Mesalamine

Warnings and Precautions Renal impairment

1 INDICATIONS AND USAGE Mesalamine delayed-release capsules are an aminosalicylate indicated for: Treatment of mildly to moderately active ulcerative colitis in patients 5 years of age and older. ( 1.1 ) Maintenance of remission of ulcerative colitis in adults. ( 1.2 ) 1.1 Treatment of Mildly to Moderately Active Ulcerative Colitis Mesalamine delayed-release capsules are indicated for the treatment of mildly to moderately active ulcerative colitis in patients 5 years of age and older. 1.2 Maintenance of Remission of Ulcerative Colitis Mesalamine delayed-release capsules are indicated for the maintenance of remission of ulcerative colitis in adults.

2 DOSAGE AND ADMINISTRATION Important Administration Instructions : Do not substitute two mesalamine delayed-release 400 mg capsules with one mesalamine delayed-release 800 mg tablet. ( 2.1 ) Evaluate renal function prior to initiation of mesalamine delayed-release capsules. ( 2.1 , 5.1 ) Take with or without food. ( 2.1 ) Swallow the capsules whole; do not cut, break, crush or chew. ( 2.1 ) For patients who are unable to swallow the capsules, the capsules can be opened and the inner tablets swallowed. ( 2.1 ) Drink an adequate amount of fluids. ( 2.1 , 5.7 ) Treatment of Mildly to Moderately Active Ulcerative Colitis: Adults: 800 mg (two 400 mg capsules) three times daily for 6 weeks. Pediatric Patients 5 years or older: See weight-based dosing table in the full prescribing information; twice daily dosing for 6 weeks. ( 2.2 ) Maintenance of Remission of Ulcerative Colitis: Adults: 1.6 grams (four 400 mg capsules) daily, in two to four divided doses. ( 2.3 ) 2.1 Important Administration Instructions Do not substitute two mesalamine delayed-release 400 mg capsules with one mesalamine delayed-release 800 mg tablet. Evaluate renal function prior to initiation of mesalamine delayed-release capsules. Take mesalamine delayed-release capsules with or without food. Swallow the capsules whole; do not cut, break, crush or chew the capsules. For patients who are unable to swallow the capsules whole, carefully open the capsule(s) and swallow the contents (four 100 mg tablets). Open the number of capsules required to make up a complete dose [see Dosage and Administration ( 2.2 , 2.3 )] . There are 4 tablets per capsule. Ensure all tablets per capsule are swallowed and no tablets are retained in the mouth. Swallow the tablets whole; do not cut, break, crush or chew the tablets. Drink an adequate amount of fluids [see Warnings and Precautions ( 5.7 )] . Intact, partially intact, and/or tablet shells have been reported in the stool; Instruct patients to contact their healthcare provider if this occurs repeatedly. Protect mesalamine delayed-release capsules from moisture. Close the container tightly and leave any desiccant pouches present in the bottle along with the capsules. 2.2 Dosage for Treatment of Mildly to Moderately Active Ulcerative Colitis Adults For adults, the recommended dosage of mesalamine delayed-release capsules is 800 mg (two 400 mg capsules) three times daily (total daily dosage of 2.4 grams) for a duration of 6 weeks [see Clinical Studies ( 14.1 )] . Pediatrics For pediatric patients 5 years of age and older, the recommended total daily dosage of mesalamine delayed-release capsules is weight-based (up to maximum of 2.4 grams per day) divided into two daily doses for a duration of 6 weeks (see Table 1). Table 1. Pediatric Dosage by Weight Weight Group (kg) Daily Dosage (mg/kg/day) Maximum Daily Dosage (grams per day) Morning Dosage Afternoon Dosage 17 to 32 36 to 71 1.2 two 400 mg capsules one 400 mg capsules 33 to 53 37 to 61 2 three 400 mg capsules two 400 mg capsules 54 to 90 27 to 44 2.4 three 400 mg capsules three 400 mg capsules 2.3 Dosage for Maintenance of Remission of Ulcerative Colitis The recommended dosage of mesalamine delayed-release capsules in adults is 1.6 grams (four 400 mg capsules) daily in two to four divided doses.

3 DOSAGE FORMS AND STRENGTHS Mesalamine delayed-release capsules are clear capsules imprinted with “TEVA” and “5907” on both the cap and the body in black ink. Each capsule contains four reddish-brown, film-coated round 100 mg mesalamine tablets. Delayed-release capsules (containing four 100 mg tablets): 400 mg ( 3 )

4 CONTRAINDICATIONS Mesalamine delayed-release capsules are contraindicated in patients with known or suspected hypersensitivity to salicylates or aminosalicylates or to any of the ingredients of mesalamine delayed-release capsules [see Warnings and Precautions ( 5.3 ), Adverse Reactions ( 6.2 ), Description ( 11 )] . Known or suspected hypersensitivity to salicylates or aminosalicylates or to any of the ingredients of mesalamine delayed-release capsules. ( 4 , 5.3 )

6 ADVERSE REACTIONS The most serious adverse reactions seen in mesalamine clinical trials or with other products that contain or are metabolized to mesalamine are: Renal Impairment [see Warnings and Precautions ( 5.1 )] Mesalamine-Induced Acute Intolerance Syndrome [see Warnings and Precautions ( 5.2 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.3 )] Hepatic Failure [see Warnings and Precautions ( 5.4 )] Severe Cutaneous Adverse Reactions [see Warnings and Precautions ( 5.5 )] Photosensitivity [see Warnings and Precautions ( 5.6 )] Nephrolithiasis [see Warnings and Precautions ( 5.7 )] The most common adverse reactions (≥5%) are: Adults: eructation, abdominal pain, constipation, dizziness, rhinitis, back pain, and rash. ( 6.1 ) Pediatrics: nasopharyngitis, headache, abdominal pain, dizziness, sinusitis, rash, cough and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 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 mesalamine has been established based on adequate and well-controlled studies of mesalamine delayed-release tablets. In total, mesalamine delayed-release 400 mg tablets have been evaluated in 2690 patients with ulcerative colitis in controlled and open-label trials. Below is a description of the adverse reactions of mesalamine delayed-release tablets in these adequate and well-controlled studies. Clinical studies supporting mesalamine delayed-release tablets use for the treatment of mildly to moderately active ulcerative colitis included two 6-week, placebo-controlled, randomized, double-blind studies in adults with mildly to moderately active ulcerative colitis (Studies 1 and 2), and one 6-week, randomized, double-blind, study of 2 dosage levels in children with mildly to moderately active ulcerative colitis (Study 3). Clinical studies supporting the use of mesalamine delayed-release tablets in the maintenance of remission of ulcerative colitis included a 6-month, randomized, double-blind, placebo-controlled, multi-center study (Study 4) and four active-controlled maintenance trials comparing mesalamine delayed-release with sulfasalazine. Mesalamine delayed-release tablets have been evaluated in 427 adults and 107 children with ulcerative colitis in these controlled studies. Treatment of Mildly to Moderately Active Ulcerative Colitis Adults In a 6-week placebo-controlled clinical study (Study 1) involving 105 patients, 53 of whom were randomized to mesalamine delayed-release tablets 2.4 grams per day [see Clinical Studies ( 14.1 )], 4% of the mesalamine delayed release tablets-treated patients in 2.4 grams per day group discontinued therapy because of adverse reactions as compared to 0% of the placebo-treated patients. The average age of patients was 41 years and 49% of patients were male. Adverse reactions leading to withdrawal from mesalamine delayed-release tablets included (each in one patient): diarrhea and colitis flare; dizziness, nausea, joint pain, and headache. The most common adverse reactions in patients treated with mesalamine delayed release tablets 2.4 grams per day in Study 1 are listed in Table 2 below. Table 2. Most Common Adverse Reactions Reported in Study 1 for the Treatment of Mild to Moderate Ulcerative Colitis in Adults* Adverse Reaction % of Patients with Adverse Reactions Mesalamine Delayed-Release 2.4 grams per day Placebo (n = 53) (n = 52) Eructation 26 19 Abdominal pain 21 12 Constipation 11 0 Dizziness 9 8 Rhinitis 8 6 Back pain 6 4 Rash 6 4 Dyspepsia 4 0 Flu syndrome 4 2 * At Least 2% of Patients in the Mesalamine Delayed-Release Tablets Group and at a Rate Greater than Placebo Pediatric Patients 5 to 17 Years Old A randomiz …

7 DRUG INTERACTIONS Nephrotoxic Agents including NSAIDs: Increased risk of nephrotoxicity; monitor for changes in renal function and mesalamine-related adverse reactions. ( 7.1 ) Azathioprine or 6-Mercaptopurine: Increased risk of blood disorders; monitor complete blood cell counts and platelet counts. ( 7.2 ) 7.1 Nephrotoxic Agents, Including Non-Steroidal Anti-Inflammatory Drugs The concurrent use of mesalamine with known nephrotoxic agents, including non-steroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity. Monitor patients taking nephrotoxic drugs for changes in renal function and mesalamine-related adverse reactions [see Warnings and Precautions ( 5.1 )] . 7.2 Azathioprine or 6-Mercaptopurine The concurrent use of mesalamine with azathioprine or 6-mercaptopurine and/or other drugs known to cause myelotoxicity may increase the risk for blood disorders, bone marrow failure, and associated complications. If concomitant use of mesalamine delayed-release capsules and azathioprine or 6-mercaptopurine cannot be avoided, monitor blood tests, including complete blood cell counts and platelet counts. 7.3 Interference With Urinary Normetanephrine Measurements Use of mesalamine delayed-release capsules may lead to spuriously elevated test results when measuring urinary normetanephrine by liquid chromatography with electrochemical detection [see Warnings and Precautions ( 5.9 )] . Consider an alternative, selective assay for normetanephrine.

8 USE IN SPECIFIC POPULATIONS Geriatric Patients: Increased risk of blood dyscrasias; monitor complete blood cell counts and platelet counts. ( 8.5 ) 8.1 Pregnancy Risk Summary There are no adequate and well controlled studies of mesalamine use in pregnant women. Limited published human data on mesalamine show no increase in the overall rate of congenital malformations. Some data show an increased rate of preterm birth, stillbirth, and low birth weight; however, these adverse pregnancy outcomes are also associated with active inflammatory bowel disease. Furthermore, all pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major malformations, and 15% to 20% for pregnancy loss. No evidence of fetal harm was observed in animal reproduction studies of mesalamine in rats and rabbits at oral doses approximately 1.9 times (rat) and 3.9 times (rabbit) the recommended human dose. Mesalamine should be used during pregnancy only if clearly needed. Human Data Mesalamine crosses the placenta. In prospective and retrospective studies of over 600 women exposed to mesalamine during pregnancy, the observed rate of congenital malformations was not increased above the background rate in the general population. Some data show an increased rate of preterm birth, stillbirth, and low birth weight, but it is unclear whether this was due to underlying maternal disease, drug exposure, or both, as active inflammatory bowel disease is also associated with adverse pregnancy outcomes. Animal data Reproduction studies with mesalamine were performed during organogenesis in rats and rabbits at oral doses up to 480 mg/kg/day. There was no evidence of impaired fertility or harm to the fetus. These mesalamine doses were about 1.9 times (rat) and 3.9 times (rabbit) the recommended human dose, based on body surface area. 8.2 Lactation Mesalamine and its N-acetyl metabolite are present in human milk. In published lactation studies, maternal mesalamine doses from various oral and rectal formulations and products ranged from 500 mg to 3 g daily. The concentration of mesalamine in milk ranged from non-detectable to 0.11 mg/L. The concentration of the N-acetyl-5-aminosalicylic acid metabolite ranged from 5 mg/L to 18.1 mg/L. Based on these concentrations, estimated infant daily doses for an exclusively breastfed infant are 0 mg/kg/day to 0.017 mg/kg/day of mesalamine and 0.75 mg/kg/day to 2.72 mg/kg/day of N-acetyl-5-aminosalicylic acid. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for mesalamine and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition. Caution should be exercised when mesalamine delayed-release capsules are administered to a nursing woman. 8.4 Pediatric Use The safety and effectiveness of mesalamine delayed-release capsules for the treatment of mildly to moderately active ulcerative colitis in pediatric patients 5 to 17 years of age has been established based on adequate and well-controlled studies using mesalamine delayed-release 400 mg tablets. Use of mesalamine delayed-release capsules in these pediatric age groups is supported by evidence from adequate and well controlled studies of mesalamine delayed-release 400 mg tablets in adults and a single 6-week study in 82 pediatric patients 5 to 17 years of age [see Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14.1 )] . The safety and effectiveness of mesalamine delayed-release capsules for the treatment of mildly to moderately active ulcerative colitis in pediatric patients below the age of 5 years have not been established. The safety and effectiveness of mesalamine delayed-release capsules in the maintenance of remission of ulcerative colitis in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of mesalamine delayed-release tablets did not include sufficient numbers of patients aged 65 y …

12.1 Mechanism of Action The mechanism of action of mesalamine is not fully understood, but appears to be a topical anti-inflammatory effect on colonic epithelial cells. Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase pathways, that is, prostanoids, and through the lipoxygenase pathways, that is, leukotrienes and hydroxyeicosatetraenoic acids, is increased in patients with ulcerative colitis, and it is possible that mesalamine diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin production in the colon.

11 DESCRIPTION Each Mesalamine delayed-release capsule for oral administration contains four 100 mg tablets of mesalamine, USP an aminosalicylate. Mesalamine delayed-release capsules contain acrylic based resin, methacrylic acid copolymer (Eudragit S), which dissolves at pH 7 or greater and releases mesalamine in the terminal ileum and beyond for topical anti-inflammatory action in the colon. Mesalamine, USP (also referred to as 5-aminosalicylic acid or 5-ASA) has the chemical name 5-amino-2-hydroxybenzoic acid. Its structural formula is: C 7 H 7 NO 3 M.W. 153.14 Inactive Ingredients: Each capsule contains colloidal silicon dioxide, dibutyl sebacate, hypromellose, iron oxide black, iron oxide red, lactose monohydrate, magnesium stearate, methacrylic acid copolymer, polyethylene glycol, potassium hydroxide, povidone, propylene glycol, shellac, sodium starch glycolate (potato), strong ammonia solution and talc. 1

10 OVERDOSAGE Mesalamine delayed-release capsules is an aminosalicylate, and symptoms of salicylate toxicity include nausea, vomiting and abdominal pain, tachypnea, hyperpnea, tinnitus, and neurologic symptoms (headache, dizziness, confusion, seizures). Severe salicylate intoxication may lead to electrolyte and blood pH imbalance and potentially to other organ (e.g., renal and liver) involvement. There is no specific antidote for mesalamine overdose; however, conventional therapy for salicylate toxicity may be beneficial in the event of acute overdosage and may include gastrointestinal tract decontamination to prevent of further absorption. Correct fluid and electrolyte imbalance by the administration of appropriate intravenous therapy and maintain adequate renal function. Mesalamine delayed-release capsules is a pH dependent delayed-release product and this factor should be considered when treating a suspected overdose.

16 HOW SUPPLIED/STORAGE AND HANDLING Mesalamine delayed-release capsules are available as clear capsules imprinted with “TEVA” and “5907” on both the cap and the body in black ink. Each capsule contains four reddish-brown, film-coated round 100 mg mesalamine tablets. NDC 0093-5907-86 Bottle of 180 capsules Store at 20o to 25oC (68o to 77oF) [see USP Controlled Room Temperature].