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 tablets 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.

3 DOSAGE FORMS AND STRENGTHS Mesalamine delayed-release tablets, USP: 800 mg (red to dark red, modified oval, film-coated, biconvex, unscored tablets printed with AN360 in black ink on one side and plain on the other side). Delayed-release tablets: 800 mg (3)

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)

5 WARNINGS AND PRECAUTIONS Renal Impairment : Assess renal function at the beginning to 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 : Consider the iron content of mesalamine delayed-release 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 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, and hematologic abnormalities. Evaluate patients immediately if signs or symptoms of a hypersensitivity reaction are present. Discontinue mesalamine delayed-release if an alternative etiology for the signs or symptoms cannot be established. 5.4 Hepatic Failure There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered mesalamine. Evaluate the risks and benefits of using mesalamine delayed-release in patients with known liver impairment. 5.5 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported with use of mesalamine [see Adverse Reactions (6.2)] . Discontinue mesalamine delayed-release at the first appearance of signs or symptoms of severe cutaneous adverse reactions, or other signs of hypersensitivity and consider further evaluation. 5.6 Photosensitivity Patients treated with mesalamine or sulfasalazine who have pre-existing skin conditions such as atopic dermatitis and atopic eczema have reported more severe photosensitivity reactions. Advise patients to avoid sun exposure, wear protective clothing, and use a broad-spectrum sunscreen when outdoors. 5.7 Nephrolithiasis Cases of nephrolithiasis have been reported with the use of mesalamine, including stones of 100% mesalamine content. Mesalamine-containing stones are radiotransparent and undetectable by standard radiography or computed tomography (CT). Ensure adequate fluid intake during treatment with mesalamine delayed-release. 5.8 Iron Content of Mesalamine Delayed-Release Mesalamine delayed-release contains iron oxide as a colorant in the coating of the delayed-release tablets. Each 800 mg delayed-release tablet contains 0.72 mg of iron. The total content of iron is 4.3 mg at the recommended daily dosage [see Dosage and Administration (2.2) ] . Before prescribing mesalamine delayed-release to patients receiving iron supplementation or those at risk for developing iron overload, consider the combined daily amount of iron from all sources, including mesalamine delayed-release. 5.9 Interference with Laboratory Tests Use of mesalamine delayed-release may lead to spuriously elevated test results when measuring urinary normetanephrine by liquid chromatography with electrochemical detection because of the similarity in the chromatograms of normetanephrine and the main metabolite of mesalamine, N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA). Consider an alternative, selective assay for normetanephrine.

6 ADVERSE REACTIONS The following serious or clinically significant adverse reactions 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 Amneal Pharmaceuticals at 1-877-835-5472 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 800 mg tablets have been evaluated in 896 patients with ulcerative colitis in controlled studies. Three six-week, active-controlled studies were conducted comparing mesalamine delayed-release 800 mg tablets 4.8 grams per day with mesalamine delayed-release tablets 400 mg 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 800 mg tablet 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 800 mg 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 800 mg tablet group and in 4.2% of patients in the mesalamine delayed-release 400 mg 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 800 mg tablet 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) ] , pericardial effusion, vasodilation, migraine. Endocrine : Nephrogenic diabetes insipidus. Gastrointestinal : Dry mouth, stomatitis, oral ulcers, anorexia, increased appetite, eructation, pancreatitis, cholecystitis, gastritis, gastroenteritis, gastrointestinal bleeding, perforated peptic ulcer (rare), constipation, hemorrhoids, rectal hemorrhage, bloody diarrhea, tenesmus, stool abnormality. Hepatic : There have been rare reports of hepatotoxicity, including jaundice, cholestatic jaundice, hepatitis, and possible hepatocellular damage including liver necrosis and liver failure. Some of these cases were fatal. Asymptomatic elevations of liver enzymes which usually resolve during continued use or with discontinuation of the drug have also been reported. One case of Kawasaki-like syndrome, that included changes in liver enzymes, was also reported [see Warnings and Precautions (5.4) ]. Hematologic : Agranulocytosis (rare), aplastic anemia (rare), anemia, thrombocytopenia, leukopenia, eosinophilia, lymphadenopathy. Musculoskeletal : Gout, rheumatoid arthritis, arthritis, arthralgia, joint disorder, myalgia, hypertonia. Neurological/Psychiatric : Anxiety, depression, somnolence, insomnia, nervousness, confusion, emotional lability, dizziness, vertigo, tremor, paresthesia, hyperesthesia, peripheral neuropathy (rare), Guillain-Barré syndrome (rare), transverse myelitis (rare), and intracranial hypertension. Respiratory/Pulmonary : Sinusitis, rhinitis, pharyngitis, asthma exacerbation, pleuritis/pleurisy, bronchitis, eosinophilic pneumonia, interstitial pneumonitis. Skin : Alopecia, psoriasis (rare), pyoderma gangrenosum (rare), erythema nodosum, acne, dry skin, sweating, pruritus, urticaria, rash, SJS/TEN, DRESS, and AGEP [see Warnings and Precautions (5.5) ] . Special Senses : Ear pain, tinnitus, ear congestion, ear disorder, conjunctivitis, eye pain, blurred vision, vision abnormality, taste perversion. Renal/Urogenital : Renal failure (rare), interstitial nephritis, minimal change disease, nephrolithiasis [see Warnings and Precautions (5.1, 5.7) ] , dysuria, urinary frequency and urgency, hematuria, epididymitis, decreased libido, dysmenorrhea, menorrhagia. Urine discoloration occurring ex-vivo caused by contact of mesalamine, including inactive metabolite, with surfaces or water treated with hypochlorite containing bleach. Laboratory Abnormalities : Elevated AST (SGOT) or ALT (SGPT), elevated alkaline phosphatase, elevated GGT, elevated LDH, elevated bilirubin, elevated serum creatinine and BUN.

16 HOW SUPPLIED/STORAGE AND HANDLING Mesalamine delayed-release tablets, USP 800 mg are available as red to dark red, modified oval, film-coated, biconvex, unscored tablets printed with AN360 in black ink on one side and plain on the other side. They are supplied as follows: Bottles of 180 tablets with child-resistant closure: NDC 65162-360-18 Protect from moisture. Tablets can be dispensed without desiccant for up to 6 weeks. Store at 20° to 25° C (68° to 77° F); excursions permitted between 15° to 30° C (59° to 86° F) [see USP Controlled Room Temperature]