5 WARNINGS AND PRECAUTIONS

5.1 Renal Impairment

Renal impairment, including minimal change disease, 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. 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 delayed-release tablets therapy and periodically while on therapy. Evaluate the risks and benefits of using mesalamine delayed-release tablets in patients with known renal impairment, history of renal disease, or taking concomitant nephrotoxic drugs. Discontinue mesalamine delayed-release tablets 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. 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. Monitor 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

Hypersensitivity reactions have been reported in patients taking sulfasalazine. Some of these patients may have a similar reaction to mesalamine delayed-release tablets 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 delayed-release tablets if an alternative etiology for the signs or 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 mesalamine. Evaluate the risks and benefits of using mesalamine delayed-release tablets 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 with the use of mesalamine [see Adverse Reactions (6.2)]. Discontinue mesalamine delayed-release tablets at the first appearance of signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

5.6 Upper Gastrointestinal 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. Avoid mesalamine delayed-release tablets in patients at risk of upper gastrointestinal tract obstruction.

5.7 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.

5.8 Nephrolithiasis

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

5.9 Interference with Laboratory Tests

Use of mesalamine delayed-release tablets 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 the main metabolite of mesalamine, N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA). Consider an alternative, selective assay for normetanephrine.

7 DRUG INTERACTIONS

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

In animal reproduction studies, there were no adverse developmental outcomes with administration of oral mesalamine during organogenesis to pregnant rats and rabbits at doses 1.8 and 2.9 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. 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 2,500 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 rats at doses up to 1,000 mg/kg/day (1.8 times the maximum recommended human dose based on a body surface area comparison) and rabbits at doses up to 800 mg/kg/day (2.9 times the maximum recommended human dose 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 in breastfed infants exposed to mesalamine (see Clinical Considerations). There is no information on the effects of the drug on milk production. The lack of clinical data during lactation precludes a clear determination of the risk of mesalamine delayed-release tablets 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 delayed-release tablets and any potential adverse effects on the breastfed child from mesalamine delayed-release tablets 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 (RID 0% to 0.1%) of mesalamine and 0.03 to 1.4 mg/kg/day of N-acetyl-5-aminosalicylic acid.

8.4 Pediatric Use

The safety and effectiveness of mesalamine delayed-release tablets have been established for the treatment of mildly to moderately active ulcerative colitis in pediatric patients weighing at least 24 kg. Use of mesalamine delayed-release tablets in this population is supported by evidence from adequate and well-controlled trials in adults, a multicenter, randomized, double-blind, parallel group trial in 105 pediatric patients 5 to 17 years of age, and additional pharmacokinetic analyses. The safety profile in pediatric patients was similar to that observed in adults [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.2)].

The safety and effectiveness of mesalamine delayed-release tablets have not been established in patients weighing less than 24 kg.

8.5 Geriatric Use

Clinical trials of mesalamine delayed-release tablets 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 who were 65 years or older who were taking mesalamine-containing products such as mesalamine delayed-release tablets compared to younger patients. Monitor complete blood cell counts and platelet counts in elderly patients during treatment with mesalamine delayed-release tablets.

Systemic exposures are increased in elderly subjects [see Clinical Pharmacology (12.3)].

In general, consider the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients when prescribing mesalamine delayed-release tablets. Consider starting at the low end of the dosing range for induction in elderly patients [see Dosage and Administration (2), Use in Specific Populations (8.6)].

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 delayed-release tablets 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 delayed-release tablets if renal function deteriorates while on therapy [see Warnings and Precautions (5.1), Adverse Reactions (6.2), Drug Interactions (7.1)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In a 104-week dietary carcinogenicity study in CD-1 mice, mesalamine at doses up to 2,500 mg/kg/day was not tumorigenic. This dose is 2.2 times the maximum recommended human dose (based on a body surface area comparison) of mesalamine delayed-release tablets. Furthermore, 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 is 1.4 times the recommended human dose (based on a body surface area comparison) of mesalamine delayed-release tablets.

Mutagenesis

No evidence of mutagenicity was observed in an in vitro Ames test or 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 (0.7 times the maximum recommended human dose based on a body surface area comparison).

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 2,400 mg/kg in mice and 1,150 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.

17 PATIENT COUNSELING INFORMATION

Renal Impairment

Inform patients that mesalamine delayed-release tablets may decrease their renal function, especially if they have known renal impairment or are taking nephrotoxic drugs, and periodic monitoring of renal function will be performed while they are on therapy. Advise patients to complete all blood tests ordered by their healthcare provider [see Warnings and Precautions (5.1)].

Mesalamine-Induced Acute Intolerance Syndrome and Other Hypersensitivity Reactions

Instruct patients to stop taking mesalamine delayed-release tablets and report to their healthcare provider if they experience new or worsening symptoms of acute intolerance syndrome (cramping, abdominal pain, bloody diarrhea, fever, headache, and rash) or other symptoms suggestive of mesalamine-induced hypersensitivity [see Warnings and Precautions (5.2, 5.3)].

Hepatic Failure

Advise patients with known liver disease to contact their healthcare provider if they experience signs or symptoms of worsening liver function [see Warnings and Precautions (5.4)].

Severe Cutaneous Adverse Reactions

Inform patients of the signs and symptoms of severe cutaneous adverse reactions. Instruct patients to stop taking mesalamine delayed-release tablets and report to their healthcare provider at first appearance of a severe cutaneous adverse reaction or other sign of hypersensitivity [see Warnings and Precautions (5.5)].

Upper Gastrointestinal Tract Obstruction

Advise patients to contact their healthcare provider if they experience signs and symptoms of upper gastrointestinal tract obstruction [see Warnings and Precautions (5.6)].

Photosensitivity

Advise patients with pre-existing skin conditions to avoid sun exposure, wear protective clothing, and use a broad-spectrum sunscreen when outdoors [see Warnings and Precautions (5.7)].

Nephrolithiasis

Instruct patients to drink an adequate amount of fluids during treatment in order to minimize the risk of kidney stone formation and to contact their healthcare provider if they experience signs or symptoms of a kidney stone (e.g., severe side or back pain, blood in the urine) [see Warnings and Precautions (5.8)].

Blood Disorders

Inform elderly patients and those taking azathioprine or 6-mercaptopurine of the risk for blood disorders and the need for periodic monitoring of complete blood cell counts and platelet counts while on therapy. Advise patients to complete all blood tests ordered by their healthcare provider [see Drug Interactions (7.2), Use in Specific Populations (8.5)].

Administration

Instruct patients:

• Swallow mesalamine delayed-release tablets whole; do not split or crush.
• Take mesalamine delayed-release tablets with food [see Clinical Pharmacology (12.3)].
• Urine may become discolored reddish-brown while taking mesalamine delayed-release tablets when it comes in contact with surfaces or water treated with hypochlorite-containing bleach. If discolored urine is observed, advise patients to observe their urine flow. Report to the healthcare provider only if urine is discolored on leaving the body, before contact with any surface or water (e.g., in the toilet).
• Drink an adequate amount of fluids [see Warnings and Precautions (5.8)].

2 DOSAGE AND ADMINISTRATION

Administration Instructions

• Evaluate renal function prior to initiation of mesalamine delayed-release tablets and periodically while on therapy.
• Swallow mesalamine delayed-release tablets whole; do not split or crush.
• Administer mesalamine delayed-release tablets with food [see Clinical Pharmacology (12.3)].
• Drink an adequate amount of fluids [see Warnings and Precautions (5.8)].

Adults

• The recommended dosage for the induction of remission in adult patients with mildly to moderately active ulcerative colitis is 2.4 g to 4.8 g (two to four 1.2-g tablets) taken once daily.
• The recommended dosage for the maintenance of remission is 2.4 g (two 1.2-g tablets) taken once daily.

Pediatric Patients
The recommended dosage for treatment of mildly to moderately active ulcerative colitis in pediatric patients weighing at least 24 kg who can swallow tablets whole is shown in Table 1:
Table 1: Recommended Dosage of Mesalamine Delayed-Release Tablets for the Treatment of Mildly to Moderately Active Ulcerative Colitis in Pediatric Patients Weighing at least 24 kg

Weight of Pediatric Patient	Once Daily Mesalamine Delayed-Release Tablets Dosage
Week 0 to Week 8	After Week 8
24 kg to 35 kg	2.4 g (two 1.2-g tablets)	1.2 g (one 1.2-g tablet)
Greater than 35 kg to 50 kg	3.6 g (three 1.2-g tablets)	2.4 g (two 1.2-g tablets)
Greater than 50 kg	4.8 g (four 1.2-g tablets)	2.4 g (two 1.2-g tablets)