osteosarcoma and in pJIA. Clinical studies evaluating the use of methotrexate in pediatric patients with pJIA demonstrated safety comparable to that observed in adults with RA [see Adverse Reactions (6.1) ]. The safety and effectiveness of Methotrexate Injection have not been established in pediatric patients for the treatment of breast cancer, squamous cell carcinoma of the head and neck, gestational trophoblastic neoplasia, rheumatoid arthritis, and psoriasis. Additional risk information is described below. Risks of Serious Adverse Reactions due to Benzyl Alcohol-Preservative Due to the risk of serious adverse reactions and fatal gasping syndrome following administration of intravenous solutions containing the preservative benzyl alcohol in neonates, use only preservative-free Methotrexate Injection in neonates and low birth weight infants. The “gasping syndrome” is characterized by CNS depression, metabolic acidosis, and gasping respirations. Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature neonates and low birth weight infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions include gradual neurological deterioration, seizures, intracranial hemorrhage, hematological abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol.

cal deterioration, seizures, intracranial hemorrhage, hematological abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. When prescribing in infants (non-neonate, non-low birth weight), if a preservative-free formulation of Methotrexate Injection is not available and use of a benzyl alcohol-containing formulation is necessary, consider the combined daily metabolic load of benzyl alcohol from all sources including Methotrexate Injection (Methotrexate Injection contains 9.4 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known . Do not administer methotrexate formulations containing benzyl alcohol intrathecally due to the risk of severe neurotoxicity [see Warnings and Precautions (5.3) ]. Leukemia/Lymphoma Serious neurotoxicity, frequently manifested as generalized or focal seizures, has been reported with unexpectedly increased frequency among pediatric patients with acute lymphoblastic leukemia who were treated with intermediate-dose intravenous methotrexate (1 g/m 2 ) [see Warnings and Precautions (5.8) ]. 8.5 Geriatric Use Clinical studies of methotrexate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 8.6 Renal Impairment Methotrexate elimination is reduced in patients with renal impairment [creatinine clearance (CLcr) less than 90 mL/min, calculated using Cockcroft-Gault] [see Clinical Pharmacology (12.3) ] . Patients with renal impairment are at increased risk for methotrexate adverse reactions. Follow recommendations to promote methotrexate elimination and decrease risk of acute kidney injury and other methotrexate toxicities in patients who are receiving intermediate- or high-dose regimens [see Dosage and Administration (2.2) and Warnings and Precautions (5.6) ]. Consider reducing the dose or discontinuing Methotrexate Injection in patients with renal impairment as appropriate. 8.7 Hepatic Impairment The pharmacokinetics and safety of methotrexate in patients with hepatic impairment is unknown. Patients with hepatic impairment may be at increased risk for methotrexate adverse reaction based on elimination characteristics of methotrexate [see Clinical Pharmacology (12.3) ]. Consider reducing the dose or discontinuing Methotrexate Injection in patients with hepatic impairment as appropriate [see Warnings and Precautions (5.7) ].

8.1 Pregnancy Risk Summary Methotrexate Injection is contraindicated in pregnant women with non-neoplastic diseases. Based on published reports and its mechanism of action, methotrexate can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman [see Data and Clinical Pharmacology (12.1) ]. There are no animal data that meet current standards for nonclinical developmental toxicity studies. Advise pregnant women with neoplastic diseases of the potential risk to a fetus. The preservative benzyl alcohol can cross the placenta; when possible, use the preservative-free formulation when Methotrexate Injection is needed during pregnancy to treat a neoplastic disease [see Warnings and Precautions (5.3) and Use in Specific Populations (8.4) ] . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Human Data Published data from case reports, literature reviews, and observational studies report that methotrexate exposure during pregnancy is associated with an increased risk of embryo-fetal toxicity and fetal death. Methotrexate exposure during the first trimester of pregnancy is associated with an increased incidence of spontaneous abortions and multiple adverse developmental outcomes, including skull anomalies, facial dysmorphism, CNS abnormalities, limb abnormalities, and sometimes cardiac anomalies and intellectual impairment. Adverse outcomes associated with exposure during second and third trimesters of pregnancy include intrauterine growth restriction and functional abnormalities. Because methotrexate is widely distributed and persists in the body for a prolonged period, there is a potential risk to the fetus from preconception methotrexate exposure. A prospective multicenter study evaluated pregnancy outcomes in women taking methotrexate less than or equal to 30 mg per week after conception. The rate of spontaneous abortion/miscarriage in pregnant women exposed to methotrexate was 42.5% (95% confidence interval [95% CI] 29.2–58.7), which was higher than in unexposed patients with autoimmune disease (22.5%, 95% CI 16.8–29.7) and unexposed patients with non-autoimmune disease (17.3%, 95% CI 13–22.8). Of the live births, the rate of major birth defects in pregnant women exposed to methotrexate after conception was higher than in unexposed patients with autoimmune disease (adjusted odds ratio (OR) 1.8 [95% CI 0.6–5.7]) and unexposed patients with non-autoimmune disease (adjusted OR 3.1 [95% CI 1.03–9.5]) (2.9%). Major birth defects associated with pregnancies exposed to methotrexate after conception were not always consistent with methotrexate-associated adverse developmental outcomes.

8.2 Lactation Risk Summary Limited published literature reports the presence of methotrexate in human milk in low amounts, with the highest breast milk to plasma concentration ration reported to be 0.08:1. No information is available on the effects of methotrexate on a breastfed infant or on milk production. Because of the potential for serious adverse reactions from methotrexate in breastfed infants, advise women not to breastfeed during treatment with Methotrexate Injection and for 1 week after the last dose.

8.3 Females and Males of Reproductive Potential Methotrexate can cause malformations and fetal death at doses less than or equal to the recommended clinical doses [see Use in Specific Populations (8.1) ] . Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating Methotrexate Injection [see Contraindications (4) and Use in Specific Populations (8.1) ]. Contraception Females Advise females of reproductive potential to use effective contraception during and for 6 months after the last dose of Methotrexate Injection therapy. Males Methotrexate can cause chromosomal damage to sperm cells. Advise males with female partners of reproductive potential to use effective contraception during and for 3 months after the last dose of Methotrexate Injection therapy. Infertility Females Based on published reports of female infertility after therapy with methotrexate, advise females of reproductive potential that Methotrexate Injection can cause impairment of fertility and menstrual dysfunction during and after cessation of therapy. It is not known if the infertility may be reversed in all affected females. Males Based on published reports of male infertility after therapy with methotrexate, advise males that Methotrexate Injection can cause oligospermia or infertility during and after cessation of therapy. It is not known if the infertility may be reversed in all affected males.

8.4 Pediatric Use The safety and effectiveness of Methotrexate Injection in pediatric patients have been established for ALL, meningeal leukemia prophylaxis and treatment, non-Hodgkin lymphoma, osteosarcoma and in pJIA. Clinical studies evaluating the use of methotrexate in pediatric patients with pJIA demonstrated safety comparable to that observed in adults with RA [see Adverse Reactions (6.1) ]. The safety and effectiveness of Methotrexate Injection have not been established in pediatric patients for the treatment of breast cancer, squamous cell carcinoma of the head and neck, gestational trophoblastic neoplasia, rheumatoid arthritis, and psoriasis. Additional risk information is described below. Risks of Serious Adverse Reactions due to Benzyl Alcohol-Preservative Due to the risk of serious adverse reactions and fatal gasping syndrome following administration of intravenous solutions containing the preservative benzyl alcohol in neonates, use only preservative-free Methotrexate Injection in neonates and low birth weight infants. The “gasping syndrome” is characterized by CNS depression, metabolic acidosis, and gasping respirations. Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature neonates and low birth weight infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions include gradual neurological deterioration, seizures, intracranial hemorrhage, hematological abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. When prescribing in infants (non-neonate, non-low birth weight), if a preservative-free formulation of Methotrexate Injection is not available and use of a benzyl alcohol-containing formulation is necessary, consider the combined daily metabolic load of benzyl alcohol from all sources including Methotrexate Injection (Methotrexate Injection contains 9.4 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known . Do not administer methotrexate formulations containing benzyl alcohol intrathecally due to the risk of severe neurotoxicity [see Warnings and Precautions (5.3) ]. Leukemia/Lymphoma Serious neurotoxicity, frequently manifested as generalized or focal seizures, has been reported with unexpectedly increased frequency among pediatric patients with acute lymphoblastic leukemia who were treated with intermediate-dose intravenous methotrexate (1 g/m 2 ) [see Warnings and Precautions (5.8) ].

10 OVERDOSAGE Manifestations Overdosage, including fatal overdosage, has occurred with methotrexate [see Warnings and Precautions (5.19 )]. Manifestations of overdosage include adverse reactions reported at pharmacologic doses, particularly hematologic and gastrointestinal reactions (e.g., leukopenia, thrombocytopenia, anemia, pancytopenia, myelosuppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, or gastrointestinal bleeding). In some cases, no symptoms were reported; however, sepsis or septic shock, renal failure, and aplastic anemia were also reported. Manifestations of intrathecal overdosage include CNS symptoms (e.g., headache, nausea and vomiting, seizure or convulsion, and acute toxic encephalopathy). In some cases, no symptoms were reported; however, cerebellar herniation associated with increased intracranial pressure and acute toxic encephalopathy have also been reported. Management Leucovorin and levoleucovorin are indicated to diminish the toxicity and counteract the effect of inadvertently administered overdosages of methotrexate. Administer leucovorin or levoleucovorin as soon as possible after overdosage (refer to the leucovorin or levoleucovorin prescribing information). Monitor serum methotrexate concentrations closely to guide leucovorin or levoleucovorin therapy. Monitor serum creatinine concentrations closely because high serum methotrexate concentrations may cause renal damage leading to acute renal failure. Glucarpidase is indicated for the treatment of toxic methotrexate concentrations in patients with delayed methotrexate clearance due to impaired renal function (refer to the glucarpidase prescribing information). If glucarpidase is used, do not administer leucovorin within 2 hours before or after a dose of glucarpidase because leucovorin is a substrate for glucarpidase. Hydration and urinary alkalinization may be necessary to prevent the precipitation of methotrexate and/or its metabolites in the renal tubules. Neither hemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination. However, effective clearance of methotrexate has been reported with acute, intermittent hemodialysis using a high-flux dialyzer.

11 DESCRIPTION Methotrexate is a folate analog metabolic inhibitor with the chemical name of N -[4-[[(2,4-diamino-6-pteridinyl) methyl]methylamino]benzoyl]-L-glutamic acid and a molecular weight of 454.44. The molecular formula is C 20 H 22 N 8 O 5 , and the structural formula is shown below: Methotrexate Injection, USP with preservative is supplied in sterile multiple-dose vials for intravenous, intramuscular, or subcutaneous use. Each 25 mg/mL, 2 mL vial contains 50 mg methotrexate equivalent to 54.8 mg of methotrexate sodium, 18.8 mg of benzyl alcohol as a preservative and Sodium chloride 5.2 mg. May contain sodium hydroxide and/or hydrochloric acid to adjust the pH to 8.5. Preservative-free Methotrexate Injection, USP is supplied in sterile single-dose vials for intravenous, intramuscular, subcutaneous, or intrathecal use. Each 25 mg/mL, 40 mL vial contains 1000 mg methotrexate equivalent to 1096.7 mg of methotrexate sodium, and the following inactive ingredients: Sodium chloride 196 mg. May contain sodium hydroxide and/or hydrochloric acid to adjust the pH to 8.5. methotrexate-structure

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Methotrexate inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be utilized as carriers of one-carbon groups in the synthesis of purine nucleotides and thymidylate. Therefore, methotrexate interferes with DNA synthesis, repair, and cellular replication. Actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary bladder are in general more sensitive to this effect of methotrexate. The mechanism of action in rheumatoid arthritis, pJIA, and in psoriasis is unknown. 12.3 Pharmacokinetics Distribution After intravenous administration, the initial volume of distribution is approximately 0.18 L/kg (18% of body weight) and steady-state volume of distribution is approximately 0.4 L/to 0.8 L/kg (40% to 80% of body weight). Methotrexate competes with reduced folates for active transport across cell membranes by means of a single carrier-mediated active transport process. At serum concentrations greater than 100 micromolar, passive diffusion becomes a major pathway by which effective intracellular concentrations can be achieved. Methotrexate in serum is approximately 50% protein bound. Methotrexate may be displaced from plasma albumin by various compounds, including sulfonamides, salicylates, tetracyclines, chloramphenicol, and phenytoin. Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given intravenously, intramuscularly, or subcutaneously. Elimination The terminal half-life reported for methotrexate is approximately 3 to 10 hours for patients receiving treatment for psoriasis, or rheumatoid arthritis or low-dose antineoplastic therapy (less than 30 mg/m 2 ). Following intravenous administration of high-dose methotrexate, the terminal half-life is 8 hours to 15 hours. Metabolism Methotrexate undergoes hepatic and intracellular metabolism to polyglutamated forms that can be converted back to methotrexate by hydrolase enzymes. These polyglutamates act as inhibitors of dihydrofolate reductase and thymidylate synthetase. Small amounts of methotrexate polyglutamates may remain in tissues for extended periods. The retention and prolonged drug action of these active metabolites vary among different cells, tissues, and tumors. Methotrexate undergoes minor metabolism to 7-hydroxymethotrexate, and accumulation may become significant following high dosages. The aqueous solubility of 7-hydroxymethotrexate is 3- to 5-fold lower than the solubility of methotrexate. Excretion Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration. With intravenous administration, 80% to 90% of the administered dose is excreted unchanged in the urine within 24 hours. There is limited biliary excretion amounting to 10% or less of the administered dose. Enterohepatic recirculation of methotrexate has been proposed. Renal excretion occurs by glomerular filtration and active tubular secretion. Nonlinear elimination due to saturation of renal tubular reabsorption has been observed in psoriatic patients at doses between 7.5 mg and 30 mg.

or less of the administered dose. Enterohepatic recirculation of methotrexate has been proposed. Renal excretion occurs by glomerular filtration and active tubular secretion. Nonlinear elimination due to saturation of renal tubular reabsorption has been observed in psoriatic patients at doses between 7.5 mg and 30 mg. Specific Populations Pediatric Patients In pediatric patients receiving methotrexate for acute lymphoblastic leukemia (6.3 mg/m 2 to 30 mg/m 2 ), or for JIA (3.75 mg/m 2 to 26.2 mg/m 2 ), the terminal half-life has been reported to range from 0.7 to 5.8 hours or from 0.9 to 2.3 hours, respectively [see Use in Specific Populations (8.4)] . Patients with Renal impairment The elimination half-life of methotrexate increases with the severity of renal impairment, with high inter-individual variability [see Use in Specific Populations (8.6) ].

12.1 Mechanism of Action Methotrexate inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be utilized as carriers of one-carbon groups in the synthesis of purine nucleotides and thymidylate. Therefore, methotrexate interferes with DNA synthesis, repair, and cellular replication. Actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary bladder are in general more sensitive to this effect of methotrexate. The mechanism of action in rheumatoid arthritis, pJIA, and in psoriasis is unknown.

12.3 Pharmacokinetics Distribution After intravenous administration, the initial volume of distribution is approximately 0.18 L/kg (18% of body weight) and steady-state volume of distribution is approximately 0.4 L/to 0.8 L/kg (40% to 80% of body weight). Methotrexate competes with reduced folates for active transport across cell membranes by means of a single carrier-mediated active transport process. At serum concentrations greater than 100 micromolar, passive diffusion becomes a major pathway by which effective intracellular concentrations can be achieved. Methotrexate in serum is approximately 50% protein bound. Methotrexate may be displaced from plasma albumin by various compounds, including sulfonamides, salicylates, tetracyclines, chloramphenicol, and phenytoin. Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given intravenously, intramuscularly, or subcutaneously. Elimination The terminal half-life reported for methotrexate is approximately 3 to 10 hours for patients receiving treatment for psoriasis, or rheumatoid arthritis or low-dose antineoplastic therapy (less than 30 mg/m 2 ). Following intravenous administration of high-dose methotrexate, the terminal half-life is 8 hours to 15 hours. Metabolism Methotrexate undergoes hepatic and intracellular metabolism to polyglutamated forms that can be converted back to methotrexate by hydrolase enzymes. These polyglutamates act as inhibitors of dihydrofolate reductase and thymidylate synthetase. Small amounts of methotrexate polyglutamates may remain in tissues for extended periods. The retention and prolonged drug action of these active metabolites vary among different cells, tissues, and tumors. Methotrexate undergoes minor metabolism to 7-hydroxymethotrexate, and accumulation may become significant following high dosages. The aqueous solubility of 7-hydroxymethotrexate is 3- to 5-fold lower than the solubility of methotrexate. Excretion Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration. With intravenous administration, 80% to 90% of the administered dose is excreted unchanged in the urine within 24 hours. There is limited biliary excretion amounting to 10% or less of the administered dose. Enterohepatic recirculation of methotrexate has been proposed. Renal excretion occurs by glomerular filtration and active tubular secretion. Nonlinear elimination due to saturation of renal tubular reabsorption has been observed in psoriatic patients at doses between 7.5 mg and 30 mg. Specific Populations Pediatric Patients In pediatric patients receiving methotrexate for acute lymphoblastic leukemia (6.3 mg/m 2 to 30 mg/m 2 ), or for JIA (3.75 mg/m 2 to 26.2 mg/m 2 ), the terminal half-life has been reported to range from 0.7 to 5.8 hours or from 0.9 to 2.3 hours, respectively [see Use in Specific Populations (8.4)] . Patients with Renal impairment The elimination half-life of methotrexate increases with the severity of renal impairment, with high inter-individual variability [see Use in Specific Populations (8.6) ].

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Methotrexate has been evaluated in a number of animal studies for carcinogenic potential with inconclusive results. There is evidence that methotrexate causes chromosomal damage to animal somatic cells and human bone marrow cells [see Use in Specific Populations ( 8.1 , 8.2 , 8.3 )] .

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Methotrexate has been evaluated in a number of animal studies for carcinogenic potential with inconclusive results. There is evidence that methotrexate causes chromosomal damage to animal somatic cells and human bone marrow cells [see Use in Specific Populations ( 8.1 , 8.2 , 8.3 )] .

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Methotrexate Injection, USP is a clear, yellow, sterile solution available with preservative (multiple-dose vials) and preservative-free (single-dose vials) as follows: Strength/Fill volume NDC number Pack style With Preservative 50 mg/2 mL (25 mg/mL) 62332-711-05 Carton containing five (5) multiple-dose vials Preservative-free 1 g/40 mL (25 mg/mL) 62332-712-01 Carton containing one (1) single-dose vial Carton contents NDC Methotrexate Injection USP, With Preservative, 5 multiple-dose vials 50 mg/2 mL (25 mg/mL) 62332-711-05 Preservative-free Methotrexate Injection USP, 1 single-dose vial 1 g/40 mL (25 mg/mL) 62332-712-01 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light. After first puncture, store multiple-dose vials at 2°C to 8°C, and use within 30 days. Methotrexate Injection, USP is a hazardous drug. Follow applicable special handling and disposal procedures. 1

<table cellspacing="0" cellpadding="0" border="0" width="100%"><colgroup><col width="27.08%"/><col width="22.44%"/><col width="50.48%"/></colgroup><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="center" valign="top"><content styleCode="bold">Strength/Fill volume</content> </td><td styleCode="Rrule" align="center" valign="top"><content styleCode="bold">NDC number</content> </td><td styleCode="Rrule" align="center" valign="top"><content styleCode="bold">Pack style</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3" align="justify" valign="top">With Preservative </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">50 mg/2 mL (25 mg/mL) </td><td styleCode="Rrule" align="center" valign="top"> 62332-711-05</td><td styleCode="Rrule" align="center" valign="top"> Carton containing five (5) multiple-dose vials</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3" valign="top">Preservative-free </td></tr><tr><td styleCode="Lrule Rrule" valign="top">1 g/40 mL (25 mg/mL) </td><td styleCode="Rrule" align="center" valign="top"> 62332-712-01</td><td styleCode="Rrule" align="center" valign="top"> Carton containing one (1) single-dose vial</td></tr></tbody></table> <table cellspacing="0" cellpadding="0" border="0" width="100%"><colgroup><col width="50%"/><col width="50%"/></colgroup><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="center" valign="top"><content styleCode="bold">Carton contents</content> </td><td styleCode="Rrule" align="center" valign="top"><content styleCode="bold">NDC</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="2" align="left" valign="top"> Methotrexate Injection USP, With Preservative, 5 multiple-dose vials</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="center" valign="top">50 mg/2 mL (25 mg/mL) </td><td styleCode="Rrule" align="center" valign="top">62332-711-05 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="2" align="left" valign="top"> Preservative-free Methotrexate Injection USP, 1 single-dose vial</td></tr><tr><td styleCode="Lrule Rrule" align="center" valign="top">1 g/40 mL (25 mg/mL) </td><td styleCode="Rrule" align="center" valign="top">62332-712-01 </td></tr></tbody></table>

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Embryo-Fetal Toxicity Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Contraindications (4) , Warnings and Precautions (5.1) , and Use in Specific Populations (8.1) ]. Advise females of reproductive potential to use effective contraception during Methotrexate Injection therapy and for 6 months after the last dose [see Use in Specific Populations (8.3) ]. Advise males of reproductive potential to use effective contraception during Methotrexate Injection therapy and for 3 months after the last dose [see Use in Specific Populations (8.3) ]. Hypersensitivity Reactions Advise patients of the potential risk of hypersensitivity and that Methotrexate Injection is contraindicated in patients with a history of severe hypersensitivity to methotrexate. Advise patients to seek immediate medical attention if signs or symptoms of a hypersensitivity reaction occur [see Warnings and Precautions (5.2) ]. Myelosuppression and Serious Infections Advise patient to contact their healthcare provider immediately for new onset fever, symptoms of infection, easy bruising or persistent bleeding [see Warnings and Precautions ( 5.4 , 5.5 )]. Renal Toxicity Advise patients that methotrexate can cause renal toxicity. Advise patients to immediately contact their healthcare provider for signs or symptoms of renal toxicity, such as marked increases or decreases in urinary output [see Warnings and Precautions (5.6 )]. Hepatotoxicity Advise patients to report signs or symptoms of hepatic toxicity and avoidance of alcohol during methotrexate treatment [see Warnings and Precautions (5.7) ]. Neurotoxicity Advise patient to contact their healthcare provider immediately if they develop new neurological symptoms [see Warnings and Precautions (5.8) ]. Gastrointestinal Toxicity Advise patients to contact their healthcare provider if they develop diarrhea, vomiting, or stomatitis. Advise patients to immediately contact their healthcare provider for high fever, rigors, persistent or severe abdominal pain, severe constipation, hematemesis, or melena [see Warnings and Precautions (5.9) ]. Pulmonary Toxicity Advise patients to contact their healthcare provider for symptoms of cough, fever, and dyspnea [see Warnings and Precautions (5.10) ]. Dermatologic Toxicity Advise patients that Methotrexate Injection can cause serious skin rash and to immediately contact their healthcare provider for new or worsening skin rash. Advise patients to avoid excessive sun exposure and to use sun protection measures [see Warnings and Precautions (5.11) ] . Secondary Malignancies Advise patients on the risk of second primary malignancies during treatment with Methotrexate Injection [see Warnings and Precautions (5.13) ]. Lactation Advise women not to breastfeed during treatment with Methotrexate Injection and for 1 week after the last dose [see Use in Specific Populations (8.2) ]. Infertility Advise females and males of reproductive potential that Methotrexate Injection may cause impairment of fertility [see Use in Specific Populations (8.3) ] . Drug Interactions Advise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions (7) ] .

jection may cause impairment of fertility [see Use in Specific Populations (8.3) ] . Drug Interactions Advise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions (7) ] . Instruct patients being treated for neoplastic indication to not take products containing folic acid or folinic acid unless directed to do so by their healthcare provider [see Warnings and Precautions (5.12) ]. Manufactured for: Alembic Pharmaceuticals, Inc. Bedminster, NJ 07921, USA. Manufactured by: Alembic Pharmaceuticals Limited Panelav - 389 350, Gujarat, India. Revised: 11/2025

FDA-APPROVED PATIENT LABELING Patient Information METHOTREXATE (Meth-oh-trex-ate) Injection for intravenous, intramuscular, subcutaneous, or intrathecal use What is the most important information I should know about Methotrexate Injection? Methotrexate Injection can cause serious side effects that may be severe and lead to death, including: Harm to an unborn baby, including birth defects or death of an unborn baby. Females who can become pregnant: Your healthcare provider should do a pregnancy test before you start taking Methotrexate Injection to see if you are pregnant. If you are being treated for a medical condition other than cancer, do not receive or take Methotrexate Injection if you are pregnant. See “Do not receive Methotrexate Injection if ”. If you are taking Methotrexate Injection to treat your cancer, you and your healthcare provider will decide if you will receive or take Methotrexate Injection if you are pregnant. Use effective birth control (contraception) during treatment and for 6 months after your last dose of Methotrexate Injection. Ask your healthcare provider what forms of birth control you can use during this time. Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with Methotrexate Injection. Males with female partners who are able to become pregnant: Use effective birth control during treatment and for 3 months after your last dose of Methotrexate Injection. Tell your healthcare provider right away if your female partner becomes pregnant during treatment with Methotrexate Injection. Severe allergic reactions. Severe allergic reactions can happen with Methotrexate Injection. Do not receive Methotrexate Injection if you have had a severe allergic reaction to methotrexate in the past. Get medical help right away if you develop any of the signs or symptoms of a severe allergic reaction to Methotrexate Injection, including: skin rash, itching, and hives swelling of the face, lips, tongue, or throat, or trouble swallowing dizziness or lightheadedness trouble breathing wheezing throat tightness runny or stuffy nose fast heart rate chest pain feeling faint Decreased blood cell counts. Methotrexate Injection can affect your bone marrow and cause decreased red blood cell counts, white blood cell counts, and platelet counts, and a condition where your bone marrow cannot produce these blood cells (aplastic anemia). These decreased blood cell counts can be severe and may lead to a serious infection, the need for blood transfusions, treatment in a hospital, and can be life-threatening. Your healthcare provider will check your blood cell counts before you start and during treatment with Methotrexate Injection. Your healthcare provider will watch you closely for infections during treatment with Methotrexate Injection. Call your healthcare provider right away if you develop: a new fever (temperature of 100.4°F or higher) symptoms of infection easy bruising or bleeding that will not stop Your healthcare provider may give you medicines to support your blood counts or give you transfusions if needed, and change your dose or stop your treatment with Methotrexate Injection if needed. Serious infections. People who receive treatment with Methotrexate Injection have an increased risk of developing serious infections that can be life-threatening or lead to death.

ort your blood counts or give you transfusions if needed, and change your dose or stop your treatment with Methotrexate Injection if needed. Serious infections. People who receive treatment with Methotrexate Injection have an increased risk of developing serious infections that can be life-threatening or lead to death. These infections include: bacterial infections hepatitis B infection that comes back (reactivation) fungal infections tuberculosis (TB) infection that is new or that comes back (reactivation) viral infections shingles (herpes zoster) certain infections that happen because your immune system is weakened cytomegalovirus infections Your healthcare provider will closely watch you for signs and symptoms of infection during treatment with Methotrexate Injection. Your healthcare provider may hold or stop your treatment with Methotrexate Injection if you develop a serious infection. Kidney problems. Methotrexate Injection can cause kidney damage including sudden kidney failure that may not go away (irreversible). People who already have kidney problems have an increased risk of kidney problems with Methotrexate Injection. Your healthcare provider will check your kidney function during treatment, and will hold or stop Methotrexate Injection treatment as needed for severe kidney damage. Call your healthcare provider right away if you have signs or symptoms of kidney problems such as a big change in the amount of urine that you make, either increased or decreased. Liver problems. Methotrexate Injection can cause severe liver problems including liver scarring (fibrosis), cirrhosis, and liver failure that may not get better (possibly irreversible) and can cause death. In people with psoriasis who receive Methotrexate Injection, liver fibrosis or cirrhosis may happen without any symptoms or abnormal liver tests. The risk for liver problems in people with psoriasis increases with the amount of Methotrexate Injection that you receive over time. Your healthcare provider will do tests to monitor your liver function before you start and during treatment with Methotrexate Injection, and may hold or stop your treatment with Methotrexate Injection, if needed. The risk of liver problems is increased with heavy use of alcohol. Avoid drinking alcohol during Methotrexate Injection treatment. Tell your healthcare provider if you develop any signs or symptoms of liver problems during treatment with Methotrexate Injection, including: tiredness swelling in your legs, feet, or ankles easy bleeding or bruising weight loss loss of appetite itchy skin nausea yellowing of your skin or the white part of your eyes difficulty thinking clearly weakness Brain and spinal cord (nervous system) problems. Methotrexate Injection can cause nervous system problems that can be severe and last for a short time or last for a long time. These nervous system problems can get progressively worse, may not get better (possibly irreversible), and can cause death. Serious nervous system problems can happen in children who receive Methotrexate Injection, including seizures that can begin on one side of the brain (focal seizures) or on both sides of the brain (generalized seizures). The risk for a nervous system problem called leukoencephalopathy is increased in people who have had radiation treatment to their head and spine (craniospinal irradiation) in the past. Call your healthcare provider if you develop any new neurological symptoms. People who receive high-dose Methotrexate Injection can develop sudden symptoms that are like the symptoms of a stroke, but they last a short time and may go away (transient). People who receive injections of Methotrexate Injection into their spine (intrathecal methotrexate) can develop inflammation of the lining around the spinal nerves.

igh-dose Methotrexate Injection can develop sudden symptoms that are like the symptoms of a stroke, but they last a short time and may go away (transient). People who receive injections of Methotrexate Injection into their spine (intrathecal methotrexate) can develop inflammation of the lining around the spinal nerves. Call your healthcare provider right away if you or your child develop any new signs or symptoms of a nervous system problem during treatment with Methotrexate Injection, including: confusion coma weakness on one side of your body headache sudden blindness that goes away back pain seizures stiff neck fever Severe stomach and intestine (gastrointestinal) problems . Methotrexate Injection can cause diarrhea, vomiting, mouth sores, stomach and intestinal inflammation with severe bleeding, and tears in the intestinal wall (perforation), and can lead to death. People who have stomach ulcers (peptic ulcer disease) or ulcerative colitis (UC) have a higher risk of developing severe stomach and intestine problems with Methotrexate Injection. Your healthcare provider may hold or stop your treatment with Methotrexate Injection if any of these severe stomach and intestinal problems happen, and treat you as needed. Call your healthcare provider if you develop diarrhea, vomiting, inflammation or sores in your mouth. Call your healthcare provider right away if you develop: high fever severe constipation shaking chills if you are vomiting blood stomach-area (abdomen) pain that is severe or does not go away. blood in your stools Lung problems. Lung problems can happen suddenly (acute) with Methotrexate Injection or they can develop over a long period-of-time (chronic). Lung problems may not get better (possibly irreversible) and can cause death in anyone taking Methotrexate Injection. Your healthcare provider will monitor you for lung problems during treatment with Methotrexate Injection. Your healthcare provider may hold or stop your treatment with Methotrexate Injection, if needed. Call your healthcare provider if you develop symptoms of a lung problem, including: cough, fever, and trouble breathing. Skin reactions. Severe skin reactions can happen with Methotrexate Injection, that can be serious and can lead to death. In people with psoriasis: Your psoriasis may get worse if you are exposed to sunlight or other types of ultraviolet light. Methotrexate Injection can cause reactivation of skin reactions that can happen after radiation therapy (radiation recall), sunburns to come back (photodermatitis) and severe sunburn reactions. Limit sunlight exposure during treatment with Methotrexate Injection. Use a broad-spectrum ultraviolet sunscreen and lip balm with a Sun Protection Factor (SPF) of 30 or greater and wear a hat and protective clothing when you will be exposed to sunlight during treatment with Methotrexate Injection. Call your healthcare provider right away if you develop a new or worsening skin rash during treatment with Methotrexate Injection. See “What are the possible side effects of Methotrexate Injection?” for more information about side effects. What is Methotrexate Injection?

ht during treatment with Methotrexate Injection. Call your healthcare provider right away if you develop a new or worsening skin rash during treatment with Methotrexate Injection. See “What are the possible side effects of Methotrexate Injection?” for more information about side effects. What is Methotrexate Injection? Methotrexate Injection is a prescription medicine used: in adults and children: in combination with other chemotherapy medicines to treat acute lymphoblastic leukemia (ALL) to help prevent (prophylaxis) and to treat leukemia that spreads to the covering of the brain and spinal cord (meninges) to treat non-Hodgkin lymphoma in combination with other chemotherapy medicines to treat osteosarcoma in adults: in combination with other chemotherapy medicines to treat breast cancer alone to treat squamous cell carcinoma of the head and neck in combination with other chemotherapy medicines to treat gestational trophoblastic neoplasia Methotrexate Injection is a prescription medicine used: in adults to treat rheumatoid arthritis (RA) in children to treat polyarticular juvenile idiopathic arthritis (pJIA) in adults to treat severe psoriasis Do not receive Methotrexate Injection if you: have had a severe allergic reaction to Methotrexate Injection. See “What is the most important information I should know about Methotrexate Injection?” you are pregnant and are being treated, or will be treated with Methotrexate Injection for rheumatoid arthritis, pJIA, or severe psoriasis, or for any disease other than cancer. Methotrexate Injection can cause harm to an unborn baby including birth defects or death of an unborn baby. See “What is the most important information I should know about Methotrexate Injection?” Before you receive Methotrexate Injection, tell your healthcare provider about all of your medical conditions, including if you: have kidney problems or are receiving dialysis treatments have liver problems have a history of neurologic problems, including seizures drink alcohol-containing beverages during treatment with Methotrexate Injection, or if there are any changes in the amount of alcoholic beverages you drink have fluid in your stomach-area (ascites) have lung problems or fluid in your lungs (pleural effusion) plan to have any surgeries with general anesthesia, including dental surgery have stomach ulcers (peptic ulcer disease) have ulcerative colitis have recently received or are scheduled to receive a vaccine. You should not receive live vaccines during treatment with Methotrexate Injection. are breastfeeding or plan to breastfeed. Methotrexate may pass into your breast milk. Do not breastfeed during treatment and for 1 week after your last dose of Methotrexate Injection. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking certain medicines can affect the amount of methotrexate in your blood and can increase your risk for serious side effects. How will I receive or take Methotrexate Injection? Depending on your medical condition and the dose of Methotrexate Injection that is prescribed by your healthcare provider, Methotrexate Injection can be given to you: through an intravenous (IV) line in your vein by injection into a large muscle (intramuscular injection) injected under your skin (subcutaneous injection) for certain diseases the preservative-free formulation of Methotrexate Injection can also be injected through your spine directly into your spinal fluid. If you are receiving Methotrexate Injection to treat your cancer: Your healthcare provider will decide your dose, how you will receive Methotrexate Injection, and how often you need to receive it, depending on your medical condition that is being treated.

be injected through your spine directly into your spinal fluid. If you are receiving Methotrexate Injection to treat your cancer: Your healthcare provider will decide your dose, how you will receive Methotrexate Injection, and how often you need to receive it, depending on your medical condition that is being treated. If you are receiving high-dose Methotrexate Injection to treat your cancer, you will receive the medicine leucovorin to help prevent severe side effects (“rescue”) to your bone marrow and other normal cells in your body. You will also receive intravenous (IV) fluids and other medicines to help prevent and treat side effects. If you are receiving a “moderate-dose” of Methotrexate Injection to treat your cancer, you may also receive leucovorin. Do not take folic acid or folinic acid during treatment with Methotrexate Injection to treat your cancer , unless your healthcare provider tells you to. Taking folic acid or folinic acid with Methotrexate Injection may make your treatment less effective. Your healthcare provider will do blood tests to check for side effects during treatment with Methotrexate Injection. Your healthcare provider may stop your treatment, change when you receive your treatment, or change the dose of your treatment if you have certain side effects while receiving Methotrexate Injection. If you are receiving Methotrexate Injection for treatment of severe psoriasis, rheumatoid arthritis, or polyarticular juvenile idiopathic arthritis: You should receive your Methotrexate Injection dose 1 time each week, not every day. Serious side effects and death have happened in people who mistakenly have taken Methotrexate Injection every day instead of 1 time each week. Take folic acid or folinic acid every day during treatment with Methotrexate Injection, as instructed by your healthcare provider, to help reduce the chance of developing certain side effects, such as mouth sores. If you receive too much Methotrexate Injection call your healthcare provider or go to your nearest hospital emergency room right way. You will need to receive a medicine as soon as possible to help reduce side effects that could be severe and could cause death. In all patients receiving Methotrexate Injection: If you miss receiving a dose of Methotrexate Injection, call your healthcare provider for instructions about when to receive your next dose of Methotrexate Injection. What are the possible side effects of Methotrexate Injection? Methotrexate Injection can cause serious side effects, including: See “ What is the most important information I should know about Methotrexate Injection?” Tumor lysis syndrome (TLS) . TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure and the need for dialysis treatment, abnormal heart rhythm, seizure, and sometimes death. Your healthcare provider may do blood tests to check you for TLS if you are receiving Methotrexate Injection as a cancer treatment. Your healthcare provider will treat you as needed to prevent or manage TLS if you develop it during treatment with Methotrexate Injection. New (secondary) cancers . New (secondary) cancers can happen in people who take or receive Methotrexate Injection at any dose. Certain blood cancers can happen during treatment with low-dose Methotrexate Injection. In some cases, these blood cancers may completely go away (regress completely) after Methotrexate Injection is stopped. If you develop one of these blood cancers during treatment with Methotrexate Injection, your healthcare provider will stop your treatment, and treat as needed if the new cancer does not go away after Methotrexate Injection is stopped. Increased risk of soft tissue and bone problems due to receiving Methotrexate Injection in combination with radiation therapy.

during treatment with Methotrexate Injection, your healthcare provider will stop your treatment, and treat as needed if the new cancer does not go away after Methotrexate Injection is stopped. Increased risk of soft tissue and bone problems due to receiving Methotrexate Injection in combination with radiation therapy. In people who receive Methotrexate Injection, some soft tissue in your body may die and some bone cells may die. People who receive radiation therapy in combination with Methotrexate Injection have an increased risk of this happening. The most common side effects of Methotrexate Injection include: mouth sores or ulcers nausea decreased white blood cell count. See “ What is the most important information I should know about Methotrexate Injection? ” upset stomach Possible fertility problems (infertility) in males and females. Methotrexate Injection can cause fertility problems in males and females, and cause sperm production to stop in males, and menstrual problems in females. In females, your periods (menstrual cycle) may be irregular or completely stop when you receive Methotrexate Injection. Your periods may or may not return to normal following treatment. It is not known if your fertility will return after treatment. Talk to your healthcare provider about your risk for infertility if this is a concern for you. These are not all of the possible side effects of Methotrexate Injection. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of Methotrexate Injection. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about Methotrexate Injection that is written for health professionals. What are the ingredients in Methotrexate Injection? Active ingredient: methotrexate. Inactive ingredients for Methotrexate Injection Preservative-free: sodium chloride. May contain sodium hydroxide and/or hydrochloric acid to adjust pH to 8.5. Inactive ingredients for Methotrexate Injection with Preservative: benzyl alcohol and sodium chloride. May contain sodium hydroxide and/or hydrochloric acid to adjust pH to 8.5. For more information, call 1-866-210-9797. Manufactured for: Alembic Pharmaceuticals, Inc. Bedminster, NJ 07921, USA. Manufactured by: Alembic Pharmaceuticals Limited Panelav - 389 350, Gujarat, India. This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 11/2025

<table cellspacing="0" cellpadding="0" border="0" width="100%"><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="center" valign="top"><content styleCode="bold">Patient Information</content> <content styleCode="bold">METHOTREXATE (Meth-oh-trex-ate)</content> <content styleCode="bold">Injection</content> <content styleCode="bold">for intravenous, intramuscular,</content> <content styleCode="bold">subcutaneous, or intrathecal use</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="bold">What is the most important information I should know about Methotrexate Injection?</content> <content styleCode="bold">Methotrexate Injection can cause serious side effects that may be severe and lead to death, including:</content> <content styleCode="bold">Harm to an unborn baby, including birth defects or death of an unborn baby.</content> <content styleCode="bold">Females who can become pregnant:</content> <list listType="unordered" styleCode="disc"><item>Your healthcare provider should do a pregnancy test before you start taking Methotrexate Injection to see if you are pregnant.</item><item><content styleCode="bold">If you are being treated for a medical condition other than cancer, do not receive or take Methotrexate Injection if you are pregnant. </content>See <content styleCode="bold">&#x201C;Do not receive Methotrexate Injection if</content>&#x201D;.</item><item>If you are taking Methotrexate Injection to treat your cancer, you and your healthcare provider will decide if you will receive or take Methotrexate Injection if you are pregnant.</item><item>Use effective birth control (contraception) during treatment and for <content styleCode="bold">6 </content>months after your last dose of Methotrexate Injection. Ask your healthcare provider what forms of birth control you can use during this time.</item></list><content styleCode="bold">Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with Methotrexate Injection.</content> <content styleCode="bold">Males with female partners who are able to become pregnant:</content> <list listType="unordered" styleCode="disc"><item>Use effective birth control during treatment and for <content styleCode="bold">3 </content>months after your last dose of Methotrexate Injection.<content styleCode="bold">Tell your healthcare provider right away if your female partner becomes pregnant during treatment with Methotrexate Injection.</content> <content styleCode="bold">Severe allergic reactions. </content>Severe allergic reactions can happen with Methotrexate Injection. </item><item><content styleCode="bold">Do not receive Methotrexate Injection </content>if you have had a severe allergic reaction to methotrexate in the past.<content styleCode="bold">Get medical help right away if you develop any of the signs or symptoms of a severe allergic reaction to Methotrexate Injection, </content>including: <list listType="unordered" styleCode="disc"><item>skin rash, itching, and hives</item><item>swelling of the face, lips, tongue, or throat, or trouble swallowing</item><item>dizziness or lightheadedness</item><item>trouble breathing</item><item>wheezing</item><item>throat tightness</item><item>runny or stuffy nose</item><item>fast heart rate</item><item>chest pain</item><item>feeling faint</item></list> <content styleCode="bold">Decreased blood cell counts.

r trouble swallowing</item><item>dizziness or lightheadedness</item><item>trouble breathing</item><item>wheezing</item><item>throat tightness</item><item>runny or stuffy nose</item><item>fast heart rate</item><item>chest pain</item><item>feeling faint</item></list> <content styleCode="bold">Decreased blood cell counts. </content>Methotrexate Injection can affect your bone marrow and cause decreased red blood cell counts, white blood cell counts, and platelet counts, and a condition where your bone marrow cannot produce these blood cells (aplastic anemia). These decreased blood cell counts can be severe and may lead to a serious infection, the need for blood transfusions, treatment in a hospital, and can be life-threatening. Your healthcare provider will check your blood cell counts before you start and during treatment with Methotrexate Injection. Your healthcare provider will watch you closely for infections during treatment with Methotrexate Injection. <content styleCode="bold">Call your healthcare provider right away if you develop:</content> </item><item>a new fever (temperature of 100.4&#xB0;F or higher)</item><item>symptoms of infection</item><item>easy bruising or bleeding that will not stop Your healthcare provider may give you medicines to support your blood counts or give you transfusions if needed, and change your dose or stop your treatment with Methotrexate Injection if needed. <content styleCode="bold">Serious infections. </content>People who receive treatment with Methotrexate Injection have an increased risk of developing serious infections that can be life-threatening or lead to death. These infections include: </item><item>bacterial infections</item><item>hepatitis B infection that comes back (reactivation)</item><item>fungal infections</item><item>tuberculosis (TB) infection that is new or that comes back (reactivation)</item><item>viral infections</item><item>shingles (herpes zoster)</item><item>certain infections that happen because your immune system is weakened</item><item>cytomegalovirus infections Your healthcare provider will closely watch you for signs and symptoms of infection during treatment with Methotrexate Injection. Your healthcare provider may hold or stop your treatment with Methotrexate Injection if you develop a serious infection. <content styleCode="bold">Kidney problems. </content>Methotrexate Injection can cause kidney damage including sudden kidney failure that may not go away (irreversible). People who already have kidney problems have an increased risk of kidney problems with Methotrexate Injection. Your healthcare provider will check your kidney function during treatment, and will hold or stop Methotrexate Injection treatment as needed for severe kidney damage. <content styleCode="bold">Call your healthcare provider right away </content>if you have signs or symptoms of kidney problems such as a big change in the amount of urine that you make, either increased or decreased. <content styleCode="bold">Liver problems. </content>Methotrexate Injection can cause severe liver problems including liver scarring (fibrosis), cirrhosis, and liver failure that may not get better (possibly irreversible) and can cause death. </item><item><content styleCode="bold">In people with psoriasis </content>who receive Methotrexate Injection, liver fibrosis or cirrhosis may happen without any symptoms or abnormal liver tests.

liver scarring (fibrosis), cirrhosis, and liver failure that may not get better (possibly irreversible) and can cause death. </item><item><content styleCode="bold">In people with psoriasis </content>who receive Methotrexate Injection, liver fibrosis or cirrhosis may happen without any symptoms or abnormal liver tests. The risk for liver problems in people with psoriasis increases with the amount of Methotrexate Injection that you receive over time.</item><item>Your healthcare provider will do tests to monitor your liver function before you start and during treatment with Methotrexate Injection, and may hold or stop your treatment with Methotrexate Injection, if needed.</item><item><content styleCode="bold">The risk of liver problems is increased with heavy use of alcohol. Avoid drinking alcohol during Methotrexate Injection treatment.</content> <content styleCode="bold">Tell your healthcare provider if you develop any signs or symptoms of liver problems </content>during treatment with Methotrexate Injection, including: </item><item>tiredness</item><item>swelling in your legs, feet, or ankles</item><item>easy bleeding or bruising</item><item>weight loss</item><item>loss of appetite</item><item>itchy skin</item><item>nausea</item><item>yellowing of your skin or the white part of your eyes</item><item>difficulty thinking clearly</item><item>weakness <content styleCode="bold">Brain and spinal cord (nervous system) problems. </content>Methotrexate Injection can cause nervous system problems that can be severe and last for a short time or last for a long time. These nervous system problems can get progressively worse, may not get better (possibly irreversible), and can cause death. </item><item>Serious nervous system problems can happen in children who receive Methotrexate Injection, including seizures that can begin on one side of the brain (focal seizures) or on both sides of the brain (generalized seizures).</item><item>The risk for a nervous system problem called leukoencephalopathy is increased in people who have had radiation treatment to their head and spine (craniospinal irradiation) in the past. Call your healthcare provider if you develop any new neurological symptoms.</item><item>People who receive high-dose Methotrexate Injection can develop sudden symptoms that are like the symptoms of a stroke, but they last a short time and may go away (transient).</item><item>People who receive injections of Methotrexate Injection into their spine (intrathecal methotrexate) can develop inflammation of the lining around the spinal nerves. <content styleCode="bold">Call your healthcare provider right away if you or your child develop any new signs or symptoms of a nervous system problem </content>during treatment with Methotrexate Injection, including: </item><item>confusion</item><item>coma</item><item>weakness on one side of your body</item><item>headache</item><item>sudden blindness that goes away</item><item>back pain</item><item>seizures</item><item>stiff neck</item><item>fever <content styleCode="bold">Severe stomach and intestine (gastrointestinal) problems</content>. Methotrexate Injection can cause diarrhea, vomiting, mouth sores, stomach and intestinal inflammation with severe bleeding, and tears in the intestinal wall (perforation), and can lead to death. </item><item>People who have stomach ulcers (peptic ulcer disease) or ulcerative colitis (UC) have a higher risk of developing severe stomach and intestine problems with Methotrexate Injection.</item><item>Your healthcare provider may hold or stop your treatment with Methotrexate Injection if any of these severe stomach and intestinal problems happen, and treat you as needed.</item><item>Call your healthcare provider if you develop diarrhea, vomiting, inflammation or sores in your mouth.

thotrexate Injection.</item><item>Your healthcare provider may hold or stop your treatment with Methotrexate Injection if any of these severe stomach and intestinal problems happen, and treat you as needed.</item><item>Call your healthcare provider if you develop diarrhea, vomiting, inflammation or sores in your mouth. <content styleCode="bold">Call your healthcare provider right away if you develop:</content> <list listType="unordered" styleCode="disc"><item>high fever</item><item>severe constipation</item><item>shaking chills</item><item>if you are vomiting blood</item><item>stomach-area (abdomen) pain that is severe or does not go away.</item><item>blood in your stools</item></list> <content styleCode="bold">Lung problems. </content>Lung problems can happen suddenly (acute) with Methotrexate Injection or they can develop over a long period-of-time (chronic). Lung problems may not get better (possibly irreversible) and can cause death in anyone taking Methotrexate Injection. Your healthcare provider will monitor you for lung problems during treatment with Methotrexate Injection. Your healthcare provider may hold or stop your treatment with Methotrexate Injection, if needed. <content styleCode="bold">Call your healthcare provider </content>if you develop symptoms of a lung problem, including: cough, fever, and trouble breathing. <content styleCode="bold">Skin reactions. </content>Severe skin reactions can happen with Methotrexate Injection, that can be serious and can lead to death. </item><item><content styleCode="bold">In people with psoriasis: </content>Your psoriasis may get worse if you are exposed to sunlight or other types of ultraviolet light.</item><item>Methotrexate Injection can cause reactivation of skin reactions that can happen after radiation therapy (radiation recall), sunburns to come back (photodermatitis) and severe sunburn reactions.</item></list> Limit sunlight exposure during treatment with Methotrexate Injection. Use a broad-spectrum ultraviolet sunscreen and lip balm with a Sun Protection Factor (SPF) of 30 or greater and wear a hat and protective clothing when you will be exposed to sunlight during treatment with Methotrexate Injection. <content styleCode="bold">Call your healthcare provider right away if you develop a new or worsening skin rash during treatment with Methotrexate Injection.</content> See <content styleCode="bold">&#x201C;What are the possible side effects of Methotrexate Injection?&#x201D; </content>for more information about side effects.

ent styleCode="bold">Call your healthcare provider right away if you develop a new or worsening skin rash during treatment with Methotrexate Injection.</content> See <content styleCode="bold">&#x201C;What are the possible side effects of Methotrexate Injection?&#x201D; </content>for more information about side effects. </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="bold">What is Methotrexate Injection?</content> <content styleCode="bold">Methotrexate Injection is a prescription medicine used:</content> <content styleCode="bold">in adults and children:</content> <list listType="unordered" styleCode="disc"><item>in combination with other chemotherapy medicines to treat acute lymphoblastic leukemia (ALL) to help prevent (prophylaxis) and to treat leukemia that spreads to the covering of the brain and spinal cord (meninges)</item><item>to treat non-Hodgkin lymphoma</item><item>in combination with other chemotherapy medicines to treat osteosarcoma <content styleCode="bold">in adults:</content> </item><item>in combination with other chemotherapy medicines to treat breast cancer</item><item>alone to treat squamous cell carcinoma of the head and neck</item><item>in combination with other chemotherapy medicines to treat gestational trophoblastic neoplasia <content styleCode="bold">Methotrexate Injection is a prescription medicine used:</content> </item><item>in adults to treat rheumatoid arthritis (RA)</item><item>in children to treat polyarticular juvenile idiopathic arthritis (pJIA)</item></list><list listType="unordered" styleCode="disc"><item>in adults to treat severe psoriasis</item></list></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="bold">Do not receive Methotrexate Injection if you:</content> <list listType="unordered" styleCode="disc"><item>have had a severe allergic reaction to Methotrexate Injection. See <content styleCode="bold">&#x201C;What is the most important information I should know about Methotrexate Injection?&#x201D;</content></item><item>you are pregnant and are being treated, or will be treated with Methotrexate Injection for rheumatoid arthritis, pJIA, or severe psoriasis, or for any disease other than cancer. Methotrexate Injection can cause harm to an unborn baby including birth defects or death of an unborn baby. See <content styleCode="bold">&#x201C;What is the most important information I should know about Methotrexate Injection?&#x201D;</content></item></list></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="bold">Before you receive Methotrexate Injection, tell your healthcare provider about all of your medical conditions, including if you:</content> <list listType="unordered" styleCode="disc"><item>have kidney problems or are receiving dialysis treatments</item><item>have liver problems</item><item>have a history of neurologic problems, including seizures</item><item>drink alcohol-containing beverages during treatment with Methotrexate Injection, or if there are any changes in the amount of alcoholic beverages you drink</item><item>have fluid in your stomach-area (ascites)</item><item>have lung problems or fluid in your lungs (pleural effusion)</item><item>plan to have any surgeries with general anesthesia, including dental surgery</item><item>have stomach ulcers (peptic ulcer disease)</item><item>have ulcerative colitis</item><item>have recently received or are scheduled to receive a vaccine. You should not receive live vaccines during treatment with Methotrexate Injection.</item><item>are breastfeeding or plan to breastfeed. Methotrexate may pass into your breast milk.

ulcers (peptic ulcer disease)</item><item>have ulcerative colitis</item><item>have recently received or are scheduled to receive a vaccine. You should not receive live vaccines during treatment with Methotrexate Injection.</item><item>are breastfeeding or plan to breastfeed. Methotrexate may pass into your breast milk. Do not breastfeed during treatment and for 1 week after your last dose of Methotrexate Injection.</item></list> Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking certain medicines can affect the amount of methotrexate in your blood and can increase your risk for serious side effects. </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="bold">How will I receive or take Methotrexate Injection?</content> <list listType="unordered" styleCode="disc"><item>Depending on your medical condition and the dose of Methotrexate Injection that is prescribed by your healthcare provider, Methotrexate Injection can be given to you:<list listType="unordered" styleCode="disc"><item>through an intravenous (IV) line in your vein</item><item>by injection into a large muscle (intramuscular injection)</item><item>injected under your skin (subcutaneous injection)</item><item>for certain diseases the preservative-free formulation of Methotrexate Injection can also be injected through your spine directly into your spinal fluid.</item></list> <content styleCode="bold">If you are receiving Methotrexate Injection to treat your cancer:</content> </item><item>Your healthcare provider will decide your dose, how you will receive Methotrexate Injection, and how often you need to receive it, depending on your medical condition that is being treated.</item><item>If you are receiving high-dose Methotrexate Injection to treat your cancer, you will receive the medicine leucovorin to help prevent severe side effects (&#x201C;rescue&#x201D;) to your bone marrow and other normal cells in your body. You will also receive intravenous (IV) fluids and other medicines to help prevent and treat side effects.</item><item>If you are receiving a &#x201C;moderate-dose&#x201D; of Methotrexate Injection to treat your cancer, you may also receive leucovorin.</item><item><content styleCode="bold">Do not take folic acid or folinic acid during treatment with Methotrexate Injection to treat your cancer</content>, unless your healthcare provider tells you to. Taking folic acid or folinic acid with Methotrexate Injection may make your treatment less effective.</item><item>Your healthcare provider will do blood tests to check for side effects during treatment with Methotrexate Injection.</item><item>Your healthcare provider may stop your treatment, change when you receive your treatment, or change the dose of your treatment if you have certain side effects while receiving Methotrexate Injection. <content styleCode="bold">If you are receiving Methotrexate Injection for treatment of severe psoriasis, rheumatoid arthritis, or</content> <content styleCode="bold">polyarticular juvenile idiopathic arthritis:</content> </item><item>You should receive your Methotrexate Injection dose 1 time each week, not every day. Serious side effects and death have happened in people who mistakenly have taken Methotrexate Injection every day instead of 1 time each week.</item><item>Take folic acid or folinic acid every day during treatment with Methotrexate Injection, as instructed by your healthcare provider, to help reduce the chance of developing certain side effects, such as mouth sores.</item><item>If you receive too much Methotrexate Injection call your healthcare provider or go to your nearest hospital emergency room right way.

ay during treatment with Methotrexate Injection, as instructed by your healthcare provider, to help reduce the chance of developing certain side effects, such as mouth sores.</item><item>If you receive too much Methotrexate Injection call your healthcare provider or go to your nearest hospital emergency room right way. You will need to receive a medicine as soon as possible to help reduce side effects that could be severe and could cause death.</item></list> <content styleCode="bold">In all patients receiving Methotrexate Injection:</content> <list listType="unordered" styleCode="disc"><item>If you miss receiving a dose of Methotrexate Injection, call your healthcare provider for instructions about when to receive your next dose of Methotrexate Injection.</item></list></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="bold">What are the possible side effects of Methotrexate Injection?</content> <content styleCode="bold">Methotrexate Injection can cause serious side effects, including:</content> <list listType="unordered" styleCode="disc"><item>See &#x201C;<content styleCode="bold">What is the most important information I should know about Methotrexate Injection?&#x201D;</content></item><item><content styleCode="bold">Tumor lysis syndrome (TLS)</content>. TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure and the need for dialysis treatment, abnormal heart rhythm, seizure, and sometimes death. Your healthcare provider may do blood tests to check you for TLS if you are receiving Methotrexate Injection as a cancer treatment. Your healthcare provider will treat you as needed to prevent or manage TLS if you develop it during treatment with Methotrexate Injection.</item><item><content styleCode="bold">New (secondary) cancers</content>. New (secondary) cancers can happen in people who take or receive Methotrexate</item><item>Injection at any dose.</item></list><list listType="unordered" styleCode="Circle"><item>Certain blood cancers can happen during treatment with low-dose Methotrexate Injection. In some cases, these blood cancers may completely go away (regress completely) after Methotrexate Injection is stopped.</item><item>If you develop one of these blood cancers during treatment with Methotrexate Injection, your healthcare provider will stop your treatment, and treat as needed if the new cancer does not go away after Methotrexate Injection is stopped.</item></list><list listType="unordered" styleCode="disc"><item><content styleCode="bold">Increased risk of soft tissue and bone problems due to receiving Methotrexate Injection in combination with radiation therapy. </content>In people who receive Methotrexate Injection, some soft tissue in your body may die and some bone cells may die. People who receive radiation therapy in combination with Methotrexate Injection have an increased risk of this happening. The most common side effects of Methotrexate Injection include: </item><item>mouth sores or ulcers</item><item>nausea</item><item>decreased white blood cell count. See &#x201C;<content styleCode="bold">What is the most important information I should know about Methotrexate Injection?</content>&#x201D;</item><item>upset stomach</item></list> <content styleCode="bold">Possible fertility problems (infertility) in males and females. </content>Methotrexate Injection can cause fertility problems in males and females, and cause sperm production to stop in males, and menstrual problems in females. In females, your periods (menstrual cycle) may be irregular or completely stop when you receive Methotrexate Injection. Your periods may or may not return to normal following treatment. It is not known if your fertility will return after treatment.

e sperm production to stop in males, and menstrual problems in females. In females, your periods (menstrual cycle) may be irregular or completely stop when you receive Methotrexate Injection. Your periods may or may not return to normal following treatment. It is not known if your fertility will return after treatment. Talk to your healthcare provider about your risk for infertility if this is a concern for you. These are not all of the possible side effects of Methotrexate Injection. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="bold">General information about the safe and effective use of Methotrexate Injection.</content> Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about Methotrexate Injection that is written for health professionals. </td></tr><tr><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="bold">What are the ingredients in Methotrexate Injection?</content> <content styleCode="bold">Active ingredient: methotrexate.</content> <content styleCode="bold">Inactive ingredients for Methotrexate Injection Preservative-free: </content>sodium chloride. May contain sodium hydroxide and/or hydrochloric acid to adjust pH to 8.5. <content styleCode="bold">Inactive ingredients for Methotrexate Injection with Preservative: </content>benzyl alcohol and sodium chloride. May contain sodium hydroxide and/or hydrochloric acid to adjust pH to 8.5. For more information, call 1-866-210-9797. Manufactured for: <content styleCode="bold">Alembic Pharmaceuticals, Inc.</content> Bedminster, NJ 07921, USA. Manufactured by: <content styleCode="bold">Alembic Pharmaceuticals Limited</content> Panelav - 389 350, Gujarat, India. </td></tr></tbody></table>

WARNING: EMBRYO-FETAL TOXICITY, HYPERSENSITIVITY REACTIONS, BENZYL ALCOHOL TOXICITY, and OTHER SERIOUS ADVERSE REACTIONS Methotrexate Injection can cause embryo-fetal toxicity, including fetal death. For non-neoplastic diseases, Methotrexate Injection is contraindicated in pregnancy. Advise females and males of reproductive potential to use effective contraception [see Contraindications (4) , Warnings and Precautions (5.1) , and Use in Specific Populations (8.1 , 8.3 )] . Methotrexate Injection is contraindicated in patients with a history of severe hypersensitivity reactions to methotrexate, including anaphylaxis [see Contraindications (4) and Warnings and Precautions (5.2) ] . Formulations with benzyl alcohol can cause severe central nervous toxicity or metabolic acidosis. Use only preservative-free Methotrexate Injection for treatment of neonates or low birth weight infants and for intrathecal use. Do not use benzyl alcohol-containing formulations for high-dose regimens unless immediate treatment is required and preservative-free formulations are not available [see Dosage and Administration (2.1) and Warnings and Precautions (5.3) ] . Other serious adverse reactions, including death, have been reported with methotrexate. Closely monitor for infections and adverse reactions of the bone marrow, kidneys, liver, nervous system, gastrointestinal tract, lungs, and skin. Withhold or discontinue Methotrexate Injection as appropriate [see Warnings and Precautions (5.4 , 5.5 , 5.6 , 5.7 , 5.8 , 5.9 , 5.10 , 5.11 )] . WARNING: EMBRYO-FETAL TOXICITY, HYPERSENSITIVITY REACTIONS, BENZYL ALCOHOL TOXICITY, and OTHER SERIOUS ADVERSE REACTIONS See full prescribing information for complete boxed warning. Methotrexate Injection can cause embryo-fetal toxicity, including fetal death. Use in non-neoplastic diseases is contraindicated during pregnancy. Advise females and males of reproductive potential to use effective contraception during and after treatment with Methotrexate Injection. ( 4 , 5.1 , 8.1 , 8.3 ) Methotrexate Injection is contraindicated in patients with a history of severe hypersensitivity reactions to methotrexate, including anaphylaxis. ( 4 , 5.2 ) Formulations with benzyl alcohol can cause severe central nervous toxicity or metabolic acidosis. Use only preservative-free Methotrexate Injection for treatment of neonates or low birth weight infants, and for intrathecal use. Do not use benzyl alcohol-containing formulations for high-dose regimens unless immediate treatment is required and preservative-free formulations are not available. ( 2.1 , 5.3 ) O ther serious adverse reactions, including death, have been reported with methotrexate. Closely monitor for infections and adverse reactions of the bone marrow, kidneys, liver, nervous system, gastrointestinal tract, lungs, and skin. Withhold or discontinue Methotrexate Injection as appropriate. ( 5.4 , 5.5 , 5.6 , 5.7 , 5.8 , 5.9 , 5.10 , 5.11 )

1 INDICATIONS AND USAGE Methotrexate Injection is a folate analog metabolic inhibitor indicated for: The following neoplastic diseases for the: ◦ Treatment of adult and pediatric patients with acute lymphoblastic leukemia as part of a combination chemotherapy regimen. ( 1.1 ) ◦ Prophylaxis and treatment of adult and pediatric patients with meningeal leukemia. ( 1.2 ) ◦ Treatment of adult and pediatric patients with non-Hodgkin lymphoma. ( 1.3 ) ◦ Treatment of adult and pediatric patients with osteosarcoma as part of a combination chemotherapy regimen. ( 1.4 ) ◦ Treatment of adults with breast cancer as part of a combination chemotherapy regimen. ( 1.5 ) ◦ Treatment of adults with squamous cell carcinoma of the head and neck as a single agent. ( 1.6 ) ◦ Treatment of adults with gestational trophoblastic neoplasia as part of a combination chemotherapy regimen. ( 1.7 ) Treatment of adults with rheumatoid arthritis (RA). ( 1.8 ) Treatment of pediatric patients with polyarticular juvenile idiopathic arthritis (pJIA). ( 1.9 ) Treatment of adults with severe psoriasis. ( 1.10 ) 1.1 Acute Lymphoblastic Leukemia Methotrexate Injection is indicated for the treatment of adult and pediatric patients with acute lymphoblastic leukemia (ALL) as part of a combination chemotherapy regimen. 1.2 Meningeal Leukemia: Prophylaxis and Treatment Methotrexate Injection is indicated for the prophylaxis and treatment of meningeal leukemia in adult and pediatric patients. 1.3 Non-Hodgkin Lymphoma Methotrexate Injection is indicated for the treatment of adults and pediatric patients with non-Hodgkin lymphoma. 1.4 Osteosarcoma Methotrexate Injection is indicated for the treatment of adults and pediatric patients with osteosarcoma as part of a combination chemotherapy regimen. 1.5 Breast Cancer Methotrexate Injection is indicated for the treatment of adults with breast cancer as part of a combination chemotherapy regimen. 1.6 Squamous Cell Carcinoma of the Head and Neck Methotrexate Injection is indicated for the treatment of adults with squamous cell carcinoma of the head and neck as a single agent. 1.7 Gestational Trophoblastic Neoplasia Methotrexate Injection is indicated for the treatment of adults with gestational trophoblastic neoplasia (GTN) as part of a combination chemotherapy regimen. 1.8 Rheumatoid Arthritis Methotrexate Injection is indicated for the treatment of adults with rheumatoid arthritis (RA). 1.9 Polyarticular Juvenile Idiopathic Arthritis Methotrexate Injection is indicated for the treatment of pediatric patients with polyarticular Juvenile Idiopathic Arthritis (pJIA). 1.10 Psoriasis Methotrexate Injection is indicated for the treatment of adults with severe psoriasis.

2 DOSAGE AND ADMINISTRATION Verify pregnancy status in females of reproductive potential before starting Methotrexate Injection. ( 2.1 , 4 , 5.1 ) Neoplastic diseases: Refer to the prescribing information for disease specific dosing recommendations. Follow guidelines for high-dose regimens. ( 2.2 , 2.3 , 2.4 , 2.5 , 2.6 , 2.7 , 2.8 , 2.9 ) RA: Recommended starting dosage of 7.5 mg once weekly intramuscularly; adjust dose to achieve an optimal response. ( 2.10 ) pJIA: Recommended starting dosage of 10 mg/m 2 once weekly subcutaneously or intramuscularly; adjust dose to achieve an optimal response. ( 2.11 ) Psoriasis: Recommended dosage of 10 mg to 25 mg once weekly intramuscularly or intravenously; adjust dose to achieve optimal response. Once achieved, reduce to lowest possible dosage. ( 2.12 ) 2.1 Important Dosage and Safety Information Use only preservative-free Methotrexate Injection for treatment of neonates or low birth weight infants and for intrathecal use. Do not use benzyl alcohol-containing formulations for high-dose regimens unless immediate treatment is required and preservative-free formulations are not available [see Warnings and Precautions (5.3) and Use in Specific Populations (8.4) ]. Verify pregnancy status in females of reproductive potential before starting Methotrexate Injection [see Contraindications (4) and Warnings and Precautions (5.1) ]. For patients switching between a methotrexate product administered orally and Methotrexate Injection, consider potential differences in bioavailability . 2.2 Recommended Monitoring and Concomitant Therapies for Intermediate- and High-Dose Regimens To decrease the risk of severe adverse reactions [see Warnings and Precautions (5) ] : Administer leucovorin rescue in patients receiving Methotrexate Injection doses of 500 mg/m 2 or greater (e.g., high-dose) . Consider leucovorin rescue for patients receiving Methotrexate Injection doses between 100 mg/m 2 to less than 500 mg/m 2 (e.g., intermediate-dose). Refer to the leucovorin prescribing information for additional information. For high-dose Methotrexate Injection regimens, follow the supportive care and monitoring instructions below. Also consider for patients receiving intermediate-dose Methotrexate Injection regimens. - Monitor serum creatinine, electrolytes, at baseline and at least daily during therapy - Administer intravenous fluids starting before the first dose and continuing throughout treatment to maintain adequate hydration and urine output - Alkalinize urine starting before the first dose and continuing throughout treatment to maintain a urinary pH of 7 or higher - Monitor methotrexate concentrations at least daily and adjust hydration and leucovorin dosing as needed Administer glucarpidase in patients who have toxic plasma methotrexate concentrations (>1 micromole per liter) and delayed methotrexate clearance due to impaired renal function (refer to the glucarpidase prescribing information for additional information). 2.3 Recommended Dosage for Acute Lymphoblastic Leukemia Methotrexate Injection is used as part of a multi-drug regimen. The recommended dosage varies from 10 to 5,000 mg/m 2 intravenously. For high-dose Methotrexate Injection regimens, use leucovorin rescue in accordance with high-dose methotrexate regimen guidelines [see Dosage and Administration (2.2) ] . Lower doses (e.g., 20 to 30 mg/m 2 per week) may be used intramuscularly.

gimen. The recommended dosage varies from 10 to 5,000 mg/m 2 intravenously. For high-dose Methotrexate Injection regimens, use leucovorin rescue in accordance with high-dose methotrexate regimen guidelines [see Dosage and Administration (2.2) ] . Lower doses (e.g., 20 to 30 mg/m 2 per week) may be used intramuscularly. Individualize the dose and schedule of Methotrexate Injection based on disease state, patient risk category, concurrent drugs used, phase of treatment, and response to treatment. 2.4 Recommended Dosage for Meningeal Leukemia: Prophylaxis and Treatment Use only preservative-free Methotrexate Injection for intrathecal use. Prior to administration, dilute preservative-free Methotrexate Injection to a concentration of 1 mg/mL in preservative-free 0.9% Sodium Chloride Injection, USP. The recommended intrathecal dose of Methotrexate Injection (preservative-free) is based on age: less than 1 year: 6 mg 1 to less than 2 years: 8 mg 2 to less than 3 years: 10 mg 3 to less than 9 years: 12 mg greater than or equal to 9 years: 12 to 15 mg For treatment of meningeal leukemia, intrathecal methotrexate may be given at intervals of 2 or more days up to twice weekly; however, administration at intervals of less than 1 week may result in increased subacute toxicity. For meningeal leukemia prophylaxis, Methotrexate Injection is administered no more than once weekly. For patients with Down Syndrome, administer leucovorin rescue with intrathecal Methotrexate Injection. 2.5 Recommended Dosage for Non-Hodgkin Lymphoma The recommended dosage of Methotrexate Injection varies. When used in combination, recommended dosages range from 10 mg/m 2 to 8,000 mg/m 2 intravenously. When used as a single agent, recommended dosages include 8,000 mg/m 2 intravenously for central nervous system-directed therapy or 5 to 75 mg intravenously for cutaneous forms of non-Hodgkin lymphoma. As part of a combination chemotherapy regimen, a recommended dosage of Methotrexate Injection is 1,000 mg/m 2 or 3,000 mg/m 2 as an intravenous infusion over 24 hours followed by leucovorin rescue in accordance with high-dose methotrexate regimen guidelines [see Dosage and Administration (2.2) ] . For central nervous system-directed therapy, a recommended dosage of Methotrexate Injection is 8,000 mg/m 2 as an intravenous infusion over 4 hours as a single agent or in combination with immunochemotherapy at doses ranging from 3,000 mg/m 2 to 8,000 mg/m 2 followed by leucovorin rescue in accordance with high-dose methotrexate regimen guidelines [see Dosage and Administration (2.2) ] . For intrathecal Methotrexate Injection (preservative-free), the recommended dose is based on age [see Dosage and Administration (2.4) ] . The frequency of administration varies based on whether it is being used for treatment or prophylaxis, and other factors. 2.6 Recommended Dosage for Osteosarcoma The recommended dosage of Methotrexate Injection is typically 12 g/m 2 (maximum 20 g/dose) as an intravenous infusion over 4 hours administered as a component of a combination chemotherapy regimen. Administer leucovorin rescue in accordance with high-dose methotrexate regimen guidelines [see Dosage and Administration (2.2) ]. Subsequent doses may need to be adjusted based on observed peak serum methotrexate concentrations. Dosage and schedule may vary based upon factors such as patient comorbidities, disease state, and prior treatments. 2.7 Recommended Dosage for Breast Cancer A recommended dosage of Methotrexate Injection is 40 mg/m 2 intravenously as a component of a cyclophosphamide- and fluorouracil-based multi-drug regimen. 2.8 Recommended Dosage for Squamous Cell Carcinoma of Head and Neck The recommended dosage of Methotrexate Injection ranges from 40 to 60 mg/m 2 intravenously once weekly.

mmended dosage of Methotrexate Injection is 40 mg/m 2 intravenously as a component of a cyclophosphamide- and fluorouracil-based multi-drug regimen. 2.8 Recommended Dosage for Squamous Cell Carcinoma of Head and Neck The recommended dosage of Methotrexate Injection ranges from 40 to 60 mg/m 2 intravenously once weekly. 2.9 Recommended Dosage for Gestational Trophoblastic Neoplasia For patients with low-risk gestational trophoblastic neoplasia (GTN) a recommended dosage for Methotrexate Injection is 30 mg/m 2 to 200 mg/m 2 or 0.4 mg/kg to 1 mg/kg intravenously or intramuscularly. For patients with high-risk GTN, a recommended dosage for Methotrexate Injection is 300 mg/m 2 over 12 hours as an intravenous infusion as a component of a multi-drug regimen. 2.10 Recommended Dosage for Rheumatoid Arthritis The recommended starting dosage of Methotrexate Injection is 7.5 mg once weekly, administered intramuscularly with escalation to achieve optimal response. Dosages of more than 20 mg once weekly result in an increased risk of serious adverse reactions, including myelosuppression. When responses are observed, the majority occurred between 3 and 6 weeks from initiation of treatment; however, responses have occurred up to 12 weeks after treatment initiation. Administer folic acid or folinic acid to reduce the risk of methotrexate adverse reactions [see Warnings and Precautions (5.12) ]. 2.11 Recommended Dosage for Polyarticular Juvenile Idiopathic Arthritis The recommended starting dosage of Methotrexate Injection is 10 mg/m 2 once weekly administered subcutaneously or intramuscularly, with escalation to achieve optimal response. Dosages over 30 mg/m 2 per week may result in an increased risk of serious adverse reactions, including myelosuppression. When responses are observed, the majority occurred between 3 and 6 weeks from initiation of treatment; however, responses have occurred up to 12 weeks after treatment initiation. Administer folic acid or folinic acid to reduce the risk of methotrexate adverse reactions [see Warnings and Precautions (5.12) ]. 2.12 Recommended Dosage for Psoriasis The recommended dosage of Methotrexate Injection is 10 mg to 25 mg intramuscularly or intravenously once weekly until adequate response is achieved. Adjust the dose gradually to achieve optimal clinical response; do not exceed 25 mg per week. Once optimal clinical response has been achieved, reduce the dosage to the lowest possible dosing regimen. Administer folic acid or folinic acid to reduce the risk of methotrexate adverse reactions [see Warnings and Precautions (5.12) ]. 2.13 Dosage Modifications for Adverse Reactions Discontinue Methotrexate Injection for: Anaphylaxis or other severe hypersensitivity reactions [see Warnings and Precautions (5.2) ] Lymphoproliferative disease [see Warnings and Precautions (5.13 )] Withhold, dose reduce or discontinue Methotrexate Injection as appropriate for: Myelosuppression [see Warnings and Precautions (5.4) ] Withhold or discontinue Methotrexate Injection as appropriate for: Serious infections [see Warnings and Precautions (5.5) ] Renal toxicity [see Warnings and Precautions (5.6) ] Hepatotoxicity [see Warnings and Precautions (5.7) ] Neurotoxicity [see Warnings and Precautions (5.8) ] Gastrointestinal toxicity [see Warnings and Precautions (5.9) ] Pulmonary toxicity [see Warnings and Precautions (5.10) ] Dermatologic reactions [see Warnings and Precautions (5.11) ] 2.14 Administration and Handling Information Methotrexate Injection is a hazardous drug. Follow applicable special handling and disposable procedures. 1 Preservative-Free (Single-Dose Vial) Methotrexate Injection preservative-free may be administered by intramuscular, intravenous, subcutaneous, or intrathecal injection.

.14 Administration and Handling Information Methotrexate Injection is a hazardous drug. Follow applicable special handling and disposable procedures. 1 Preservative-Free (Single-Dose Vial) Methotrexate Injection preservative-free may be administered by intramuscular, intravenous, subcutaneous, or intrathecal injection. Use only preservative-free Methotrexate Injection for treatment of neonates or low birth weight infants and for intrathecal use [see Warning and Precautions (5.3) and Use in Specific Populations (8.4) ] . Use preservative-free Methotrexate Injection for high-dose regimens unless immediate treatment is required, and preservative-free formulations are not available [see Warning and Precautions (5.3) and Use in Specific Populations (8.4) ] . Preservative-free Methotrexate Injection may be further diluted before use with preservative-free 0.9% Sodium Chloride Injection, USP. Diluted product should be used within 4 hours when stored at room temperature (20°C to 25°C) or 24 hours when stored under refrigeration (2°C to 8°C). Visually inspect for particulate matter and discoloration prior to administration. Discard if particulate matter or discoloration is observed.

3 DOSAGE FORMS AND STRENGTHS Injection: Methotrexate Injection, USP is a clear, yellowish solution and is supplied in single-dose vials (preservative-free) in the following strengths: Preservative-Free (Single-Dose Vial) 50 mg/2 mL, 100 mg/4 mL, 200 mg/8 mL and 250 mg/10 mL (25 mg/mL) Injection: Preservative-free (single-dose vials): 50 mg/2 mL, 100 mg/4 mL, 200 mg/8 mL and 250 mg/10 mL (25 mg/mL)

4 CONTRAINDICATIONS Methotrexate Injection is contraindicated in: Patients with history of severe hypersensitivity to methotrexate [see Warnings and Precautions (5.2) ] . Pregnancy in patients with non-neoplastic diseases [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1) ] . History of severe hypersensitivity to methotrexate. ( 4 ) Pregnancy: in patients with non-neoplastic diseases. ( 4 )

5 WARNINGS AND PRECAUTIONS Secondary malignancies can occur. ( 5.13 ) Tumor lysis syndrome can occur in patients with rapidly growing tumors. ( 5.14 ) Immunizations and Risks associated with Live Vaccines: Immunizations may be ineffective. Live vaccines are not recommended due to risk of disseminated infection. ( 5.15 ) Infertility: Can cause impairment of fertility, oligospermia, and menstrual dysfunction. ( 5.16 , 8.3 ) 5.1 Embryo-Fetal Toxicity Based on published reports and its mechanism of action, methotrexate can cause embryo-fetal toxicity, including fetal death when administered to a pregnant woman. Methotrexate Injection is contraindicated for use in pregnant women with non-neoplastic diseases. Advise pregnant women with neoplastic diseases of the potential risk to a fetus. The preservative benzyl alcohol can cross the placenta; when possible, use the preservative-free formulation when Methotrexate Injection is needed during pregnancy to treat a neoplastic disease [see Warnings and Precautions (5.3) ] . Advise females of reproductive potential to use effective contraception during Methotrexate Injection treatment and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during Methotrexate Injection treatment and for 3 months after the last dose [see Contraindications (4) and Use in Specific Populations (8.1 , 8.3 , 8.4 )] . 5.2 Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis, can occur with methotrexate [see Adverse Reactions (6.1) ]. If signs or symptoms of anaphylaxis or any other serious hypersensitivity reaction occurs, immediately discontinue Methotrexate Injection and institute appropriate therapy [see Contraindications (4) ] . 5.3 Risks of Serious Adverse Reactions due to Benzyl Alcohol-Preservative Formulations with benzyl alcohol can cause severe central nervous toxicity or metabolic acidosis, if used in neonates or low birth weight infants, intrathecally, or in high-dose regimens. Use only preservative-free Methotrexate Injection for treatment of neonates or low birth weight infants and for intrathecal use. Do not use benzyl alcohol-containing formulations for high-dose regimens unless immediate treatment is required, and preservative-free formulations are not available. The preservative benzyl alcohol can cross the placenta; when possible, use the preservative-free formulation when Methotrexate Injection is needed during pregnancy to treat a neoplastic disease [see Use in Specific Populations (8.1) ] . Serious and Fatal Adverse Reactions Including Gasping Syndrome in Neonates and Low Birth Weight Infants Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low birth weight infants treated with drugs containing benzyl alcohol, including Methotrexate Injection with preservative. The “gasping syndrome” is characterized by central nervous system (CNS) depression, metabolic acidosis, and gasping respirations. When prescribing in infants (non-neonate, non-low birth weight), if a preservative-free formulation of Methotrexate Injection is not available and use of a benzyl alcohol-containing formulation is necessary, consider the combined daily metabolic load of benzyl alcohol from all sources including Methotrexate Injection (Methotrexate Injection contains 9.4 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol.

otrexate Injection is not available and use of a benzyl alcohol-containing formulation is necessary, consider the combined daily metabolic load of benzyl alcohol from all sources including Methotrexate Injection (Methotrexate Injection contains 9.4 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known [see Use in Specific Populations (8.4) ]. Neurotoxicity Due to Intrathecal Administration Serious neurotoxicity can occur following the intrathecal administration of Methotrexate Injection containing the preservative benzyl alcohol. Metabolic Acidosis with High-Dose Therapy Severe metabolic acidosis can occur with Methotrexate Injection that contains the preservative benzyl alcohol. 5.4 Myelosuppression Methotrexate suppresses hematopoiesis and can cause severe and life-threatening pancytopenia, anemia, aplastic anemia, leukopenia, neutropenia, and thrombocytopenia [see Adverse Reactions (6.1) ]. Obtain blood counts at baseline and periodically during treatment. Monitor patients for possible clinical complications of myelosuppression. Provide supportive care and withhold, reduce dose, or discontinue Methotrexate Injection as needed. 5.5 Serious Infections Patients treated with methotrexate are at increased risk for developing life-threatening or fatal bacterial, fungal, or viral infections including opportunistic infections such as Pneumocystis jiroveci pneumonia, invasive fungal infections, hepatitis B reactivation, tuberculosis primary infection or reactivation, and disseminated Herpes zoster and cytomegalovirus infections. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with Methotrexate Injection. Withhold or discontinue Methotrexate Injection in patients who develop serious infections . 5.6 Renal Toxicity Methotrexate can cause renal toxicity including irreversible acute renal failure. Monitor renal function and withhold or discontinue Methotrexate Injection as needed for severe renal toxicity. For patients receiving high-dose regimens, follow recommendations to decrease the risk of renal injury and mitigate renal toxicity [see Dosage and Administration (2.2) ]. Patients with impaired renal function are at increased risk for methotrexate toxicity [see Use in Specific Populations (8.6) ]. Consider administration of glucarpidase in patients with toxic plasma methotrexate concentrations (>1 micromole per liter) and delayed clearance due to impaired renal function. [see Dosage and Administration (2.2) ] . 5.7 Hepatotoxicity Methotrexate can cause severe and potentially irreversible hepatotoxicity including fibrosis, cirrhosis, and fatal liver failure [see Adverse Reactions (6.1 , 6.2 )]. In patients with psoriasis, fibrosis or cirrhosis may occur in the absence of symptoms or abnormal liver function tests. In patients with psoriasis, the risk of hepatotoxicity appears to increase with total cumulative dose and generally occurs after receipt of a total cumulative dose of 1.5 g or more. The safety of Methotrexate Injection in patients with liver disease is unknown. Avoid use of Methotrexate Injection in patients with chronic liver disease, unless benefits clearly outweigh the risks. The risk of hepatotoxicity is increased with heavy alcohol consumption. Assess liver function prior to initiating Methotrexate Injection and monitor liver function tests during treatment. Withhold or discontinue Methotrexate Injection as appropriate. 5.8 Neurotoxicity Methotrexate can cause severe acute and chronic neurotoxicity which can be progressive, irreversible, and fatal.

nsumption. Assess liver function prior to initiating Methotrexate Injection and monitor liver function tests during treatment. Withhold or discontinue Methotrexate Injection as appropriate. 5.8 Neurotoxicity Methotrexate can cause severe acute and chronic neurotoxicity which can be progressive, irreversible, and fatal. Serious neurotoxicity, including generalized and focal seizures, have occurred in pediatric patients [see Use in Specific Populations (8.4) ] . Monitor patients for signs of neurotoxicity and withhold or discontinue Methotrexate Injection when appropriate. Leukoencephalopathy Leukoencephalopathy can occur with intermediate and high-dose intravenous regimens, intrathecal methotrexate, and low-dose methotrexate therapy. The risk of leukoencephalopathy is increased with prior cranial radiation. Transient Acute Neurologic Syndrome A transient acute stroke-like syndrome can occur with high-dose methotrexate. Clinical manifestations include confusion, hemiparesis, transient blindness, seizures, and coma. Neurologic Adverse Reactions Associated with Intrathecal Administration Intrathecal methotrexate can cause the following additional neurologic adverse reactions: Acute chemical arachnoiditis manifested by symptoms such as headache, back pain, nuchal rigidity, and fever. Subacute myelopathy characterized by paraparesis or paraplegia. Avoid the intrathecal use of Methotrexate Injection that contains the preservative benzyl alcohol because of the risk of serious neurotoxicity [see Warnings and Precautions (5.3) ]. 5.9 Gastrointestinal Toxicity Methotrexate can cause diarrhea, vomiting, stomatitis, hemorrhagic enteritis and fatal intestinal perforation [see Adverse Reactions (6.1) ] . Patients with peptic ulcer disease or ulcerative colitis are at a greater risk of developing severe gastrointestinal adverse reactions. Withhold or discontinue Methotrexate Injection for severe gastrointestinal toxicity, and institute appropriate supportive care as needed. 5.10 Pulmonary Toxicity Methotrexate-induced pulmonary toxicity including acute or chronic interstitial pneumonitis and irreversible or fatal cases can occur at all dose levels. Monitor patients for signs of pulmonary toxicity and withhold or discontinue Methotrexate Injection as appropriate. 5.11 Dermatologic Reactions Severe, including fatal, dermatologic reactions, such as toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, can occur with methotrexate [see Adverse Reactions (6.1 , 6.2 )]. Psoriasis may be aggravated by concomitant exposure to ultraviolet radiation. Methotrexate can cause radiation recall, photodermatitis (sunburn) reactivation, photosensitivity, and severe sunburn reactions. Advise patients to limit sun exposure while taking Methotrexate Injection. Advise patients when outdoors to wear a hat and protective clothing and use a broad-spectrum Ultraviolet A (UVA)/Ultraviolet B (UVB) sunscreen and lip balm (SPF≥30) to help protect against sunburn. Monitor patients for signs of dermatologic toxicity and withhold or permanently discontinue Methotrexate Injection for severe dermatologic adverse reactions. 5.12 Folic Acid Supplementation Neoplastic Diseases Products containing folic acid or its derivatives may decrease the clinical effectiveness of methotrexate. Avoid use of products containing folic acid or folinic acid unless clinically indicated [see Drug Interactions (7.1) ] . Non-neoplastic Diseases Folate deficiency may increase methotrexate adverse reactions. Administer folic acid or folinic acid to patients with rheumatoid arthritis, pJIA, and psoriasis [see Dosage and Administration (2.10 , 2.11 , 2.12 )] . 5.13 Secondary Malignancies Secondary malignancies can occur at all dose levels of methotrexate.

iseases Folate deficiency may increase methotrexate adverse reactions. Administer folic acid or folinic acid to patients with rheumatoid arthritis, pJIA, and psoriasis [see Dosage and Administration (2.10 , 2.11 , 2.12 )] . 5.13 Secondary Malignancies Secondary malignancies can occur at all dose levels of methotrexate. In some cases, lymphoproliferative disease that occurred during therapy with low-dose methotrexate regressed completely following withdrawal of methotrexate. If lymphoproliferative disease occurs, discontinue Methotrexate Injection and institute appropriate treatment if lymphoma does not regress. 5.14 Tumor Lysis Syndrome Methotrexate can induce tumor lysis syndrome in patients with rapidly growing tumors. Institute appropriate treatment for prevention and management of tumor lysis syndrome. 5.15 Immunization and Risks Associated with Live Vaccines Immunization during Methotrexate Injection treatment may be ineffective. Disseminated infections following administration of live vaccines have been reported. Update immunizations according to immunization guidelines prior to initiating Methotrexate Injection. Immunization with live vaccines is not recommended during treatment. The interval between live vaccinations and initiation of Methotrexate Injection should be in accordance with current vaccination guidelines for patients on immunosuppressive therapies. 5.16 Infertility Based on published reports, methotrexate can cause impairment of fertility, oligospermia, and menstrual dysfunction. It is not known if the infertility may be reversible in affected patients. Discuss the risk of effects on reproduction with female and male patients of reproductive potential [see Use in Specific Populations (8.3) ]. 5.17 Increased Risk of Adverse Reactions Due to Third-Space Accumulation Methotrexate can exit slowly from third-space accumulations resulting in prolonged terminal plasma half-life and toxicity. Evacuate significant third-space accumulations prior to Methotrexate Injection administration [see Clinical Pharmacology (12.3) ]. 5.18 Increased Risk of Soft Tissue and Bone Toxicity with Concomitant Radiotherapy Concomitant radiation therapy increases the risk of soft tissue necrosis and osteonecrosis associated with methotrexate. 5.19 Risk of Serious Adverse Reactions with Medication Errors Serious adverse reactions, including death, have occurred due to medication errors. Most commonly, these errors occurred in patients who were taking methotrexate daily when a weekly dosing regimen was prescribed. Ensure that patients receive the recommended dosage, because medication errors have led to death.

6 ADVERSE REACTIONS The following adverse reactions are described, or described in greater detail, in other sections: Hypersensitivity Reactions [see Warnings and Precautions (5.2) ] Myelosuppression [see Warnings and Precautions (5.4) ] Serious Infections [see Warnings and Precautions (5.5) ] Renal Toxicity [see Warnings and Precautions (5.6) ] Hepatotoxicity [see Warnings and Precautions (5.7) ] Neurotoxicity [see Warnings and Precautions (5.8) ] Gastrointestinal Toxicity [see Warnings and Precautions (5.9) ] Pulmonary Toxicity [see Warnings and Precautions (5.10) ] Dermatologic Reactions [see Warnings and Precautions (5.11) ] Secondary Malignancies [see Warnings and Precautions (5.13) ] Tumor Lysis Syndrome [see Warnings and Precautions (5.14) ] Increased Risk of Adverse Reactions due to Third-Space Accumulation [see Warnings and Precautions (5.17) ] Common adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Eugia US LLC 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 and other studies 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 practice. Commonly reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse reactions are infection, malaise, fatigue, chills, fever, and dizziness. Rheumatoid Arthritis The approximate incidences of methotrexate-attributed (i.e., placebo rate subtracted) adverse reactions in 12- to 18-week double-blind studies in patients (n = 128) with RA treated with low-dose oral (7.5 mg per week to 15 mg per week) pulse methotrexate are listed below. Most patients were on concomitant NSAIDs and some received corticosteroids. Hepatic histology was not examined in these short-term studies. Incidence ≥10%: Elevated liver function tests 15%, nausea/vomiting 10%. Incidence 3% to <10%: Stomatitis, thrombocytopenia (platelet count less than 100,000/mm 3 ). Incidence 1% to <3%: Rash/pruritus/dermatitis, diarrhea, alopecia, leukopenia (white blood cell count less than 3,000/mm 3 ), pancytopenia, dizziness. Two other controlled trials of patients (n = 680) with RA on 7.5 mg per week to 15 mg per week oral doses showed the following adverse reactions: Incidence 1%: Interstitial pneumonitis. Other less common adverse reactions: Decreased hematocrit, headache, upper respiratory infection, anorexia, arthralgias, chest pain, coughing, dysuria, eye discomfort, epistaxis, fever, infection, sweating, tinnitus, vaginal discharge. Polyarticular Juvenile Idiopathic Arthritis (pJIA) The approximate incidences of adverse reactions reported in patients 2 to 18 years of age with pJIA treated with oral, weekly doses of methotrexate (5 mg/m 2 per week to 20 mg/m 2 per week or 0.1 mg/kg per week to 0.65 mg/kg per week) were as follows (most patients were receiving concomitant NSAIDs, and some received corticosteroids): elevated liver function tests, 14%; gastrointestinal reactions (e.g., nausea, vomiting, diarrhea), 11%; stomatitis, 2%; leukopenia, 2%; headache, 1.2%; alopecia, 0.5%; dizziness, 0.2%; rash, 0.2%.

7 DRUG INTERACTIONS Refer to full prescribing information for drug interactions with Methotrexate Injection. 7.1 Effects of Other Drugs on Methotrexate Drugs that Increase Methotrexate Exposure Coadministration of methotrexate with the following products may increase methotrexate plasma concentrations, which may increase the risk of methotrexate severe adverse reactions. Increased organ specific adverse reactions may also occur when methotrexate is coadministered with hepatotoxic or nephrotoxic products. If coadministration cannot be avoided, monitor closely for methotrexate adverse reactions when coadministered with: Penicillin or sulfonamide antibiotics Highly protein bound drugs (e.g., oral anticoagulants, phenytoin, salicylates, sulfonamides, sulfonylureas, and tetracyclines) Proton pump inhibitors Probenecid Antifolate drugs (e.g., dapsone, pemetrexed, pyrimethamine and sulfonamides) Aspirin and other nonsteroidal anti-inflammatory drugs Unexpectedly severe and fatal gastrointestinal toxicity can occur with concomitant administration of methotrexate (primarily at high dose) and nonsteroidal anti-inflammatory drugs (NSAIDs). Mercaptopurine Hepatotoxic products Weak acids (e.g., salicylates) Nephrotoxic products Hematotoxic agents Nitrous Oxide Coadministration of methotrexate with nitrous oxide anesthesia potentiates the effect of methotrexate on folate-dependent metabolic pathways, which may increase the risk of severe methotrexate adverse reactions. Avoid nitrous oxide anesthesia in patients receiving methotrexate. Consider alternative therapies in patients who have received prior nitrous oxide anesthesia. Folic Acid Coadministration of methotrexate with folic acid or its derivatives decreases the clinical effectiveness of methotrexate in patients with neoplastic diseases. Methotrexate competes with reduced folates for active transport across cell membranes. Instruct patients to take folic or folinic acid only as directed by their healthcare provider [see Warnings and Precautions (5.12) ]. 7.2 Effects of Methotrexate on Other Drugs Theophylline Coadministration of methotrexate with theophylline increases theophylline plasma concentrations which may increase the risk of theophylline adverse reactions. Monitor theophylline levels and adjust the theophylline dosage in accordance with approved product labeling.

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2 ) Pediatric use: Intermediate-dose methotrexate can cause serious neurotoxicity in patients with acute lymphoblastic leukemia. ( 8.4 ) 8.1 Pregnancy Risk Summary Methotrexate Injection is contraindicated in pregnant women with non-neoplastic diseases. Based on published reports and its mechanism of action, methotrexate can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman [see Data and Clinical Pharmacology (12.1) ]. There are no animal data that meet current standards for nonclinical developmental toxicity studies. Advise pregnant women with neoplastic diseases of the potential risk to a fetus. The preservative benzyl alcohol can cross the placenta; when possible, use the preservative-free formulation when Methotrexate Injection is needed during pregnancy to treat a neoplastic disease [see Warnings and Precautions (5.3) and Use in Specific Populations (8.4) ] . 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. Data Human Data Published data from case reports, literature reviews, and observational studies report that methotrexate exposure during pregnancy is associated with an increased risk of embryo-fetal toxicity and fetal death. Methotrexate exposure during the first trimester of pregnancy is associated with an increased incidence of spontaneous abortions and multiple adverse developmental outcomes, including skull anomalies, facial dysmorphism, CNS abnormalities, limb abnormalities, and sometimes cardiac anomalies and intellectual impairment. Adverse outcomes associated with exposure during second and third trimesters of pregnancy include intrauterine growth restriction and functional abnormalities. Because methotrexate is widely distributed and persists in the body for a prolonged period, there is a potential risk to the fetus from preconception methotrexate exposure. A prospective multicenter study evaluated pregnancy outcomes in women taking methotrexate less than or equal to 30 mg per week after conception. The rate of spontaneous abortion/miscarriage in pregnant women exposed to methotrexate was 42.5% (95% confidence interval [95% CI] 29.2 to 58.7), which was higher than in unexposed patients with autoimmune disease (22.5%, 95% CI 16.8 to 29.7) and unexposed patients with non-autoimmune disease (17.3%, 95% CI 13 to 22.8). Of the live births, the rate of major birth defects in pregnant women exposed to methotrexate after conception was higher than in unexposed patients with autoimmune disease (adjusted odds ratio (OR) 1.8 [95% CI 0.6 to 5.7]) and unexposed patients with non-autoimmune disease (adjusted OR 3.1 [95% CI 1.03 to 9.5]) (2.9%). Major birth defects associated with pregnancies exposed to methotrexate after conception were not always consistent with methotrexate-associated adverse developmental outcomes. 8.2 Lactation Risk Summary Limited published literature reports the presence of methotrexate in human milk in low amounts, with the highest breast milk to plasma concentration ration reported to be 0.08:1. No information is available on the effects of methotrexate on a breastfed infant or on milk production.

outcomes. 8.2 Lactation Risk Summary Limited published literature reports the presence of methotrexate in human milk in low amounts, with the highest breast milk to plasma concentration ration reported to be 0.08:1. No information is available on the effects of methotrexate on a breastfed infant or on milk production. Because of the potential for serious adverse reactions from methotrexate in breastfed infants, advise women not to breastfeed during treatment with Methotrexate Injection and for 1 week after the last dose. 8.3 Females and Males of Reproductive Potential Methotrexate can cause malformations and fetal death at doses less than or equal to the recommended clinical doses [see Use in Specific Populations (8.1) ] . Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating Methotrexate Injection [see Contraindications (4) and Use in Specific Populations (8.1) ]. Contraception Females Advise females of reproductive potential to use effective contraception during and for 6 months after the last dose of Methotrexate Injection therapy. Males Methotrexate can cause chromosomal damage to sperm cells. Advise males with female partners of reproductive potential to use effective contraception during and for 3 months after the last dose of Methotrexate Injection therapy. Infertility Females Based on published reports of female infertility after therapy with methotrexate, advise females of reproductive potential that Methotrexate Injection can cause impairment of fertility and menstrual dysfunction during and after cessation of therapy. It is not known if the infertility may be reversed in all affected females. Males Based on published reports of male infertility after therapy with methotrexate, advise males that Methotrexate Injection can cause oligospermia or infertility during and after cessation of therapy. It is not known if the infertility may be reversed in all affected males. 8.4 Pediatric Use The safety and effectiveness of Methotrexate Injection in pediatric patients have been established for ALL, meningeal leukemia prophylaxis and treatment, non-Hodgkin lymphoma, osteosarcoma and in pJIA. Clinical studies evaluating the use of methotrexate in pediatric patients with pJIA demonstrated safety comparable to that observed in adults with RA [see Adverse Reactions (6.1) ]. The safety and effectiveness of Methotrexate Injection have not been established in pediatric patients for the treatment of breast cancer, squamous cell carcinoma of the head and neck, gestational trophoblastic neoplasia, rheumatoid arthritis, and psoriasis. Additional risk information is described below. Risks of Serious Adverse Reactions due to Benzyl Alcohol-Preservative Due to the risk of serious adverse reactions and fatal gasping syndrome following administration of intravenous solutions containing the preservative benzyl alcohol in neonates, use only preservative-free Methotrexate Injection in neonates and low birth weight infants. The “gasping syndrome” is characterized by CNS depression, metabolic acidosis, and gasping respirations. Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature neonates and low birth weight infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions include gradual neurological deterioration, seizures, intracranial hemorrhage, hematological abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse.

es in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions include gradual neurological deterioration, seizures, intracranial hemorrhage, hematological abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. When prescribing in infants (non-neonate, non-low birth weight), if a preservative-free formulation of Methotrexate Injection is not available and use of a benzyl alcohol-containing formulation is necessary, consider the combined daily metabolic load of benzyl alcohol from all sources including Methotrexate Injection (Methotrexate Injection contains 9.4 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known . Do not administer methotrexate formulations containing benzyl alcohol intrathecally due to the risk of severe neurotoxicity [see Warnings and Precautions (5.3) ]. Leukemia/Lymphoma Serious neurotoxicity, frequently manifested as generalized or focal seizures, has been reported with unexpectedly increased frequency among pediatric patients with acute lymphoblastic leukemia who were treated with intermediate-dose intravenous methotrexate (1 g/m 2 ) [see Warnings and Precautions (5.8) ]. 8.5 Geriatric Use Clinical studies of methotrexate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 8.6 Renal Impairment Methotrexate elimination is reduced in patients with renal impairment [creatinine clearance (CLcr) less than 90 mL/min, calculated using Cockcroft-Gault] [see Clinical Pharmacology (12.3) ] . Patients with renal impairment are at increased risk for methotrexate adverse reactions. Follow recommendations to promote methotrexate elimination and decrease risk of acute kidney injury and other methotrexate toxicities in patients who are receiving intermediate- or high-dose regimens [see Dosage and Administration (2.2) and Warnings and Precautions (5.6) ]. Consider reducing the dose or discontinuing Methotrexate Injection in patients with renal impairment as appropriate. 8.7 Hepatic Impairment The pharmacokinetics and safety of methotrexate in patients with hepatic impairment is unknown. Patients with hepatic impairment may be at increased risk for methotrexate adverse reaction based on elimination characteristics of methotrexate [see Clinical Pharmacology (12.3) ] . Consider reducing the dose or discontinuing Methotrexate Injection in patients with hepatic impairment as appropriate [see Warnings and Precautions (5.7) ].

8.1 Pregnancy Risk Summary Methotrexate Injection is contraindicated in pregnant women with non-neoplastic diseases. Based on published reports and its mechanism of action, methotrexate can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman [see Data and Clinical Pharmacology (12.1) ]. There are no animal data that meet current standards for nonclinical developmental toxicity studies. Advise pregnant women with neoplastic diseases of the potential risk to a fetus. The preservative benzyl alcohol can cross the placenta; when possible, use the preservative-free formulation when Methotrexate Injection is needed during pregnancy to treat a neoplastic disease [see Warnings and Precautions (5.3) and Use in Specific Populations (8.4) ] . 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. Data Human Data Published data from case reports, literature reviews, and observational studies report that methotrexate exposure during pregnancy is associated with an increased risk of embryo-fetal toxicity and fetal death. Methotrexate exposure during the first trimester of pregnancy is associated with an increased incidence of spontaneous abortions and multiple adverse developmental outcomes, including skull anomalies, facial dysmorphism, CNS abnormalities, limb abnormalities, and sometimes cardiac anomalies and intellectual impairment. Adverse outcomes associated with exposure during second and third trimesters of pregnancy include intrauterine growth restriction and functional abnormalities. Because methotrexate is widely distributed and persists in the body for a prolonged period, there is a potential risk to the fetus from preconception methotrexate exposure. A prospective multicenter study evaluated pregnancy outcomes in women taking methotrexate less than or equal to 30 mg per week after conception. The rate of spontaneous abortion/miscarriage in pregnant women exposed to methotrexate was 42.5% (95% confidence interval [95% CI] 29.2 to 58.7), which was higher than in unexposed patients with autoimmune disease (22.5%, 95% CI 16.8 to 29.7) and unexposed patients with non-autoimmune disease (17.3%, 95% CI 13 to 22.8). Of the live births, the rate of major birth defects in pregnant women exposed to methotrexate after conception was higher than in unexposed patients with autoimmune disease (adjusted odds ratio (OR) 1.8 [95% CI 0.6 to 5.7]) and unexposed patients with non-autoimmune disease (adjusted OR 3.1 [95% CI 1.03 to 9.5]) (2.9%). Major birth defects associated with pregnancies exposed to methotrexate after conception were not always consistent with methotrexate-associated adverse developmental outcomes.

10 OVERDOSAGE Manifestations Overdosage, including fatal overdosage, has occurred with methotrexate [see Warnings and Precautions (5.19) ]. Manifestations of overdosage include adverse reactions reported at pharmacologic doses, particularly hematologic and gastrointestinal reactions (e.g., leukopenia, thrombocytopenia, anemia, pancytopenia, myelosuppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, or gastrointestinal bleeding). In some cases, no symptoms were reported; however, sepsis or septic shock, renal failure, and aplastic anemia were also reported. Manifestations of intrathecal overdosage include CNS symptoms (e.g., headache, nausea and vomiting, seizure or convulsion, and acute toxic encephalopathy). In some cases, no symptoms were reported; however, cerebellar herniation associated with increased intracranial pressure and acute toxic encephalopathy have also been reported. Management Leucovorin and levoleucovorin are indicated to diminish the toxicity and counteract the effect of inadvertently administered overdosages of methotrexate. Administer leucovorin or levoleucovorin as soon as possible after overdosage (refer to the leucovorin or levoleucovorin prescribing information). Monitor serum methotrexate concentrations closely to guide leucovorin or levoleucovorin therapy. Monitor serum creatinine concentrations closely because high serum methotrexate concentrations may cause renal damage leading to acute renal failure. Glucarpidase is indicated for the treatment of toxic methotrexate concentrations in patients with delayed methotrexate clearance due to impaired renal function (refer to the glucarpidase prescribing information). If glucarpidase is used, do not administer leucovorin within 2 hours before or after a dose of glucarpidase because leucovorin is a substrate for glucarpidase. Hydration and urinary alkalinization may be necessary to prevent the precipitation of methotrexate and/or its metabolites in the renal tubules. Neither hemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination. However, effective clearance of methotrexate has been reported with acute, intermittent hemodialysis using a high-flux dialyzer.

11 DESCRIPTION Methotrexate, USP is a folate analog metabolic inhibitor with the chemical name of N -[4-[[(2,4-diamino-6-pteridinyl) methyl]methylamino]benzoyl]-L-glutamic acid and a molecular weight of 454.44. The molecular formula is C 20 H 22 N 8 O 5, and the structural formula is shown below: Preservative-free Methotrexate Injection, USP is supplied in sterile single-dose vials for intravenous, intramuscular, subcutaneous, or intrathecal use. Each 25 mg/mL, 2 mL, 4 mL, 8 mL and 10 mL vial contains 50 mg, 100 mg, 200 mg, and 250 mg methotrexate, USP equivalent to 54.8 mg, 109.6 mg, 219.3 mg and 274.18 mg of methotrexate sodium respectively, and the following inactive ingredients: Sodium chloride 9.8 mg, 19.6 mg, 39.2 mg and 49 mg respectively. May contain sodium hydroxide and/or hydrochloric acid to adjust pH between 7.0 to 9.0. checmical structure

or less of the administered dose. Enterohepatic recirculation of methotrexate has been proposed. Renal excretion occurs by glomerular filtration and active tubular secretion. Nonlinear elimination due to saturation of renal tubular reabsorption has been observed in psoriatic patients at doses between 7.5 mg and 30 mg. Specific Populations Pediatric Patients In pediatric patients receiving methotrexate for acute lymphoblastic leukemia (6.3 mg/m 2 to 30 mg/m 2 ), or for JIA (3.75 mg/m 2 to 26.2 mg/m 2 ), the terminal half-life has been reported to range from 0.7 to 5.8 hours or from 0.9 to 2.3 hours, respectively [see Use in Specific Populations (8.4) ] . Patients with Renal impairment The elimination half-life of methotrexate increases with the severity of renal impairment, with high inter-individual variability [see Use in Specific Populations (8.6) ].

12.3 Pharmacokinetics Distribution After intravenous administration, the initial volume of distribution is approximately 0.18 L/kg (18% of body weight) and steady-state volume of distribution is approximately 0.4 L/to 0.8 L/kg (40% to 80% of body weight). Methotrexate competes with reduced folates for active transport across cell membranes by means of a single carrier-mediated active transport process. At serum concentrations greater than 100 micromolar, passive diffusion becomes a major pathway by which effective intracellular concentrations can be achieved. Methotrexate in serum is approximately 50% protein bound. Methotrexate may be displaced from plasma albumin by various compounds, including sulfonamides, salicylates, tetracyclines, chloramphenicol, and phenytoin. Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given intravenously, intramuscularly, or subcutaneously. Elimination The terminal half-life reported for methotrexate is approximately 3 to 10 hours for patients receiving treatment for psoriasis, or rheumatoid arthritis or low-dose antineoplastic therapy (less than 30 mg/m 2 ). Following intravenous administration of high-dose methotrexate, the terminal half-life is 8 hours to 15 hours. Metabolism Methotrexate undergoes hepatic and intracellular metabolism to polyglutamated forms that can be converted back to methotrexate by hydrolase enzymes. These polyglutamates act as inhibitors of dihydrofolate reductase and thymidylate synthetase. Small amounts of methotrexate polyglutamates may remain in tissues for extended periods. The retention and prolonged drug action of these active metabolites vary among different cells, tissues, and tumors. Methotrexate undergoes minor metabolism to 7-hydroxymethotrexate, and accumulation may become significant following high dosages. The aqueous solubility of 7-hydroxymethotrexate is 3- to 5-fold lower than the solubility of methotrexate. Excretion Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration. With intravenous administration, 80% to 90% of the administered dose is excreted unchanged in the urine within 24 hours. There is limited biliary excretion amounting to 10% or less of the administered dose. Enterohepatic recirculation of methotrexate has been proposed. Renal excretion occurs by glomerular filtration and active tubular secretion. Nonlinear elimination due to saturation of renal tubular reabsorption has been observed in psoriatic patients at doses between 7.5 mg and 30 mg. Specific Populations Pediatric Patients In pediatric patients receiving methotrexate for acute lymphoblastic leukemia (6.3 mg/m 2 to 30 mg/m 2 ), or for JIA (3.75 mg/m 2 to 26.2 mg/m 2 ), the terminal half-life has been reported to range from 0.7 to 5.8 hours or from 0.9 to 2.3 hours, respectively [see Use in Specific Populations (8.4) ] . Patients with Renal impairment The elimination half-life of methotrexate increases with the severity of renal impairment, with high inter-individual variability [see Use in Specific Populations (8.6) ].

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Methotrexate has been evaluated in a number of animal studies for carcinogenic potential with inconclusive results. There is evidence that methotrexate causes chromosomal damage to animal somatic cells and human bone marrow cells [see Use in Specific Populations (8.1 , 8.2 , 8.3 )] .

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Methotrexate has been evaluated in a number of animal studies for carcinogenic potential with inconclusive results. There is evidence that methotrexate causes chromosomal damage to animal somatic cells and human bone marrow cells [see Use in Specific Populations (8.1 , 8.2 , 8.3 )] .

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Methotrexate Injection, USP is a sterile, clear, yellowish solution available with preservative-free (single-dose vials) as follows: Strength/Fill volume NDC number Pack style Preservative-free 50 mg/2 mL 55150-510-01 Single-Dose Vial packaged individually 55150-510-05 Single-Dose Vials in a carton of 5 100 mg/4 mL 55150-511-01 Single-Dose Vial packaged individually 55150-511-10 Single-Dose Vials in a carton of 10 200 mg/8 mL 55150-512-01 Single-Dose Vial packaged individually 55150-512-10 Single-Dose Vials in a carton of 10 250 mg/10 mL 55150-513-01 Single-Dose Vial packaged individually Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light. Methotrexate Injection, USP is a hazardous drug. Follow applicable special handling and disposal procedures. 1 The vial stopper is not made with natural rubber latex.

<table cellspacing="0" cellpadding="0" border="0" width="100%"><colgroup><col width="23.04%"/><col width="16.38%"/><col width="60.58%"/></colgroup><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold"> Strength/Fill volume </content> </td><td styleCode="Rrule" align="left" valign="middle"><content styleCode="bold">NDC number</content> </td><td styleCode="Rrule" align="left" valign="middle"><content styleCode="bold">Pack style</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3" valign="middle">Preservative-free </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" rowspan="2" valign="middle">50 mg/2 mL </td><td styleCode="Rrule" valign="middle">55150-510-01 </td><td styleCode="Rrule" valign="middle">Single-Dose Vial packaged individually </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">55150-510-05 </td><td styleCode="Rrule" valign="middle">Single-Dose Vials in a carton of 5 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" rowspan="2" valign="middle">100 mg/4 mL </td><td styleCode="Rrule" valign="middle">55150-511-01 </td><td styleCode="Rrule" valign="middle">Single-Dose Vial packaged individually </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">55150-511-10 </td><td styleCode="Rrule" valign="middle">Single-Dose Vials in a carton of 10 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" rowspan="2" valign="middle">200 mg/8 mL </td><td styleCode="Rrule" valign="middle">55150-512-01 </td><td styleCode="Rrule" valign="middle">Single-Dose Vial packaged individually </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">55150-512-10 </td><td styleCode="Rrule" valign="middle">Single-Dose Vials in a carton of 10 </td></tr><tr><td styleCode="Lrule Rrule" valign="middle">250 mg/10 mL </td><td styleCode="Rrule" valign="middle">55150-513-01 </td><td styleCode="Rrule" valign="middle">Single-Dose Vial packaged individually </td></tr></tbody></table>

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Embryo-Fetal Toxicity Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Contraindications (4) , Warnings and Precautions (5.1) , and Use in Specific Populations (8.1) ]. Advise females of reproductive potential to use effective contraception during Methotrexate Injection therapy and for 6 months after the last dose [see Use in Specific Populations (8.3) ]. Advise males of reproductive potential to use effective contraception during Methotrexate Injection therapy and for 3 months after the last dose [see Use in Specific Populations (8.3) ]. Hypersensitivity Reactions Advise patients of the potential risk of hypersensitivity and that Methotrexate Injection is contraindicated in patients with a history of severe hypersensitivity to methotrexate. Advise patients to seek immediate medical attention if signs or symptoms of a hypersensitivity reaction occur [see Warnings and Precautions (5.2) ]. Myelosuppression and Serious Infections Advise patient to contact their healthcare provider immediately for new onset fever, symptoms of infection, easy bruising or persistent bleeding [see Warnings and Precautions (5.4 , 5.5 )]. Renal Toxicity Advise patients that methotrexate can cause renal toxicity. Advise patients to immediately contact their healthcare provider for signs or symptoms of renal toxicity, such as marked increases or decreases in urinary output [see Warnings and Precautions (5.6) ]. Hepatotoxicity Advise patients to report signs or symptoms of hepatic toxicity and avoidance of alcohol during methotrexate treatment [see Warnings and Precautions (5.7) ]. Neurotoxicity Advise patient to contact their healthcare provider immediately if they develop new neurological symptoms [see Warnings and Precautions (5.8) ]. Gastrointestinal Toxicity Advise patients to contact their healthcare provider if they develop diarrhea, vomiting, or stomatitis. Advise patients to immediately contact their healthcare provider for high fever, rigors, persistent or severe abdominal pain, severe constipation, hematemesis, or melena [see Warnings and Precautions (5.9) ]. Pulmonary Toxicity Advise patients to contact their healthcare provider for symptoms of cough, fever, and dyspnea [see Warnings and Precautions (5.10) ]. Dermatologic Toxicity Advise patients that Methotrexate Injection can cause serious skin rash and to immediately contact their healthcare provider for new or worsening skin rash. Advise patients to avoid excessive sun exposure and to use sun protection measures [see Warnings and Precautions (5.11) ] . Secondary Malignancies Advise patients on the risk of second primary malignancies during treatment with Methotrexate Injection [see Warnings and Precautions (5.13) ]. Lactation Advise women not to breastfeed during treatment with Methotrexate Injection and for 1 week after the last dose [see Use in Specific Populations (8.2) ]. Infertility Advise females and males of reproductive potential that Methotrexate Injection may cause impairment of fertility [see Use in Specific Populations (8.3) ] . Drug Interactions Advise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions (7) ] .

jection may cause impairment of fertility [see Use in Specific Populations (8.3) ] . Drug Interactions Advise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions (7) ] . Instruct patients being treated for neoplastic indication to not take products containing folic acid or folinic acid unless directed to do so by their healthcare provider [see Warnings and Precautions (5.12) ]. Distributed by: Eugia US LLC 279 Princeton-Hightstown Rd. E. Windsor, NJ 08520 Manufactured by: Eugia Pharma Specialities Limited Hyderabad - 500032 India

Patient Information Methotrexate (Meth-oh-trex-ate) Injection for intravenous, intramuscular, subcutaneous, or intrathecal use What is the most important information I should know about Methotrexate Injection? Methotrexate Injection can cause serious side effects that may be severe and lead to death, including: Harm to an unborn baby, including birth defects or death of an unborn baby. Females who can become pregnant: Your healthcare provider should do a pregnancy test before you start taking Methotrexate Injection to see if you are pregnant. I f you are being treated for a medical condition other than cancer, do not receive or take Methotrexate Injection if you are pregnant. See “Do not receive Methotrexate Injection if”. If you are taking Methotrexate Injection to treat your cancer, you and your healthcare provider will decide if you will receive or take Methotrexate Injection if you are pregnant. Use effective birth control (contraception) during treatment and for 6 months after your last dose of Methotrexate Injection. Ask your healthcare provider what forms of birth control you can use during this time. Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with Methotrexate Injection. Males with female partners who are able to become pregnant: Use effective birth control during treatment and for 3 months after your last dose of Methotrexate Injection. Tell your healthcare provider right away if your female partner becomes pregnant during treatment with Methotrexate Injection. Severe allergic reactions . Severe allergic reactions can happen with Methotrexate Injection. Do not receive Methotrexate Injection if you have had a severe allergic reaction to methotrexate in the past. Get medical help right away if you develop any of the signs or symptoms of a severe allergic reaction to Methotrexate Injection , including: o skin rash, itching, and hives o throat tightness o swelling of the face, lips, tongue, or throat, or trouble swallowing o runny or stuffy nose o dizziness or lightheadedness o fast heart rate o trouble breathing o chest pain o wheezing o feeling faint Decreased blood cell counts . Methotrexate Injection can affect your bone marrow and cause decreased red blood cell counts, white blood cell counts, and platelet counts, and a condition where your bone marrow cannot produce these blood cells (aplastic anemia). These decreased blood cell counts can be severe and may lead to a serious infection, the need for blood transfusions, treatment in a hospital, and can be life-threatening. Your healthcare provider will check your blood cell counts before you start and during treatment with Methotrexate Injection. Your healthcare provider will watch you closely for infections during treatment with Methotrexate Injection. Call your healthcare provider right away if you develop: a new fever (temperature of 100.4°F or higher) • symptoms of infection • easy bruising or bleeding that will not stop Your healthcare provider may give you medicines to support your blood counts or give you transfusions if needed, and change your dose or stop your treatment with Methotrexate Injection if needed. Serious infections . People who receive treatment with Methotrexate Injection have an increased risk of developing serious infections that can be life-threatening or lead to death.

rt your blood counts or give you transfusions if needed, and change your dose or stop your treatment with Methotrexate Injection if needed. Serious infections . People who receive treatment with Methotrexate Injection have an increased risk of developing serious infections that can be life-threatening or lead to death. These infections include: bacterial infections • hepatitis B infection that comes back (reactivation) fungal infections • tuberculosis (TB) infection that is new or that comes back (reactivation) viral infections • shingles (herpes zoster) certain infections that happen because your immune system is weakened • cytomegalovirus infections Your healthcare provider will closely watch you for signs and symptoms of infection during treatment with Methotrexate Injection. Your healthcare provider may hold or stop your treatment with Methotrexate Injection if you develop a serious infection. Kidney problems. Methotrexate Injection can cause kidney damage including sudden kidney failure that may not go away (irreversible). People who already have kidney problems have an increased risk of kidney problems with Methotrexate Injection. Your healthcare provider will check your kidney function during treatment, and will hold or stop Methotrexate Injection treatment as needed for severe kidney damage. Call your healthcare provider right away if you have signs or symptoms of kidney problems such as a big change in the amount of urine that you make, either increased or decreased. Liver problems. Methotrexate Injection can cause severe liver problems including liver scarring (fibrosis), cirrhosis, and liver failure that may not get better (possibly irreversible) and can cause death. In people with psoriasis who receive Methotrexate Injection, liver fibrosis or cirrhosis may happen without any symptoms or abnormal liver tests. The risk for liver problems in people with psoriasis increases with the amount of Methotrexate Injection that you receive over time. Your healthcare provider will do tests to monitor your liver function before you start and during treatment with Methotrexate Injection, and may hold or stop your treatment with Methotrexate Injection, if needed. The risk of liver problems is increased with heavy use of alcohol. Avoid drinking alcohol during Methotrexate Injection treatment. Tell your healthcare provider if you develop any signs or symptoms of liver problems during treatment with Methotrexate Injection, including: tiredness • swelling in your legs, feet, or ankles easy bleeding or bruising • weight loss loss of appetite • itchy skin nausea • yellowing of your skin or the white part of your eyes difficulty thinking clearly • weakness Brain and spinal cord (nervous system) problems. Methotrexate Injection can cause nervous system problems that can be severe and last for a short time or last for a long time. These nervous system problems can get progressively worse, may not get better (possibly irreversible), and can cause death. Serious nervous system problems can happen in children who receive Methotrexate Injection, including seizures that can begin on one side of the brain (focal seizures) or on both sides of the brain (generalized seizures). The risk for a nervous system problem called leukoencephalopathy is increased in people who have had radiation treatment to their head and spine (craniospinal irradiation) in the past. Call your healthcare provider if you develop any new neurological symptoms. People who receive high-dose Methotrexate Injection can develop sudden symptoms that are like the symptoms of a stroke, but they last a short time and may go away (transient). People who receive injections of Methotrexate Injection into their spine (intrathecal methotrexate) can develop inflammation of the lining around the spinal nerves.

igh-dose Methotrexate Injection can develop sudden symptoms that are like the symptoms of a stroke, but they last a short time and may go away (transient). People who receive injections of Methotrexate Injection into their spine (intrathecal methotrexate) can develop inflammation of the lining around the spinal nerves. Call your healthcare provider right away if you or your child develop any new signs or symptoms of a nervous system problem during treatment with Methotrexate Injection, including: confusion • coma weakness on one side of your body • headache sudden blindness that goes away • back pain seizures • stiff neck • fever Severe stomach and intestine (gastrointestinal) problems. Methotrexate Injection can cause diarrhea, vomiting, mouth sores, stomach and intestinal inflammation with severe bleeding, and tears in the intestinal wall (perforation), and can lead to death. People who have stomach ulcers (peptic ulcer disease) or ulcerative colitis (UC) have a higher risk of developing severe stomach and intestine problems with Methotrexate Injection. Your healthcare provider may hold or stop your treatment with Methotrexate Injection if any of these severe stomach and intestinal problems happen, and treat you as needed. Call your healthcare provider if you develop diarrhea, vomiting, inflammation or sores in your mouth. Call your healthcare provider right away if you develop: o high fever o severe constipation o shaking chills o if you are vomiting blood o stomach-area (abdomen) pain that is severe or does not go away. o blood in your stools Lung problems. Lung problems can happen suddenly (acute) with Methotrexate Injection or they can develop over a long period-of-time (chronic). Lung problems may not get better (possibly irreversible) and can cause death in anyone taking Methotrexate Injection. Your healthcare provider will monitor you for lung problems during treatment with Methotrexate Injection. Your healthcare provider may hold or stop your treatment with Methotrexate Injection, if needed. Call your healthcare provider if you develop symptoms of a lung problem, including: cough, fever, and trouble breathing. Skin reactions. Severe skin reactions can happen with Methotrexate Injection, that can be serious and can lead to death. In people with psoriasis: Your psoriasis may get worse if you are exposed to sunlight or other types of ultraviolet light. Methotrexate Injection can cause reactivation of skin reactions that can happen after radiation therapy (radiation recall), sunburns to come back (photodermatitis) and severe sunburn reactions. Limit sunlight exposure during treatment with Methotrexate Injection. Use a broad-spectrum ultraviolet sunscreen and lip balm with a Sun Protection Factor (SPF) of 30 or greater and wear a hat and protective clothing when you will be exposed to sunlight during treatment with Methotrexate Injection. Call your healthcare provider right away if you develop a new or worsening skin rash during treatment with Methotrexate Injection. See “What are the possible side effects of Methotrexate Injection?” for more information about side effects. What is Methotrexate Injection?

ht during treatment with Methotrexate Injection. Call your healthcare provider right away if you develop a new or worsening skin rash during treatment with Methotrexate Injection. See “What are the possible side effects of Methotrexate Injection?” for more information about side effects. What is Methotrexate Injection? Methotrexate Injection is a prescription medicine used: in adults and children: in combination with other chemotherapy medicines to treat acute lymphoblastic leukemia (ALL) to help prevent (prophylaxis) and to treat leukemia that spreads to the covering of the brain and spinal cord (meninges) to treat non-Hodgkin lymphoma in combination with other chemotherapy medicines to treat osteosarcoma in adults: in combination with other chemotherapy medicines to treat breast cancer alone to treat squamous cell carcinoma of the head and neck in combination with other chemotherapy medicines to treat gestational trophoblastic neoplasia Methotrexate Injection is a prescription medicine used: in adults to treat rheumatoid arthritis (RA) in children to treat polyarticular juvenile idiopathic arthritis (pJIA) in adults to treat severe psoriasis Do not receive Methotrexate Injection if you: have had a severe allergic reaction to Methotrexate Injection. See “What is the most important information I should know about Methotrexate Injection?” you are pregnant and are being treated, or will be treated with Methotrexate Injection for rheumatoid arthritis, pJIA, or severe psoriasis, or for any disease other than cancer. Methotrexate Injection can cause harm to an unborn baby including birth defects or death of an unborn baby. See “What is the most important information I should know about Methotrexate Injection?” Before you receive Methotrexate Injection, tell your healthcare provider about all of your medical conditions, including if you: have kidney problems or are receiving dialysis treatments have liver problems have a history of neurologic problems, including seizures drink alcohol-containing beverages during treatment with Methotrexate Injection, or if there are any changes in the amount of alcoholic beverages you drink have fluid in your stomach-area (ascites) have lung problems or fluid in your lungs (pleural effusion) plan to have any surgeries with general anesthesia, including dental surgery have stomach ulcers (peptic ulcer disease) have ulcerative colitis have recently received or are scheduled to receive a vaccine. You should not receive live vaccines during treatment with Methotrexate Injection. are breastfeeding or plan to breastfeed. Methotrexate may pass into your breast milk. Do not breastfeed during treatment and for 1 week after your last dose of Methotrexate Injection. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking certain medicines can affect the amount of methotrexate in your blood and can increase your risk for serious side effects. How will I receive or take Methotrexate Injection? Depending on your medical condition and the dose of Methotrexate Injection that is prescribed by your healthcare provider, Methotrexate Injection can be given to you: o through an intravenous (IV) line in your vein o by injection into a large muscle (intramuscular injection) o injected under your skin (subcutaneous injection) o for certain diseases the preservative-free formulation of Methotrexate Injection can also be injected through your spine directly into your spinal fluid. If you are receiving Methotrexate Injection to treat your cancer: Your healthcare provider will decide your dose, how you will receive Methotrexate Injection, and how often you need to receive it, depending on your medical condition that is being treated.

be injected through your spine directly into your spinal fluid. If you are receiving Methotrexate Injection to treat your cancer: Your healthcare provider will decide your dose, how you will receive Methotrexate Injection, and how often you need to receive it, depending on your medical condition that is being treated. If you are receiving high-dose Methotrexate Injection to treat your cancer, you will receive the medicine leucovorin to help prevent severe side effects (“rescue”) to your bone marrow and other normal cells in your body. You will also receive intravenous (IV) fluids and other medicines to help prevent and treat side effects. If you are receiving a “moderate-dose” of Methotrexate Injection to treat your cancer, you may also receive leucovorin. Do not take folic acid or folinic acid during treatment with Methotrexate Injection to treat your cancer, unless your healthcare provider tells you to. Taking folic acid or folinic acid with Methotrexate Injection may make your treatment less effective. Your healthcare provider will do blood tests to check for side effects during treatment with Methotrexate Injection. Your healthcare provider may stop your treatment, change when you receive your treatment, or change the dose of your treatment if you have certain side effects while receiving Methotrexate Injection. If you are receiving Methotrexate Injection for treatment of severe psoriasis, rheumatoid arthritis, or polyarticular juvenile idiopathic arthritis: You should receive your Methotrexate Injection dose 1 time each week, not every day. Serious side effects and death have happened in people who mistakenly have taken Methotrexate Injection every day instead of 1 time each week. Take folic acid or folinic acid every day during treatment with Methotrexate Injection, as instructed by your healthcare provider, to help reduce the chance of developing certain side effects, such as mouth sores. If you receive too much Methotrexate Injection call your healthcare provider or go to your nearest hospital emergency room right way. You will need to receive a medicine as soon as possible to help reduce side effects that could be severe and could cause death. In all patients receiving Methotrexate Injection: If you miss receiving a dose of Methotrexate Injection, call your healthcare provider for instructions about when to receive your next dose of Methotrexate Injection. What are the possible side effects of Methotrexate Injection? Methotrexate Injection can cause serious side effects, including: See “What is the most important information I should know about Methotrexate Injection? ” Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure and the need for dialysis treatment, abnormal heart rhythm, seizure, and sometimes death. Your healthcare provider may do blood tests to check you for TLS if you are receiving Methotrexate Injection as a cancer treatment. Your healthcare provider will treat you as needed to prevent or manage TLS if you develop it during treatment with Methotrexate Injection. New (secondary) cancers. New (secondary) cancers can happen in people who take or receive Methotrexate Injection at any dose. o Certain blood cancers can happen during treatment with low-dose Methotrexate Injection. In some cases, these blood cancers may completely go away (regress completely) after Methotrexate Injection is stopped. o If you develop one of these blood cancers during treatment with Methotrexate Injection, your healthcare provider will stop your treatment, and treat as needed if the new cancer does not go away after Methotrexate Injection is stopped. Increased risk of soft tissue and bone problems due to receiving Methotrexate Injection in combination with radiation therapy.

during treatment with Methotrexate Injection, your healthcare provider will stop your treatment, and treat as needed if the new cancer does not go away after Methotrexate Injection is stopped. Increased risk of soft tissue and bone problems due to receiving Methotrexate Injection in combination with radiation therapy. In people who receive Methotrexate Injection, some soft tissue in your body may die and some bone cells may die. People who receive radiation therapy in combination with Methotrexate Injection have an increased risk of this happening. The most common side effects of Methotrexate Injection include: mouth sores or ulcers nausea decreased white blood cell count. See “ What is the most important information I should know about Methotrexate Injection?” upset stomach Possible fertility problems (infertility) in males and females . Methotrexate Injection can cause fertility problems in males and females, and cause sperm production to stop in males, and menstrual problems in females. In females, your periods (menstrual cycle) may be irregular or completely stop when you receive Methotrexate Injection. Your periods may or may not return to normal following treatment. It is not known if your fertility will return after treatment. Talk to your healthcare provider about your risk for infertility if this is a concern for you. These are not all of the possible side effects of Methotrexate Injection. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of Methotrexate Injection. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about Methotrexate Injection that is written for health professionals. What are the ingredients in Methotrexate Injection? Active ingredient: Methotrexate, USP. Inactive ingredients for Methotrexate Injection, USP Preservative-free: sodium chloride. May contain sodium hydroxide and/or hydrochloric acid to adjust pH between 7.0 to 9.0. Distributed by: Eugia US LLC 279 Princeton-Hightstown Rd. E. Windsor, NJ 08520 Manufactured by: Eugia Pharma Specialities Limited Hyderabad - 500032 India For more information, go to eugiaus.com or call 1-866-850-2876 . This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: July 2025

<table cellspacing="0" cellpadding="0" border="0" width="100%"><colgroup><col width="100%"/></colgroup><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="center" valign="top"> <content styleCode="bold">Patient Information</content> <content styleCode="bold"><content styleCode="bold"><content styleCode="bold">Methotrexate (Meth-oh-trex-ate)</content></content></content> <content styleCode="bold"><content styleCode="bold"><content styleCode="bold"><content styleCode="bold">Injection</content></content></content></content> for intravenous, intramuscular, subcutaneous, or intrathecal use</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="top"><content styleCode="bold">What is the most important information I should know about Methotrexate Injection?</content> <content styleCode="bold"> Methotrexate Injection can cause serious side effects that may be severe and lead to death, including:</content> <content styleCode="bold"> Harm to an unborn baby, including birth defects or death of an unborn baby.</content> <content styleCode="bold"> Females who can become pregnant:</content> <list listType="unordered" styleCode="disc"><item>Your healthcare provider should do a pregnancy test before you start taking Methotrexate Injection to see if you are pregnant.</item><item><content styleCode="bold"> I</content><content styleCode="bold">f you are being treated for a medical condition other than cancer, do not receive or take Methotrexate Injection if you are pregnant. </content>See <content styleCode="bold">&#x201C;Do not receive Methotrexate Injection if&#x201D;.</content></item><item>If you are taking Methotrexate Injection to treat your cancer, you and your healthcare provider will decide if you will receive or take Methotrexate Injection if you are pregnant.</item><item>Use effective birth control (contraception) during treatment and for <content styleCode="bold">6</content> months after your last dose of Methotrexate Injection. Ask your healthcare provider what forms of birth control you can use during this time.</item></list><content styleCode="bold">Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with Methotrexate Injection.</content> <content styleCode="bold"> Males with female partners who are able to become pregnant:</content> <list listType="unordered" styleCode="disc"><item>Use effective birth control during treatment and for <content styleCode="bold"> 3</content> months after your last dose of Methotrexate Injection.</item></list><content styleCode="bold">Tell your healthcare provider right away if your female partner becomes pregnant during treatment with Methotrexate Injection.</content> <content styleCode="bold"> Severe allergic reactions</content>. Severe allergic reactions can happen with Methotrexate Injection. <list listType="unordered" styleCode="disc"><item><content styleCode="bold">Do not receive Methotrexate Injection</content> if you have had a severe allergic reaction to methotrexate in the past.

ent styleCode="bold"> Severe allergic reactions</content>. Severe allergic reactions can happen with Methotrexate Injection. <list listType="unordered" styleCode="disc"><item><content styleCode="bold">Do not receive Methotrexate Injection</content> if you have had a severe allergic reaction to methotrexate in the past. </item></list><content styleCode="bold">Get medical help right away if you develop any of the signs or symptoms of a severe allergic reaction to Methotrexate Injection</content>, including: o skin rash, itching, and hives o throat tightness o swelling of the face, lips, tongue, or throat, or trouble swallowing o runny or stuffy nose o dizziness or lightheadedness o fast heart rate o trouble breathing o chest pain o wheezing o feeling faint <content styleCode="bold">Decreased blood cell counts</content>. Methotrexate Injection can affect your bone marrow and cause decreased red blood cell counts, white blood cell counts, and platelet counts, and a condition where your bone marrow cannot produce these blood cells (aplastic anemia). These decreased blood cell counts can be severe and may lead to a serious infection, the need for blood transfusions, treatment in a hospital, and can be life-threatening. Your healthcare provider will check your blood cell counts before you start and during treatment with Methotrexate Injection. Your healthcare provider will watch you closely for infections during treatment with Methotrexate Injection. <content styleCode="bold"><content styleCode="bold">Call your healthcare provider right away if you develop:</content></content><list listType="unordered" styleCode="disc"><item>a new fever (temperature of 100.4&#xB0;F or higher) &#x2022; symptoms of infection &#x2022; easy bruising or bleeding that will not stop</item></list>Your healthcare provider may give you medicines to support your blood counts or give you transfusions if needed, and change your dose or stop your treatment with Methotrexate Injection if needed. <content styleCode="bold"> Serious infections</content>. People who receive treatment with Methotrexate Injection have an increased risk of developing serious infections that can be life-threatening or lead to death. These infections include: <list listType="unordered" styleCode="disc"><item>bacterial infections &#x2022; hepatitis B infection that comes back (reactivation)</item><item>fungal infections &#x2022; tuberculosis (TB) infection that is new or that comes back (reactivation)</item><item>viral infections &#x2022; shingles (herpes zoster)</item><item>certain infections that happen because your immune system is weakened &#x2022; cytomegalovirus infections</item></list> Your healthcare provider will closely watch you for signs and symptoms of infection during treatment with Methotrexate Injection. Your healthcare provider may hold or stop your treatment with Methotrexate Injection if you develop a serious infection. <content styleCode="bold">Kidney problems.</content> Methotrexate Injection can cause kidney damage including sudden kidney failure that may not go away (irreversible). People who already have kidney problems have an increased risk of kidney problems with Methotrexate Injection. Your healthcare provider will check your kidney function during treatment, and will hold or stop Methotrexate Injection treatment as needed for severe kidney damage. <content styleCode="bold">Call your healthcare provider right away</content> if you have signs or symptoms of kidney problems such as a big change in the amount of urine that you make, either increased or decreased.

ng treatment, and will hold or stop Methotrexate Injection treatment as needed for severe kidney damage. <content styleCode="bold">Call your healthcare provider right away</content> if you have signs or symptoms of kidney problems such as a big change in the amount of urine that you make, either increased or decreased. <content styleCode="bold">Liver problems.</content> Methotrexate Injection can cause severe liver problems including liver scarring (fibrosis), cirrhosis, and liver failure that may not get better (possibly irreversible) and can cause death. <list listType="unordered" styleCode="disc"><item><content styleCode="bold">In people with psoriasis</content> who receive Methotrexate Injection, liver fibrosis or cirrhosis may happen without any symptoms or abnormal liver tests. The risk for liver problems in people with psoriasis increases with the amount of Methotrexate Injection that you receive over time.</item><item>Your healthcare provider will do tests to monitor your liver function before you start and during treatment with Methotrexate Injection, and may hold or stop your treatment with Methotrexate Injection, if needed.</item><item><content styleCode="bold">The risk of liver problems is increased with heavy use of alcohol. Avoid drinking alcohol during Methotrexate Injection treatment.</content></item></list> <content styleCode="bold">Tell your healthcare provider if you develop any signs or symptoms of liver problems</content> during treatment with Methotrexate Injection, including: <list listType="unordered" styleCode="disc"><item>tiredness &#x2022; swelling in your legs, feet, or ankles</item><item>easy bleeding or bruising &#x2022; weight loss</item><item>loss of appetite &#x2022; itchy skin</item><item>nausea &#x2022; yellowing of your skin or the white part of your eyes</item><item>difficulty thinking clearly &#x2022; weakness</item></list><content styleCode="bold">Brain and spinal cord (nervous system) problems.</content> Methotrexate Injection can cause nervous system problems that can be severe and last for a short time or last for a long time. These nervous system problems can get progressively worse, may not get better (possibly irreversible), and can cause death. <list listType="unordered" styleCode="disc"><item>Serious nervous system problems can happen in children who receive Methotrexate Injection, including seizures that can begin on one side of the brain (focal seizures) or on both sides of the brain (generalized seizures).</item><item>The risk for a nervous system problem called leukoencephalopathy is increased in people who have had radiation treatment to their head and spine (craniospinal irradiation) in the past.

ing seizures that can begin on one side of the brain (focal seizures) or on both sides of the brain (generalized seizures).</item><item>The risk for a nervous system problem called leukoencephalopathy is increased in people who have had radiation treatment to their head and spine (craniospinal irradiation) in the past. Call your healthcare provider if you develop any new neurological symptoms.</item><item>People who receive high-dose Methotrexate Injection can develop sudden symptoms that are like the symptoms of a stroke, but they last a short time and may go away (transient).</item><item>People who receive injections of Methotrexate Injection into their spine (intrathecal methotrexate) can develop inflammation of the lining around the spinal nerves.</item></list><content styleCode="bold">Call your healthcare provider right away if you or your child develop any new signs or symptoms of a nervous system problem</content> during treatment with Methotrexate Injection, including: <list listType="unordered" styleCode="disc"><item>confusion &#x2022; coma</item><item>weakness on one side of your body &#x2022; headache</item><item>sudden blindness that goes away &#x2022; back pain</item><item>seizures &#x2022; stiff neck &#x2022; fever</item></list><content styleCode="bold">Severe stomach and intestine (gastrointestinal) problems.</content> Methotrexate Injection can cause diarrhea, vomiting, mouth sores, stomach and intestinal inflammation with severe bleeding, and tears in the intestinal wall (perforation), and can lead to death. <list listType="unordered" styleCode="disc"><item>People who have stomach ulcers (peptic ulcer disease) or ulcerative colitis (UC) have a higher risk of developing severe stomach and intestine problems with Methotrexate Injection.</item><item>Your healthcare provider may hold or stop your treatment with Methotrexate Injection if any of these severe stomach and intestinal problems happen, and treat you as needed.</item><item>Call your healthcare provider if you develop diarrhea, vomiting, inflammation or sores in your mouth.</item></list><content styleCode="bold">Call your healthcare provider right away if you develop:</content> o high fever o severe constipation o shaking chills o if you are vomiting blood o stomach-area (abdomen) pain that is severe or does not go away. o blood in your stools <content styleCode="bold"> </content> <content styleCode="bold">Lung problems.</content> Lung problems can happen suddenly (acute) with Methotrexate Injection or they can develop over a long period-of-time (chronic). Lung problems may not get better (possibly irreversible) and can cause death in anyone taking Methotrexate Injection. Your healthcare provider will monitor you for lung problems during treatment with Methotrexate Injection. Your healthcare provider may hold or stop your treatment with Methotrexate Injection, if needed. <content styleCode="bold">Call your healthcare provider</content> if you develop symptoms of a lung problem, including: cough, fever, and trouble breathing. <content styleCode="bold">Skin reactions.</content> Severe skin reactions can happen with Methotrexate Injection, that can be serious and can lead to death.<list listType="unordered" styleCode="disc"><item><content styleCode="bold">In people with psoriasis:</content> Your psoriasis may get worse if you are exposed to sunlight or other types of ultraviolet light.</item><item>Methotrexate Injection can cause reactivation of skin reactions that can happen after radiation therapy (radiation recall), sunburns to come back (photodermatitis) and severe sunburn reactions.</item></list>Limit sunlight exposure during treatment with Methotrexate Injection.

her types of ultraviolet light.</item><item>Methotrexate Injection can cause reactivation of skin reactions that can happen after radiation therapy (radiation recall), sunburns to come back (photodermatitis) and severe sunburn reactions.</item></list>Limit sunlight exposure during treatment with Methotrexate Injection. Use a broad-spectrum ultraviolet sunscreen and lip balm with a Sun Protection Factor (SPF) of 30 or greater and wear a hat and protective clothing when you will be exposed to sunlight during treatment with Methotrexate Injection. <content styleCode="bold">Call your healthcare provider right away if you develop a new or worsening skin rash during treatment with Methotrexate Injection. </content> See <content styleCode="bold">&#x201C;What are the possible side effects of Methotrexate Injection?&#x201D;</content> for more information about side effects. </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="top"><content styleCode="bold">What is Methotrexate Injection? </content> <content styleCode="bold">Methotrexate Injection is a prescription medicine used: </content> <content styleCode="bold">in adults and children: </content> <list listType="unordered" styleCode="disc"><item>in combination with other chemotherapy medicines to treat acute lymphoblastic leukemia (ALL) to help prevent (prophylaxis) and to treat leukemia that spreads to the covering of the brain and spinal cord (meninges)</item><item>to treat non-Hodgkin lymphoma</item><item>in combination with other chemotherapy medicines to treat osteosarcoma</item></list><content styleCode="bold">in adults:</content> <list listType="unordered" styleCode="disc"><item>in combination with other chemotherapy medicines to treat breast cancer</item><item>alone to treat squamous cell carcinoma of the head and neck</item><item>in combination with other chemotherapy medicines to treat gestational trophoblastic neoplasia</item></list><content styleCode="bold"> Methotrexate Injection is a prescription medicine used:</content> <list listType="unordered" styleCode="disc"><item>in adults to treat rheumatoid arthritis (RA)</item><item>in children to treat polyarticular juvenile idiopathic arthritis (pJIA)</item><item>in adults to treat severe psoriasis</item></list></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="top"><content styleCode="bold">Do not receive Methotrexate Injection if you: </content> <list listType="unordered" styleCode="disc"><item>have had a severe allergic reaction to Methotrexate Injection. See<content styleCode="bold"> &#x201C;What is the most important information I should know about Methotrexate Injection?&#x201D;</content></item><item>you are pregnant and are being treated, or will be treated with Methotrexate Injection for rheumatoid arthritis, pJIA, or severe psoriasis, or for any disease other than cancer. Methotrexate Injection can cause harm to an unborn baby including birth defects or death of an unborn baby.

ion?&#x201D;</content></item><item>you are pregnant and are being treated, or will be treated with Methotrexate Injection for rheumatoid arthritis, pJIA, or severe psoriasis, or for any disease other than cancer. Methotrexate Injection can cause harm to an unborn baby including birth defects or death of an unborn baby. See <content styleCode="bold">&#x201C;What is the most important information I should know about Methotrexate Injection?&#x201D;</content></item></list><content styleCode="bold">Before you receive Methotrexate Injection, tell your healthcare provider about all of your medical conditions, including if you: </content> <list listType="unordered" styleCode="disc"><item>have kidney problems or are receiving dialysis treatments</item><item>have liver problems</item><item>have a history of neurologic problems, including seizures</item><item>drink alcohol-containing beverages during treatment with Methotrexate Injection, or if there are any changes in the amount of alcoholic beverages you drink</item><item>have fluid in your stomach-area (ascites)</item><item>have lung problems or fluid in your lungs (pleural effusion)</item><item>plan to have any surgeries with general anesthesia, including dental surgery</item><item>have stomach ulcers (peptic ulcer disease)</item><item>have ulcerative colitis</item><item>have recently received or are scheduled to receive a vaccine. You should not receive live vaccines during treatment with Methotrexate Injection.</item><item>are breastfeeding or plan to breastfeed. Methotrexate may pass into your breast milk. Do not breastfeed during treatment and for 1 week after your last dose of Methotrexate Injection.</item></list>Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking certain medicines can affect the amount of methotrexate in your blood and can increase your risk for serious side effects. </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="top"><content styleCode="bold">How will I receive or take Methotrexate Injection?</content> <list listType="unordered" styleCode="disc"><item>Depending on your medical condition and the dose of Methotrexate Injection that is prescribed by your healthcare provider, Methotrexate Injection can be given to you: o through an intravenous (IV) line in your vein o by injection into a large muscle (intramuscular injection) o injected under your skin (subcutaneous injection) o for certain diseases the preservative-free formulation of Methotrexate Injection can also be injected through your spine directly into your spinal fluid.</item></list><content styleCode="bold">If you are receiving Methotrexate Injection to treat your cancer:</content> <list listType="unordered" styleCode="disc"><item>Your healthcare provider will decide your dose, how you will receive Methotrexate Injection, and how often you need to receive it, depending on your medical condition that is being treated.</item><item>If you are receiving high-dose Methotrexate Injection to treat your cancer, you will receive the medicine leucovorin to help prevent severe side effects (&#x201C;rescue&#x201D;) to your bone marrow and other normal cells in your body. You will also receive intravenous (IV) fluids and other medicines to help prevent and treat side effects.</item><item>If you are receiving a &#x201C;moderate-dose&#x201D; of Methotrexate Injection to treat your cancer, you may also receive leucovorin.</item><item><content styleCode="bold">Do not take folic acid or folinic acid during treatment with Methotrexate Injection to treat your cancer,</content> unless your healthcare provider tells you to.

ceiving a &#x201C;moderate-dose&#x201D; of Methotrexate Injection to treat your cancer, you may also receive leucovorin.</item><item><content styleCode="bold">Do not take folic acid or folinic acid during treatment with Methotrexate Injection to treat your cancer,</content> unless your healthcare provider tells you to. Taking folic acid or folinic acid with Methotrexate Injection may make your treatment less effective.</item><item>Your healthcare provider will do blood tests to check for side effects during treatment with Methotrexate Injection.</item><item>Your healthcare provider may stop your treatment, change when you receive your treatment, or change the dose of your treatment if you have certain side effects while receiving Methotrexate Injection.</item></list><content styleCode="bold">If you are receiving Methotrexate Injection for treatment of severe psoriasis, rheumatoid arthritis, or polyarticular juvenile idiopathic arthritis:</content> <list listType="unordered" styleCode="disc"><item>You should receive your Methotrexate Injection dose 1 time each week, not every day. Serious side effects and death have happened in people who mistakenly have taken Methotrexate Injection every day instead of 1 time each week.</item><item>Take folic acid or folinic acid every day during treatment with Methotrexate Injection, as instructed by your healthcare provider, to help reduce the chance of developing certain side effects, such as mouth sores.</item><item>If you receive too much Methotrexate Injection call your healthcare provider or go to your nearest hospital emergency room right way. You will need to receive a medicine as soon as possible to help reduce side effects that could be severe and could cause death.</item></list><content styleCode="bold"/> <content styleCode="bold">In all patients receiving Methotrexate Injection:</content> <list listType="unordered" styleCode="disc"><item>If you miss receiving a dose of Methotrexate Injection, call your healthcare provider for instructions about when to receive your next dose of Methotrexate Injection.<content styleCode="bold"/></item></list></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="top"><content styleCode="bold">What are the possible side effects of Methotrexate Injection?</content> <content styleCode="bold"> Methotrexate Injection can cause serious side effects, including:</content> <list listType="unordered" styleCode="disc"><item>See <content styleCode="bold"> &#x201C;What is the most important information I should know about Methotrexate Injection?<content styleCode="bold">&#x201D;</content></content></item><item><content styleCode="bold">Tumor lysis syndrome (TLS). </content>TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure and the need for dialysis treatment, abnormal heart rhythm, seizure, and sometimes death. Your healthcare provider may do blood tests to check you for TLS if you are receiving Methotrexate Injection as a cancer treatment. Your healthcare provider will treat you as needed to prevent or manage TLS if you develop it during treatment with Methotrexate Injection.</item><item> <content styleCode="bold">New (secondary) cancers. </content>New (secondary) cancers can happen in people who take or receive Methotrexate Injection at any dose. o Certain blood cancers can happen during treatment with low-dose Methotrexate Injection. In some cases, these blood cancers may completely go away (regress completely) after Methotrexate Injection is stopped.

</content>New (secondary) cancers can happen in people who take or receive Methotrexate Injection at any dose. o Certain blood cancers can happen during treatment with low-dose Methotrexate Injection. In some cases, these blood cancers may completely go away (regress completely) after Methotrexate Injection is stopped. o If you develop one of these blood cancers during treatment with Methotrexate Injection, your healthcare provider will stop your treatment, and treat as needed if the new cancer does not go away after Methotrexate Injection is stopped.</item></list><list listType="unordered" styleCode="disc"><item><content styleCode="bold">Increased risk of soft tissue and bone problems due to receiving Methotrexate Injection in combination with radiation therapy.</content> In people who receive Methotrexate Injection, some soft tissue in your body may die and some bone cells may die. People who receive radiation therapy in combination with Methotrexate Injection have an increased risk of this happening. </item></list>The most common side effects of Methotrexate Injection include: <list listType="unordered" styleCode="disc"><item>mouth sores or ulcers</item><item>nausea</item><item>decreased white blood cell count. See &#x201C;<content styleCode="bold">What is the most important information I should know about Methotrexate Injection?&#x201D;</content></item><item>upset stomach</item></list><content styleCode="bold">Possible fertility problems (infertility) in males and females</content>. Methotrexate Injection can cause fertility problems in males and females, and cause sperm production to stop in males, and menstrual problems in females. In females, your periods (menstrual cycle) may be irregular or completely stop when you receive Methotrexate Injection. Your periods may or may not return to normal following treatment. It is not known if your fertility will return after treatment. Talk to your healthcare provider about your risk for infertility if this is a concern for you. These are not all of the possible side effects of Methotrexate Injection. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. <content styleCode="bold">General information about the safe and effective use of Methotrexate Injection. </content> Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about Methotrexate Injection that is written for health professionals. </td></tr><tr><td styleCode="Lrule Rrule" align="left" valign="top"><content styleCode="bold">What are the ingredients in Methotrexate Injection? </content> <content styleCode="bold"> Active ingredient: Methotrexate, USP.</content> <content styleCode="bold">Inactive ingredients for Methotrexate Injection, USP Preservative-free:</content> sodium chloride. May contain sodium hydroxide and/or hydrochloric acid to adjust pH between 7.0 to 9.0. Distributed by: <content styleCode="bold">Eugia US LLC</content> 279 Princeton-Hightstown Rd. E. Windsor, NJ 08520 Manufactured by: <content styleCode="bold">Eugia Pharma Specialities Limited</content> Hyderabad - 500032 India For more information, go to eugiaus.com or call 1-866-850-2876<content styleCode="bold">.</content> </td></tr></tbody></table>

WARNING: SEVERE TOXIC REACTIONS, INCLUDING EMBRYO-FETAL TOXICITY Methotrexate can cause the following severe or fatal adverse reactions. Monitor closely and modify dose or discontinue methotrexate as appropriate. Bone marrow suppression [see Warnings and Precautions ( 5.1 )] Serious infections [see Warnings and Precautions ( 5.2 )] Renal toxicity and increased toxicity with renal impairment [see Warnings and Precautions ( 5.3 )] Gastrointestinal toxicity [see Warnings and Precautions ( 5.4 )] Hepatic toxicity [see Warnings and Precautions ( 5.5 )] Pulmonary toxicity [see Warnings and Precautions ( 5.6 )] Hypersensitivity and dermatologic reactions [see Warnings and Precautions ( 5.7 )] Methotrexate can cause embryo-fetal toxicity, including fetal death. Use in pJIA is contraindicated in pregnancy. Consider the benefits and risks of XATMEP and risks to the fetus when prescribing XATMEP to a pregnant patient with a neoplastic disease. Advise females and males of reproductive potential to use effective contraception during and after treatment with XATMEP [see Contraindications ( 4 ), Warnings and Precautions ( 5.9 ), Use in Specific Populations ( 8.1 , 8.3 )]. WARNING: SEVERE TOXIC REACTIONS, INCLUDING EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning. Methotrexate can cause severe or fatal toxicities. Monitor closely and modify dose or discontinue for the following toxicities: bone marrow suppression ( 5.1 ), infection ( 5.2 ), renal ( 5.3 ), gastrointestinal ( 5.4 ), hepatic ( 5.5 ), pulmonary ( 5.6 ), hypersensitivity and dermatologic ( 5.7 ). Methotrexate can cause embryo-fetal toxicity and fetal death. Use in polyarticular juvenile idiopathic arthritis is contraindicated in pregnancy ( 4 ). Consider the benefits and risks of XATMEP and risks to the fetus when prescribing XATMEP to a pregnant patient with a neoplastic disease. Advise patients to use effective contraception during and after treatment with XATMEP ( 5.9 , 8.1 , 8.3 ).

1 INDICATIONS AND USAGE XATMEP is a folate analog metabolic inhibitor indicated for the: Treatment of pediatric patients with acute lymphoblastic leukemia (ALL) as a component of a combination chemotherapy maintenance regimen ( 1.1 ). Management of pediatric patients with active polyarticular juvenile idiopathic arthritis (pJIA) who are intolerant of or had an inadequate response to first-line therapy ( 1.2 ). 1.1 Acute Lymphoblastic Leukemia XATMEP is indicated for the treatment of pediatric patients with acute lymphoblastic leukemia (ALL) as part of a multi-phase, combination chemotherapy maintenance regimen. 1.2 Polyarticular Juvenile Idiopathic Arthritis XATMEP is indicated in the management of pediatric patients with active polyarticular juvenile idiopathic arthritis (pJIA) who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy including full dose non-steroidal anti-inflammatory agents (NSAIDs).

2 DOSAGE AND ADMINISTRATION Use another formulation of methotrexate for patients requiring dosing via routes of administration other than oral ( 2.1 ). Measure with an accurate measuring device ( 2.1 ). Recommended Dosage: ALL: 20 mg/m 2 one time weekly ( 2.2 ). pJIA: Starting dose of 10 mg/m 2 one time weekly ( 2.3 ). 2.1 Important Administration Information XATMEP is intended for oral use only. Use another formulation of methotrexate for alternative dosing in patients who require dosing via other routes of administration. Instruct patients and caregivers that the recommended dose should be taken weekly, as directed, and that mistaken daily use of the recommended dose has led to fatal toxicity [see Warnings and Precautions ( 5.15 ), Overdosage ( 10 )]. It is important that XATMEP be measured with an accurate measuring device [see Warnings and Precautions ( 5.15 ), Patient Counseling Information ( 17 )] . A household teaspoon is not an accurate measuring device. A pharmacist can provide an appropriate device and can provide instructions for measuring the correct dose. 2.2 Acute Lymphoblastic Leukemia The recommended starting dose of XATMEP, in multi-agent combination chemotherapy maintenance regimens, is 20 mg/m 2 given one time weekly. After initiating XATMEP, continuation of appropriate dosing requires periodic monitoring of absolute neutrophil count (ANC) and platelet count to assure sufficient drug exposure (that is to maintain ANC at a desirable level) and to adjust for excessive hematological toxicity. 2.3 Polyarticular Juvenile Idiopathic Arthritis The recommended starting dose of XATMEP is 10 mg/m 2 given one time weekly. Dosages should be tailored to the individual patient and adjusted gradually to achieve an optimal response. Although there is experience with doses up to 30 mg/m 2 /week in pediatric patients, doses greater than 20 mg/m 2 /week may result in a significant increase in the incidence and severity of serious toxic reactions, especially bone marrow suppression. Doses between 20 and 30 mg/m 2 /week (0.65 to 1 mg/kg/week) may have better absorption and fewer gastrointestinal side effects if methotrexate is administered by an alternative route using another formulation. Therapeutic response usually begins within 3 to 6 weeks and the patient may continue to improve for another 12 weeks or more. Certain side effects such as mouth sores may be reduced by folate supplementation with methotrexate in pJIA. 2.4 Evaluations Prior to Starting Methotrexate Assess hematologic, hepatic, and renal function before beginning, as well as periodically during and before reinstituting, therapy with XATMEP [see Warnings and Precautions ( 5.1 , 5.3 , 5.5 , 5.7 , 5.14 )] . Exclude pregnancy in females of reproductive potential before starting XATMEP [see Contraindications ( 4 ), Warnings and Precautions ( 5.9 ), Use in Specific Populations ( 8.1 , 8.3 )] . 2.5 Handling Information XATMEP is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1

4 CONTRAINDICATIONS XATMEP is contraindicated in the following: Pregnancy in patients with non-malignant diseases. XATMEP can cause embryo-fetal toxicity and fetal death when administered during pregnancy [see Warnings and Precautions ( 5.9 ), Use in Specific Populations ( 8.1 )] . Patients with severe hypersensitivity to methotrexate [see Warnings and Precautions ( 5.7 ), Adverse Reactions ( 6.1 , 6.2 )] . Pregnancy (patients with pJIA) ( 4 ). Severe hypersensitivity to methotrexate ( 4 ).

5 WARNINGS AND PRECAUTIONS Secondary malignancies can occur. In case of immunosuppression-associated lymphoma, discontinue methotrexate before starting treatment for lymphoma ( 5.8 ). Immunizations may be ineffective ( 5.10 ). Effects on reproduction: May cause impairment of fertility, oligospermia and menstrual dysfunction ( 5.11 , 8.3 ). 5.1 Bone Marrow Suppression XATMEP suppresses hematopoiesis and can cause severe and life-threatening pancytopenia, anemia, leukopenia, neutropenia, and thrombocytopenia. Obtain blood counts at baseline and periodically during treatment. Monitor patients for possible clinical complications of bone marrow suppression. Provide supportive care and modify dose or discontinue XATMEP as needed. 5.2 Serious Infections Patients treated with XATMEP are at increased risk for developing life-threatening or fatal bacterial, fungal, or viral infections including opportunistic infections such as Pneumocystis jiroveci pneumonia, invasive fungal infections, hepatitis B reactivation, tuberculosis primary infection or reactivation, and disseminated Herpes zoster and cytomegalovirus infections. Monitor patients for the signs and symptoms of infection during and after treatment with XATMEP and treat promptly. Consider dose modification or discontinuation of XATMEP in patients who develop serious infections [see Warnings and Precautions ( 5.1 )] . 5.3 Renal Toxicity and Increased Toxicity with Renal Impairment XATMEP can cause renal damage including acute renal failure. Monitor renal function to decrease the risk of renal injury and mitigate renal toxicity. Consider administration of glucarpidase in patients with toxic plasma methotrexate concentrations (> 1 micromole per liter) and delayed clearance due to impaired renal function [see glucarpidase Prescribing Information] . 5.4 Gastrointestinal Toxicity XATMEP can cause diarrhea, vomiting, stomatitis, hemorrhagic enteritis, and fatal intestinal perforation. Patients with peptic ulcer disease or ulcerative colitis are at a greater risk of developing severe gastrointestinal adverse reactions. Interrupt or discontinue XATMEP and institute appropriate supportive care as needed. Unexpectedly severe and fatal gastrointestinal toxicity can occur with concomitant administration of XATMEP (primarily at high dosage) and nonsteroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions ( 7.1 )] . 5.5 Hepatic Toxicity XATMEP can cause severe and potentially irreversible hepatotoxicity including fibrosis, cirrhosis, and fatal liver failure. Avoid use of XATMEP in patients with chronic liver disease. Assess liver function prior to initiating XATMEP and monitor liver function tests during treatment. Interrupt or discontinue XATMEP as appropriate. Transient asymptomatic acute liver enzyme elevations are common and are not predictive of subsequent hepatic disease. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis. Other risk factors for hepatotoxicity include alcoholism, obesity, diabetes, hyperlipidemia, previous significant exposure to liver toxins, history of liver disease, family history of inheritable liver disease, persistent abnormal liver chemistry findings, duration of therapy, and advanced age. 5.6 Pulmonary Toxicity Methotrexate-induced pulmonary toxicity including acute or chronic interstitial pneumonitis and irreversible or fatal cases can occur at all dose levels.

iver disease, family history of inheritable liver disease, persistent abnormal liver chemistry findings, duration of therapy, and advanced age. 5.6 Pulmonary Toxicity Methotrexate-induced pulmonary toxicity including acute or chronic interstitial pneumonitis and irreversible or fatal cases can occur at all dose levels. Monitor patients for signs of pulmonary toxicity and interrupt or discontinue XATMEP as appropriate. 5.7 Hypersensitivity and Dermatologic Reactions Severe, including fatal, dermatologic reactions, such as toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, erythema multiforme, can occur with methotrexate. Discontinue XATMEP if severe dermatologic reactions occur. Anaphylaxis can occur with methotrexate. If anaphylaxis or any other serious hypersensitivity reaction occurs, immediately discontinue methotrexate and institute appropriate therapy. Methotrexate is contraindicated for use in patients with a history of severe hypersensitivity. Radiation dermatitis and sunburn may be “recalled” by the use of methotrexate. 5.8 Secondary Malignancies Secondary malignancies can occur at all dose levels of methotrexate. There have been instances of lymphoproliferative disease associated with low-dose oral methotrexate which have regressed completely following withdrawal of methotrexate without institution of antineoplastic therapy. Discontinue XATMEP first and institute appropriate treatment if the lymphoma does not regress. 5.9 Embryo-Fetal Toxicity Based on published reports and methotrexate’s mechanism of action, methotrexate can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman. In pregnant women with non-malignant diseases, methotrexate is contraindicated. Consider the benefits and risks of XATMEP and risks to the fetus when prescribing XATMEP to a pregnant patient with a neoplastic disease. Advise females of reproductive potential to use effective contraception during therapy and for 6 months after the final dose. Advise males of reproductive potential to use effective contraception during and for at least 3 months after the final methotrexate dose [see Contraindications ( 4 ), Use in Specific Populations ( 8.1 , 8.3 ), Clinical Pharmacology ( 12.1 )] . 5.10 Ineffective Immunization and Risks Associated with Live Vaccines Immunization may be ineffective when given during XATMEP therapy. Immunization with live virus vaccines is not recommended. There have been reports of disseminated vaccinia infections after smallpox immunization in patients receiving methotrexate therapy. 5.11 Effects on Reproduction Based on published reports, methotrexate can cause impairment of fertility, oligospermia, and menstrual dysfunction. It is not known if the infertility is reversible in affected patients. Discuss the risk of effects on reproduction with female and male patients [see Use in Specific Populations ( 8.3 )] . 5.12 Increased Toxicity Due to Third-Space Accumulation Methotrexate can exit slowly from third‑space accumulations resulting in prolonged terminal plasma half-life and toxicity. Evacuate significant third-space accumulations prior to methotrexate administration [see Clinical Pharmacology ( 12.3 )] . 5.13 Soft Tissue and Bone Toxicity with Radiation Therapy Concomitant radiation therapy increases the risk of soft tissue necrosis and osteonecrosis associated with methotrexate. 5.14 Laboratory Tests Closely monitor patients undergoing XATMEP therapy so that toxic effects are detected promptly. In general, monitoring of the following parameters is recommended: hematology at least monthly, renal function and liver function every 1 to 2 months [see Warnings and Precautions ( 5.1 , 5.3 , 5.5 )] .

5.14 Laboratory Tests Closely monitor patients undergoing XATMEP therapy so that toxic effects are detected promptly. In general, monitoring of the following parameters is recommended: hematology at least monthly, renal function and liver function every 1 to 2 months [see Warnings and Precautions ( 5.1 , 5.3 , 5.5 )] . Increase monitoring frequency during initial dosing, dose changes, or during periods of increased risk of elevated methotrexate blood levels (e.g., dehydration). Liver Function Tests Transient liver function test abnormalities are observed frequently after methotrexate administration and are usually not cause for modification of methotrexate therapy. Persistent liver function test abnormalities, and/or depression of serum albumin may be indicators of serious liver toxicity and require evaluation [see Warnings and Precautions ( 5.5 )] . Pulmonary Function Tests Pulmonary function tests may be useful if methotrexate-induced lung disease is suspected, especially if baseline measurements are available [see Warnings and Precautions ( 5.6 )] . 5.15 Risk of Improper Dosing Both the physician and pharmacist should emphasize to the patient that the recommended dose is taken one time weekly, as directed, and that mistaken daily use of the recommended dose has led to fatal toxicity [see Dosage and Administration ( 2.1 ), Overdosage ( 10 )] . Advise patients to measure XATMEP with an accurate milliliter measuring device. Inform patients that a household teaspoon is not an accurate measuring device and could lead to overdosage, which can result in serious adverse reactions [see Overdosage ( 10 )] . Advise patients to ask their pharmacist to recommend an appropriate measuring device and for instructions for measuring the correct dose [see Dosage and Administration ( 2.1 ), Patient Counseling Information ( 17 )] .

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling. Bone Marrow Suppression [see Warnings and Precautions ( 5.1 )] Serious Infections [see Warnings and Precautions ( 5.2 )] Renal Toxicity and Increased Toxicity with Renal Impairment [see Warnings and Precautions ( 5.3 )] Gastrointestinal Toxicity [see Warnings and Precautions ( 5.4 )] Hepatic Toxicity [see Warnings and Precautions ( 5.5 )] Pulmonary Toxicity [see Warnings and Precautions ( 5.6 )] Hypersensitivity and Dermatologic Reactions [see Warnings and Precautions ( 5.7 )] Secondary Malignancies [see Warnings and Precautions ( 5.8 )] Ineffective Immunization and Risks Associated with Live Vaccines [see Warnings and Precautions ( 5.10 )] Infertility [see Warnings and Precautions ( 5.11 )] Increased Toxicity Due to Third‑Space Accumulation [see Warnings and Precautions ( 5.12 )] Soft Tissue and Bone Toxicity with Radiation Therapy [see Warnings and Precautions ( 5.13 )] Most common adverse reactions are: ulcerative stomatitis, leukopenia, nausea, abdominal distress, and elevated liver function tests. Other frequently reported adverse reactions are malaise, fatigue, chills and fever, dizziness and decreased resistance to infection ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Azurity Pharmaceuticals, Inc., at 1-855-379-0383 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 practice. The most frequently reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse reactions are malaise, fatigue, chills, fever, dizziness, and decreased resistance to infection. Folate deficiency states may increase methotrexate toxicity. Polyarticular Juvenile Idiopathic Arthritis The approximate incidences of adverse reactions reported in pediatric patients with JIA treated with oral, weekly doses of methotrexate (5 to 20 mg/m 2 /week or 0.1 to 0.65 mg/kg/week) were as follows (virtually all patients were receiving concomitant nonsteroidal anti-inflammatory drugs, and some also were taking low doses of corticosteroids): elevated liver function tests, 14%; gastrointestinal reactions (e.g., nausea, vomiting, diarrhea), 11%; stomatitis, 2%; leukopenia, 2%; headache, 1.2%; alopecia, 0.5%; dizziness, 0.2%; and rash, 0.2%. Although there is experience with dosing up to 30 mg/m 2 /week in JIA, the published data for doses above 20 mg/m 2 /week are too limited to provide reliable estimates of adverse reaction rates. 6.2 Postmarketing Experience Additional adverse reactions which have been identified during postmarketing use of methotrexate are listed below by organ system.

dosing up to 30 mg/m 2 /week in JIA, the published data for doses above 20 mg/m 2 /week are too limited to provide reliable estimates of adverse reaction rates. 6.2 Postmarketing Experience Additional adverse reactions which have been identified during postmarketing use of methotrexate are listed below by organ system. Blood and Lymphatic System Disorders: Suppressed hematopoiesis causing anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, thrombocytopenia, lymphadenopathy, lymphoproliferative disorders (including reversible), hypogammaglobulinemia Cardiovascular: Thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus), pericarditis, pericardial effusion, hypotension Eye Disorders: Optic neuropathy, transient blindness, blurred vision, ocular irritation, conjunctivitis, xerophthalmia Gastrointestinal Disorders: Gingivitis, pharyngitis, stomatitis, anorexia, nausea, vomiting, diarrhea, hematemesis, melena, gastrointestinal ulceration and bleeding, enteritis, pancreatitis Hepatobiliary Disorders: Hepatotoxicity, acute hepatitis, chronic fibrosis and cirrhosis, decreased serum albumin, liver enzyme elevations Immune System Disorders: Vasculitis, lymphomas, and anaphylactoid reactions Infections: Fatal opportunistic infections (most commonly Pneumocystis jiroveci pneumonia). There have also been reports of other infections, pneumonia, sepsis, nocardiosis, histoplasmosis, cryptococcosis, Herpes zoster , Herpes simplex hepatitis, and disseminated Herpes simplex Metabolism: Hyperglycemia and tumor lysis syndrome Musculoskeletal System: Stress fracture, soft tissue necrosis, osteonecrosis, arthralgia, myalgia, osteoporosis Nervous System Disorders: Headaches, drowsiness, blurred vision, transient blindness, speech impairment (including dysarthria and aphasia), hemiparesis, paresis and convulsions have also occurred following administration of methotrexate. Following low doses, there have been reports of transient subtle cognitive dysfunction, mood alteration, unusual cranial sensations, leukoencephalopathy, or encephalopathy. Renal Disorders: Azotemia, hematuria, proteinuria, cystitis Reproductive Disorders: Defective oogenesis or spermatogenesis, menstrual dysfunction, loss of libido, impotence, vaginal discharge, gynecomastia Respiratory Disorders: Pulmonary fibrosis, respiratory failure, chronic interstitial obstructive pulmonary disease, pleuritic pain and thickening alveolitis Skin Disorders: Erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, skin necrosis, skin ulceration, accelerated nodulosis, and exfoliative dermatitis.

7 DRUG INTERACTIONS Oral Antibiotics: May increase hematologic and gastrointestinal toxicity. Monitor patients accordingly ( 7.1 ). Nitrous Oxide: May increase the risk of toxicity ( 7.1 ). NSAIDs, Aspirin, and Steroids: May elevate and prolong serum methotrexate levels and increase gastrointestinal toxicity. Monitor patients accordingly ( 7.1 ). 7.1 Effect of Other Drugs on XATMEP Oral Antibiotics Penicillins may reduce the renal clearance of methotrexate; increased serum concentrations of methotrexate with concomitant hematologic and gastrointestinal toxicity have been observed with methotrexate. Monitor patients accordingly [see Warnings and Precautions ( 5.1 , 5.4 )] . Trimethoprim/sulfamethoxazole has been reported to increase bone marrow suppression in patients receiving methotrexate. Monitor patients accordingly [see Warnings and Precautions ( 5.1 )] . Hepatotoxins The potential for increased hepatotoxicity when methotrexate is administered with other hepatotoxic agents has not been evaluated; however, hepatotoxicity has been reported in such cases. Monitor patients receiving XATMEP with other potential hepatotoxins (e.g., azathioprine, retinoids, and sulfasalazine) for possible signs of hepatotoxicity. Probenecid Probenecid may reduce renal elimination of methotrexate. Consider alternative drugs. Nitrous Oxide The use of nitrous oxide anesthesia potentiates the effect of methotrexate on folate-dependent metabolic pathways, resulting in the potential for increase toxicity. Avoid the simultaneous use of nitrous oxide and methotrexate. Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), Aspirin, and Steroids Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate levels, resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs and salicylates are administered concomitantly with lower doses of methotrexate, including XATMEP. These drugs have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite the potential interactions, studies of methotrexate in patients with rheumatoid arthritis, including patients with polyarticular juvenile idiopathic arthritis (pJIA), have usually included concurrent use of constant dosage regimens of NSAIDs, without apparent problems. It should be appreciated, however, that the doses used in pJIA (10 mg/m 2 /week as starting dose) are somewhat lower than those used in acute lymphoblastic leukemia and that larger doses could lead to unexpected toxicity. Aspirin, NSAIDs, and/or low dose steroids may be continued, although the possibility of increased toxicity with concomitant use of NSAIDs including salicylates has not been fully explored. Steroids may be reduced gradually in patients who respond to methotrexate. 7.2 Effect of XATMEP on Other Drugs Theophylline Methotrexate may decrease the clearance of theophylline. Monitor theophylline levels when coadministered with XATMEP.

8 USE IN SPECIFIC POPULATIONS Lactation: Advise women not to breastfeed ( 8.2 ). 8.1 Pregnancy Risk Summary Based on published reports and methotrexate’s mechanism of action, methotrexate is a teratogen that can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman [see Data and Clinical Pharmacology ( 12.1 )] . In pregnant women with non-malignant disease, XATMEP is contraindicated. Consider the benefits and risks of XATMEP and risks to the fetus when prescribing XATMEP to a pregnant patient with a neoplastic disease. There are no animal data that meet current standards for nonclinical developmental toxicity studies. The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Human Data Published data from cases, literature reviews, and observational studies report that methotrexate exposure during pregnancy is associated with an increased risk of embryo-fetal toxicity and fetal death. Methotrexate exposure during the first trimester of pregnancy is associated with an increased incidence of spontaneous abortions and multiple adverse developmental outcomes, including skull anomalies, facial dysmorphism, central nervous system abnormalities, limb abnormalities, and sometimes cardiac anomalies and intellectual impairment. Adverse outcomes associated with exposure during second and third trimesters of pregnancy include intrauterine growth restriction and functional abnormalities. Because methotrexate is widely distributed and persists in the body for a prolonged period, there is a potential risk to the fetus from preconception methotrexate exposure. A prospective multicenter study by U.S. and European teratology information services evaluated pregnancy outcomes in women taking methotrexate less than or equal to 30 mg/week after conception. The rate of spontaneous abortion/miscarriage in pregnant women exposed to methotrexate was 42.5% (95% confidence interval [95% CI] 29.2-58.7), which was higher than in unexposed autoimmune disease comparators (22.5%, 95% CI 16.8-29.7) and unexposed nonautoimmune disease comparators (17.3%, 95% CI 13-22.8). Of the live births, the rate of major birth defects in pregnant women exposed to methotrexate after conception was higher than in autoimmune disease comparators (adjusted odds ratio (OR) 1.8 [95% CI 0.6-5.7]) and nonautoimmune disease comparators (adjusted OR 3.1 [95% CI 1.03-9.5]). Major birth defects associated with pregnancies exposed to methotrexate after conception were not always consistent with methotrexate-associated adverse developmental outcomes. 8.2 Lactation Risk Summary Limited published literature report the presence of methotrexate in human milk in low amounts. The highest breast milk to plasma concentration ratio demonstrated was 0.08:1. No information is available on the effects of methotrexate on a breastfed infant or on milk production. Because of the potential for serious adverse reactions, including myelosuppression, from methotrexate in breastfed infants, advise women not to breastfeed during XATMEP therapy. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Test for pregnancy prior to initiating therapy with XATMEP.

milk production. Because of the potential for serious adverse reactions, including myelosuppression, from methotrexate in breastfed infants, advise women not to breastfeed during XATMEP therapy. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Test for pregnancy prior to initiating therapy with XATMEP. Contraception Females XATMEP can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )] . Advise females of reproductive potential to use effective contraception during and for 6 months after the final methotrexate dose. Males Methotrexate can cause chromosomal damage to sperm cells. Advise males with female partners of reproductive potential to use effective contraception during and for at least 3 months after the final methotrexate dose. Infertility Females Based on published reports of female infertility after therapy with methotrexate, advise females of reproductive potential that XATMEP can cause impairment of fertility and menstrual dysfunction during and after cessation of therapy. It is not known if the infertility may be reversed in all affected females. Males Based on published reports of male infertility after therapy with methotrexate, advise males of reproductive potential that XATMEP can cause oligospermia or infertility during and after cessation of therapy. It is not known if the infertility may be reversed in all affected males. 8.4 Pediatric Use Safety and effectiveness of XATMEP in pediatric patients have been established for the treatment of pediatric patients with acute lymphoblastic leukemia (ALL) as part of a multi-phase, combination chemotherapy maintenance regimen and for the management of pediatric patients with active polyarticular juvenile idiopathic arthritis (pJIA) [see Clinical Studies ( 14 )] . 8.6 Renal Impairment Methotrexate elimination is reduced in patients with impaired renal function. Monitor patients with renal impairment for an extended period of time. Consider a dose reduction or, in some cases, discontinue XATMEP administration [see Warnings and Precautions ( 5.3 )] . 8.7 Hepatic Impairment The effect of hepatic impairment on methotrexate pharmacokinetics has not been studied. Patients with hepatic impairment may be more susceptible to hepatotoxicity [see Warnings and Precautions ( 5.5 )] . Consider dose adjustments or alternative treatments in patients with baseline hepatic impairment.

8.1 Pregnancy Risk Summary Based on published reports and methotrexate’s mechanism of action, methotrexate is a teratogen that can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman [see Data and Clinical Pharmacology ( 12.1 )] . In pregnant women with non-malignant disease, XATMEP is contraindicated. Consider the benefits and risks of XATMEP and risks to the fetus when prescribing XATMEP to a pregnant patient with a neoplastic disease. There are no animal data that meet current standards for nonclinical developmental toxicity studies. The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Human Data Published data from cases, literature reviews, and observational studies report that methotrexate exposure during pregnancy is associated with an increased risk of embryo-fetal toxicity and fetal death. Methotrexate exposure during the first trimester of pregnancy is associated with an increased incidence of spontaneous abortions and multiple adverse developmental outcomes, including skull anomalies, facial dysmorphism, central nervous system abnormalities, limb abnormalities, and sometimes cardiac anomalies and intellectual impairment. Adverse outcomes associated with exposure during second and third trimesters of pregnancy include intrauterine growth restriction and functional abnormalities. Because methotrexate is widely distributed and persists in the body for a prolonged period, there is a potential risk to the fetus from preconception methotrexate exposure. A prospective multicenter study by U.S. and European teratology information services evaluated pregnancy outcomes in women taking methotrexate less than or equal to 30 mg/week after conception. The rate of spontaneous abortion/miscarriage in pregnant women exposed to methotrexate was 42.5% (95% confidence interval [95% CI] 29.2-58.7), which was higher than in unexposed autoimmune disease comparators (22.5%, 95% CI 16.8-29.7) and unexposed nonautoimmune disease comparators (17.3%, 95% CI 13-22.8). Of the live births, the rate of major birth defects in pregnant women exposed to methotrexate after conception was higher than in autoimmune disease comparators (adjusted odds ratio (OR) 1.8 [95% CI 0.6-5.7]) and nonautoimmune disease comparators (adjusted OR 3.1 [95% CI 1.03-9.5]). Major birth defects associated with pregnancies exposed to methotrexate after conception were not always consistent with methotrexate-associated adverse developmental outcomes.

Risk Summary Based on published reports and methotrexate’s mechanism of action, methotrexate is a teratogen that can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman [see Data and Clinical Pharmacology ( 12.1 )] . In pregnant women with non-malignant disease, XATMEP is contraindicated. Consider the benefits and risks of XATMEP and risks to the fetus when prescribing XATMEP to a pregnant patient with a neoplastic disease. There are no animal data that meet current standards for nonclinical developmental toxicity studies. The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Risk Summary Limited published literature report the presence of methotrexate in human milk in low amounts. The highest breast milk to plasma concentration ratio demonstrated was 0.08:1. No information is available on the effects of methotrexate on a breastfed infant or on milk production. Because of the potential for serious adverse reactions, including myelosuppression, from methotrexate in breastfed infants, advise women not to breastfeed during XATMEP therapy.

8.4 Pediatric Use Safety and effectiveness of XATMEP in pediatric patients have been established for the treatment of pediatric patients with acute lymphoblastic leukemia (ALL) as part of a multi-phase, combination chemotherapy maintenance regimen and for the management of pediatric patients with active polyarticular juvenile idiopathic arthritis (pJIA) [see Clinical Studies ( 14 )] .

10 OVERDOSAGE Manifestations Fatal overdosage has occurred with methotrexate. Manifestations of overdosage include adverse reactions reported at pharmacologic doses, particularly hematologic and gastrointestinal reactions (e.g., leukopenia, thrombocytopenia, anemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, or gastrointestinal bleeding). In some cases, no symptoms were reported. Management Leucovorin and levoleucovorin are indicated to diminish the toxicity and counteract the effect of inadvertently administered overdosages of methotrexate. Administer leucovorin or levoleucovorin as soon as possible after overdosage (refer to the leucovorin or levoleucovorin Prescribing Information). Monitor serum methotrexate concentrations closely to guide leucovorin or levoleucovorin therapy. Monitor serum creatinine concentrations closely because high serum methotrexate concentrations may cause renal damage leading to acute renal failure. Glucarpidase is indicated for the treatment of toxic methotrexate concentrations in patients with delayed methotrexate clearance due to impaired renal function (refer to the glucarpidase Prescribing Information). If glucarpidase is used, do not administer leucovorin within 2 hours before or after a dose of glucarpidase because leucovorin is a substrate for glucarpidase. In cases of massive overdosage, hydration and urinary alkalinization may be necessary to prevent the precipitation of methotrexate and/or its metabolites in the renal tubules. Neither hemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination. However, effective clearance of methotrexate has been reported with acute, intermittent hemodialysis using a high-flux dialyzer.

11 DESCRIPTION XATMEP contains methotrexate, a folate analog metabolic inhibitor. Chemically methotrexate is N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]-benzoyl]-L-glutamic acid. The structural formula is: XATMEP is a clear yellow to orange oral solution that contains 2.5 mg of methotrexate per milliliter (equivalent to 2.74 mg of methotrexate sodium/mL). Inactive ingredients include purified water, sodium citrate, citric acid, methylparaben sodium, propylparaben sodium, and sucralose. It may also contain sodium hydroxide or hydrochloric acid for pH adjustment. Structural Formula

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Methotrexate inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be utilized as carriers of one-carbon groups in the synthesis of purine nucleotides and thymidylate. Therefore, methotrexate interferes with DNA synthesis, repair, and cellular replication. Actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary bladder are in general more sensitive to this effect of methotrexate. The mechanism of action in pJIA is unknown; it may affect immune function. 12.2 Pharmacodynamics Two reports describe in vitro methotrexate inhibition of DNA precursor uptake by stimulated mono-nuclear cells, and another describes in animal polyarthritis partial correction by methotrexate of spleen cell hyporesponsiveness and suppressed IL 2 production. Other laboratories, however, have been unable to demonstrate similar effects. 12.3 Pharmacokinetics Absorption In pediatric patients with ALL, oral absorption of methotrexate appears to be dose dependent; the absorption of doses greater than 40 mg/m 2 is significantly less than that of lower doses. The extent of oral absorption ranges from 23% to 95%, and the time to peak concentration (T max ) ranges from 0.7 hours to 4 hours after an oral dose of 15 mg/m 2 . In pediatric patients with pJIA, mean serum concentrations were 0.59 micromolar (range, 0.03 to 1.40) at 1 hour, 0.44 micromolar (range, 0.01 to 1.00) at 2 hours, and 0.29 micromolar (range 0.06 to 0.58) at 3 hours following oral administration of methotrexate at a dose of 6.4 mg/m 2 /week to 11.2 mg/m 2 /week. Effect of Food The administration of XATMEP with food did not affect the area under the curve (AUC), but decreased the maximal concentrations (C max ) by 50% and delayed the absorption. Distribution After intravenous administration, the initial volume of distribution is approximately 0.18 L/kg (18% of body weight) and steady-state volume of distribution is approximately 0.4 to 0.8 L/kg (40% to 80% of body weight). Methotrexate competes with reduced folates for active transport across cell membranes by means of a single carrier-mediated active transport process. At serum concentrations greater than 100 micromolar, passive diffusion becomes a major pathway by which effective intracellular concentrations can be achieved. Methotrexate in serum is approximately 50% protein bound. Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given orally. Elimination In adults, the half-life of methotrexate following administration of low dose methotrexate (less than 30 mg/m 2 ) ranges from 3 hours to 10 hours. In pediatric patients receiving methotrexate for ALL (6.3 mg/m 2 to 30 mg/m 2 ), the terminal half-life has been reported to range from 0.7 hours to 5.8 hours. In pediatric patients receiving methotrexate for JIA (3.75 mg/m 2 to 26.2 mg/m 2 ), the terminal half-life has been reported to range from 0.9 hours to 2.3 hours. Metabolism Methotrexate undergoes hepatic and intracellular metabolism to polyglutamated forms which can be converted back to methotrexate by hydrolase enzymes. These polyglutamates act as inhibitors of dihydrofolate reductase and thymidylate synthetase. Small amounts of methotrexate polyglutamates may remain in tissues for extended periods.

undergoes hepatic and intracellular metabolism to polyglutamated forms which can be converted back to methotrexate by hydrolase enzymes. These polyglutamates act as inhibitors of dihydrofolate reductase and thymidylate synthetase. Small amounts of methotrexate polyglutamates may remain in tissues for extended periods. The retention and prolonged drug action of these active metabolites vary among different cells, tissues and tumors. A small amount of metabolism to 7‑hydroxymethotrexate may occur at doses commonly prescribed. The aqueous solubility of 7‑hydroxymethotrexate is 3- to 5-fold lower than the parent compound. Methotrexate is partially metabolized by intestinal flora after oral administration. Excretion Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration. With IV administration, 80% to 90% of the administered dose is excreted unchanged in the urine within 24 hours. There is limited biliary excretion amounting to 10% or less of the administered dose. Enterohepatic recirculation of methotrexate has been proposed. Renal excretion occurs by glomerular filtration and active tubular secretion. Nonlinear elimination due to saturation of renal tubular reabsorption has been observed in patients at doses between 7.5 mg and 30 mg. Impaired renal function, as well as concurrent use of drugs such as weak organic acids that also undergo tubular secretion, can markedly increase methotrexate serum levels. Methotrexate clearance decreases at higher doses. Delayed drug clearance has been identified as one of the major factors responsible for methotrexate toxicity. When a patient has delayed drug elimination due to compromised renal function, a third-space effusion, or other causes, methotrexate serum concentrations may remain elevated for prolonged periods.

12.1 Mechanism of Action Methotrexate inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be utilized as carriers of one-carbon groups in the synthesis of purine nucleotides and thymidylate. Therefore, methotrexate interferes with DNA synthesis, repair, and cellular replication. Actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary bladder are in general more sensitive to this effect of methotrexate. The mechanism of action in pJIA is unknown; it may affect immune function.

12.2 Pharmacodynamics Two reports describe in vitro methotrexate inhibition of DNA precursor uptake by stimulated mono-nuclear cells, and another describes in animal polyarthritis partial correction by methotrexate of spleen cell hyporesponsiveness and suppressed IL 2 production. Other laboratories, however, have been unable to demonstrate similar effects.

12.3 Pharmacokinetics Absorption In pediatric patients with ALL, oral absorption of methotrexate appears to be dose dependent; the absorption of doses greater than 40 mg/m 2 is significantly less than that of lower doses. The extent of oral absorption ranges from 23% to 95%, and the time to peak concentration (T max ) ranges from 0.7 hours to 4 hours after an oral dose of 15 mg/m 2 . In pediatric patients with pJIA, mean serum concentrations were 0.59 micromolar (range, 0.03 to 1.40) at 1 hour, 0.44 micromolar (range, 0.01 to 1.00) at 2 hours, and 0.29 micromolar (range 0.06 to 0.58) at 3 hours following oral administration of methotrexate at a dose of 6.4 mg/m 2 /week to 11.2 mg/m 2 /week. Effect of Food The administration of XATMEP with food did not affect the area under the curve (AUC), but decreased the maximal concentrations (C max ) by 50% and delayed the absorption. Distribution After intravenous administration, the initial volume of distribution is approximately 0.18 L/kg (18% of body weight) and steady-state volume of distribution is approximately 0.4 to 0.8 L/kg (40% to 80% of body weight). Methotrexate competes with reduced folates for active transport across cell membranes by means of a single carrier-mediated active transport process. At serum concentrations greater than 100 micromolar, passive diffusion becomes a major pathway by which effective intracellular concentrations can be achieved. Methotrexate in serum is approximately 50% protein bound. Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given orally. Elimination In adults, the half-life of methotrexate following administration of low dose methotrexate (less than 30 mg/m 2 ) ranges from 3 hours to 10 hours. In pediatric patients receiving methotrexate for ALL (6.3 mg/m 2 to 30 mg/m 2 ), the terminal half-life has been reported to range from 0.7 hours to 5.8 hours. In pediatric patients receiving methotrexate for JIA (3.75 mg/m 2 to 26.2 mg/m 2 ), the terminal half-life has been reported to range from 0.9 hours to 2.3 hours. Metabolism Methotrexate undergoes hepatic and intracellular metabolism to polyglutamated forms which can be converted back to methotrexate by hydrolase enzymes. These polyglutamates act as inhibitors of dihydrofolate reductase and thymidylate synthetase. Small amounts of methotrexate polyglutamates may remain in tissues for extended periods. The retention and prolonged drug action of these active metabolites vary among different cells, tissues and tumors. A small amount of metabolism to 7‑hydroxymethotrexate may occur at doses commonly prescribed. The aqueous solubility of 7‑hydroxymethotrexate is 3- to 5-fold lower than the parent compound. Methotrexate is partially metabolized by intestinal flora after oral administration. Excretion Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration. With IV administration, 80% to 90% of the administered dose is excreted unchanged in the urine within 24 hours. There is limited biliary excretion amounting to 10% or less of the administered dose. Enterohepatic recirculation of methotrexate has been proposed. Renal excretion occurs by glomerular filtration and active tubular secretion. Nonlinear elimination due to saturation of renal tubular reabsorption has been observed in patients at doses between 7.5 mg and 30 mg.

ing to 10% or less of the administered dose. Enterohepatic recirculation of methotrexate has been proposed. Renal excretion occurs by glomerular filtration and active tubular secretion. Nonlinear elimination due to saturation of renal tubular reabsorption has been observed in patients at doses between 7.5 mg and 30 mg. Impaired renal function, as well as concurrent use of drugs such as weak organic acids that also undergo tubular secretion, can markedly increase methotrexate serum levels. Methotrexate clearance decreases at higher doses. Delayed drug clearance has been identified as one of the major factors responsible for methotrexate toxicity. When a patient has delayed drug elimination due to compromised renal function, a third-space effusion, or other causes, methotrexate serum concentrations may remain elevated for prolonged periods.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Methotrexate has been evaluated in a number of animal studies for carcinogenic potential with inconclusive results. Although there is evidence that methotrexate causes chromosomal damage to animal somatic cells and human bone marrow cells, the clinical significance remains uncertain.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Methotrexate has been evaluated in a number of animal studies for carcinogenic potential with inconclusive results. Although there is evidence that methotrexate causes chromosomal damage to animal somatic cells and human bone marrow cells, the clinical significance remains uncertain.

14 CLINICAL STUDIES Polyarticular Juvenile Idiopathic Arthritis Clinical trials in patients with polyarticular juvenile idiopathic arthritis were performed using other formulations of methotrexate. In a 6-month, double-blind, placebo-controlled trial of 127 pediatric patients with juvenile idiopathic arthritis (JIA) (mean age, 10.1 years; age range 2.5 to 18 years, mean duration of disease, 5.1 years) on background non-steroidal anti-inflammatory drugs (NSAIDs) and/or prednisone, methotrexate given one time weekly at an oral dose of 10 mg/m 2 provided significant clinical improvement compared to placebo as measured by either the physician’s global assessment, or by a patient composite (25% reduction in the articular-severity score plus improvement in parent and physician global assessments of disease activity). Over two-thirds of the patients in this trial had polyarticular-course JIA, and the numerically greatest response was seen in this subgroup treated with 10 mg/m 2 /week methotrexate. The overwhelming majority of the remaining patients had systemic-course JIA. All patients were unresponsive to NSAIDs; approximately one-third were using low dose corticosteroids. Weekly methotrexate at a dose of 5 mg/m 2 was not significantly more effective than placebo in this trial.

16 HOW SUPPLIED/STORAGE AND HANDLING XATMEP is a clear yellow to orange oral solution that contains 2.5 mg of methotrexate per milliliter (equivalent to 2.74 mg of methotrexate sodium/mL). It is packaged in a high-density polyethylene (HDPE) bottle with a child-resistant cap and tamper-evident seal. XATMEP is available in bottles of 60 mL (NDC 52652-2001-6) and 120 mL (NDC 52652-2001-1). Store XATMEP refrigerated (2°C to 8°C/36°F to 46°F) tightly closed in the original container prior to dispensing. Once dispensed, patients may store XATMEP either refrigerated (2°C to 8°C/36°F to 46°F) or at room temperature (20°C to 25°C/68°F to 77°F) with excursions permitted to 15°C to 30°C/59°F to 86°F [see USP Controlled Room Temperature]. If stored at room temperature, discard after 60 days. Avoid freezing and excessive heat.

17 PATIENT COUNSELING INFORMATION Importance of Proper Dosing and Administration Advise patients that the recommended dose should be taken one time weekly, as directed, and that mistaken daily use of the recommended dose has led to fatal toxicity [see Dosage and Administration ( 2.1 ), Warnings and Precautions ( 5.15 )] . Advise patients and caregivers to measure XATMEP with an accurate milliliter measuring device. A household teaspoon is not an accurate measuring device. Advise patients and caregivers to ask their pharmacist to recommend an appropriate measuring device and for instructions for measuring the correct dose. Bone Marrow Suppression and Serious Infections Advise patients to contact their healthcare provider for new onset fever, symptoms of infection, easy bruising or persistent bleeding [see Warnings and Precautions ( 5.1 , 5.2 )] . Renal Toxicity Advise patients that methotrexate can cause renal toxicity [see Warnings and Precautions ( 5.3 )] . Gastrointestinal Toxicity Advise patients to contact their healthcare provider if they develop diarrhea, vomiting, or stomatitis [see Warnings and Precautions ( 5.4 )] . Hepatic Toxicity Advise patients concerning the risk of hepatic toxicity and avoidance of alcohol during methotrexate treatment [see Warnings and Precautions ( 5.5 )] . Pulmonary Toxicity Advise patients to contact their healthcare provider for symptoms of cough, fever, and dyspnea [see Warnings and Precautions ( 5.6 )] . Hypersensitivity Reactions Advise patients concerning the risk for severe hypersensitivity reactions due to XATMEP treatment. These can be fatal and may include severe dermatologic reactions such as toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, and erythema multiforme. Advise patients to contact their healthcare provider for signs of a new or worsening rash [see Warnings and Precautions ( 5.7 )] . Secondary Malignancies Advise patients that there is a risk of secondary malignancies during or following treatment with XATMEP [see Warnings and Precautions ( 5.8 )] . Embryo-Fetal Toxicity Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Boxed Warning , Contraindications ( 4 ), Warnings and Precautions ( 5.9 ), Use in Specific Populations ( 8.1 )] . Advise females of reproductive potential to use effective contraception during XATMEP therapy and for 6 months after the final dose [see Use in Specific Populations ( 8.3 )] . Advise males of reproductive potential to use effective contraception during XATMEP therapy and for 3 months after the final dose [see Use in Specific Populations ( 8.3 )] . Ineffective Immunization and Risks Associated with Live Vaccines Advise patients to avoid receiving vaccines during treatment with XATMEP because they may not be effective and live virus vaccines may cause infection [see Warnings and Precautions ( 5.10 )] . Infertility Advise patients of reproductive potential that XATMEP may cause impairment of fertility, oligospermia, and menstrual dysfunction [see Warnings and Precautions ( 5.11 ), Use in Specific Populations ( 8.3 )] . Lactation Advise females not to breastfeed during therapy with XATMEP [see Use in Specific Populations ( 8.2 )] .

dvise patients of reproductive potential that XATMEP may cause impairment of fertility, oligospermia, and menstrual dysfunction [see Warnings and Precautions ( 5.11 ), Use in Specific Populations ( 8.3 )] . Lactation Advise females not to breastfeed during therapy with XATMEP [see Use in Specific Populations ( 8.2 )] . Proper Storage and Disposal Advise patients to store XATMEP either refrigerated (2°C to 8°C/36°F to 46°F) or at room temperature (20°C to 25°C/68°F to 77°F) with excursions permitted to 15°C to 30°C/59°F to 86°F. If stored at room temperature, discard after 60 days. Inform patients and caregivers of the need for proper storage and disposal of dispensing bottles and dosing devices [see References ( 15 )] .

Manufactured for: Azurity Pharmaceuticals, Inc. Wilmington, MA 01887 USA U.S. Patent: 9,259,427; 9,855,215 This product’s label may have been updated. For current full prescribing information, please visit www.xatmep.com PI100072.03 Rev. 9/2020