Pentasa (Page 2 of 3)

PRECAUTIONS

General

Caution should be exercised if PENTASA is administered to patients with impaired hepatic function.

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 cannot be ascertained, 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, prompt withdrawal is required. If a rechallenge is performed later in order to validate the hypersensitivity, it should be carried out under close medical supervision at reduced dose and only if clearly needed.

Renal

Caution should be exercised if PENTASA is administered to patients with impaired renal function. Single reports of nephrotic syndrome and interstitial nephritis associated with mesalamine therapy have been described in the foreign literature. There have been rare reports of interstitial nephritis in patients receiving PENTASA. In animal studies, a 13-week oral toxicity study in mice and 13-week and 52-week oral toxicity studies in rats and cynomolgus monkeys have shown the kidney to be the major target organ of mesalamine toxicity. Oral daily doses of 2400 mg/kg in mice and 1150 mg/kg in rats produced renal lesions including granular and hyaline casts, tubular degeneration, tubular dilation, renal infarct, papillary necrosis, tubular necrosis, and interstitial nephritis. In cynomolgus monkeys, oral daily doses of 250 mg/kg or higher produced nephrosis, papillary edema, and interstitial fibrosis. Patients with preexisting renal disease, increased BUN or serum creatinine, or proteinuria should be carefully monitored, especially during the initial phase of treatment. Mesalamine-induced nephrotoxicity should be suspected in patients developing renal dysfunction during treatment.

Interference with Laboratory Tests

Use of mesalamine 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 mesalamine’s main metabolite, N-acetylaminosalicylic acid (N-Ac-5-ASA). An alternative, selective assay for normetanephrine should be considered.

Drug Interactions

There are no data on interactions between PENTASA and other drugs.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 104-week dietary carcinogenicity study of mesalamine, CD-1 mice were treated with doses up to 2500 mg/kg/day and it was not tumorigenic. For a 50 kg person of average height (1.46 m2 body surface area), this represents 2.5 times the recommended human dose on a body surface area basis (2960 mg/m2 /day). In a 104-week dietary carcinogenicity study in Wistar rats, mesalamine up to a dose of 800 mg/kg/day was not tumorigenic. This dose represents 1.5 times the recommended human dose on a body surface area basis.

No evidence of mutagenicity was observed in an in vitro Ames test and in an in vivo mouse micronucleus test.

No effects on fertility or reproductive performance were observed in male or female rats at oral doses of mesalamine up to 400 mg/kg/day (0.8 times the recommended human dose based on body surface area).

Semen abnormalities and infertility in men, which have been reported in association with sulfasalazine, have not been seen with PENTASA capsules during controlled clinical trials.

Pregnancy

Category B. Reproduction studies have been performed in rats at doses up to 1000 mg/kg/day (5900 mg/M2) and rabbits at doses of 800 mg/kg/day (6856 mg/M2) and have revealed no evidence of teratogenic effects or harm to the fetus due to mesalamine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, PENTASA should be used during pregnancy only if clearly needed.

Mesalamine is known to cross the placental barrier.

Nursing Mothers

Minute quantities of mesalamine were distributed to breast milk and amniotic fluid of pregnant women following sulfasalazine therapy. When treated with sulfasalazine at a dose equivalent to 1.25 g/day of mesalamine, 0.02 μg/mL to 0.08 μg/mL and trace amounts of mesalamine were measured in amniotic fluid and breast milk, respectively. N-acetylmesalamine, in quantities of 0.07 μg/mL to 0.77 μg/mL and 1.13 μg/mL to 3.44 μg/mL, was identified in the same fluids, respectively.

Caution should be exercised when PENTASA is administered to a nursing woman.

No controlled studies with PENTASA during breast-feeding have been carried out. Hypersensitivity reactions like diarrhea in the infant cannot be excluded.

Pediatric Use

Safety and efficacy of PENTASA in pediatric patients have not been established.

ADVERSE REACTIONS

In combined domestic and foreign clinical trials, more than 2100 patients with ulcerative colitis or Crohn’s disease received PENTASA therapy. Generally, PENTASA therapy was well tolerated. The most common events (ie, greater than or equal to 1%) were diarrhea (3.4%), headache (2.0%), nausea (1.8%), abdominal pain (1.7%), dyspepsia (1.6%), vomiting (1.5%), and rash (1.0%).

In two domestic placebo-controlled trials involving over 600 ulcerative colitis patients, adverse events were fewer in PENTASA® (mesalamine)-treated patients than in the placebo group (PENTASA 14% vs placebo 18%) and were not dose-related. Events occurring in more than 1% are shown in the table below. Of these, only nausea and vomiting were more frequent in the PENTASA group. Withdrawal from therapy due to adverse events was more common on placebo than PENTASA (7% vs 4%).

Table 1. Adverse Events Occurring in More than 1% of Either Placebo or PENTASA Patients in Domestic Placebo-controlled Ulcerative Colitis Trials. (PENTASA Comparison to Placebo)
Event PENTASAn=451 Placebon=173
DiarrheaHeadacheNauseaAbdominal PainMelena (Bloody Diarrhea)RashAnorexiaFeverRectal UrgencyNausea and VomitingWorsening of Ulcerative ColitisAcne 16 (3.5%)10 (2.2%)14 (3.1%)5 (1.1%)4 (0.9%)6 (1.3%)5 (1.1%)4 (0.9%)1 (0.2%)5 (1.1%)2 (0.4%)1 (0.2%) 13 (7.5%)6 (3.5%)—–7 (4.0%)6 (3.5%)2 (1.2%)2 (1.2%)2 (1.2%)4 (2.3%)—–2 (1.2%)2 (1.2%)

Clinical laboratory measurements showed no significant abnormal trends for any test, including measurement of hematological, liver, and kidney function.

The following adverse events, presented by body system, were reported infrequently (ie, less than 1%) during domestic ulcerative colitis and Crohn’s disease trials. In many cases, the relationship to PENTASA has not been established.

Gastrointestinal: abdominal distention, anorexia, constipation, duodenal ulcer, dysphagia, eructation, esophageal ulcer, fecal incontinence, GGTP increase, GI bleeding, increased alkaline phosphatase, LDH increase, mouth ulcer, oral moniliasis, pancreatitis, rectal bleeding, SGOT increase, SGPT increase, stool abnormalities (color or texture change), thirst

Dermatological: acne, alopecia, dry skin, eczema, erythema nodosum, nail disorder, photosensitivity, pruritus, sweating, urticaria

Nervous System: depression, dizziness, insomnia, somnolence, paresthesia

Cardiovascular: palpitations, pericarditis, vasodilation

Other: albuminuria, amenorrhea, amylase increase, arthralgia, asthenia, breast pain, conjunctivitis, ecchymosis, edema, fever, hematuria, hypomenorrhea, Kawasaki-like syndrome, leg cramps, lichen planus, lipase increase, malaise, menorrhagia, metrorrhagia, myalgia, pulmonary infiltrates, thrombocythemia, thrombocytopenia, urinary frequency

One week after completion of an 8-week ulcerative colitis study, a 72-year-old male, with no previous history of pulmonary problems, developed dyspnea. The patient was subsequently diagnosed with interstitial pulmonary fibrosis without eosinophilia by one physician and bronchiolitis obliterans with organizing pneumonitis by a second physician. A causal relationship between this event and mesalamine therapy has not been established.

Published case reports and/or spontaneous postmarketing surveillance have described infrequent instances of pericarditis, fatal myocarditis, chest pain and T-wave abnormalities, hypersensitivity pneumonitis, pancreatitis, nephrotic syndrome, interstitial nephritis, hepatitis, aplastic anemia, pancytopenia, leukopenia, agranulocytosis, or anemia while receiving mesalamine therapy. Anemia can be a part of the clinical presentation of inflammatory bowel disease. Allergic reactions, which could involve eosinophilia, can be seen in connection with PENTASA therapy.

Postmarketing ReportsThe following events have been identified during post-approval use of the PENTASA brand of mesalamine in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of seriousness, frequency of reporting, or potential causal connection to mesalamine:

Gastrointestinal: Reports of hepatotoxicity, including elevated liver enzymes (SGOT/AST, SGPT/ALT, GGT, LDH, alkaline phosphatase, bilirubin), hepatitis, jaundice, cholestatic jaundice, cirrhosis, and possible hepatocellular damage including liver necrosis and liver failure. Some of these cases were fatal. One case of Kawasaki-like syndrome which included hepatic function changes was also reported.

Other: Postmarketing reports of anaphylactic reaction, Steven-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), pneumonitis, granulocytopenia, systemic lupus erythematosis, acute renal failure, chronic renal failure and angioedema have been received in patients taking PENTASA.

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