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.

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.

12.3 Pharmacokinetics Absorption Plasma concentrations of mesalamine (5-aminosalicylic acid; 5-ASA) and its metabolite, N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA) are highly variable following administration of mesalamine delayed-release tablets. Following single dose oral administration of mesalamine delayed-release 800 mg tablet in healthy subjects (N = 139) under fasted conditions, the mean C max , AUC 8-48h and AUC 0-tldc values were 208 ng/mL, 2,296 ng.h/mL, and 2533 ng.h/mL, respectively. The median [range] T max for mesalamine following administration of mesalamine delayed-release 800 mg tablet was approximately 24 hours [4 hours to 72 hours], reflecting the delayed-release characteristics of the formulation. Based on cumulative urinary recovery of mesalamine and N-Ac-5-ASA from single dose studies in healthy subjects, approximately 20% of the orally administered mesalamine in mesalamine delayed-release tablets is systemically absorbed. Food Effect: A high calorie (800 to 1,000 calories), high fat (approximately 50 % of total caloric content) meal increased mesalamine C max by 2.4-fold and mesalamine systemic exposure (AUC 8-48 and AUC 0-tldc ) by 2.8-fold; the median lag-time increased by 8 hours and median t max by 6 hours (from 24 hours to 30 hours) [see Dosage and Administration (2.1) ] . Comparative exposure between one mesalamine delayed-release 800 mg tablet and two mesalamine delayed-release 400 mg oral products is unknown [see Dosage and Administration (2.1) ] . Elimination Metabolism The absorbed mesalamine is acetylated in the gut mucosal wall and by the liver to N-Ac-5-ASA. Excretion Absorbed mesalamine is excreted mainly by the kidneys as N-acetyl-5-aminosalicylic acid. Unabsorbed mesalamine is excreted in feces.