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 mesalamine delayed-release tablets that contain mesalamine or are converted to mesalamine.

It is recommended that patients have an evaluation of renal function prior to initiation of mesalamine delayed-release tablet therapy and periodically while on therapy. Exercise caution when using mesalamine delayed-release tablets in patients with known renal dysfunction or a history of renal disease.

In animal studies, the kidney was the principal organ for toxicity [see Drug Interactions (7.1) and 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 an exacerbation of ulcerative colitis. 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, and sometimes fever, headache, and rash. Observe patients closely for worsening of these symptoms while on treatment. If acute intolerance syndrome is suspected, promptly discontinue treatment with mesalamine delayed-release tablets.

5.3 Hypersensitivity Reactions

Some patients who have experienced a hypersensitivity reaction to sulfasalazine may have a similar reaction to mesalamine delayed-release tablets or to other compounds that contain or are converted to mesalamine.

Mesalamine-induced cardiac hypersensitivity reactions (myocarditis and pericarditis) have been reported with mesalamine delayed-release tablets and other mesalamine medications. Take caution in prescribing this medicine to patients with conditions predisposing them to the development of myocarditis or pericarditis.

5.4 Hepatic Impairment

There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered mesalamine. Exercise caution when administering mesalamine delayed-release tablets to patients with liver disease.

5.5 Upper GI Tract Obstruction

Pyloric stenosis or other organic or functional obstruction in the upper gastrointestinal tract may cause prolonged gastric retention of mesalamine delayed-release tablets which would delay mesalamine release in the colon.

5.6 Photosensitivity

Patients with pre-existing skin conditions such as atopic dermatitis and atopic eczema have reported more severe photosensitivity reactions.

5.7 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-acetyl-5-aminosalicylic acid (N-Ac-5-ASA). Consider an alternative, selective assay for normetanephrine.

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 tablets have been evaluated in 1368 patients with ulcerative colitis in controlled and open-label trials.

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: lupus-like syndrome, drug fever

Cardiac Disorders: 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

Immune System Disorders: anaphylactic reaction, angioedema,Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS)

Musculoskeletal and Connective Tissue Disorders: myalgia, lupus-like syndrome

Neurological/Psychiatric: peripheral neuropathy, Guillain-Barre syndrome, transverse myelitis, intracranial hypertension

Renal Disorders: interstitial nephritis, nephrogenic diabetes insipidus

Respiratory, Thoracic and Mediastinal Disorders: interstitial lung disease, hypersensitivity pneumonitis (including interstitial pneumonitis, allergic alveolitis, eosinophilic pneumonitis)

Skin: psoriasis, pyoderma gangrenosum, erythema nodosum, photosensitivity

Urogenital: reversible oligospermia

7.1 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 renal reactions.

7.2 Azathioprine or 6-mercaptopurine

The concurrent use of mesalamine with azathioprine or 6-mercaptopurine and/or any other drugs known to cause myelotoxicity may increase the risk for blood disorders, bone marrow failure, and associated complications.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness of mesalamine delayed-release tablets in pediatric patients have not been established.

8.5 Geriatric Use

Reports from uncontrolled clinical studies and postmarketing reporting systems suggested a higher incidence of blood dyscrasias (i.e., neutropenia and pancytopenia) in patients who were 65 years or older who were taking mesalamine-containing products such as mesalamine delayed-release tablets. Take caution to monitor blood cell counts closely during mesalamine therapy.

Clinical trials of mesalamine delayed-release tablets did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Systemic exposures are increased in elderly subjects [see Clinical Pharmacology (12.3)]. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concurrent disease or other drug therapy in elderly patients.

12.1 Mechanism of Action

The mechanism of action of mesalamine is not fully understood, but it appears to have a topical anti-inflammatory effect on the colonic epithelial cells. Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase and lipoxygenase pathways, is increased in patients with chronic inflammatory bowel disease, and it is possible that mesalamine diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin production in the colon.

Mesalamine has the potential to inhibit the activation of nuclear factor kappa B (NFкB) and consequently the production of key pro-inflammatory cytokines. It has been proposed that reduced expression of PPARγ nuclear receptors (γ-form of peroxisome proliferator-activated receptors) may be implicated in ulcerative colitis. There is evidence that mesalamine produces pharmacodynamic effects through direct activation of PPARγ receptors in the colonic/rectal epithelium.

12.2 Pharmacodynamics

The pharmacodynamic actions of mesalamine occur in the colonic/rectal mucosae local to the delivery of drug from mesalamine delayed-release tablets into the lumen. There is information suggesting that severity of colonic inflammation in ulcerative colitis patients treated with mesalamine is inversely correlated with mucosal concentrations of mesalamine. Plasma concentrations representing systemically absorbed mesalamine are not believed to contribute extensively to efficacy.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

In animal studies with mesalamine, 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.

14.1 Active, Mild to Moderate Ulcerative Colitis

Two similarly designed, randomized, double-blind, placebo-controlled trials were conducted in 517 adult patients with active, mild to moderate ulcerative colitis. The study population was primarily Caucasian (80%), had a mean age of 42 years (6% age 65 years or older), and was approximately 50% male. Both studies used mesalamine delayed-release tablet doses of 2.4 g/day and 4.8 g/day administered once daily for 8 weeks except for the 2.4 g/day group in Study 1, which was given in two divided doses (1.2 g twice daily). The primary efficacy endpoint in both trials was to compare the percentage of patients in remission after 8 weeks of treatment for the mesalamine delayed-release tablet treatment groups versus placebo. Remission was defined as an Ulcerative Colitis Disease Activity Index (UC-DAI) of ≤ 1, with scores of zero for rectal bleeding and for stool frequency, and a sigmoidoscopy score reduction of 1 point or more from baseline.

In both studies, the mesalamine delayed-release tablet doses of 2.4 g/day and 4.8 g/day demonstrated superiority over placebo in the primary efficacy endpoint (Table 5). Both mesalamine delayed-release tablet doses also provided consistent benefit in secondary efficacy parameters, including clinical improvement, treatment failure, clinical remission, and sigmoidoscopic improvement. Mesalamine delayed-release tablets 2.4 g/day and 4.8 g/day had similar efficacy profiles.

14.2 Maintenance of Remission in Patients with Ulcerative Colitis

A multicenter, randomized, double-blind, active comparator study was conducted in a total of 826 adult patients in remission from ulcerative colitis. The study population had a mean age of 45 years (8% age 65 years or older), were 52% male, and were primarily Caucasian (64%).

Maintenance of remission was assessed using a modified Ulcerative Colitis Disease Activity Index (UC-DAI). For this trial, maintenance of remission was based on maintaining endoscopic remission defined as a modified UC-DAI endoscopy subscore of ≤ 1. An endoscopy subscore of 0 represented normal mucosal appearance with intact vascular pattern and no friability or granulation. For this trial the endoscopy score definition of 1 (mild disease) was modified such that it could include erythema, decreased vascular pattern, and minimal granularity; however, it could not include friability.

Subjects were randomized in a 1:1 ratio to receive either mesalamine delayed-release tablets 2.4 g/day administered once daily or mesalamine delayed release 1.6 g/day administered as 0.8 g twice daily. The proportion of patients who maintained remission at Month 6 in this study using mesalamine delayed-release tablets 2.4 g once daily (83.7%) was similar to that seen using the comparator (mesalamine delayed release) 1.6 g/day (81.5%).