budesonide

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). 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 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 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 Experienced by ≥ 2% of the budesonide rectal foam or Placebo group and at higher frequency in the budesonide rectal foam group. (Studies 1 and 2) Adverse Reaction Budesonide Rectal Foam 2 mg/25 mL N=268 n (%) Placebo N=278 n (%) Decreased blood cortisol Decreased blood cortisol was defined as a morning cortisol level of <5 mcg/dL. 46 (17) 6 (2) Adrenal insufficiency Adrenal insufficiency was defined as a cortisol level of <18 mcg/dL at 30 minutes post-challenge with ACTH. 10 (4) 2 (1) Nausea 6 (2) 2 (1) 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). 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) 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. 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 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 ID="_RefID0EFOAC" width="98.04%"><caption>Table 1: Summary of Adverse Reactions in 2 Placebo-Controlled Trials<footnote ID="_Ref106190145">Experienced by &#x2265; 2% of the budesonide rectal foam or Placebo group and at higher frequency in the budesonide rectal foam group.</footnote> (Studies 1 and 2)</caption><col width="33%"/><col width="34%"/><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> <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<footnote ID="_Ref106190253">Decreased blood cortisol was defined as a morning cortisol level of &lt;5 mcg/dL.</footnote></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<footnote ID="_Ref106190272">Adrenal insufficiency was defined as a cortisol level of &lt;18 mcg/dL at 30 minutes post-challenge with ACTH.</footnote></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>

<table ID="_RefID0ELBAE" width="99.02%"><caption>Table 2: Summary of Glucocorticoid Related Effects in Two Placebo-Controlled Trials (Studies 1 and 2)</caption><col width="33%"/><col width="34%"/><col width="34%"/><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> <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)<footnote ID="_Ref106190377">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.</footnote></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>