DRUG INTERACTIONS
Carcinogenesis, Mutagenesis, Impairment of Fertility
Lifetime oral carcinogenicity studies were conducted in CD-1 mice and Sprague-Dawley rats. Pilocarpine did not induce tumors in mice at any dosage studied (up to 30 mg/kg/day, which yielded a systemic exposure approximately 50 times larger than the maximum systemic exposure observed clinically). In rats, a dosage of 18 mg/kg/day, which yielded a systemic exposure approximately 100 times larger than the maximum systemic exposure observed clinically, resulted in a statistically significant increase in the incidence of benign pheochromocytomas in both males and females, and a statistically significant increase in the incidence of hepatocellular adenomas in female rats. The tumorigenicity observed in rats was observed only at a large multiple of the maximum labeled clinical dose, and may not be relevant to clinical use.
No evidence that pilocarpine has the potential to cause genetic toxicity was obtained in a series of studies that included: 1) bacterial assays (Salmonella and E. coli) for reverse gene mutations; 2) an in vitro chromosome aberration assay in a Chinese hamster ovary cell line; 3) an in vivo chromosome aberration assay (micronucleus test) in mice; and 4) a primary DNA damage assay (unscheduled DNA synthesis) in rat hepatocyte primary cultures.
Oral administration of pilocarpine to male and female rats at a dosage of 18 mg/kg/day, which yielded a systemic exposure approximately 100 times larger than the maximum systemic exposure observed clinically, resulted in impaired reproductive function, including reduced fertility, decreased sperm motility, and morphologic evidence of abnormal sperm. It is unclear whether the reduction in fertility was due to effects on male animals, female animals, or both males and females. In dogs, exposure to pilocarpine at a dosage of 3 mg/kg/day (approximately 3 times the maximum recommended human dose when compared on the basis of body surface area (mg/m2) estimates) for six months resulted in evidence of impaired spermatogenesis. The data obtained in these studies suggest that pilocarpine may impair the fertility of male and female humans. Pilocarpine hydrochloride tablets should be administered to individuals who are attempting to conceive a child only if the potential benefit justifies potential impairment of fertility.
Pregnancy
Teratogenic effects
Pregnancy Category C
Pilocarpine was associated with a reduction in the mean fetal body weight and an increase in the incidence of skeletal variations when given to pregnant rats at a dosage of 90 mg/kg/day (approximately 26 times the maximum recommended dose for a 50 kg human when compared on the basis of body surface area (mg/m2) estimates). These effects may have been secondary to maternal toxicity. In another study, oral administration of pilocarpine to female rats during gestation and lactation at a dosage of 36 mg/kg/day (approximately 10 times the maximum recommended dose for a 50 kg human when compared on the basis of body surface area (mg/m2) estimates) resulted in an increased incidence of stillbirths; decreased neonatal survival and reduced mean body weight of pups were observed at dosages of 18 mg/kg/day (approximately 5 times the maximum recommended dose for a 50 kg human when compared on the basis of body surface area (mg/m2) estimates) and above. There are no adequate and well-controlled studies in pregnant women. Pilocarpine hydrochloride tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
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CONTRAINDICATIONS
Pilocarpine hydrochloride tablets are contraindicated in patients with uncontrolled asthma, known hypersensitivity to pilocarpine, and when miosis is undesirable, e.g., in acute iritis and in narrow-angle (angle closure) glaucoma.
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