Lescol XL (Page 5 of 7)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

A 2-year study was performed in rats at dose levels of 6, 9, and 18-24 (escalated after 1 year) mg/kg/day. These treatment levels represented plasma drug levels of approximately 9, 13, and 26-35 times the mean human plasma drug concentration after a 40 mg oral dose. A low incidence of forestomach squamous papillomas and 1 carcinoma of the forestomach at the 24 mg/kg/day dose level was considered to reflect the prolonged hyperplasia induced by direct contact exposure to fluvastatin sodium rather than to a systemic effect of the drug. In addition, an increased incidence of thyroid follicular cell adenomas and carcinomas was recorded for males treated with 18-24 mg/kg/day. The increased incidence of thyroid follicular cell neoplasm in male rats with fluvastatin sodium appears to be consistent with findings from other HMG-CoA reductase inhibitors. In contrast to other HMG-CoA reductase inhibitors, no hepatic adenomas or carcinomas were observed.

The carcinogenicity study conducted in mice at dose levels of 0.3, 15 and 30 mg/kg/day revealed, as in rats, a statistically significant increase in forestomach squamous cell papillomas in males and females at 30 mg/kg/day and in females at 15 mg/kg/day. These treatment levels represented plasma drug levels of approximately 0.05, 2, and 7 times the mean human plasma drug concentration after a 40 mg oral dose.

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 ; malignant transformation assay in BALB/3T3 cells; unscheduled DNA synthesis in rat primary hepatocytes; chromosomal aberrations in V79 Chinese Hamster cells; HGPRT V79 Chinese Hamster cells. In addition, there was no evidence of genotoxicity in vivo in either a rat chromosome aberration study or mouse micronucleus test.

In a study in rats at dose levels for females of 0.6, 2 and 6 mg/kg/day and at dose levels for males of 2, 10 and 20 mg/kg/day, fluvastatin sodium had no adverse effects on the fertility or reproductive performance.

Seminal vesicles and testes were small in hamsters treated for 3 months at 20 mg/kg/day (approximately three times the 40 mg human daily dose based on surface area, mg/m2). There was tubular degeneration and aspermatogenesis in testes as well as vesiculitis of seminal vesicles. Vesiculitis of seminal vesicles and edema of the testes were also seen in rats treated for 2 years at 18 mg/kg/day (approximately 4 times the human Cmax achieved with a 40 mg daily dose).

Fluvastatin sodium produced delays in skeletal development in rats at doses of 12 mg/kg/day and in rabbits at doses of 10 mg/kg/day. Malaligned thoracic vertebrae were seen in rats at 36 mg/kg, a dose that produced maternal toxicity. These doses resulted in 2 times (rat at 12 mg/kg) or 5 times (rabbit at 10 mg/kg) the 40 mg human exposure based on mg/m2 surface area. A study in which female rats were dosed during the third trimester at 12 and 24 mg/kg/day resulted in maternal mortality at or near term and postpartum. In addition, fetal and neonatal lethality were apparent. No effects on the dam or fetus occurred at 2 mg/kg/day. A second study at levels of 2, 6, 12 and 24 mg/kg/day confirmed the findings in the first study with neonatal mortality beginning at 6 mg/kg. A modified Segment III study was performed at dose levels of 12 or 24 mg/kg/day with or without the presence of concurrent supplementation with mevalonic acid, a product of HMG-CoA reductase which is essential for cholesterol biosynthesis. The concurrent administration of mevalonic acid completely prevented the maternal and neonatal mortality but did not prevent low body weights in pups at 24 mg/kg on Days 0 and 7 postpartum.

14 CLINICAL STUDIES

Figure 1. Primary Endpoint – Recurrent Cardiac Events (Cardiac Death, Nonfatal MI or Revascularization Procedure) (ITT Population)Figure 2. Lescol® Intervention Prevention Study — Primary and Secondary EndpointsFigure 3 Change in Minimum Lumen Diameter (mm)Figure 4 Change in % Diameter Stenosis

14.1 Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia

LESCOL XL has been studied in five controlled studies of patients with primary hypercholesterolemia and mixed dyslipidemia. LESCOL XL was administered to over 900 patients in trials from 4 to 26 weeks in duration. In the three largest of these studies, LESCOL XL given as a single daily dose of 80 mg significantly reduced Total-C, LDL-C, TG and Apo B and resulted in increases in HDL-C (Table 5).

In patients with primary mixed dyslipidemia as defined by baseline plasma TG levels ≥ 200 mg/dL and < 400 mg/dL, treatment with LESCOL XL produced significant decreases in Total-C, LDL-C, TG and Apo B and variable increases in HDL-C (Table 5).

Table 5. Median Percent Change in Lipid Parameters From Baseline to Week 24 Endpoint All Active Controlled Trials (LESCOL XL)
* Data for LESCOL XL 80 mg tablet from three 24-week controlled trials.
Total Chol TG LDL Apo B HDL
Dose N % ∆ N % ∆ N % ∆ N % ∆ N % ∆
All Patients
LESCOL XL 80 mg* 750-25750-19748-35745-27750+7
Baseline TG ≥ 200 mg/dL
LESCOL XL 80 mg* 239-25239-25237-33235-27239+11

14.2 Heterozygous Familial Hypercholesterolemia in Pediatric Patients

Fluvastatin sodium was studied in two open-label, uncontrolled, dose-titration studies. The first study enrolled 29 pre-pubertal boys, 9 to 12 years of age, who had an LDL-C level > 90th percentile for age and one parent with primary hypercholesterolemia and either a family history of premature ischemic heart disease or tendon xanthomas. The mean baseline LDL-C was 226 mg/dL (range 137-354 mg/dL). All patients were started on fluvastatin capsules 20 mg daily with dose adjustments every 6 weeks to 40 mg daily then 80 mg daily (40 mg twice daily) to achieve an LDL-C goal between 96.7 to 123.7 mg/dL. Endpoint analyses were performed at Year 2. Fluvastatin sodium decreased plasma levels of Total-C and LDL-C by 21% and 27%, respectively. The mean achieved LDL-C was 161 mg/dL (range 74-336 mg/dL).

The second study enrolled 85 male and female patients, 10 to 16 years of age, who had an LDL-C > 190 mg/dL or LDL-C > 160 mg/dL and one or more risk factors for coronary heart disease, or LDL-C > 160 mg/dL and a proven LDL-receptor defect. The mean baseline LDL-C was 225 mg/dL (range 148-343 mg/dL). All patients were started on fluvastatin capsules 20 mg daily with dose adjustments every 6 weeks to 40 mg daily then 80 mg daily (LESCOL 80 mg XL tablet) to achieve an LDL-C goal of < 130 mg/dL. Endpoint analyses were performed at Week 114. Fluvastatin sodium decreased plasma levels of Total-C and LDL-C by 22% and 28%, respectively. The mean achieved LDL-C was 159 mg/dL (range 90 to 295 mg/dL).

The majority of patients in both studies (83% in the first study and 89% in the second study) were titrated to the maximum daily dose of 80 mg. At study endpoint, 26% to 30% of patients in both studies achieved a targeted LDL-C goal of < 130 mg/dL. The long-term efficacy of fluvastatin sodium therapy in childhood to reduce morbidity and mortality in adulthood has not been established.

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