Mesalamine

1 INDICATIONS AND USAGE Mesalamine delayed-release tablets are indicated for the treatment of moderately active ulcerative colitis in adults. Limitations of Use : Safety and effectiveness of mesalamine delayed-release tablets beyond 6 weeks have not been established. Mesalamine delayed-release tablets are an aminosalicylate indicated for the treatment of moderately active ulcerative colitis in adults. ( 1 ) Limitation of Use : Safety and effectiveness of mesalamine delayed-release tablets beyond 6 weeks have not been established ( 1 )

2 DOSAGE AND ADMINISTRATION Important Administration Instructions : Do not substitute one mesalamine delayed-release 800 mg tablet for two mesalamine delayed-release 400 mg oral products. ( 2.1 ) Evaluate renal function prior to initiation of mesalamine delayed-release tablets. ( 2.1 , 5.1 ) Take on an empty stomach, at least 1 hour before and 2 hours after a meal. ( 2.1 ) Swallow whole; do not cut, break or chew the tablets. ( 2.1 ) Drink an adequate amount of fluids. ( 2.1 , 5.7 ) Treatment of Moderately Active Ulcerative Colitis : Recommended dosage is 1,600 mg (two 800 mg tablets) three times daily for 6 weeks. ( 2.2 ) 2.1 Important Administration Instructions Do not substitute one mesalamine delayed-release 800 mg tablet for two mesalamine delayed-release 400 mg oral products [see Clinical Pharmacology ( 12.3 )] . Evaluate renal function prior to initiation of mesalamine delayed-release tablets. Take mesalamine delayed-release tablets on an empty stomach, at least 1 hour before and 2 hours after a meal [see Clinical Pharmacology ( 12.3 )] . Swallow mesalamine delayed-release tablets whole. Do not cut, break 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 tablets from moisture. 2.2 Dosage Information For the treatment of moderately active ulcerative colitis, the recommended dosage of mesalamine delayed-release tablets in adults is 1,600 mg (two 800 mg tablets) three times daily (total daily dosage of 4.8 grams) for a duration of 6 weeks.

5 WARNINGS AND PRECAUTIONS Renal Impairment : Assess renal function at the beginning of treatment and periodically during treatment. Evaluate the risks and benefits in patients with known renal impairment or taking nephrotoxic drugs; monitor renal function. Discontinue mesalamine delayed-release if renal function deteriorates. ( 5.1 , 7.1 , 8.6 ) Mesalamine-induced Acute Intolerance Syndrome : Symptoms may be difficult to distinguish from an ulcerative colitis exacerbation; monitor for worsening symptoms; discontinue if acute intolerance syndrome suspected. ( 5.2 ) Hypersensitivity Reactions, including Myocarditis and Pericarditis : Evaluate patients immediately and discontinue if a hypersensitivity reaction is suspected. ( 5.3) Hepatic Failure : Evaluate the risks and benefits in patients with known liver impairment. ( 5.4 ) Severe Cutaneous Adverse Reactions : Discontinue at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation. ( 5.5 ) Photosensitivity : Advise patients with pre-existing skin conditions to avoid sun exposure, wear protective clothing, and use a broad-spectrum sunscreen when outdoors. ( 5.6 ) Nephrolithiasis: Mesalamine-containing stones are undetectable by standard radiography or computed tomography (CT). Ensure adequate hydration during treatment. ( 5.7 ) Iron Content of Mesalamine Delayed-Release Tablets : Consider the iron content of mesalamine delayed-release tablets in patients taking iron supplementation and those at risk of iron overload. ( 5.8 ) Interference with Laboratory Tests : Use of mesalamine may lead to spuriously elevated test results when measuring urinary normetanephrine by liquid chromatography with electrochemical detection. ( 5.9 ) 5.1 Renal Impairment Renal impairment, including minimal change disease, acute and chronic interstitial nephritis, and, rarely, renal failure, has been reported in patients taking products such as mesalamine delayed-release tablets that contain or are converted to mesalamine [see Adverse Reactions ( 6.2 )] . In animal studies, the kidney was the principal organ of mesalamine toxicity [see Adverse Reactions ( 6.2 ), Nonclinical Toxicology ( 13.2 )] . Evaluate renal function prior to initiation of mesalamine delayed-release and periodically while on therapy. Evaluate the risks and benefits of using mesalamine delayed-release in patients with known renal impairment or history of renal disease or taking concomitant nephrotoxic drugs. Discontinue mesalamine delayed-release if renal function deteriorates while on therapy [see Drug Interactions ( 7.1 ), Use in Specific Populations ( 8.6 )] . 5.2 Mesalamine-Induced Acute Intolerance Syndrome Mesalamine has been associated with an acute intolerance syndrome that may be difficult to distinguish from an exacerbation of ulcerative colitis. Exacerbation of the symptoms of colitis has been reported in 2.3% of mesalamine delayed-release-treated patients in controlled clinical trials. This acute reaction, characterized by cramping, abdominal pain, bloody diarrhea, and occasionally by fever, headache, malaise, pruritus, rash, and conjunctivitis, has been reported after the initiation of mesalamine delayed-release tablets as well as other mesalamine products. Symptoms usually abate when mesalamine delayed-release tablets are discontinued. Monitor patients for worsening of these symptoms while on treatment. If acute intolerance syndrome is suspected, promptly discontinue treatment with mesalamine delayed-release. 5.3 Hypersensitivity Reactions Hypersensitivity reactions have been reported in patients taking sulfasalazine. Some patients may have a similar reaction to mesalamine delayed-release tablets or to other compounds that contain or are converted to mesalamine. As with sulfasalazine, mesalamine-induced hypersensitivity reactions may present as internal organ involvement, including myocarditis, pericarditis, nephritis, hepatitis, pneumonitis, an…

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

7 DRUG INTERACTIONS Nephrotoxic Agents including NSAIDs : Increased risk of nephrotoxicity; monitor for changes in renal function and mesalamine­related 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 nonsteroidal 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 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 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.

8.1 Pregnancy Risk Summary Limited published data on mesalamine use in pregnant women are insufficient to inform a drug-associated risk. No fetal harm was observed in animal reproduction studies of mesalamine in rats and rabbits at oral doses approximately 0.97 times (rat) and 1.95 times (rabbit) the recommended human dose ( see Data) . The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data 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 harm to the fetus. These mesalamine doses were about 0.97 times (rat) and 1.95 times (rabbit) the recommended human dose of 4.8 grams per day, based on body surface area.

6 ADVERSE REACTIONS The following serious or clinically significant adverse described elsewhere in labeling 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 (≥2%) are headache, nausea, nasopharyngitis, abdominal pain, and worsening of ulcerative colitis ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993 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. Mesalamine delayed-release has been evaluated in 896 patients with ulcerative colitis in controlled studies. Three six-week, active-controlled studies were conducted comparing mesalamine delayed-release 4.8 grams per day with mesalamine-delayed release tablets 2.4 grams per day in patients with mildly to moderately active ulcerative colitis. In these studies, 727 patients were dosed with mesalamine delayed-release (800 mg) tablets and 732 patients were dosed with mesalamine delayed-release (400 mg) tablets. The most common reactions reported in the mesalamine delayed-release group were headache (4.7%), nausea (2.8%), nasopharyngitis (2.5%), abdominal pain (2.3%), diarrhea (1.7%), and dyspepsia (1.7%); Table 1 enumerates adverse reactions that occurred in the three studies. The most common reactions in patients with moderately active ulcerative colitis (602 patients dosed with mesalamine delayed-release and 618 patients dosed with mesalamine delayed-release 400 mg) were the same as all treated patients. Discontinuations due to adverse reactions occurred in 3.9% of patients in the mesalamine delayed-release group and in 4.2% of patients in the mesalamine delayed-release tablet comparator group. The most common cause for discontinuation was gastrointestinal symptoms associated with ulcerative colitis. Serious adverse reactions occurred in 0.8% of patients in the mesalamine delayed-release group and in 1.8% of patients in the mesalamine delayed-release tablet comparator group. The majority involved the gastrointestinal system. Table 1. Adverse Reactions Occurring in ≥1% of All Treated Patients (Three studies combined) Adverse Reaction Mesalamine delayed-release 2.4 grams per day (400 mg Tablet) (N = 732) Mesalamine delayed-release 4.8 grams per day (800 mg Tablet) (N = 727) Headache 4.9 % 4.7 % Nausea 2.9 % 2.8 % Nasopharyngitis 1.4 % 2.5 % Abdominal pain 2.3 % 2.3 % Diarrhea 1.9 % 1.7 % Dyspepsia 0.8 % 1.7 % Vomiting 1.6 % 1.4 % Flatulence 0.7 % 1.2 % Influenza 1.2 % 1.0 % Pyrexia 1.2 % 0.7 % Cough 1.4 % 0.3 % N = number of patients within specified treatment group Percent = percentage of patients in category and treatment group 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of mesalamine delayed-release or other mesalamine-containing products or products that are metabolized to mesalamine. 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. Body as a Whole : Facial edema, edema, peripheral edema, asthenia, chills, infection, malaise, pain, neck pain, chest pain, back pain, abdominal enlargement, lupus-like syndrome, drug fever (rare). Cardiovascular : Pericarditis (rare) and myocarditis (rare) [see Warnings and Precautions ( 5.3…