General Impaired Hepatic or Renal Function: Since BLOCADREN (timolol) is partially metabolized in the liver and excreted mainly by the kidneys, dosage reductions may be necessary when hepatic and/or renal insufficiency is present. Dosing in the Presence of Marked Renal Failure: Although the pharmacokinetics of BLOCADREN (timolol) are not greatly altered by renal impairment, marked hypotensive responses have been seen in patients with marked renal impairment undergoing dialysis after 20 mg doses. Dosing in such patients should therefore be especially cautious. Muscle Weakness: Beta-adrenergic blockade has been reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g., diplopia, ptosis, and generalized weakness). Timolol has been reported rarely to increase muscle weakness in some patients with myasthenia gravis or myasthenic symptoms. Cerebrovascular Insufficiency: Because of potential effects of beta-adrenergic blocking agents relative to blood pressure and pulse, these agents should be used with caution in patients with cerebrovascular insufficiency. If signs or symptoms suggesting reduced cerebral blood flow are observed, consideration should be given to discontinuing these agents. Carcinogenesis, Mutagenesis, Impairment of Fertility In a two-year study of timolol maleate in rats, there was a statistically significant increase in the incidence of adrenal pheochromocytomas in male rats administered 300 mg/kg/day (250 times** the maximum recommended human dose). Similar differences were not observed in rats administered doses equivalent to approximately 20 or 80 times** the maximum recommended human dose. In a lifetime study in mice, there were statistically significant increases in the incidence of benign and malignant pulmonary tumors, benign uterine polyps and mammary adenocarcinoma in female mice at 500 mg/kg/day (approximately 400 times** the maximum recommended human dose), but not at 5 or 50 mg/kg/day. In a subsequent study in female mice, in which post-mortem examinations were limited to uterus and lungs, a statistically significant increase in the incidence of pulmonary tumors was again observed at 500 mg/kg/day. The increased occurrence of mammary adenocarcinoma was associated with elevations in serum prolactin that occurred in female mice administered timolol at 500 mg/kg/day, but not at doses of 5 or 50 mg/kg/day. An increased incidence of mammary adenocarcinomas in rodents has been associated with administration of several other therapeutic agents which elevate serum prolactin, but no correlation between serum prolactin levels and mammary tumors has been established in man. Furthermore, in adult human female subjects who received oral dosages of up to 60 mg of timolol maleate, the maximum recommended daily human oral dosage, there were no clinically meaningful changes in serum prolactin. Timolol maleate was devoid of mutagenic potential when evaluated in vivo (mouse) in the micronucleus test and cytogenetic assay (doses up to 800 mg/kg) and in vitro in a neoplastic cell transformation assay (up to 100 µg/mL). In Ames tests the highest concentrations of timolol employed, 5000 or 10,000 µg/plate, were associated with statistically significant elevations of revertants observed with tester strain TA100 (in seven replicate assays), but not in three additional strains. In the assays with tester strain TA100, no consistent dose response relationship was observed, nor did the ratio of test to control revertants reach 2. A ratio of 2 is usually considered the criterion for a positive Ames test. Reproduction and fertility studies in rats showed no adverse effect on male or female fertility at doses up to 125 times** the maximum recommended human dose. Pregnancy Pregnancy Category C. Teratogenicity studies with timolol in mice, rats and rabbits at doses up to 50 mg/kg/day (approximately 40 times** the maximum recommended daily human dose) showed no evidence of fetal malformations. Although delayed fetal ossification was observed at this dose in rats, there were no adverse effects on postnatal development of offspring. Doses of 1000 mg/kg/day (approximately 830 times** the maximum recommended daily human dose) were maternotoxic in mice and resulted in an increased number of fetal resorptions. Increased fetal resorptions were also seen in rabbits at doses of approximately 40 times** the maximum recommended daily human dose, in this case without apparent maternotoxicity. There are no adequate and well-controlled studies in pregnant women. BLOCADREN (timolol) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers Timolol maleate has been detected in human milk. Because of the potential for serious adverse reactions from timolol in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in pediatric patients have not been established. ** Based on patient weight of 50 kg Last reviewed on RxList: 12/9/2008
This monograph has been modified to include the generic and brand name in many instances.