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warnings and cautions
5 WARNINGS AND PRECAUTIONS Renal impairment may occur. Assess renal function at the beginning of treatment and periodically during therapy. ( 5.1 ) Acute exacerbation of colitis symptoms can occur. ( 5.2 ) Use caution with pre-existing liver disease. ( 5.4 ) 5.1 Renal Impairment Renal impairment, including minimal change nephropathy, acute and chronic interstitial nephritis, and, rarely, renal failure, has been reported in patients given products such as APRISO that contain mesalamine or are converted to mesalamine. It is recommended that patients have an evaluation of renal function prior to initiation of APRISO therapy and periodically while on therapy. Exercise caution when using APRISO in patients with known renal dysfunction or a history of renal disease. In animal studies, the kidney was the principal organ for toxicity [see Nonclinical Toxicology ( 13.2 )]. 5.2 Mesalamine-Induced Acute Intolerance Syndrome Mesalamine has been associated with an acute intolerance syndrome that may be difficult to distinguish from a flare of inflammatory bowel disease. Although the exact frequency of occurrence has not been determined, it has occurred in 3% of patients in controlled clinical trials of mesalamine or sulfasalazine. Symptoms include cramping, acute abdominal pain and bloody diarrhea, sometimes fever, headache, and rash. If acute intolerance syndrome is suspected, promptly discontinue treatment with APRISO. 5.3 Hypersensitivity Some patients who have experienced a hypersensitivity reaction to sulfasalazine may have a similar reaction to APRISO capsules or to other compounds that contain or are converted to mesalamine. 5.4 Hepatic Impairment There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered mesalamine. Caution should be exercised when administering APRISO to patients with liver disease.
6 ADVERSE REACTIONS The most common adverse reactions (incidence ≥3%) are headache, diarrhea, upper abdominal pain, nausea, nasopharyngitis, flu or flu-like illness, sinusitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Valeant Pharmaceuticals North America LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience The data described below reflect exposure to APRISO in 557 patients, including 354 exposed for at least 6 months and 250 exposed for greater than one year. APRISO was studied in two placebo-controlled trials (n = 367 treated with APRISO) and in one open-label, long-term study (n = 190 additional patients). The population consisted of patients with ulcerative colitis; the mean age was 47 years, 54% were female, and 93% were white. Patients received doses of APRISO 1.5 g administered orally once per day for six months in the placebo-controlled trials and for up to 24 months in the open-label study. Because clinical studies 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. In the two placebo-controlled trials, 59% of APRISO-treated patients experienced an adverse reaction compared with 64% of placebo patients. Most adverse reactions with APRISO were mild or moderate in severity. Severe adverse reactions occurred in 6% of APRISO-treated patients and 5% of placebo-treated patients. Discontinuations due to adverse reactions occurred in 11% of APRISO-treated patients and 17% of placebo-treated patients; the most common adverse reaction resulting in study discontinuation was recurrence of ulcerative colitis (APRISO 6%, placebo 14%). The most common reactions reported with APRISO (≥3%) are shown in Table 1 below. Table 1: Treatment-Emergent Adverse Reactions during Clinical Trials Occurring in at Least 3% of APRISO-Treated Patients and at a Greater Rate than with Placebo MedDRA Preferred Term APRISO 1.5 g/day N=367 Placebo N=185 Headache 11% 8% Diarrhea 8% 7% Abdominal Pain Upper 5% 3% Nausea 4% 3% Nasopharyngitis 4% 3% Influenza & Influenza-like illness 4% 4% Sinusitis 3% 3% The following adverse reactions, presented by body system, were reported at a frequency less than 3% in patients treated with APRISO for up to 24 months in controlled and open-label trials. Ear and Labyrinth Disorders : tinnitus, vertigo Dermatological Disorder : alopecia Gastrointestinal : abdominal pain lower, rectal hemorrhage Laboratory Abnormalities : increased triglycerides, decreased hematocrit and hemoglobin General Disorders and Administration Site Disorders : fatigue Hepatic : hepatitis cholestatic, transaminases increased Renal Disorders : creatinine clearance decreased, hematuria Musculoskeletal : pain, arthralgia Respiratory : dyspnea 6.2 Adverse Reaction Information from Other Sources The following adverse reactions have been identified during clinical trials of a product similar to APRISO and post approval use of other mesalamine-containing products such as APRISO. Because many of these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole : lupus-like syndrome, drug fever Cardiovascular : pericarditis, pericardial effusion, myocarditis Gastrointestinal : pancreatitis, cholecystitis, gastritis, gastroenteritis, gastrointestinal bleeding, perforated peptic ulcer Hepatic : jaundice, cholestatic jaundice, hepatitis, liver necrosis, liver failure, Kawasaki-like syndrome including changes in liver enzymes Hematologic : agranulocytosis, aplastic anemia Nervous System : intracranial hypertension Neurological/Psychiatric : peripheral neuropathy, Guillain-Barré syndrome, transverse myelitis Renal and Urinary : nephrogenic diabetes insipidus Respiratory/Pulmonary : eosinophilic pneumonia, interstitial pneumonitis Skin : psoriasis, pyoderma gangrenosum, erythema nodosum Renal/Urogenital : reversible oligospermia