Mesalamine (Page 2 of 5)

6.1 Clinical Trials Experience

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.

The data described below reflect exposure to mesalamine extended-release capsules in 557 patients, including 354 exposed for at least 6 months and 250 exposed for greater than one year. Mesalamine extended-release capsules were studied in two placebo-controlled trials (n=367 treated with mesalamine extended-release capsules) 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 mesalamine extended-release capsules 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.

In the two placebo-controlled trials, the most common reactions reported in at least 3% of mesalamine extended-release capsules-treated patients and at a greater rate than placebo are shown in Table 1 below.

Table 1: Common Adverse Reactions *in Clinical Trials of Adults with Ulcerative Colitis
Mesalamine
Extended-Release Capsules
1.5 g once daily
N=367
Placebo
N=185
*
Reported in at least 3% of mesalamine extended-release capsules-treated patients and at a greater rate than with placebo

Headache

11%

8%

Diarrhea

8%

7%

Upper Abdominal Pain

5%

3%

Nausea

4%

3%

Nasopharyngitis

4%

3%

The following adverse reactions, presented by body system, were reported at a frequency less than 3% in patients treated with mesalamine extended-release capsules for up to 24 months in controlled and open-label trials.

Ear and Labyrinth Disorders: tinnitus, vertigo

Dermatological Disorder: alopecia

Gastrointestinal: lower abdominal pain, 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 Postmarketing Experience

The following adverse reactions have been identified during post approval use of mesalamine extended-release capsules or other mesalamine-containing products. 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 [ see Warnings and Precautions (5.3)]

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, interstitial nephritis, renal failure, minimal change disease, nephrolithiasis [ see Warnings and Precautions (5.1, 5.7)]

  • Urine discoloration occurring ex-vivo caused by contact of mesalamine, including inactive metabolite, with surfaces or water treated with hypochlorite-containing bleach.

Respiratory/Pulmonary: eosinophilic pneumonia, interstitial pneumonitis, pleurisy/pleuritis

Skin: psoriasis, pyoderma gangrenosum, erythema nodosum, SJS/TEN, DRESS, and AGEP [ see Warnings and Precautions (5.5)]

Renal/Urogenital: reversible oligospermia

7 DRUG INTERACTIONS

7.1 Antacids

Because the dissolution of the coating of the granules in mesalamine extended-release capsules depends on pH, avoid co-administration of mesalamine extended-release capsules with antacids [ see Dosage and Administration (2)] .

7.2 Nephrotoxic Agents, Including Non-Steroidal Anti-Inflammatory Drugs

The concurrent use of mesalamine with known nephrotoxic agents, including non-steroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity. Monitor patients taking nephrotoxic drugs for changes in renal function and mesalamine-related adverse reactions [ see Warnings and Precautions (5.1)].

7.3 Azathioprine or 6-Mercaptopurine

The concurrent use of mesalamine with azathioprine or 6-mercaptopurine and/or other drugs known to cause myelotoxicity may increase the risk for blood disorders, bone marrow failure, and associated complications. If concomitant use of mesalamine extended-release capsules and azathioprine or 6-mercaptopurine cannot be avoided, monitor blood tests, including complete blood cell counts and platelet counts.

7.4 Interference with Urinary Normetanephrine Measurements

Use of mesalamine extended-release capsules may lead to spuriously elevated test results when measuring urinary normetanephrine by liquid chromatography with electrochemical detection [ see Warnings and Precautions (5.9)] . Consider an alternative, selective assay for normetanephrine.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Published data from meta-analyses, cohort studies and case series on the use of mesalamine during pregnancy have not reliably informed an association with mesalamine and major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data).

In animal reproduction studies, there were no adverse developmental outcomes with administration of oral mesalamine during organogenesis to pregnant rats and rabbits at doses 1.7 and 5.4 times, respectively, the maximum recommended human dose (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Disease-associated maternal and embryo/fetal risk

Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with ulcerative colitis. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth.

Data

Human Data

Published data from meta-analyses, cohort studies and case series on the use of mesalamine during early pregnancy (first trimester) and throughout pregnancy have not reliably informed an association of mesalamine and major birth defects, miscarriage, or adverse maternal or fetal outcomes. There is no clear evidence that mesalamine exposure in early pregnancy is associated with an increased risk in major congenital malformations, including cardiac malformations. Published epidemiologic studies have important methodological limitations which hinder interpretation of the data, including inability to control for confounders, such as underlying maternal disease, and maternal use of concomitant medications, and missing information on the dose and duration of use for mesalamine products.

Animal Data

Reproduction studies with mesalamine during organogenesis have been performed in rats at oral doses up to 320 mg/kg/day (about 1.7 times the recommended human dose based on a body surface area comparison) and rabbits at doses up to 495 mg/kg/day (about 5.4 times the recommended human dose based on a body surface area comparison) and have revealed no evidence of harm to the fetus due to mesalamine.

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