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<table ID="ID281" width="590" styleCode="Noautorules"><col width="481"/><col width="109"/><tbody><tr><td colspan="2" align="left" valign="top">Warnings and Precautions </td></tr><tr><td align="left" valign="top">Immunosuppression and Increased Risk of Infection ( <linkHtml href="#ID102">5.3</linkHtml>) </td><td align="right" valign="top">06/2024 </td></tr><tr><td align="left" valign="top">Kaposi&apos;s Sarcoma ( <linkHtml href="#ID274">5.4</linkHtml>) </td><td align="right" valign="top">06/2024 </td></tr></tbody></table>

1 INDICATIONS AND USAGE Budesonide delayed-release capsules are corticosteroid indicated for: Treatment of mild to moderate active Crohn's disease involving the ileum and/or the ascending colon, in patients 8 years and older. ( 1.1 ) Maintenance of clinical remission of mild to moderate Crohn's disease involving the ileum and/or the ascending colon for up to 3 months in adults. ( 1.2 ) 1.1 Treatment of Mild to Moderate Active Crohn’s Disease Budesonide delayed-release capsules are indicated for the treatment of mild to moderate active Crohn's disease involving the ileum and/or the ascending colon in patients 8 years of age and older. 1.2 Maintenance of Clinical Remission of Mild to Moderate Crohn’s Disease Budesonide delayed-release capsules are indicated for the maintenance of clinical remission of mild to moderate Crohn's disease involving the ileum and/or the ascending colon for up to 3 months in adults.

2 DOSAGE AND ADMINISTRATION Administration Instructions ( 2.1 ) Take once daily in the morning. Swallow whole. Do not chew or crush. For patients unable to swallow an intact capsule, open the capsules and empty the granules onto one tablespoonful of applesauce. Mix and consume the entire contents within 30 minutes. Do not chew or crush. Follow with 8 ounces of water. Avoid consumption of grapefruit juice for the duration of therapy. Recommended Dosage Mild to moderate active Crohn's disease ( 2.2 ) Adults: 9 mg once daily for up to 8 weeks; repeat 8 week treatment courses for recurring episodes of active disease. Pediatrics 8 to 17 years who weigh more than 25 kg: 9 mg once daily for up to 8 weeks, followed by 6 mg once daily in the morning for 2 weeks. Maintenance of clinical remission of mild to moderate Crohn's disease ( 2.3 ) Adults: 6 mg once daily for up to 3 months; taper to complete cessation after 3 months. Continued treatment for more than 3 months has not been shown to provide substantial clinical benefit. When switching from oral prednisolone, begin tapering prednisolone concomitantly with initiating budesonide delayed-release capsules. Hepatic Impairment Consider reducing the dosage to 3 mg once daily in adult patients with moderate hepatic impairment (Child-Pugh Class B). ( 2.4 , 5.1 , 8.6 ) 2.1 Administration Instructions Take budesonide delayed-release capsules once daily in the morning. Swallow budesonide delayed-release capsules whole. Do not chew or crush. For patients unable to swallow an intact capsule, budesonide delayed-release capsules can be opened and administered as follows: Place one tablespoonful of applesauce into a clean container (e.g., empty bowl). The applesauce used should not be hot and should be soft enough to be swallowed without chewing. Open the capsule(s). Carefully empty all the granules inside the capsule(s) on the applesauce. Mix the granules with the applesauce. Consume the entire contents within 30 minutes of mixing. Do not chew or crush the granules. Do not save the applesauce and granules for future use. Follow the applesauce and granules immediately with a glass (8 ounces) of cool water to ensure complete swallowing of the granules. Avoid consumption of grapefruit juice for the duration of budesonide delayed-release capsules therapy [see Drug Interactions ( 7.1 )]. 2.2 Treatment of Mild to Moderate Active Crohn’s Disease The recommended dosage of budesonide delayed-release capsules is: Adults 9 mg orally once daily for up to 8 weeks. Repeated 8 week courses of budesonide delayed-release capsules can be given for recurring episodes of active disease. Pediatric patients 8 to 17 years who weigh more than 25 kg 9 mg orally once daily for up to 8 weeks, followed by 6 mg once daily for 2 weeks. 2.3 Maintenance of Clinical Remission of Mild to Moderate Crohn’s Disease The recommended dosage in adults, following an 8 week course(s) of treatment for active disease and once the patient's symptoms are controlled (CDAI less than 150), is budesonide delayed-release capsules 6 mg orally once daily for maintenance of clinical remission up to 3 months. If symptom control is still maintained at 3 months an attempt to taper to complete cessation is recommended. Continued treatment with budesonide delayed-release capsules 6 mg for more than 3 months has not been shown to provide substantial clinical benefit.

ce daily for maintenance of clinical remission up to 3 months. If symptom control is still maintained at 3 months an attempt to taper to complete cessation is recommended. Continued treatment with budesonide delayed-release capsules 6 mg for more than 3 months has not been shown to provide substantial clinical benefit. Patients with mild to moderate active Crohn's disease involving the ileum and/or ascending colon have been switched from oral prednisolone to budesonide delayed-release capsules with no reported episodes of adrenal insufficiency. Since prednisolone should not be stopped abruptly, tapering should begin concomitantly with initiating budesonide delayed-release capsules treatment. 2.4 Dosage Adjustment in Adult Patients with Hepatic Impairment Consider reducing the dosage of budesonide delayed-release capsules to 3 mg once daily for adult patients with moderate hepatic impairment (Child-Pugh Class B). Avoid use in patients with severe hepatic impairment (Child-Pugh Class C) [see Warnings and Precautions ( 5.1 ), Use in Specific Populations ( 8.6 )] .

3 DOSAGE FORMS AND STRENGTHS Delayed-Release Capsules: 3 mg ( 3 ) Budesonide Delayed-Release Capsules, 3 mg are white to off-white, free flowing pellets, filled in size '1' hard gelatin capsules having opaque light-orange colored cap printed with "720" in black ink and opaque white body.

4 CONTRAINDICATIONS Hypersensitivity to budesonide or any of the ingredients in budesonide delayed-release capsules. ( 4 ) Budesonide delayed-release capsules are contraindicated in patients with hypersensitivity to budesonide or any of the ingredients of budesonide delayed-release capsules. Serious hypersensitivity reactions, including anaphylaxis have occurred [see Adverse Reactions ( 6.2 )].

5 WARNINGS AND PRECAUTIONS Hypercorticism and Adrenal Axis Suppression : May occur with treatment; monitor for signs and symptoms; pediatrics and patients with hepatic impairment may be at increased risk. ( 2.4 , 5.1 , 8.4 , 8.6 ) Symptoms of Steroid Withdrawal in Patients Transferred from Other Systemic Corticosteroids : Taper slowly from corticosteroids with high systemic effects; monitor for withdrawal symptoms and unmasking of allergies (rhinitis, eczema). ( 5.2 ) Immunosuppression and Increased Risk of Infection : Increased risk of viral, bacterial, fungal, protozoal and helminthic infections, including potentially fatal varicella and measles infection. Monitor patients for new or worsening infection and consider drug discontinuation. Avoid use in patients with fungal infections, Strongyloides infestation, cerebral malaria and ocular herpes simplex. Screen for hepatitis B infection. ( 5.3 ) Karposi's Sarcoma : Reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. ( 5.4 ) Other Corticosteroid Effects : Monitor patients with concomitant conditions where corticosteroids may have unwanted effects (e.g., hypertension, diabetes mellitus). ( 5.5 ) 5.1 Hypercorticism and Adrenal Axis Suppression Systemic effects such as hypercorticism and adrenal axis suppression may occur with use of corticosteroids, including budesonide delayed-release capsules [see Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.2 )] . Pediatric patients with Crohn's disease have a slightly higher systemic exposure of budesonide and increased cortisol suppression than adults with Crohn's disease [see Use in Specific Populations ( 8.4 ), Clinical Pharmacology ( 12.2 )] . Monitor patients for signs and symptoms of hypercorticism and adrenal axis suppression during treatment with budesonide delayed-release capsules. Patients with moderate to severe hepatic impairment (Child-Pugh Class B and C respectively) could be at an increased risk of hypercorticism and adrenal axis suppression due to an increased systemic exposure of oral budesonide. Avoid use in patients with severe hepatic impairment (Child-Pugh Class C). Monitor for increased signs and/or symptoms of hypercorticism and consider reducing the dosage in patients with moderate hepatic impairment (Child-Pugh Class B) [see Dosage and Administration ( 2.4 ), Use in Specific Populations ( 8.6 ), Clinical Pharmacology ( 12.3 )] . Corticosteroids, including budesonide delayed-release capsules, can reduce the response of the hypothalamus-pituitary-adrenal (HPA) axis to stress. In situations where patients are subject to surgery or other stress situations, supplementation with a systemic corticosteroid is recommended. 5.2 Symptoms of Steroid Withdrawal in Patients Transferred from Other Systemic Corticosteroids Monitor patients who are transferred from corticosteroid treatment with high systemic effects to corticosteroids with lower systemic availability, such as budesonide delayed-release capsules, since symptoms attributed to withdrawal of steroid therapy, including those of acute adrenal axis suppression or benign intracranial hypertension, may develop. Adrenocortical function monitoring may be required in these patients and the dose of corticosteroid treatment with high systemic effects should be reduced cautiously.

symptoms attributed to withdrawal of steroid therapy, including those of acute adrenal axis suppression or benign intracranial hypertension, may develop. Adrenocortical function monitoring may be required in these patients and the dose of corticosteroid treatment with high systemic effects should be reduced cautiously. Replacement of systemic corticosteroids with budesonide delayed-release capsules may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug. 5.3 Immunosuppression and Increased Risk of Infection Corticosteroids, including budesonide delayed-release capsules, suppress the immune system and increase the risk of infection with any pathogen, including viral, bacterial, fungal, protozoan, or helminthic pathogens. Corticosteroids can: Reduce resistance to new infections Exacerbate existing infections Increase the risk of disseminated infections Increase the risk of reactivation or exacerbation of latent infections Mask some signs of infection Corticosteroid-associated infections can be mild but can be severe and at times fatal. The rate of infectious complications increases with increasing corticosteroid dosages. Monitor patients for the development of infection and consider discontinuation of budesonide delayed-release capsules if the patient develops an infection while on treatment. Tuberculosis If budesonide delayed-release capsules is used in patients with latent tuberculosis or tuberculin reactivity, reactivation of tuberculosis may occur. Closely monitor such patients for reactivation. During prolonged budesonide delayed-release capsules therapy, patients with latent tuberculosis or tuberculin reactivity should receive chemoprophylaxis. Varicella Zoster and Measles Viral Infections Varicella and measles can have a serious or even fatal course in non-immune pediatric and adult patients taking corticosteroids, including budesonide delayed-release capsules. In corticosteroid-treated patients who have not had these diseases or are non-immune, particular care should be taken to avoid exposure to varicella and measles: If a budesonide delayed-release capsules-treated patient is exposed to varicella, prophylaxis with varicella zoster immune globulin may be indicated. If varicella develops, treatment with antiviral agents may be considered. If a budesonide delayed-release capsules-treated patient is exposed to measles, prophylaxis with immunoglobulin may be indicated. Hepatitis B Virus Reactivation Hepatitis B virus reactivation can occur in patients who are hepatitis B carriers treated with immunosuppressive dosages of corticosteroids, including budesonide delayed-release capsules. Reactivation can also occur infrequently in corticosteroid-treated patients who appear to have resolved hepatitis B infection. Screen patients for hepatitis B infection before initiating immunosuppressive (e.g., prolonged) treatment with budesonide delayed-release capsules. For patients who show evidence of hepatitis B infection, recommend consultation with physicians with expertise in managing hepatitis B regarding monitoring and consideration for hepatitis B antiviral therapy. Fungal Infections Corticosteroids, including budesonide delayed-release capsules, may exacerbate systemic fungal infections; therefore, avoid budesonide delayed-release capsules use in the presence of such infections. For patients on chronic budesonide delayed-release capsules therapy who develop systemic fungal infections, budesonide delayed-release capsules withdrawal or dosage reduction is recommended. Amebiasis Corticosteroids, including budesonide delayed-release capsules, may activate latent amebiasis.

ence of such infections. For patients on chronic budesonide delayed-release capsules therapy who develop systemic fungal infections, budesonide delayed-release capsules withdrawal or dosage reduction is recommended. Amebiasis Corticosteroids, including budesonide delayed-release capsules, may activate latent amebiasis. Therefore, it is recommended that latent amebiasis or active amebiasis be ruled out before initiating budesonide delayed-release capsules in patients who have spent time in the tropics or patients with unexplained diarrhea. Strongyloides Infestation Avoid budesonide delayed-release capsules in patients with known or suspected Strongyloides (threadworm) infection. Corticosteroid-induced immunosuppression may lead to Strongyloides superinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia. Cerebral Malaria Avoid corticosteroids, including budesonide delayed-release capsules, in patients with cerebral malaria. Ocular Herpes Simplex Avoid corticosteroids, including budesonide delayed-release capsules, in patients with active ocular herpes simplex. 5.4 Kaposi’s Sarcoma Kaposi's sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement of Kaposi's sarcoma. 5.5 Other Corticosteroid Effects Monitor patients with hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or with any other condition where corticosteroids may have unwanted effects.

6 ADVERSE REACTIONS Most common adverse reactions (≥ 5%) in adults are: headache, respiratory infection, nausea, back pain, dyspepsia, dizziness, abdominal pain, flatulence, vomiting, fatigue and pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Northstar Rx LLC at 1-800-206-7821 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following clinically significant adverse reactions are described elsewhere in labeling: Hypercorticism and adrenal axis suppression [see Warnings and Precautions (5.1 )] Symptoms of steroid withdrawal in those patients transferred from other systemic corticosteroids [see Warnings and Precautions ( 5.2 )] Immunosuppression and increased risk of infection [see Warnings and Precautions ( 5.3 )] Kaposi's sarcoma [see Warnings and Precautions ( 5.4 )] Other corticosteroid effects [see Warnings and Precautions ( 5.5 )] 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. Adults The data described below reflect exposure to budesonide delayed-release capsules in 520 patients with Crohn's disease, including 520 exposed to 9 mg per day (total daily dose) for 8 weeks and 145 exposed to 6 mg per day for one year in placebo controlled clinical trials. Of the 520 patients, 38% were males and the age range was 17 to 74 years. Treatment of Mild to Moderate Active Crohn's Disease The safety of budesonide delayed-release capsules was evaluated in 651 adult patients in five clinical trials of 8 weeks duration in patients with active mild to moderate Crohn's disease. The most common adverse reactions, occurring in greater than or equal to 5% of the patients, are listed in Table 1. Table 1 Common Adverse Reactions 1 in 8-Week Treatment Clinical Trials 1 Occurring in greater than or equal to 5% of the patients in any treated group. 2 Prednisolone tapering scheme: either 40 mg in week 1 to 2, thereafter tapering with 5 mg per week; or 40 mg in week 1 to 2, 30 mg in week 3 to 4, thereafter tapering with 5 mg per week. 3 This drug is not approved for the treatment of Crohn's disease in the United States. Adverse Reaction Budesonide Delayed-Release Capsules 9 mg n=520 Number (%) Placebo n=107 Number (%) Prednisolone 2 40 mg n=145 Number (%) Comparator 3 n=88 Number (%) Headache 107(21) 19(18) 31(21) 11(13) Respiratory Infection 55(11) 7(7) 20(14) 5(6) Nausea 57(11) 10(9) 18(12) 7(8) Back Pain 36(7) 10(9) 17(12) 5(6) Dyspepsia 31(6) 4(4) 17(12) 3(3) Dizziness 38(7) 5(5) 18(12) 5(6) Abdominal Pain 32(6) 18(17) 6(4) 10(11) Flatulence 30(6) 6(6) 12(8) 5(6) Vomiting 29(6) 6(6) 6(4) 6(7) Fatigue 25(5) 8(7) 11(8) 0(0) Pain 24(5) 8(7) 17(12) 2(2) The incidence of signs and symptoms of hypercorticism reported by active questioning of patients in 4 of the 5 short-term clinical trials are displayed in Table 2. Table 2 Summary and Incidence of Signs/Symptoms of Hypercorticism in 8-Week Treatment Clinical Trials 1 Prednisolone tapering scheme: either 40 mg in week 1 to 2, thereafter tapering with 5 mg/week; or 40 mg in week 1 to 2, 30 mg in week 3 to 4, thereafter tapering with 5 mg/week. 2 Statistically significantly different from budesonide delayed-release capsules 9 mg. 3 including hair growth increased, local and hair growth increased, general.

scheme: either 40 mg in week 1 to 2, thereafter tapering with 5 mg/week; or 40 mg in week 1 to 2, 30 mg in week 3 to 4, thereafter tapering with 5 mg/week. 2 Statistically significantly different from budesonide delayed-release capsules 9 mg. 3 including hair growth increased, local and hair growth increased, general. Budesonide Delayed-Release Capsules 9 mg n=427 Placebo n=107 Prednisolone 1 40 mg n=145 Signs/Symptom Number (%) Number (%) Number (%) Total 145 (34%) 29 (27%) 69 (48%) Acne 63(15) 14(13) 33(23) 2 Bruising Easily 63(15) 12(11) 13(9) Moon Face 46(11) 4(4) 53(37) 2 Swollen Ankles 32(7) 6(6) 13(9) Hirsutism 3 22(5) 2(2) 5(3) Buffalo hump 6(1) 2(2) 5(3) Skin Striae 4(1) 2(2) 0(0) Maintenance of Clinical Remission of Mild to Moderate Crohn's Disease The safety of budesonide delayed-release capsules was evaluated in 233 adult patients in four long-term clinical trials (52 weeks) of maintenance of clinical remission in patients with mild to moderate Crohn's disease. A total of 145 patients were treated with budesonide delayed-release capsules 6 mg once daily. The adverse reaction profile of budesonide delayed-release capsules 6 mg once daily in maintenance of Crohn's disease was similar to that of short-term treatment with budesonide delayed-release capsules 9 mg once daily in active Crohn's disease. In the long-term clinical trials, the following adverse reactions occurred in greater than or equal to 5% and are not listed in Table 1: diarrhea (10%); sinusitis (8%); infection viral (6%); and arthralgia (5%). Signs/symptoms of hypercorticism reported by active questioning of patients in the long-term maintenance clinical trials are displayed in Table 3. Table 3 Summary and Incidence of Signs/Symptoms of Hypercorticism in Long-Term Clinical Trials Budesonide Delayed-Release Capsules 3 mg n=88 Budesonide Delayed-release Capsules 6 mg n=145 Placebo n=143 Signs/Symptom Number (%) Number (%) Number (%) Bruising easily 4(5) 15(10) 5(4) Acne 4(5) 14(10) 3(2) Moon face 3(3) 6(4) 0 Hirsutism 2(2) 5(3) 1(1) Swollen ankles 2(2) 3(2) 3(2) Buffalo hump 1(1) 1(1) 0 Skin striae 2(2) 0 0 The incidence of signs/symptoms of hypercorticism as described above in long-term maintenance clinical trials was similar to that seen in the short-term treatment clinical trials.

4(5) 14(10) 3(2) Moon face 3(3) 6(4) 0 Hirsutism 2(2) 5(3) 1(1) Swollen ankles 2(2) 3(2) 3(2) Buffalo hump 1(1) 1(1) 0 Skin striae 2(2) 0 0 The incidence of signs/symptoms of hypercorticism as described above in long-term maintenance clinical trials was similar to that seen in the short-term treatment clinical trials. Less Common Adverse Reactions in Treatment and Maintenance Clinical Trials Less common adverse reactions (less than 5%), occurring in adult patients treated with budesonide delayed-release capsules 9 mg (total daily dose) in short-term treatment clinical studies and/or budesonide delayed-release capsules 6 mg (total daily dose) in long-term maintenance clinical trials, with an incidence are listed below by system organ class: Cardiac disorders: palpitation, tachycardia Eye disorders: eye abnormality, vision abnormal General disorders and administration site conditions: asthenia, chest pain, dependent edema, face edema, flu-like disorder, malaise, fever Gastrointestinal disorders: anus disorder, enteritis, epigastric pain, gastrointestinal fistula, glossitis, hemorrhoids, intestinal obstruction, tongue edema, tooth disorder Infections and infestations: Ear infection - not otherwise specified, bronchitis, abscess, rhinitis, urinary tract infection, thrush Investigations: weight increased Metabolism and nutrition disorders: appetite increased Musculoskeletal and connective tissue disorders: arthritis, cramps, myalgia Nervous system disorders: hyperkinesia, paresthesia, tremor, vertigo, somnolence, amnesia Psychiatric disorders: agitation, confusion, insomnia, nervousness, sleep disorder Renal and urinary disorders: dysuria, micturition frequency, nocturia Reproductive system and breast disorders: intermenstrual bleeding, menstrual disorder Respiratory, thoracic and mediastinal disorders: dyspnea, pharynx disorder Skin and subcutaneous tissue disorders: alopecia, dermatitis, eczema, skin disorder, sweating increased, purpura Vascular disorders: flushing, hypertension Bone Mineral Density A randomized, open, parallel-group multicenter safety clinical trial specifically compared the effect of budesonide delayed-release capsules (less than 9 mg per day) and prednisolone (less than 40 mg per day) on bone mineral density over 2 years when used at doses adjusted to disease severity. Bone mineral density decreased significantly less with budesonide delayed-release capsules than with prednisolone in steroid-naïve patients, whereas no difference could be detected between treatment groups for steroid-dependent patients and previous steroid users. The incidence of symptoms associated with hypercorticism was significantly higher with prednisolone treatment. Clinical Laboratory Test Findings The following potentially clinically significant laboratory changes in clinical trials, irrespective of relationship to budesonide delayed-release capsules, were reported in greater than or equal to 1% of patients: hypokalemia, leukocytosis, anemia, hematuria, pyuria, erythrocyte sedimentation rate increased, alkaline phosphatase increased, atypical neutrophils, c-reactive protein increased and adrenal insufficiency. Pediatrics-Treatment of Mild to Moderate Active Crohn's Disease Adverse reactions reported in pediatric patients 8 to 17 years of age, who weigh more than 25 kg, were similar to those reactions described above in adult patients. 6.2 Postmarketing Experience The following adverse reactions have been reported during post-approval use of budesonide delayed-release capsules. 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.

ce The following adverse reactions have been reported during post-approval use of budesonide delayed-release capsules. 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. Immune System Disorders: Anaphylactic reactions Nervous System Disorders: Benign intracranial hypertension Psychiatric Disorders: Mood swings

<table ID="ID114" width="105%" styleCode="Noautorules"><caption>Table 1 Common Adverse Reactions ¹in 8-Week Treatment Clinical Trials </caption><col width="20%"/><col width="21%"/><col width="16%"/><col width="20%"/><col width="21%"/><tfoot><tr><td align="left" colspan="5"><paragraph styleCode="Footnote">¹Occurring in greater than or equal to 5% of the patients in any treated group. </paragraph></td></tr><tr><td align="left" colspan="5"><paragraph styleCode="Footnote">²Prednisolone tapering scheme: either 40 mg in week 1 to 2, thereafter tapering with 5 mg per week; or 40 mg in week 1 to 2, 30 mg in week 3 to 4, thereafter tapering with 5 mg per week. </paragraph></td></tr><tr><td align="left" colspan="5"><paragraph styleCode="Footnote">³This drug is not approved for the treatment of Crohn&apos;s disease in the United States.

o 2, thereafter tapering with 5 mg per week; or 40 mg in week 1 to 2, 30 mg in week 3 to 4, thereafter tapering with 5 mg per week. </paragraph></td></tr><tr><td align="left" colspan="5"><paragraph styleCode="Footnote">³This drug is not approved for the treatment of Crohn&apos;s disease in the United States. </paragraph></td></tr></tfoot><tbody><tr><td align="left" styleCode="Lrule Toprule Botrule Rrule" valign="bottom"><content styleCode="bold">Adverse Reaction</content> </td><td align="center" styleCode=" Toprule Botrule Rrule" valign="top"><content styleCode="bold">Budesonide Delayed-Release Capsules</content> <content styleCode="bold">9 mg</content> <content styleCode="bold">n=520</content> <content styleCode="bold">Number (%)</content> </td><td align="center" styleCode=" Toprule Botrule Rrule" valign="top"><content styleCode="bold">Placebo</content> <content styleCode="bold">n=107</content> <content styleCode="bold">Number (%)</content> </td><td align="center" styleCode=" Toprule Botrule Rrule" valign="top"><content styleCode="bold">Prednisolone ²</content> <content styleCode="bold">40 mg</content> <content styleCode="bold">n=145</content> <content styleCode="bold">Number (%)</content> </td><td align="center" styleCode=" Toprule Botrule Rrule" valign="top"><content styleCode="bold">Comparator ³</content> <content styleCode="bold">n=88</content> <content styleCode="bold">Number (%)</content> </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Headache </td><td align="center" styleCode=" Botrule Rrule" valign="top">107(21) </td><td align="center" styleCode=" Botrule Rrule" valign="top">19(18) </td><td align="center" styleCode=" Botrule Rrule" valign="top">31(21) </td><td align="center" styleCode=" Botrule Rrule" valign="top">11(13) </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Respiratory Infection </td><td align="center" styleCode=" Botrule Rrule" valign="top">55(11) </td><td align="center" styleCode=" Botrule Rrule" valign="top">7(7) </td><td align="center" styleCode=" Botrule Rrule" valign="top">20(14) </td><td align="center" styleCode=" Botrule Rrule" valign="top">5(6) </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Nausea </td><td align="center" styleCode=" Botrule Rrule" valign="top">57(11) </td><td align="center" styleCode=" Botrule Rrule" valign="top">10(9) </td><td align="center" styleCode=" Botrule Rrule" valign="top">18(12) </td><td align="center" styleCode=" Botrule Rrule" valign="top">7(8) </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Back Pain </td><td align="center" styleCode=" Botrule Rrule">36(7) </td><td align="center" styleCode=" Botrule Rrule">10(9) </td><td align="center" styleCode=" Botrule Rrule">17(12) </td><td align="center" styleCode=" Botrule Rrule">5(6) </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Dyspepsia </td><td align="center" styleCode=" Botrule Rrule">31(6) </td><td align="center" styleCode=" Botrule Rrule">4(4) </td><td align="center" styleCode=" Botrule Rrule">17(12) </td><td align="center" styleCode=" Botrule Rrule">3(3) </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Dizziness </td><td align="center" styleCode=" Botrule Rrule">38(7) </td><td align="center" styleCode=" Botrule Rrule">5(5) </td><td align="center" styleCode=" Botrule Rrule">18(12) </td><td align="center" styleCode=" Botrule Rrule">5(6) </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Abdominal Pain </td><td align="center" styleCode=" Botrule Rrule">32(6) </td><td align="center" styleCode=" Botrule Rrule">18(17) </td><td align="center" styleCode=" Botrule Rrule">6(4) </td><td align="center" styleCode=" Botrule Rrule">10(11) </td></tr><tr><td align="left" styleCode="Lrule B

Code="Lrule Botrule Rrule">Abdominal Pain </td><td align="center" styleCode=" Botrule Rrule">32(6) </td><td align="center" styleCode=" Botrule Rrule">18(17) </td><td align="center" styleCode=" Botrule Rrule">6(4) </td><td align="center" styleCode=" Botrule Rrule">10(11) </td></tr><tr><td align="left" styleCode="Lrule B otrule Rrule">Flatulence </td><td align="center" styleCode=" Botrule Rrule">30(6) </td><td align="center" styleCode=" Botrule Rrule">6(6) </td><td align="center" styleCode=" Botrule Rrule">12(8) </td><td align="center" styleCode=" Botrule Rrule">5(6) </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Vomiting </td><td align="center" styleCode=" Botrule Rrule">29(6) </td><td align="center" styleCode=" Botrule Rrule">6(6) </td><td align="center" styleCode=" Botrule Rrule">6(4) </td><td align="center" styleCode=" Botrule Rrule">6(7) </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Fatigue </td><td align="center" styleCode=" Botrule Rrule">25(5) </td><td align="center" styleCode=" Botrule Rrule">8(7) </td><td align="center" styleCode=" Botrule Rrule">11(8) </td><td align="center" styleCode=" Botrule Rrule">0(0) </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Pain </td><td align="center" styleCode=" Botrule Rrule">24(5) </td><td align="center" styleCode=" Botrule Rrule">8(7) </td><td align="center" styleCode=" Botrule Rrule">17(12) </td><td align="center" styleCode=" Botrule Rrule">2(2) </td></tr></tbody></table> <table ID="ID116" width="100%" styleCode="Noautorules"><caption>Table 2 Summary and Incidence of Signs/Symptoms of Hypercorticism in 8-Week Treatment Clinical Trials</caption><col width="22%"/><col width="26%"/><col width="20%"/><col width="30%"/><tfoot><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">¹Prednisolone tapering scheme: either 40 mg in week 1 to 2, thereafter tapering with 5 mg/week; or 40 mg in week 1 to 2, 30 mg in week 3 to 4, thereafter tapering with 5 mg/week. </paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">²Statistically significantly different from budesonide delayed-release capsules 9 mg. </paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">³including hair growth increased, local and hair growth increased, general.

left" colspan="4"><paragraph styleCode="Footnote">²Statistically significantly different from budesonide delayed-release capsules 9 mg. </paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">³including hair growth increased, local and hair growth increased, general. </paragraph></td></tr></tfoot><tbody><tr><td styleCode="Lrule Toprule Rrule" valign="top"/><td align="center" styleCode=" Toprule Botrule Rrule" valign="top"><content styleCode="bold">Budesonide Delayed-Release Capsules</content> <content styleCode="bold">9 mg</content> <content styleCode="bold">n=427</content> </td><td align="center" styleCode=" Toprule Botrule Rrule" valign="top"><content styleCode="bold">Placebo</content> <content styleCode="bold">n=107</content> </td><td align="center" styleCode=" Toprule Botrule Rrule" valign="top"><content styleCode="bold">Prednisolone ¹</content> <content styleCode="bold">40 mg</content> <content styleCode="bold">n=145</content> </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule"><content styleCode="bold">Signs/Symptom</content> </td><td align="center" styleCode=" Botrule Rrule"><content styleCode="bold">Number (%)</content> </td><td align="center" styleCode=" Botrule Rrule"><content styleCode="bold">Number (%)</content> </td><td align="center" styleCode=" Botrule Rrule"><content styleCode="bold">Number (%)</content> </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Total </td><td align="center" styleCode=" Botrule Rrule">145 (34%) </td><td align="center" styleCode=" Botrule Rrule">29 (27%) </td><td align="center" styleCode=" Botrule Rrule">69 (48%) </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Acne </td><td align="center" styleCode=" Botrule Rrule" valign="top">63(15) </td><td align="center" styleCode=" Botrule Rrule" valign="top">14(13) </td><td align="center" styleCode=" Botrule Rrule" valign="top">33(23) ² </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Bruising Easily </td><td align="center" styleCode=" Botrule Rrule" valign="top">63(15) </td><td align="center" styleCode=" Botrule Rrule" valign="top">12(11) </td><td align="center" styleCode=" Botrule Rrule" valign="top">13(9) </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Moon Face </td><td align="center" styleCode=" Botrule Rrule" valign="top">46(11) </td><td align="center" styleCode=" Botrule Rrule" valign="top">4(4) </td><td align="center" styleCode=" Botrule Rrule" valign="top">53(37) ² </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Swollen Ankles </td><td align="center" styleCode=" Botrule Rrule">32(7) </td><td align="center" styleCode=" Botrule Rrule">6(6) </td><td align="center" styleCode=" Botrule Rrule">13(9) </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Hirsutism ³ </td><td align="center" styleCode=" Botrule Rrule">22(5) </td><td align="center" styleCode=" Botrule Rrule">2(2) </td><td align="center" styleCode=" Botrule Rrule">5(3) </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Buffalo hump </td><td align="center" styleCode=" Botrule Rrule">6(1) </td><td align="center" styleCode=" Botrule Rrule" valign="top">2(2) </td><td align="center" styleCode=" Botrule Rrule">5(3) </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Skin Striae </td><td align="center" styleCode=" Botrule Rrule">4(1) </td><td align="center" styleCode=" Botrule Rrule" valign="top">2(2) </td><td align="center" styleCode=" Botrule Rrule">0(0) </td></tr></tbody></table>

nter" styleCode=" Botrule Rrule">5(3) </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Skin Striae </td><td align="center" styleCode=" Botrule Rrule">4(1) </td><td align="center" styleCode=" Botrule Rrule" valign="top">2(2) </td><td align="center" styleCode=" Botrule Rrule">0(0) </td></tr></tbody></table> <table ID="ID118" width="92%" styleCode="Noautorules"><caption>Table 3 Summary and Incidence of Signs/Symptoms of Hypercorticism in Long-Term Clinical Trials</caption><col width="21%"/><col width="24%"/><col width="25%"/><col width="28%"/><tbody><tr><td styleCode="Lrule Toprule Rrule" valign="top"/><td align="center" styleCode=" Toprule Botrule Rrule" valign="top"><content styleCode="bold">Budesonide Delayed-Release Capsules</content> <content styleCode="bold">3 mg</content> <content styleCode="bold">n=88</content> </td><td align="center" styleCode=" Toprule Botrule Rrule" valign="top"><content styleCode="bold">Budesonide Delayed-release Capsules</content> <content styleCode="bold">6 mg</content> <content styleCode="bold">n=145</content> </td><td align="center" styleCode=" Toprule Botrule Rrule" valign="top"><content styleCode="bold">Placebo</content> <content styleCode="bold">n=143</content> </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule"><content styleCode="bold">Signs/Symptom</content> </td><td align="center" styleCode=" Botrule Rrule"><content styleCode="bold">Number (%)</content> </td><td align="center" styleCode=" Botrule Rrule"><content styleCode="bold">Number (%)</content> </td><td align="center" styleCode=" Botrule Rrule"><content styleCode="bold">Number (%)</content> </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Bruising easily </td><td align="center" styleCode=" Botrule Rrule" valign="top">4(5) </td><td align="center" styleCode=" Botrule Rrule" valign="top">15(10) </td><td align="center" styleCode=" Botrule Rrule" valign="top">5(4) </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Acne </td><td align="center" styleCode=" Botrule Rrule" valign="top">4(5) </td><td align="center" styleCode=" Botrule Rrule" valign="top">14(10) </td><td align="center" styleCode=" Botrule Rrule" valign="top">3(2) </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Moon face </td><td align="center" styleCode=" Botrule Rrule" valign="top">3(3) </td><td align="center" styleCode=" Botrule Rrule" valign="top">6(4) </td><td align="center" styleCode=" Botrule Rrule" valign="top">0 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Hirsutism </td><td align="center" styleCode=" Botrule Rrule">2(2) </td><td align="center" styleCode=" Botrule Rrule">5(3) </td><td align="center" styleCode=" Botrule Rrule">1(1) </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Swollen ankles </td><td align="center" styleCode=" Botrule Rrule">2(2) </td><td align="center" styleCode=" Botrule Rrule">3(2) </td><td align="center" styleCode=" Botrule Rrule">3(2) </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Buffalo hump </td><td align="center" styleCode=" Botrule Rrule">1(1) </td><td align="center" styleCode=" Botrule Rrule" valign="top">1(1) </td><td align="center" styleCode=" Botrule Rrule">0 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Skin striae </td><td align="center" styleCode=" Botrule Rrule">2(2) </td><td align="center" styleCode=" Botrule Rrule" valign="top">0 </td><td align="center" styleCode=" Botrule Rrule">0 </td></tr></tbody></table>

7 DRUG INTERACTIONS CYP3A4 Inhibitors (e.g., ketoconazole, grapefruit juice) : Can increase systemic budesonide concentrations: avoid use. ( 2.1 , 7.1 ) 7.1 CYP3A4 Inhibitors Budesonide is a substrate for CYP3A4. Avoid use with CYP3A4 inhibitors. Concomitant oral administration of a strong CYP3A4 inhibitor (ketoconazole) caused an eight-fold increase of the systemic exposure to oral budesonide. Inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, erythromycin, and cyclosporine) can increase systemic budesonide concentrations [see Clinical Pharmacology ( 12.3 )] . Grapefruit Juice Avoid ingestion of grapefruit juice with budesonide. Intake of grapefruit juice which inhibits CYP3A4 activity with budesonide can increase the systemic exposure for budesonide [see Clinical Pharmacology ( 12.3 )] .

8 USE IN SPECIFIC POPULATIONS Pregnancy : Based on animal data, may cause fetal harm. ( 8.1 ) 8.1 Pregnancy Risk Summary Limited published studies report on the use of budesonide in pregnant women; however, the data are insufficient to inform a drug-associated risk for major birth defects and miscarriage. There are clinical considerations [see Clinical Considerations]. In animal reproduction studies with pregnant rats and rabbits, administration of subcutaneous budesonide during organogenesis at doses approximately 0.5 times or 0.05 times, respectively, the maximum recommended human dose, resulted in increased fetal loss, decreased pup weights, and skeletal abnormalities. Maternal toxicity was observed in both rats and rabbits at these dose levels [ see Data ]. Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage of the indicated population is 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% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Some published epidemiological studies show an association of adverse pregnancy outcomes in women with Crohn's disease, including preterm birth and low birth weight infants, during periods of increased disease activity (including increased stool frequency and abdominal pain). Pregnant women with Crohn's disease should be counseled regarding the importance of controlling disease. Fetal/Neonatal adverse reactions Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Infants should be carefully observed for signs of hypoadrenalism, such as poor feeding, irritability, weakness, and vomiting, and managed accordingly [see Warnings and Precautions ( 5.1 )]. Data Animal Data Budesonide was teratogenic and embryolethal in rabbits and rats. In an embryo-fetal development study in pregnant rats dosed subcutaneously with budesonide during the period of organogenesis from gestation days 6 to 15 there were effects on fetal development and survival at subcutaneous doses up to approximately 500 mcg/kg in rats (approximately 0.5 times the maximum recommended human dose on a body surface area basis). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 6 to 18, there was an increase in maternal abortion, and effects on fetal development and reduction in litter weights at subcutaneous doses up to approximately 25 mcg/kg in rabbits (approximately 0.05 times the maximum recommended human dose on a body surface area basis). Maternal toxicity, including reduction in body weight gain, was observed at subcutaneous doses of 5 mcg/kg in rabbits (approximately 0.01 times the maximum recommended human dose on a body surface area basis) and 500 mcg/kg in rats (approximately 0.5 times the maximum recommended human dose on a body surface area basis). In a peri-and post-natal development study, rats dosed subcutaneously with budesonide during the period of Day 15 post coitum to Day 21 postpartum, budesonide had no effects on delivery but did have an effect on growth and development of offspring.

times the maximum recommended human dose on a body surface area basis). In a peri-and post-natal development study, rats dosed subcutaneously with budesonide during the period of Day 15 post coitum to Day 21 postpartum, budesonide had no effects on delivery but did have an effect on growth and development of offspring. In addition, offspring survival was reduced and surviving offspring had decreased mean body weights at birth and during lactation at exposures 0.02 times the MRHD (on a mg/m 2 basis at maternal subcutaneous doses of 20 mcg/kg/day and higher). These findings occurred in the presence of maternal toxicity. 8.2 Lactation Risk Summary Lactation studies have not been conducted with oral budesonide, including budesonide delayed-release capsules, and no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production. One published study reports that budesonide is present in human milk following maternal inhalation of budesonide [ see Data ]. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for budesonide delayed-release capsules and any potential adverse effects on the breastfed infant from budesonide delayed-release capsules, or from the underlying maternal condition. Data One published study reports that budesonide is present in human milk following maternal inhalation of budesonide which resulted in infant doses approximately 0.3% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.4 and 0.5. Budesonide plasma concentrations were not detected and no adverse events were noted in the breastfed infants following maternal use of inhaled budesonide. The recommended daily dose of budesonide delayed-release capsules is higher (up to 9 mg daily) compared with inhaled budesonide (up to 800 mcg daily) given to mothers in the above described study. The maximum budesonide plasma concentration following a 9 mg daily dose (in both single- and repeated-dose pharmacokinetic studies) of oral budesonide is approximately 2.15 to 4.31 ng/mL which is up to 10 times higher than the 0.43 to 0.86 ng/mL for a 800 mcg daily dose of inhaled budesonide at steady state in the above inhalation study. Assuming the coefficient of extrapolation between the inhaled and oral doses is constant across all dose levels, at therapeutic doses of budesonide delayed-release capsules, budesonide exposure to the nursing child may be up to 10 times higher than that by budesonide inhalation. 8.4 Pediatric Use The safety and effectiveness of budesonide delayed-release capsules have been established in pediatric patients 8 to 17 years of age who weigh more than 25 kg for the treatment of mild to moderate active Crohn's disease involving the ileum and/or the ascending colon. Use of budesonide delayed-release capsules in this age group is supported by evidence from adequate and well controlled studies of budesonide delayed-release capsules in adults, with additional data from 2 clinical studies in 149 pediatric patients treated up to 8 weeks and one pharmacokinetic study in 8 pediatric patients [see Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ), and Clinical Studies ( 14.1 )] . The observed safety profile of budesonide delayed-release capsules in pediatric patients is consistent with its known safety profile in adults and no new safety concerns were identified [see Adverse Reactions ( 6.1 )] . The safety and effectiveness of budesonide delayed-release capsules have not been established in pediatric patients less than 8 years of age for the treatment of mild to moderate active Crohn's disease involving the ileum and/or the ascending colon.

new safety concerns were identified [see Adverse Reactions ( 6.1 )] . The safety and effectiveness of budesonide delayed-release capsules have not been established in pediatric patients less than 8 years of age for the treatment of mild to moderate active Crohn's disease involving the ileum and/or the ascending colon. The safety and effectiveness of budesonide delayed-release capsules have not been established in pediatric patients for the maintenance of clinical remission of mild to moderate Crohn's disease. An open-label study to evaluate the safety and tolerability of budesonide delayed-release capsules as maintenance treatment in pediatric patients aged 5 to 17 years was conducted, and did not establish the safety and efficacy of maintenance of clinical remission. Systemic corticosteroids, including budesonide delayed-release capsules, may cause a reduction of growth velocity in pediatric patients. Pediatric patients with Crohn's disease have a 17% higher mean systemic exposure and cortisol suppression than adults with Crohn's disease [see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.2 )] . 8.5 Geriatric Use Clinical studies of budesonide delayed-release capsules did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Of the 651 patients treated with budesonide delayed-release capsules in clinical studies, 17 (3%) were greater than or equal to 65 years of age and none were greater than 74 years of age. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6 Hepatic Impairment Patients with moderate to severe hepatic impairment (Child-Pugh Class B and C, respectively) could be at an increased risk of hypercorticism and adrenal axis suppression due to an increased systemic exposure to budesonide [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)] . Avoid use in patients with severe hepatic impairment (Child-Pugh Class C). Monitor for increased signs and/or symptoms of hypercorticism and consider dosage reduction in patients with moderate hepatic impairment (Child-Pugh Class B) [see Dosage and Administration (2.4)] . No dosage adjustment is needed in patients with mild hepatic impairment (Child-Pugh Class A).

8.1 Pregnancy Risk Summary Limited published studies report on the use of budesonide in pregnant women; however, the data are insufficient to inform a drug-associated risk for major birth defects and miscarriage. There are clinical considerations [see Clinical Considerations]. In animal reproduction studies with pregnant rats and rabbits, administration of subcutaneous budesonide during organogenesis at doses approximately 0.5 times or 0.05 times, respectively, the maximum recommended human dose, resulted in increased fetal loss, decreased pup weights, and skeletal abnormalities. Maternal toxicity was observed in both rats and rabbits at these dose levels [ see Data ]. Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage of the indicated population is 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% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Some published epidemiological studies show an association of adverse pregnancy outcomes in women with Crohn's disease, including preterm birth and low birth weight infants, during periods of increased disease activity (including increased stool frequency and abdominal pain). Pregnant women with Crohn's disease should be counseled regarding the importance of controlling disease. Fetal/Neonatal adverse reactions Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Infants should be carefully observed for signs of hypoadrenalism, such as poor feeding, irritability, weakness, and vomiting, and managed accordingly [see Warnings and Precautions ( 5.1 )]. Data Animal Data Budesonide was teratogenic and embryolethal in rabbits and rats. In an embryo-fetal development study in pregnant rats dosed subcutaneously with budesonide during the period of organogenesis from gestation days 6 to 15 there were effects on fetal development and survival at subcutaneous doses up to approximately 500 mcg/kg in rats (approximately 0.5 times the maximum recommended human dose on a body surface area basis). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 6 to 18, there was an increase in maternal abortion, and effects on fetal development and reduction in litter weights at subcutaneous doses up to approximately 25 mcg/kg in rabbits (approximately 0.05 times the maximum recommended human dose on a body surface area basis). Maternal toxicity, including reduction in body weight gain, was observed at subcutaneous doses of 5 mcg/kg in rabbits (approximately 0.01 times the maximum recommended human dose on a body surface area basis) and 500 mcg/kg in rats (approximately 0.5 times the maximum recommended human dose on a body surface area basis). In a peri-and post-natal development study, rats dosed subcutaneously with budesonide during the period of Day 15 post coitum to Day 21 postpartum, budesonide had no effects on delivery but did have an effect on growth and development of offspring.

times the maximum recommended human dose on a body surface area basis). In a peri-and post-natal development study, rats dosed subcutaneously with budesonide during the period of Day 15 post coitum to Day 21 postpartum, budesonide had no effects on delivery but did have an effect on growth and development of offspring. In addition, offspring survival was reduced and surviving offspring had decreased mean body weights at birth and during lactation at exposures 0.02 times the MRHD (on a mg/m 2 basis at maternal subcutaneous doses of 20 mcg/kg/day and higher). These findings occurred in the presence of maternal toxicity.

8.2 Lactation Risk Summary Lactation studies have not been conducted with oral budesonide, including budesonide delayed-release capsules, and no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production. One published study reports that budesonide is present in human milk following maternal inhalation of budesonide [ see Data ]. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for budesonide delayed-release capsules and any potential adverse effects on the breastfed infant from budesonide delayed-release capsules, or from the underlying maternal condition. Data One published study reports that budesonide is present in human milk following maternal inhalation of budesonide which resulted in infant doses approximately 0.3% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.4 and 0.5. Budesonide plasma concentrations were not detected and no adverse events were noted in the breastfed infants following maternal use of inhaled budesonide. The recommended daily dose of budesonide delayed-release capsules is higher (up to 9 mg daily) compared with inhaled budesonide (up to 800 mcg daily) given to mothers in the above described study. The maximum budesonide plasma concentration following a 9 mg daily dose (in both single- and repeated-dose pharmacokinetic studies) of oral budesonide is approximately 2.15 to 4.31 ng/mL which is up to 10 times higher than the 0.43 to 0.86 ng/mL for a 800 mcg daily dose of inhaled budesonide at steady state in the above inhalation study. Assuming the coefficient of extrapolation between the inhaled and oral doses is constant across all dose levels, at therapeutic doses of budesonide delayed-release capsules, budesonide exposure to the nursing child may be up to 10 times higher than that by budesonide inhalation.

8.4 Pediatric Use The safety and effectiveness of budesonide delayed-release capsules have been established in pediatric patients 8 to 17 years of age who weigh more than 25 kg for the treatment of mild to moderate active Crohn's disease involving the ileum and/or the ascending colon. Use of budesonide delayed-release capsules in this age group is supported by evidence from adequate and well controlled studies of budesonide delayed-release capsules in adults, with additional data from 2 clinical studies in 149 pediatric patients treated up to 8 weeks and one pharmacokinetic study in 8 pediatric patients [see Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ), and Clinical Studies ( 14.1 )] . The observed safety profile of budesonide delayed-release capsules in pediatric patients is consistent with its known safety profile in adults and no new safety concerns were identified [see Adverse Reactions ( 6.1 )] . The safety and effectiveness of budesonide delayed-release capsules have not been established in pediatric patients less than 8 years of age for the treatment of mild to moderate active Crohn's disease involving the ileum and/or the ascending colon. The safety and effectiveness of budesonide delayed-release capsules have not been established in pediatric patients for the maintenance of clinical remission of mild to moderate Crohn's disease. An open-label study to evaluate the safety and tolerability of budesonide delayed-release capsules as maintenance treatment in pediatric patients aged 5 to 17 years was conducted, and did not establish the safety and efficacy of maintenance of clinical remission. Systemic corticosteroids, including budesonide delayed-release capsules, may cause a reduction of growth velocity in pediatric patients. Pediatric patients with Crohn's disease have a 17% higher mean systemic exposure and cortisol suppression than adults with Crohn's disease [see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.2 )] .

8.5 Geriatric Use Clinical studies of budesonide delayed-release capsules did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Of the 651 patients treated with budesonide delayed-release capsules in clinical studies, 17 (3%) were greater than or equal to 65 years of age and none were greater than 74 years of age. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE Reports of acute toxicity and/or death following overdosage of glucocorticoids are rare. Treatment consists of immediate gastric lavage or emesis followed by supportive and symptomatic therapy. If corticosteroids are used at excessive doses for prolonged periods, systemic corticosteroid effects such as hypercorticism and adrenal axis suppression may occur. For chronic overdosage in the case of severe disease requiring continuous steroid therapy, the dosage may be reduced temporarily. Single oral doses of 200 and 400 mg/kg were lethal in female and male mice, respectively. The signs of acute toxicity were decreased motor activity, piloerection and generalized edema.

11 DESCRIPTION Budesonide USP, the active ingredient of budesonide delayed-release capsules, is a synthetic corticosteroid. Budesonide is designated chemically as (RS)-11β, 16α, 17,21- tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with butyraldehyde. Budesonide is provided as a mixture of two epimers (22R and 22S). The molecular formula of budesonide is C 25 H 34 O 6 and its molecular weight is 430.5. Its structural formula is: Budesonide, USP is a white to off-white, odorless, crystalline powder that is practically insoluble in water and heptane, sparingly soluble in ethanol, and freely soluble in chloroform. Its partition coefficient between octanol and water at pH 5 is 1.6 x 10 3 ionic strength 0.01. Each capsule for oral administration contains 3 mg of micronized budesonide with the following inactive ingredients: acetyltributyl citrate, ethylcellulose aqueous dispersion, gelatin, iron oxide red, iron oxide yellow, methacrylic acid copolymer dispersion, polysorbate 80, simethicone emulsion, sodium lauryl sulfate, sugar spheres, talc, titanium dioxide and triethyl citrate. The capsule shell is printed with black pharmaceutical ink which contains following ingredients: iron oxide black, potassium hydroxide, propylene glycol and shellac. budesonide

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Budesonide is an anti-inflammatory corticosteroid and has a high glucocorticoid effect and a weak mineralocorticoid effect, and the affinity of budesonide to glucocorticoid receptors, which reflects the intrinsic potency of the drug, is about 200-fold that of cortisol and 15-fold that of prednisolone. 12.2 Pharmacodynamics Treatment with glucocorticoids, including budesonide delayed-release capsules is associated with a suppression of endogenous cortisol concentrations and an impairment of the hypothalamus-pituitary-adrenal (HPA) axis function. There was a positive correlation between the percent (%) reduction of AUC 0-24 of plasma cortisol and systemic exposure to budesonide both in pediatric and adult patients. Adults Plasma cortisol suppression was compared following five days' administration of budesonide delayed-release capsules and prednisolone in a crossover study in healthy volunteers. The mean decrease in the area under the plasma cortisol concentration-time curve over 24 hour (AUC 0-24 ) was greater (78%) with prednisolone 20 mg per day compared to 45% with budesonide delayed-release capsules 9 mg per day. Pediatrics The effect of budesonide on endogenous cortisol concentrations was compared between pediatrics (n=8, aged 9 to 14 years) and adults (n=6) with active Crohn's disease following administration of budesonide delayed-release capsules 9 mg once daily for 7 days. Compared to baseline values before treatment, the mean decrease in the AUC 0-24 of cortisol was 64% (±18%) in pediatrics and 50% (±27%) in adults after budesonide delayed-release capsules treatment [see Warnings and Precautions ( 5.1 ), Adverse Reactions ( 6.1 ) and Use in Specific Populations ( 8.4 )] . The responses to adrenocorticotropin challenge (i.e., ACTH stimulation test) was studied in pediatric patients aged 8 to 17 years, with mild to moderate active Crohn's disease in randomized, double-blind, active control study [see Clinical Studies ( 14.1 )] . After 8 weeks of treatment with 9 mg once daily budesonide delayed-release capsules or with prednisolone, administered at tapering doses starting from 1 mg/kg, the proportion of patients with normal response to the ACTH challenge was 6% in the budesonide group compared to none in the prednisolone group; the proportion of patients with morning p-cortisol of greater than 5 mcg/dL was 50% in the budesonide group compared to 22% in the prednisolone group. The mean morning p-cortisol was 6.3 mcg/dL in the budesonide group and 2.6 mcg/dL in the prednisolone group (Table 4). Table 4 Proportion of Pediatric Patients 8 to 17 years old with Peak Endogenous Cortisol Levels (above 18 mcg/dL) after ACTH Stimulation and Normal Response* to ACTH Challenge Following Administration of Budesonide Delayed-ReleaseCapsulesor Prednisolone for 8 weeks *The normal response to ACTH challenge included 3 criteria, as defined in the cosyntropin label: 1) morning cortisol level above 5 mcg/dL; 2) increase in cortisol level by at least 7 mcg/dL above the morning (pre-challenge) level following ACTH challenge; and cortisol level of above 18 mcg/dL following ACTH challenge. Cortisol concentration was measured at 30 min after intravenous or intramuscular injection of 0.25 mg cosyntropin at baseline and at week 8 after treatment.

rtisol level by at least 7 mcg/dL above the morning (pre-challenge) level following ACTH challenge; and cortisol level of above 18 mcg/dL following ACTH challenge. Cortisol concentration was measured at 30 min after intravenous or intramuscular injection of 0.25 mg cosyntropin at baseline and at week 8 after treatment. Budesonide Prednisolone Peak plasma cortisol above 18 mcg/dL At baseline 91% (20/22) 91% (21/23) At week 8 25% (4/16) 0% (0/18) Normal response* to ACTH challenge At baseline 73% (16/22) 78% (18/23) At week 8 6% (1/16) 0% (0/18) 12.3 Pharmacokinetics Absorption Mean oral bioavailability of budesonide ranged from 9% to 21% both in patients and in healthy subjects, demonstrating a high first-pass elimination of the drug. Budesonide pharmacokinetics were dose-proportional following repeated administration in the dose range of 3 to 15 mg. No accumulation of budesonide was observed following repeated dosing. Following oral administration of a single dose of 9 mg budesonide delayed-release capsules in healthy subjects under fasting condition, the mean peak plasma concentration (C max ) and the area under the plasma concentration time curve (AUC) for budesonide were 1.50 ± 0.79 ng/mL and 14.13 ± 7.33 ng•hr/mL, respectively. The time to peak concentration (T max ) varied between 2 and 8 hours with a median value of 3.5 hours. In a different study, following oral administration of 9 mg budesonide delayed-release capsules for five days in healthy subjects, the mean C max and the steady state AUC for budesonide were 2.28 ± 0.77 ng/mL and 15.93 ± 6.29 ng•hr/mL, respectively. Following administration of 9 mg budesonide delayed-release capsules once daily in patients with active Crohn's disease, the mean C max and AUC were 1.7 ± 0.9 ng/mL and 15.1 ± 8.5 ng•hr/mL, respectively. Following administration of budesonide delayed-release capsules, the T max ranged in individual patients from 0.5 to 10 hours. Concomitant administration of a high-fat meal delayed the T max of budesonide by 2.3 hours compared to that under fasted conditions but did not significantly affect the AUC in healthy subjects. The mean C max and AUC of budesonide were similar when single dose of budesonide delayed-release capsules (9 mg) was administered after opening the capsules and sprinkling the granules on applesauce versus as intact capsules in the fasted state (N=24) in healthy subjects. The T max ranged from 3 to 10 hours with a median of 4 hours after administration of sprinkled granules on appleasauce. Distribution The mean volume of distribution (V ss ) of budesonide varied between 2.2 and 3.9 L/kg in healthy subjects and in patients. Plasma protein binding was estimated to be 85% to 90% in the concentration range 0.43 to 99.02 ng/mL, independent of gender. The erythrocyte/plasma partition ratio at clinically relevant concentrations was about 0.8. Elimination Budesonide had a plasma clearance, 0.9 to 1.8 L/min in healthy adults. Mean plasma clearance after intravenous administration of budesonide in patients with Crohn's disease was 1.0 L/min. These plasma clearance values approached the estimated liver blood flow, and, accordingly, suggest that budesonide is a high hepatic clearance drug. The plasma elimination half-life after administration of intravenous doses ranged between 2 and 3.6 hours, and did not differ between healthy adults and patients with Crohn's disease. The mean ± SD plasma elimination half-life after a single dose of budesonide delayed-release capsules (9 mg) in the fasted state (N=24) in healthy subjects was 6.3 ± 1.6 hours and ranged between 2 and 8 hours. Metabolism Following absorption, budesonide is subject to high first pass metabolism (80% to 90%).

's disease. The mean ± SD plasma elimination half-life after a single dose of budesonide delayed-release capsules (9 mg) in the fasted state (N=24) in healthy subjects was 6.3 ± 1.6 hours and ranged between 2 and 8 hours. Metabolism Following absorption, budesonide is subject to high first pass metabolism (80% to 90%). In vitro experiments in human liver microsomes demonstrated that budesonide is rapidly and extensively biotransformed, mainly by CYP3A4, to its 2 major metabolites, 6β-hydroxy budesonide and 16α-hydroxy prednisolone. The corticosteroid activity of these metabolites was negligible (less than 1/100) in relation to that of the parent compound. In vivo investigations with intravenous doses in healthy subjects were in agreement with the in vitro findings. Excretion Budesonide was excreted in urine and feces in the form of metabolites. After oral as well as intravenous administration of micronized [ 3 H]-budesonide, approximately 60% of the recovered radioactivity was found in urine. The major metabolites, including 6β-hydroxy budesonide and 16α-hydroxy prednisolone, are mainly renally excreted, intact or in conjugated forms. No unchanged budesonide was detected in urine. Specific Populations Age: Pediatric Population (8 years and older) The pharmacokinetics of budesonide were investigated in pediatric patients aged 9 to 14 years (n=8) after oral administration of budesonide delayed-release capsules and intravenous administration of budesonide. Following administration of 9 mg budesonide delayed-release capsules once daily for 7 days, the median time to peak plasma concentration of budesonide was 5 hours and the mean peak plasma concentration was 2.58 ± 1.51 ng/mL. The mean AUC was 17.78 ± 5.25 ng•hr/mL and 17% higher than that in adult patients with Crohn's disease in the same study. The mean absolute oral availability was 9.2% (3 to 17%; n=4) in pediatric patients. After single dose administration of intravenous budesonide (n=4), the mean volume of distribution (V ss ) was 2.2 ± 0.4 L/kg and mean clearance was 0.81 ± 0.2 L/min. The mean elimination half-life was 1.9 hours in pediatric patients. The body-weight normalized clearance in pediatric patients was 20.5 mL/min/kg in comparison to 15.9 mL/min/kg in adult patients after intravenous administration [see Warnings and Precautions ( 5.1 ), Use in Specific Population ( 8.4 )] . Hepatic Impairment In patients with mild (Child-Pugh Class A, n=4) or moderate (Child-Pugh Class B, n=4) hepatic impairment, budesonide 4 mg was administered orally as a single dose. The patients with moderate hepatic impairment had a 3.5-fold higher AUC compared to the healthy subjects with normal hepatic function while the patients with mild hepatic impairment had an approximately 1.4-fold higher AUC. The C max values demonstrated similar increases [see Dosage and Administration ( 2.4 ), Warnings and Precautions ( 5.1 )] . The increased systemic exposure in patients with mild hepatic impairment was not considered to be clinically relevant. Patients with severe liver impairment (Child-Pugh Class C) were not studied. Drug Interaction Studies Budesonide is metabolized via CYP3A4. Potent inhibitors of CYP3A4 can increase the plasma concentrations of budesonide several-fold. Conversely, induction of CYP3A4 potentially could result in the lowering of budesonide plasma concentrations. Effects of Other Drugs on Budesonide Ketoconazole In an open, non-randomized, cross-over study, 6 healthy subjects were given budesonide 10 mg as a single dose, either alone or concomitantly with the last ketoconazole dose of 3 days treatment with ketoconazole 100 mg twice daily. Co-administration of ketoconazole resulted in an eight-fold increase in AUC of budesonide, compared to budesonide alone [see Drug Interactions ( 7.1 )] .

were given budesonide 10 mg as a single dose, either alone or concomitantly with the last ketoconazole dose of 3 days treatment with ketoconazole 100 mg twice daily. Co-administration of ketoconazole resulted in an eight-fold increase in AUC of budesonide, compared to budesonide alone [see Drug Interactions ( 7.1 )] . Grapefruit Juice In an open, randomized, cross-over study, 8 healthy subjects were given budesonide delayed-release capsules 3 mg, either alone, or concomitantly with 600 mL concentrated grapefruit juice (which inhibits CYP3A4 activity predominantly in the intestinal mucosa), on the last of 4 daily administrations. Concomitant administration of grapefruit juice resulted in a 2-fold increase of the bioavailability of budesonide compared to budesonide alone [see Drug Interactions ( 7.1 )] . Oral Contraceptives (CYP3A4 Substrates) In a parallel study, the pharmacokinetics of budesonide were not significantly different between healthy female subjects who received oral contraceptives containing desogestrel 0.15 mg and ethinyl estradiol 30 μg and healthy female subjects who did not receive oral contraceptives. Budesonide 4.5 mg once daily (one-half the recommended dose) for one week did not affect the plasma concentrations of ethinyl estradiol, a CYP3A4 substrate. The effect of budesonide 9 mg once daily on the plasma concentrations of ethinyl estradiol was not studied. Omeprazole In a study in 11 healthy subjects, performed in a double-blind, randomized, placebo controlled manner, the effect of 5 to 6 days treatment with omeprazole 20 mg once daily on the pharmacokinetics of budesonide administered as budesonide delayed-release capsules 9 mg as a single dose was investigated. Omeprazole 20 mg once daily did not affect the absorption or pharmacokinetics of budesonide. Cimetidine In an open, non-randomized, cross-over study, the potential effect of cimetidine on the pharmacokinetics of budesonide was studied. Six healthy subjects received cimetidine 1 gram daily (200 mg with meals and 400 mg at night) for 2 separate 3-day periods. Budesonide 4 mg was administered either alone or on the last day of one of the cimetidine treatment periods. Co-administration of cimetidine resulted in a 52% and 31% increase in the budesonide peak plasma concentration and the AUC of budesonide, respectively.

12.1 Mechanism of Action Budesonide is an anti-inflammatory corticosteroid and has a high glucocorticoid effect and a weak mineralocorticoid effect, and the affinity of budesonide to glucocorticoid receptors, which reflects the intrinsic potency of the drug, is about 200-fold that of cortisol and 15-fold that of prednisolone.

12.2 Pharmacodynamics Treatment with glucocorticoids, including budesonide delayed-release capsules is associated with a suppression of endogenous cortisol concentrations and an impairment of the hypothalamus-pituitary-adrenal (HPA) axis function. There was a positive correlation between the percent (%) reduction of AUC 0-24 of plasma cortisol and systemic exposure to budesonide both in pediatric and adult patients. Adults Plasma cortisol suppression was compared following five days' administration of budesonide delayed-release capsules and prednisolone in a crossover study in healthy volunteers. The mean decrease in the area under the plasma cortisol concentration-time curve over 24 hour (AUC 0-24 ) was greater (78%) with prednisolone 20 mg per day compared to 45% with budesonide delayed-release capsules 9 mg per day. Pediatrics The effect of budesonide on endogenous cortisol concentrations was compared between pediatrics (n=8, aged 9 to 14 years) and adults (n=6) with active Crohn's disease following administration of budesonide delayed-release capsules 9 mg once daily for 7 days. Compared to baseline values before treatment, the mean decrease in the AUC 0-24 of cortisol was 64% (±18%) in pediatrics and 50% (±27%) in adults after budesonide delayed-release capsules treatment [see Warnings and Precautions ( 5.1 ), Adverse Reactions ( 6.1 ) and Use in Specific Populations ( 8.4 )] . The responses to adrenocorticotropin challenge (i.e., ACTH stimulation test) was studied in pediatric patients aged 8 to 17 years, with mild to moderate active Crohn's disease in randomized, double-blind, active control study [see Clinical Studies ( 14.1 )] . After 8 weeks of treatment with 9 mg once daily budesonide delayed-release capsules or with prednisolone, administered at tapering doses starting from 1 mg/kg, the proportion of patients with normal response to the ACTH challenge was 6% in the budesonide group compared to none in the prednisolone group; the proportion of patients with morning p-cortisol of greater than 5 mcg/dL was 50% in the budesonide group compared to 22% in the prednisolone group. The mean morning p-cortisol was 6.3 mcg/dL in the budesonide group and 2.6 mcg/dL in the prednisolone group (Table 4). Table 4 Proportion of Pediatric Patients 8 to 17 years old with Peak Endogenous Cortisol Levels (above 18 mcg/dL) after ACTH Stimulation and Normal Response* to ACTH Challenge Following Administration of Budesonide Delayed-ReleaseCapsulesor Prednisolone for 8 weeks *The normal response to ACTH challenge included 3 criteria, as defined in the cosyntropin label: 1) morning cortisol level above 5 mcg/dL; 2) increase in cortisol level by at least 7 mcg/dL above the morning (pre-challenge) level following ACTH challenge; and cortisol level of above 18 mcg/dL following ACTH challenge. Cortisol concentration was measured at 30 min after intravenous or intramuscular injection of 0.25 mg cosyntropin at baseline and at week 8 after treatment. Budesonide Prednisolone Peak plasma cortisol above 18 mcg/dL At baseline 91% (20/22) 91% (21/23) At week 8 25% (4/16) 0% (0/18) Normal response* to ACTH challenge At baseline 73% (16/22) 78% (18/23) At week 8 6% (1/16) 0% (0/18)

<table ID="ID262" width="100%" styleCode="Noautorules"><caption>Table 4 Proportion of Pediatric Patients 8 to 17 years old with Peak Endogenous Cortisol Levels (above 18 mcg/dL) after ACTH Stimulation and Normal Response* to ACTH Challenge Following Administration of Budesonide Delayed-ReleaseCapsulesor Prednisolone for 8 weeks</caption><col width="213"/><col width="213"/><col width="213"/><tfoot><tr><td align="left" colspan="3"><paragraph styleCode="Footnote">*The normal response to ACTH challenge included 3 criteria, as defined in the cosyntropin label:</paragraph></td></tr><tr><td align="left" colspan="3"><paragraph styleCode="Footnote">1) morning cortisol level above 5 mcg/dL; 2) increase in cortisol level by at least 7 mcg/dL above the morning (pre-challenge) level following ACTH challenge; and cortisol level of above 18 mcg/dL following ACTH challenge. Cortisol concentration was measured at 30 min after intravenous or intramuscular injection of 0.25 mg cosyntropin at baseline and at week 8 after treatment.</paragraph></td></tr></tfoot><tbody><tr><td align="left" styleCode="Lrule Toprule Botrule Rrule" valign="top"> </td><td align="center" styleCode=" Toprule Botrule Rrule" valign="top">Budesonide </td><td align="center" styleCode=" Toprule Botrule Rrule" valign="top">Prednisolone </td></tr><tr><td colspan="3" align="center" styleCode="Lrule Botrule Rrule" valign="top">Peak plasma cortisol above 18 mcg/dL </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">At baseline </td><td align="center" styleCode=" Botrule Rrule" valign="top">91% (20/22) </td><td align="center" styleCode=" Botrule Rrule" valign="top">91% (21/23) </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">At week 8 </td><td align="center" styleCode=" Botrule Rrule" valign="top">25% (4/16) </td><td align="center" styleCode=" Botrule Rrule" valign="top">0% (0/18) </td></tr><tr><td colspan="3" align="center" styleCode="Lrule Botrule Rrule" valign="top">Normal response* to ACTH challenge </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">At baseline </td><td align="center" styleCode=" Botrule Rrule" valign="top">73% (16/22) </td><td align="center" styleCode=" Botrule Rrule" valign="top">78% (18/23) </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">At week 8 </td><td align="center" styleCode=" Botrule Rrule" valign="top">6% (1/16) </td><td align="center" styleCode=" Botrule Rrule" valign="top">0% (0/18) </td></tr></tbody></table>

12.3 Pharmacokinetics Absorption Mean oral bioavailability of budesonide ranged from 9% to 21% both in patients and in healthy subjects, demonstrating a high first-pass elimination of the drug. Budesonide pharmacokinetics were dose-proportional following repeated administration in the dose range of 3 to 15 mg. No accumulation of budesonide was observed following repeated dosing. Following oral administration of a single dose of 9 mg budesonide delayed-release capsules in healthy subjects under fasting condition, the mean peak plasma concentration (C max ) and the area under the plasma concentration time curve (AUC) for budesonide were 1.50 ± 0.79 ng/mL and 14.13 ± 7.33 ng•hr/mL, respectively. The time to peak concentration (T max ) varied between 2 and 8 hours with a median value of 3.5 hours. In a different study, following oral administration of 9 mg budesonide delayed-release capsules for five days in healthy subjects, the mean C max and the steady state AUC for budesonide were 2.28 ± 0.77 ng/mL and 15.93 ± 6.29 ng•hr/mL, respectively. Following administration of 9 mg budesonide delayed-release capsules once daily in patients with active Crohn's disease, the mean C max and AUC were 1.7 ± 0.9 ng/mL and 15.1 ± 8.5 ng•hr/mL, respectively. Following administration of budesonide delayed-release capsules, the T max ranged in individual patients from 0.5 to 10 hours. Concomitant administration of a high-fat meal delayed the T max of budesonide by 2.3 hours compared to that under fasted conditions but did not significantly affect the AUC in healthy subjects. The mean C max and AUC of budesonide were similar when single dose of budesonide delayed-release capsules (9 mg) was administered after opening the capsules and sprinkling the granules on applesauce versus as intact capsules in the fasted state (N=24) in healthy subjects. The T max ranged from 3 to 10 hours with a median of 4 hours after administration of sprinkled granules on appleasauce. Distribution The mean volume of distribution (V ss ) of budesonide varied between 2.2 and 3.9 L/kg in healthy subjects and in patients. Plasma protein binding was estimated to be 85% to 90% in the concentration range 0.43 to 99.02 ng/mL, independent of gender. The erythrocyte/plasma partition ratio at clinically relevant concentrations was about 0.8. Elimination Budesonide had a plasma clearance, 0.9 to 1.8 L/min in healthy adults. Mean plasma clearance after intravenous administration of budesonide in patients with Crohn's disease was 1.0 L/min. These plasma clearance values approached the estimated liver blood flow, and, accordingly, suggest that budesonide is a high hepatic clearance drug. The plasma elimination half-life after administration of intravenous doses ranged between 2 and 3.6 hours, and did not differ between healthy adults and patients with Crohn's disease. The mean ± SD plasma elimination half-life after a single dose of budesonide delayed-release capsules (9 mg) in the fasted state (N=24) in healthy subjects was 6.3 ± 1.6 hours and ranged between 2 and 8 hours. Metabolism Following absorption, budesonide is subject to high first pass metabolism (80% to 90%). In vitro experiments in human liver microsomes demonstrated that budesonide is rapidly and extensively biotransformed, mainly by CYP3A4, to its 2 major metabolites, 6β-hydroxy budesonide and 16α-hydroxy prednisolone.

urs. Metabolism Following absorption, budesonide is subject to high first pass metabolism (80% to 90%). In vitro experiments in human liver microsomes demonstrated that budesonide is rapidly and extensively biotransformed, mainly by CYP3A4, to its 2 major metabolites, 6β-hydroxy budesonide and 16α-hydroxy prednisolone. The corticosteroid activity of these metabolites was negligible (less than 1/100) in relation to that of the parent compound. In vivo investigations with intravenous doses in healthy subjects were in agreement with the in vitro findings. Excretion Budesonide was excreted in urine and feces in the form of metabolites. After oral as well as intravenous administration of micronized [ 3 H]-budesonide, approximately 60% of the recovered radioactivity was found in urine. The major metabolites, including 6β-hydroxy budesonide and 16α-hydroxy prednisolone, are mainly renally excreted, intact or in conjugated forms. No unchanged budesonide was detected in urine. Specific Populations Age: Pediatric Population (8 years and older) The pharmacokinetics of budesonide were investigated in pediatric patients aged 9 to 14 years (n=8) after oral administration of budesonide delayed-release capsules and intravenous administration of budesonide. Following administration of 9 mg budesonide delayed-release capsules once daily for 7 days, the median time to peak plasma concentration of budesonide was 5 hours and the mean peak plasma concentration was 2.58 ± 1.51 ng/mL. The mean AUC was 17.78 ± 5.25 ng•hr/mL and 17% higher than that in adult patients with Crohn's disease in the same study. The mean absolute oral availability was 9.2% (3 to 17%; n=4) in pediatric patients. After single dose administration of intravenous budesonide (n=4), the mean volume of distribution (V ss ) was 2.2 ± 0.4 L/kg and mean clearance was 0.81 ± 0.2 L/min. The mean elimination half-life was 1.9 hours in pediatric patients. The body-weight normalized clearance in pediatric patients was 20.5 mL/min/kg in comparison to 15.9 mL/min/kg in adult patients after intravenous administration [see Warnings and Precautions ( 5.1 ), Use in Specific Population ( 8.4 )] . Hepatic Impairment In patients with mild (Child-Pugh Class A, n=4) or moderate (Child-Pugh Class B, n=4) hepatic impairment, budesonide 4 mg was administered orally as a single dose. The patients with moderate hepatic impairment had a 3.5-fold higher AUC compared to the healthy subjects with normal hepatic function while the patients with mild hepatic impairment had an approximately 1.4-fold higher AUC. The C max values demonstrated similar increases [see Dosage and Administration ( 2.4 ), Warnings and Precautions ( 5.1 )] . The increased systemic exposure in patients with mild hepatic impairment was not considered to be clinically relevant. Patients with severe liver impairment (Child-Pugh Class C) were not studied. Drug Interaction Studies Budesonide is metabolized via CYP3A4. Potent inhibitors of CYP3A4 can increase the plasma concentrations of budesonide several-fold. Conversely, induction of CYP3A4 potentially could result in the lowering of budesonide plasma concentrations. Effects of Other Drugs on Budesonide Ketoconazole In an open, non-randomized, cross-over study, 6 healthy subjects were given budesonide 10 mg as a single dose, either alone or concomitantly with the last ketoconazole dose of 3 days treatment with ketoconazole 100 mg twice daily. Co-administration of ketoconazole resulted in an eight-fold increase in AUC of budesonide, compared to budesonide alone [see Drug Interactions ( 7.1 )] .

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies with budesonide were conducted in rats and mice. In a two-year study in Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in male rats at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). In addition, there were increased incidences of primary hepatocellular tumors in male rats at 25 mcg/kg (approximately 0.023 times the maximum recommended human dose on a body surface area basis) and above. No tumorigenicity was seen in female rats at oral doses up to 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). In an additional two-year study in male Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). However, it caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). The concurrent reference corticosteroids (prednisolone and triamcinolone acetonide) showed similar findings. In a 91-week study in mice, budesonide caused no treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately 0.1 times the maximum recommended human dose on a body surface area basis). Budesonide was not genotoxic in the Ames test, the mouse lymphoma cell forward gene mutation (TK +/- ) test, the human lymphocyte chromosome aberration test, the Drosophila melanogaster sex-linked recessive lethality test, the rat hepatocyte UDS test and the mouse micronucleus test. In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg (approximately 0.07 times the maximum recommended human dose on a body surface area basis). However, it caused a decrease in prenatal viability and viability in pups at birth and during lactation, along with a decrease in maternal body-weight gain, at subcutaneous doses of 20 mcg/kg (approximately 0.02 times the maximum recommended human dose on a body surface area basis) and above. No such effects were noted at 5 mcg/kg (approximately 0.005 times the maximum recommended human dose on a body surface area basis).

14 CLINICAL STUDIES 14.1 Treatment of Mild to Moderate Active Crohn’s Disease Adults The efficacy of budesonide delayed-release capsules were evaluated in 994 patients with mild to moderate active Crohn's disease of the ileum and/or ascending colon in 5 randomized and double-blind studies of 8 weeks duration. The study patients ranged in age from 17 to 85 (mean 35), 40% were male and 97% were white. The Crohn's Disease Activity Index (CDAI) was the main clinical assessment used for determining efficacy in these 5 studies. 1 The CDAI is a validated index based on subjective aspects rated by the patient (frequency of liquid or very soft stools, abdominal pain rating and general well-being) and objective observations (number of extraintestinal symptoms, need for antidiarrheal drugs, presence of abdominal mass, body weight and hematocrit). Clinical improvement, defined as a CDAI score of less than or equal to 150 assessed after 8 weeks of treatment, was the primary efficacy variable in these 5 comparative efficacy studies of budesonide delayed-release capsules. Safety assessments in these studies included monitoring of adverse reactions. A checklist of potential symptoms of hypercorticism was used. One study (Study 1) compared the efficacy of budesonide delayed-release capsules 9 mg daily in the morning to a comparator. At baseline, the median CDAI was 272. budesonide delayed-release capsules 9 mg daily resulted in a significantly higher clinical improvement rate at Week 8 than the comparator. See Table 5. Table 5 Clinical Improvement Rates (CDAI less than or equal to 150) After 8 weeks of Treatment 1. p=0.0004 compared to comparator. 2. p=0.001 compared to placebo. 3. This drug is not approved for the treatment of Crohn's disease in the United States. Clinical Study Budesonide Delayed-Release Capsules 9 mg Daily Budesonide Delayed-Release Capsules 4.5 mg Twice Daily Comparator 3 Placebo Prednisolone 1 62/91 (69%) 1 37/83 (45%) 2 31/61 (51%) 2 13/64 (20%) 3 38/79 (48%) 41/78 (53%) 13/40 (33%) 4 35/58 (60%) 25/60 (42%) 35/58 (60%) 5 45/86 (52%) 56/85 (65%) Two placebo-controlled clinical trials (Studies 2 and 3) were conducted. Study 2 involved 258 patients and tested the effects of graded doses of budesonide delayed-release capsules (1.5 mg twice daily, 4.5 mg twice daily, or 7.5 mg twice daily) versus placebo. At baseline, the median CDAI was 290. The 1.5 mg twice daily arm (data not shown) could not be differentiated from placebo. The 4.5 mg twice daily arm was statistically different from placebo (Table 5), while no additional benefit was seen when the daily budesonide delayed-release capsules dose was increased to 15 mg per day (data not shown). Study 3 was a 3-armed parallel group study. The groups were treated with budesonide delayed-release capsules 9 mg once daily, budesonide delayed-release capsules 4.5 mg twice daily and placebo for 8 weeks, followed by a 2-week double-blind taper phase. The median CDAI at baseline was 263. Neither 9 mg daily nor 4.5 mg twice daily budesonide delayed-release capsules dose levels were statistically different from placebo (Table 5). The recommended dosage of budesonide delayed-release capsules for the treatment of mild to moderate active Crohn's disease involving the ileum and/or the ascending colon in adults is 9 mg once daily in the morning for up to 8 weeks [see Dosage and Administration ( 2.1 )] .

tatistically different from placebo (Table 5). The recommended dosage of budesonide delayed-release capsules for the treatment of mild to moderate active Crohn's disease involving the ileum and/or the ascending colon in adults is 9 mg once daily in the morning for up to 8 weeks [see Dosage and Administration ( 2.1 )] . Two clinical trials (Studies 4 and 5) compared budesonide delayed-release capsules with oral prednisolone (initial dose 40 mg per day). Study 4 was a 3-armed parallel group study. The groups were treated with budesonide delayed-release capsules 9 mg once daily, budesonide delayed-release capsules 4.5 mg twice daily and prednisolone 40 mg (tapered dose) for 8 weeks, followed by a 4-week double blind taper phase. At baseline, the median CDAI was 277. Equal clinical improvement rates (60%) were seen in the budesonide delayed-release capsules 9 mg daily and the prednisolone groups in Study 4. In Study 5, 13% fewer patients in the budesonide delayed-release capsules group experienced clinical improvement than in the prednisolone group (no statistical difference) (Table 5). The proportion of patients with normal plasma cortisol values (greater than 64.58 ng/mL) was significantly higher in the budesonide delayed-release capsules groups in both trials (60% to 66%) than in the prednisolone groups (26% to 28%) at Week 8. Pediatrics (8 to 17 Years of Age) The effectiveness of budesonide delayed-release capsules, in pediatric patients aged 8 to 17 years, who weigh more than 25 kg with mild to moderate active Crohn's disease (defined as Crohn's Disease Activity Index (CDAI) ≥ 200) involving the ileum and/or the ascending colon, was assessed in one randomized, double-blind, active control study. This study compared budesonide delayed-release capsules 9 mg once daily, with prednisolone, administered at tapering doses starting from 1 mg/kg. Twenty-two (22) patients were treated with budesonide delayed-release capsules and 24 patients were treated with prednisolone. After 8 weeks of treatment, 55% (95% CI: 32%, 77%) of patients treated with budesonide delayed-release capsules reached the endpoint (CDAI ≤150), as compared to 68% (95% CI: 47%, 89%) of patients treated with prednisolone. The average number of liquid or very soft stools per day (assessed over 7 days) decreased from 1.49 at baseline to 0.96 after treatment with budesonide delayed-release capsules and 2.00 at baseline to 0.52 after treatment with prednisolone. The average daily abdominal pain rating (where 0=none, 1=mild, 2=moderate, and 3=severe) decreased from 1.49 at baseline to 0.54 after treatment with budesonide delayed-release capsules and 1.64 at baseline to 0.38 after 8 weeks of treatment with prednisolone. Use of budesonide delayed-release capsules in this age group is supported by evidence from adequate and well-controlled studies of budesonide delayed-release capsules in adults, and by safety and pharmacokinetic studies performed in pediatric patients. 14.2 Maintenance of Clinical Remission of Mild to Moderate Crohn’s Disease Adults The efficacy of budesonide delayed-release capsules for maintenance of clinical remission were evaluated in four double-blind, placebo-controlled, 12-month trials in which 380 patients were randomized and treated once daily with 3 mg or 6 mg budesonide delayed-release capsules or placebo. Patients ranged in age from 18 to 73 (mean 37) years. Sixty percent of the patients were female and 99% were Caucasian. The mean CDAI at entry was 96. Among the four clinical trials, approximately 75% of the patients enrolled had exclusively ileal disease. Colonoscopy was not performed following treatment.

or placebo. Patients ranged in age from 18 to 73 (mean 37) years. Sixty percent of the patients were female and 99% were Caucasian. The mean CDAI at entry was 96. Among the four clinical trials, approximately 75% of the patients enrolled had exclusively ileal disease. Colonoscopy was not performed following treatment. Budesonide delayed-release capsules 6 mg per day prolonged the time to relapse, defined as an increase in CDAI of at least 60 units to a total score greater than 150 or withdrawal due to disease deterioration. The median time to relapse in the pooled population of the 4 studies was 154 days for patients taking placebo, and 268 days for patients taking budesonide delayed-release capsules 6 mg per day. Budesonide delayed-release capsules 6 mg per day reduced the proportion of patients with loss of symptom control relative to placebo in the pooled population for the 4 studies at 3 months (28% versus 45% for placebo).

<table ID="ID258" width="100%" styleCode="Noautorules"><caption>Table 5 Clinical Improvement Rates (CDAI less than or equal to 150) After 8 weeks of Treatment</caption><col width="194"/><col width="194"/><col width="194"/><col width="194"/><col width="194"/><col width="194"/><tfoot><tr><td align="left" colspan="6"><paragraph styleCode="Footnote">^1.p=0.0004 compared to comparator. </paragraph></td></tr><tr><td align="left" colspan="6"><paragraph styleCode="Footnote">^2. p=0.001 compared to placebo. </paragraph></td></tr><tr><td align="left" colspan="6"><paragraph styleCode="Footnote">^3. This drug is not approved for the treatment of Crohn&apos;s disease in the United States. </paragraph></td></tr></tfoot><tbody><tr><td align="center" styleCode="Lrule Toprule Botrule Rrule"><content styleCode="bold">Clinical Study</content> </td><td align="center" styleCode=" Toprule Botrule Rrule"><content styleCode="bold">Budesonide Delayed-Release Capsules</content> <content styleCode="bold">9 mg Daily</content> </td><td align="center" styleCode=" Toprule Botrule Rrule"><content styleCode="bold">Budesonide Delayed-Release Capsules</content> <content styleCode="bold">4.5 mg Twice Daily</content> </td><td align="center" styleCode=" Toprule Botrule Rrule"> <content styleCode="bold">Comparator ³</content> </td><td align="center" styleCode=" Toprule Botrule Rrule"><content styleCode="bold">Placebo</content> </td><td align="center" styleCode=" Toprule Botrule Rrule"><content styleCode="bold">Prednisolone</content> </td></tr><tr><td align="center" styleCode="Lrule Botrule Rrule">1 </td><td align="center" styleCode=" Botrule Rrule">62/91 (69%) ¹ </td><td styleCode=" Botrule Rrule"/><td align="center" styleCode=" Botrule Rrule">37/83 (45%) </td><td styleCode=" Botrule Rrule"/><td styleCode=" Botrule Rrule"/></tr><tr><td align="center" styleCode="Lrule Botrule Rrule">2 </td><td styleCode=" Botrule Rrule"/><td align="center" styleCode=" Botrule Rrule">31/61 (51%) ² </td><td styleCode=" Botrule Rrule"/><td align="center" styleCode=" Botrule Rrule">13/64 (20%) </td><td styleCode=" Botrule Rrule"/></tr><tr><td align="center" styleCode="Lrule Botrule Rrule">3 </td><td align="center" styleCode=" Botrule Rrule">38/79 (48%) </td><td align="center" styleCode=" Botrule Rrule">41/78 (53%) </td><td styleCode=" Botrule Rrule"/><td align="center" styleCode=" Botrule Rrule">13/40 (33%) </td><td styleCode=" Botrule Rrule"/></tr><tr><td align="center" styleCode="Lrule Botrule Rrule">4 </td><td align="center" styleCode=" Botrule Rrule">35/58 (60%) </td><td align="center" styleCode=" Botrule Rrule">25/60 (42%) </td><td styleCode=" Botrule Rrule"/><td styleCode=" Botrule Rrule"/><td align="center" styleCode=" Botrule Rrule">35/58 (60%) </td></tr><tr><td align="center" styleCode="Lrule Botrule Rrule">5 </td><td align="center" styleCode=" Botrule Rrule">45/86 (52%) </td><td styleCode=" Botrule Rrule"/><td styleCode=" Botrule Rrule"/><td styleCode=" Botrule Rrule"/><td align="center" styleCode=" Botrule Rrule">56/85 (65%) </td></tr></tbody></table>

16 HOW SUPPLIED/STORAGE AND HANDLING Budesonide Delayed-Release Capsules 3 mg are white to off-white, free flowing pellets, filled in size '1' hard gelatin capsules having opaque light-orange colored cap printed with "720" in black ink and opaque white body and are supplied as follows: NDC: 70518-4613-00 NDC: 70518-4613-01 OUTER PACKAGING: 50 in 1 BOX PACKAGING: 1 in 1 POUCH Store at 20°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature]. Keep container tightly closed. Repackaged and Distributed By: Remedy Repack, Inc. 625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

17 PATIENT COUNSELING INFORMATION Advise Patients to read the FDA-Approved patient labeling (Patient Information). Hypercorticism and Adrenal Axis Suppression Advise patients that budesonide delayed-release capsules may cause hypercorticism and adrenal axis suppression and to follow a taper schedule, as instructed by their healthcare provider if transferring to budesonide delayed-release capsules from systemic corticosteroids [see Warnings and Precautions ( 5.1 , 5.2 )]. Advise patients that replacement of systemic corticosteroids with budesonide delayed-release capsules may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug. Immunosuppression and Increased Risk of Infection Advise patients to avoid exposure to people with varicella (chicken pox) or measles. Advise patients inform their healthcare provider if they are exposed to varicella or measles or if they develop a new or worsening infection [see Warnings and Precautions ( 5.3 )] . Kaposi's Sarcoma Advise patients that Kaposi's sarcoma has been reported in patients receiving corticosteroids for chronic conditions and to inform their healthcare provider if they experience signs or symptoms of Kaposi's sarcoma [see Warnings and Precautions ( 5.4 )] . Pregnancy Advise female patients that budesonide delayed-release capsules may cause fetal harm and to inform their healthcare provider with a known or suspected pregnancy [see Use in Specific Populations ( 8.1 )] . Administration Take budesonide delayed-release capsules once daily in the morning. Swallow budesonide delayed-release capsules whole. Do not chew or crush. For patients unable to swallow an intact capsule, budesonide delayed-release capsules can be opened and administered as follows: Place one tablespoonful of applesauce into a clean container (e.g., empty bowl). The applesauce used should not be hot and should be soft enough to be swallowed without chewing. Open the capsule(s). Carefully empty all the granules inside the capsule(s) on the applesauce. Mix the granules with the applesauce. Consume the entire contents within 30 minutes of mixing. Do not chew or crush the granules. Do not save the applesauce and granules for future use. Follow the applesauce and granules immediately with a glass (8 ounces) of cool water to ensure complete swallowing of the granules. Avoid consumption of grapefruit juice for the duration of their budesonide delayed-release capsules therapy [see Drug Interactions ( 7.1 )].

SPL PATIENT PACKAGE INSERT PATIENT INFORMATION Budesonide (bue des' oh nide) Delayed-Release Capsules Read this Patient Information before you start taking budesonide delayed-release capsules and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. What are budesonide delayed-release capsules ? Budesonide delayed-release capsules are prescription corticosteroid medicine used to treat mild to moderate Crohn's disease that affects part of the small intestine (ileum) and part of the large intestine (ascending colon): in people 8 years of age and older with active Crohn's disease in adults to help keep symptoms from coming back for up to 3 months It is not known if budesonide delayed-release capsules are safe and effective in children under 8 years of age, or in children 8 to 17 years of age who weigh 55 pounds (25 kg) or less, for the treatment of mild to moderate active Crohn's disease that affects part of the small intestine (ileum) and part of the large intestine (ascending colon). It is not known if budesonide delayed-release capsules are safe and effective in children to help keep symptoms of mild to moderate Crohn's disease that affects part of the small intestine (ileum) and part of the large intestine (ascending colon) from coming back. Who should not take budesonide delayed-release capsules? Do not take budesonide delayed-release capsules if: you are allergic to budesonide or any of the ingredients in budesonide delayed-release capsules. See the end of this leaflet for a complete list of ingredients in budesonide delayed-release capsules. Before you take budesonide delayed-release capsules tell your healthcare provider if you have any other medical conditions including if you: have liver problems. are planning to have surgery. have chicken pox or measles or have recently been near anyone with chicken pox or measles. have an infection, including fungal and threadworm (Strongyloides) infections. have diabetes or glaucoma or have a family history of diabetes or glaucoma. have cataracts. have or had tuberculosis. have high blood pressure (hypertension). have decreased bone mineral density (osteoporosis). have stomach ulcers. have malaria of the brain (cerebral malaria). are pregnant or plan to become pregnant. Budesonide delayed-release capsules may harm your unborn baby. Talk to your healthcare provider about the possible risk to your unborn baby if you take budesonide delayed-release capsules when you are pregnant. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during your treatment with budesonide delayed-release capsules. are breastfeeding or plan to breastfeed. It is not known if budesonide passes into your breast milk or if it will affect your baby. Talk to your healthcare provider about the best way to feed your baby if you take budesonide delayed-release capsules. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Budesonide delayed-release capsules and other medicines may affect each other causing side effects. How should I take budesonide delayed-release capsules ? Take budesonide delayed-release capsules exactly as your healthcare provider tells you. Your healthcare provider will tell you how many budesonide delayed-release capsules to take.

ed-release capsules and other medicines may affect each other causing side effects. How should I take budesonide delayed-release capsules ? Take budesonide delayed-release capsules exactly as your healthcare provider tells you. Your healthcare provider will tell you how many budesonide delayed-release capsules to take. Your healthcare provider may change your dose if needed. Take budesonide delayed-release capsules 1 time each day in the morning. Take budesonide delayed-release capsules whole. Do not chew or crush budesonide delayed-release capsules before swallowing. For patients, unable to swallow a whole capsule, budesonide delayed-release capsules can be opened and administered as follows: Place 1 tablespoonful of applesauce into a clean container, such as an empty bowl. The applesauce used should not be hot and should be soft enough to be swallowed without chewing. Open the capsule. You may need to use more than 1 budesonide delayed-release capsules for the dose prescribed by your healthcare provider. Carefully empty all of the granules inside the capsule on the applesauce. Stir the granules with the applesauce. Swallow the applesauce and granules mixture within 30 minutes after preparing it. Follow the applesauce and granules immediately with a glass (8 ounces) of cool water to help with complete swallowing of the granules. Do not chew or crush the granules. Do not save the applesauce and granules for later use. If you take too much budesonide delayed-release capsules call your healthcare provider right away or go to the nearest hospital emergency room. What should I avoid while taking budesonide delayed-release capsules? Do not drink grapefruit juice during your treatment with budesonide delayed-release capsules. Drinking grapefruit juice can increase the level of budesonide in your blood. What are the possible side effects of budesonide delayed-release capsules? Budesonide delayed-release capsules may cause serious side effects, including: Effects of having too much corticosteroid medicine in your blood (hypercorticism). Long-time use of budesonide delayed-release capsules can cause you to have too much corticosteroid medicine in your blood. Tell your healthcare provider if you have any of the following signs and symptoms of hypercorticism: acne thicker or more hair on your body and face bruise easily a fatty pad or hump between your shoulders (buffalo hump) rounding of your face (moon face) pink or purple stretch marks on the skin of your abdomen, thighs, breasts and arms ankle swelling Adrenal suppression. When budesonide delayed-release capsules are taken for a long period of time (chronic use), adrenal suppression can happen. This is a condition in which the adrenal glands do not make enough steroid hormones. Symptoms of adrenal suppression include: tiredness, weakness, nausea and vomiting and low blood pressure. Tell your healthcare provider if you are under stress or have any symptoms of adrenal suppression during treatment with budesonide delayed-release capsules. Worsening of allergies. If you take certain other corticosteroid medicines to treat allergies, switching to budesonide delayed-release capsules may cause your allergies to come back. These allergies may include a skin condition called eczema or inflammation inside your nose (rhinitis). Tell your healthcare provider if any of your allergies become worse while taking budesonide delayed-release capsules. Decreased ability of your body to fight infections (immunosuppression) and increased risk of infection . Corticosteroid medicines, including budesonide delayed-release capsules, lower the ability of your immune system to fight infections and increase the risk of infections caused by virus, bacteria, fungi, protozoan, or certain parasites.

your body to fight infections (immunosuppression) and increased risk of infection . Corticosteroid medicines, including budesonide delayed-release capsules, lower the ability of your immune system to fight infections and increase the risk of infections caused by virus, bacteria, fungi, protozoan, or certain parasites. Corticosteroid medicines including budesonide delayed-release capsules can also: o make current infections worse o increase the risk of infections spreading (disseminated) o increase the risk of making infections active again or making infections worse that have not been active (latent) o hide (mask) some signs of infection These infections can be mild, but can be severe and lead to death. Your healthcare provide should check you closely for signs and symptoms of an infection while taking budesonide delayed-release capsules. Tell your healthcare provider right away about any signs or symptoms of a new or worsening infection while taking budesonide delayed-release capsules, including flu-like symptoms such as:. fever cough chills pain stomach area (abdominal) pain feeling tired aches nausea and vomiting diarrhea o Tuberculosis: If you have inactive (latent) tuberculosis, your tuberculosis may become active again while taking budesonide delayed-release capsules your healthcare provider should check you closely for signs and symptoms of tuberculosis while taking budesonide delayed-release capsules. o Chicken pox and measles: People taking corticosteroid medicines, including E budesonide delayed-release capsules, who have not had chicken pox or measles, should avoid contact with people who have these diseases. Tell your healthcare provider right away if you come in contact with anyone who has chicken pox or measles. o Hepatitis B Virus (HBV) reactivation: If you are a carrier of HBV, the virus can become an active infection again while taking budesonide delayed-release capsules. Your healthcare provider will test you for HBV before you start taking budesonide delayed-release capsules. o Amebiasis: Inactive (latent) amebiasis before you start taking budesonide delayed-release capsules. Your healthcare provider should check you for amebiasis before you start taking budesonide delayed-release capsules in people who have spent time in the tropcs or have unexplained diarrhea. Kaposi's Sarcoma. Kaposi's sarcoma has happened in people who receive corticosteroid therapy, most often for treatment of long-lasting (chronic) conditions. The most common side effects of budesonide delayed-release capsules in adults include: headache vomiting stomach area (abdominal) pain back pain infection in your air passages (respiratory infection) tiredness gas indigestion nausea pain dizziness The most common side effects of budesonide delayed-release capsules in children 8 to 17 years of age, who weigh more than 55 pounds (25 kg), are similar to the most common side effects in adults. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of budesonide delayed-release capsules. For more information, ask your healthcare provider 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 store budesonide delayed-release capsules? Store budesonide delayed-release capsules at room temperature between 68°F to 77°F (20°C to 25°C). Keep budesonide delayed-release capsules in a tightly closed container. Budesonide delayed-release capsules come in child-resistant bottles. Keep budesonide delayed-release capsules and all medicines out of the reach of children.

desonide delayed-release capsules at room temperature between 68°F to 77°F (20°C to 25°C). Keep budesonide delayed-release capsules in a tightly closed container. Budesonide delayed-release capsules come in child-resistant bottles. Keep budesonide delayed-release capsules and all medicines out of the reach of children. General information about the safe and effective use of budesonide delayed-release capsules Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use budesonide delayed-release capsules for a condition for which it was not prescribed. Do not give budesonide delayed-release capsules to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about budesonide delayed-release capsules that is written for health professionals. Please address medical inquiries to, Northstar Rx LLC at Tel.: 1-800-206-7821. What are the ingredients in budesonide delayed-release capsules ? Active ingredient: budesonide, USP Inactive ingredients: acetyltributyl citrate, ethylcellulose aqueous dispersion, gelatin, iron oxide red, iron oxide yellow, methacrylic acid copolymer dispersion, polysorbate 80, simethicone emulsion, sodium lauryl sulfate, sugar spheres, talc, titanium dioxide and triethyl citrate. The capsule shell is printed with black pharmaceutical ink which contains following ingredients: iron oxide black, potassium hydroxide, propylene glycol and shellac. This Patient Information has been approved by the U.S. Food and Drug Administration. Repackaged and Distributed By: Remedy Repack, Inc. 625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762 Rev.: 01/25

<table width="591" ID="ID280" styleCode="Noautorules"><colgroup><col width="252"/><col width="13"/><col width="6"/><col width="320"/></colgroup><tbody><tr><td align="center" colspan="4" styleCode="Lrule Toprule Botrule Rrule" valign="top"><content styleCode="bold">PATIENT INFORMATION</content> <content styleCode="bold">Budesonide (bue des&apos; oh nide) Delayed-Release Capsules</content></td></tr><tr><td align="left" colspan="4" styleCode="Lrule Botrule Rrule" valign="top">Read this Patient Information before you start taking budesonide delayed-release capsules and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.</td></tr><tr><td align="left" colspan="4" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">What are budesonide delayed-release capsules ?</content> Budesonide delayed-release capsules are prescription corticosteroid medicine used to treat mild to moderate Crohn&apos;s disease that affects part of the small intestine (ileum) and part of the large intestine (ascending colon): <list listType="unordered" styleCode="Disc"><item>in people 8 years of age and older with active Crohn&apos;s disease</item><item>in adults to help keep symptoms from coming back for up to 3 months</item></list> It is not known if budesonide delayed-release capsules are safe and effective in children under 8 years of age, or in children 8 to 17 years of age who weigh 55 pounds (25 kg) or less, for the treatment of mild to moderate active Crohn&apos;s disease that affects part of the small intestine (ileum) and part of the large intestine (ascending colon). It is not known if budesonide delayed-release capsules are safe and effective in children to help keep symptoms of mild to moderate Crohn&apos;s disease that affects part of the small intestine (ileum) and part of the large intestine (ascending colon) from coming back. </td></tr><tr><td align="left" colspan="4" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">Who should not take budesonide delayed-release capsules?</content> <content styleCode="bold">Do not take budesonide delayed-release capsules if:</content><list listType="unordered" styleCode="Disc"><item>you are allergic to budesonide or any of the ingredients in budesonide delayed-release capsules.

nt styleCode="bold">Who should not take budesonide delayed-release capsules?</content> <content styleCode="bold">Do not take budesonide delayed-release capsules if:</content><list listType="unordered" styleCode="Disc"><item>you are allergic to budesonide or any of the ingredients in budesonide delayed-release capsules. See the end of this leaflet for a complete list of ingredients in budesonide delayed-release capsules.</item></list></td></tr><tr><td align="left" colspan="4" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">Before you take budesonide delayed-release capsules tell your healthcare provider if you have any other medical conditions including if you:</content><list listType="unordered" styleCode="Disc"><item>have liver problems.</item><item>are planning to have surgery.</item><item>have chicken pox or measles or have recently been near anyone with chicken pox or measles.</item><item>have an infection, including fungal and threadworm (Strongyloides) infections.</item><item>have diabetes or glaucoma or have a family history of diabetes or glaucoma.</item><item>have cataracts.</item><item>have or had tuberculosis.</item><item>have high blood pressure (hypertension).</item><item>have decreased bone mineral density (osteoporosis).</item><item>have stomach ulcers.</item><item>have malaria of the brain (cerebral malaria).</item><item>are pregnant or plan to become pregnant. Budesonide delayed-release capsules may harm your unborn baby. Talk to your healthcare provider about the possible risk to your unborn baby if you take budesonide delayed-release capsules when you are pregnant. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during your treatment with budesonide delayed-release capsules.</item><item>are breastfeeding or plan to breastfeed. It is not known if budesonide passes into your breast milk or if it will affect your baby. Talk to your healthcare provider about the best way to feed your baby if you take budesonide delayed-release capsules.</item></list><content styleCode="bold">Tell your healthcare provider about all the medicines you take,</content>including prescription and over-the-counter medicines, vitamins, and herbal supplements. Budesonide delayed-release capsules and other medicines may affect each other causing side effects. </td></tr><tr><td align="left" colspan="4" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">How should I take budesonide delayed-release capsules ?</content><list listType="unordered" styleCode="Disc"><item>Take budesonide delayed-release capsules exactly as your healthcare provider tells you.</item><item>Your healthcare provider will tell you how many budesonide delayed-release capsules to take. Your healthcare provider may change your dose if needed.</item><item>Take budesonide delayed-release capsules 1 time each day in the morning.</item><item>Take budesonide delayed-release capsules whole. Do not chew or crush budesonide delayed-release capsules before swallowing.</item><item>For patients, unable to swallow a whole capsule, budesonide delayed-release capsules can be opened and administered as follows:</item></list><list listType="ordered" styleCode="Arabic"><item>Place 1 tablespoonful of applesauce into a clean container, such as an empty bowl. The applesauce used should not be hot and should be soft enough to be swallowed without chewing.</item><item>Open the capsule. You may need to use more than 1 budesonide delayed-release capsules for the dose prescribed by your healthcare provider.</item><item>Carefully empty all of the granules inside the capsule on the applesauce.</item><item>Stir the granules with the applesauce.</item><item>Swallow the applesauce and granules mixture within 30 minutes after preparing it.

budesonide delayed-release capsules for the dose prescribed by your healthcare provider.</item><item>Carefully empty all of the granules inside the capsule on the applesauce.</item><item>Stir the granules with the applesauce.</item><item>Swallow the applesauce and granules mixture within 30 minutes after preparing it. Follow the applesauce and granules immediately with a glass (8 ounces) of cool water to help with complete swallowing of the granules.</item><item>Do not chew or crush the granules.</item><item>Do not save the applesauce and granules for later use.</item></list><list listType="unordered" styleCode="Disc"><item>If you take too much budesonide delayed-release capsules call your healthcare provider right away or go to the nearest hospital emergency room.</item></list></td></tr><tr><td align="left" colspan="4" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">What should I avoid while taking budesonide delayed-release capsules?</content><list listType="unordered" styleCode="Disc"><item>Do not drink grapefruit juice during your treatment with budesonide delayed-release capsules. Drinking grapefruit juice can increase the level of budesonide in your blood.</item></list></td></tr><tr><td align="left" colspan="4" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">What are the possible side effects of budesonide delayed-release capsules?</content> <content styleCode="bold">Budesonide delayed-release capsules may cause serious side effects, including:</content><list listType="unordered" styleCode="Disc"><item><content styleCode="bold">Effects of having too much corticosteroid medicine in your blood (hypercorticism).</content>Long-time use of budesonide delayed-release capsules can cause you to have too much corticosteroid medicine in your blood. Tell your healthcare provider if you have any of the following signs and symptoms of hypercorticism: </item></list></td></tr><tr><td colspan="2" styleCode="Lrule" valign="top"><list listType="unordered" styleCode="Circle"><item>acne</item></list></td><td colspan="2" styleCode="Rrule" valign="top"><list listType="unordered" styleCode="Circle"><item>thicker or more hair on your body and face</item></list></td></tr><tr><td colspan="2" styleCode="Lrule" valign="top"><list listType="unordered" styleCode="Circle"><item>bruise easily</item></list></td><td colspan="2" styleCode="Rrule" valign="top"><list listType="unordered" styleCode="Circle"><item>a fatty pad or hump between your shoulders (buffalo hump)</item></list></td></tr><tr><td colspan="2" styleCode="Lrule" valign="top"><list listType="unordered" styleCode="Circle"><item>rounding of your face (moon face)</item></list></td><td colspan="2" styleCode="Rrule" valign="top"><list listType="unordered" styleCode="Circle"><item>pink or purple stretch marks on the skin of your abdomen, thighs, breasts and arms</item></list></td></tr><tr><td colspan="2" styleCode="Lrule" valign="top"><list listType="unordered" styleCode="Circle"><item>ankle swelling</item></list></td><td colspan="2" styleCode="Rrule" valign="top"/></tr><tr><td align="left" colspan="4" styleCode="Lrule Rrule" valign="top"><list listType="unordered" styleCode="Disc"><item><content styleCode="bold">Adrenal suppression.</content>When budesonide delayed-release capsules are taken for a long period of time (chronic use), adrenal suppression can happen. This is a condition in which the adrenal glands do not make enough steroid hormones. Symptoms of adrenal suppression include: tiredness, weakness, nausea and vomiting and low blood pressure. Tell your healthcare provider if you are under stress or have any symptoms of adrenal suppression during treatment with budesonide delayed-release capsules.

h the adrenal glands do not make enough steroid hormones. Symptoms of adrenal suppression include: tiredness, weakness, nausea and vomiting and low blood pressure. Tell your healthcare provider if you are under stress or have any symptoms of adrenal suppression during treatment with budesonide delayed-release capsules. </item><item><content styleCode="bold">Worsening of allergies.</content>If you take certain other corticosteroid medicines to treat allergies, switching to budesonide delayed-release capsules may cause your allergies to come back. These allergies may include a skin condition called eczema or inflammation inside your nose (rhinitis). Tell your healthcare provider if any of your allergies become worse while taking budesonide delayed-release capsules. </item><item><content styleCode="bold">Decreased ability of your body to fight infections (immunosuppression) and increased risk of infection</content>. Corticosteroid medicines, including budesonide delayed-release capsules, lower the ability of your immune system to fight infections and increase the risk of infections caused by virus, bacteria, fungi, protozoan, or certain parasites. Corticosteroid medicines including budesonide delayed-release capsules can also: </item></list> o make current infections worse o increase the risk of infections spreading (disseminated) o increase the risk of making infections active again or making infections worse that have not been active (latent) o hide (mask) some signs of infection These infections can be mild, but can be severe and lead to death. Your healthcare provide should check you closely for signs and symptoms of an infection while taking budesonide delayed-release capsules. Tell your healthcare provider right away about any signs or symptoms of a new or worsening infection while taking budesonide delayed-release capsules, including flu-like symptoms such as:. </td></tr><tr><td colspan="3" styleCode="Lrule" valign="top"><list listType="unordered" styleCode="Circle"><item>fever</item></list></td><td styleCode="Rrule" valign="top"><list listType="unordered" styleCode="Circle"><item>cough</item></list></td></tr><tr><td colspan="3" styleCode="Lrule" valign="top"><list listType="unordered" styleCode="Circle"><item>chills</item></list></td><td styleCode="Rrule" valign="top"><list listType="unordered" styleCode="Circle"><item>pain</item></list></td></tr><tr><td colspan="3" styleCode="Lrule" valign="top"><list listType="unordered" styleCode="Circle"><item>stomach area (abdominal) pain</item></list></td><td styleCode="Rrule" valign="top"><list listType="unordered" styleCode="Circle"><item>feeling tired</item></list></td></tr><tr><td colspan="3" styleCode="Lrule" valign="top"><list listType="unordered" styleCode="Circle"><item>aches</item></list></td><td styleCode="Rrule" valign="top"><list listType="unordered" styleCode="Circle"><item>nausea and vomiting</item></list></td></tr><tr><td colspan="3" styleCode="Lrule" valign="top"><list listType="unordered" styleCode="Circle"><item>diarrhea</item></list></td><td styleCode="Rrule" valign="top"/></tr><tr><td align="left" colspan="4" styleCode="Lrule Rrule" valign="top">o Tuberculosis: If you have inactive (latent) tuberculosis, your tuberculosis may become active again while taking budesonide delayed-release capsules your healthcare provider should check you closely for signs and symptoms of tuberculosis while taking budesonide delayed-release capsules. o Chicken pox and measles: People taking corticosteroid medicines, including E budesonide delayed-release capsules, who have not had chicken pox or measles, should avoid contact with people who have these diseases. Tell your healthcare provider right away if you come in contact with anyone who has chicken pox or measles.

Chicken pox and measles: People taking corticosteroid medicines, including E budesonide delayed-release capsules, who have not had chicken pox or measles, should avoid contact with people who have these diseases. Tell your healthcare provider right away if you come in contact with anyone who has chicken pox or measles. o Hepatitis B Virus (HBV) reactivation: If you are a carrier of HBV, the virus can become an active infection again while taking budesonide delayed-release capsules. Your healthcare provider will test you for HBV before you start taking budesonide delayed-release capsules. o Amebiasis: Inactive (latent) amebiasis before you start taking budesonide delayed-release capsules. Your healthcare provider should check you for amebiasis before you start taking budesonide delayed-release capsules in people who have spent time in the tropcs or have unexplained diarrhea. <list listType="unordered" styleCode="Disc"><item><content styleCode="bold">Kaposi&apos;s Sarcoma.</content>Kaposi&apos;s sarcoma has happened in people who receive corticosteroid therapy, most often for treatment of long-lasting (chronic) conditions. </item></list></td></tr><tr><td align="left" colspan="4" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">The most common side effects of budesonide delayed-release capsules in adults include:</content></td></tr><tr><td styleCode="Lrule" valign="top"><list listType="unordered" styleCode="Disc"><item>headache</item></list></td><td colspan="3" styleCode="Rrule" valign="top"><list listType="unordered" styleCode="Disc"><item>vomiting</item></list></td></tr><tr><td styleCode="Lrule" valign="top"><list listType="unordered" styleCode="Disc"><item>stomach area (abdominal) pain</item></list></td><td colspan="3" styleCode="Rrule" valign="top"><list listType="unordered" styleCode="Disc"><item>back pain</item></list></td></tr><tr><td styleCode="Lrule" valign="top"><list listType="unordered" styleCode="Disc"><item>infection in your air passages (respiratory infection)</item></list></td><td colspan="3" styleCode="Rrule" valign="top"><list listType="unordered" styleCode="Disc"><item>tiredness</item></list></td></tr><tr><td styleCode="Lrule" valign="top"><list listType="unordered" styleCode="Disc"><item>gas</item></list></td><td colspan="3" styleCode="Rrule" valign="top"><list listType="unordered" styleCode="Disc"><item>indigestion</item></list></td></tr><tr><td styleCode="Lrule" valign="top"><list listType="unordered" styleCode="Disc"><item>nausea</item></list></td><td colspan="3" styleCode="Rrule" valign="top"><list listType="unordered" styleCode="Disc"><item>pain</item></list></td></tr><tr><td styleCode="Lrule" valign="top"/><td colspan="3" styleCode="Rrule" valign="top"><list listType="unordered" styleCode="Disc"><item>dizziness</item></list></td></tr><tr><td align="left" colspan="4" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">The most common side effects of budesonide delayed-release capsules in children</content>8 to 17 years of age, who weigh more than 55 pounds (25 kg), are similar to the most common side effects in adults. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of budesonide delayed-release capsules. For more information, ask your healthcare provider or pharmacist. <content styleCode="bold">Call your doctor for medical advice about side effects.

althcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of budesonide delayed-release capsules. For more information, ask your healthcare provider or pharmacist. <content styleCode="bold">Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</content></td></tr><tr><td align="left" colspan="4" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">How should I store budesonide delayed-release capsules?</content><list listType="unordered" styleCode="Disc"><item>Store budesonide delayed-release capsules at room temperature between 68&#xB0;F to 77&#xB0;F (20&#xB0;C to 25&#xB0;C).</item><item>Keep budesonide delayed-release capsules in a tightly closed container.</item><item>Budesonide delayed-release capsules come in child-resistant bottles.</item></list><content styleCode="bold">Keep budesonide delayed-release capsules and all medicines out of the reach of children.</content></td></tr><tr><td align="left" colspan="4" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">General information about the safe and effective use of budesonide delayed-release capsules</content> Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use budesonide delayed-release capsules for a condition for which it was not prescribed. Do not give budesonide delayed-release capsules to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about budesonide delayed-release capsules that is written for health professionals. <content styleCode="bold">Please address medical inquiries to, Northstar Rx LLC at Tel.: 1-800-206-7821.</content></td></tr><tr><td align="left" colspan="4" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">What are the ingredients in budesonide delayed-release capsules ?</content> <content styleCode="bold">Active ingredient:</content>budesonide, USP <content styleCode="bold">Inactive ingredients:</content>acetyltributyl citrate, ethylcellulose aqueous dispersion, gelatin, iron oxide red, iron oxide yellow, methacrylic acid copolymer dispersion, polysorbate 80, simethicone emulsion, sodium lauryl sulfate, sugar spheres, talc, titanium dioxide and triethyl citrate. The capsule shell is printed with black pharmaceutical ink which contains following ingredients: iron oxide black, potassium hydroxide, propylene glycol and shellac. This Patient Information has been approved by the U.S. Food and Drug Administration. </td></tr><tr><td align="center" colspan="4" styleCode="Lrule Botrule Rrule" valign="top"><paragraph><content styleCode="bold">Repackaged and Distributed By:</content></paragraph><paragraph><content styleCode="bold">Remedy Repack, Inc.</content></paragraph><paragraph><content styleCode="bold">625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762</content></paragraph></td></tr><tr><td align="right" colspan="4" styleCode="Lrule Botrule Rrule" valign="top">Rev.: 01/25</td></tr></tbody></table>

1 INDICATIONS AND USAGE Budesonide extended-release tablets are indicated for the induction of remission in patients with active, mild to moderate ulcerative colitis. Budesonide extended-release tablets are a glucocorticosteroid indicated for the induction of remission in patients with active, mild to moderate ulcerative colitis. ( 1 )

2 DOSAGE AND ADMINISTRATION The recommended dosage for the induction of remission in adult patients with active, mild to moderate ulcerative colitis is one 9 mg tablet to be taken once daily in the morning with or without food for up to 8 weeks. ( 2.1 ) 2.1 Mild to Moderate Ulcerative Colitis The recommended dosage for the induction of remission in adult patients with active, mild to moderate ulcerative colitis is 9 mg taken orally once daily in the morning with or without food for up to 8 weeks. Budesonide extended-release tablets should be swallowed whole and not chewed or crushed. 2.2 CYP3A4 Inhibitors If concomitant administration with ketoconazole, or any other CYP3A4 inhibitor, is indicated, patients should be closely monitored for increased signs and/or symptoms of hypercorticism. Avoid grapefruit juice, which is known to inhibit CYP3A4, when taking budesonide extended-release tablets. In these cases, discontinuation of budesonide extended- release tablets or the CYP3A4 inhibitor should be considered [see Drug Interactions ( 7 ) and Clinical Pharmacology ( 12.3 ) ] . 2.1 Mild to Moderate Ulcerative Colitis The recommended dosage for the induction of remission in adult patients with active, mild to moderate ulcerative colitis is 9 mg taken orally once daily in the morning with or without food for up to 8 weeks. Budesonide extended-release tablets should be swallowed whole and not chewed or crushed. 2.2 CYP3A4 Inhibitors If concomitant administration with ketoconazole, or any other CYP3A4 inhibitor, is indicated, patients should be closely monitored for increased signs and/or symptoms of hypercorticism. Avoid grapefruit juice, which is known to inhibit CYP3A4, when taking budesonide extended-release tablets. In these cases, discontinuation of budesonide extended- release tablets or the CYP3A4 inhibitor should be considered [see Drug Interactions ( 7 ) and Clinical Pharmacology ( 12.3 ) ] .

4 CONTRAINDICATIONS Budesonide extended-release tablets are contraindicated in patients with hypersensitivity to budesonide or any of the ingredients of budesonide extended-release tablets. Anaphylactic reactions have occurred with other budesonide formulations [see Adverse Reactions ( 6.2 )]. Known hypersensitivity to budesonide or any of the ingredients in budesonide extended-release tablets ( 4 )

5 WARNINGS AND PRECAUTIONS Hypercorticism and adrenal suppression: May occur with treatment; monitor for signs and symptoms. ( 5.1 ) Transferring patients from systemic glucocorticoids: Risk of impaired adrenal function when transferring from glucocorticoid treatment with higher systemic effects to glucocorticoid treatment with lower systemic effects, such as budesonide extended-release tablets. Taper patients slowly from systemic corticosteroids if transferring to budesonide extended-release tablets. ( 5.2 ) Immunosuppression and Increased Risk of Infection: Increased risk of viral, bacterial, fungal, protozoal and helminthic infections, including potentially fatal varicella and measles infection. Monitor patients for new or worsening infection and consider drug discontinuation. Avoid use in patients with fungal infections, Strongyloides infestation, cerebral malaria and ocular herpes simplex. Screen for hepatitis B infection. ( 5.3 ) Kaposi’s Sarcoma: Reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. ( 5.4 ) 5.1 Hypercorticism and Adrenal Axis Suppression Systemic effects such as hypercorticism and adrenal suppression may occur with use corticosteroids, including budesonide extended-release tablets. Monitor patients for signs and symptoms of hypercorticism and adrenal axis suppression during treatment with budesonide extended-release tablets. Patients with moderate to severe liver disease should be monitored for increased signs and/or symptoms of hypercorticism. Discontinuing the use of budesonide extended-release tablets should be considered in these patients [see Use in Specific Populations ( 8.6 )]. Glucocorticosteroids, including budesonide extended-release tablets, can reduce the response of the hypothalamus-pituitary-adrenal (HPA) axis to stress. In situations where patients are subject to surgery or other stress situations, supplementation with a systemic glucocorticosteroid is recommended. 5.2 Transferring Patients from Systemic Glucocorticosteroid Therapy Care is needed in patients who are transferred from glucocorticosteroid treatment with higher systemic effects to glucocorticosteroids with lower systemic effects, such as budesonide extended-release tablets, since symptoms attributed to withdrawal of steroid therapy, including those of acute adrenal suppression or benign intracranial hypertension, may develop. Adrenocortical function monitoring may be required in these patients, and the dose of glucocorticosteroid treatment with high systemic effects should be reduced cautiously. Replacement of systemic glucocorticosteroids with budesonide extended-release tablets may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug. 5.3 Immunosuppression and Increased Risk of Infection Corticosteroids, including budesonide extended-release tablets, suppress the immune system and increase the risk of infection with any pathogen, including viral, bacterial, fungal, protozoan, or helminthic pathogens. Corticosteroids can: Reduce resistance to new infections Exacerbate existing infections Increase the risk of disseminated infections Increase the risk of reactivation or exacerbation of latent infections Mask some signs of infection Corticosteroid-associated infections can be mild but can be severe and at times fatal. The rate of infectious complications increases with increasing corticosteroid dosages.

s Increase the risk of disseminated infections Increase the risk of reactivation or exacerbation of latent infections Mask some signs of infection Corticosteroid-associated infections can be mild but can be severe and at times fatal. The rate of infectious complications increases with increasing corticosteroid dosages. Monitor patients for the development of infection and consider discontinuation of budesonide extended-release tablets if the patient develops an infection while on treatment. Tuberculosis If budesonide extended-release tablets are used in patients with latent tuberculosis or tuberculin reactivity, reactivation of tuberculosis may occur. Closely monitor such patients for reactivation. During prolonged budesonide extended-release tablet therapy, patients with latent tuberculosis or tuberculin reactivity should receive chemoprophylaxis. Varicella Zoster and Measles Viral Infections Varicella and measles can have a serious or even fatal course in non-immune patients taking corticosteroids, including budesonide extended-release tablets. In corticosteroid-treated patients who have not had these diseases or are non-immune, particular care should be taken to avoid exposure to varicella and measles: If a budesonide extended-release tablets-treated patient is exposed to varicella, prophylaxis with varicella zoster immune globulin may be indicated. If varicella develops, treatment with antiviral agents may be considered. If a budesonide extended-release tablets-treated patient is exposed to measles, prophylaxis with immunoglobulin may be indicated. Hepatitis B Virus Reactivation Hepatitis B virus reactivation can occur in patients who are hepatitis B carriers treated with immunosuppressive dosages of corticosteroids, including budesonide extended-release tablets. Reactivation can also occur infrequently in corticosteroid-treated patients who appear to have resolved hepatitis B infection. Screen patients for hepatitis B infection before initiating immunosuppressive (e.g., prolonged) treatment with budesonide extended-release tablets. For patients who show evidence of hepatitis B infection, recommend consultation with physicians with expertise in managing hepatitis B regarding monitoring and consideration for hepatitis B antiviral therapy. Fungal Infections Corticosteroids, including budesonide extended-release tablets, may exacerbate systemic fungal infections; therefore, avoid budesonide extended-release tablets use in the presence of such infections. For patients on chronic budesonide extended-release tablets therapy who develop systemic fungal infections, budesonide extended-release tablets withdrawal or dosage reduction is recommended. Amebiasis Corticosteroids, including budesonide extended-release tablets, may activate latent amebiasis. Therefore, it is recommended that latent amebiasis or active amebiasis be ruled out before initiating budesonide extended-release tablets in patients who have spent time in the tropics or patients with unexplained diarrhea. Strongyloides Infestation Avoid budesonide extended-release tablets in patients with known or suspected Strongyloides (threadworm) infection. Corticosteroids-induced immunosuppression may lead to Strongyloides superinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia. Cerebral Malaria Avoid corticosteroids, including budesonide extended-release tablets, in patients with cerebral malaria. 5.4 Kaposi’s Sarcoma Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement of Kaposi’s sarcoma.

, including budesonide extended-release tablets, in patients with cerebral malaria. 5.4 Kaposi’s Sarcoma Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement of Kaposi’s sarcoma. 5.5 Increased Systemic Glucocorticoid Susceptibility Reduced liver function affects the elimination of glucocorticosteroids, and increased systemic availability of oral budesonide has been demonstrated in patients with liver cirrhosis [seeUse in Specific Populations ( 8.6 )] . 5.6 Other Glucocorticosteroid Effects Caution should be taken in patients with hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or with any other condition where glucocorticosteroids may have unwanted effects.

6 ADVERSE REACTIONS Systemic glucocorticosteroid use may result in the following: Hypercorticism and Adrenal Suppression [see Warnings and Precautions ( 5.1 )] Symptoms of steroid withdrawal in those patients transferring from Systemic Glucocorticosteroid Therapy [see Warnings and Precautions ( 5.2 )] Immunosuppression and Increased Risk of Infection [see Warnings and Precautions ( 5.3 )] Kaposi’s Sarcoma [see Warnings and Precautions ( 5.4 )] Increased Systemic Glucocorticoid Susceptibility [see Warnings and Precautions ( 5. 5 )] Other Glucocorticosteroid Effects [see Warnings and Precautions ( 5. 6 )] Most common adverse reactions (incidence ≥2%) are headache, nausea, decreased blood cortisol, upper abdominal pain, fatigue, flatulence, abdominal distension, acne, urinary tract infection, arthralgia, and constipation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Oceanside Pharmaceuticals at 1-800-321-4576 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 safety of budesonide extended-release tablets has been evaluated in controlled and open-label clinical trials which enrolled a combined total of 1,105 patients with ulcerative colitis. In two 8-week, placebo-controlled studies in patients with active disease (Study 1 and Study 2), a total of 255 patients received budesonide extended-release tablets 9 mg, 254 patients received budesonide extended-release tablets 6 mg, and 258 patients received placebo. They ranged in age from 18-77 years (mean=43), 56% were male, and 75% were Caucasian. The most common adverse reactions were headache, nausea, decreased blood cortisol, upper abdominal pain, fatigue, flatulence, abdominal distension, acne, urinary tract infection, arthralgia, and constipation. The adverse reactions occurring in 2% or more of patients on therapy with budesonide extended-release tablets 9 mg are summarized in Table 1. Table 1: Summary of Adverse Reactions in Two Placebo-Controlled Trials Experienced by at Least 2% of the Budesonide Extended-Release Tablets 9 mg Group (Studies 1 and 2) Budesonide Extended- Release Tablets 9 mg (N=255) n (%) Budesonide Extended- Release Tablets 6 mg (N=254) n (%) Placebo (N=258) n (%) Headache 29 (11.4) 37 (14.6) 27 (10.5) Nausea 13 (5.1) 12 (4.7) 11 (4.3) Decreased blood cortisol 11 (4.3) 6 (2.4) 1 (0.4) Upper abdominal pain 10 (3.9) 8 (3.1) 5 (1.9) Fatigue 8 (3.1) 5 (2.0) 5 (1.9) Flatulence 6 (2.4) 8 (3.1) 5 (1.9) Abdominal distension 6 (2.4) 4 (1.6) 2 (0.8) Acne 6 (2.4) 2 (0.8) 5 (1.9) Urinary tract infection 5 (2.0) 1 (0.4) 1 (0.4) Arthralgia 5 (2.0) 5 (2.0) 4 (1.6) Constipation 5 (2.0) 1 (0.4) 2 (0.8) Of budesonide extended-release tablets 9 mg patients, a total of 15% discontinued treatment due to any adverse event (including adverse reactions) compared with 17% in the placebo group. Table 2 summarizes the percentages of patients reporting glucocorticoid-related effects in the 2 placebo-controlled studies.

2 (0.8) Of budesonide extended-release tablets 9 mg patients, a total of 15% discontinued treatment due to any adverse event (including adverse reactions) compared with 17% in the placebo group. Table 2 summarizes the percentages of patients reporting glucocorticoid-related effects in the 2 placebo-controlled studies. Table 2: Summary of Glucocorticoid-Related Effects in Two Placebo-Controlled Trials (Studies 1 and 2) Budesonide Extended- Release Tablets 9 mg (N=255) n (%) Budesonide Extended- Release Tablets 6 mg (N=254) n (%) Placebo (N=258) n (%) Overall 26 (10.2) 19 (7.5) 27 (10.5) Mood changes 9 (3.5) 10 (3.9) 11 (4.3) Sleep changes 7 (2.7) 10 (3.9) 12 (4.7) Insomnia 6 (2.4) 6 (2.4) 8 (3.1) Acne 6 (2.4) 2 (0.8) 5 (1.9) Moon face 3 (1.2) 3 (1.2) 4 (1.6) Fluid retention 2 (0.8) 3 (1.2) 3 (1.2) Hirsutism 1 (0.4) 0 0 Striae rubrae 0 0 2 (0.8) Flushing 0 1 (0.4) 3 (1.2) No clinically significant differences were observed with respect to the overall percentages of patients with any glucocorticoid-related effects between budesonide extended-release tablets and placebo after 8 weeks of induction therapy. Study 3 was an open-label study evaluating budesonide extended-release tablets 9 mg once daily for 8 weeks in 60 patients who had previously completed an 8-week induction study (Study 1) but had not achieved remission. Among patients who took budesonide extended-release tablets 9 mg up to 16 weeks cumulatively across Study 1 and Study 3 combined, similar rates of adverse reactions and glucocorticoid-related effects were seen compared to those who took budesonide extended-release tablets 9 mg for 8 weeks in Study 1. In Study 4, the safety of long-term treatment with budesonide extended-release tablets 6 mg was evaluated in a placebo-controlled 12-month maintenance study of 123 patients. Patients who had previously completed 8 weeks of therapy in any induction study (Study 1, 2, or 3) and were in remission were randomized to budesonide extended-release tablets 6 mg or placebo once daily for 12 months. In patients who took budesonide extended-release tablets 6 mg for up to 12 months, similar rates of adverse reactions were seen between placebo and budesonide extended-release tablets 6 mg. After up to 12 months of study treatment, 77% (27/35) of the patients in the budesonide extended-release tablets 6 mg and 74% (29/39) of the patients in the placebo treatment groups had normal bone density scans. In Study 4, the glucocorticoid-related effects were similar in patients with up to 12 months of therapy with budesonide extended-release tablets 6 mg and placebo (Table 3). Table 3: Summary of Glucocorticoid-Related Effects Over 12-Month Treatment (Study 4) Budesonide Extended- Release Tablets 6 mg (N=62) n (%) Placebo (N=61) n (%) Overall 9 (14.5) 7 (11.5) Insomnia 4 (6.5) 4 (6.6) Mood changes 4 (6.5) 2 (3.3) Moon face 3 (4.8) 3 (4.9) Sleep changes 3 (4.8) 3 (4.9) Acne 3 (4.8) 0 Hirsutism 3 (4.8) 0 Flushing 1 (1.6) 1 (1.6) Fluid retention 1 (1.6) 1 (1.6) 6.2 Postmarketing Experience In addition to adverse events reported from clinical trials, the following adverse reactions have been identified during post-approval use of oral budesonide. 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. These events have been chosen for inclusion due to either their seriousness, frequency of reporting or causal connection to budesonide extended-release tablets, or a combination of these factors.

in size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting or causal connection to budesonide extended-release tablets, or a combination of these factors. Gastrointestinal Disorders: diarrhea, rectal bleeding General Disorders and Administrative Site Conditions: peripheral edema Immune System Disorders: anaphylactic reactions Musculoskeletal and Connective Tissue Disorders: muscle cramps/spasms Nervous System Disorders: benign intracranial hypertension, dizziness Psychiatric Disorders: mood swings Skin and Subcutaneous Tissue Disorders: rash Vascular Disorders: increased blood pressure

<table ID="_RefID0E6DAE" cellpadding="0pt" cellspacing="0pt" width="100%"><caption>Table 1: Summary of Adverse Reactions in Two Placebo-Controlled Trials Experienced by at Least 2% of the Budesonide Extended-Release Tablets 9 mg Group (Studies 1 and 2)</caption><col width="34%"/><col width="24%"/><col width="21%"/><col width="21%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td align="center" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Budesonide Extended- Release Tablets</content></paragraph><paragraph><content styleCode="bold">9 mg</content> <content styleCode="bold">(N=255)</content> <content styleCode="bold">n (%)</content></paragraph></td><td align="center" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Budesonide Extended- Release Tablets</content></paragraph><paragraph><content styleCode="bold">6 mg</content> <content styleCode="bold">(N=254)</content> <content styleCode="bold">n (%)</content></paragraph></td><td align="center" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Placebo</content> <content styleCode="bold">(N=258)</content> <content styleCode="bold">n (%)</content></paragraph></td></tr><tr><td valign="top"><paragraph>Headache</paragraph></td><td align="center" valign="top"><paragraph>29 (11.4)</paragraph></td><td align="center" valign="top"><paragraph>37 (14.6)</paragraph></td><td align="center" valign="top"><paragraph>27 (10.5)</paragraph></td></tr><tr><td valign="top"><paragraph>Nausea</paragraph></td><td align="center" valign="top"><paragraph>13 (5.1)</paragraph></td><td align="center" valign="top"><paragraph>12 (4.7)</paragraph></td><td align="center" valign="top"><paragraph>11 (4.3)</paragraph></td></tr><tr><td valign="top"><paragraph>Decreased blood cortisol</paragraph></td><td align="center" valign="top"><paragraph>11 (4.3)</paragraph></td><td align="center" valign="top"><paragraph>6 (2.4)</paragraph></td><td align="center" valign="top"><paragraph>1 (0.4)</paragraph></td></tr><tr><td valign="top"><paragraph>Upper abdominal pain</paragraph></td><td align="center" valign="top"><paragraph>10 (3.9)</paragraph></td><td align="center" valign="top"><paragraph>8 (3.1)</paragraph></td><td align="center" valign="top"><paragraph>5 (1.9)</paragraph></td></tr><tr><td valign="top"><paragraph>Fatigue</paragraph></td><td align="center" valign="top"><paragraph>8 (3.1)</paragraph></td><td align="center" valign="top"><paragraph>5 (2.0)</paragraph></td><td align="center" valign="top"><paragraph>5 (1.9)</paragraph></td></tr><tr><td valign="top"><paragraph>Flatulence</paragraph></td><td align="center" valign="top"><paragraph>6 (2.4)</paragraph></td><td align="center" valign="top"><paragraph>8 (3.1)</paragraph></td><td align="center" valign="top"><paragraph>5 (1.9)</paragraph></td></tr><tr><td valign="top"><paragraph>Abdominal distension</paragraph></td><td align="center" valign="top"><paragraph>6 (2.4)</paragraph></td><td align="center" valign="top"><paragraph>4 (1.6)</paragraph></td><td align="center" valign="top"><paragraph>2 (0.8)</paragraph></td></tr><tr><td valign="top"><paragraph>Acne</paragraph></td><td align="center" valign="top"><paragraph>6 (2.4)</paragraph></td><td align="center" valign="top"><paragraph>2 (0.8)</paragraph></td><td align="center" valign="top"><paragraph>5 (1.9)</paragraph></td></tr><tr><td valign="top"><paragraph>Urinary tract infection</paragraph></td><td align="center" valign="top"><paragraph>5 (2.0)</par

nter" valign="top"><paragraph>6 (2.4)</paragraph></td><td align="center" valign="top"><paragraph>2 (0.8)</paragraph></td><td align="center" valign="top"><paragraph>5 (1.9)</paragraph></td></tr><tr><td valign="top"><paragraph>Urinary tract infection</paragraph></td><td align="center" valign="top"><paragraph>5 (2.0)</par agraph></td><td align="center" valign="top"><paragraph>1 (0.4)</paragraph></td><td align="center" valign="top"><paragraph>1 (0.4)</paragraph></td></tr><tr><td valign="top"><paragraph>Arthralgia</paragraph></td><td align="center" valign="top"><paragraph>5 (2.0)</paragraph></td><td align="center" valign="top"><paragraph>5 (2.0)</paragraph></td><td align="center" valign="top"><paragraph>4 (1.6)</paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph>Constipation</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>5 (2.0)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>1 (0.4)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>2 (0.8)</paragraph></td></tr></tbody></table>

graph>Constipation</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>5 (2.0)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>1 (0.4)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>2 (0.8)</paragraph></td></tr></tbody></table> <table ID="_RefID0EULAE" cellpadding="0pt" cellspacing="0pt" width="100%"><caption>Table 2: Summary of Glucocorticoid-Related Effects in Two Placebo-Controlled Trials (Studies 1 and 2)</caption><col width="34%"/><col width="24%"/><col width="21%"/><col width="21%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td align="center" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Budesonide Extended- Release Tablets</content></paragraph><paragraph><content styleCode="bold">9 mg</content> <content styleCode="bold">(N=255)</content> <content styleCode="bold">n (%)</content></paragraph></td><td align="center" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Budesonide Extended- Release Tablets</content></paragraph><paragraph><content styleCode="bold">6 mg</content> <content styleCode="bold">(N=254)</content> <content styleCode="bold">n (%)</content></paragraph></td><td align="center" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Placebo</content> <content styleCode="bold">(N=258)</content> <content styleCode="bold">n (%)</content></paragraph></td></tr><tr><td valign="top"><paragraph>Overall</paragraph></td><td align="center" valign="top"><paragraph>26 (10.2)</paragraph></td><td align="center" valign="top"><paragraph>19 (7.5)</paragraph></td><td align="center" valign="top"><paragraph>27 (10.5)</paragraph></td></tr><tr><td valign="top"><paragraph>Mood changes</paragraph></td><td align="center" valign="top"><paragraph>9 (3.5)</paragraph></td><td align="center" valign="top"><paragraph>10 (3.9)</paragraph></td><td align="center" valign="top"><paragraph>11 (4.3)</paragraph></td></tr><tr><td valign="top"><paragraph>Sleep changes</paragraph></td><td align="center" valign="top"><paragraph>7 (2.7)</paragraph></td><td align="center" valign="top"><paragraph>10 (3.9)</paragraph></td><td align="center" valign="top"><paragraph>12 (4.7)</paragraph></td></tr><tr><td valign="top"><paragraph>Insomnia</paragraph></td><td align="center" valign="top"><paragraph>6 (2.4)</paragraph></td><td align="center" valign="top"><paragraph>6 (2.4)</paragraph></td><td align="center" valign="top"><paragraph>8 (3.1)</paragraph></td></tr><tr><td valign="top"><paragraph>Acne</paragraph></td><td align="center" valign="top"><paragraph>6 (2.4)</paragraph></td><td align="center" valign="top"><paragraph>2 (0.8)</paragraph></td><td align="center" valign="top"><paragraph>5 (1.9)</paragraph></td></tr><tr><td valign="top"><paragraph>Moon face</paragraph></td><td align="center" valign="top"><paragraph>3 (1.2)</paragraph></td><td align="center" valign="top"><paragraph>3 (1.2)</paragraph></td><td align="center" valign="top"><paragraph>4 (1.6)</paragraph></td></tr><tr><td valign="top"><paragraph>Fluid retention</paragraph></td><td align="center" valign="top"><paragraph>2 (0.8)</paragraph></td><td align="center" valign="top"><paragraph>3 (1.2)</paragraph></td><td align="center" valign="top"><paragraph>3 (1.2)</paragraph></td></tr><tr><td valign="top"><paragraph>Hirsutism</paragraph></td><td align="center" valign="top"><paragraph>1 (0.4)</paragraph></td><td align="center" valign="top"><paragraph>0</paragraph></td><td align="center" valign="top"><paragraph>0</paragraph></td></tr><tr><td valign="top"><paragraph>Striae rubrae</paragraph></td><td align="center" valign="top"><paragraph>0</paragraph></td><td align="center" valign="top"><paragraph>0</paragraph></td><td align="center" valign="top"><paragraph>2 (0

raph>0</paragraph></td><td align="center" valign="top"><paragraph>0</paragraph></td></tr><tr><td valign="top"><paragraph>Striae rubrae</paragraph></td><td align="center" valign="top"><paragraph>0</paragraph></td><td align="center" valign="top"><paragraph>0</paragraph></td><td align="center" valign="top"><paragraph>2 (0 .8)</paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph>Flushing</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>1 (0.4)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>3 (1.2)</paragraph></td></tr></tbody></table>

top"><paragraph>Flushing</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>1 (0.4)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>3 (1.2)</paragraph></td></tr></tbody></table> <table ID="_RefID0EZSAE" cellpadding="0pt" cellspacing="0pt" width="67.44%"><caption>Table 3: Summary of Glucocorticoid-Related Effects Over 12-Month Treatment (Study 4)</caption><col width="20%"/><col width="25%"/><col width="31%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td align="center" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Budesonide Extended- Release Tablets 6 mg</content> <content styleCode="bold">(N=62)</content> <content styleCode="bold">n (%)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Placebo</content> <content styleCode="bold">(N=61)</content> <content styleCode="bold">n (%)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Overall</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>9 (14.5)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7 (11.5)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Insomnia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4 (6.5)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4 (6.6)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Mood changes</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4 (6.5)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2 (3.3)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Moon face</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3 (4.8)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3 (4.9)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Sleep changes</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3 (4.8)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3 (4.9)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Acne</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3 (4.8)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hirsutism</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3 (4.8)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Flushing</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (1.6)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (1.6)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Fluid retention</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>1 (1.6)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>1 (1.6)</paragraph></td></tr></tbody></table>

7 DRUG INTERACTIONS Avoid cytochrome P450 3A4 inhibitors (e.g., ketoconazole, grapefruit juice). May cause increased systemic corticosteroid effects. ( 2.2 , 7 , 12.3 ) 7.1 Interaction with CYP3A4 Inhibitors Concomitant oral administration of ketoconazole (a known inhibitor of CYP3A4 activity in the liver and in the intestinal mucosa) caused an eight-fold increase of the systemic exposure to oral budesonide. If treatment with inhibitors of CYP3A4 activity (such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, erythromycin) is indicated, discontinuation of budesonide extended-release tablets should be considered. After extensive intake of grapefruit juice (which inhibits CYP3A4 activity predominantly in the intestinal mucosa), the systemic exposure for oral budesonide increased about two times. Ingestion of grapefruit or grapefruit juice should be avoided in connection with budesonide extended-release tablets administration [see Dosage and Administration ( 2 ) and Clinical Pharmacology ( 12.3 )]. 7.2 Inhibitors of Gastric Acid Secretion Since the dissolution of the coating of budesonide extended-release tablets are pH dependent, the release properties and uptake of the compound may be altered when budesonide extended-release tablets are used after treatment with gastric acid reducing agents (e.g., proton pump inhibitors (PPIs), H 2 blockers and antacids). 7.1 Interaction with CYP3A4 Inhibitors Concomitant oral administration of ketoconazole (a known inhibitor of CYP3A4 activity in the liver and in the intestinal mucosa) caused an eight-fold increase of the systemic exposure to oral budesonide. If treatment with inhibitors of CYP3A4 activity (such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, erythromycin) is indicated, discontinuation of budesonide extended-release tablets should be considered. After extensive intake of grapefruit juice (which inhibits CYP3A4 activity predominantly in the intestinal mucosa), the systemic exposure for oral budesonide increased about two times. Ingestion of grapefruit or grapefruit juice should be avoided in connection with budesonide extended-release tablets administration [see Dosage and Administration ( 2 ) and Clinical Pharmacology ( 12.3 )].

vity predominantly in the intestinal mucosa), the systemic exposure for oral budesonide increased about two times. Ingestion of grapefruit or grapefruit juice should be avoided in connection with budesonide extended-release tablets administration [see Dosage and Administration ( 2 ) and Clinical Pharmacology ( 12.3 )]. 7.2 Inhibitors of Gastric Acid Secretion Since the dissolution of the coating of budesonide extended-release tablets are pH dependent, the release properties and uptake of the compound may be altered when budesonide extended-release tablets are used after treatment with gastric acid reducing agents (e.g., proton pump inhibitors (PPIs), H 2 blockers and antacids).

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm. ( 8.1 ) Hepatic Impairment: Monitor patients for signs and/or symptoms of hypercorticism. ( 5. 5 , 8.6 ) 8.1 Pregnancy Risk Summary Limited published studies report on the use of budesonide in pregnant women; however, the data are insufficient to inform a drug-associated risk for major birth defects and miscarriage. There are clinical considerations (see Clinical Considerations). In animal reproduction studies with pregnant rats and rabbits, subcutaneous administration of budesonide during organogenesis at doses 0.5 times and 0.05 times, respectively, the maximum recommended human dose, resulted in increased fetal loss, decreased pup weights, and skeletal abnormalities. Maternal toxicity was observed in both rats and rabbits at these dose levels ( see Data ). Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage of the indicated population is 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% to 4%, and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryofetal Risk Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with ulcerative colitis. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth. Fetal/Neonatal Adverse Reactions Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Infants should be carefully observed for signs of hypoadrenalism, such as poor feeding, irritability, weakness, and vomiting, and managed accordingly [ see Warnings and Precautions ( 5.1 )] . Data Animal Data Budesonide was teratogenic and embryolethal in rabbits and rats. In an embryofetal development study in pregnant rats dosed subcutaneously with budesonide during the period of organogenesis from gestation days 6-15 there were effects on fetal development and survival at subcutaneous doses up to approximately 500 mcg/kg in rats (approximately 0.5 times the maximum recommended human dose on a body surface area basis). In an embryofetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 6-18, there was an increase in maternal abortion, and effects on fetal development and reduction in litter weights at subcutaneous doses up to approximately 25 mcg/kg in rabbits (approximately 0.05 times the maximum recommended human dose on a body surface area basis). Maternal toxicity, including reduction in body weight gain, was observed at subcutaneous doses of 5 mcg/kg in rabbits (approximately 0.01 times the maximum recommended human dose on a body surface area basis) and 500 mcg/kg in rats (approximately 0.5 times the maximum recommended human dose on a body surface area basis). In a peri- and postnatal development study, rats dosed subcutaneously with budesonide during the period of Day 15 post coitum to Day 21 postpartum, budesonide had no effects on delivery but did have an effect on growth and development of offspring.

times the maximum recommended human dose on a body surface area basis). In a peri- and postnatal development study, rats dosed subcutaneously with budesonide during the period of Day 15 post coitum to Day 21 postpartum, budesonide had no effects on delivery but did have an effect on growth and development of offspring. In addition, offspring survival was reduced, and surviving offspring had decreased mean body weights at birth and during lactation at exposures 0.02 times the MRHD (on a mg/m 2 basis at maternal subcutaneous doses of 20 mcg/kg/day and higher). These findings occurred in the presence of maternal toxicity. 8.2 Lactation Risk Summary Lactation studies have not been conducted with budesonide extended-release tablets or other oral budesonide products and no information is available on the effects of budesonide on the breastfed infant or the effects of the drug on milk production. One published study reports that budesonide is present in human milk following maternal inhalation of budesonide ( see Data) . The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for budesonide extended-release tablets and any potential adverse effects on the breastfed infant from budesonide extended-release tablets, or from the underlying maternal condition. Data One published study reports that budesonide is present in human milk following maternal inhalation of budesonide which resulted in infant doses approximately 0.3% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.4 and 0.5. Budesonide plasma concentrations were not detected, and no adverse events were noted in the breastfed infants following maternal use of inhaled budesonide. The recommended daily dose of budesonide extended-release tablets is higher (9 mg daily) compared with inhaled budesonide (up to 800 mcg daily) given to mothers in the above described study. The maximum budesonide plasma concentration following a 9 mg daily dose (in both single- and repeated-dose pharmacokinetic studies) of oral budesonide is approximately 5 to 10 nmol/L which is up to 10 times higher than the 1 to 2 nmol/L for a 800 mcg daily dose of inhaled budesonide at steady state in the above inhalation study. Assuming the coefficient of extrapolation between the inhaled and oral doses is constant across all dose levels, at therapeutic doses of budesonide extended-release tablets, budesonide exposure to the nursing child may be up to 10 times higher than that by budesonide inhalation. 8.4 Pediatric Use Safety and effectiveness of budesonide extended-release tablets in pediatric patients have not been established. Glucocorticosteroids, such as budesonide extended-release tablets, may cause a reduction of growth velocity in pediatric patients. 8.5 Geriatric Use Clinical studies of budesonide extended-release tablets did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, budesonide extended-release tablets should be used cautiously in elderly patients due to the potential for decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6 Hepatic Impairment Patients with moderate to severe liver disease should be monitored for increased signs and/or symptoms of hypercorticism. Discontinuing the use of budesonide extended-release tablets should be considered in these patients [ see Warnings and Precautions ( 5.5 )] .

8.1 Pregnancy Risk Summary Limited published studies report on the use of budesonide in pregnant women; however, the data are insufficient to inform a drug-associated risk for major birth defects and miscarriage. There are clinical considerations (see Clinical Considerations). In animal reproduction studies with pregnant rats and rabbits, subcutaneous administration of budesonide during organogenesis at doses 0.5 times and 0.05 times, respectively, the maximum recommended human dose, resulted in increased fetal loss, decreased pup weights, and skeletal abnormalities. Maternal toxicity was observed in both rats and rabbits at these dose levels ( see Data ). Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage of the indicated population is 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% to 4%, and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryofetal Risk Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with ulcerative colitis. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth. Fetal/Neonatal Adverse Reactions Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Infants should be carefully observed for signs of hypoadrenalism, such as poor feeding, irritability, weakness, and vomiting, and managed accordingly [ see Warnings and Precautions ( 5.1 )] . Data Animal Data Budesonide was teratogenic and embryolethal in rabbits and rats. In an embryofetal development study in pregnant rats dosed subcutaneously with budesonide during the period of organogenesis from gestation days 6-15 there were effects on fetal development and survival at subcutaneous doses up to approximately 500 mcg/kg in rats (approximately 0.5 times the maximum recommended human dose on a body surface area basis). In an embryofetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 6-18, there was an increase in maternal abortion, and effects on fetal development and reduction in litter weights at subcutaneous doses up to approximately 25 mcg/kg in rabbits (approximately 0.05 times the maximum recommended human dose on a body surface area basis). Maternal toxicity, including reduction in body weight gain, was observed at subcutaneous doses of 5 mcg/kg in rabbits (approximately 0.01 times the maximum recommended human dose on a body surface area basis) and 500 mcg/kg in rats (approximately 0.5 times the maximum recommended human dose on a body surface area basis). In a peri- and postnatal development study, rats dosed subcutaneously with budesonide during the period of Day 15 post coitum to Day 21 postpartum, budesonide had no effects on delivery but did have an effect on growth and development of offspring. In addition, offspring survival was reduced, and surviving offspring had decreased mean body weights at birth and during lactation at exposures 0.02 times the MRHD (on a mg/m 2 basis at maternal subcutaneous doses of 20 mcg/kg/day and higher).

s on delivery but did have an effect on growth and development of offspring. In addition, offspring survival was reduced, and surviving offspring had decreased mean body weights at birth and during lactation at exposures 0.02 times the MRHD (on a mg/m 2 basis at maternal subcutaneous doses of 20 mcg/kg/day and higher). These findings occurred in the presence of maternal toxicity.

8.4 Pediatric Use Safety and effectiveness of budesonide extended-release tablets in pediatric patients have not been established. Glucocorticosteroids, such as budesonide extended-release tablets, may cause a reduction of growth velocity in pediatric patients.

8.5 Geriatric Use Clinical studies of budesonide extended-release tablets did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, budesonide extended-release tablets should be used cautiously in elderly patients due to the potential for decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE Reports of acute toxicity and/or death following overdosage of glucocorticosteroids are rare. Treatment consists of immediate gastric lavage or emesis followed by supportive and symptomatic therapy. If glucocorticosteroids are used at excessive doses for prolonged periods, systemic glucocorticosteroid effects, such as hypercorticism and adrenal suppression may occur. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage may be reduced temporarily. Single oral budesonide doses of 200 and 400 mg/kg were lethal in female and male mice, respectively. The signs of acute toxicity were decreased motor activity, piloerection and generalized edema.

11 DESCRIPTION Budesonide extended-release tablets, for oral administration, contain budesonide, a synthetic corticosteroid, as the active ingredient. Budesonide is designated chemically as (RS)-11β, 16α, 17,21 tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with butyraldehyde. Budesonide is provided as a mixture of two epimers (22R and 22S). The empirical formula of budesonide is C 25 H 34 O 6 and its molecular weight is 430.5. Its structural formula is: Budesonide is a white to off-white, odorless, crystalline powder that is practically insoluble in water, sparingly soluble in alcohol, and freely soluble in chloroform. Budesonide extended-release tablets, a delayed and extended-release tablet, is coated with a polymer film, which breaks down at or above pH 7. The tablet core contains budesonide with polymers that provide for extended release of budesonide. Each tablet contains the following inactive ingredients: stearic acid, lecithin, microcrystalline cellulose, hydroxypropyl cellulose, lactose, silicon dioxide, magnesium stearate, methacrylic acid copolymer types A and B, talc, triethyl citrate, and titanium dioxide. uceris-1.jpg

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Budesonide has a high topical glucocorticosteroid (GCS) activity and substantial first-pass elimination. The formulation contains budesonide in an extended-release tablet core. The tablet core is enteric coated to protect dissolution in gastric juice which delays budesonide release until exposure to a pH ≥7 in the small intestine. Upon disintegration of the coating, the core matrix provides extended release of budesonide in a time dependent manner. 12.2 Pharmacodynamics Budesonide has a high glucocorticoid effect and a weak mineralocorticoid effect, and the affinity of budesonide to GCS receptors, which reflects the intrinsic potency of the drug, is about 200-fold that of cortisol and 15-fold that of prednisolone. Treatment with systemically active GCS, including budesonide extended-release tablets, is associated with a suppression of endogenous cortisol concentrations and an impairment of the hypothalamus-pituitary-adrenal (HPA) axis function. Markers, indirect and direct, of this are cortisol levels in plasma or urine and response to ACTH stimulation. In a study assessing the response to ACTH stimulation test in patients treated with budesonide extended-release tablets 9 mg once daily, the proportion of patients with abnormal response was 47% at 4 weeks and 79% at 8 weeks. 12.3 Pharmacokinetics Absorption Following single oral administration of budesonide extended-release tablets 9 mg in healthy subjects, peak plasma concentration (C max ) was 1.35 ± 0.96 ng/mL, the time to peak concentration (T max ) on average was 13.3 ± 5.9 hours, although it varied across different individual patients, and the area under the plasma concentration time curve (AUC) was approximately 16.43 ± 10.52 ng·hr/mL. The pharmacokinetic parameters of budesonide extended-release tablets 9 mg have a high degree of variability among subjects. There was no accumulation of budesonide with respect to both AUC and C max following 7 days of budesonide extended-release tablets 9 mg once daily dosing. Food Effect A food-effect study involving administration of budesonide extended-release tablets to healthy volunteers under fasting conditions and with a high-fat meal indicated that the C max was decreased by 27% while there was no significant decrease in AUC. Additionally, a mean delay in absorption lag time of 2.4 hours was observed under fed conditions. Distribution The mean volume of distribution (V SS ) of budesonide varies between 2.2 and 3.9 L/kg in healthy subjects and in patients. Plasma protein binding is estimated to be 85 to 90% in the concentration range 1 to 230 nmol/L, independent of gender. The erythrocyte/plasma partition ratio at clinically relevant concentrations is about 0.8. Elimination Metabolism Following absorption, budesonide is subject to high first-pass metabolism (80-90%). In vitro experiments in human liver microsomes demonstrate that budesonide is rapidly and extensively biotransformed, mainly by CYP3A4, to its 2 major metabolites, 6β-hydroxy budesonide and 16α-hydroxy prednisolone. The glucocorticoid activity of these metabolites is negligible (<1/100) in relation to that of the parent compound. In vivo investigations with intravenous doses in healthy subjects are in agreement with the in vitro findings and demonstrate that budesonide has a high plasma clearance, 0.9-1.8 L/min.

roxy prednisolone. The glucocorticoid activity of these metabolites is negligible (<1/100) in relation to that of the parent compound. In vivo investigations with intravenous doses in healthy subjects are in agreement with the in vitro findings and demonstrate that budesonide has a high plasma clearance, 0.9-1.8 L/min. These high plasma clearance values approach the estimated liver blood flow, and, accordingly, suggest that budesonide is a high hepatic clearance drug. The plasma elimination half-life, t 1/2 , after administration of intravenous doses ranges between 2 and 3.6 hours. Excretion Budesonide is excreted in urine and feces in the form of metabolites. After oral as well as intravenous administration of micronized [ 3 H]-budesonide, approximately 60% of the recovered radioactivity is found in urine. The major metabolites, including 6β-hydroxy budesonide and 16α-hydroxy prednisolone, are mainly renally excreted, intact or in conjugated forms. No unchanged budesonide is detected in urine. Specific Populations Patients with Renal Impairment The pharmacokinetics of budesonide in patients with renal impairment have not been studied. Intact budesonide is not renally excreted, but metabolites are to a large extent, and might therefore reach higher levels in patients with impaired renal function. However, these metabolites have negligible corticosteroid activity as compared with budesonide (<1/100). Patients with Hepatic Impairment In patients with liver cirrhosis, systemic availability of orally administered budesonide correlates with disease severity and is, on average, 2.5-fold higher compared with healthy controls. Patients with mild liver disease are minimally affected. Patients with severe liver dysfunction were not studied. Absorption parameters were not altered, and for the intravenous dose, no significant differences in CL or V SS were observed. Drug Interaction Studies Budesonide is metabolized via CYP3A4. Potent inhibitors of CYP3A4 can increase the plasma levels of budesonide several-fold. Co-administration of ketoconazole results in an eight-fold increase in AUC of budesonide, compared to budesonide alone. Grapefruit juice, an inhibitor of gut mucosal CYP3A, approximately doubles the systemic exposure of oral budesonide. Conversely, induction of CYP3A4 can result in the lowering of budesonide plasma levels [see Dosage and Administration ( 2 ) and Drug Interactions ( 7 )]. Oral contraceptives containing ethinyl estradiol, which are also metabolized by CYP3A4, do not affect the pharmacokinetics of budesonide. Budesonide does not affect the plasma levels of oral contraceptives (i.e., ethinyl estradiol).

12.1 Mechanism of Action Budesonide has a high topical glucocorticosteroid (GCS) activity and substantial first-pass elimination. The formulation contains budesonide in an extended-release tablet core. The tablet core is enteric coated to protect dissolution in gastric juice which delays budesonide release until exposure to a pH ≥7 in the small intestine. Upon disintegration of the coating, the core matrix provides extended release of budesonide in a time dependent manner.

12.2 Pharmacodynamics Budesonide has a high glucocorticoid effect and a weak mineralocorticoid effect, and the affinity of budesonide to GCS receptors, which reflects the intrinsic potency of the drug, is about 200-fold that of cortisol and 15-fold that of prednisolone. Treatment with systemically active GCS, including budesonide extended-release tablets, is associated with a suppression of endogenous cortisol concentrations and an impairment of the hypothalamus-pituitary-adrenal (HPA) axis function. Markers, indirect and direct, of this are cortisol levels in plasma or urine and response to ACTH stimulation. In a study assessing the response to ACTH stimulation test in patients treated with budesonide extended-release tablets 9 mg once daily, the proportion of patients with abnormal response was 47% at 4 weeks and 79% at 8 weeks.

12.3 Pharmacokinetics Absorption Following single oral administration of budesonide extended-release tablets 9 mg in healthy subjects, peak plasma concentration (C max ) was 1.35 ± 0.96 ng/mL, the time to peak concentration (T max ) on average was 13.3 ± 5.9 hours, although it varied across different individual patients, and the area under the plasma concentration time curve (AUC) was approximately 16.43 ± 10.52 ng·hr/mL. The pharmacokinetic parameters of budesonide extended-release tablets 9 mg have a high degree of variability among subjects. There was no accumulation of budesonide with respect to both AUC and C max following 7 days of budesonide extended-release tablets 9 mg once daily dosing. Food Effect A food-effect study involving administration of budesonide extended-release tablets to healthy volunteers under fasting conditions and with a high-fat meal indicated that the C max was decreased by 27% while there was no significant decrease in AUC. Additionally, a mean delay in absorption lag time of 2.4 hours was observed under fed conditions. Distribution The mean volume of distribution (V SS ) of budesonide varies between 2.2 and 3.9 L/kg in healthy subjects and in patients. Plasma protein binding is estimated to be 85 to 90% in the concentration range 1 to 230 nmol/L, independent of gender. The erythrocyte/plasma partition ratio at clinically relevant concentrations is about 0.8. Elimination Metabolism Following absorption, budesonide is subject to high first-pass metabolism (80-90%). In vitro experiments in human liver microsomes demonstrate that budesonide is rapidly and extensively biotransformed, mainly by CYP3A4, to its 2 major metabolites, 6β-hydroxy budesonide and 16α-hydroxy prednisolone. The glucocorticoid activity of these metabolites is negligible (<1/100) in relation to that of the parent compound. In vivo investigations with intravenous doses in healthy subjects are in agreement with the in vitro findings and demonstrate that budesonide has a high plasma clearance, 0.9-1.8 L/min. These high plasma clearance values approach the estimated liver blood flow, and, accordingly, suggest that budesonide is a high hepatic clearance drug. The plasma elimination half-life, t 1/2 , after administration of intravenous doses ranges between 2 and 3.6 hours. Excretion Budesonide is excreted in urine and feces in the form of metabolites. After oral as well as intravenous administration of micronized [ 3 H]-budesonide, approximately 60% of the recovered radioactivity is found in urine. The major metabolites, including 6β-hydroxy budesonide and 16α-hydroxy prednisolone, are mainly renally excreted, intact or in conjugated forms. No unchanged budesonide is detected in urine. Specific Populations Patients with Renal Impairment The pharmacokinetics of budesonide in patients with renal impairment have not been studied. Intact budesonide is not renally excreted, but metabolites are to a large extent, and might therefore reach higher levels in patients with impaired renal function. However, these metabolites have negligible corticosteroid activity as compared with budesonide (<1/100). Patients with Hepatic Impairment In patients with liver cirrhosis, systemic availability of orally administered budesonide correlates with disease severity and is, on average, 2.5-fold higher compared with healthy controls. Patients with mild liver disease are minimally affected. Patients with severe liver dysfunction were not studied.

atic Impairment In patients with liver cirrhosis, systemic availability of orally administered budesonide correlates with disease severity and is, on average, 2.5-fold higher compared with healthy controls. Patients with mild liver disease are minimally affected. Patients with severe liver dysfunction were not studied. Absorption parameters were not altered, and for the intravenous dose, no significant differences in CL or V SS were observed. Drug Interaction Studies Budesonide is metabolized via CYP3A4. Potent inhibitors of CYP3A4 can increase the plasma levels of budesonide several-fold. Co-administration of ketoconazole results in an eight-fold increase in AUC of budesonide, compared to budesonide alone. Grapefruit juice, an inhibitor of gut mucosal CYP3A, approximately doubles the systemic exposure of oral budesonide. Conversely, induction of CYP3A4 can result in the lowering of budesonide plasma levels [see Dosage and Administration ( 2 ) and Drug Interactions ( 7 )]. Oral contraceptives containing ethinyl estradiol, which are also metabolized by CYP3A4, do not affect the pharmacokinetics of budesonide. Budesonide does not affect the plasma levels of oral contraceptives (i.e., ethinyl estradiol).

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity Carcinogenicity studies with budesonide were conducted in rats and mice. In a two-year study in Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in male rats at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). In addition, there were increased incidences of primary hepatocellular tumors in male rats at 25 mcg/kg (approximately 0.023 times the maximum recommended human dose on a body surface area basis) and above. No tumorigenicity was seen in female rats at oral doses up to 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). In an additional two-year study in male Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). However, it caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). The concurrent reference glucocorticosteroids (prednisolone and triamcinolone acetonide) showed similar findings. In a 91-week study in mice, budesonide caused no treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately 0.1 times the maximum recommended human dose on a body surface area basis). Mutagenesis Budesonide was not genotoxic in the Ames test, the mouse lymphoma cell forward gene mutation (TK +/- ) test, the human lymphocyte chromosome aberration test, the Drosophila melanogaster sex-linked recessive lethality test, the rat hepatocycte unscheduled DNA synthesis (UDS) test and the mouse micronucleus test. Impairment of Fertility In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg (approximately 0.07 times the maximum recommended human dose on a body surface area basis). However, it caused a decrease in prenatal viability and viability in pups at birth and during lactation, along with a decrease in maternal body weight gain, at subcutaneous doses of 20 mcg/kg (approximately 0.02 times the maximum recommended human dose on a body surface area basis) and above. No such effects were noted at 5 mcg/kg (approximately 0.005 times the maximum recommended human dose on a body surface area basis).

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity Carcinogenicity studies with budesonide were conducted in rats and mice. In a two-year study in Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in male rats at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). In addition, there were increased incidences of primary hepatocellular tumors in male rats at 25 mcg/kg (approximately 0.023 times the maximum recommended human dose on a body surface area basis) and above. No tumorigenicity was seen in female rats at oral doses up to 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). In an additional two-year study in male Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). However, it caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). The concurrent reference glucocorticosteroids (prednisolone and triamcinolone acetonide) showed similar findings. In a 91-week study in mice, budesonide caused no treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately 0.1 times the maximum recommended human dose on a body surface area basis). Mutagenesis Budesonide was not genotoxic in the Ames test, the mouse lymphoma cell forward gene mutation (TK +/- ) test, the human lymphocyte chromosome aberration test, the Drosophila melanogaster sex-linked recessive lethality test, the rat hepatocycte unscheduled DNA synthesis (UDS) test and the mouse micronucleus test. Impairment of Fertility In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg (approximately 0.07 times the maximum recommended human dose on a body surface area basis). However, it caused a decrease in prenatal viability and viability in pups at birth and during lactation, along with a decrease in maternal body weight gain, at subcutaneous doses of 20 mcg/kg (approximately 0.02 times the maximum recommended human dose on a body surface area basis) and above. No such effects were noted at 5 mcg/kg (approximately 0.005 times the maximum recommended human dose on a body surface area basis).

14 CLINICAL STUDIES Induction of Remission in Active, Mild to Moderate Ulcerative Colitis Two similarly designed, randomized, double-blind, placebo-controlled studies were conducted in a total of 970 adult patients with active, mild to moderate ulcerative colitis (UC) which was defined as an Ulcerative Colitis Disease Activity Index (UCDAI of ≥4 and ≤10). Eight hundred ninety-nine of these patients had histology consistent with active UC; this was considered the primary analysis population. UCDAI is a four-component scale (total score of 0 to 12) that encompasses the clinical assessments of stool frequency, rectal bleeding, mucosal appearance and physician’s rating of disease activity (score of 0 to 3 for each of the components). The baseline median UCDAI score in both studies was 7. In Study 1, 56% of patients were male, and the median age was 42 years. In Study 2, 57% of patients were male, and the median age was 44 years. In Study 1, 50% of patients were Caucasian, 7% were African American, and 34% were Asian. In Study 2, more than 99% were Caucasian. Both studies compared budesonide extended-release tablets 9 mg and 6 mg with placebo and included an active reference arm (a mesalamine 2.4 g in Study 1 and a budesonide* 9 mg not approved for the treatment of UC in Study 2). The primary endpoint was induction of remission after 8 weeks of treatment. Remission was defined as a UCDAI score of ≤1, with subscores of 0 for rectal bleeding, stool frequency, and mucosal appearance and with a ≥1 point reduction in an endoscopy-only score. In both studies, budesonide extended-release tablets 9 mg extended-release tablets demonstrated superiority to placebo in inducing remission (Table 4). Table 4: Induction of Remission in Studies 1 and 2 Treatment Group Treatment Group Study 1 n/N (%) Study 2 n/N (%) Budesonide extended-release tablets 9 mg 22/123 (17.9) 19/109 (17.4) Budesonide extended-release tablets 6 mg 16/121 (13.2) 9/109 (8.3) Reference arm* 15/124 (12.1) 13/103 (12.6) Placebo 9/121 (7.4) 4/89 (4.5) Treatment difference between budesonide extended-release tablets 9 mg and placebo (95% CI) † 10.4% (2.2%, 18.7%) 12.9% (4.6%, 21.3%) The primary analysis population included only patients that had histology consistent with active UC. CI=Confidence Interval *The reference arm in Study 1 is a delayed release mesalamine 2.4 g; the reference arm in Study 2 is a budesonide 9 mg not approved for the treatment of UC. † p<0.025 for budesonide extended-release tablets 9 mg vs. placebo in both Studies 1 and 2 based on the Chi-square test (alpha=0.025)

<table ID="_RefID0EKKAG" cellpadding="0pt" cellspacing="0pt" width="100%"><caption>Table 4: Induction of Remission in Studies 1 and 2 Treatment Group</caption><col width="45%"/><col width="28%"/><col width="28%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Treatment Group</content></paragraph></td><td align="center" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Study 1</content> <content styleCode="bold">n/N (%)</content></paragraph></td><td align="center" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Study 2</content> <content styleCode="bold">n/N (%)</content></paragraph></td></tr><tr><td valign="top"><paragraph>Budesonide extended-release tablets 9 mg</paragraph></td><td align="center" valign="top"><paragraph>22/123 (17.9)</paragraph></td><td align="center" valign="top"><paragraph>19/109 (17.4)</paragraph></td></tr><tr><td valign="top"><paragraph>Budesonide extended-release tablets 6 mg</paragraph></td><td align="center" valign="top"><paragraph>16/121 (13.2)</paragraph></td><td align="center" valign="top"><paragraph>9/109 (8.3)</paragraph></td></tr><tr><td valign="top"><paragraph>Reference arm*</paragraph></td><td align="center" valign="top"><paragraph>15/124 (12.1)</paragraph></td><td align="center" valign="top"><paragraph>13/103 (12.6)</paragraph></td></tr><tr><td valign="top"><paragraph>Placebo</paragraph></td><td align="center" valign="top"><paragraph>9/121 (7.4)</paragraph></td><td align="center" valign="top"><paragraph>4/89 (4.5)</paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph>Treatment difference between budesonide extended-release tablets 9 mg and placebo (95% CI) ^&#x2020;</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>10.4% (2.2%, 18.7%)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>12.9% (4.6%, 21.3%)</paragraph></td></tr></tbody></table>

16 HOW SUPPLIED/STORAGE AND HANDLING Budesonide extended-release tablets 9 mg are white, round, biconvex tablets and debossed with “MX9”. They are supplied as follows: NDC 68682-309-30 Bottles of 30 tablets Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature]. Keep container tightly closed. Protect from light and moisture.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Patients treated with budesonide extended-release tablets should receive the following information and instructions. This information is intended to aid the patient in the safe and effective use of budesonide extended-release tablets. Hypercorticism and Adrenal Suppression Advise patients that budesonide extended-release tablets may cause systemic glucocorticosteroid effects of hypercorticism and adrenal suppression. Taper slowly from systemic corticosteroids if transferring to budesonide extended-release tablets [see Warnings and Precautions ( 5.1 ) and ( 5.2 )] . Immunosuppression and Increased Risk of Infection Advise patients to avoid exposure to people with varicella (chicken pox) or measles. Advise patients to inform their healthcare provider if they are exposed to varicella or measles or develop a new or worsening infection [seeWarnings and Precautions ( 5.3 )]. Kaposi’s Sarcoma Advise patients that Kaposi’s sarcoma has been reported in patients receiving corticosteroids for chronic conditions and to inform their healthcare provider if they experience signs or symptoms of Kaposi’s sarcoma [seeWarnings and Precautions ( 5.4 )]. How to Take Budesonide Extended-Release Tablets Advise patients to swallow budesonide extended-release tablets whole with water. Do not chew or crush. Avoid the consumption of grapefruit juice for the duration of budesonide extended-release tablets therapy [see Dosage and Administration ( 2 )] . Pregnancy Advise female patients that budesonide extended-release tablets may cause fetal harm and to inform their healthcare provider with a known or suspected pregnancy [seeUse in Specific Populations ( 8.1 )] . Distributed by: Oceanside Pharmaceuticals, a division of Bausch Health US, LLC Bridgewater, NJ 08807 USA Manufactured by: Cosmo S.p.A. Milan, 20045 Italy By license of Cosmo Technologies Ltd., Dublin, Ireland Patented. See https://patents.salix.com for US patent information. © 2024 Oceanside Pharmaceuticals, Inc. or its affiliates 9628702

Patient Information PATIENT INFORMATION Budesonide (bew DEH so nide) Extended-Release Tablets What are budesonide extended-release tablets? Budesonide extended-release tablets are a prescription corticosteroid medicine used to help get active mild to moderate ulcerative colitis (UC) under control (induce remission). It is not known if budesonide extended-release tablets are safe and effective in children. Who should not take budesonide extended-release tablets? Do not take budesonide extended-release tablets if: you are allergic to budesonide or any of the ingredients in budesonide extended-release tablets. See the end of this leaflet for a complete list of ingredients in budesonide extended-release tablets. What should I tell my healthcare provider before taking budesonide extended-release tablets? Before you take budesonide extended-release tablets tell your healthcare provider about all of your medical conditions, including if you: have liver problems. are planning to have surgery. have chickenpox or measles or have recently been near anyone with chickenpox or measles. have an infection, including fungal and threadworm ( Strongyloides ) infections. have or had a family history of diabetes, cataracts or glaucoma. have or had tuberculosis. have high blood pressure (hypertension). have decreased bone mineral density (osteoporosis). have stomach ulcers. have malaria of the brain (cerebral malaria). are pregnant or plan to become pregnant. Budesonide extended-release tablets may harm your unborn baby. Tell your healthcare provider if you are pregnant or think you are pregnant. are breastfeeding or plan to breastfeed. Budesonide extended-release tablets can pass into your breast milk and may harm your baby. You and your healthcare provider should decide if you will take budesonide extended-release tablets or breastfeed. You should not do both. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Budesonide extended-release tablets and other medicines may affect each other causing side effects. Especially tell your healthcare provider if you take another medicine that contains corticosteroids for other conditions, such as allergies or asthma. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I take budesonideextended-release tablets? Take budesonide extended-release tablets exactly as your healthcare provider tells you to take them. Take budesonide extended-release tablets 1 time each day in the morning with or without food. Take budesonide extended-release tablets whole with water. Do not chew, crush, or break budesonide extended-release tablets before swallowing. If you take too much of budesonide extended-release tablets, call your healthcare provider right away or go to the nearest hospital emergency room. What should I avoid while taking budesonideextended-release tablets? Do not eat grapefruit or drink grapefruit juice while taking budesonide extended-release tablets. Eating grapefruit or drinking grapefruit juice can increase the level of budesonide extended-release tablets in your blood. What are the possible side effects of budesonideextended-release tablets? Budesonide extended-release tablets may cause serious side effects, including: Effects of having too much corticosteroid medicine in your blood (hypercorticism).

t juice can increase the level of budesonide extended-release tablets in your blood. What are the possible side effects of budesonideextended-release tablets? Budesonide extended-release tablets may cause serious side effects, including: Effects of having too much corticosteroid medicine in your blood (hypercorticism). Long-time use of budesonide extended-release tablets can cause you to have too much glucocorticosteroid medicine in your blood. Tell your healthcare provider if you have any of the following signs and symptoms of hypercorticism: acne bruise easily rounding of your face (moon face) ankle swelling thicker or more hair on your body and face a fatty pad or hump between your shoulders (buffalo hump) pink or purple stretch marks on the skin of your abdomen, thighs, breasts and arms Adrenal suppression. When budesonide extended-release tablets are taken for a long period of time (chronic use), the adrenal glands do not make enough steroid hormones (adrenal suppression). Tell your healthcare provider if you are under stress or have any symptoms of adrenal suppression during treatment with budesonide extended-release tablets including: tiredness weakness nausea vomiting low blood pressure Decreased ability of your body to fight infections (immunosuppression) and increased risk of infection. Corticosteroid medicines, including budesonide extended-release tablets, lower the ability of your immune system to fight infections and increase the risk of infections caused by viruses, bacteria, fungi, protozoan, or certain parasites. Corticosteroid medicines, including budesonide extended-release tablets, can also: make current infections worse increase the risk of infections spreading (disseminated) increase the risk of making infections active again or making infections worse that have not been active (latent) hide (mask) some signs of infection These infections can be mild but can be severe and lead to death. Your healthcare provider should check you closely for signs and symptoms of an infection while taking budesonide extended-release tablets. Tell your healthcare provider right away about any signs or symptoms of a new or worsening infection while taking budesonide extended-release tablets, including flu-like symptoms such as: fever chills stomach area (abdominal) pain aches diarrhea cough pain feeling tired nausea and vomiting Tuberculosis: If you have inactive (latent) tuberculosis, your tuberculosis may become active again while taking budesonide extended-release tablets. Your healthcare provider should check you closely for signs and symptoms of tuberculosis while taking budesonide extended-release tablets. Chickenpox and measles: People taking corticosteroid medicines, including budesonide extended-release tablets, who have not had chickenpox or measles, should avoid contact with people who have these diseases. Tell your healthcare provider right away if you come in contact with anyone who has chickenpox or measles. Hepatitis B virus (HBV) reactivation: If you are a carrier of HBV, the virus can become an active infection again while taking budesonide extended-release tablets. Your healthcare provider will test you for HBV before you start taking budesonide extended-release tablets. Amebiasis: Inactive (latent) amebiasis may become an active infection while taking budesonide extended-release tablets. Your healthcare provider should check you for amebiasis before you start taking budesonide extended-release tablets in people who have spent time in the tropics or have unexplained diarrhea. Kaposi’s sarcoma. Kaposi’s sarcoma has happened in people who received corticosteroid therapy, most often for treatment of long-lasting (chronic) conditions. Worsening of allergies.

sis before you start taking budesonide extended-release tablets in people who have spent time in the tropics or have unexplained diarrhea. Kaposi’s sarcoma. Kaposi’s sarcoma has happened in people who received corticosteroid therapy, most often for treatment of long-lasting (chronic) conditions. Worsening of allergies. If you take certain other corticosteroid medicines to treat allergies, switching to budesonide extended-release tablets may cause your allergies to come back. These allergies may include eczema (a skin disease) or rhinitis (inflammation inside your nose). Tell your healthcare provider if any of your allergies become worse while taking budesonide extended-release tablets. The most common side effects of budesonideextended-release tablets include: headache nausea decreased blood cortisol levels stomach-area pain tiredness stomach or intestinal gas bloating acne urinary tract infection joint pain constipation Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of budesonide extended-release tablets. For more information, ask your healthcare provider 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 store budesonideextended-release tablets? Store budesonide extended-release tablets at room temperature, 77°F (25°C); excursions permitted to 59°F to 86°F (15°C to 30°C). Keep the bottle tightly closed to protect budesonide extended-release tablets from light and moisture. Keep budesonide extended-release tablets and all medicines out of the reach of children. General information about the safe and effective use of budesonideextended-release tablets. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use budesonide extended-release tablets for a condition for which it was not prescribed. Do not give budesonide extended-release tablets to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about budesonide extended-release tablets that is written for health professionals. For more information, call 1-800-321-4576. What are the ingredients in budesonideextended-release tablets? Active ingredient: budesonide Inactive ingredients: stearic acid, lecithin, microcrystalline cellulose, hydroxypropyl cellulose, lactose, silicon dioxide, magnesium stearate, methacrylic acid copolymer types A and B, talc, triethyl citrate, and titanium dioxide. Distributed by: Oceanside Pharmaceuticals, a division of Bausch Health US, LLC Bridgewater, NJ 08807 USA Manufactured by: Cosmo S.p.A. Milan, 20045 Italy By license of Cosmo Technologies Ltd., Dublin, Ireland Patented. See https://patents.salix.com for US patent information © 2024 Oceanside Pharmaceuticals, Inc. or its affiliates This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 06/2024

<table width="100%"><col width="100%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">PATIENT INFORMATION</content></paragraph><paragraph><content styleCode="bold">Budesonide (bew DEH so nide)</content></paragraph><paragraph><content styleCode="bold">Extended-Release Tablets</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What are budesonide extended-release tablets?</content></paragraph><list listType="unordered"><item>Budesonide extended-release tablets are a prescription corticosteroid medicine used to help get active mild to moderate ulcerative colitis (UC) under control (induce remission).</item><item>It is not known if budesonide extended-release tablets are safe and effective in children.</item></list></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Who should not take budesonide extended-release tablets?</content></paragraph><paragraph>Do not take budesonide extended-release tablets if:</paragraph><list listType="unordered"><item>you are allergic to budesonide or any of the ingredients in budesonide extended-release tablets. See the end of this leaflet for a complete list of ingredients in budesonide extended-release tablets.</item></list></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What should I tell my healthcare provider before taking budesonide extended-release tablets?</content></paragraph><paragraph><content styleCode="bold">Before you take budesonide extended-release tablets tell your healthcare provider about all of your medical conditions, including if you:</content></paragraph><list listType="unordered"><item>have liver problems.</item><item>are planning to have surgery.</item><item>have chickenpox or measles or have recently been near anyone with chickenpox or measles.</item><item>have an infection, including fungal and threadworm ( <content styleCode="italics">Strongyloides</content>) infections. </item><item>have or had a family history of diabetes, cataracts or glaucoma.</item><item>have or had tuberculosis.</item><item>have high blood pressure (hypertension).</item><item>have decreased bone mineral density (osteoporosis).</item><item>have stomach ulcers.</item><item>have malaria of the brain (cerebral malaria).</item><item>are pregnant or plan to become pregnant. Budesonide extended-release tablets may harm your unborn baby. Tell your healthcare provider if you are pregnant or think you are pregnant.</item><item>are breastfeeding or plan to breastfeed. Budesonide extended-release tablets can pass into your breast milk and may harm your baby. You and your healthcare provider should decide if you will take budesonide extended-release tablets or breastfeed. You should not do both.</item></list><paragraph><content styleCode="bold">Tell your healthcare provider about all the medicines you take,</content>including prescription and over-the-counter medicines, vitamins, and herbal supplements. Budesonide extended-release tablets and other medicines may affect each other causing side effects. </paragraph><paragraph>Especially tell your healthcare provider if you take another medicine that contains corticosteroids for other conditions, such as allergies or asthma. Know the medicines you take.

rbal supplements. Budesonide extended-release tablets and other medicines may affect each other causing side effects. </paragraph><paragraph>Especially tell your healthcare provider if you take another medicine that contains corticosteroids for other conditions, such as allergies or asthma. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">How should I take budesonideextended-release tablets?</content></paragraph><list listType="unordered"><item>Take budesonide extended-release tablets exactly as your healthcare provider tells you to take them.</item><item>Take budesonide extended-release tablets 1 time each day in the morning with or without food.</item><item>Take budesonide extended-release tablets whole with water. Do not chew, crush, or break budesonide extended-release tablets before swallowing.</item><item>If you take too much of budesonide extended-release tablets, call your healthcare provider right away or go to the nearest hospital emergency room.</item></list></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What should I avoid while taking budesonideextended-release tablets?</content></paragraph><list listType="unordered"><item>Do not eat grapefruit or drink grapefruit juice while taking budesonide extended-release tablets. Eating grapefruit or drinking grapefruit juice can increase the level of budesonide extended-release tablets in your blood.</item></list></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What are the possible side effects of budesonideextended-release tablets?</content></paragraph><paragraph>Budesonide extended-release tablets may cause serious side effects, including:</paragraph><list listType="unordered"><item><content styleCode="bold">Effects of having too much corticosteroid medicine in your blood (hypercorticism).</content>Long-time use of budesonide extended-release tablets can cause you to have too much glucocorticosteroid medicine in your blood. Tell your healthcare provider if you have any of the following signs and symptoms of hypercorticism: </item><item>acne</item><item>bruise easily</item><item>rounding of your face (moon face)</item><item>ankle swelling</item><item>thicker or more hair on your body and face</item><item>a fatty pad or hump between your shoulders (buffalo hump)</item><item>pink or purple stretch marks on the skin of your abdomen, thighs, breasts and arms</item><item><content styleCode="bold">Adrenal suppression.</content>When budesonide extended-release tablets are taken for a long period of time (chronic use), the adrenal glands do not make enough steroid hormones (adrenal suppression). </item><item>Tell your healthcare provider if you are under stress or have any symptoms of adrenal suppression during treatment with budesonide extended-release tablets including:</item><item>tiredness</item><item>weakness</item><item>nausea</item><item>vomiting</item><item>low blood pressure</item><item><content styleCode="bold">Decreased ability of your body to fight infections (immunosuppression) and increased risk of infection.</content></item><item>Corticosteroid medicines, including budesonide extended-release tablets, lower the ability of your immune system to fight infections and increase the risk of infections caused by viruses, bacteria, fungi, protozoan, or certain parasites.

ections (immunosuppression) and increased risk of infection.</content></item><item>Corticosteroid medicines, including budesonide extended-release tablets, lower the ability of your immune system to fight infections and increase the risk of infections caused by viruses, bacteria, fungi, protozoan, or certain parasites. Corticosteroid medicines, including budesonide extended-release tablets, can also:</item><item>make current infections worse</item><item>increase the risk of infections spreading (disseminated)</item><item>increase the risk of making infections active again or making infections worse that have not been active (latent)</item><item>hide (mask) some signs of infection</item><item>These infections can be mild but can be severe and lead to death. Your healthcare provider should check you closely for signs and symptoms of an infection while taking budesonide extended-release tablets. Tell your healthcare provider right away about any signs or symptoms of a new or worsening infection while taking budesonide extended-release tablets, including flu-like symptoms such as:</item><item>fever</item><item>chills</item><item>stomach area (abdominal) pain</item><item>aches</item><item>diarrhea</item><item>cough</item><item>pain</item><item>feeling tired</item><item>nausea and vomiting</item><item>Tuberculosis: If you have inactive (latent) tuberculosis, your tuberculosis may become active again while taking budesonide extended-release tablets. Your healthcare provider should check you closely for signs and symptoms of tuberculosis while taking budesonide extended-release tablets.</item><item>Chickenpox and measles: People taking corticosteroid medicines, including budesonide extended-release tablets, who have not had chickenpox or measles, should avoid contact with people who have these diseases. Tell your healthcare provider right away if you come in contact with anyone who has chickenpox or measles.</item><item>Hepatitis B virus (HBV) reactivation: If you are a carrier of HBV, the virus can become an active infection again while taking budesonide extended-release tablets. Your healthcare provider will test you for HBV before you start taking budesonide extended-release tablets.</item><item>Amebiasis: Inactive (latent) amebiasis may become an active infection while taking budesonide extended-release tablets. Your healthcare provider should check you for amebiasis before you start taking budesonide extended-release tablets in people who have spent time in the tropics or have unexplained diarrhea.</item><item><content styleCode="bold">Kaposi&#x2019;s sarcoma.</content>Kaposi&#x2019;s sarcoma has happened in people who received corticosteroid therapy, most often for treatment of long-lasting (chronic) conditions. </item><item><content styleCode="bold">Worsening of allergies.</content>If you take certain other corticosteroid medicines to treat allergies, switching to budesonide extended-release tablets may cause your allergies to come back. These allergies may include eczema (a skin disease) or rhinitis (inflammation inside your nose). Tell your healthcare provider if any of your allergies become worse while taking budesonide extended-release tablets.

treat allergies, switching to budesonide extended-release tablets may cause your allergies to come back. These allergies may include eczema (a skin disease) or rhinitis (inflammation inside your nose). Tell your healthcare provider if any of your allergies become worse while taking budesonide extended-release tablets. </item></list><paragraph><content styleCode="bold">The most common side effects of budesonideextended-release tablets include:</content></paragraph><list listType="unordered"><item>headache</item><item>nausea</item><item>decreased blood</item><item>cortisol levels</item><item>stomach-area pain</item><item>tiredness</item><item>stomach or intestinal gas</item><item>bloating</item><item>acne</item><item>urinary tract infection</item><item>joint pain</item><item>constipation</item></list><paragraph>Tell your healthcare provider if you have any side effect that bothers you or that does not go away.</paragraph><paragraph>These are not all the possible side effects of budesonide extended-release tablets. For more information, ask your healthcare provider or pharmacist.</paragraph><paragraph>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">How should I store budesonideextended-release tablets?</content></paragraph><list listType="unordered"><item>Store budesonide extended-release tablets at room temperature, 77&#xB0;F (25&#xB0;C); excursions permitted to 59&#xB0;F to 86&#xB0;F (15&#xB0;C to 30&#xB0;C).</item><item>Keep the bottle tightly closed to protect budesonide extended-release tablets from light and moisture.</item></list><paragraph><content styleCode="bold">Keep budesonide extended-release tablets and all medicines out of the reach of children.</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">General information about the safe and effective use of budesonideextended-release tablets.</content></paragraph><paragraph>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use budesonide extended-release tablets for a condition for which it was not prescribed. Do not give budesonide extended-release tablets to other people, even if they have the same symptoms you have. It may harm them.</paragraph><paragraph>You can ask your healthcare provider or pharmacist for information about budesonide extended-release tablets that is written for health professionals.</paragraph><paragraph>For more information, call 1-800-321-4576.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What are the ingredients in budesonideextended-release tablets?</content></paragraph><paragraph><content styleCode="bold">Active ingredient:</content>budesonide </paragraph><paragraph><content styleCode="bold">Inactive ingredients:</content>stearic acid, lecithin, microcrystalline cellulose, hydroxypropyl cellulose, lactose, silicon dioxide, magnesium stearate, methacrylic acid copolymer types A and B, talc, triethyl citrate, and titanium dioxide. </paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Distributed by:</content></paragraph><paragraph>Oceanside Pharmaceuticals, a division of</paragraph><paragraph>Bausch Health US, LLC</paragraph><paragraph>Bridgewater, NJ 08807 USA</paragraph><paragraph><content styleCode="bold">Manufactured by:</content></paragraph><paragraph>Cosmo S.p.A.</paragraph><paragraph>Milan, 20045 Italy</paragraph><paragraph>By license of Cosmo Technologies Ltd., Dublin, Ireland</paragraph><paragraph>Patented.

alth US, LLC</paragraph><paragraph>Bridgewater, NJ 08807 USA</paragraph><paragraph><content styleCode="bold">Manufactured by:</content></paragraph><paragraph>Cosmo S.p.A.</paragraph><paragraph>Milan, 20045 Italy</paragraph><paragraph>By license of Cosmo Technologies Ltd., Dublin, Ireland</paragraph><paragraph>Patented. See https://patents.salix.com for US patent information</paragraph><paragraph>&#xA9; 2024 Oceanside Pharmaceuticals, Inc. or its affiliates</paragraph></td></tr></tbody></table>

1 INDICATIONS AND USAGE UCERIS rectal foam is indicated for the induction of remission in patients with active mild to moderate distal ulcerative colitis extending up to 40 cm from the anal verge. UCERIS rectal foam is a glucocorticosteroid indicated for the induction of remission in patients with active mild to moderate distal ulcerative colitis extending up to 40 cm from the anal verge. ( 1 )

2 DOSAGE AND ADMINISTRATION • The recommended dosage is 1 metered dose administered twice daily for 2 weeks followed by 1 metered dose administered once daily for 4 weeks. ( 2.1 ) • For rectal administration only. ( 2.2 ) • Warm the canister in the hands while shaking it vigorously for 10 to 15 seconds prior to use. ( 2.2 ) 2.1 Recommended Dosage The recommended dosage regimen is 1 metered dose administered rectally twice daily for 2 weeks followed by 1 metered dose administered rectally once daily for 4 weeks. 2.2 Administration Instructions Advise patients: • UCERIS rectal foam is only to be applied rectally. It is not for oral use. • Before using UCERIS rectal foam, use the bathroom to empty your bowels. • Each applicator is coated with a lubricant. If additional lubrication is needed, petrolatum or petroleum jelly can also be used. • Warm the canister in the hands while shaking it vigorously for 10 to 15 seconds prior to use. • UCERIS rectal foam can be used in a standing, lying or sitting position (e.g., while using the toilet). • Apply UCERIS rectal foam in the morning and the evening for the first 2 weeks of treatment; then once daily in the evening for the next 4 weeks. When applied in the evening, use immediately prior to bedtime. Try not to empty your bowels again until the next morning. • Avoid concomitant use of CYP3A4 inhibitors (e.g., ketoconazole, grapefruit juice) during treatment with UCERIS rectal foam.

3 DOSAGE FORMS AND STRENGTHS UCERIS rectal foam is formulated as an emulsion which is filled into an aluminum canister with an aerosol propellant. It is available in 1 strength: 2 mg budesonide per metered dose. UCERIS rectal foam contains 2 mg budesonide per metered dose. ( 3 )

4 CONTRAINDICATIONS UCERIS rectal foam is contraindicated in patients with a history of a known hypersensitivity to budesonide or any of the ingredients of UCERIS rectal foam. Reactions have included anaphylaxis [see Adverse Reactions ( 6.2 )] . Known hypersensitivity to budesonide or any of the ingredients in UCERIS rectal foam. ( 4 )

5 WARNINGS AND PRECAUTIONS • Hypercorticism and adrenal suppression: Follow general warnings concerning glucocorticosteroids. ( 5.1 ) • Impaired Adrenal Function in Patients Transferred from Other Glucocorticoids: Taper slowly from glucocorticosteroids with high systemic effects; monitor for withdrawal symptoms and unmasking of allergies (rhinitis, eczema). ( 5.2 ) • Increased Risk of Infection, including serious and fatal chicken pox and measles: Monitor patients with active or quiescent tuberculosis infection, untreated fungal, bacterial, systemic viral or parasitic infections, or ocular herpes simplex. ( 5.3 ) • Other Glucocorticosteroid Effects: Monitor patients with other conditions where glucocorticoids may have unwanted effects. ( 5.4 ) • Flammable Contents: The contents of UCERIS rectal foam are flammable. Instruct the patient to avoid fire, flame and smoking during and immediately following administration. ( 5.5 ) 5.1 Hypercorticism and Adrenal Axis Suppression When glucocorticosteroids are used chronically, systemic effects such as hypercorticism and adrenal suppression may occur. Glucocorticosteroids can reduce the response of the hypothalamus-pituitary-adrenal (HPA) axis to stress. In situations where patients are subject to surgery or other stress situations, supplementation with a systemic glucocorticosteroid is recommended. Since UCERIS rectal foam contains a glucocorticosteroid, general warnings concerning glucocorticoids should be followed [see Clinical Pharmacology ( 12.2 )]. Reduced liver function affects the elimination of glucocorticosteroids, and increased systemic availability of oral budesonide has been demonstrated in patients with liver cirrhosis [see Use in Specific Populations ( 8.6 )] . 5.2 Impaired Adrenal Suppression in Patients Transferred from Other Glucocorticoids Monitor patients who are transferred from glucocorticosteroid treatment with higher systemic effects to glucocorticosteroids with lower systemic effects, such as UCERIS rectal foam, since symptoms attributed to withdrawal of steroid therapy, including those of acute adrenal suppression or benign intracranial hypertension, may develop. Adrenocortical function monitoring may be required in these patients and the dose of glucocorticosteroid treatment with high systemic effects should be reduced cautiously. Replacement of systemic glucocorticosteroids with UCERIS rectal foam may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug. 5.3 Increased Risk of Infection Patients who are on drugs that suppress the immune system are more susceptible to infection than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in susceptible patients or patients on immunosuppressant doses of glucocorticosteroids. In patients who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route and duration of glucocorticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior glucocorticosteroid treatment to the risk is also not known. If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated (see prescribing information for VZIG and IG).

to the risk is also not known. If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated (see prescribing information for VZIG and IG). If chicken pox develops, treatment with antiviral agents may be considered. Glucocorticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection, untreated fungal, bacterial, systemic viral or parasitic infections, or ocular herpes simplex. 5.4 Other Glucocorticosteroid Effects Monitor patients with hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or with any other condition where glucocorticosteroids may have unwanted effects. 5.5 Flammable Contents The contents of UCERIS rectal foam include n-butane, isobutane and propane as propellants which are flammable. Instruct the patient to avoid fire, flame, and smoking during and immediately following administration. Patients should temporarily discontinue use of UCERIS rectal foam before initiation of bowel preparation for colonoscopy and consult their healthcare provider before resuming therapy.

6 ADVERSE REACTIONS Serious and important adverse reactions include: • Hypercorticism and adrenal axis suppression [see Warnings and Precautions ( 5.1 )] • Symptoms of steroid withdrawal in those patients transferring from systemic glucocorticosteroid therapy [see Warnings and Precautions ( 5.2 )] • Increased susceptibility to infection [see Warnings and Precautions ( 5.3 )] • Other glucocorticosteroid effects [see Warnings and Precautions ( 5.4 )] Most common adverse reactions (≥ 2%) are decreased blood cortisol, adrenal insufficiency, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Salix Pharmaceuticals at 1-800-321-4576 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to UCERIS rectal foam in 332 patients with active mild to moderate distal ulcerative colitis extending up to 40 cm from the anal verge. The median duration of exposure was 42 days. This included 14 patients exposed for at least 6 months. UCERIS rectal foam was studied primarily in 2 placebo-controlled, 6-week trials in patients with active disease (Study 1 and Study 2). In these trials, 268 patients received UCERIS rectal foam 2 mg twice a day for 2 weeks followed by 2 mg once a day for 4 weeks [see Clinical Studies ( 14 )] . The most common adverse reactions (≥ 2% of the UCERIS rectal foam or Placebo group and at higher frequency in the UCERIS rectal foam group) were decreased blood cortisol, adrenal insufficiency, and nausea ( Table 1 ). Decreased blood cortisol was defined as a morning cortisol level of <5 mcg/dL. Adrenal insufficiency was defined as a cortisol level of <18 mcg/dL at 30 minutes post-challenge with adrenocorticotropic hormone (ACTH). A total of 10% of UCERIS rectal foam-treated patients discontinued treatment due to an adverse reaction compared with 4% of placebo-treated patients. Table 1:Summary of Adverse Reactions in 2 Placebo-Controlled Trials* (Studies 1 and 2) Adverse Reaction UCERIS Rectal Foam 2 mg/25 mL N=268 n (%) Placebo N=278 n (%) Decreased blood cortisol 46 (17) 6 (2) Adrenal insufficiency† 10 (4) 2 (1) Nausea 6 (2) 2 (1) Of the 46 UCERIS rectal foam treated patients with decreased blood cortisol (defined as a morning cortisol level of <5 mcg/dL) reported as an adverse event, none had adrenal insufficiency (defined as a cortisol level of <18 mcg/dL at 30 minutes post-challenge with ACTH) (see Table 2 ). All cases of adrenal insufficiency resolved. Table 2 summarizes the percentages of patients reporting glucocorticoid related effects in the 2 placebo-controlled trials (Studies 1 and 2). Table 2: Summary of Glucocorticoid Related Effects in Two Placebo-Controlled Trials (Studies 1 and 2) Adverse Reaction UCERIS Rectal Foam 2 mg/25 mL N=268 n (%) Placebo N=278 n (%) Overall 60 (22) 10 (4) Blood cortisol decreased 46 (17)* 6 (2) Adrenal insufficiency 10 (4) 2 (1) Insomnia 1 (0.4) 1 (0.4) Sleep disorder 1 (0.4) 0 Acne 1 (0.4) 0 Depression 1 (0.4) 1 (0.4) Hyperglycemia 1 (0.4) 0 No clinically significant differences were observed with respect to the overall percentages of patients with any glucocorticoid related effects between UCERIS rectal foam and placebo after 6 weeks of therapy.

mnia 1 (0.4) 1 (0.4) Sleep disorder 1 (0.4) 0 Acne 1 (0.4) 0 Depression 1 (0.4) 1 (0.4) Hyperglycemia 1 (0.4) 0 No clinically significant differences were observed with respect to the overall percentages of patients with any glucocorticoid related effects between UCERIS rectal foam and placebo after 6 weeks of therapy. For additional details on morning cortisol levels and the response to the ACTH stimulation test, see Clinical Pharmacology ( 12.2 ) . 6.2 Postmarketing Experience In addition to adverse reactions reported from clinical trials for UCERIS rectal foam, the following adverse reactions have been identified during post-approval use of other oral and rectal formulations of budesonide. 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. Cardiac disorders: hypertension Gastrointestinal disorders: pancreatitis General disorders and administration site conditions: pyrexia, peripheral edema Immune system disorders: anaphylactic reactions Nervous system disorders: dizziness, benign intracranial hypertension Psychiatric disorders: mood swings Skin and subcutaneous tissue disorders: pruritus, maculopapular rash, allergic dermatitis

<table ID="_RefID0ECMAC" width="100%"><caption>Table 1:Summary of Adverse Reactions in 2 Placebo-Controlled Trials* (Studies 1 and 2)</caption><col width="33%"/><col width="33%"/><col width="33%"/><tbody><tr><td styleCode="Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td align="center" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">UCERIS Rectal Foam</content> <content styleCode="bold">2 mg/25 mL</content> <content styleCode="bold">N=268</content> <content styleCode="bold">n (%)</content></paragraph></td><td align="center" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Placebo</content> <content styleCode="bold">N=278</content> <content styleCode="bold">n (%)</content></paragraph></td></tr><tr><td valign="top"><paragraph>Decreased blood cortisol</paragraph></td><td align="center" valign="top"><paragraph>46 (17)</paragraph></td><td align="center" valign="top"><paragraph>6 (2)</paragraph></td></tr><tr><td valign="top"><paragraph>Adrenal insufficiency&#x2020;</paragraph></td><td align="center" valign="top"><paragraph>10 (4)</paragraph></td><td align="center" valign="top"><paragraph>2 (1)</paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph>Nausea</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>6 (2)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>2 (1)</paragraph></td></tr></tbody></table>

valign="top"><paragraph>2 (1)</paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph>Nausea</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>6 (2)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>2 (1)</paragraph></td></tr></tbody></table> <table width="100%"><caption>Table 2: Summary of Glucocorticoid Related Effects in Two Placebo-Controlled Trials (Studies 1 and 2)</caption><col width="33%"/><col width="33%"/><col width="33%"/><tbody><tr><td styleCode="Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td align="center" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">UCERIS Rectal Foam</content> <content styleCode="bold">2 mg/25 mL</content> <content styleCode="bold">N=268</content> <content styleCode="bold">n (%)</content></paragraph></td><td align="center" styleCode="Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Placebo</content> <content styleCode="bold">N=278</content> <content styleCode="bold">n (%)</content></paragraph></td></tr><tr><td valign="top"><paragraph>Overall</paragraph></td><td align="center" valign="top"><paragraph>60 (22)</paragraph></td><td align="center" valign="top"><paragraph>10 (4)</paragraph></td></tr><tr><td valign="top"><paragraph>Blood cortisol decreased </paragraph></td><td align="center" valign="top"><paragraph>46 (17)* </paragraph></td><td align="center" valign="top"><paragraph>6 (2)</paragraph></td></tr><tr><td valign="top"><paragraph>Adrenal insufficiency</paragraph></td><td align="center" valign="top"><paragraph>10 (4)</paragraph></td><td align="center" valign="top"><paragraph>2 (1)</paragraph></td></tr><tr><td valign="top"><paragraph>Insomnia</paragraph></td><td align="center" valign="top"><paragraph>1 (0.4)</paragraph></td><td align="center" valign="top"><paragraph>1 (0.4)</paragraph></td></tr><tr><td valign="top"><paragraph>Sleep disorder</paragraph></td><td align="center" valign="top"><paragraph>1 (0.4)</paragraph></td><td align="center" valign="top"><paragraph>0</paragraph></td></tr><tr><td valign="top"><paragraph>Acne</paragraph></td><td align="center" valign="top"><paragraph>1 (0.4)</paragraph></td><td align="center" valign="top"><paragraph>0</paragraph></td></tr><tr><td valign="top"><paragraph>Depression</paragraph></td><td align="center" valign="top"><paragraph>1 (0.4)</paragraph></td><td align="center" valign="top"><paragraph>1 (0.4)</paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph>Hyperglycemia</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>1 (0.4)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>0</paragraph></td></tr></tbody></table>

7 DRUG INTERACTIONS CYP3A4 Inhibitors (e.g., ketoconazole, grapefruit juice): May cause increased systemic corticosteroid effects; avoid concomitant use. ( 7.1 ) 7.1 CYP3A4 Inhibitors The active ingredient of UCERIS rectal foam, budesonide, is metabolized by CYP3A4. Inhibitors of CYP3A4 activity (such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, erythromycin, cyclosporine and grapefruit juice) can increase systemic budesonide concentrations. Avoid concomitant use of CYP3A4 inhibitors with UCERIS rectal foam [see Clinical Pharmacology ( 12.3 )] .

8 USE IN SPECIFIC POPULATIONS • Pregnancy: Based on animal data, may cause fetal harm. ( 8.1 ) • Hepatic Impairment: Monitor patients for signs and/or symptoms of hypercorticism. ( 8.6 ) 8.1 Pregnancy Risk Summary Limited published studies report on the use of budesonide in pregnant women; however, the data are insufficient to inform a drug-associated risk for major birth defects and miscarriage. There are clinical considerations (see Clinical Considerations) . In animal reproduction studies with pregnant rats and rabbits, subcutaneous administration of budesonide during organogenesis at doses 1.2 times and 0.12 times, respectively, the human intrarectal dose of 4 mg/day, resulted in increased fetal loss, decreased pup weights, and skeletal abnormalities. Maternal toxicity was observed in both rats and rabbits at these dose levels (see Data). Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage of the indicated population is 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 of 2% to 4%, and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with ulcerative colitis. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth. Fetal/Neonatal Adverse Reactions Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Infants should be carefully observed for signs of hypoadrenalism, such as poor feeding, irritability, weakness, and vomiting, and managed accordingly [see Warnings and Precautions (5.1)] . Data Animal Data Budesonide was teratogenic and embryolethal in rabbits and rats. In an embryo-fetal development study in pregnant rats dosed subcutaneously with budesonide during the period of organogenesis from gestation days 6-15 there were effects on fetal development and survival at subcutaneous doses up to approximately 500 mcg/kg in rats (approximately 1.2 times the recommended human intrarectal dose on a body surface area basis). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 6-18, there was an increase in maternal abortion, and effects on fetal development and reduction in litter weights at subcutaneous doses up to approximately 25 mcg/kg in rabbits (approximately 0.12 times the recommended human intrarectal dose of 4 mg/day on a body surface area basis). Maternal toxicity, including reduction in body weight gain, was observed at subcutaneous doses of 5 mcg/kg in rabbits (approximately 0.02 times the recommended human intrarectal dose on a body surface area basis) and 500 mcg/kg in rats (approximately 1.2 times the recommended human intrarectal dose of 4 mg/day on a body surface area basis). In a pre-and post-natal development study, rats dosed subcutaneously with budesonide during the period of Day 15 post coitum to Day 21 postpartum, budesonide had no effects on delivery but did have an effect on growth and development of offspring.

mended human intrarectal dose of 4 mg/day on a body surface area basis). In a pre-and post-natal development study, rats dosed subcutaneously with budesonide during the period of Day 15 post coitum to Day 21 postpartum, budesonide had no effects on delivery but did have an effect on growth and development of offspring. In addition, offspring survival was reduced, and surviving offspring had decreased mean body weights at birth and during lactation at exposures 0.05 times the MRHD (on a mg/m 2 basis at maternal subcutaneous doses of 20 mcg/kg/day and higher). These findings occurred in the presence of maternal toxicity. 8.2 Lactation Risk Summary Lactation studies have not been conducted with UCERIS rectal foam or other rectally administered budesonide products and no information is available on the effects of budesonide on the breastfed infant or the effects of the drug on milk production. One published study reports that budesonide is present in human milk following maternal inhalation of budesonide (see Data) . The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for UCERIS rectal foam and any potential adverse effects on the breastfed child from UCERIS rectal foam or from the underlying maternal condition. Data One published study reports that budesonide is present in human milk following maternal inhalation of budesonide and the milk/plasma ratio ranged between 0.4 and 0.5. Budesonide plasma concentrations were not detected, and no adverse events were noted in the breastfed infants following maternal use of inhaled budesonide. The systemic exposure (AUC 0-12 ) following administration of 400 mcg twice a day of inhaled budesonide ranged from 1.27 to 2.26 ng*hr/mL. The estimated budesonide AUC 0-12 following rectal administration of 2 mg twice a day UCERIS was 4.31 ng*hr/mL [see Clinical Pharmacology ( 12.3 )] . Budesonide exposure to the nursing child may be higher with maternal rectal administration of UCERIS than with maternal inhaled administration of budesonide. 8.4 Pediatric Use The safety and effectiveness of UCERIS rectal foam has not been established in pediatric patients. Children who are treated with corticosteroids by any route may experience a decrease in their growth velocity. This negative impact of corticosteroids on growth has been in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression. The long-term effects of this reduction in growth velocity associated with corticosteroid treatment, including the impact on final adult height, are unknown. Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in children than some commonly used tests of HPA axis function. The linear growth of children treated with corticosteroids by any route should be monitored (e.g., via stadiometry), and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of other treatment alternatives. In order to minimize the potential growth effects of corticosteroids, children should be titrated to the lowest effective dose. 8.5 Geriatric Use Clinical studies with UCERIS rectal foam did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

fferences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6 Hepatic Impairment No dosage adjustment is needed for patients with mild (Child-Pugh Class A) hepatic impairment. Patients with moderate to severe hepatic impairment (Child-Pugh Class B or C) should be monitored for increased signs and/or symptoms of hypercorticism. Discontinuing the use of UCERIS rectal foam should be considered in these patients if signs of hypercorticism are observed [see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 )] .

8.1 Pregnancy Risk Summary Limited published studies report on the use of budesonide in pregnant women; however, the data are insufficient to inform a drug-associated risk for major birth defects and miscarriage. There are clinical considerations (see Clinical Considerations) . In animal reproduction studies with pregnant rats and rabbits, subcutaneous administration of budesonide during organogenesis at doses 1.2 times and 0.12 times, respectively, the human intrarectal dose of 4 mg/day, resulted in increased fetal loss, decreased pup weights, and skeletal abnormalities. Maternal toxicity was observed in both rats and rabbits at these dose levels (see Data). Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage of the indicated population is 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 of 2% to 4%, and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with ulcerative colitis. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth. Fetal/Neonatal Adverse Reactions Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Infants should be carefully observed for signs of hypoadrenalism, such as poor feeding, irritability, weakness, and vomiting, and managed accordingly [see Warnings and Precautions (5.1)] . Data Animal Data Budesonide was teratogenic and embryolethal in rabbits and rats. In an embryo-fetal development study in pregnant rats dosed subcutaneously with budesonide during the period of organogenesis from gestation days 6-15 there were effects on fetal development and survival at subcutaneous doses up to approximately 500 mcg/kg in rats (approximately 1.2 times the recommended human intrarectal dose on a body surface area basis). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 6-18, there was an increase in maternal abortion, and effects on fetal development and reduction in litter weights at subcutaneous doses up to approximately 25 mcg/kg in rabbits (approximately 0.12 times the recommended human intrarectal dose of 4 mg/day on a body surface area basis). Maternal toxicity, including reduction in body weight gain, was observed at subcutaneous doses of 5 mcg/kg in rabbits (approximately 0.02 times the recommended human intrarectal dose on a body surface area basis) and 500 mcg/kg in rats (approximately 1.2 times the recommended human intrarectal dose of 4 mg/day on a body surface area basis). In a pre-and post-natal development study, rats dosed subcutaneously with budesonide during the period of Day 15 post coitum to Day 21 postpartum, budesonide had no effects on delivery but did have an effect on growth and development of offspring.

mended human intrarectal dose of 4 mg/day on a body surface area basis). In a pre-and post-natal development study, rats dosed subcutaneously with budesonide during the period of Day 15 post coitum to Day 21 postpartum, budesonide had no effects on delivery but did have an effect on growth and development of offspring. In addition, offspring survival was reduced, and surviving offspring had decreased mean body weights at birth and during lactation at exposures 0.05 times the MRHD (on a mg/m 2 basis at maternal subcutaneous doses of 20 mcg/kg/day and higher). These findings occurred in the presence of maternal toxicity.

8.4 Pediatric Use The safety and effectiveness of UCERIS rectal foam has not been established in pediatric patients. Children who are treated with corticosteroids by any route may experience a decrease in their growth velocity. This negative impact of corticosteroids on growth has been in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression. The long-term effects of this reduction in growth velocity associated with corticosteroid treatment, including the impact on final adult height, are unknown. Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in children than some commonly used tests of HPA axis function. The linear growth of children treated with corticosteroids by any route should be monitored (e.g., via stadiometry), and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of other treatment alternatives. In order to minimize the potential growth effects of corticosteroids, children should be titrated to the lowest effective dose.

8.5 Geriatric Use Clinical studies with UCERIS rectal foam did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE Acute overdosage with UCERIS rectal foam is unlikely. However, UCERIS rectal foam is absorbed systemically and chronic overdosage may result in signs/symptoms of hypercorticism [see Warnings and Precautions ( 5.1 )] .

11 DESCRIPTION UCERIS rectal foam contains budesonide, a non-halogenated synthetic glucocorticoid, as the active ingredient. It is a mixture of the 2 epimers (22R and 22S) differing in the position of an acetal chain. Both epimers are active glucocorticoids applied in a mixture of approximately 1:1. Budesonide is designated chemically as (RS)-11β, 16α, 17,21 tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with butyraldehyde. The empirical formula of budesonide is C 25 H 34 O 6 and its molecular weight is 430.5. Its structural formula is: UCERIS rectal foam contains 2 mg budesonide per metered dose. Inactive ingredients: cetyl alcohol, citric acid monohydrate, edetate disodium, emulsifying wax, polyoxyl (10) stearyl ether, propylene glycol, and purified water. Propellant: n-butane, isobutane, and propane. formula

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Budesonide has glucocorticosteroid (GCS) activity. 12.2 Pharmacodynamics Treatment with glucocorticosteroids, including UCERIS rectal foam, is associated with a suppression of endogenous cortisol concentrations and an impairment of the hypothalamic-pituitary-adrenal (HPA) axis function. These effects were measured by determination of plasma cortisol concentrations and responses to adrenocorticotropin challenge (i.e., ACTH stimulation test) in 2 placebo-controlled, 6-week trials in patients with active disease [see Clinical Studies (14)] . These trials enrolled subjects with post-ACTH stimulation cortisol levels of >18 mcg/dL at baseline. Subjects received UCERIS rectal foam 2 mg or a placebo twice daily for 2 weeks followed by once daily for 4 weeks. Normal morning serum cortisol levels >5 mcg/dL were maintained in 85% and 84% of UCERIS rectal foam treated subjects during Weeks 1 and 2 (twice daily treatment) and 93% and 94% during Weeks 4 and 6 (once daily treatment), respectively (see Table 3 ). At baseline (predose), 84% of subjects in the UCERIS rectal foam group had a normal response to the ACTH challenge and at Week 6, 63% of subjects had a normal response to the ACTH challenge; in the placebo group, these values were 86% and 76%, respectively (see Table 3 ). ACTH stimulation test was not performed routinely during the twice daily treatment period (Weeks 1 and 2). Table 3: Proportion of Subjects with Normal Endogenous Cortisol Levels (>5 mcg/dL) During the Study and Proportion of Subjects with Normal Response to ACTH Challenge Cortisol Parameter UCERIS Rectal Foam 2 mg/25 mL N=268 n (%) Placebo N=278 n (%) Total cortisol ˃5 mcg/dL (lower limit of normal range) Baseline 259/268 (96.6) 275/278 (98.9) Week 1 224/263 (85.2) 264/269 (98.1) Week 2 216/257 (84.0) 263/266 (98.9) Week 4 218/235 (92.8) 243/249 (97.6) Week 6 211/224 (94.2) 234/241 (97.1) Normal response to ACTH challenge Baseline 222/266 (83.5) 238/278 (85.6) Week 6 148/236 (62.7) 180/237 (75.9) 12.3 Pharmacokinetics Absorption Distal Ulcerative Colitis Patients Based on population pharmacokinetic analysis from sparse PK samples from phase 3 studies,the estimated AUC 0-12 following administration of UCERIS rectal foam 2 mg twice a day was 4.31 ng*hr/mL with a CV of 64% in the target patient population. Distribution The volume of distribution (V SS ) of budesonide varies between 2.2 and 3.9 L/kg in healthy subjects and in patients. Plasma protein binding is estimated to be 85 to 90% in the concentration range of 1 to 230 nmol/L, independent of gender. The erythrocyte/plasma partition ratio at clinically relevant concentrations is approximately 0.8. Elimination Metabolism Following absorption, budesonide is subject to first-pass metabolism. In vitro experiments in human liver microsomes demonstrate that budesonide is rapidly and extensively biotransformed, mainly by CYP3A4, to its 2 major metabolites, 6β-hydroxy budesonide and 16α-hydroxy prednisolone. The glucocorticoid activity of these metabolites is negligible (<1/100) in relation to that of the parent compound. In vivo investigations with intravenous doses in healthy subjects demonstrate that budesonide has a plasma clearance of 0.9-1.8 L/min. These plasma clearance values approach the estimated liver blood flow, suggesting that budesonide is a high hepatic clearance drug. Excretion Budesonide is excreted in urine and feces in the form of metabolites.

h intravenous doses in healthy subjects demonstrate that budesonide has a plasma clearance of 0.9-1.8 L/min. These plasma clearance values approach the estimated liver blood flow, suggesting that budesonide is a high hepatic clearance drug. Excretion Budesonide is excreted in urine and feces in the form of metabolites. After oral as well as intravenous administration of micronized [ 3 H]-budesonide, approximately 60% of the recovered radioactivity is found in urine. The major metabolites, including 6β-hydroxybudesonide and 16α-hydroxyprednisolone, are mainly renally excreted, intact or in conjugated forms. No unchanged budesonide is detected in urine. Specific Populations Patients with Renal Impairment The pharmacokinetics of budesonide in patients with renal impairment has not been studied. Intact budesonide is not renally excreted, but metabolites are to a large extent, and might therefore reach higher levels in patients with impaired renal function. However, these metabolites have negligible corticosteroid activity as compared with budesonide. Patients with Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of UCERIS rectal foam has not been studied. In a study in patients with mild to moderate hepatic impairment (Child-Pugh Class A and Child-Pugh Class B) dosed with budesonide 4 mg oral capsules, systemic exposure was similar between patients with mild hepatic impairment (Child-Pugh Class A; n=4) and healthy subjects (n=8), and 3.5-fold higher in patients with moderate hepatic impairment (Child-Pugh Class B; n=4) than in healthy subjects. For the intravenous dose, no significant differences in CL or V SS are observed. Patients with severe liver dysfunction (Child-Pugh Class C) were not studied [see Use in Specific Populations (8.6)]. Drug Interaction Studies Budesonide is metabolized via CYP3A4. Potent inhibitors of CYP3A4 can increase the plasma concentrations of budesonide. Co-administration of ketoconazole (inhibitor of CYP3A4) results in an 8-fold increase in AUC of oral budesonide, compared to budesonide alone. Grapefruit juice, an inhibitor of gut mucosal CYP3A, approximately doubles the systemic exposure of oral budesonide. Conversely, induction of CYP3A4 can result in the lowering of budesonide plasma concentrations. The effect of CYP3A4 inhibitors and inducers on the pharmacokinetics of UCERIS rectal foam have not been studied [see Dosage and Administration ( 2 ) and Drug Interactions ( 7 )] . Oral contraceptives containing ethinyl estradiol, which are also metabolized by CYP3A4, do not affect the pharmacokinetics of oral budesonide. Budesonide does not affect the plasma concentrations of oral contraceptives (i.e., ethinyl estradiol). In vitro interaction studies performed with budesonide showed that budesonide did not inhibit human cytochrome P450 isoenzymes CYP1A2, CYP2B6, CYP2C9, CYP2D6, or CYP2E1 at concentrations ranging from 0.11 to 1130 ng/mL. Isoenzyme CYP3A4 was inhibited at the highest concentration tested but the IC 50 was >1130 ng/mL. UCERIS rectal foam is not expected to inhibit these enzymes in clinical use. No significant induction of CYP1A2, CYP2B6, CYP2C9 or CYP3A4/5 expression was observed in human hepatocytes in vitro at budesonide concentrations up to 9000 nM (3.88 mcg/mL). In an in vitro study, budesonide was not a substrate of human transporters OATP1B3 and may be a weak substrate of OATP1B1. Budesonide at concentrations up to 300 nM (129 ng/mL) did not inhibit OATP1B1 or OATP1B3. Budesonide was not a substrate of BCRP and was a weak substrate of P-glycoprotein. Budesonide was a weak inhibitor of P-glycoprotein (IC 50 9.78 µM or 4.21 mcg/mL) and BCRP (IC 50 43.1 µM or 18.6 mcg/mL). UCERIS rectal foam is not expected to inhibit these transporters in clinical use.

12.2 Pharmacodynamics Treatment with glucocorticosteroids, including UCERIS rectal foam, is associated with a suppression of endogenous cortisol concentrations and an impairment of the hypothalamic-pituitary-adrenal (HPA) axis function. These effects were measured by determination of plasma cortisol concentrations and responses to adrenocorticotropin challenge (i.e., ACTH stimulation test) in 2 placebo-controlled, 6-week trials in patients with active disease [see Clinical Studies (14)] . These trials enrolled subjects with post-ACTH stimulation cortisol levels of >18 mcg/dL at baseline. Subjects received UCERIS rectal foam 2 mg or a placebo twice daily for 2 weeks followed by once daily for 4 weeks. Normal morning serum cortisol levels >5 mcg/dL were maintained in 85% and 84% of UCERIS rectal foam treated subjects during Weeks 1 and 2 (twice daily treatment) and 93% and 94% during Weeks 4 and 6 (once daily treatment), respectively (see Table 3 ). At baseline (predose), 84% of subjects in the UCERIS rectal foam group had a normal response to the ACTH challenge and at Week 6, 63% of subjects had a normal response to the ACTH challenge; in the placebo group, these values were 86% and 76%, respectively (see Table 3 ). ACTH stimulation test was not performed routinely during the twice daily treatment period (Weeks 1 and 2). Table 3: Proportion of Subjects with Normal Endogenous Cortisol Levels (>5 mcg/dL) During the Study and Proportion of Subjects with Normal Response to ACTH Challenge Cortisol Parameter UCERIS Rectal Foam 2 mg/25 mL N=268 n (%) Placebo N=278 n (%) Total cortisol ˃5 mcg/dL (lower limit of normal range) Baseline 259/268 (96.6) 275/278 (98.9) Week 1 224/263 (85.2) 264/269 (98.1) Week 2 216/257 (84.0) 263/266 (98.9) Week 4 218/235 (92.8) 243/249 (97.6) Week 6 211/224 (94.2) 234/241 (97.1) Normal response to ACTH challenge Baseline 222/266 (83.5) 238/278 (85.6) Week 6 148/236 (62.7) 180/237 (75.9)

<table ID="_RefID0EWPAE" width="100%"><caption>Table 3: Proportion of Subjects with Normal Endogenous Cortisol Levels (&gt;5 mcg/dL) During the Study and Proportion of Subjects with Normal Response to ACTH Challenge</caption><col width="33%"/><col width="17%"/><col width="17%"/><col width="17%"/><col width="17%"/><tbody><tr><td styleCode="Toprule " valign="bottom"><paragraph><content styleCode="bold">Cortisol Parameter</content></paragraph></td><td align="center" colspan="2" styleCode="Toprule " valign="bottom"><paragraph><content styleCode="bold">UCERIS Rectal Foam</content> <content styleCode="bold">2 mg/25 mL</content> <content styleCode="bold">N=268</content> <content styleCode="bold">n (%)</content></paragraph></td><td align="center" colspan="2" styleCode="Toprule " valign="bottom"><paragraph><content styleCode="bold">Placebo</content> <content styleCode="bold">N=278</content> <content styleCode="bold">n (%)</content></paragraph></td></tr><tr><td colspan="5" valign="top"><paragraph><content styleCode="bold"><content styleCode="italics">Total cortisol &#x2C3;5 mcg/dL</content></content> <content styleCode="bold"><content styleCode="italics">(lower limit of normal range)</content></content></paragraph></td></tr><tr><td valign="top"><paragraph>Baseline</paragraph></td><td align="center" valign="top"><paragraph>259/268</paragraph></td><td align="center" valign="top"><paragraph>(96.6)</paragraph></td><td align="center" valign="top"><paragraph>275/278</paragraph></td><td align="center" valign="top"><paragraph>(98.9)</paragraph></td></tr><tr><td valign="top"><paragraph>Week 1</paragraph></td><td align="center" valign="top"><paragraph>224/263</paragraph></td><td align="center" valign="top"><paragraph>(85.2)</paragraph></td><td align="center" valign="top"><paragraph>264/269</paragraph></td><td align="center" valign="top"><paragraph>(98.1)</paragraph></td></tr><tr><td valign="top"><paragraph>Week 2</paragraph></td><td align="center" valign="top"><paragraph>216/257</paragraph></td><td align="center" valign="top"><paragraph>(84.0)</paragraph></td><td align="center" valign="top"><paragraph>263/266</paragraph></td><td align="center" valign="top"><paragraph>(98.9)</paragraph></td></tr><tr><td valign="top"><paragraph>Week 4</paragraph></td><td align="center" valign="top"><paragraph>218/235</paragraph></td><td align="center" valign="top"><paragraph>(92.8)</paragraph></td><td align="center" valign="top"><paragraph>243/249</paragraph></td><td align="center" valign="top"><paragraph>(97.6)</paragraph></td></tr><tr><td valign="top"><paragraph>Week 6</paragraph></td><td align="center" valign="top"><paragraph>211/224 </paragraph></td><td align="center" valign="top"><paragraph>(94.2)</paragraph></td><td align="center" valign="top"><paragraph>234/241</paragraph></td><td align="center" valign="top"><paragraph>(97.1)</paragraph></td></tr><tr><td colspan="5" valign="top"><paragraph><content styleCode="bold"><content styleCode="italics">Normal response to ACTH challenge</content></content></paragraph></td></tr><tr><td valign="top"><paragraph>Baseline</paragraph></td><td align="center" valign="top"><paragraph>222/266</paragraph></td><td align="center" valign="top"><paragraph>(83.5)</paragraph></td><td align="center" valign="top"><paragraph>238/278</paragraph></td><td align="center" valign="top"><paragraph>(85.6)</paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph>Week 6</paragraph></td><td align="center" styleCode="Botrule " valign="top"><p

er" valign="top"><paragraph>(83.5)</paragraph></td><td align="center" valign="top"><paragraph>238/278</paragraph></td><td align="center" valign="top"><paragraph>(85.6)</paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph>Week 6</paragraph></td><td align="center" styleCode="Botrule " valign="top"><p aragraph>148/236</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>(62.7)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>180/237</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>(75.9)</paragraph></td></tr></tbody></table>

12.3 Pharmacokinetics Absorption Distal Ulcerative Colitis Patients Based on population pharmacokinetic analysis from sparse PK samples from phase 3 studies,the estimated AUC 0-12 following administration of UCERIS rectal foam 2 mg twice a day was 4.31 ng*hr/mL with a CV of 64% in the target patient population. Distribution The volume of distribution (V SS ) of budesonide varies between 2.2 and 3.9 L/kg in healthy subjects and in patients. Plasma protein binding is estimated to be 85 to 90% in the concentration range of 1 to 230 nmol/L, independent of gender. The erythrocyte/plasma partition ratio at clinically relevant concentrations is approximately 0.8. Elimination Metabolism Following absorption, budesonide is subject to first-pass metabolism. In vitro experiments in human liver microsomes demonstrate that budesonide is rapidly and extensively biotransformed, mainly by CYP3A4, to its 2 major metabolites, 6β-hydroxy budesonide and 16α-hydroxy prednisolone. The glucocorticoid activity of these metabolites is negligible (<1/100) in relation to that of the parent compound. In vivo investigations with intravenous doses in healthy subjects demonstrate that budesonide has a plasma clearance of 0.9-1.8 L/min. These plasma clearance values approach the estimated liver blood flow, suggesting that budesonide is a high hepatic clearance drug. Excretion Budesonide is excreted in urine and feces in the form of metabolites. After oral as well as intravenous administration of micronized [ 3 H]-budesonide, approximately 60% of the recovered radioactivity is found in urine. The major metabolites, including 6β-hydroxybudesonide and 16α-hydroxyprednisolone, are mainly renally excreted, intact or in conjugated forms. No unchanged budesonide is detected in urine. Specific Populations Patients with Renal Impairment The pharmacokinetics of budesonide in patients with renal impairment has not been studied. Intact budesonide is not renally excreted, but metabolites are to a large extent, and might therefore reach higher levels in patients with impaired renal function. However, these metabolites have negligible corticosteroid activity as compared with budesonide. Patients with Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of UCERIS rectal foam has not been studied. In a study in patients with mild to moderate hepatic impairment (Child-Pugh Class A and Child-Pugh Class B) dosed with budesonide 4 mg oral capsules, systemic exposure was similar between patients with mild hepatic impairment (Child-Pugh Class A; n=4) and healthy subjects (n=8), and 3.5-fold higher in patients with moderate hepatic impairment (Child-Pugh Class B; n=4) than in healthy subjects. For the intravenous dose, no significant differences in CL or V SS are observed. Patients with severe liver dysfunction (Child-Pugh Class C) were not studied [see Use in Specific Populations (8.6)]. Drug Interaction Studies Budesonide is metabolized via CYP3A4. Potent inhibitors of CYP3A4 can increase the plasma concentrations of budesonide. Co-administration of ketoconazole (inhibitor of CYP3A4) results in an 8-fold increase in AUC of oral budesonide, compared to budesonide alone. Grapefruit juice, an inhibitor of gut mucosal CYP3A, approximately doubles the systemic exposure of oral budesonide. Conversely, induction of CYP3A4 can result in the lowering of budesonide plasma concentrations.

inhibitor of CYP3A4) results in an 8-fold increase in AUC of oral budesonide, compared to budesonide alone. Grapefruit juice, an inhibitor of gut mucosal CYP3A, approximately doubles the systemic exposure of oral budesonide. Conversely, induction of CYP3A4 can result in the lowering of budesonide plasma concentrations. The effect of CYP3A4 inhibitors and inducers on the pharmacokinetics of UCERIS rectal foam have not been studied [see Dosage and Administration ( 2 ) and Drug Interactions ( 7 )] . Oral contraceptives containing ethinyl estradiol, which are also metabolized by CYP3A4, do not affect the pharmacokinetics of oral budesonide. Budesonide does not affect the plasma concentrations of oral contraceptives (i.e., ethinyl estradiol). In vitro interaction studies performed with budesonide showed that budesonide did not inhibit human cytochrome P450 isoenzymes CYP1A2, CYP2B6, CYP2C9, CYP2D6, or CYP2E1 at concentrations ranging from 0.11 to 1130 ng/mL. Isoenzyme CYP3A4 was inhibited at the highest concentration tested but the IC 50 was >1130 ng/mL. UCERIS rectal foam is not expected to inhibit these enzymes in clinical use. No significant induction of CYP1A2, CYP2B6, CYP2C9 or CYP3A4/5 expression was observed in human hepatocytes in vitro at budesonide concentrations up to 9000 nM (3.88 mcg/mL). In an in vitro study, budesonide was not a substrate of human transporters OATP1B3 and may be a weak substrate of OATP1B1. Budesonide at concentrations up to 300 nM (129 ng/mL) did not inhibit OATP1B1 or OATP1B3. Budesonide was not a substrate of BCRP and was a weak substrate of P-glycoprotein. Budesonide was a weak inhibitor of P-glycoprotein (IC 50 9.78 µM or 4.21 mcg/mL) and BCRP (IC 50 43.1 µM or 18.6 mcg/mL). UCERIS rectal foam is not expected to inhibit these transporters in clinical use.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity Carcinogenicity studies with budesonide were conducted in rats and mice. In a 2-year study in Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in male rats at an oral dose of 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). In addition, there were increased incidences of primary hepatocellular tumors in male rats at 25 mcg/kg (approximately 0.06 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area) and above. No tumorigenicity was seen in female rats at oral doses up to 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). In an additional 2-year study in male Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). However, it caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). The concurrent reference glucocorticosteroids (prednisolone and triamcinolone acetonide) showed similar findings. In a 91-week study in mice, budesonide caused no treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately 0.24 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). Mutagenesis Budesonide showed no evidence of mutagenic potential in the Ames test, the mouse lymphoma cell forward gene mutation (TK+/-) test, the human lymphocyte chromosome aberration test, the Drosophila melanogaster sex-linked recessive lethality test, the rat hepatocyte UDS test or the mouse micronucleus test. Impairment of Fertility In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg (approximately 0.20 times recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). However, it caused a decrease in prenatal viability and viability in pups at birth and during lactation, along with a decrease in maternal body-weight gain, at subcutaneous doses of 20 mcg/kg (approximately 0.05 times recommended intrarectal dose of 4 mg/day in humans, based on the body surface area) and above. No such effects were noted at 5 mcg/kg.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity Carcinogenicity studies with budesonide were conducted in rats and mice. In a 2-year study in Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in male rats at an oral dose of 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). In addition, there were increased incidences of primary hepatocellular tumors in male rats at 25 mcg/kg (approximately 0.06 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area) and above. No tumorigenicity was seen in female rats at oral doses up to 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). In an additional 2-year study in male Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). However, it caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). The concurrent reference glucocorticosteroids (prednisolone and triamcinolone acetonide) showed similar findings. In a 91-week study in mice, budesonide caused no treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately 0.24 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). Mutagenesis Budesonide showed no evidence of mutagenic potential in the Ames test, the mouse lymphoma cell forward gene mutation (TK+/-) test, the human lymphocyte chromosome aberration test, the Drosophila melanogaster sex-linked recessive lethality test, the rat hepatocyte UDS test or the mouse micronucleus test. Impairment of Fertility In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg (approximately 0.20 times recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). However, it caused a decrease in prenatal viability and viability in pups at birth and during lactation, along with a decrease in maternal body-weight gain, at subcutaneous doses of 20 mcg/kg (approximately 0.05 times recommended intrarectal dose of 4 mg/day in humans, based on the body surface area) and above. No such effects were noted at 5 mcg/kg.

14 CLINICAL STUDIES The safety and efficacy of UCERIS rectal foam were evaluated in 2 replicate, randomized, double-blind, placebo-controlled, multi-center trials (Studies 1 and 2). Participants in the trials were adult patients with active mild-to-moderate distal ulcerative colitis with disease extending at least 5 cm but no further than 40 cm from the anal verge (confirmed by endoscopy). To be eligible, patients had to have a Modified Mayo Disease Activity Index (MMDAI) score between 5 and 10, inclusive, a rectal bleeding subscore of 2 or 3, and an endoscopy subscore of 2 or 3. The MMDAI score ranges from 0 to 12 and has 4 subscales that are each scored from 0 (normal) to 3 (most severe): stool frequency, rectal bleeding, findings on endoscopy, and physician global assessment. An endoscopy subscore of 2 is defined by marked erythema, lack of vascular pattern, friability, and erosions; an endoscopy subscore of 3 is defined by spontaneous bleeding and ulceration. Oral and rectal corticosteroids, and rectal 5-aminosalicylic acid (5-ASA) products were prohibited during the course of the trials but were allowed as rescue therapy. Oral 5-ASA products were allowed at doses ≤ 4.8 grams/day. In total, 546 subjects were randomized in these trials: 267 subjects to UCERIS rectal foam and 279 subjects to placebo. In each trial (Study 1 and Study 2), patients received UCERIS rectal foam 2 mg or placebo twice daily for 2 weeks followed by once daily for 4 weeks. The median age was 41 years and 42 years, 5% and 8% were ≥ 65 years of age, and 43% and 45% were male, in Studies 1 and 2, respectively. In each of these trials, 90% were Caucasian, 7-8% were African American, and 3% were Asian or Other. The majority of patients had a baseline diagnosis of proctosigmoiditis (69% and 74%) in Studies 1 and 2, respectively. The remaining patients had a baseline diagnosis of proctitis. Concomitant oral 5-ASA use at baseline was 59% and 51% in Studies 1 and 2, respectively. Baseline MMDAI total score was 7.8 and 7.9 in the UCERIS rectal foam group and placebo group, respectively, of Study 1; and 7.9 and 8.0 in the UCERIS rectal foam group and placebo group, respectively, of Study 2. The mean stool frequency subscore at baseline was 1.8 and 1.9 in the UCERIS rectal foam group and placebo group, respectively, of Study 1; and 1.7 and 1.8 in the UCERIS rectal foam group and placebo group, respectively, of Study 2. In each trial (Study 1 and Study 2), the primary endpoint was the proportion of subjects who were in remission after 6 weeks of treatment. Remission was defined as a decrease or no change in the stool frequency subscore from baseline, a rectal bleeding subscore of 0, and an endoscopy score of 0 or 1. (An endoscopy subscore of zero is defined by normal or inactive disease; an endoscopy subscore of 1 is defined by erythema and decreased vascular pattern.) In each trial (Study 1 and Study 2), a higher proportion of patients in the UCERIS rectal foam group than in the placebo group were in remission at Week 6 and had a rectal bleeding subscore of 0 at Week 6 ( Table 4 ).

r inactive disease; an endoscopy subscore of 1 is defined by erythema and decreased vascular pattern.) In each trial (Study 1 and Study 2), a higher proportion of patients in the UCERIS rectal foam group than in the placebo group were in remission at Week 6 and had a rectal bleeding subscore of 0 at Week 6 ( Table 4 ). Table 4: Efficacy Results: Studies 1 and 2 Study 1 Efficacy Endpoint UCERIS Rectal Foam N=133 Placebo N=132 p-value Treatment Difference (95% CI) Remission at Week 6 38.3% 25.8% 0.032 12.6% (1.5%, 23.7%) Rectal Bleeding subscore = 0 at Week 6 46.6% 28.0% 0.002 18.6% (7.2%, 30%) Study 2 UCERIS Rectal Foam N=134 Placebo N=147 p-value Treatment Difference (95% CI) Remission at Week 6 44.0% 22.4% <0.001 21.6% (10.8%, 32.4%) Rectal Bleeding subscore = 0 at Week 6 50.0% 28.6% <0.001 21.4% (10.3%, 32.6%) CI: Confidence Interval In Study 1, the percentage of patients with endoscopy subscore of 0 or 1 at Week 6 was 55.6% in the UCERIS rectal foam group versus 43.2% in the placebo group. In Study 2, the percentage of patients with endoscopy subscore of 0 or 1 at Week 6 was 56.0% in the UCERIS rectal foam group versus 36.7% in the placebo group (an endoscopy subscore of 0 is defined by normal or inactive disease; an endoscopy subscore of 1 is defined by erythema and decreased vascular pattern). In patients that met the primary endpoint of remission in Study 1, the mean (SD) decrease in stool frequency subscore was 1.2 (0.9) in the UCERIS rectal foam group and 1.2 (0.8) in the placebo group. In patients that met the primary endpoint of remission in Study 2, the mean (SD) decrease in stool frequency subscore was 1.3 (0.8) in the UCERIS rectal foam group and 1.1 (0.9) in the placebo group.

<table ID="_RefID0ED4AE" width="100%"><caption>Table 4: Efficacy Results: Studies 1 and 2</caption><col width="23%"/><col width="19%"/><col width="20%"/><col width="20%"/><col width="19%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td colspan="4" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold"> Study 1</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Efficacy Endpoint</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">UCERIS Rectal Foam</content> <content styleCode="bold">N=133</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Placebo</content> <content styleCode="bold">N=132</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">p-value</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Treatment Difference</content> <content styleCode="bold">(95% CI)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Remission at Week 6</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>38.3%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>25.8%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>0.032</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12.6% (1.5%, 23.7%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Rectal Bleeding subscore = 0 at Week 6</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>46.6%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>28.0%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>0.002</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>18.6% (7.2%, 30%)</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold"> Study 2</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">UCERIS Rectal Foam</content> <content styleCode="bold">N=134</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Placebo</content> <content styleCode="bold">N=147</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">p-value</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Treatment Difference</content> <content styleCode="bold">(95% CI)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Remission at Week 6</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>44.0%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>22.4%</paragra

nt></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Remission at Week 6</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>44.0%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>22.4%</paragra ph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>&lt;0.001</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>21.6% (10.8%, 32.4%)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Rectal Bleeding subscore = 0 at Week 6</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>50.0%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>28.6%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>&lt;0.001</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>21.4% (10.3%, 32.6%)</paragraph></td></tr></tbody></table>

16 HOW SUPPLIED/STORAGE AND HANDLING UCERIS rectal foam is supplied as a kit containing 2 aerosol canisters with 28 PVC applicators coated with paraffin lubricant for administration of the foam (NDC 65649-651-03). Each canister (NDC 65649-651-02) is labeled with a net weight of 33.4 g and contains 14 metered doses. Storage Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Handling UCERIS rectal foam contains a flammable propellant. Do not have the canister burned after use and do not spray contents directly towards flames. • Do not expose to heat or store at temperatures above 120°F (49°C). • Flammable. Avoid fire, flame, or smoking during and immediately following administration. • Contents under pressure. Do not puncture or incinerate. DO NOT REFRIGERATE.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( PATIENT INFORMATION and INSTRUCTIONS FOR USE ). Administration Advise patients: • UCERIS rectal foam is only to be applied rectally. It is not for oral use. • Before using UCERIS rectal foam, use the bathroom to empty your bowels. • Each applicator is coated with a lubricant. If additional lubrication is needed, petrolatum or petroleum jelly can also be used. • Warm the canister in the hands while shaking it vigorously for 10 to 15 seconds prior to use. • UCERIS rectal foam can be used in a standing, lying or sitting position (e.g., while using the toilet). • Apply UCERIS rectal foam in the morning and the evening for the first 2 weeks of treatment; then once daily in the evening for the next 4 weeks. When applied in the evening, use immediately prior to bedtime. Try not to empty your bowels again until the next morning. • Avoid consumption of grapefruit or grapefruit juice during treatment with UCERIS rectal foam. • Avoid fire, flame, and smoking during and immediately following administration since UCERIS rectal foam is flammable. Hypercorticism and Adrenal Suppression Advise patients that UCERIS rectal foam may cause hypercorticism and adrenal suppression and that they should taper slowly from systemic corticosteroids if transferring to UCERIS rectal foam [see Warnings and Precautions ( 5.1 ), ( 5.2 )] . Advise patients that replacement of systemic glucocorticosteroids with UCERIS rectal foam may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug. Increased Risk of Infection Advise patients to avoid exposure to people with chicken pox or measles and if exposed, consult a physician. Also, inform patients that they are at increased risk of developing a variety of infections, including worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex and to contact their physician if they develop any symptoms of infection [see Warnings and Precautions ( 5.3 )] . Pregnancy Advise female patients that UCERIS rectal foam may cause fetal harm and to inform their healthcare provider with a known or suspected pregnancy [see Use in Specific Populations ( 8.1 )] . Distributed by: Salix Pharmaceuticals, a division of Bausch Health US, LLC Bridgewater, NJ 08807 USA Manufactured by: ASM Aerosol-Service AG Industriestrasse 11 CH-4313 Möhlin Switzerland Product marketed and distributed under license from Dr. Falk Pharma. UCERIS is a trademark of Salix Pharmaceuticals, Inc. or its affiliates. © 2020 Salix Pharmaceuticals, Inc. or its affiliates 9614101 EX00152

Patient Information UCERIS ® (u SAIR us) (budesonide) rectal foam What is UCERIS rectal foam? UCERIS rectal foam is a prescription corticosteroid medicine used to help get mild to moderate active ulcerative colitis that extends from the rectum to the sigmoid colon under control (induce remission). It is not known if UCERIS rectal foam is safe and effective in children. Who should not use UCERIS rectal foam? Do not use UCERIS rectal foam if you are allergic to budesonide or any of the ingredients in UCERIS rectal foam. See the end of this leaflet for a complete list of ingredients in UCERIS rectal foam. What should I tell my healthcare provider before using UCERIS rectal foam? Before you use UCERIS rectal foam, tell your healthcare provider about all of your medical conditions, including if you: • have liver problems. • are planning to have surgery. • have chicken pox or measles or have recently been near anyone with chicken pox or measles. • have an infection. • have or had a family history of diabetes, cataracts or glaucoma. • have or had tuberculosis. • have high blood pressure (hypertension). • have decreased bone mineral density (osteoporosis). • have stomach ulcers. • are pregnant or plan to become pregnant. It is not known if UCERIS rectal foam may harm your unborn baby. Tell your healthcare provider if you are pregnant or think you are pregnant. • are breastfeeding or plan to breastfeed. UCERIS rectal foam can pass into your breast milk and may harm your baby. You and your healthcare provider should decide if you will use UCERIS rectal foam or breastfeed. You should not do both. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. UCERIS rectal foam and other medicines may affect each other causing side effects. Especially tell your healthcare provider if you take another medicine that contains corticosteroids for other conditions, such as allergies or asthma. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I use UCERIS rectal foam? See the “Instructions for Use” at the end of this Patient Information for detailed information about the right way to use UCERIS rectal foam. • Use UCERIS rectal foam exactly as your healthcare provider tells you to use it. • UCERIS rectal foam should only be used rectally (through the anus).Do not take UCERIS rectal foam by mouth. • Warm the UCERIS rectal foam canister by holding it in your hands while shaking it (vigorously) for 10 to 15 seconds. • UCERIS rectal foam is used twice a day for the first 2 weeks of treatment (in the morning and in the evening). After 2 weeks, use UCERIS rectal foam 1 time a day in the evening, before bedtime for 4 weeks. • If you use too much UCERIS rectal foam, call your healthcare provider right away. • You should stop using UCERIS rectal foam before preparing for a colonoscopy. Call your healthcare provider before restarting UCERIS rectal foam after your colonoscopy. What should I avoid while using UCERIS rectal foam? • Do not eat grapefruit or drink grapefruit juice while using UCERIS rectal foam. Eating grapefruit or drinking grapefruit juice can increase the level of UCERIS rectal foam in your blood. • UCERIS rectal foam is flammable. Avoid fire, flame and smoking during and right after using UCERIS rectal foam. What are the possible side effects of UCERIS rectal foam?

uit juice while using UCERIS rectal foam. Eating grapefruit or drinking grapefruit juice can increase the level of UCERIS rectal foam in your blood. • UCERIS rectal foam is flammable. Avoid fire, flame and smoking during and right after using UCERIS rectal foam. What are the possible side effects of UCERIS rectal foam? UCERIS rectal foam may cause serious side effects, including: • Effects of having too much corticosteroid medicine in your blood (hypercorticism). Long-time use of UCERIS rectal foam can cause you to have too much glucocorticosteroid medicine in your blood. Tell your healthcare provider if you have any of the following signs and symptoms of hypercorticism: • acne • bruise easily • rounding of your face (moon face) • ankle swelling • thicker or more hair on your body and face • a fatty pad or hump between your shoulders (buffalo hump) • pink or purple stretch marks on the skin of your abdomen, thighs, breasts and arms • Adrenal suppression. When UCERIS rectal foam is used for a long period of time (chronic use), the adrenal glands may not make enough steroid hormones (adrenal suppression). Tell your healthcare provider if you are under stress or have any symptoms of adrenal suppression during treatment with UCERIS rectal foam including: o tiredness o weakness o nausea o vomiting o low blood pressure • Immune system effects and a higher chance of infections. UCERIS rectal foam may weaken your immune system. Taking medicines that weaken your immune system makes you more likely to get infections. Avoid contact with people who have contagious diseases such as chicken pox or measles while using UCERIS rectal foam. Tell your healthcare provider about any signs or symptoms of infection during treatment with UCERIS rectal foam, including: • fever • chills • aches • feeling tired • pain • nausea or vomiting • Worsening of allergies. If you take certain other corticosteroid medicines to treat allergies, switching to UCERIS rectal foam may cause your allergies to come back. These allergies may include eczema (a skin disease) or inflammation inside your nose (rhinitis). Tell your healthcare provider if any of your allergies become worse while using UCERIS rectal foam. The most common side effects of UCERIS rectal foam include: • decreased blood cortisol levels • adrenal insufficiency • nausea Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of UCERIS rectal foam. For more information, ask your healthcare provider 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 store UCERIS rectal foam? • Store UCERIS rectal foam at room temperature, between 68° to 77°F (20° to 25°C). • Do not store the UCERIS rectal foam container near heat or store at temperatures above 120°F (49°C). • Do not puncture or burn the UCERIS rectal foam canister. • Do not refrigerate. Keep UCERIS rectal foam and all medicines out of reach of children. General information about the safe and effective use of UCERIS rectal foam. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use UCERIS rectal foam for a condition for which it was not prescribed. Do not give UCERIS rectal foam to other people, even if they have the same symptoms you have. It may harm them. This Patient Information leaflet summarizes the most important information about UCERIS rectal foam. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about UCERIS rectal foam that is written for health professionals.

ay harm them. This Patient Information leaflet summarizes the most important information about UCERIS rectal foam. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about UCERIS rectal foam that is written for health professionals. For more information, go to www.ucerisfoam.com What are the ingredients in UCERIS rectal foam? Active ingredient: budesonide Inactive ingredients: cetyl alcohol, citric acid monohydrate, edetate disodium, emulsifying wax, polyoxyl (10) stearyl ether, propylene glycol, and purified water Propellant: n-butane, isobutane, and propane Distributed by: Salix Pharmaceuticals, a division of Bausch Health US, LLC Bridgewater, NJ 08807 USA Manufactured by: ASM Aerosol-Service AG Industriestrasse 11 CH-4313 Möhlin Switzerland Product marketed and distributed under license from Dr. Falk Pharma. UCERIS is a trademark of Salix Pharmaceuticals, Inc. or its affiliates. © 2020 Salix Pharmaceuticals, Inc. or its affiliates This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 04/2020 9614101 EX00152

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Instructions for Use UCERIS ® (u SAIR us) (budesonide) rectal foam Read the Patient Information and Instructions for Use that comes with UCERIS rectal foam before you start using it and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. Talk to your healthcare provider if you have any questions. Before using UCERIS rectal foam, you should use the bathroom to empty your bowels. You may use UCERIS rectal foam while in a standing position, in a lying position, or in a sitting position (for example, while using the toilet). Applicators should be used only 1 time. You should use a new applicator for each dose. Figure A Each kit contains ( See Figure A ) : • Complete Prescribing Information • Patient Information and Instructions for Use • 2 canisters containing 14 doses each • 4 trays of single-use applicators (7 applicators per tray) • Applicator throw away (disposal) bags for use after each dose Preparing to use UCERIS rectal foam Figure B Step 1: Twist Safety Tab to Remove Before the first use, remove the safety tab from under the pump dome (See Figure B) . The canister cannot be used if safety tab is not removed. Step 2: Attach the Applicator The applicators are in a tray. Hold the tray firmly and pull to remove 1 applicator. Push the applicator firmly onto the nozzle of the canister (See Figure C) . Each applicator is coated with a lubricant. If needed, you can apply an additional lubricant, such as Vaseline (petrolatum, petroleum jelly). Figure C Step 3: Align Notch to Nozzle To unlock the canister, twist the dome on the top of the canister until the semicircular notch underneath the dome is in line with the nozzle (See Figure D) . Figure D Step 4: Warm and Shake Canister Warm the canister by holding it in your hands while shaking it vigorously for 10 to 15 seconds (See Figure E) . Figure E Step 5: Turn the Canister Upside Down Place your pointer finger (forefinger) on the top of pump dome and then turn the canister upside down (See Figure F) . The canister will only work properly when held with the pump dome pointing down. Figure F Step 6: Insert the Applicator into Rectum Insert the applicator into your rectum as far as it is comfortable. The easiest way to use UCERIS rectal foam is to keep 1 foot on the floor and raise the other foot onto a firm surface such as a chair or stool (See Figure G) . Figure G Step 7: Give a Dose of UCERIS Rectal Foam To give a dose of UCERIS rectal foam, use your pointer finger (forefinger) to fully push down the pump dome 1 time and hold it for about 2 seconds in that position (See Figure H) . Figure H Step 8: Release and Hold Release finger pressure on the pump dome and hold the applicator in place for 10 to 15 seconds (See Figure I) . Figure I Step 9: Remove the Applicator (See Figure J) The foam will still expand a little and may drop out of the applicator or anus. Figure J Step 10: Remove Applicator from Canister Remove the applicator from the canister and place the used applicator in the applicator throw away (disposal) bag provided (See Figure K) . Throw the applicator throw away (disposal) bag away in your household trash. Figure K Step 11: Twist Notch on Dome Away from Nozzle To prevent loss of UCERIS rectal foam from the canister between uses, turn the pump dome around so that the semicircular notch faces the opposite direction to the nozzle (See Figure L) .

. Throw the applicator throw away (disposal) bag away in your household trash. Figure K Step 11: Twist Notch on Dome Away from Nozzle To prevent loss of UCERIS rectal foam from the canister between uses, turn the pump dome around so that the semicircular notch faces the opposite direction to the nozzle (See Figure L) . Wash your hands with soap and water after using the UCERIS rectal foam. Try not to empty your bowels until the next morning. Figure L Distributed by: Salix Pharmaceuticals, a division of Bausch Health US, LLC Bridgewater, NJ 08807 USA Manufactured by: ASM Aerosol-Service AG Industriestrasse 11 CH-4313 Möhlin Switzerland Product marketed and distributed under license from Dr. Falk Pharma. UCERIS is a trademark of Salix Pharmaceuticals, Inc. or its affiliates. © 2020 Salix Pharmaceuticals, Inc. or its affiliates This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: 04/2020 9614101 EX00152 instructions for use budesonide-6 budesonide-8 figure d ifu-fige ifu6 figure g figure h ifu-figi ifu-figj ifu-figk figurel

<table width="100%"><col width="72%"/><col width="28%"/><tbody><tr><td align="center" rowspan="2" styleCode="Toprule " valign="top"><paragraph><renderMultiMedia ID="id519894839" referencedObject="ID_7d4626f1-cd05-45e6-803c-2964320e3d55"/> <content styleCode="bold">Figure B</content></paragraph></td><td styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Step 1: Twist Safety Tab to Remove</content></paragraph><paragraph>Before the first use, remove the safety tab from</paragraph><paragraph>under the pump dome <content styleCode="bold">(See Figure B)</content>.</paragraph><paragraph><content styleCode="bold">The canister cannot be used if safety tab is not removed.</content></paragraph></td></tr><tr><td valign="top"/></tr><tr><td valign="top"> <renderMultiMedia ID="id1520658877" referencedObject="B600D1DB-B1AA-42FF-A438-BEE9EFFA2F93"/></td><td valign="top"><paragraph><content styleCode="bold">Step 2: Attach the Applicator</content></paragraph><paragraph>The applicators are in a tray. Hold the tray firmly and pull to remove 1 applicator.</paragraph><paragraph>Push the applicator firmly onto the nozzle of the canister <content styleCode="bold">(See Figure C)</content>.</paragraph><paragraph>Each applicator is coated with a lubricant. If needed, you can apply an additional lubricant, such as Vaseline (petrolatum, petroleum jelly).</paragraph></td></tr><tr><td align="center" valign="top"><paragraph><content styleCode="bold">Figure C</content></paragraph></td><td valign="top"><paragraph> </paragraph></td></tr><tr><td valign="top"><paragraph> </paragraph></td><td valign="top"/></tr><tr><td valign="top"><renderMultiMedia ID="id644860055" referencedObject="ID_467474d5-ef67-49e8-b22c-7536a3502431"/></td><td valign="top"><paragraph><content styleCode="bold">Step 3: Align Notch to Nozzle</content></paragraph><paragraph>To unlock the canister, twist the dome on the top of the canister until the semicircular notch underneath the dome is in line with the nozzle <content styleCode="bold">(See Figure D)</content>. </paragraph></td></tr><tr><td align="center" valign="top"><paragraph><content styleCode="bold">Figure D</content></paragraph></td><td valign="top"><paragraph> </paragraph></td></tr><tr><td valign="top"><paragraph> </paragraph></td><td valign="top"><paragraph> </paragraph></td></tr><tr><td valign="top"><renderMultiMedia ID="id-1155534037" referencedObject="D97C2CF3-FEC0-48CA-A0D5-2AD246721F01"/></td><td rowspan="3" valign="top"><paragraph><content styleCode="bold">Step 4: Warm and Shake Canister</content></paragraph><paragraph>Warm the canister by holding it in your hands while shaking it vigorously for 10 to 15 seconds <content styleCode="bold">(See Figure E)</content>.</paragraph></td></tr><tr><td align="center" valign="top"><paragraph><content styleCode="bold">Figure E</content></paragraph></td></tr><tr><td valign="top"><paragraph> </paragraph></td></tr><tr><td valign="top"><renderMultiMedia ID="id-608202755" referencedObject="ID_1d6d3b1a-8b50-47d9-985e-8cc3a958cab0"/></td><td valign="top"><paragraph><content styleCode="bold">Step 5: Turn the Canister Upside Down</content></paragraph><paragraph>Place your pointer finger (forefinger) on the top of pump dome and then turn the canister upside down <content styleCode="bold">(See Figure F)</content>.

d6d3b1a-8b50-47d9-985e-8cc3a958cab0"/></td><td valign="top"><paragraph><content styleCode="bold">Step 5: Turn the Canister Upside Down</content></paragraph><paragraph>Place your pointer finger (forefinger) on the top of pump dome and then turn the canister upside down <content styleCode="bold">(See Figure F)</content>. </paragraph><paragraph><content styleCode="bold">The canister will only work properly when held with the pump dome pointing down.</content></paragraph></td></tr><tr><td align="center" valign="top"><paragraph><content styleCode="bold">Figure F</content></paragraph></td><td valign="top"><paragraph> </paragraph></td></tr><tr><td valign="top"/><td valign="top"><paragraph> </paragraph></td></tr><tr><td valign="top"><renderMultiMedia ID="id2070914339" referencedObject="ID_0b6547c1-f12d-416b-9772-306dba3a5325"/></td><td valign="top"><paragraph><content styleCode="bold">Step 6: Insert the Applicator into Rectum</content></paragraph><paragraph>Insert the applicator into your rectum as far as it is comfortable. </paragraph><paragraph>The easiest way to use UCERIS rectal foam is to keep 1 foot on the floor and raise the other foot onto a firm surface such as a chair or stool <content styleCode="bold">(See Figure G)</content>. </paragraph></td></tr><tr><td align="center" valign="top"><paragraph><content styleCode="bold">Figure G</content></paragraph></td><td valign="top"><paragraph> </paragraph></td></tr><tr><td valign="top"><paragraph> </paragraph></td><td valign="top"><paragraph> </paragraph></td></tr><tr><td valign="top"><renderMultiMedia ID="id-653451554" referencedObject="ID_8c213199-35cb-4722-bf07-f452c1158b9c"/></td><td valign="top"><paragraph><content styleCode="bold">Step 7: Give a Dose of UCERIS Rectal Foam</content></paragraph><paragraph>To give a dose of UCERIS rectal foam, use your pointer finger (forefinger) to fully push down the pump dome 1 time and hold it for about 2 seconds in that position <content styleCode="bold">(See Figure H)</content>. </paragraph></td></tr><tr><td align="center" valign="top"><paragraph><content styleCode="bold">Figure H</content></paragraph></td><td valign="top"><paragraph> </paragraph></td></tr><tr><td valign="top"><paragraph> </paragraph></td><td valign="top"><paragraph> </paragraph></td></tr><tr><td valign="top"><renderMultiMedia ID="id-1372848468" referencedObject="ID_0f2d7b97-bb41-44a4-b571-03697512a7f1"/></td><td valign="top"><paragraph><content styleCode="bold">Step 8: Release and Hold</content></paragraph><paragraph>Release finger pressure on the pump dome and hold the applicator in place for 10 to 15 seconds <content styleCode="bold">(See Figure I)</content>.</paragraph></td></tr><tr><td align="center" valign="top"><paragraph><content styleCode="bold">Figure I</content></paragraph></td><td valign="top"><paragraph> </paragraph></td></tr><tr><td valign="top"><paragraph> </paragraph></td><td valign="top"><paragraph> </paragraph></td></tr><tr><td valign="top"><renderMultiMedia ID="id-1317253616" referencedObject="FEDA14BC-9F08-4B67-B505-8373A44D0D10"/></td><td valign="top"><paragraph><content styleCode="bold">Step 9: Remove the Applicator </content></paragraph><paragraph><content styleCode="bold">(See Figure J)</content></paragraph><paragraph>The foam will still expand a little and may drop out of the applicator or anus.

bject="FEDA14BC-9F08-4B67-B505-8373A44D0D10"/></td><td valign="top"><paragraph><content styleCode="bold">Step 9: Remove the Applicator </content></paragraph><paragraph><content styleCode="bold">(See Figure J)</content></paragraph><paragraph>The foam will still expand a little and may drop out of the applicator or anus. </paragraph></td></tr><tr><td align="center" valign="top"><paragraph><content styleCode="bold">Figure J</content></paragraph></td><td valign="top"><paragraph> </paragraph></td></tr><tr><td valign="top"><paragraph> </paragraph></td><td valign="top"><paragraph> </paragraph></td></tr><tr><td valign="top"><renderMultiMedia ID="id429321075" referencedObject="ID_11312611-86ad-4a4f-9470-5af05ec2264d"/></td><td valign="top"><paragraph><content styleCode="bold">Step 10: Remove Applicator from Canister</content></paragraph><paragraph>Remove the applicator from the canister and place the used applicator in the applicator throw away (disposal) bag provided <content styleCode="bold">(See Figure K)</content>. Throw the applicator throw away (disposal) bag away in your household trash.</paragraph></td></tr><tr><td align="center" valign="top"><paragraph><content styleCode="bold">Figure K</content></paragraph></td><td valign="top"><paragraph> </paragraph></td></tr><tr><td valign="top"><paragraph> </paragraph></td><td valign="top"><paragraph> </paragraph></td></tr><tr><td valign="top"><renderMultiMedia ID="id102927442" referencedObject="D0BBAF4D-DDF9-4CCE-B437-6AB757559832"/></td><td valign="top"><paragraph><content styleCode="bold">Step 11: Twist Notch on Dome Away from Nozzle</content></paragraph><paragraph>To prevent loss of UCERIS rectal foam from the canister between uses, turn the pump dome around so that the semicircular notch faces the opposite direction to the nozzle <content styleCode="bold">(See Figure L)</content>.</paragraph><paragraph><content styleCode="bold">Wash your hands with soap and water after using the UCERIS rectal foam. Try not to empty your bowels until the next morning.</content></paragraph></td></tr><tr><td align="center" styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">Figure L</content></paragraph></td><td styleCode="Botrule " valign="top"/></tr></tbody></table>

1 INDICATIONS AND USAGE Budesonide rectal foam is indicated for the induction of remission in patients with active mild to moderate distal ulcerative colitis extending up to 40 cm from the anal verge. Budesonide rectal foam is a glucocorticosteroid indicated for the induction of remission in patients with active mild to moderate distal ulcerative colitis extending up to 40 cm from the anal verge.

2 DOSAGE AND ADMINISTRATION • The recommended dosage is 1 metered dose administered twice daily for 2 weeks followed by 1 metered dose administered once daily for 4 weeks. ( 2.1 ) • For rectal administration only. ( 2.2 ) • Warm the canister in the hands while shaking it vigorously for 10 to 15 seconds prior to use. ( 2.2 ) 2.1 Recommended Dosage The recommended dosage regimen is 1 metered dose administered rectally twice daily for 2 weeks followed by 1 metered dose administered rectally once daily for 4 weeks. 2.2 Administration Instructions Advise patients: • Budesonide rectal foam is only to be applied rectally. It is not for oral use. • Before using budesonide rectal foam, use the bathroom to empty your bowels. • Each applicator is coated with a lubricant. If additional lubrication is needed, petrolatum or petroleum jelly can also be used. • Warm the canister in the hands while shaking it vigorously for 10 to 15 seconds prior to use. • Budesonide rectal foam can be used in a standing, lying or sitting position (e.g., while using the toilet). • Apply budesonide rectal foam in the morning and the evening for the first 2 weeks of treatment; then once daily in the evening for the next 4 weeks. When applied in the evening, use immediately prior to bedtime. Try not to empty your bowels again until the next morning. • Avoid concomitant use of CYP3A4 inhibitors (e.g., ketoconazole, grapefruit juice) during treatment with budesonide rectal foam.

3 DOSAGE FORMS AND STRENGTHS Budesonide rectal foam is formulated as an emulsion which is filled into an aluminum canister with an aerosol propellant. It is available in 1 strength: 2 mg budesonide per metered dose. Budesonide rectal foam contains 2 mg budesonide per metered dose. ( 3 )

4 CONTRAINDICATIONS Budesonide rectal foam is contraindicated in patients with a history of a known hypersensitivity to budesonide or any of the ingredients of budesonide rectal foam. Reactions have included anaphylaxis [see Adverse Reactions ( 6.2 )] . Known hypersensitivity to budesonide or any of the ingredients in budesonide rectal foam. ( 4 )

5 WARNINGS AND PRECAUTIONS • Hypercorticism and adrenal suppression: Follow general warnings concerning glucocorticosteroids. ( 5.1 ) • Impaired Adrenal Function in Patients Transferred from Other Glucocorticoids: Taper slowly from glucocorticosteroids with high systemic effects; monitor for withdrawal symptoms and unmasking of allergies (rhinitis, eczema). ( 5.2 ) • Increased Risk of Infection, including serious and fatal chicken pox and measles: Monitor patients with active or quiescent tuberculosis infection, untreated fungal, bacterial, systemic viral or parasitic infections, or ocular herpes simplex. ( 5.3 ) • Other Glucocorticosteroid Effects: Monitor patients with other conditions where glucocorticoids may have unwanted effects. ( 5.4 ) • Flammable Contents: The contents of budesonide rectal foam are flammable. Instruct the patient to avoid fire, flame and smoking during and immediately following administration. ( 5.5 ) 5.1 Hypercorticism and Adrenal Axis Suppression When glucocorticosteroids are used chronically, systemic effects such as hypercorticism and adrenal suppression may occur. Glucocorticosteroids can reduce the response of the hypothalamus-pituitary-adrenal (HPA) axis to stress. In situations where patients are subject to surgery or other stress situations, supplementation with a systemic glucocorticosteroid is recommended. Since budesonide rectal foam contains a glucocorticosteroid, general warnings concerning glucocorticoids should be followed [see Clinical Pharmacology ( 12.2 )] . Reduced liver function affects the elimination of glucocorticosteroids, and increased systemic availability of oral budesonide has been demonstrated in patients with liver cirrhosis [see Use in Specific Populations ( 8.6 )] . 5.2 Impaired Adrenal Suppression in Patients Transferred from Other Glucocorticoids Monitor patients who are transferred from glucocorticosteroid treatment with higher systemic effects to glucocorticosteroids with lower systemic effects, such as budesonide rectal foam, since symptoms attributed to withdrawal of steroid therapy, including those of acute adrenal suppression or benign intracranial hypertension, may develop. Adrenocortical function monitoring may be required in these patients and the dose of glucocorticosteroid treatment with high systemic effects should be reduced cautiously. Replacement of systemic glucocorticosteroids with budesonide rectal foam may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug. 5.3 Increased Risk of Infection Patients who are on drugs that suppress the immune system are more susceptible to infection than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in susceptible patients or patients on immunosuppressant doses of glucocorticosteroids. In patients who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route and duration of glucocorticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior glucocorticosteroid treatment to the risk is also not known. If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated (see prescribing information for VZIG and IG).

to the risk is also not known. If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated (see prescribing information for VZIG and IG). If chicken pox develops, treatment with antiviral agents may be considered. Glucocorticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection, untreated fungal, bacterial, systemic viral or parasitic infections, or ocular herpes simplex. 5.4 Other Glucocorticosteroid Effects Monitor patients with hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or with any other condition where glucocorticosteroids may have unwanted effects. 5.5 Flammable Contents The contents of budesonide rectal foam include n-butane, isobutane and propane as propellants which are flammable. Instruct the patient to avoid fire, flame, and smoking during and immediately following administration. Patients should temporarily discontinue use of budesonide rectal foam before initiation of bowel preparation for colonoscopy and consult their healthcare provider before resuming therapy.

6 ADVERSE REACTIONS Serious and important adverse reactions include: • Hypercorticism and adrenal axis suppression [see Warnings and Precautions ( 5.1 )] • Symptoms of steroid withdrawal in those patients transferring from systemic glucocorticosteroid therapy [see Warnings and Precautions ( 5.2 )] • Increased susceptibility to infection [see Warnings and Precautions ( 5.3 )] • Other glucocorticosteroid effects [see Warnings and Precautions ( 5.4 )] Most common adverse reactions (≥ 2%) are decreased blood cortisol, adrenal insufficiency, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Padagis at 1-866-634-9120 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to budesonide rectal foam in 332 patients with active mild to moderate distal ulcerative colitis extending up to 40 cm from the anal verge. The median duration of exposure was 42 days. This included 14 patients exposed for at least 6 months. Budesonide rectal foam was studied primarily in 2 placebo-controlled, 6-week trials in patients with active disease (Study 1 and Study 2). In these trials, 268 patients received budesonide rectal foam 2 mg twice a day for 2 weeks followed by 2 mg once a day for 4 weeks [see Clinical Studies ( 14 )] . The most common adverse reactions (≥ 2% of the budesonide rectal foam or Placebo group and at higher frequency in the budesonide rectal foam group) were decreased blood cortisol, adrenal insufficiency, and nausea ( Table 1 ). Decreased blood cortisol was defined as a morning cortisol level of <5 mcg/dL. Adrenal insufficiency was defined as a cortisol level of <18 mcg/dL at 30 minutes post-challenge with adrenocorticotropic hormone (ACTH). A total of 10% of budesonide rectal foam-treated patients discontinued treatment due to an adverse reaction compared with 4% of placebo-treated patients. Table 1: Summary of Adverse Reactions in 2 Placebo-Controlled Trials * (Studies 1 and 2) Adverse Reaction Budesonide Rectal Foam 2 mg/25 mL N=268 n (%) Placebo N=278 n (%) Decreased blood cortisol # 46 (17) 6 (2) Adrenal insufficiency † 10 (4) 2 (1) Nausea 6 (2) 2 (1) * Experienced by ≥ 2% of the budesonide rectal foam or Placebo group and at higher frequency in the budesonide rectal foam group. # Decreased blood cortisol was defined as a morning cortisol level of <5 mcg/dL. † Adrenal insufficiency was defined as a cortisol level of <18 mcg/dL at 30 minutes post-challenge with ACTH. Of the 46 budesonide rectal foam treated patients with decreased blood cortisol (defined as a morning cortisol level of <5 mcg/dL) reported as an adverse event, none had adrenal insufficiency (defined as a cortisol level of <18 mcg/dL at 30 minutes post-challenge with ACTH) (see Table 2 ). All cases of adrenal insufficiency resolved. Table 2 summarizes the percentages of patients reporting glucocorticoid related effects in the 2 placebo-controlled trials (Studies 1 and 2).

nt, none had adrenal insufficiency (defined as a cortisol level of <18 mcg/dL at 30 minutes post-challenge with ACTH) (see Table 2 ). All cases of adrenal insufficiency resolved. Table 2 summarizes the percentages of patients reporting glucocorticoid related effects in the 2 placebo-controlled trials (Studies 1 and 2). Table 2: Summary of Glucocorticoid Related Effects in Two Placebo-Controlled Trials (Studies 1 and 2) Adverse Reaction Budesonide Rectal Foam 2 mg/25 mL N=268 n (%) Placebo N=278 n (%) Overall 60 (22) 10 (4) Blood cortisol decreased 46 (17) * 6 (2) Adrenal insufficiency 10 (4) 2 (1) Insomnia 1 (0.4) 1 (0.4) Sleep disorder 1 (0.4) 0 Acne 1 (0.4) 0 Depression 1 (0.4) 1 (0.4) Hyperglycemia 1 (0.4) 0 * Decreases in serum cortisol levels associated with budesonide treatment were seen at Weeks 1 and 2 (twice daily treatment) in the budesonide rectal foam group, but gradually returned to baseline levels during the 4 weeks of once daily treatment. No clinically significant differences were observed with respect to the overall percentages of patients with any glucocorticoid related effects between budesonide rectal foam and placebo after 6 weeks of therapy. For additional details on morning cortisol levels and the response to the ACTH stimulation test, see Clinical Pharmacology ( 12.2 ) . 6.2 Postmarketing Experience In addition to adverse reactions reported from clinical trials for budesonide rectal foam, the following adverse reactions have been identified during post-approval use of other oral and rectal formulations of budesonide. 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. Cardiac disorders: hypertension Gastrointestinal disorders: pancreatitis General disorders and administration site conditions: pyrexia, peripheral edema Immune system disorders: anaphylactic reactions Nervous system disorders: dizziness, benign intracranial hypertension Psychiatric disorders: mood swings Skin and subcutaneous tissue disorders: pruritus, maculopapular rash, allergic dermatitis

<table width="100%"><col width="33%"/><col width="33%"/><col width="33%"/><tbody><tr><td styleCode="Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td align="center" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Budesonide Rectal Foam</content></paragraph><paragraph><content styleCode="bold">2 mg/25 mL</content></paragraph><paragraph><content styleCode="bold">N=268</content></paragraph><paragraph><content styleCode="bold">n (%)</content></paragraph></td><td align="center" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">N=278</content></paragraph><paragraph><content styleCode="bold">n (%)</content></paragraph></td></tr><tr><td valign="top"><paragraph>Decreased blood cortisol ^#</paragraph></td><td align="center" valign="top"><paragraph>46 (17)</paragraph></td><td align="center" valign="top"><paragraph>6 (2)</paragraph></td></tr><tr><td valign="top"><paragraph>Adrenal insufficiency^&#x2020;</paragraph></td><td align="center" valign="top"><paragraph>10 (4)</paragraph></td><td align="center" valign="top"><paragraph>2 (1)</paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph>Nausea</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>6 (2)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>2 (1)</paragraph></td></tr></tbody></table>

valign="top"><paragraph>2 (1)</paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph>Nausea</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>6 (2)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>2 (1)</paragraph></td></tr></tbody></table> <table width="100%"><col width="33%"/><col width="33%"/><col width="33%"/><tbody><tr><td styleCode="Botrule " valign="bottom"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">Budesonide Rectal Foam</content></paragraph><paragraph><content styleCode="bold">2 mg/25 mL</content></paragraph><paragraph><content styleCode="bold">N=268</content></paragraph><paragraph><content styleCode="bold">n (%)</content></paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">N=278</content></paragraph><paragraph><content styleCode="bold">n (%)</content></paragraph></td></tr><tr><td valign="top"><paragraph>Overall</paragraph></td><td align="center" valign="top"><paragraph>60 (22)</paragraph></td><td align="center" valign="top"><paragraph>10 (4)</paragraph></td></tr><tr><td valign="top"><paragraph>Blood cortisol decreased</paragraph></td><td align="center" valign="top"><paragraph>46 (17)^*</paragraph></td><td align="center" valign="top"><paragraph>6 (2)</paragraph></td></tr><tr><td valign="top"><paragraph>Adrenal insufficiency</paragraph></td><td align="center" valign="top"><paragraph>10 (4)</paragraph></td><td align="center" valign="top"><paragraph>2 (1)</paragraph></td></tr><tr><td valign="top"><paragraph>Insomnia</paragraph></td><td align="center" valign="top"><paragraph>1 (0.4)</paragraph></td><td align="center" valign="top"><paragraph>1 (0.4)</paragraph></td></tr><tr><td valign="top"><paragraph>Sleep disorder</paragraph></td><td align="center" valign="top"><paragraph>1 (0.4)</paragraph></td><td align="center" valign="top"><paragraph>0</paragraph></td></tr><tr><td valign="top"><paragraph>Acne</paragraph></td><td align="center" valign="top"><paragraph>1 (0.4)</paragraph></td><td align="center" valign="top"><paragraph>0</paragraph></td></tr><tr><td valign="top"><paragraph>Depression</paragraph></td><td align="center" valign="top"><paragraph>1 (0.4)</paragraph></td><td align="center" valign="top"><paragraph>1 (0.4)</paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph>Hyperglycemia</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>1 (0.4)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>0</paragraph></td></tr></tbody></table>

7 DRUG INTERACTIONS CYP3A4 Inhibitors (e.g., ketoconazole, grapefruit juice): May cause increased systemic corticosteroid effects; avoid concomitant use. ( 7.1 ) 7.1 CYP3A4 Inhibitors The active ingredient of budesonide rectal foam, budesonide, is metabolized by CYP3A4. Inhibitors of CYP3A4 activity (such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, erythromycin, cyclosporine and grapefruit juice) can increase systemic budesonide concentrations. Avoid concomitant use of CYP3A4 inhibitors with budesonide rectal foam [see Clinical Pharmacology ( 12.3 )].

8 USE IN SPECIFIC POPULATIONS • Pregnancy: Based on animal data, may cause fetal harm. ( 8.1 ) • Hepatic Impairment: Monitor patients for signs and/or symptoms of hypercorticism. ( 8.6 ) 8.1 Pregnancy Risk Summary Limited published studies report on the use of budesonide in pregnant women; however, the data are insufficient to inform a drug-associated risk for major birth defects and miscarriage. There are clinical considerations (see Clinical Considerations) . In animal reproduction studies with pregnant rats and rabbits, subcutaneous administration of budesonide during organogenesis at doses 1.2 times and 0.12 times, respectively, the human intrarectal dose of 4 mg/day, resulted in increased fetal loss, decreased pup weights, and skeletal abnormalities. Maternal toxicity was observed in both rats and rabbits at these dose levels (see Data) . Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage of the indicated population is 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 of 2% to 4%, and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with ulcerative colitis. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth. Fetal/Neonatal Adverse Reactions Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Infants should be carefully observed for signs of hypoadrenalism, such as poor feeding, irritability, weakness, and vomiting, and managed accordingly [see Warnings and Precautions ( 5.1 )] . Data Animal Data Budesonide was teratogenic and embryolethal in rabbits and rats. In an embryo-fetal development study in pregnant rats dosed subcutaneously with budesonide during the period of organogenesis from gestation days 6-15 there were effects on fetal development and survival at subcutaneous doses up to approximately 500 mcg/kg in rats (approximately 1.2 times the recommended human intrarectal dose on a body surface area basis). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 6-18, there was an increase in maternal abortion, and effects on fetal development and reduction in litter weights at subcutaneous doses up to approximately 25 mcg/kg in rabbits (approximately 0.12 times the recommended human intrarectal dose of 4 mg/day on a body surface area basis). Maternal toxicity, including reduction in body weight gain, was observed at subcutaneous doses of 5 mcg/kg in rabbits (approximately 0.02 times the recommended human intrarectal dose on a body surface area basis) and 500 mcg/kg in rats (approximately 1.2 times the recommended human intrarectal dose of 4 mg/day on a body surface area basis). In a pre-and post-natal development study, rats dosed subcutaneously with budesonide during the period of Day 15 post coitum to Day 21 postpartum, budesonide had no effects on delivery but did have an effect on growth and development of offspring.

mended human intrarectal dose of 4 mg/day on a body surface area basis). In a pre-and post-natal development study, rats dosed subcutaneously with budesonide during the period of Day 15 post coitum to Day 21 postpartum, budesonide had no effects on delivery but did have an effect on growth and development of offspring. In addition, offspring survival was reduced, and surviving offspring had decreased mean body weights at birth and during lactation at exposures 0.05 times the MRHD (on a mg/m 2 basis at maternal subcutaneous doses of 20 mcg/kg/day and higher). These findings occurred in the presence of maternal toxicity. 8.2 Lactation Risk Summary Lactation studies have not been conducted with budesonide rectal foam or other rectally administered budesonide products and no information is available on the effects of budesonide on the breastfed infant or the effects of the drug on milk production. One published study reports that budesonide is present in human milk following maternal inhalation of budesonide (see Data) . The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for budesonide rectal foam and any potential adverse effects on the breastfed child from budesonide rectal foam or from the underlying maternal condition. Data One published study reports that budesonide is present in human milk following maternal inhalation of budesonide and the milk/plasma ratio ranged between 0.4 and 0.5. Budesonide plasma concentrations were not detected, and no adverse events were noted in the breastfed infants following maternal use of inhaled budesonide. The systemic exposure (AUC 0-12 ) following administration of 400 mcg twice a day of inhaled budesonide ranged from 1.27 to 2.26 ng*hr/mL. The estimated budesonide AUC 0-12 following rectal administration of 2 mg twice a day budesonide was 4.31 ng*hr/mL [see Clinical Pharmacology ( 12.3 )] . Budesonide exposure to the nursing child may be higher with maternal rectal administration of budesonide than with maternal inhaled administration of budesonide. 8.4 Pediatric Use The safety and effectiveness of budesonide rectal foam has not been established in pediatric patients. Children who are treated with corticosteroids by any route may experience a decrease in their growth velocity. This negative impact of corticosteroids on growth has been in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression. The long-term effects of this reduction in growth velocity associated with corticosteroid treatment, including the impact on final adult height, are unknown. Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in children than some commonly used tests of HPA axis function. The linear growth of children treated with corticosteroids by any route should be monitored (e.g., via stadiometry), and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of other treatment alternatives. In order to minimize the potential growth effects of corticosteroids, children should be titrated to the lowest effective dose. 8.5 Geriatric Use Clinical studies with budesonide rectal foam did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

fferences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6 Hepatic Impairment No dosage adjustment is needed for patients with mild (Child-Pugh Class A) hepatic impairment. Patients with moderate to severe hepatic impairment (Child-Pugh Class B or C) should be monitored for increased signs and/or symptoms of hypercorticism. Discontinuing the use of budesonide rectal foam should be considered in these patients if signs of hypercorticism are observed [see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 )] .

8.1 Pregnancy Risk Summary Limited published studies report on the use of budesonide in pregnant women; however, the data are insufficient to inform a drug-associated risk for major birth defects and miscarriage. There are clinical considerations (see Clinical Considerations) . In animal reproduction studies with pregnant rats and rabbits, subcutaneous administration of budesonide during organogenesis at doses 1.2 times and 0.12 times, respectively, the human intrarectal dose of 4 mg/day, resulted in increased fetal loss, decreased pup weights, and skeletal abnormalities. Maternal toxicity was observed in both rats and rabbits at these dose levels (see Data) . Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage of the indicated population is 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 of 2% to 4%, and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with ulcerative colitis. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth. Fetal/Neonatal Adverse Reactions Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Infants should be carefully observed for signs of hypoadrenalism, such as poor feeding, irritability, weakness, and vomiting, and managed accordingly [see Warnings and Precautions ( 5.1 )] . Data Animal Data Budesonide was teratogenic and embryolethal in rabbits and rats. In an embryo-fetal development study in pregnant rats dosed subcutaneously with budesonide during the period of organogenesis from gestation days 6-15 there were effects on fetal development and survival at subcutaneous doses up to approximately 500 mcg/kg in rats (approximately 1.2 times the recommended human intrarectal dose on a body surface area basis). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 6-18, there was an increase in maternal abortion, and effects on fetal development and reduction in litter weights at subcutaneous doses up to approximately 25 mcg/kg in rabbits (approximately 0.12 times the recommended human intrarectal dose of 4 mg/day on a body surface area basis). Maternal toxicity, including reduction in body weight gain, was observed at subcutaneous doses of 5 mcg/kg in rabbits (approximately 0.02 times the recommended human intrarectal dose on a body surface area basis) and 500 mcg/kg in rats (approximately 1.2 times the recommended human intrarectal dose of 4 mg/day on a body surface area basis). In a pre-and post-natal development study, rats dosed subcutaneously with budesonide during the period of Day 15 post coitum to Day 21 postpartum, budesonide had no effects on delivery but did have an effect on growth and development of offspring.

8.4 Pediatric Use The safety and effectiveness of budesonide rectal foam has not been established in pediatric patients. Children who are treated with corticosteroids by any route may experience a decrease in their growth velocity. This negative impact of corticosteroids on growth has been in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression. The long-term effects of this reduction in growth velocity associated with corticosteroid treatment, including the impact on final adult height, are unknown. Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in children than some commonly used tests of HPA axis function. The linear growth of children treated with corticosteroids by any route should be monitored (e.g., via stadiometry), and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of other treatment alternatives. In order to minimize the potential growth effects of corticosteroids, children should be titrated to the lowest effective dose.

8.5 Geriatric Use Clinical studies with budesonide rectal foam did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE Acute overdosage with budesonide rectal foam is unlikely. However, budesonide rectal foam is absorbed systemically and chronic overdosage may result in signs/symptoms of hypercorticism [see Warnings and Precautions ( 5.1 )] .

11 DESCRIPTION Budesonide rectal foam contains budesonide, a non-halogenated synthetic glucocorticoid, as the active ingredient. It is a mixture of the 2 epimers (22R and 22S) differing in the position of an acetal chain. Both epimers are active glucocorticoids applied in a mixture of approximately 1:1. Budesonide is designated chemically as (RS)-11β, 16α, 17,21 tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with butyraldehyde. The empirical formula of budesonide is C 25 H 34 O 6 and its molecular weight is 430.5. Its structural formula is: Budesonide rectal foam contains 2 mg budesonide per metered dose. Inactive ingredients: cetyl alcohol, citric acid monohydrate, edetate disodium, emulsifying wax, polyoxyl (10) stearyl ether, propylene glycol, and purified water. Propellant: n-butane, isobutane, and propane. structure

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Budesonide has glucocorticosteroid (GCS) activity. 12.2 Pharmacodynamics Treatment with glucocorticosteroids, including budesonide rectal foam, is associated with a suppression of endogenous cortisol concentrations and an impairment of the hypothalamic-pituitary-adrenal (HPA) axis function. These effects were measured by determination of plasma cortisol concentrations and responses to adrenocorticotropin challenge (i.e., ACTH stimulation test) in 2 placebo-controlled, 6-week trials in patients with active disease [see Clinical Studies ( 14 )] . These trials enrolled subjects with post-ACTH stimulation cortisol levels of >18 mcg/dL at baseline. Subjects received budesonide rectal foam 2 mg or a placebo twice daily for 2 weeks followed by once daily for 4 weeks. Normal morning serum cortisol levels >5 mcg/dL were maintained in 85% and 84% of budesonide rectal foam treated subjects during Weeks 1 and 2 (twice daily treatment) and 93% and 94% during Weeks 4 and 6 (once daily treatment), respectively (see Table 3 ). At baseline (predose), 84% of subjects in the budesonide rectal foam group had a normal response to the ACTH challenge and at Week 6, 63% of subjects had a normal response to the ACTH challenge; in the placebo group, these values were 86% and 76%, respectively (see Table 3 ). ACTH stimulation test was not performed routinely during the twice daily treatment period (Weeks 1 and 2). Table 3: Proportion of Subjects with Normal Endogenous Cortisol Levels (>5 mcg/dL) During the Study and Proportion of Subjects with Normal Response to ACTH Challenge Cortisol Parameter Budesonide Rectal Foam 2 mg/25 mL N=268 n (%) Placebo N=278 n (%) Total cortisol > 5 mcg/dL (lower limit of normal range) Baseline 259/268 (96.6) 275/278 (98.9) Week 1 224/263 (85.2) 264/269 (98.1) Week 2 216/257 (84.0) 263/266 (98.9) Week 4 218/235 (92.8) 243/249 (97.6) Week 6 211/224 (94.2) 234/241 (97.1) Normal response to ACTH challenge a Baseline 222/266 (83.5) 238/278 (85.6) Week 6 b 148/236 (62.7) 180/237 (75.9) a The normal response to ACTH challenge included 3 criteria, as defined in the cosyntropin label: 1) morning cortisol level >5 mcg/dL; 2) increase in cortisol level by ≥7 mcg/dL above the morning (pre-challenge) level following ACTH challenge; and cortisol level of >18 mcg/dL following ACTH challenge. b Denominator includes 20 subjects in the budesonide rectal foam arm and 2 subjects in the placebo arm who discontinued prior to Week 6 due to adverse events related to low cortisol or abnormal response to ACTH challenge. 12.3 Pharmacokinetics Absorption Distal Ulcerative Colitis Patients Based on population pharmacokinetic analysis from sparse PK samples from phase 3 studies, the estimated AUC 0-12 following administration of budesonide rectal foam 2 mg twice a day was 4.31 ng*hr/mL with a CV of 64% in the target patient population. Distribution The volume of distribution (V SS ) of budesonide varies between 2.2 and 3.9 L/kg in healthy subjects and in patients. Plasma protein binding is estimated to be 85 to 90% in the concentration range of 1 to 230 nmol/L, independent of gender. The erythrocyte/plasma partition ratio at clinically relevant concentrations is approximately 0.8. Elimination Metabolism Following absorption, budesonide is subject to first-pass metabolism.

ients. Plasma protein binding is estimated to be 85 to 90% in the concentration range of 1 to 230 nmol/L, independent of gender. The erythrocyte/plasma partition ratio at clinically relevant concentrations is approximately 0.8. Elimination Metabolism Following absorption, budesonide is subject to first-pass metabolism. In vitro experiments in human liver microsomes demonstrate that budesonide is rapidly and extensively biotransformed, mainly by CYP3A4, to its 2 major metabolites, 6β-hydroxy budesonide and 16α-hydroxy prednisolone. The glucocorticoid activity of these metabolites is negligible (<1/100) in relation to that of the parent compound. In vivo investigations with intravenous doses in healthy subjects demonstrate that budesonide has a plasma clearance of 0.9-1.8 L/min. These plasma clearance values approach the estimated liver blood flow, suggesting that budesonide is a high hepatic clearance drug. Excretion Budesonide is excreted in urine and feces in the form of metabolites. After oral as well as intravenous administration of micronized [ 3 H]-budesonide, approximately 60% of the recovered radioactivity is found in urine. The major metabolites, including 6β-hydroxybudesonide and 16α-hydroxyprednisolone, are mainly renally excreted, intact or in conjugated forms. No unchanged budesonide is detected in urine. Specific Populations Patients with Renal Impairment The pharmacokinetics of budesonide in patients with renal impairment has not been studied. Intact budesonide is not renally excreted, but metabolites are to a large extent, and might therefore reach higher levels in patients with impaired renal function. However, these metabolites have negligible corticosteroid activity as compared with budesonide. Patients with Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of budesonide rectal foam has not been studied. In a study in patients with mild to moderate hepatic impairment (Child-Pugh Class A and Child-Pugh Class B) dosed with budesonide 4 mg oral capsules, systemic exposure was similar between patients with mild hepatic impairment (Child-Pugh Class A; n=4) and healthy subjects (n=8), and 3.5-fold higher in patients with moderate hepatic impairment (Child-Pugh Class B; n=4) than in healthy subjects. For the intravenous dose, no significant differences in CL or V SS are observed. Patients with severe liver dysfunction (Child-Pugh Class C) were not studied [see Use in Specific Populations ( 8.6 )] . Drug Interaction Studies Budesonide is metabolized via CYP3A4. Potent inhibitors of CYP3A4 can increase the plasma concentrations of budesonide. Co-administration of ketoconazole (inhibitor of CYP3A4) results in an 8-fold increase in AUC of oral budesonide, compared to budesonide alone. Grapefruit juice, an inhibitor of gut mucosal CYP3A, approximately doubles the systemic exposure of oral budesonide. Conversely, induction of CYP3A4 can result in the lowering of budesonide plasma concentrations. The effect of CYP3A4 inhibitors and inducers on the pharmacokinetics of budesonide rectal foam have not been studied [see Dosage and Administration ( 2 ) and Drug Interactions ( 7 )] . Oral contraceptives containing ethinyl estradiol, which are also metabolized by CYP3A4, do not affect the pharmacokinetics of oral budesonide. Budesonide does not affect the plasma concentrations of oral contraceptives (i.e., ethinyl estradiol). In vitro interaction studies performed with budesonide showed that budesonide did not inhibit human cytochrome P450 isoenzymes CYP1A2, CYP2B6, CYP2C9, CYP2D6, or CYP2E1 at concentrations ranging from 0.11 to 1130 ng/mL. Isoenzyme CYP3A4 was inhibited at the highest concentration tested but the IC 50 was >1130 ng/mL. Budesonide rectal foam is not expected to inhibit these enzymes in clinical use.

did not inhibit human cytochrome P450 isoenzymes CYP1A2, CYP2B6, CYP2C9, CYP2D6, or CYP2E1 at concentrations ranging from 0.11 to 1130 ng/mL. Isoenzyme CYP3A4 was inhibited at the highest concentration tested but the IC 50 was >1130 ng/mL. Budesonide rectal foam is not expected to inhibit these enzymes in clinical use. No significant induction of CYP1A2, CYP2B6, CYP2C9 or CYP3A4/5 expression was observed in human hepatocytes in vitro at budesonide concentrations up to 9000 nM (3.88 mcg/mL). In an in vitro study, budesonide was not a substrate of human transporters OATP1B3 and may be a weak substrate of OATP1B1. Budesonide at concentrations up to 300 nM (129 ng/mL) did not inhibit OATP1B1 or OATP1B3. Budesonide was not a substrate of BCRP and was a weak substrate of P-glycoprotein. Budesonide was a weak inhibitor of P-glycoprotein (IC 50 9.78 μM or 4.21 mcg/mL) and BCRP (IC 50 43.1 μM or 18.6 mcg/mL). Budesonide rectal foam is not expected to inhibit these transporters in clinical use.

12.2 Pharmacodynamics Treatment with glucocorticosteroids, including budesonide rectal foam, is associated with a suppression of endogenous cortisol concentrations and an impairment of the hypothalamic-pituitary-adrenal (HPA) axis function. These effects were measured by determination of plasma cortisol concentrations and responses to adrenocorticotropin challenge (i.e., ACTH stimulation test) in 2 placebo-controlled, 6-week trials in patients with active disease [see Clinical Studies ( 14 )] . These trials enrolled subjects with post-ACTH stimulation cortisol levels of >18 mcg/dL at baseline. Subjects received budesonide rectal foam 2 mg or a placebo twice daily for 2 weeks followed by once daily for 4 weeks. Normal morning serum cortisol levels >5 mcg/dL were maintained in 85% and 84% of budesonide rectal foam treated subjects during Weeks 1 and 2 (twice daily treatment) and 93% and 94% during Weeks 4 and 6 (once daily treatment), respectively (see Table 3 ). At baseline (predose), 84% of subjects in the budesonide rectal foam group had a normal response to the ACTH challenge and at Week 6, 63% of subjects had a normal response to the ACTH challenge; in the placebo group, these values were 86% and 76%, respectively (see Table 3 ). ACTH stimulation test was not performed routinely during the twice daily treatment period (Weeks 1 and 2). Table 3: Proportion of Subjects with Normal Endogenous Cortisol Levels (>5 mcg/dL) During the Study and Proportion of Subjects with Normal Response to ACTH Challenge Cortisol Parameter Budesonide Rectal Foam 2 mg/25 mL N=268 n (%) Placebo N=278 n (%) Total cortisol > 5 mcg/dL (lower limit of normal range) Baseline 259/268 (96.6) 275/278 (98.9) Week 1 224/263 (85.2) 264/269 (98.1) Week 2 216/257 (84.0) 263/266 (98.9) Week 4 218/235 (92.8) 243/249 (97.6) Week 6 211/224 (94.2) 234/241 (97.1) Normal response to ACTH challenge a Baseline 222/266 (83.5) 238/278 (85.6) Week 6 b 148/236 (62.7) 180/237 (75.9) a The normal response to ACTH challenge included 3 criteria, as defined in the cosyntropin label: 1) morning cortisol level >5 mcg/dL; 2) increase in cortisol level by ≥7 mcg/dL above the morning (pre-challenge) level following ACTH challenge; and cortisol level of >18 mcg/dL following ACTH challenge. b Denominator includes 20 subjects in the budesonide rectal foam arm and 2 subjects in the placebo arm who discontinued prior to Week 6 due to adverse events related to low cortisol or abnormal response to ACTH challenge.

<table width="100%"><col width="38%"/><col width="15%"/><col width="15%"/><col width="15%"/><col width="15%"/><tbody><tr><td styleCode="Toprule " valign="bottom"><paragraph><content styleCode="bold">Cortisol Parameter</content></paragraph></td><td align="center" colspan="2" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Budesonide Rectal Foam</content></paragraph><paragraph><content styleCode="bold">2 mg/25 mL</content></paragraph><paragraph><content styleCode="bold">N=268</content></paragraph><paragraph><content styleCode="bold">n (%)</content></paragraph></td><td align="center" colspan="2" styleCode="Toprule " valign="top"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">N=278</content></paragraph><paragraph><content styleCode="bold">n (%)</content></paragraph></td></tr><tr><td colspan="5" valign="top"><paragraph><content styleCode="bold"><content styleCode="italics">Total cortisol </content>&gt;<content styleCode="italics">5 mcg/dL</content></content></paragraph><paragraph><content styleCode="bold"><content styleCode="italics">(lower limit of normal range)</content></content></paragraph></td></tr><tr><td valign="top"><paragraph>Baseline</paragraph></td><td align="center" valign="top"><paragraph>259/268</paragraph></td><td align="center" valign="top"><paragraph>(96.6)</paragraph></td><td align="center" valign="top"><paragraph>275/278</paragraph></td><td align="center" valign="top"><paragraph>(98.9)</paragraph></td></tr><tr><td valign="top"><paragraph>Week 1</paragraph></td><td align="center" valign="top"><paragraph>224/263</paragraph></td><td align="center" valign="top"><paragraph>(85.2)</paragraph></td><td align="center" valign="top"><paragraph>264/269</paragraph></td><td align="center" valign="top"><paragraph>(98.1)</paragraph></td></tr><tr><td valign="top"><paragraph>Week 2</paragraph></td><td align="center" valign="top"><paragraph>216/257</paragraph></td><td align="center" valign="top"><paragraph>(84.0)</paragraph></td><td align="center" valign="top"><paragraph>263/266</paragraph></td><td align="center" valign="top"><paragraph>(98.9)</paragraph></td></tr><tr><td valign="top"><paragraph>Week 4</paragraph></td><td align="center" valign="top"><paragraph>218/235</paragraph></td><td align="center" valign="top"><paragraph>(92.8)</paragraph></td><td align="center" valign="top"><paragraph>243/249</paragraph></td><td align="center" valign="top"><paragraph>(97.6)</paragraph></td></tr><tr><td valign="top"><paragraph>Week 6</paragraph></td><td align="center" valign="top"><paragraph>211/224</paragraph></td><td align="center" valign="top"><paragraph>(94.2)</paragraph></td><td align="center" valign="top"><paragraph>234/241</paragraph></td><td align="center" valign="top"><paragraph>(97.1)</paragraph></td></tr><tr><td colspan="5" valign="top"><paragraph><content styleCode="bold"><content styleCode="italics">Normal response to ACTH challenge^a</content></content></paragraph></td></tr><tr><td valign="top"><paragraph>Baseline</paragraph></td><td align="center" valign="top"><paragraph>222/266</paragraph></td><td align="center" valign="top"><paragraph>(83.5)</paragraph></td><td align="center" valign="top"><paragraph>238/278</paragraph></td><td align="center" valign="top"><paragraph>(85.6)</paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph>Week 6^b</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>148/236

(83.5)</paragraph></td><td align="center" valign="top"><paragraph>238/278</paragraph></td><td align="center" valign="top"><paragraph>(85.6)</paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph>Week 6^b</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>148/236 </paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>(62.7)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>180/237</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>(75.9)</paragraph></td></tr></tbody></table>

12.3 Pharmacokinetics Absorption Distal Ulcerative Colitis Patients Based on population pharmacokinetic analysis from sparse PK samples from phase 3 studies, the estimated AUC 0-12 following administration of budesonide rectal foam 2 mg twice a day was 4.31 ng*hr/mL with a CV of 64% in the target patient population. Distribution The volume of distribution (V SS ) of budesonide varies between 2.2 and 3.9 L/kg in healthy subjects and in patients. Plasma protein binding is estimated to be 85 to 90% in the concentration range of 1 to 230 nmol/L, independent of gender. The erythrocyte/plasma partition ratio at clinically relevant concentrations is approximately 0.8. Elimination Metabolism Following absorption, budesonide is subject to first-pass metabolism. In vitro experiments in human liver microsomes demonstrate that budesonide is rapidly and extensively biotransformed, mainly by CYP3A4, to its 2 major metabolites, 6β-hydroxy budesonide and 16α-hydroxy prednisolone. The glucocorticoid activity of these metabolites is negligible (<1/100) in relation to that of the parent compound. In vivo investigations with intravenous doses in healthy subjects demonstrate that budesonide has a plasma clearance of 0.9-1.8 L/min. These plasma clearance values approach the estimated liver blood flow, suggesting that budesonide is a high hepatic clearance drug. Excretion Budesonide is excreted in urine and feces in the form of metabolites. After oral as well as intravenous administration of micronized [ 3 H]-budesonide, approximately 60% of the recovered radioactivity is found in urine. The major metabolites, including 6β-hydroxybudesonide and 16α-hydroxyprednisolone, are mainly renally excreted, intact or in conjugated forms. No unchanged budesonide is detected in urine. Specific Populations Patients with Renal Impairment The pharmacokinetics of budesonide in patients with renal impairment has not been studied. Intact budesonide is not renally excreted, but metabolites are to a large extent, and might therefore reach higher levels in patients with impaired renal function. However, these metabolites have negligible corticosteroid activity as compared with budesonide. Patients with Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of budesonide rectal foam has not been studied. In a study in patients with mild to moderate hepatic impairment (Child-Pugh Class A and Child-Pugh Class B) dosed with budesonide 4 mg oral capsules, systemic exposure was similar between patients with mild hepatic impairment (Child-Pugh Class A; n=4) and healthy subjects (n=8), and 3.5-fold higher in patients with moderate hepatic impairment (Child-Pugh Class B; n=4) than in healthy subjects. For the intravenous dose, no significant differences in CL or V SS are observed. Patients with severe liver dysfunction (Child-Pugh Class C) were not studied [see Use in Specific Populations ( 8.6 )] . Drug Interaction Studies Budesonide is metabolized via CYP3A4. Potent inhibitors of CYP3A4 can increase the plasma concentrations of budesonide. Co-administration of ketoconazole (inhibitor of CYP3A4) results in an 8-fold increase in AUC of oral budesonide, compared to budesonide alone. Grapefruit juice, an inhibitor of gut mucosal CYP3A, approximately doubles the systemic exposure of oral budesonide. Conversely, induction of CYP3A4 can result in the lowering of budesonide plasma concentrations.

inhibitor of CYP3A4) results in an 8-fold increase in AUC of oral budesonide, compared to budesonide alone. Grapefruit juice, an inhibitor of gut mucosal CYP3A, approximately doubles the systemic exposure of oral budesonide. Conversely, induction of CYP3A4 can result in the lowering of budesonide plasma concentrations. The effect of CYP3A4 inhibitors and inducers on the pharmacokinetics of budesonide rectal foam have not been studied [see Dosage and Administration ( 2 ) and Drug Interactions ( 7 )] . Oral contraceptives containing ethinyl estradiol, which are also metabolized by CYP3A4, do not affect the pharmacokinetics of oral budesonide. Budesonide does not affect the plasma concentrations of oral contraceptives (i.e., ethinyl estradiol). In vitro interaction studies performed with budesonide showed that budesonide did not inhibit human cytochrome P450 isoenzymes CYP1A2, CYP2B6, CYP2C9, CYP2D6, or CYP2E1 at concentrations ranging from 0.11 to 1130 ng/mL. Isoenzyme CYP3A4 was inhibited at the highest concentration tested but the IC 50 was >1130 ng/mL. Budesonide rectal foam is not expected to inhibit these enzymes in clinical use. No significant induction of CYP1A2, CYP2B6, CYP2C9 or CYP3A4/5 expression was observed in human hepatocytes in vitro at budesonide concentrations up to 9000 nM (3.88 mcg/mL). In an in vitro study, budesonide was not a substrate of human transporters OATP1B3 and may be a weak substrate of OATP1B1. Budesonide at concentrations up to 300 nM (129 ng/mL) did not inhibit OATP1B1 or OATP1B3. Budesonide was not a substrate of BCRP and was a weak substrate of P-glycoprotein. Budesonide was a weak inhibitor of P-glycoprotein (IC 50 9.78 μM or 4.21 mcg/mL) and BCRP (IC 50 43.1 μM or 18.6 mcg/mL). Budesonide rectal foam is not expected to inhibit these transporters in clinical use.

14 CLINICAL STUDIES The safety and efficacy of budesonide rectal foam were evaluated in 2 replicate, randomized, double-blind, placebo-controlled, multi-center trials (Studies 1 and 2). Participants in the trials were adult patients with active mild-to-moderate distal ulcerative colitis with disease extending at least 5 cm but no further than 40 cm from the anal verge (confirmed by endoscopy). To be eligible, patients had to have a Modified Mayo Disease Activity Index (MMDAI) score between 5 and 10, inclusive, a rectal bleeding subscore of 2 or 3, and an endoscopy subscore of 2 or 3. The MMDAI score ranges from 0 to 12 and has 4 subscales that are each scored from 0 (normal) to 3 (most severe): stool frequency, rectal bleeding, findings on endoscopy, and physician global assessment. An endoscopy subscore of 2 is defined by marked erythema, lack of vascular pattern, friability, and erosions; an endoscopy subscore of 3 is defined by spontaneous bleeding and ulceration. Oral and rectal corticosteroids, and rectal 5-aminosalicylic acid (5-ASA) products were prohibited during the course of the trials but were allowed as rescue therapy. Oral 5-ASA products were allowed at doses ≤ 4.8 grams/day. In total, 546 subjects were randomized in these trials: 267 subjects to budesonide rectal foam and 279 subjects to placebo. In each trial (Study 1 and Study 2), patients received budesonide rectal foam 2 mg or placebo twice daily for 2 weeks followed by once daily for 4 weeks. The median age was 41 years and 42 years, 5% and 8% were ≥ 65 years of age, and 43% and 45% were male, in Studies 1 and 2, respectively. In each of these trials, 90% were Caucasian, 7-8% were African American, and 3% were Asian or Other. The majority of patients had a baseline diagnosis of proctosigmoiditis (69% and 74%) in Studies 1 and 2, respectively. The remaining patients had a baseline diagnosis of proctitis. Concomitant oral 5-ASA use at baseline was 59% and 51% in Studies 1 and 2, respectively. Baseline MMDAI total score was 7.8 and 7.9 in the budesonide rectal foam group and placebo group, respectively, of Study 1; and 7.9 and 8.0 in the budesonide rectal foam group and placebo group, respectively, of Study 2. The mean stool frequency subscore at baseline was 1.8 and 1.9 in the budesonide rectal foam group and placebo group, respectively, of Study 1; and 1.7 and 1.8 in the budesonide rectal foam group and placebo group, respectively, of Study 2. In each trial (Study 1 and Study 2), the primary endpoint was the proportion of subjects who were in remission after 6 weeks of treatment. Remission was defined as a decrease or no change in the stool frequency subscore from baseline, a rectal bleeding subscore of 0, and an endoscopy score of 0 or 1. (An endoscopy subscore of zero is defined by normal or inactive disease; an endoscopy subscore of 1 is defined by erythema and decreased vascular pattern.) In each trial (Study 1 and Study 2), a higher proportion of patients in the budesonide rectal foam group than in the placebo group were in remission at Week 6 and had a rectal bleeding subscore of 0 at Week 6 ( Table 4 ).

active disease; an endoscopy subscore of 1 is defined by erythema and decreased vascular pattern.) In each trial (Study 1 and Study 2), a higher proportion of patients in the budesonide rectal foam group than in the placebo group were in remission at Week 6 and had a rectal bleeding subscore of 0 at Week 6 ( Table 4 ). Table 4: Efficacy Results: Studies 1 and 2 Study 1 Efficacy Endpoint Budesonide Rectal Foam N=133 Placebo N=132 p-value b Treatment Difference (95% CI) Remission at Week 6 a 38.3% 25.8% 0.032 12.6% (1.5%, 23.7%) Rectal Bleeding subscore = 0 at Week 6 46.6% 28.0% 0.002 18.6% (7.2%, 30%) Study 2 Budesonide Rectal Foam N=134 Placebo N=147 p-value b Treatment Difference (95% CI) Remission at Week 6 a 44.0% 22.4% <0.001 21.6% (10.8%, 32.4%) Rectal Bleeding subscore = 0 at Week 6 50.0% 28.6% <0.001 21.4% (10.3%, 32.6%) a Remission was defined as an endoscopy subscore of 0 or 1, a rectal bleeding subscore of 0, and a decrease or no change in stool frequency subscore from baseline. b p-values obtained from the Cochran-Mantel-Haenszel (CMH) test. CI: Confidence Interval In Study 1, the percentage of patients with endoscopy subscore of 0 or 1 at Week 6 was 55.6% in the budesonide rectal foam group versus 43.2% in the placebo group. In Study 2, the percentage of patients with endoscopy subscore of 0 or 1 at Week 6 was 56.0% in the budesonide rectal foam group versus 36.7% in the placebo group (an endoscopy subscore of 0 is defined by normal or inactive disease; an endoscopy subscore of 1 is defined by erythema and decreased vascular pattern). In patients that met the primary endpoint of remission in Study 1, the mean (SD) decrease in stool frequency subscore was 1.2 (0.9) in the budesonide rectal foam group and 1.2 (0.8) in the placebo group. In patients that met the primary endpoint of remission in Study 2, the mean (SD) decrease in stool frequency subscore was 1.3 (0.8) in the budesonide rectal foam group and 1.1 (0.9) in the placebo group.

<table width="100%"><col width="29%"/><col width="18%"/><col width="18%"/><col width="18%"/><col width="18%"/><tbody><tr><td align="center" colspan="5" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Study 1</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Efficacy Endpoint</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph><content styleCode="bold">Budesonide</content></paragraph><paragraph><content styleCode="bold">Rectal Foam</content></paragraph><paragraph><content styleCode="bold">N=133</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">N=132</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph><content styleCode="bold">p-value^b</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph><content styleCode="bold">Treatment</content></paragraph><paragraph><content styleCode="bold">Difference</content></paragraph><paragraph><content styleCode="bold">(95% CI)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Remission at Week 6^a</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>38.3%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>25.8%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>0.032</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>12.6%</paragraph><paragraph>(1.5%, 23.7%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Rectal Bleeding subscore</paragraph><paragraph>= 0 at Week 6</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>46.6%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>28.0%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>0.002</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>18.6%</paragraph><paragraph>(7.2%, 30%)</paragraph></td></tr><tr><td align="center" colspan="5" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Study 2</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"/><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph><content styleCode="bold">Budesonide</content></paragraph><paragraph><content styleCode="bold">Rectal Foam</content></paragraph><paragraph><content styleCode="bold">N=134</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">N=147</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph><content styleCode="bold">p-value^b</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule B

Code="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">N=147</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph><content styleCode="bold">p-value^b</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule B otrule " valign="middle"><paragraph><content styleCode="bold">Treatment</content></paragraph><paragraph><content styleCode="bold">Difference</content></paragraph><paragraph><content styleCode="bold">(95% CI)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Remission at Week 6^a</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>44.0%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>22.4%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>&lt;0.001</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>21.6%</paragraph><paragraph>(10.8%, 32.4%)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>Rectal Bleeding subscore</paragraph><paragraph>= 0 at Week 6</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>50.0%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>28.6%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>&lt;0.001</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>21.4%</paragraph><paragraph>(10.3%, 32.6%)</paragraph></td></tr></tbody></table>

16 HOW SUPPLIED/STORAGE AND HANDLING Budesonide rectal foam is supplied as a kit containing 2 aerosol canisters with 28 PVC applicators coated with paraffin lubricant for administration of the foam (NDC 45802-627-86). Each canister (NDC 45802-627-01) is labeled with a net weight of 33.4 g and contains 14 metered doses. Storage Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Handling Budesonide rectal foam contains a flammable propellant. Do not have the canister burned after use and do not spray contents directly towards flames. • Do not expose to heat or store at temperatures above 120°F (49°C). • Flammable. Avoid fire, flame, or smoking during and immediately following administration. • Contents under pressure. Do not puncture or incinerate. DO NOT REFRIGERATE.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Administration Advise patients: • Budesonide rectal foam is only to be applied rectally. It is not for oral use. • Before using budesonide rectal foam, use the bathroom to empty your bowels. • Each applicator is coated with a lubricant. If additional lubrication is needed, petrolatum or petroleum jelly can also be used. • Warm the canister in the hands while shaking it vigorously for 10 to 15 seconds prior to use. • Budesonide rectal foam can be used in a standing, lying or sitting position (e.g., while using the toilet). • Apply budesonide rectal foam in the morning and the evening for the first 2 weeks of treatment; then once daily in the evening for the next 4 weeks. When applied in the evening, use immediately prior to bedtime. Try not to empty your bowels again until the next morning. • Avoid consumption of grapefruit or grapefruit juice during treatment with budesonide rectal foam. • Avoid fire, flame, and smoking during and immediately following administration since budesonide rectal foam is flammable. Hypercorticism and Adrenal Suppression Advise patients that budesonide rectal foam may cause hypercorticism and adrenal suppression and that they should taper slowly from systemic corticosteroids if transferring to budesonide rectal foam [see Warnings and Precautions ( 5.1 ), ( 5.2 )] . Advise patients that replacement of systemic glucocorticosteroids with budesonide rectal foam may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug. Increased Risk of Infection Advise patients to avoid exposure to people with chicken pox or measles and if exposed, consult a physician. Also, inform patients that they are at increased risk of developing a variety of infections, including worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex and to contact their physician if they develop any symptoms of infection [see Warnings and Precautions ( 5.3 )] . Pregnancy Advise female patients that budesonide rectal foam may cause fetal harm and to inform their healthcare provider with a known or suspected pregnancy [see Use in Specific Populations ( 8.1 )] . Manufactured By Padagis, Yeruham 8050315, Israel Distributed By Padagis, Allegan, MI 49010 www.padagis.com Rev 06-22 5Q200 RC J2

Instructions for Use Budesonide (bue-DES-oh-nide) rectal foam Read the Patient Information and Instructions for Use that comes with budesonide rectal foam before you start using it and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. Talk to your healthcare provider if you have any questions. Before using budesonide rectal foam, you should use the bathroom to empty your bowels. You may use budesonide rectal foam while in a standing position, in a lying position, or in a sitting position (for example, while using the toilet). Applicators should be used only 1 time. You should use a new applicator for each dose. Each kit contains ( See Figure A ): • Complete Prescribing Information • Patient Information and Instructions for Use • 2 canisters containing 14 doses each • 4 trays of single-use applicators (7 applicators per tray) • Applicator throw away (disposal) bags for use after each dose Preparing to use budesonide rectal foam Figure B Step 1: Twist Safety Tab to Remove Before the first use, remove the safety tab from under the pump dome (See Figure B) . The canister cannot be used if safety tab is not removed. Figure C Step 2: Attach the Applicator The applicators are in a tray. Hold the tray firmly and pull to remove 1 applicator. Push the applicator firmly onto the nozzle of the canister (See Figure C) . Each applicator is coated with a lubricant. If needed, you can apply an additional lubricant, such as Vaseline (petrolatum, petroleum jelly). Figure D Step 3: Align Notch to Nozzle To unlock the canister, twist the dome on the top of the canister until the semicircular notch underneath the dome is in line with the nozzle (See Figure D) . Figure E Step 4: Warm and Shake Canister Warm the canister by holding it in your hands while shaking it vigorously for 10 to 15 seconds (See Figure E) . Figure F Step 5: Turn the Canister Upside Down Place your pointer finger (forefinger) on the top of pump dome and then turn the canister upside down (See Figure F) . The canister will only work properly when held with the pump dome pointing down. Figure G Step 6: Insert the Applicator into Rectum Insert the applicator into your rectum as far as it is comfortable. The easiest way to use budesonide rectal foam is to keep 1 foot on the floor and raise the other foot onto a firm surface such as a chair or stool (See Figure G) . Figure H Step 7: Give a Dose of Budesonide Rectal Foam To give a dose of budesonide rectal foam, use your pointer finger (forefinger) to fully push down the pump dome 1 time and hold it for about 2 seconds in that position (See Figure H) . Figure I Step 8: Release and Hold Release finger pressure on the pump dome and hold the applicator in place for 10 to 15 seconds (See Figure I) . Figure J Step 9: Remove the Applicator (See Figure J) The foam will still expand a little and may drop out of the applicator or anus. Figure K Step 10: Remove Applicator from Canister Remove the applicator from the canister and place the used applicator in the applicator throw away (disposal) bag provided (See Figure K) . Throw the applicator throw away (disposal) bag away in your household trash.

a little and may drop out of the applicator or anus. Figure K Step 10: Remove Applicator from Canister Remove the applicator from the canister and place the used applicator in the applicator throw away (disposal) bag provided (See Figure K) . Throw the applicator throw away (disposal) bag away in your household trash. Figure L Step 11: Twist Notch on Dome Away from Nozzle To prevent loss of budesonide rectal foam from the canister between uses, turn the pump dome around so that the semicircular notch faces the opposite direction to the nozzle (See Figure L) . Wash your hands with soap and water after using the budesonide rectal foam. Try not to empty your bowels until the next morning. Manufactured By Padagis Yeruham 8050315, Israel Distributed By Padagis Allegan, MI 49010 • www.padagis.com Revised: 06/2022 5Q200 RC J2 This Instructions for Use has been approved by the U.S. Food and Drug Administration. figure-a figure-b figure-c figure-d figure-e figure-f figure-g figure-h figure-i figure-j figure-k figure-l

<table width="100%"><col width="50%"/><col width="50%"/><tbody><tr styleCode="Toprule"><td align="center" valign="top"><renderMultiMedia ID="id-766929542" referencedObject="ID_8c70b1fb-8642-4c45-afa8-0af73bf2a97e"/><paragraph><content styleCode="bold">Figure B</content></paragraph></td><td valign="top"><paragraph><content styleCode="bold">Step 1: Twist Safety Tab to Remove</content></paragraph><paragraph>Before the first use, remove the safety tab from under the pump dome <content styleCode="bold">(See Figure B)</content>.</paragraph><paragraph><content styleCode="bold">The canister cannot be used if safety tab is not removed.</content></paragraph></td></tr><tr><td align="center" valign="top"><renderMultiMedia ID="id-263762878" referencedObject="ID_172da024-7385-48a7-bc92-662c1927ade6"/><paragraph><content styleCode="bold">Figure C</content></paragraph></td><td valign="top"><paragraph><content styleCode="bold">Step 2: Attach the Applicator</content></paragraph><paragraph>The applicators are in a tray. Hold the tray firmly and pull to remove 1 applicator.</paragraph><paragraph>Push the applicator firmly onto the nozzle of the canister <content styleCode="bold">(See Figure C)</content>. Each applicator is coated with a lubricant.

p 2: Attach the Applicator</content></paragraph><paragraph>The applicators are in a tray. Hold the tray firmly and pull to remove 1 applicator.</paragraph><paragraph>Push the applicator firmly onto the nozzle of the canister <content styleCode="bold">(See Figure C)</content>. Each applicator is coated with a lubricant. If needed, you can apply an additional lubricant, such as Vaseline (petrolatum, petroleum jelly).</paragraph></td></tr><tr><td align="center" valign="top"><renderMultiMedia ID="id774825072" referencedObject="ff852af8-af4a-4c61-8f18-fb640e20e1be"/><paragraph><content styleCode="bold">Figure D</content></paragraph></td><td valign="top"><paragraph><content styleCode="bold">Step 3: Align Notch to Nozzle</content></paragraph><paragraph>To unlock the canister, twist the dome on the top of the canister until the semicircular notch underneath the dome is in line with the nozzle <content styleCode="bold">(See Figure D)</content>.</paragraph></td></tr><tr><td align="center" valign="top"><renderMultiMedia ID="id1223788368" referencedObject="ID_4984f70f-5616-4e91-9e41-a90ea5b6e42f"/><paragraph><content styleCode="bold">Figure E</content></paragraph></td><td valign="top"><paragraph><content styleCode="bold">Step 4: Warm and Shake Canister</content></paragraph><paragraph>Warm the canister by holding it in your hands while shaking it vigorously for 10 to 15 seconds <content styleCode="bold">(See Figure E)</content>.</paragraph></td></tr><tr><td align="center" valign="top"><renderMultiMedia ID="id-1605415638" referencedObject="ID_4c117c81-2071-4c37-ae6c-b5b34914a7ae"/><paragraph><content styleCode="bold">Figure F</content></paragraph></td><td valign="top"><paragraph><content styleCode="bold">Step 5: Turn the Canister Upside Down</content></paragraph><paragraph>Place your pointer finger (forefinger) on the top of pump dome and then turn the canister upside down <content styleCode="bold">(See Figure F)</content>.</paragraph><paragraph><content styleCode="bold">The canister will only work properly when held with the pump dome pointing down.</content></paragraph></td></tr><tr><td align="center" valign="top"><renderMultiMedia ID="id164215430" referencedObject="ID_23e0fc05-e92c-4055-8ba5-48e6bbce0243"/><paragraph><content styleCode="bold">Figure G</content></paragraph></td><td valign="top"><paragraph><content styleCode="bold">Step 6: Insert the Applicator into Rectum</content></paragraph><paragraph>Insert the applicator into your rectum as far as it is comfortable.</paragraph><paragraph>The easiest way to use budesonide rectal foam is to keep 1 foot on the floor and raise the other foot onto a firm surface such as a chair or stool <content styleCode="bold">(See Figure G)</content>.</paragraph></td></tr><tr><td align="center" valign="top"><renderMultiMedia ID="id-999963869" referencedObject="ID_1a7b06c9-9670-4db9-b486-541269f62c8c"/><paragraph><content styleCode="bold">Figure H</content></paragraph></td><td valign="top"><paragraph><content styleCode="bold">Step 7: Give a Dose of Budesonide Rectal Foam</content></paragraph><paragraph>To give a dose of budesonide rectal foam, use your pointer finger (forefinger) to fully push down the pump dome 1 time and hold it for about 2 seconds in that position <content styleCode="bold">(See Figure H)</content>.</paragraph></td></tr><tr><td align="center" valign="top"><renderMultiMedia ID="id-534503675" referencedObject="e5bf0d04-fdf7-4ce9-ad6f-2759d18bcdae"/><paragraph><content styleCode="bold">Figure I</content></paragraph></td><td valign="top"><paragraph><content styleCode="bold">Step 8: Release and Hold</content></paragraph><paragraph>Release finger pressure on the pump dome and hold the applicator in place for 10 to 15 seconds <content styleCode="bold">(See Figure I)</content>.</paragraph></td></tr><tr><td align="cent

tent></paragraph></td><td valign="top"><paragraph><content styleCode="bold">Step 8: Release and Hold</content></paragraph><paragraph>Release finger pressure on the pump dome and hold the applicator in place for 10 to 15 seconds <content styleCode="bold">(See Figure I)</content>.</paragraph></td></tr><tr><td align="cent er" valign="top"><renderMultiMedia ID="id-280340749" referencedObject="df043778-633b-4610-abc2-cf80957345e6"/><paragraph><content styleCode="bold">Figure J</content></paragraph></td><td valign="top"><paragraph><content styleCode="bold">Step 9: Remove the Applicator</content></paragraph><paragraph><content styleCode="bold">(See Figure J)</content></paragraph><paragraph>The foam will still expand a little and may drop out of the applicator or anus.</paragraph></td></tr><tr><td align="center" valign="top"><renderMultiMedia ID="id9188167" referencedObject="ID_07fbd3d8-0a22-4c3c-ab94-64d261d4a137"/><paragraph><content styleCode="bold">Figure K</content></paragraph></td><td valign="top"><paragraph><content styleCode="bold">Step 10: Remove Applicator from Canister</content></paragraph><paragraph>Remove the applicator from the canister and place the used applicator in the applicator throw away (disposal) bag provided <content styleCode="bold">(See Figure K)</content>. Throw the applicator throw away (disposal) bag away in your household trash.</paragraph></td></tr><tr styleCode="Botrule"><td align="center" valign="top"><renderMultiMedia ID="id539324282" referencedObject="eadd46af-7763-478e-bd91-de50f4bac704"/><paragraph><content styleCode="bold">Figure L</content></paragraph></td><td valign="top"><paragraph><content styleCode="bold">Step 11: Twist Notch on Dome Away from Nozzle</content></paragraph><paragraph>To prevent loss of budesonide rectal foam from the canister between uses, turn the pump dome around so that the semicircular notch faces the opposite direction to the nozzle <content styleCode="bold">(See Figure L)</content>.</paragraph><paragraph><content styleCode="bold">Wash your hands with soap and water after using the budesonide rectal foam. Try not to empty your bowels until the next morning.</content></paragraph></td></tr></tbody></table>

Patient Information Patient Information Budesonide (bue-DES-oh-nide) rectal foam What is Budesonide rectal foam? • Budesonide rectal foam is a prescription corticosteroid medicine used to help get mild to moderate active ulcerative colitis that extends from the rectum to the sigmoid colon under control (induce remission). • It is not known if budesonide rectal foam is safe and effective in children. It is not known if budesonide rectal foam is safe and effective in children. Who should not use budesonide rectal foam? Do not use budesonide rectal foam if you are allergic to budesonide or any of the ingredients in budesonide rectal foam. See the end of this leaflet for a complete list of ingredients in budesonide rectal foam. What should I tell my healthcare provider before using budesonide rectal foam? Before you use budesonide rectal foam, tell your healthcare provider about all of your medical conditions, including if you: • have liver problems. • are planning to have surgery. • have chicken pox or measles or have recently been near anyone with chicken pox or measles. • have an infection. • have or had a family history of diabetes, cataracts or glaucoma. • have or had tuberculosis. • have high blood pressure (hypertension). • have decreased bone mineral density (osteoporosis). • have stomach ulcers. • are pregnant or plan to become pregnant. Budesonide rectal foam may harm your unborn baby. Tell your healthcare provider if you are pregnant or think you are pregnant. • are breastfeeding or plan to breastfeed. Budesonide can pass into your breast milk and may harm your baby. You and your healthcare provider should decide if you will use budesonide rectal foam or breastfeed. You should not do both. are planning to have surgery. have chicken pox or measles or have recently been near anyone with chicken pox or measles. have an infection. have or had a family history of diabetes, cataracts or glaucoma. have or had tuberculosis. have high blood pressure (hypertension). have decreased bone mineral density (osteoporosis). have stomach ulcers. are pregnant or plan to become pregnant. Budesonide rectal foam may harm your unborn baby. Tell your healthcare provider if you are pregnant or think you are pregnant. are breastfeeding or plan to breastfeed. Budesonide can pass into your breast milk and may harm your baby. You and your healthcare provider should decide if you will use budesonide rectal foam or breastfeed. You should not do both. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Budesonide rectal foam and other medicines may affect each other causing side effects. Especially tell your healthcare provider if you take another medicine that contains corticosteroids for other conditions, such as allergies or asthma. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I use budesonide rectal foam? See the “Instructions for Use” at the end of this Patient Information for detailed information about the right way to use budesonide rectal foam. • Use budesonide rectal foam exactly as your healthcare provider tells you to use it. • Budesonide rectal foam should only be used rectally (through the anus). Do not take budesonide rectal foam by mouth. • Warm the budesonide rectal foam canister by holding it in your hands while shaking it vigorously for 10 to 15 seconds.

budesonide rectal foam exactly as your healthcare provider tells you to use it. • Budesonide rectal foam should only be used rectally (through the anus). Do not take budesonide rectal foam by mouth. • Warm the budesonide rectal foam canister by holding it in your hands while shaking it vigorously for 10 to 15 seconds. • Budesonide rectal foam is used twice a day for the first 2 weeks of treatment (in the morning and in the evening). After 2 weeks, use budesonide rectal foam 1 time a day in the evening, before bedtime for 4 weeks. • If you use too much budesonide rectal foam, call your healthcare provider right away. • You should stop using budesonide rectal foam before preparing for a colonoscopy. Call your healthcare provider before restarting budesonide rectal foam after your colonoscopy. Budesonide rectal foam should only be used rectally (through the anus). Do not take budesonide rectal foam by mouth. Warm the budesonide rectal foam canister by holding it in your hands while shaking it vigorously for 10 to 15 seconds. Budesonide rectal foam is used twice a day for the first 2 weeks of treatment (in the morning and in the evening). After 2 weeks, use budesonide rectal foam 1 time a day in the evening, before bedtime for 4 weeks. If you use too much budesonide rectal foam, call your healthcare provider right away. You should stop using budesonide rectal foam before preparing for a colonoscopy. Call your healthcare provider before restarting budesonide rectal foam after your colonoscopy. What should I avoid while using budesonide rectal foam? • Do not eat grapefruit or drink grapefruit juice while using budesonide rectal foam. Eating grapefruit or drinking grapefruit juice can increase the level of budesonide rectal foam in your blood. • Budesonide rectal foam is flammable. Avoid fire, flame and smoking during and right after using budesonide rectal foam. Budesonide rectal foam is flammable. Avoid fire, flame and smoking during and right after using budesonide rectal foam. What are the possible side effects of budesonide rectal foam? Budesonide rectal foam may cause serious side effects, including: • Effects of having too much corticosteroid medicine in your blood (hypercorticism). Long-time use of budesonide rectal foam can cause you to have too much glucocorticosteroid medicine in your blood. Tell your healthcare provider if you have any of the following signs and symptoms of hypercorticism: o acne o bruise easily o rounding of your face (moon face) o ankle swelling o thicker or more hair on your body and face o a fatty pad or hump between your shoulders (buffalo hump) o pink or purple stretch marks on the skin of your abdomen, thighs, breasts and arms • Adrenal suppression. When budesonide rectal foam is used for a long period of time (chronic use), the adrenal glands may not make enough steroid hormones (adrenal suppression). Tell your healthcare provider if you are under stress or have any symptoms of adrenal suppression during treatment with budesonide rectal foam including: o tiredness o weakness o nausea o vomiting o low blood pressure • Immune system effects and a higher chance of infections. Budesonide rectal foam may weaken your immune system. Taking medicines that weaken your immune system makes you more likely to get infections. Avoid contact with people who have contagious diseases such as chicken pox or measles while using budesonide rectal foam. acne bruise easily rounding of your face (moon face) ankle swelling thicker or more hair on your body and face a fatty pad or hump between your shoulders (buffalo hump) pink or purple stretch marks on the skin of your abdomen, thighs, breasts and arms Adrenal suppression.

or measles while using budesonide rectal foam. acne bruise easily rounding of your face (moon face) ankle swelling thicker or more hair on your body and face a fatty pad or hump between your shoulders (buffalo hump) pink or purple stretch marks on the skin of your abdomen, thighs, breasts and arms Adrenal suppression. When budesonide rectal foam is used for a long period of time (chronic use), the adrenal glands may not make enough steroid hormones (adrenal suppression). Tell your healthcare provider if you are under stress or have any symptoms of adrenal suppression during treatment with budesonide rectal foam including: tiredness weakness nausea vomiting low blood pressure Immune system effects and a higher chance of infections. Budesonide rectal foam may weaken your immune system. Taking medicines that weaken your immune system makes you more likely to get infections. Avoid contact with people who have contagious diseases such as chicken pox or measles while using budesonide rectal foam. Tell your healthcare provider about any signs or symptoms of infection during treatment with budesonide rectal foam, including: o fever o chills o aches o feeling tired o pain o nausea or vomiting • Worsening of allergies. If you take certain other corticosteroid medicines to treat allergies, switching to budesonide rectal foam may cause your allergies to come back. These allergies may include eczema (a skin disease) or inflammation inside your nose (rhinitis). Tell your healthcare provider if any of your allergies become worse while using budesonide rectal foam. fever chills aches feeling tired pain nausea or vomiting Worsening of allergies. If you take certain other corticosteroid medicines to treat allergies, switching to budesonide rectal foam may cause your allergies to come back. These allergies may include eczema (a skin disease) or inflammation inside your nose (rhinitis). Tell your healthcare provider if any of your allergies become worse while using budesonide rectal foam. The most common side effects of budesonide rectal foam include: • decreased blood cortisol levels • adrenal insufficiency • nausea adrenal insufficiency nausea Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of budesonide rectal foam. For more information, ask your healthcare provider 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 store budesonide rectal foam? • Store budesonide rectal foam at room temperature, between 68°F to 77°F (20°C to 25°C). • Do not store the budesonide rectal foam container near heat or store at temperatures above 120°F (49°C). • Do not puncture or burn the budesonide rectal foam canister. • Do not refrigerate. Do not store the budesonide rectal foam container near heat or store at temperatures above 120°F (49°C). Do not puncture or burn the budesonide rectal foam canister. Do not refrigerate. Keep budesonide rectal foam and all medicines out of the reach of children. General information about the safe and effective use of budesonide rectal foam. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use budesonide rectal foam for a condition for which it was not prescribed. Do not give budesonide rectal foam to other people, even if they have the same symptoms you have. It may harm them. This Patient Information leaflet summarizes the most important information about budesonide rectal foam. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about budesonide rectal foam that is written for health professionals.

them. This Patient Information leaflet summarizes the most important information about budesonide rectal foam. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about budesonide rectal foam that is written for health professionals. For more information, go to www.padagis.com What are the ingredients in budesonide rectal foam? Active ingredient: budesonide Inactive ingredients: cetyl alcohol, citric acid monohydrate, edetate disodium, emulsifying wax, polyoxyl (10) stearyl ether, propylene glycol, and purified water Propellant: n-butane, isobutane, and propane Manufactured by Padagis, Yeruham 8050315, Israel Distributed By Padagis, Allegan, MI 49010 www.padagis.com This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 06/2022

<table width="100%"><col width="100%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Patient Information</content></paragraph><paragraph><content styleCode="bold">Budesonide (bue-DES-oh-nide)</content></paragraph><paragraph><content styleCode="bold">rectal foam</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What is Budesonide rectal foam?</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>Budesonide rectal foam is a prescription corticosteroid medicine used to help get mild to moderate active ulcerative colitis that extends from the rectum to the sigmoid colon under control (induce remission). </item><item><caption>&#x2022;</caption>It is not known if budesonide rectal foam is safe and effective in children.</item></list><paragraph>It is not known if budesonide rectal foam is safe and effective in children.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Who should not use budesonide rectal foam?</content></paragraph><paragraph>Do not use budesonide rectal foam if you are allergic to budesonide or any of the ingredients in budesonide rectal foam. See the end of this leaflet for a complete list of ingredients in budesonide rectal foam.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What should I tell my healthcare provider before using budesonide rectal foam?</content></paragraph><paragraph><content styleCode="bold">Before you use budesonide rectal foam, tell your healthcare provider about all of your medical conditions, including if you:</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>have liver problems. </item><item><caption>&#x2022;</caption>are planning to have surgery. </item><item><caption>&#x2022;</caption>have chicken pox or measles or have recently been near anyone with chicken pox or measles. </item><item><caption>&#x2022;</caption>have an infection. </item><item><caption>&#x2022;</caption>have or had a family history of diabetes, cataracts or glaucoma. </item><item><caption>&#x2022;</caption>have or had tuberculosis. </item><item><caption>&#x2022;</caption>have high blood pressure (hypertension). </item><item><caption>&#x2022;</caption>have decreased bone mineral density (osteoporosis). </item><item><caption>&#x2022;</caption>have stomach ulcers. </item><item><caption>&#x2022;</caption>are pregnant or plan to become pregnant. Budesonide rectal foam may harm your unborn baby. Tell your healthcare provider if you are pregnant or think you are pregnant. </item><item><caption>&#x2022;</caption>are breastfeeding or plan to breastfeed. Budesonide can pass into your breast milk and may harm your baby. You and your healthcare provider should decide if you will use budesonide rectal foam or breastfeed. You should not do both.</item></list><paragraph>are planning to have surgery. </paragraph><paragraph>have chicken pox or measles or have recently been near anyone with chicken pox or measles. </paragraph><paragraph>have an infection. </paragraph><paragraph>have or had a family history of diabetes, cataracts or glaucoma. </paragraph><paragraph>have or had tuberculosis. </paragraph><paragraph>have high blood pressure (hypertension).

pox or measles or have recently been near anyone with chicken pox or measles. </paragraph><paragraph>have an infection. </paragraph><paragraph>have or had a family history of diabetes, cataracts or glaucoma. </paragraph><paragraph>have or had tuberculosis. </paragraph><paragraph>have high blood pressure (hypertension). </paragraph><paragraph>have decreased bone mineral density (osteoporosis). </paragraph><paragraph>have stomach ulcers. </paragraph><paragraph>are pregnant or plan to become pregnant. Budesonide rectal foam may harm your unborn baby. Tell your healthcare provider if you are pregnant or think you are pregnant. </paragraph><paragraph>are breastfeeding or plan to breastfeed. Budesonide can pass into your breast milk and may harm your baby. You and your healthcare provider should decide if you will use budesonide rectal foam or breastfeed. You should not do both.</paragraph><paragraph><content styleCode="bold">Tell your healthcare provider about all the medicines you take,</content> including prescription and over-the-counter medicines, vitamins, and herbal supplements. Budesonide rectal foam and other medicines may affect each other causing side effects. Especially tell your healthcare provider if you take another medicine that contains corticosteroids for other conditions, such as allergies or asthma.</paragraph><paragraph>Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">How should I use budesonide rectal foam?</content></paragraph><paragraph><content styleCode="bold">See the &#x201C;Instructions for Use&#x201D; at the end of this Patient Information for detailed information about the right way to use budesonide rectal foam.</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>Use budesonide rectal foam exactly as your healthcare provider tells you to use it. </item><item><caption>&#x2022;</caption><content styleCode="bold">Budesonide rectal foam should only be used rectally (through the anus). Do not</content> take budesonide rectal foam by mouth. </item><item><caption>&#x2022;</caption>Warm the budesonide rectal foam canister by holding it in your hands while shaking it vigorously for 10 to 15 seconds. </item><item><caption>&#x2022;</caption>Budesonide rectal foam is used twice a day for the first 2 weeks of treatment (in the morning and in the evening). After 2 weeks, use budesonide rectal foam 1 time a day in the evening, before bedtime for 4 weeks. </item><item><caption>&#x2022;</caption>If you use too much budesonide rectal foam, call your healthcare provider right away. </item><item><caption>&#x2022;</caption>You should stop using budesonide rectal foam before preparing for a colonoscopy. Call your healthcare provider before restarting budesonide rectal foam after your colonoscopy.</item></list><paragraph><content styleCode="bold">Budesonide rectal foam should only be used rectally (through the anus). Do not</content> take budesonide rectal foam by mouth. </paragraph><paragraph>Warm the budesonide rectal foam canister by holding it in your hands while shaking it vigorously for 10 to 15 seconds. </paragraph><paragraph>Budesonide rectal foam is used twice a day for the first 2 weeks of treatment (in the morning and in the evening). After 2 weeks, use budesonide rectal foam 1 time a day in the evening, before bedtime for 4 weeks. </paragraph><paragraph>If you use too much budesonide rectal foam, call your healthcare provider right away. </paragraph><paragraph>You should stop using budesonide rectal foam before preparing for a colonoscopy.

vening). After 2 weeks, use budesonide rectal foam 1 time a day in the evening, before bedtime for 4 weeks. </paragraph><paragraph>If you use too much budesonide rectal foam, call your healthcare provider right away. </paragraph><paragraph>You should stop using budesonide rectal foam before preparing for a colonoscopy. Call your healthcare provider before restarting budesonide rectal foam after your colonoscopy.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What should I avoid while using budesonide rectal foam?</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>Do not eat grapefruit or drink grapefruit juice while using budesonide rectal foam. Eating grapefruit or drinking grapefruit juice can increase the level of budesonide rectal foam in your blood. </item><item><caption>&#x2022;</caption>Budesonide rectal foam is flammable. Avoid fire, flame and smoking during and right after using budesonide rectal foam.</item></list><paragraph>Budesonide rectal foam is flammable. Avoid fire, flame and smoking during and right after using budesonide rectal foam.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What are the possible side effects of budesonide rectal foam?</content></paragraph><paragraph><content styleCode="bold">Budesonide rectal foam may cause serious side effects, including:</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption><content styleCode="bold">Effects of having too much corticosteroid medicine in your blood (hypercorticism).</content> Long-time use of budesonide rectal foam can cause you to have too much glucocorticosteroid medicine in your blood. Tell your healthcare provider if you have any of the following signs and symptoms of hypercorticism: <list listType="unordered"><item><caption>o</caption>acne </item><item><caption>o</caption>bruise easily </item><item><caption>o</caption>rounding of your face (moon face) </item><item><caption>o</caption>ankle swelling </item><item><caption>o</caption>thicker or more hair on your body and face </item><item><caption>o</caption>a fatty pad or hump between your shoulders (buffalo hump) </item><item><caption>o</caption>pink or purple stretch marks on the skin of your abdomen, thighs, breasts and arms </item></list></item><item><caption>&#x2022;</caption><content styleCode="bold">Adrenal suppression.</content> When budesonide rectal foam is used for a long period of time (chronic use), the adrenal glands may not make enough steroid hormones (adrenal suppression). Tell your healthcare provider if you are under stress or have any symptoms of adrenal suppression during treatment with budesonide rectal foam including: <list listType="unordered"><item><caption>o</caption>tiredness </item><item><caption>o</caption>weakness </item><item><caption>o</caption>nausea </item><item><caption>o</caption>vomiting</item><item><caption>o</caption>low blood pressure</item></list></item><item><caption>&#x2022;</caption><content styleCode="bold">Immune system effects and a higher chance of infections.</content> Budesonide rectal foam may weaken your immune system. Taking medicines that weaken your immune system makes you more likely to get infections.

n>o</caption>low blood pressure</item></list></item><item><caption>&#x2022;</caption><content styleCode="bold">Immune system effects and a higher chance of infections.</content> Budesonide rectal foam may weaken your immune system. Taking medicines that weaken your immune system makes you more likely to get infections. Avoid contact with people who have contagious diseases such as chicken pox or measles while using budesonide rectal foam.</item></list><paragraph>acne </paragraph><paragraph>bruise easily </paragraph><paragraph>rounding of your face (moon face) </paragraph><paragraph>ankle swelling </paragraph><paragraph>thicker or more hair on your body and face </paragraph><paragraph>a fatty pad or hump between your shoulders (buffalo hump) </paragraph><paragraph>pink or purple stretch marks on the skin of your abdomen, thighs, breasts and arms </paragraph><paragraph><content styleCode="bold">Adrenal suppression.</content> When budesonide rectal foam is used for a long period of time (chronic use), the adrenal glands may not make enough steroid hormones (adrenal suppression). Tell your healthcare provider if you are under stress or have any symptoms of adrenal suppression during treatment with budesonide rectal foam including: </paragraph><paragraph>tiredness </paragraph><paragraph>weakness </paragraph><paragraph>nausea </paragraph><paragraph>vomiting</paragraph><paragraph>low blood pressure</paragraph><paragraph><content styleCode="bold">Immune system effects and a higher chance of infections.</content> Budesonide rectal foam may weaken your immune system. Taking medicines that weaken your immune system makes you more likely to get infections. Avoid contact with people who have contagious diseases such as chicken pox or measles while using budesonide rectal foam.</paragraph><paragraph>Tell your healthcare provider about any signs or symptoms of infection during treatment with budesonide rectal foam, including: </paragraph><list listType="unordered"><item><caption> </caption><list listType="unordered"><item><caption>o</caption>fever </item><item><caption>o</caption>chills </item><item><caption>o</caption>aches </item><item><caption>o</caption>feeling tired </item><item><caption>o</caption>pain </item><item><caption>o</caption>nausea or vomiting</item></list></item><item><caption>&#x2022;</caption><content styleCode="bold">Worsening of allergies.</content> If you take certain other corticosteroid medicines to treat allergies, switching to budesonide rectal foam may cause your allergies to come back. These allergies may include eczema (a skin disease) or inflammation inside your nose (rhinitis). Tell your healthcare provider if any of your allergies become worse while using budesonide rectal foam.</item></list><paragraph>fever </paragraph><paragraph>chills </paragraph><paragraph>aches </paragraph><paragraph>feeling tired </paragraph><paragraph>pain </paragraph><paragraph>nausea or vomiting</paragraph><paragraph><content styleCode="bold">Worsening of allergies.</content> If you take certain other corticosteroid medicines to treat allergies, switching to budesonide rectal foam may cause your allergies to come back. These allergies may include eczema (a skin disease) or inflammation inside your nose (rhinitis).

agraph><paragraph><content styleCode="bold">Worsening of allergies.</content> If you take certain other corticosteroid medicines to treat allergies, switching to budesonide rectal foam may cause your allergies to come back. These allergies may include eczema (a skin disease) or inflammation inside your nose (rhinitis). Tell your healthcare provider if any of your allergies become worse while using budesonide rectal foam.</paragraph><paragraph>The most common side effects of budesonide rectal foam include:</paragraph><list listType="unordered"><item><caption>&#x2022;</caption>decreased blood cortisol levels </item><item><caption>&#x2022;</caption>adrenal insufficiency </item><item><caption>&#x2022;</caption>nausea</item></list><paragraph>adrenal insufficiency </paragraph><paragraph>nausea</paragraph><paragraph>Tell your healthcare provider if you have any side effect that bothers you or that does not go away.</paragraph><paragraph>These are not all the possible side effects of budesonide rectal foam. For more information, ask your healthcare provider or pharmacist.</paragraph><paragraph>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">How should I store budesonide rectal foam?</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>Store budesonide rectal foam at room temperature, between 68&#xB0;F to 77&#xB0;F (20&#xB0;C to 25&#xB0;C). </item><item><caption>&#x2022;</caption>Do not store the budesonide rectal foam container near heat or store at temperatures above 120&#xB0;F (49&#xB0;C). </item><item><caption>&#x2022;</caption>Do not puncture or burn the budesonide rectal foam canister. </item><item><caption>&#x2022;</caption>Do not refrigerate.</item></list><paragraph>Do not store the budesonide rectal foam container near heat or store at temperatures above 120&#xB0;F (49&#xB0;C). </paragraph><paragraph>Do not puncture or burn the budesonide rectal foam canister. </paragraph><paragraph>Do not refrigerate.</paragraph><paragraph><content styleCode="bold">Keep budesonide rectal foam and all medicines out of the reach of children.</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">General information about the safe and effective use of budesonide rectal foam.</content></paragraph><paragraph>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use budesonide rectal foam for a condition for which it was not prescribed. Do not give budesonide rectal foam to other people, even if they have the same symptoms you have. It may harm them.</paragraph><paragraph>This Patient Information leaflet summarizes the most important information about budesonide rectal foam. If you would like more information, talk with your healthcare provider.

ibed. Do not give budesonide rectal foam to other people, even if they have the same symptoms you have. It may harm them.</paragraph><paragraph>This Patient Information leaflet summarizes the most important information about budesonide rectal foam. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about budesonide rectal foam that is written for health professionals.</paragraph><paragraph>For more information, go to <content styleCode="bold">www.padagis.com</content></paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">What are the ingredients in budesonide rectal foam?</content></paragraph><paragraph><content styleCode="bold">Active ingredient:</content> budesonide</paragraph><paragraph><content styleCode="bold">Inactive ingredients:</content> cetyl alcohol, citric acid monohydrate, edetate disodium, emulsifying wax, polyoxyl (10) stearyl ether, propylene glycol, and purified water</paragraph><paragraph><content styleCode="bold">Propellant:</content> n-butane, isobutane, and propane</paragraph><paragraph>Manufactured by Padagis, Yeruham 8050315, Israel</paragraph><paragraph>Distributed By Padagis, Allegan, MI 49010</paragraph><paragraph>www.padagis.com</paragraph></td></tr></tbody></table>