6 ADVERSE REACTIONS The most serious adverse reactions seen in DELZICOL 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) ] The most common adverse reactions (≥5%) are A dults : eructation, abdominal pain, constipation, dizziness, rhinitis, back pain, and rash (6.1) P ediatric s : nasopharyngitis, headache, abdominal pain, dizziness, sinusitis, rash, cough and diarrhea (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Allergan at 1-800-678-1605 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 DELZICOL 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 randomized, double-blind, 6-week study of 2 dosage levels of mesalamine delayed-release 400 mg tablets (Study 3) was conducted in 82 pediatric patients 5 to 17 years of age with mildly to moderately active ulcerative colitis. All patients were divided by body weight category (17 to less than 33 kg, 33 to less than 54 kg, and 54 to 90 kg) and randomly assigned to receive a low dosage (1.2, 2, and 2.4 grams per day for the respective body weight category) or a high dosage (2.0, 3.6, and 4.8 grams per day). The high dosage regimen is not recommended because it was not found to be more effective than the recommended low dosage regimen [see Dosage and Administration (2.2) , Clinical Studies (14.1) ]. Duration of exposure to mesalamine among the 82 patients in the study ranged from 12 to 50 days (mean of 40 days in each dosage group). The majority (88%) of patients in each group were treated for more than 5 weeks. Table 3 provides a summary of the specific reported adverse reactions. Table 3. Adverse Reactions ≥ 5% Reported in Study 3 for the Treatment of Mild to Moderate Ulcerative Colitis in Pediatric Patients* Adverse Reaction % of Patients with Adverse Reactions Low Dosage High Dosage (n=41) (n=41) Nasopharyngitis 15 12 Headache 10 5 Abdominal pain 10 2 Dizziness 7 2 Sinusitis 7 0 Rash 5 5 Cough 5 0 Diarrhea 5 0 Fatigue 2 10 Pyrexia 0 7 Increased Lipase 0 5 Low Dosage = mesalamine 400 mg delayed-release tablet 1.2 to 2.4 grams/day; High Dosage = mesalamine 400 mg delayed-release tablet 2.0 to 4.8 grams/day. Dosage was dependent on body weight. Adverse Reactions reported at the 1-week telephone follow-up visit are included. * At Least 5% of Patients in the low dosage or high dosage group Twelve percent of the patients in the low dosage group (5 patients) and 2% of the patients in the high dosage group (1 patient) had serious adverse reactions. The serious adverse reactions consisted of sinusitis, adenovirus infection, and pancreatitis in one patient each in the low dosage group. Abdominal pain and decreased body mass index occurred in one patient and bloody diarrhea and sclerosing cholangitis also occurred in one patient in the low dosage group. Anemia and syncope occurred in one patient in the high dosage group. Five patients were withdrawn from the study due to adverse reactions: 3 (7%) in the low dosage group (1 patient each with adenovirus infection, sclerosing cholangitis, and pancreatitis) and 2 patients (5%) in the high dosage group (1 patient with increased amylase and increased lipase, and 1 patient with upper abdominal pain). In general, the nature and severity of reactions in the pediatric population was similar to those reported in adult populations of patients with ulcerative colitis. Maintenance of Remission of Ulcerative Colitis Clinical studies supporting the use of mesalamine delayed release tablets in the maintenance of remission of ulcerative colitis in adults included a randomized, double-blind, multi-center, placebo-controlled clinical trial of 6 months’ duration in 264 patients (Study 4) [see Clinical Studies (14.2) ]. In Study 4, a randomized, double-blind, multi-center, placebo-controlled clinical trial of 6 months’ duration, 87 patients were randomized to receive mesalamine delayed release tablets 1.6 grams per /day compared to 87 patients randomized to placebo. The average age of patients in Study 4 was 42 years and 55 % of patients were male. Adverse reactions leading to study withdrawal in patients using mesalamine delayed release tablets included (each in one patient): anxiety, stomatitis and asthenia. In addition to the adverse reactions listed in Table 2, the following occurred at a frequency of 2% or greater in patients who received mesalamine delayed-release tablets in Study 4: abdominal enlargement, gastroenteritis, gastrointestinal hemorrhage, infection, joint disorder, nervousness, paresthesia, hemorrhoids, tenesmus, urinary frequency and vision abnormalities. 6.2 Postmarketing Experience In addition to the adverse reactions reported above in clinical trials involving mesalamine delayed-release tablets, the adverse reactions listed below have been identified during post-approval use of mesalamine delayed-release tablets and other mesalamine-containing products. 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: Neck pain, facial edema, edema, lupus-like syndrome, drug fever. Cardiovascular: Pericarditis, myocarditis [see Warnings and Precautions (5.3) ]. Endocrine: Nephrogenic diabetes insipidus. Gastrointestinal: Anorexia, pancreatitis, gastritis, increased appetite, cholecystitis, dry mouth, oral ulcers, perforated peptic ulcer, bloody diarrhea. Hematologic: Agranulocytosis, aplastic anemia, thrombocytopenia, eosinophilia, leukopenia, anemia, lymphadenopathy. Musculoskeletal: Gout. Nervous: Depression, somnolence, emotional lability, hyperesthesia, vertigo, confusion, tremor, peripheral neuropathy, transverse myelitis, Guillain-Barré syndrome, intracranial hypertension. Renal: Renal failure, interstitial nephritis, minimal change nephropathy [see Warnings and Precautions (5.1) ]. Respiratory/Pulmonary: Eosinophilic pneumonia, interstitial pneumonitis, asthma exacerbation, pleuritis. Skin: Alopecia, psoriasis, pyoderma gangrenosum, dry skin, erythema nodosum, urticaria. Special Senses: Eye pain, taste perversion, blurred vision, tinnitus. Urogenital: Dysuria, urinary urgency, hematuria, epididymitis, menorrhagia, reversible oligospermia. Laboratory Abnormalities: Elevated AST (SGOT) or ALT (SGPT), elevated alkaline phosphatase, elevated GGT, elevated LDH, elevated bilirubin, elevated serum creatinine and BUN.