Liver Enzymes: HMG-CoA reductase inhibitors have been associated with biochemical abnormalities of liver function. Persistent increases of serum transaminase (ALT, AST) values to more than 3 times the upper limit of normal (occurring on two or more not necessarily sequential occasions) have been reported in less than 1.0% of patients treated with cerivastatin sodium in the US over an average period of 11 months. Most of these abnormalities occurred within the first 6 weeks of treatment, resolved after discontinuation of the drug, and were not associated with cholestasis. In most cases, these biochemical abnormalities were asymptomatic.

It is recommended that liver function tests be performed before the initiation of treatment, at 6 and 12 weeks after initiation of therapy or elevation in dose, and periodically thereafter, e. g., semiannually. Patients who develop increased transaminase levels should be monitored with a second liver function evaluation to confirm the finding and be followed thereafter with frequent liver function tests until the abnormality(ies) return to normal. Should an increase in AST or ALT of three times the upper limit of normal or greater persist, withdrawal of cerivastatin sodium therapy is recommended. Active liver disease or unexplained transaminase elevations are contraindications to the use of BAYCOL (cerivastatin sodium tablets) (see CONTRAINDICATIONS).

Caution should be exercised when cerivastatin sodium is administered to patients with a history of liver disease or heavy alcohol ingestion (see CLINICAL PHARMACOLOGY: Pharmacokinetics, Metabolism).

Such patients should be started at the low end of the recommended dosing range and closely monitored. Skeletal Muscle: Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with other HMG-CoA reductase inhibitors. Myopathy, defined as muscle aching or muscle weakness, associated with increases in plasma creatine kinase (CK) values to greater than 10 times the upper limit of normal, was rare (~ 0.2%) in U. S. cerivastatin clinical trials. Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CK. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. BAYCOL (cerivastatin sodium tablets therapy should be discontinued if markedly elevated CK levels occur or myopathy is diagnosed or suspected. BAYCOL (cerivastatin sodium tablets) should be temporarily wfthheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyotysts, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine or electrolyte disorders; or uncontrolled epilepsy.

The risk of myopathy during treatment with other HMG-CoA reductase inhibitors is increased with concurrent administration of cyclosporine, fibric acid derivatives, erythromycin, azole antifungals or lipid- lowering doses of niacin.

Uncomplicated myalgia has been observed infrequently in patients treated with cerivastatin sodium at rates that could not be distinguished from placebo.

The use of fibrates alone occasionally may be associated with myopathy. The combined use of HMG- CoA inhibitors and fibrates generally should be avoided.

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 (see INDICATIONS AND USAGE).

Cerivastatin sodium may elevate creatine kinase and transaminase levels (see ADVERSE REACTIONS). This should be considered in the differential diagnosis of chest pain in a patient on therapy with cerivastatin sodium.

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.

Information for Patients

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

Drug Interactions

Immunosuppressive Drugs, Fibric Acid Derivatives, Niacin (Nicotinic Acid), Erythromycin, Azole Antifungals (See

WARNINGS

ANTACID (Magnesium-Aluminum Hydroxide): Cerivastatin plasma concentrations were not affected by co-administration of antacid.

CIMETlDINE: Cerivastatin plasma concentrations were not affected by co-administration of cimetidine.

CHOLESTYRAMINE: The influence of the bile-acidsequestering agent cholestyramine on the pharmacokinetits of cerivastatin sodium was evaluated in 12 healthy males in 2 separate randomized crossover studies. In the first study, concomitant administration of 0.2 mg cerivastatin sodium and 12 g cholestyramine resulted in decreases of more than 22% for AUC and 40% for C_max when compared to dosing cerivastatin sodium alone. However, in the second study, administration of 12 g cholestyramine 1 hour before the evening meal and 0.3 mg cerivastatin sodium approximately 4 hours after the same evening meal resulted in a decrease in the cerivastatin AUC of less than 8%, and a decrease in C_max of about 30% when compared to dosing cerivastatin sodium alone. Therefore, it would be expected that a dosing schedule of cerivastatin sodium given at bedtime and cholestyramine given before the evening meal would not result in a significant decrease in the clinical effect of cerivastatin sodium.

DIGOXIN: Plasma digoxin levels and digoxin clearance at steady-state were not affected by co-administration of 0.2 mg cerivastatin sodium. Cerivastatin plasma concentrations were also not affected by co-administration of digoxin.

WARFARIN: Co- administration of warfarin and cerivastatin to healthy volunteers did not result in any changes in prothrombin time or clotting factor VII when compared to co-administration of warfarin and placebo. The AUC and C_max of both the (R) and (S) isomers of warfarin were unaffected by concurrent dosing of 0.3 mg cerivastatin sodium. Co-administration of warfarin and cerivastatin did not alter the pharmacokinetics of cerivastatin sodium.

ERYTHROMYCIN: In hypercholesterolemic patients, steady-state cerivastatin AUC and Cmax increased approximately 50% and 24% respectively after 10 days with co-administration of erythromycin, a known inhibitor of cytochrome P450 3A4.

OTHER CONCOMITANT THERAPY: Although specific interaction studies were not performed, in clinical studies, cerivastatin sodium was used concomitantly with angiotensin- converting enzyme (ACE) inhibitors, betablockers, calcium-channel blockers, diuretics, and nonsteroidal anti-inflammatory drugs (NSAIDs) without evidence of clinically significant adverse interactions.

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.

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.

CNS and other Toxicities: Chronic administration of cerivastatin to rodent and non- rodent species demonstrated the principal toxicologic targets and effects observed with other HMG- CoA reductase inhibitors: Hemorrhage and edema in multiple organs and tissues including CNS (dogs); cataracts (dogs); degeneration of muscle fibers (dogs, rats, and mice); hyperkeratosis in the nonglandular stomach (rats and mice, this organ has no human equivalent); liver lesions (dogs, rats, and mice).

CNS lesions were characterized by multifocal bleeding with fibrinoid degeneration of vessel walls in the plexus chorioideus of the brain stem and in the ciliary body of the eye at 0.1 mg/kg/day in the dog. This dose resulted in plasma levels of cerivastatin (C_max), that were about 23 times higher than the mean values in humans taking 0.3 mg/day.† No CNS lesions were observed after chronic treatment with cerivastatin for up to two years in the mouse (C_max up to 7 times that of humans at 0.3 mg/day) and rat (Cmax a up to 2 times that of humans).

Carcinogenesis, Mutagenesis, Impairment of Fertility

A 2-year study was conducted in rats at average daily doses of cerivastatin of 0.007, 0.034, or 0.158 mg/kg. The high dosage level corresponded to plasma drug levels (AUC) of approximately 1-2 times the mean human plasma drug concentrations after a 0.3- mg oral dose, Tumor incidences of treated rats were comparable to controls in all treatment groups. In a 2-year carcinogenicity study in mice with 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 29.1 mg/kg and hepatocellular carcinomas were significantly increased in male mice at 21.8 mg/kg. These doses were in the range of human exposure (dose of 0.3 mg/day).

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 viva in a mouse Micronucleus Test; there was equivocal evidence of mutagenicity in a mouse Dominant Lethal Test.

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, a dose that produced plasma drug levels (Cmax) about 1 2 times higher than mean plasma drug levels for humans receiving 0.3 mg cerivastatin/ day. At a dose of 0.3 mg/ kg/ day (plasma Cmax 4 - 5 times the human level), the length of gestation was marginally prolonged, stillbirths were increased, and the survival rate up to day 4 postpartum was decreased. In the fetuses (Fl), a marginal reduction in fetal weight and delay in bone development was observed. In the matinn of the Fl generation, there was a reduced number of emale rats that B littered.

In the testicles of dogs treated chronically with cerivastatin at a dose of 0.008 mg/kg/day approximately 2 fold the human exposure at doses of d. 3 mg based on C_max), atrophy, vacuolization of the germinal epithelium, spermatidic giant cells, and focal oligospermia were observed. In another l-year study in dogs treated with 0.1 mg/kg/day (approximately 23 fold the human exposure at doses of 0.3 mg based on C_max), 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.

Pregnancy

Pregnancy Category X: (See CONTRAINDICATIONS): Cerivastatin caused a significant increase in incomplete ossification of the lumbar center of the vertebrae in rats at an oral dose of 0.72 mg/kg. Cerivastatin did not cause any anomalies or malformations in rabbits at oral doses up to 0.75 mg/kg. These doses resulted in plasma levels (C_max) 6-7 times the human exposure for rats and 3- 4 times the human exposure for rabbits (human dose 0.3 mg). Cerivastatin crossed the placenta and was found in fetal liver, gastrointestinal tract, and kidneys when pregnant rats were given a single oral dose of 2 mg/kg.

Safety in pregnant women has not been established. Cerivastatin 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. 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 (see CONTRAINDICATIONS), treatment should be immediately discontinued as soon as pregnancy is recognized. If a women becomes pregnant while taking cerivastatin, the drug should be discontinued and the patient advised again as to potential hazards to the fetus.

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 (see CONTRAINDICATIONS).

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

Geriatric Use: In clinical pharmacology studies, there were no clinically relevant effects of age on the pharmacokinetics of cerivastatin sodium.

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.

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 (see CONTRAINDICATIONS and

WARNINGS

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