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In the liver, treatment at 0.5 to 200 mg/ kg/ day produced dose-related increases in the incidences of hepatocellular adenomas and carcinomas. In the thyroid gland, treatment at 200 mg/ kg/ day produced increased incidences of follicular cell adenomas and carcinomas for both male and female rats. Sporadic occurrences of hepatocellular adenomas and a hepatocellular carcinoma were observed in Sprague-Dawley rats exposed to pantoprazole in 6-month and 12-month toxicity studies. In a 24-month carcinogenicity study, Fischer 344 rats were treated orally with doses of 5 to 50 mg/ kg/ day, approximately 1 to 10 times the recommended human dose based on body surface area. In the gastric fundus, treatment at 5 to 50 mg/ kg/ day produced enterochromaffin-like (ECL) cell hyperplasia and benign and malignant neuroendocrine cell tumors. Dose selection for this study may not have been adequate to comprehensively evaluate the carcinogenic potential of pantoprazole. In a 24-month carcinogenicity study, B6C3F1 mice were treated orally with doses of 5 to 150 mg/ kg/ day, 0.5 to 15 times the recommended human dose based on body surface area. In the liver, treatment at 150 mg/ kg/ day produced increased incidences of hepatocellular adenomas and carcinomas in female mice. Treatment at 5 to 150 mg/ kg/ day also produced gastric fundic ECL cell hyperplasia. Text Continues Below
A 26-week p53 + /-transgenic mouse carcinogenicity study was not positive. Pantoprazole was positive in the in vitro human lymphocyte chromosomal aberration assays, in one of two mouse micronucleus tests for clastogenic effects, and in the in vitro Chinese hamster ovarian cell/ HGPRT forward mutation assay for mutagenic effects. Equivocal results were observed in the in vivo rat liver DNA covalent binding assay. Pantoprazole was negative in the in vitro Ames mutation assay, the in vitro unscheduled DNA synthesis (UDS) assay with rat hepatocytes, the in vitro AS52/ GPT mammalian cell-forward gene mutation assay, the in vitro thymidine kinase mutation test with mouse lymphoma L5178Y cells, and the in vivo rat bone marrow cell chromosomal aberration assay. Pantoprazole at oral doses up to 500 mg/ kg/ day in male rats (98 times the recommended human dose based on body surface area) and 450 mg/ kg/ day in female rats (88 times the recommended human dose based on body surface area) was found to have no effect on fertility and reproductive performance. Pregnancy Teratogenic Effects Pregnancy Category B Teratology studies have been performed in rats at oral doses up to 450 mg/ kg/ day (88 times the recommended human dose based on body surface area) and rabbits at oral doses up to 40 mg/ kg/ day (16 times the recommended human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to pantoprazole. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers Pantoprazole and its metabolites are excreted in the milk of rats. It is not known whether pantoprazole is excreted in human milk. Many drugs which are excreted in human milk have a potential for serious adverse reactions in nursing infants. Based on the potential for tumorigenicity shown for pantoprazole in rodent carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the benefit of the drug to the mother. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Use in Women Erosive esophagitis healing rates in the 221 women treated with PROTONIX (pantoprazole sodium) Delayed-Release Tablets in U. S. clinical trials were similar to those found in men. In the 122 women treated long-term with PROTONIX 40 mg or 20 mg, healing was maintained at a rate similar to that in men. The incidence rates of adverse events were also similar for men and women. Use in Elderly In short-term U. S. clinical trials, erosive esophagitis healing rates in the 107 elderly patients ( 65 years old) treated with PROTONIX were similar to those found in patients under the age of 65. The incidence rates of adverse events and laboratory abnormalities in patients aged 65 years and older were similar to those associated with patients younger than 65 years of age. Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results.
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