Salagen Special Precautions

General: Pilocarpine toxicity is characterized by an exaggeration of its parasympathomimetic effects. These may include headache, visual disturbance, lacrimation, sweating, respiratory distress, gastrointestinal spasm, nausea, vomiting, diarrhea, atrioventricular block, tachycardia, bradycardia, hypotension, hypertension, shock, mental confusion, cardiac arrhythmia and tremors.
The dose-related cardiovascular pharmacologic effects of pilocarpine include hypotension, hypertension, bradycardia and tachycardia.
Pilocarpine should be administered with caution to patients with known or suspected cholelithiasis or biliary tract disease. Contractions of the gallbladder or biliary smooth muscle could precipitate complications including cholecystitis, cholangitis and biliary obstruction.
Pilocarpine may increase ureteral smooth muscle tone and could theoretically precipitate renal colic (or "ureteral reflux"), particularly in patients with nephrolithiasis.
Cholinergic agonists may have dose-related central nervous system effects. This should be considered when treating patients with underlying cognitive or psychiatric disturbances.
Hepatic Insufficiency: Based on decreased plasma clearance observed in patients with moderate hepatic impairment, the starting dose in these patients should be 5 mg twice daily, followed by adjustment based on therapeutic response and tolerability.  Patients with mild hepatic insufficiency (Child-Pugh score of 5-6) do not require dosage reductions. To date, pharmacokinetic studies in subjects with severe hepatic impairment (Child-Pugh score of 10-15) have not been carried out. The use of pilocarpine in these patients is not recommended. (See Table 1.)

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Information for Patients: Patients should be informed that pilocarpine may cause visual disturbances, especially at night, that could impair their ability to drive safely.
If a patient sweats excessively while taking pilocarpine hydrochloride and cannot drink enough liquid, the patient should consult a physician. Dehydration may develop.
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: Bacterial assays (Salmonella and E. coli) for reverse gene mutations; an in vitro chromosome aberration assay in a Chinese hamster ovary cell line; an in vivo chromosome aberration assay (micronucleus test) in mice; and 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 6 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. Salagen should be administered to individuals who are attempting to conceive a child only if the potential benefit justifies potential impairment of fertility.
Use in pregnancy: Pregnancy  Category C. There are no adequate and well-controlled studies in pregnant women. Salagen should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Use in lactation: It is not known whether pilocarpine is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Salagen, a decision should be made whether to discontinue nursing or to discontinue Salagen, taking into account the importance of the drug to the mother.
Use in children: Safety and effectiveness in pediatric patients have not been established.
Use in elderly: Head and Neck Cancer Patients: In the placebo-controlled clinical trials (see Pharmacology: Clinical Studies under Actions), the mean age of patients was approximately 58 years (range 19-80). Of these patients, 97/369 (61/217 receiving pilocarpine) were >65 years. In the healthy volunteer studies, 15/150 subjects were >65 years. In both study populations, the adverse events reported by those >65 years and those ≤65 years were comparable. Of the 15 elderly volunteers (5 women, 10 men), the 5 women had higher C_max and AUC than the men. (See Pharmacokinetics under Actions.)
Sjogren’s Syndrome Patients: In the placebo-controlled clinical trials (see Pharmacology: Clinical Studies under Actions), the mean age of patients was approximately 55 years (range 21-85). The adverse events reported by those >65 years and those <65 years were comparable except for notable trends for urinary frequency, diarrhea and dizziness (see Adverse Reactions).