Mesalamine (Page 4 of 5)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Dietary mesalamine was not carcinogenic in rats at doses as high as 480 mg/kg/day, or in mice at 2000 mg/kg/day. These doses are about 2.6 and 5.4 times the recommended human dose of granulated mesalamine capsules of 1.5 g/day (30 mg/kg if 50 kg body weight assumed or 1110 mg/m2), respectively, based on body surface area.

Mesalamine was negative in the Ames test, the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test, the sister chromatid exchange assay in the Chinese hamster bone marrow test, and the mouse bone marrow micronucleus test.

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

13.2 Animal Toxicology and/or Pharmacology

Renal Toxicity

Animal studies with mesalamine (13-week and 26-week oral toxicity studies in rats, and 26-week and 52-week oral toxicity studies in dogs) have shown the kidney to be the major target organ of mesalamine toxicity. Single oral doses of 800 mg/kg (about 2.2 times the recommended human dose, on the basis of body surface area) and 1800 mg/kg (about 9.7 times the recommended human dose, on the basis of body surface area) of mesalamine were lethal to mice and rats, respectively, and resulted in gastrointestinal and renal toxicity. Oral doses of 40 mg/kg/day (about 0.20 times the human dose, on the basis of body surface area) produced minimal to slight tubular injury, and doses of 160 mg/kg/day (about 0.90 times the human dose, on the basis of body surface area) or higher in rats produced renal lesions including tubular degeneration, tubular mineralization, and papillary necrosis. Oral doses of 60 mg/kg/day (about 1.1 times the human dose, on the basis of body surface area) or higher in dogs also produced renal lesions including tubular atrophy, interstitial cell infiltration, chronic nephritis, and papillary necrosis.

14 CLINICAL STUDIES

Two similar, randomized, double-blind, placebo-controlled, multi-center studies were conducted in a total of 562 adult patients in remission from ulcerative colitis. The study populations had a mean age of 46 years (11% age 65 years or older), were 53% female, and were primarily white (92%).

Ulcerative colitis disease activity was assessed using a modified Sutherland Disease Activity Index (DAI), which is a sum of four subscores based on stool frequency, rectal bleeding, mucosal appearance on endoscopy, and physician’s rating of disease activity. Each subscore can range from 0 to 3, for a total possible DAI score of 12.

At baseline, approximately 80% of patients had a total DAI score of 0 or 1.0. Patients were randomized 2:1 to receive either mesalamine extended-release capsules 1.5 g or placebo once daily in the morning for six months. Patients were assessed at baseline, 1 month, 3 months, and 6 months in the clinic, with endoscopy performed at baseline, at end of study, or if clinical symptoms developed. Relapse was defined as a rectal bleeding subscale score of 1 or more and a mucosal appearance subscale score of 2 or more using the DAI. The analysis of the intent-to-treat population was a comparison of the proportions of patients who remained relapse-free at the end of six months of treatment. For the table below (Table 3) all patients who prematurely withdrew from the study for any reason were counted as relapses.

In both studies, the proportion of patients who remained relapse-free at six months was greater for mesalamine extended-release capsules than for placebo.

Table 3: Percentage of Ulcerative Colitis Patients Relapse-Free * Through 6 Months in
Mesalamine Extended-Release Capsules 1.5 g once daily % (# no relapse/N) Placebo % (# no relapse/N) Difference (95% C.I.) P-value
*
Relapse counted as rectal bleeding score ≥1 and mucosal appearance score ≥2, or premature withdrawal from study.

Study 1

68% (143/209)

51% (49/96)

17% (5.5, 29.2)

<0.001

Study 2

71% (117/164)

59% (55/93)

12% (0, 24.5)

0.046

Examination of gender subgroups did not identify difference in response to mesalamine extended-release capsules among these subgroups. There were too few elderly and too few African-American patients to adequately assess difference in effects in those populations.

The use of mesalamine extended-release capsules for treating ulcerative colitis beyond six months has not been evaluated in controlled clinical trials.

16 HOW SUPPLIED/STORAGE AND HANDLING

Mesalamine extended-release capsules are available as light blue opaque hard gelatin capsules containing 0.375 g mesalamine in a light blue opaque gelatin capsule with the letters “G” and “M” imprinted on either side of a black band and are available in bottles of 120 capsules (NDC 68682-113-20).

Storage:

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

Administration

Instruct patients:

Swallow the capsules whole. Do not cut, break, crush or chew the capsules.
Avoid co-administration of mesalamine extended-release capsules with antacids.
Drink an adequate amount of fluids.
Mesalamine extended-release capsules can be taken without regard to meals [see Dosage and Administration (2)].

Renal Impairment

Inform patients that mesalamine extended-release capsules may decrease their renal function, especially if they have known renal impairment or are taking nephrotoxic drugs, including NSAIDs, 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), Drug Interactions (7.2)].

Mesalamine-Induced Acute Intolerance Syndrome and Other Hypersensitivity Reactions

Inform patients of the signs and symptoms of hypersensitivity reactions. Instruct patients to stop taking mesalamine extended-release capsules 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

Inform patients with known liver disease of the signs and symptoms of worsening liver function and advise them to report to their healthcare provider if they experience such signs or symptoms [see Warnings and Precautions (5.4)].

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 (5.5)].

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 (5.6)].

Patients with Phenylketonuria

Inform patients with phenylketonuria (PKU) or their caregivers that each mesalamine extended-release capsule contains aspartame equivalent to 0.56 mg of phenylalanine, so that the recommended adult dosing provides an equivalent of 2.24 mg of phenylalanine per day [see Warnings and Precautions (5.7)].

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 (7.3), Use in Specific Populations (8.5)].

Distributed by:
Oceanside Pharmaceuticals, a division of
Bausch Health US, LLC
Bridgewater, NJ 08807 USA

U.S. Patent Number: 8,865,688

© 2020 Bausch Health Companies Inc. or its affiliates

9652002 20003056

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