5.1 Renal Impairment

Renal impairment, including minimal change disease, acute and chronic interstitial nephritis, and renal failure, has been reported in patients given products such as mesalamine rectal suppositories that contain mesalamine or are converted to mesalamine. In animal studies, the kidney was the principal organ of mesalamine toxicity [see Adverse Reactions (6.2), Nonclinical Toxicology (13.2)].

Evaluate renal function prior to initiation of mesalamine rectal suppositories and periodically while on therapy.

Evaluate the risks and benefits of using mesalamine rectal suppositories in patients with known renal impairment or a history of renal disease or taking concomitant nephrotoxic drugs [see Drug Interactions (7.1), Use in Specific Populations (8.6)].

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, malaise, pruritis, conjunctivitis, and rash. Monitor patients for worsening of these symptoms while on treatment. If acute intolerance syndrome is suspected, promptly discontinue treatment with mesalamine rectal suppositories.

5.3 Hypersensitivity Reactions

Hypersensitivity reactions have been reported in patients taking sulfasalazine. Some patients may have a similar reaction to mesalamine rectal suppositories or to other compounds that contain or are converted to mesalamine.

As with sulfasalazine, mesalamine-induced hypersensitivity reactions may present as internal organ involvement, including myocarditis, pericarditis, nephritis, hepatitis, pneumonitis and hematologic abnormalities. Evaluate patients immediately if signs or symptoms of a hypersensitivity reaction are present. Discontinue mesalamine rectal suppositories if an alternative etiology for the signs and symptoms cannot be established.

5.4 Hepatic Failure

There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered other products containing mesalamine. Evaluate the risks and benefits of using mesalamine rectal suppositories in patients with known liver impairment.

5.5 Severe Cutaneous Adverse Reactions

Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in association with the use of mesalamine [see Adverse Reactions (6.2)]. Discontinue mesalamine rectal suppositories at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

5.6 Photosensitivity

In patients treated with mesalamine or sulfasalazine who have pre-existing skin conditions such as atopic dermatitis and atopic eczema have reported more severe photosensitivity reactions. Advise patients to avoid sun exposure, wear protective clothing, and use a broad-spectrum sunscreen when outdoors.

5.7 Nephrolithiasis

Cases of nephrolithiasis have been reported with the use of mesalamine, including stones of 100% mesalamine content. Mesalamine-containing stones are radiotransparent and undetectable by standard radiography or computed tomography (CT). Ensure adequate hydration during treatment with mesalamine rectal suppositories.

5.8 Interaction with Laboratory Test for Urinary Normetanephrine

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. 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.

The most common adverse reactions in adult patients with mildly to moderately active ulcerative proctitis in double-blind, placebo-controlled trials are summarized in the Table 1 below.

In a multicenter, open-label, randomized, parallel group study in 99 patients comparing the mesalamine 1000 mg suppository administered nightly to that of the mesalamine 500 mg suppository twice daily, the most common adverse reactions in both groups were headache (14%), flatulence (5%), abdominal pain (5%), diarrhea (3%), and nausea (3%). Three (3) patients discontinued medication because of an adverse reaction; one of these adverse reactions (headache) was deemed possibly related to study medication. The recommended dosage of mesalamine rectal suppositories is 1000 mg administered rectally once daily at bedtime [see Dosage and Administration (2)].

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of mesalamine rectal suppositories or 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: drug fever, fatigue, lupus-like syndrome, medication residue

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Cardiac Disorders: myocarditis, pericarditis, pericardial effusion [see Warnings and Precautions (5.3)]

•

Endocrine: nephrogenic diabetes insipidus

•

Eye Disorders: eye swelling

•

Gastrointestinal Disorders: abdominal cramps, abdominal distension, anal pruritus, anorectal discomfort, constipation, feces discolored, flatulence, frequent bowel movements, gastrointestinal bleeding, mucus stools, nausea, painful defecation, pancreatitis, proctalgia, rectal discharge, rectal tenesmus, stomach discomfort, vomiting

•

Hepatic Disorders: cholestatic jaundice, hepatitis, jaundice, Kawasaki-like syndrome including changes in liver enzymes, liver necrosis, liver failure

•

Hematologic Disorders: agranulocytosis, aplastic anemia, thrombocytopenia

•

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

•

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

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Respiratory, Thoracic and Mediastinal Disorders: hypersensitivity pneumonitis (including allergic alveolitis, eosinophilic pneumonitis, interstitial pneumonitis), pleuritis/pleurisy

•

Skin and Subcutaneous Tissue Disorders: alopecia, erythema, erythema nodosum, pruritus, psoriasis, pyoderma gangrenosum, urticaria, SJS/TEN, DRESS and AGEP [see Warnings and Precautions (5.5)]

•

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 nephrotoxicity. Monitor patients taking nephrotoxic drugs for changes in renal function and mesalamine-related adverse reactions [see Warnings and Precautions (5.1)].

7.2 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 rectal suppositories and azathioprine or 6-mercaptopurine cannot be avoided, monitor blood tests, including complete blood cell counts and platelet counts.

7.3 Interference with Urinary Normetanephrine Measurements

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. Consider an alternative, selective assay for normetanephrine [see Warnings and Precautions (5.8)].

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of mesalamine rectal suppositories in pediatric patients for the treatment of mildly to moderately active ulcerative proctitis have not been established. Mesalamine rectal suppositories were evaluated for the treatment of ulcerative proctitis in a 6-week, open-label, single-arm study in 49 patients 5 to 17 years of age, which only included 14 patients with histologically-confirmed cases of ulcerative proctitis. However, efficacy was not demonstrated. Adverse reactions seen in pediatric patients in this trial (abdominal pain, headache, pyrexia, pharyngolaryngeal pain, diarrhea and vomiting) were similar to those seen in adult patients.

8.5 Geriatric Use

Clinical trials of mesalamine rectal suppositories did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. Reports from uncontrolled clinical studies and postmarketing reporting systems suggested a higher incidence of blood dyscrasias (i.e., agranulocytosis, neutropenia and pancytopenia) in patients receiving mesalamine-containing products such as mesalamine rectal suppositories who were 65 years or older compared to younger patients. Monitor complete blood cell counts and platelet counts in elderly patients during treatment with mesalamine rectal suppositories. In general, consider the greater frequency of decreased hepatic, renal, or cardiac function, and of concurrent disease or other drug therapy in elderly patients when prescribing mesalamine rectal suppositories [see Use in Specific Populations (8.6)].

8.6 Renal Impairment

Mesalamine is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. Evaluate renal function in all patients prior to initiation and periodically while on mesalamine rectal suppository therapy. Monitor patients with known renal impairment or history of renal disease or taking nephrotoxic drugs for decreased renal function and mesalamine-related adverse reactions [see Warnings and Precautions (5.1), Drug Interactions (7.1) and Adverse Reactions (6.2)].

12.1 Mechanism of Action

The mechanism of action of mesalamine is not fully understood, but appears to be a topical anti-inflammatory effect on colonic epithelial cells. Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase pathways, i.e., prostanoids, and through the lipoxygenase pathways, i.e., leukotrienes and hydroxyeicosatetraenoic acids, is increased in patients with ulcerative colitis, and it is possible that mesalamine diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin production in the colon.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Mesalamine caused no increase in the incidence of neoplastic lesions over controls in a 2-year study of Wistar rats fed up to 320 mg/kg/day of mesalamine admixed with diet (about 1.7 times the recommended human intra-rectal dose of mesalamine, based on body surface area).

Mesalamine was not mutagenic in the Ames test, the mouse lymphoma cell (TK+/-) forward mutation test, or the mouse micronucleus test.

No effects on fertility or reproductive performance of the male and female rats were observed at oral mesalamine doses up to 320 mg/kg/day (about 1.7 times the recommended human intra-rectal dose of mesalamine, based on body surface area).

13.2 Animal Toxicology and/or Pharmacology

Toxicology studies of mesalamine were conducted in rats, mice, rabbits and dogs, and the kidney was the main target organ of toxicity. In rats, adverse renal effects were observed at a single oral dose of 600 mg/kg (about 3.2 times the recommended human intra-rectal dose of mesalamine, based on body surface area) and at intravenous doses of > 214 mg/kg (about 1.2 times the recommended human intra-rectal dose of mesalamine, based on body surface area). In a 13-week oral gavage toxicity study in rats, papillary necrosis and/or multifocal tubular injury were observed in males receiving 160 mg/kg (about 0.86 times the recommended human intra-rectal dose of mesalamine, based on body surface area) and in both males and females at 640 mg/kg (about 3.5 times the recommended human intra-rectal dose of mesalamine, based on body surface area). In a combined 52-week toxicity and 127-week carcinogenicity study in rats, degeneration of the kidneys and hyalinization of basement membranes and Bowman’s capsule were observed at oral doses of 100 mg/kg/day (about 0.54 times the recommended human intra-rectal dose of mesalamine, based on body surface area) and above. In a 14-day rectal toxicity study of mesalamine suppositories in rabbits, intra-rectal doses up to 800 mg/kg (about 8.6 times the recommended human intra-rectal dose of mesalamine, based on body surface area) was not associated with any adverse effects. In a 6-month oral toxicity study in dogs, doses of 80 mg/kg (about 1.4 times the recommended human intra-rectal dose of mesalamine, based on body surface area) and higher caused renal pathology similar to that described for the rat. In a rectal toxicity study of mesalamine suppositories in dogs, a dose of 166.6 mg/kg (about 3 times the recommended human intra-rectal dose of mesalamine, based on body surface area) produced chronic nephritis and pyelitis. In the 12-month eye toxicity study in dogs, keratoconjunctivitis sicca (KCS) occurred at oral doses of 40 mg/kg (about 0.72 times the recommended human intra-rectal dose of mesalamine, based on body surface area) and above.