Mesalamine Controlled-Release Capsules Prescribing Information

5.1 Renal Impairment

Renal impairment, including minimal change disease, acute and chronic interstitial nephritis, and renal failure have been reported in patients given mesalamine or other products that contain mesalamine or are converted to mesalamine.

Evaluate the risks and benefits of using mesalamine in patients with known renal impairment or a history of renal disease or taking concomitant nephrotoxic drugs. Evaluate renal function in all patients prior to initiation and periodically while on therapy with mesalamine. Discontinue mesalamine if renal function deteriorates while on therapy [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. Symptoms include cramping, acute abdominal pain, bloody diarrhea, and sometimes fever, headache, and rash. Monitor patients for worsening of these symptoms while on treatment. If acute intolerance syndrome is suspected, promptly discontinue treatment with mesalamine.

5.3 Hypersensitivity Reactions

Hypersensitivity reactions have been reported in patients taking sulfasalazine. Some patients may have a similar reaction to mesalamine 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 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 in patients with known liver impairment.

5.5 Severe Cutaneous Adverse Reactions

Severe cutaneous adverse reactions, such as 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 with the use of mesalamine [see Adverse Reactions (6.2)]. Discontinue mesalamine at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation

5.6 Photosensitivity

Patients with 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 with 100% mesalamine content. Mesalamine-containing stones are radiotransparent and undetectable by standard radiography or computed tomography (CT). Ensure adequate hydration during treatment with mesalamine.

5.8 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.

More than 2,100 patients were exposed to mesalamine in clinical trials of ulcerative colitis or another gastrointestinal condition. The most common adverse reactions (i.e., greater than or equal to 1%) were diarrhea (3%), headache (2%), nausea (2%), abdominal pain (2%), dyspepsia (2%), vomiting

(2%), and rash (1%).

The safety of mesalamine was evaluated in two randomized, double-blind, placebo-controlled, dose-response trials (UC-1 and UC-2) of 624 patients with mildly to moderately active ulcerative colitis for up to 8 weeks of treatment [see Clinical Studies (14)]. The most common adverse reaction was nausea and vomiting: 1% in the mesalamine group (N = 451) and 0% in the placebo group (N = 173). Withdrawal from therapy due to adverse reactions was 7% in the mesalamine group and 4% in the placebo group.

The following adverse reactions, presented by body system, were reported in less than 1% of patients in UC-1, UC-2, and clinical trials for another gastrointestinal condition.

Blood and lymphatic system disorders: thrombocythemia, thrombocytopenia

Cardiac Disorders: palpitations, pericarditis, vasodilation

Gastrointestinal Disorders: abdominal distention, constipation, duodenal ulcer, dysphagia, eructation, esophageal ulcer, fecal incontinence, GI bleeding, mouth ulcer, pancreatitis, rectal bleeding, stool abnormalities (color or texture change)

General disorders and administration site conditions: fever, malaise

Infections and infestations: oral moniliasis, conjunctivitis

Investigations: GGTP increase, increased alkaline phosphatase, LDH increase, SGOT increase, SGPT increase, lipase increase, amylase increase

Metabolism and nutritional disorders: anorexia, edema, thirst

Musculoskeletal and connective tissue disorders: arthralgia, leg cramps, myalgia

Nervous System Disorders: dizziness, insomnia, somnolence, paresthesia

Psychiatric disorders: depression, asthenia

Renal and urinary disorders: albuminuria, hematuria, urinary frequency

Reproductive system and breast disorders: amenorrhea, breast pain, hypomenorrhea, menorrhagia, metrorrhagia

Respiratory, Thoracic and Mediastinal Disorders: pulmonary infiltrates, 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.

Skin and Subcutaneous Tissue Disorders: acne, alopecia, dry skin, eczema, erythema nodosum, nail disorder, photosensitivity, pruritus, sweating, urticaria, ecchymosis, lichen planus

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of mesalamine. 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.

Cardiac Disorders: chest pain, fatal myocarditis, pericarditis, T-wave abnormalities

Hematologic Disorders: agranulocytosis, anemia, aplastic anemia, leukopenia, pancytopenia

Hepatic Disorders: cirrhosis, jaundice, including cholestatic jaundice; hepatotoxicity, hepatitis, 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.

Immune System Disorders: anaphylactic reaction, angioedema, lupus-like syndrome, systemic lupus erythematosus

Nervous System Disorders: intracranial hypertension

Renal and Urinary Disorders: acute renal failure, chronic renal failure, interstitial nephritis, nephrogenic diabetes insipidus, nephrolithiasis, nephrotic syndrome [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

Reproductive System and Breast Disorders: reversible oligospermia

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

Skin and Subcutaneous Tissue Disorders: AGEP, DRESS, SJS/TEN [see Warnings and Precautions (5.5)]

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 any other drugs known to cause myelotoxicity may increase the risk for blood disorders, bone marrow failure, and associated complications. If concomitant use of mesalamine 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 [see Warnings and Precautions (5.8)]. Consider an alternative, selective assay for normetanephrine.

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). There are adverse effects on maternal and fetal outcomes associated with ulcerative colitis in pregnancy (see Clinical Considerations).

In animal reproduction studies, oral administration of mesalamine during organogenesis to pregnant rats at doses up to 1000 mg/kg/day (approximately 2.4 times the maximum recommended human dose of 4 g/day, based on a body surface area comparison) and rabbits at doses of 800 mg/kg/day (approximately 3.9 times the maximum recommended human dose of 4 g/day, based on a body surface area comparison) revealed no evidence of adverse developmental effects (see Data).

The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages 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 of 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, 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 pregnant rats at doses up to 1000 mg/kg/day (approximately 2.4 times the maximum recommended human dose of 4 g/day, based on a body surface area comparison) and rabbits at doses up to 800 mg/kg/day (approximately 3.9 times the maximum recommended human dose of 4 g/day based on a body surface area comparison) and have revealed no evidence of harm to the fetus due to mesalamine.

8.2 Lactation

Risk Summary

Data from published literature report the presence of mesalamine and its metabolite, N-acetyl-5-aminosalicylic acid in human milk in small amounts with relative infant doses (RID) of 0.1% or less for mesalamine (see Data). There are case reports of diarrhea observed in breastfed infants exposed to mesalamine (see Clinical Considerations). There is no information on the effects of mesalamine on milk production. The lack of clinical data during lactation precludes a clear determination of the risk of mesalamine to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for mesalamine and any potential adverse effects on the breastfed child from mesalamine or from the underlying maternal condition.

Clinical Considerations

Advise the caregiver to monitor the breastfed infant for diarrhea.

Data

In published lactation studies, maternal mesalamine doses from various oral and rectal formulations and products ranged from 500 mg to 4.8 g daily. The average concentration of mesalamine in milk ranged from non-detectable to 0.5 mg/L. The average concentration of N-acetyl-5-aminosalicylic acid in milk ranged from 0.2 to 9.3 mg/L. Based on these concentrations, estimated infant daily dosages for an exclusively breastfed infant are 0 to 0.075 mg/kg/day of mesalamine (RID 0% to 0.1%) and 0.03 to 1.4 mg/kg/day of N-acetyl-5-aminosalicylic acid.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical trials of mesalamine 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 who were 65 years or older compared to younger adult patients, which may also be associated with ulcerative colitis, use of interacting drugs, or reduced renal function. Monitor complete blood cell counts and platelet counts in patients 65 years and over during treatment with mesalamine.

In general, consider the greater frequency of decreased hepatic, renal, or cardiac function, and of concurrent disease or other drug therapy in patients 65 years and over when prescribing mesalamine.

8.6 Renal Impairment

Mesalamine is known to be substantially excreted by the kidney, and the risk of toxic reactions may be greater in patients with impaired renal function. Evaluate renal function in all patients prior to initiation and periodically while on mesalamine 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. Discontinue mesalamine if renal function deteriorates while on therapy [see Warnings and Precautions (5.1), Adverse Reactions (6.2), Drug Interactions (7.1)].

12.1 Mechanism of Action

The mechanism of action of mesalamine is not fully understood, but it 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.

12.2 Pharmacodynamics

The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of mesalamine have not been fully characterized.

12.3 Pharmacokinetics

Absorption

Following oral administration 20% to 30% of the mesalamine in mesalamine extended-release capsules is absorbed based on urinary excretion data.

Plasma mesalamine concentration peaked at approximately 1 mcg/mL 3 hours following a 1 g mesalamine extended-release capsules dose.

Oral mesalamine pharmacokinetics were nonlinear when mesalamine extended-release capsules were dosed from 250 mg to 1 g four times daily, with steady-state mesalamine plasma concentrations increasing about nine times, from 0.14 mcg/mL to 1.21 mcg/mL.

The major metabolite of mesalamine (5-aminosalicylic acid), N-acetyl-5-aminosalicylic acid, peaked at approximately 3 hours at 1.8 mcg/mL. N-acetyl-5-aminosalicylic acid pharmacokinetics were linear.

Distribution

Mesalamine is approximately 43% bound to plasma proteins at the concentration of 2.5 mcg/mL.

Elimination

Metabolism

The greater than dose proportional increase in PK of mesalamine suggests saturable first pass metabolism. The major metabolite of mesalamine, N-acetyl-5-aminosalicylic acid, is formed due to action of N-acetyltransferase in the liver and intestinal mucosa. Pharmacological activities of

N-acetyl-5-aminosalicylic acid are unknown, and other metabolites have not been identified.

Excretion

Following oral administration, plasma mesalamine concentration declined in a biphasic manner after reaching peak concentration. The literature describes a mean terminal half-life of 42 minutes for mesalamine following intravenous administration. Because of the continuous release and absorption of mesalamine from mesalamine extended-release capsules throughout the gastrointestinal tract, the true elimination half-life cannot be determined after oral administration.

N-acetyl-5-aminosalicylic acid was the primary compound excreted in the urine (19% to 30%) following mesalamine extended-release capsules dosing. About 130 mg free mesalamine was recovered in the feces following a single 1g mesalamine extended-release capsules dose. Elimination of free mesalamine and salicylates in feces increased proportionately with mesalamine extended-release capsules dose.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In a 104-week dietary carcinogenicity study of mesalamine, CD-1 mice were administered doses up to 2500 mg/kg/day and it was not tumorigenic. The 2500 mg/kg/day dose represents approximately 2.5 times the maximum recommended human dose on a body surface area basis. 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 approximately 1.5 times the maximum recommended human dose on a body surface area basis.

Mutagenesis

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

Impairment of Fertility

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 maximum recommended human dose based on body surface area).