CNS Toxicity CNS vascular lesions, characterized by perivascular hemorrhage and edema and mononu-clear cell infiltration of perivascular spaces, were seen in dogs treated with pravastatin at a dose of 25 mg/ kg/ day. These effects in dogs were observed at approximately 59 times the human dose of 80 mg/ day, based on AUC. Similar CNS vascular lesions have been observed with several other drugs in this class. A chemically similar drug in this class produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion starting at 60 mg/ kg/ day, a dose that produced mean plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose (as mea-sured by total enzyme inhibitory activity). This same drug also produced vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis in dogs treated for 14 weeks at 180 mg/ kg/ day, a dose which resulted in a mean plasma drug level similar to that seen with the 60 mg/ kg/ day dose. Carcinogenesis, Mutagenesis, Impairment of Fertility In a 2-year study in rats fed pravastatin at doses of 10, 30, or 100 mg/ kg body weight, there was an increased incidence of hepatocellular carcinomas in males at the highest dose (p 0.01). These effects in rats were observed at approximately 12 times the human dose (HD) of 80 mg, based on body surface area mg/ m 2 and at approximately 4 times the human dose, based on AUC. In a 2-year study in mice fed pravastatin at doses of 250 and 500 mg/ kg/ day, there was an increased incidence of hepatocellular carcinomas in males and females at both 250 and 500 mg/ kg/ day (p 0.0001). At these doses, lung adenomas in females were increased (p= 0.013). These effects in mice were observed at approximately 15 times (250 mg/ kg/ day) and 23 times (500 mg/ kg/ day) the human dose of 80 mg, based on AUC. In another 2-year study in mice with doses up to 100 mg/ kg/ day (producing drug exposures approximately 2 times the human dose of 80 mg, based on AUC), there were no drug-induced tumors. No evidence of mutagenicity was observed in vitro, with or without rat-liver metabolic activation, in the following studies: microbial mutagen tests, using mutant strains of Salmonella typhimurium or Escherichia coli; a forward mutation assay in L5178Y TK +/-mouse lymphoma cells; a chromosomal aberration test in hamster cells; and a gene con-version assay using Saccharomyces cerevisiae. In addition, there was no evidence of muta-genicity in either a dominant lethal test in mice or a micronucleus test in mice. In a study in rats, with daily doses up to 500 mg/ kg, pravastatin did not produce any adverse effects on fertility or general reproductive performance. However, in a study with another HMG-CoA reductase inhibitor, there was decreased fertility in male rats treated for 34 weeks at 25 mg/ kg body weight, although this effect was not observed in a subsequent fer-tility study when this same dose was administered for 11 weeks (the entire cycle of spermato-genesis, including epididymal maturation). In rats treated with this same reductase inhibitor at 180 mg/ kg/ day, seminiferous tubule degeneration (necrosis and loss of spermatogenic epithe-lium) was observed. Although not seen with pravastatin, two similar drugs in this class caused drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration, and giant cell formation in dogs. The clinical significance of these findings is unclear. Pregnancy Pregnancy Category X. See CONTRAINDICATIONS. Safety in pregnant women has not been established. Pravastatin was not teratogenic in rats at doses up to 1000 mg/ kg daily or in rabbits at doses of up to 50 mg/ kg daily. These doses resulted in 10X (rabbit) or 120X (rat) the human exposure based on surface area (mg/ meter 2 ). Rare reports of congenital anomalies have been received following intrauterine exposure to other HMG-CoA reductase inhibitors. In a review 9 of approximately 100 prospec-tively followed pregnancies in women exposed to simvastatin or lovastatin, the incidences of congenital anomalies, spontaneous abortions and fetal deaths/ stillbirths did not exceed what would be expected in the general population. The number of cases is adequate only to exclude a three-to-four-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to preg-nancy and was discontinued at some point in the first trimester when pregnancy was identi-fied. As safety in pregnant women has not been established and there is no apparent benefit to therapy with PRAVACHOL (pravastatin sodium) during pregnancy (see CONTRAINDICA-TIONS), treatment should be immediately discontinued as soon as pregnancy is recognized. PRAVACHOL should be administered to women of childbearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards. Nursing Mothers A small amount of pravastatin is excreted in human breast milk. Because of the potential for serious adverse reactions in nursing infants, women taking PRAVACHOL should not nurse (see CONTRAINDICATIONS). Pediatric Use The safety and effectiveness of PRAVACHOL in children and adolescents from 8-18 years of age have been evaluated in a placebo-controlled study of two years duration. Patients treated with pravastatin had an adverse experience profile generally similar to that of patients treated with placebo with influenza and headache commonly reported in both treatment groups. (See ADVERSE REACTIONS: Pediatric Patients.) Doses greater than 40 mg have not been studied in this population. Children and adolescent females of childbearing potential should be counseled on appropriate contraceptive methods while on pravastatin therapy (see CON-TRAINDICATIONS and PRECAUTIONS: Pregnancy). For dosing information see DOSAGE AND ADMINISTRATION: Adult Patients and Pediatric Patients. Double-blind, placebo-controlled pravastatin studies in children less than 8 years of age have not been conducted. Geriatric Use Two secondary prevention trials with pravastatin (CARE and LIPID) included a total of 6,593 sub-jects treated with pravastatin 40 mg for periods ranging up to 6 years. Across these two studies, 36.1% of pravastatin subjects were aged 65 and older and 0.8% were aged 75 and older. The beneficial effect of pravastatin in elderly subjects in reducing cardiovascular events and in modi-fying lipid profiles was similar to that seen in younger subjects. The adverse event profile in the elderly was similar to that in the overall population. Other reported clinical experience has not identified differences in responses to pravastatin between elderly and younger patients. Mean pravastatin AUCs are slightly (25-50%) higher in elderly subjects than in healthy young subjects, but mean C max , T max and t values are similar in both age groups and sub-stantial accumulation of pravastatin would not be expected in the elderly (see CLINICAL PHARMACOLOGY: Pharmacokinetics/ Metabolism). Drug Interactions Immunosuppressive Drugs, Gemfibrozil, Niacin (Nicotinic Acid), Erythromycin: See WARNINGS: Skeletal Muscle. Cytochrome P450 3A4 Inhibitors: In vitro and in vivo data indicate that pravastatin is not metabolized by cytochrome P450 3A4 to a clinically significant extent. This has been shown in studies with known cytochrome P450 3A4 inhibitors (see diltiazem and itraconazole below). Other examples of cytochrome P450 3A4 inhibitors include ketoconazole, mibefradil, and ery-thromycin. Diltiazem: Steady-state levels of diltiazem (a known, weak inhibitor of P450 3A4) had no effect on the pharmacokinetics of pravastatin. In this study, the AUC and C max of another HMG-CoA reductase inhibitor which is known to be metabolized by cytochrome P450 3A4 increased by factors of 3.6 and 4.3, respectively. Itraconazole: The mean AUC and C max for pravastatin were increased by factors of 1.7 and 2.5, respectively, when given with itraconazole (a potent P450 3A4 inhibitor which also inhibits p-glycoprotein transport) as compared to placebo. The mean t was not affected by itraconazole, suggesting that the relatively small increases in C max and AUC were due solely to increased bioavailability rather than a decrease in clearance, consistent with inhibition of p-glycoprotein transport by itraconazole. This drug transport system is thought to affect bioavail-ability and excretion of HMG-CoA reductase inhibitors, including pravastatin. The AUC and C max of another HMG-CoA reductase inhibitor which is known to be metabolized by cytochrome P450 3A4 increased by factors of 19 and 17, respectively, when given with itraconazole. Antipyrine: Since concomitant administration of pravastatin had no effect on the clearance of antipyrine, interactions with other drugs metabolized via the same hepatic cytochrome isozymes are not expected. Cholestyramine/ Colestipol: Concomitant administration resulted in an approximately 40 to 50% decrease in the mean AUC of pravastatin. However, when pravastatin was administered 1 hour before or 4 hours after cholestyramine or 1 hour before colestipol and a standard meal, there was no clinically significant decrease in bioavailability or therapeutic effect. (See DOSAGE AND ADMINISTRATION: Concomitant Therapy.) Warfarin: Concomitant administration of 40 mg pravastatin had no clinically significant effect on prothrombin time when administered in a study to normal elderly subjects who were stabilized on warfarin. Cimetidine: The AUC0-12hr for pravastatin when given with cimetidine was not significantly different from the AUC for pravastatin when given alone. A significant difference was observed between the AUC's for pravastatin when given with cimetidine compared to when administered with antacid. Digoxin: In a crossover trial involving 18 healthy male subjects given 20 mg pravastatin and 0.2 mg digoxin concurrently for 9 days, the bioavailability parameters of digoxin were not affected. The AUC of pravastatin tended to increase, but the overall bioavailability of prava-statin plus its metabolites SQ 31,906 and SQ 31,945 was not altered. Cyclosporine: Some investigators have measured cyclosporine levels in patients on pravastatin (up to 20 mg), and to date, these results indicate no clinically meaningful eleva-tions in cyclosporine levels. In one single-dose study, pravastatin levels were found to be increased in cardiac transplant patients receiving cyclosporine. Gemfibrozil: In a crossover study in 20 healthy male volunteers given concomitant single doses of pravastatin and gemfibrozil, there was a significant decrease in urinary excretion and protein binding of pravastatin. In addition, there was a significant increase in AUC, C max , and T max for the pravastatin metabolite SQ 31,906. Combination therapy with pravastatin and gemfibrozil is generally not recommended. (See WARNINGS: Skeletal Muscle.) In interaction studies with aspirin, antacids (1 hour prior to PRAVACHOL), cimetidine, nico-tinic acid, or probucol, no statistically significant differences in bioavailability were seen when PRAVACHOL (pravastatin sodium) was administered. Endocrine Function HMG-CoA reductase inhibitors interfere with cholesterol synthesis and lower circulating choles-terol levels and, as such, might theoretically blunt adrenal or gonadal steroid hormone production. Results of clinical trials with pravastatin in males and post-menopausal females were inconsistent with regard to possible effects of the drug on basal steroid hormone levels. In a study of 21 males, the mean testosterone response to human chorionic gonadotropin was sig-nificantly reduced (p 0.004) after 16 weeks of treatment with 40 mg of pravastatin. However, the percentage of patients showing a 50% rise in plasma testosterone after human chorionic gonadotropin stimulation did not change significantly after therapy in these patients. The effects of HMG-CoA reductase inhibitors on spermatogenesis and fertility have not been stud-ied in adequate numbers of patients. The effects, if any, of pravastatin on the pituitarygonadal axis in pre-menopausal females are unknown. Patients treated with pravastatin who display clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should also be exercised if an HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is administered to patients also receiving other drugs (e. g., ketoconazole, spironolactone, cimetidine) that may diminish the levels or activity of steroid hormones. In a placebo-controlled study of 214 pediatric patients with HeFH, of which 106 were treated with pravastatin (20 mg in the children aged 8-13 years and 40 mg in the adolescentsaged 14-18 years) for two years, there were no detectable differences seen in any of the endocrine parameters [ACTH, cortisol, DHEAS, FSH, LH, TSH, estradiol (girls) or testosterone (boys)] relative to placebo. There were no detectable differences seen in height and weight changes, testicular volume changes, or Tanner score relative to placebo. CNS Toxicity CNS vascular lesions, characterized by perivascular hemorrhage and edema and mononu-clear cell infiltration of perivascular spaces, were seen in dogs treated with pravastatin at a dose of 25 mg/ kg/ day. These effects in dogs were observed at approximately 59 times the human dose of 80 mg/ day, based on AUC. Similar CNS vascular lesions have been observed with several other drugs in this class. A chemically similar drug in this class produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion starting at 60 mg/ kg/ day, a dose that produced mean plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose (as mea-sured by total enzyme inhibitory activity). This same drug also produced vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis in dogs treated for 14 weeks at 180 mg/ kg/ day, a dose which resulted in a mean plasma drug level similar to that seen with the 60 mg/ kg/ day dose. Carcinogenesis, Mutagenesis, Impairment of Fertility In a 2-year study in rats fed pravastatin at doses of 10, 30, or 100 mg/ kg body weight, there was an increased incidence of hepatocellular carcinomas in males at the highest dose (p 0.01). These effects in rats were observed at approximately 12 times the human dose (HD) of 80 mg, based on body surface area mg/ m 2 and at approximately 4 times the human dose, based on AUC. In a 2-year study in mice fed pravastatin at doses of 250 and 500 mg/ kg/ day, there was an increased incidence of hepatocellular carcinomas in males and females at both 250 and 500 mg/ kg/ day (p 0.0001). At these doses, lung adenomas in females were increased (p= 0.013). These effects in mice were observed at approximately 15 times (250 mg/ kg/ day) and 23 times (500 mg/ kg/ day) the human dose of 80 mg, based on AUC. In another 2-year study in mice with doses up to 100 mg/ kg/ day (producing drug exposures approximately 2 times the human dose of 80 mg, based on AUC), there were no drug-induced tumors. No evidence of mutagenicity was observed in vitro, with or without rat-liver metabolic activation, in the following studies: microbial mutagen tests, using mutant strains of Salmonella typhimurium or Escherichia coli; a forward mutation assay in L5178Y TK +/-mouse lymphoma cells; a chromosomal aberration test in hamster cells; and a gene con-version assay using Saccharomyces cerevisiae. In addition, there was no evidence of muta-genicity in either a dominant lethal test in mice or a micronucleus test in mice. In a study in rats, with daily doses up to 500 mg/ kg, pravastatin did not produce any adverse effects on fertility or general reproductive performance. However, in a study with another HMG-CoA reductase inhibitor, there was decreased fertility in male rats treated for 34 weeks at 25 mg/ kg body weight, although this effect was not observed in a subsequent fer-tility study when this same dose was administered for 11 weeks (the entire cycle of spermato-genesis, including epididymal maturation). In rats treated with this same reductase inhibitor at 180 mg/ kg/ day, seminiferous tubule degeneration (necrosis and loss of spermatogenic epithe-lium) was observed. Although not seen with pravastatin, two similar drugs in this class caused drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration, and giant cell formation in dogs. The clinical significance of these findings is unclear. Pregnancy Pregnancy Category X. See CONTRAINDICATIONS. Safety in pregnant women has not been established. Pravastatin was not teratogenic in rats at doses up to 1000 mg/ kg daily or in rabbits at doses of up to 50 mg/ kg daily. These doses resulted in 10X (rabbit) or 120X (rat) the human exposure based on surface area (mg/ meter 2 ). Rare reports of congenital anomalies have been received following intrauterine exposure to other HMG-CoA reductase inhibitors. In a review 9 of approximately 100 prospec-tively followed pregnancies in women exposed to simvastatin or lovastatin, the incidences of congenital anomalies, spontaneous abortions and fetal deaths/ stillbirths did not exceed what would be expected in the general population. The number of cases is adequate only to exclude a three-to-four-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identi-fied. As safety in pregnant women has not been established and there is no apparent benefit to therapy with PRAVACHOL (pravastatin sodium) during pregnancy (see CONTRAINDICA-TIONS), treatment should be immediately discontinued as soon as pregnancy is recognized. PRAVACHOL should be administered to women of childbearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards. Nursing Mothers A small amount of pravastatin is excreted in human breast milk. Because of the potential for serious adverse reactions in nursing infants, women taking PRAVACHOL should not nurse (see CONTRAINDICATIONS). Pediatric Use The safety and effectiveness of PRAVACHOL in children and adolescents from 8-18 years of age have been evaluated in a placebo-controlled study of two years duration. Patients treated with pravastatin had an adverse experience profile generally similar to that of patients treated with placebo with influenza and headache commonly reported in both treatment groups. (See ADVERSE REACTIONS: Pediatric Patients.) Doses greater than 40 mg have not been studied in this population. Children and adolescent females of childbearing potential should be counseled on appropriate contraceptive methods while on pravastatin therapy (see CON-TRAINDICATIONS and PRECAUTIONS: Pregnancy). For dosing information see DOSAGE AND ADMINISTRATION: Adult Patients and Pediatric Patients. Double-blind, placebo-controlled pravastatin studies in children less than 8 years of age have not been conducted. Geriatric Use Two secondary prevention trials with pravastatin (CARE and LIPID) included a total of 6,593 sub-jects treated with pravastatin 40 mg for periods ranging up to 6 years. Across these two studies, 36.1% of pravastatin subjects were aged 65 and older and 0.8% were aged 75 and older. The beneficial effect of pravastatin in elderly subjects in reducing cardiovascular events and in modi-fying lipid profiles was similar to that seen in younger subjects. The adverse event profile in the elderly was similar to that in the overall population. Other reported clinical experience has not identified differences in responses to pravastatin between elderly and younger patients. Mean pravastatin AUCs are slightly (25-50%) higher in elderly subjects than in healthy young subjects, but mean C max , T max and t values are similar in both age groups and sub-stantial accumulation of pravastatin would not be expected in the elderly (see CLINICAL PHARMACOLOGY: Pharmacokinetics/ Metabolism). | ||||
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