ARTHROTEC (Page 9 of 11)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term animal studies to evaluate the potential for carcinogenesis and animal studies to evaluate the effects on fertility have been performed with each component of ARTHROTEC given alone.

In a 24 month rat carcinogenicity study, misoprostol administered orally at doses up to 2.4 mg/kg/day (14.4 mg/m2 /day, 24 times the recommended maximum human dose of 0.6 mg/m2 /day) was not tumorigenic. In a 21 month mouse carcinogenicity study, misoprostol administered orally at doses up to 16 mg/kg/day (48 mg/m2 /day), 80 times the recommended maximum human dose based on body surface area, was not tumorigenic.

In a 24 month rat carcinogenicity study, diclofenac sodium administered orally at up to 2 mg/kg/day (12 mg/m2 /day) was not tumorigenic. In a 24 month mouse carcinogenicity study, oral diclofenac sodium at doses up to 0.3 mg/kg/day (0.9 mg/m2 /day, 0.006 times the recommended maximum human dose based on body surface area) in males and 1 mg/kg/day (3 mg/m2 /day, 0.02 times the recommended maximum human dose based on body surface area) in females was not tumorigenic.

Mutagenesis

Diclofenac sodium and misoprostol combination in 250:1 ratio was not genotoxic in the Ames test, the Chinese hamster ovary cell (CHO/HGPRT) forward mutation test, the rat lymphocyte chromosome aberration test, or the mouse bone marrow micronucleus test.

Impairment of Fertility

The effects of diclofenac sodium and misoprostol on male or female fertility have not been studied in animals; however, there are data with diclofenac sodium and misoprostol given alone. Misoprostol, when administered to male and female breeding rats in an oral dose range of 0.1 to 10 mg/kg/day (0.6 to 60 mg/m2 /day, 1 to 100 times the recommended maximum human dose based on body surface area) produced dose-related pre- and postimplantation losses and a significant decrease in the number of live pups born at the highest dose (60 mg/m2 /day, 100 times the recommended maximum human dose based on body surface area). Diclofenac sodium at oral doses up to 4 mg/kg/day (24 mg/m2 /day, 0.16 times the recommended maximum human dose based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats.

13.2 Animal Toxicology

A reversible increase in the number of normal surface gastric epithelial cells occurred in the dog, rat, and mouse during long-term toxicology studies with misoprostol. No such increase has been observed in humans administered misoprostol for up to 1 year. An apparent response of the female mouse to misoprostol in long-term studies at 100 to 1000 times the human dose was hyperostosis, mainly of the medulla of sternebrae. Hyperostosis did not occur in long-term studies in the dog and rat and has not been seen in humans treated with misoprostol.

14 CLINICAL STUDIES

Osteoarthritis

Diclofenac sodium, as a single ingredient or in combination with misoprostol, has been shown to be effective in the management of the signs and symptoms of osteoarthritis.

Rheumatoid arthritis

Diclofenac sodium, as a single ingredient or in combination with misoprostol, has been shown to be effective in the management of the signs and symptoms of rheumatoid arthritis.

Upper gastrointestinal safety

Diclofenac, and other NSAIDs, have caused serious gastrointestinal toxicity, such as bleeding, ulceration, and perforation of the stomach, small intestine or large intestine. Misoprostol has been shown to reduce the incidence of endoscopically diagnosed NSAID-induced gastric and duodenal ulcers. In a 12-week, randomized, double-blind, dose-response study, misoprostol 200 mcg administered four, three or two times a day, was significantly more effective than placebo in reducing the incidence of gastric ulcer in osteoarthritis and rheumatoid arthritis patients using a variety of NSAIDs. The three times a day regimen was therapeutically equivalent to misoprostol 200 mcg four times a day with respect to the prevention of gastric ulcers. Misoprostol 200 mcg given two times a day was less effective than 200 mcg given three or four times a day. The incidence of NSAID-induced duodenal ulcer was also significantly reduced with all three regimens of misoprostol compared to placebo (see Table 3).

Table 3
Misoprostol 200 mcg Dosage Regimen
Placebo two times a day three times a day four times a day
N=1623; 12 weeks
*
Misoprostol significantly different from placebo (p<0.05)
Gastric ulcer 11% 6%* 3%* 3%*
Duodenal ulcer 6% 2%* 3%* 1%*

Results of a study in 572 patients with osteoarthritis demonstrate that patients receiving ARTHROTEC have a lower incidence of endoscopically defined gastric ulcers compared to patients receiving diclofenac sodium (see Table 4).

Table 4
Osteoarthritis patients with history of ulcer or erosive disease (N=572), 6 weeks Incidence of ulcers
Gastric Duodenal
*
Statistically significantly different from diclofenac (p<0.05)
ARTHROTEC 50 three times a day 3%* 6%
ARTHROTEC 75 two times a day 4%* 3%
Diclofenac sodium 75 mg two times a day 11% 7%
Placebo 3% 1%

16 HOW SUPPLIED/STORAGE AND HANDLING

ARTHROTEC (diclofenac sodium and misoprostol) delayed-release tablets are supplied as:

  • 50 mg diclofenac sodium and 200 mcg misoprostol as round, biconvex, white to off-white tablets imprinted with four “A’s” encircling a “50” in the middle on one side and “SEARLE” and “1411” on the other.
  • 75 mg diclofenac sodium and 200 mcg misoprostol as round, biconvex, white to off-white tablets imprinted with four “A’s” encircling a “75” in the middle on one side and “SEARLE” and “1421” on the other.

The dosage strengths are supplied in:

Strength NDC Number Size
ARTHROTEC 50 50 mg diclofenac sodium and 200 mcg misoprostol 0025-1411-60 bottle of 60
0025-1411-90 bottle of 90
ARTHROTEC 75 75 mg diclofenac sodium and 200 mcg misoprostol 0025-1421-60 bottle of 60

Store at 20°C to 25°C (68°F to 77°F). Excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature].

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