Cerivastatin precautions

List of precautions
General Homozygous familial hypercholesterolemia Information for patients Endocrine function Carcinogenesis Mutagenesis Impairment of fertility Pregnancy: Pregnancy category X Pediatric use Geriatric use Renal insufficiency Hepatic insufficiency
 * Concomitant endocrine treatment
 * Nursing mothers

General
Before instituting therapy with BAYCOL® (cerivastatin sodium tablets), an attempt should be made to control hypercholesterolemia with appropriate diet, exercise, weight reduction in obese patients, and treatment of underlying medical problems. Cerivastatin sodium may elevate creatine kinase and transaminase levels. This should be considered in the differential diagnosis of chest pain in a patient on therapy with cerivastatin sodium. Return to top

Homozygous familial hypercholesterolemia
Cerivastatin sodium has not been evaluated in patients with rare homozygous familial hypercholesterolemia. HMG-CoA reductase inhibitors have been reported to be less effective in these patients because they lack functional LDL receptors. Return to top

Information for patients
Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Return to top

Endocrine function
HMG-CoA reductase inhibitors interfere with cholesterol synthesis and lower cholesterol levels and, as such, might theoretically blunt adrenal or gonadal steroid hormone production. Clinical studies have shown that cerivastatin sodium has no adverse effect on sperm production and does not reduce basal plasma cortisol concentration, impair adrenal reserve or have an adverse effect on thyroid metabolism as assessed by TSH. Results of clinical trials with drugs in this class have been inconsistent with regard to drug effect on basal and reserve steroid levels. The effects of HMG-CoA reductase inhibitors on male fertility have not been studied in adequate numbers of male patients. The effects, if any, on the pituitary-gonadal axis in pre-menopausal women are unknown. Return to top

Concomitant endocrine treatment
Patients treated with cerivastatin sodium who develop clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should be exercised if an HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is administered to patients also receiving other drugs that may decrease the levels or activity of endogenous steroid hormones, e.g., ketoconazole, spironolactone, or cimetidine. Return to top

Carcinogenesis
A 2-year study was conducted in rats with dietary administration resulting in average daily doses of cerivastatin of 0.007, 0.034, or 0.158 mg/kg. The high dosage level corresponded to plasma free drug levels (AUC) of approximately 2 times those in humans following a 0.8-mg oral dose. Tumor incidences of treated rats were comparable to controls in all treatment groups. In a 2-year carcinogenicity study conducted in mice with dietary administration resulting in average daily doses of cerivastatin of 0.4, 1.8, 9.1, or 55 mg/kg hepatocellular adenomas were significantly increased in male and female mice at ≥ 9.1 mg/kg (AUCfree values about 3 times human at 0.8 mg/day). Hepatocellular carcinomas were significantly increased in male mice at ≥ 1.8 mg/k (AUCfree values in the range of human exposure at 0.8 mg/day). Return to top

Mutagenesis
No evidence of genotoxicity was observed in vitro with or without metabolic activation in the following assays: microbial mutagen tests using mutant strains of S. typhimurium or E. coli, Chinese Hamster Ovary Forward Mutation Assay, Unscheduled DNA Synthesis in rat primary hepatocytes, chromosome aberrations in Chinese Hamster Ovary cells, and spindle inhibition in human lymphocytes. In addition, there was no evidence of genotoxicity in vivo in a mouse Micronucleus Test; there was equivocal evidence of mutagenicity in a mouse Dominant Lethal Test. Return to top

Impairment of fertility
In a combined male and female rat fertility study, cerivastatin had no adverse effects on fertility or reproductive performance at doses up to 0.1 mg/kg/day (in the range of human Cmax free drug levels). At a dose of 0.3 mg/kg/day (about 3 times human Cmax free drug levels), the length of gestation was marginally prolonged, stillbirths were increased, and the survival rate up to day 4 postpartum was decreased. In the fetuses (F1), a marginal reduction in fetal weight and delay in bone development was observed. In the mating of the F1 generation, there was a reduced number of female rats that littered. In the testicles of dogs treated chronically with cerivastatin at a dose of 0.008 mg/kg/day (in the range of human Cmax free drug levels), atrophy, vacuolization of the germinal epithelium, spermatidic giant cells, and focal oligospermia were observed. In another 1-year study in dogs treated with 0.1 mg/kg/day (approximately 17-fold the human exposure at doses of 0.8 mg based on Cmax free), ejaculate volume was small and libido was decreased. Semen analysis revealed an increased number of morphologically altered spermatozoa indicating disturbances of epididymal sperm maturation that was reversible when drug administration was discontinued. Return to top

Pregnancy: Pregnancy category X
Safety in pregnant women has not been established. Cerivastatin should be administered to women of child-bearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards. Rare reports of congenital anomalies have been received following intrauterine exposure to other HMG-CoA reductase inhibitors. In a review of approximately 100 prospectively 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 identified. As safety in pregnant women has not been established and there is no apparent benefit to therapy with BAYCOL® during pregnancy, treatment should be immediately discontinued as soon as pregnancy is recognized. If a woman becomes pregnant while taking cerivastatin, the drug should be discontinued and the patient advised again as to potential hazards to the fetus. Return to top

Nursing mothers
Based on preclinical data, cerivastatin is present in breast milk in a 1.3:1 ratio (milk:plasma). Because of the potential for serious adverse reactions in nursing infants, nursing women should not take cerivastatin. Return to top

Pediatric use
Safety and effectiveness in pediatric patients have not been established. Return to top

Geriatric use
In clinical pharmacology studies, there were no clinically relevant effects of age on the pharmacokinetics of cerivastatin sodium. In one clinical study using BAYCOL 0.8 mg as the starting dose, women over 65 years of age, especially those with low body weight, were observed to be at an increased risk of myopathy. Caution should be exercised when titrating such patients to the 0.8 mg dose of BAYCOL. Return to top

Renal insufficiency
Patients with significant renal impairment (Clcr ≤ 60 mL/min/1.73m2) have increased AUC (up to 60%) and Cmax (up to 23%) and should be administered BAYCOL® with caution. Return to top

Hepatic insufficiency
Safety and effectiveness in hepatically impaired patients have not been established. Cerivastatin should be used with caution in patients who have a history of liver disease and/or consume substantial quantities of alcohol. Return to top