Fluvastatin Sodium ER 80 mg Tablet, Extended Release, 100-count — NDC 0781-8017-01 (Billing 00781-8017-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Fluvastatin is a competitive inhibitor of HMG-CoA reductase, the rate limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate, a precursor of cholesterol.

12.2Pharmacodynamics Inhibition of HMG-CoA reductase by fluvastatin accelerates the expression of LDL-receptors, followed by the uptake of LDL-C from blood to the liver, leading to a decrease in plasma LDL-C and total cholesterol. Sustained inhibition of cholesterol synthesis in the liver also decreases levels of very-low-density lipoproteins. The maximum LDL-C reduction of fluvastatin sodium extended-release tablets is usually achieved by 4 weeks and is maintained after that.

12.3Pharmacokinetics Absorption Fluvastatin administered as fluvastatin sodium extended-release 80 mg tablets reaches peak concentration in approximately 3 hours under fasting conditions, after a low-fat meal, or 2.5 hours after a low-fat meal. The mean relative bioavailability of the extended-release tablet is approximately 29% (range, 9% to 66%) compared to that of the fluvastatin immediate-release capsule administered under fasting conditions. Administration of a high-fat meal delayed the absorption (T max 6h) and increased the bioavailability of the extended-release tablet by approximately 50%.

However, the maximum concentration of fluvastatin sodium extended-release tablet seen after a high-fat meal is less than the peak concentration following a single dose or twice daily dose of the 40 mg fluvastatin capsule. Distribution Fluvastatin is 98% bound to plasma proteins. The mean volume of distribution (VD ss ) is estimated at

0.35L/kg. At therapeutic concentrations, the protein binding of fluvastatin is not affected by warfarin, salicylic acid and glyburide. Elimination Metabolism Fluvastatin is metabolized in the liver, primarily via hydroxylation of the indole ring at the 5- and 6-positions.

N-dealkylation and beta-oxidation of the side-chain also occurs. The hydroxy metabolites have some pharmacologic activity, but do not circulate in the blood. Fluvastatin has two enantiomers.

Both enantiomers of fluvastatin are metabolized in a similar manner. In vitro data indicate that fluvastatin metabolism involves multiple Cytochrome P450 (CYP) isozymes. CYP2C9 isoenzyme is primarily involved in the metabolism of fluvastatin (approximately 75%), while CYP2C8 and CYP3A4 isoenzymes are involved to a much less extent, i.e., approximately 5% and approximately 20%, respectively.

Excretion Following oral administration, fluvastatin is primarily (about 90%) excreted in the feces as metabolites, with less than 2% present as unchanged drug. Approximately 5% of a radiolabeled oral dose were recovered in urine. The elimination half-life (t 1/2 ) of fluvastatin is approximately 3 hours.

Specific Populations Geriatric Patients Plasma levels of fluvastatin are not significantly different in patients age > 65 years compared to patients age 21 to 49 years. Gender In a study evaluating the effect of age and gender on fluvastatin pharmacokinetics, there were no significant differences in fluvastatin exposures between males and females, except between younger females and younger males (both ages 21-49 years), where there was an approximate 30% increase in area under the curve (AUC) in females. Adjusting for body weight decreases the magnitude of the differences seen.

For fluvastatin sodium extended-release tablets, the AUC increases 67% and 77% for women compared to men under fasted and high- fat meal fed conditions, respectively. Pediatric Patients Pharmacokinetic data in the pediatric population are not available. Patients with Renal Impairment In patients with moderate to severe renal impairment (CLCr 10-40 mL/min), AUC and Cmax increased approximately 1.2-fold after administration of a single dose of 40 mg fluvastatin compared to healthy volunteers.

In patients with end-stage renal disease on hemodialysis, the AUC increased by approx… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Fluvastatin is a competitive inhibitor of HMG-CoA reductase, the rate limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate, a precursor of cholesterol.

12.3Pharmacokinetics Absorption Fluvastatin administered as fluvastatin sodium extended-release 80 mg tablets reaches peak concentration in approximately 3 hours under fasting conditions, after a low-fat meal, or 2.5 hours after a low-fat meal. The mean relative bioavailability of the extended-release tablet is approximately 29% (range, 9% to 66%) compared to that of the fluvastatin immediate-release capsule administered under fasting conditions. Administration of a high-fat meal delayed the absorption (T max 6h) and increased the bioavailability of the extended-release tablet by approximately 50%.

However, the maximum concentration of fluvastatin sodium extended-release tablet seen after a high-fat meal is less than the peak concentration following a single dose or twice daily dose of the 40 mg fluvastatin capsule. Distribution Fluvastatin is 98% bound to plasma proteins. The mean volume of distribution (VD ss ) is estimated at

0.35L/kg. At therapeutic concentrations, the protein binding of fluvastatin is not affected by warfarin, salicylic acid and glyburide. Elimination Metabolism Fluvastatin is metabolized in the liver, primarily via hydroxylation of the indole ring at the 5- and 6-positions.

N-dealkylation and beta-oxidation of the side-chain also occurs. The hydroxy metabolites have some pharmacologic activity, but do not circulate in the blood. Fluvastatin has two enantiomers.

Both enantiomers of fluvastatin are metabolized in a similar manner. In vitro data indicate that fluvastatin metabolism involves multiple Cytochrome P450 (CYP) isozymes. CYP2C9 isoenzyme is primarily involved in the metabolism of fluvastatin (approximately 75%), while CYP2C8 and CYP3A4 isoenzymes are involved to a much less extent, i.e., approximately 5% and approximately 20%, respectively.

Excretion Following oral administration, fluvastatin is primarily (about 90%) excreted in the feces as metabolites, with less than 2% present as unchanged drug. Approximately 5% of a radiolabeled oral dose were recovered in urine. The elimination half-life (t 1/2 ) of fluvastatin is approximately 3 hours.

Specific Populations Geriatric Patients Plasma levels of fluvastatin are not significantly different in patients age > 65 years compared to patients age 21 to 49 years. Gender In a study evaluating the effect of age and gender on fluvastatin pharmacokinetics, there were no significant differences in fluvastatin exposures between males and females, except between younger females and younger males (both ages 21-49 years), where there was an approximate 30% increase in area under the curve (AUC) in females. Adjusting for body weight decreases the magnitude of the differences seen.

For fluvastatin sodium extended-release tablets, the AUC increases 67% and 77% for women compared to men under fasted and high- fat meal fed conditions, respectively. Pediatric Patients Pharmacokinetic data in the pediatric population are not available. Patients with Renal Impairment In patients with moderate to severe renal impairment (CLCr 10-40 mL/min), AUC and Cmax increased approximately 1.2-fold after administration of a single dose of 40 mg fluvastatin compared to healthy volunteers.

In patients with end-stage renal disease on hemodialysis, the AUC increased by approximately 1.5-fold. Fluvastatin sodium extended-release tablets were not evaluated in patients with renal impairment [see Use in Specific Populations (8.6)] . However, systemic exposures after administration of fluvastatin sodium extended-release tablets are lower than after the 40 mg immediate release capsule.

Patients with Hepatic Impairment In patients with hepatic impairment due to liver cirrhosis, fluvastatin AUC and Cmax increased approximately 2.5-fold compared to healthy subjects after administration of a single 40 mg dose [see Use in Specific Populations (8.7)] . The enantiomer ratios of the two isomers of fluvastatin in hepatic impairment patients were comparable to those observed in healthy subjects. Drug… [Excerpted — this section continues on DailyMed.]

14 CLINICAL STUDIES Secondary Prevention of Cardiovascular Disease In the Fluvastatin Capsules Intervention Prevention Study (LIPS), the effect of fluvastatin capsules 40 mg administered twice daily on the risk of recurrent cardiac events (time to first occurrence of cardiac death, nonfatal myocardial infarction, or revascularization) was assessed in 1677 adult patients with CHD who had undergone a percutaneous coronary intervention (PCI) procedure (mean time from PCI to randomization = 3 days). In this multicenter, randomized, double-blind, placebo-controlled trial, patients were treated with dietary/lifestyle counseling and either fluvastatin 40 mg (n = 844) or placebo (n = 833) given twice daily for a median of 3.9 years.

The study population was 84% male, 98% White, with 37% > 65 years of age. Mean baseline lipid concentrations were: total cholesterol 201 mg/dL, LDL-C 132 mg/dL, triglycerides 70 mg/dL, and HDL-C 39 mg/dL. Fluvastatin capsules significantly reduced the risk of recurrent cardiac events (Figure 1) by 22% (p = 0.013, 181 patients in the fluvastatin capsules group versus 222 patients in the placebo group).

Revascularization procedures comprised the majority of the initial recurrent cardiac events (143 revascularization procedures in the fluvastatin capsules group and 171 in the placebo group). Consistent trends in risk reduction were observed in patients > 65 years of age. Figure 1.

Primary Endpoint – Recurrent Cardiac Events (Cardiac Death, Nonfatal MI or Revascularization Procedure) (ITT Population) Outcome data for the Fluvastatin Capsules Intervention Prevention Study are shown in Figure 2. After exclusion of revascularization procedures (CABG and repeat PCI) occurring within the first 6 months of the initial procedure involving the originally instrumental site, treatment with fluvastatin capsules was associated with a 32% (p = 0.002) reduction in risk of late revascularization procedures (CABG or PCI occurring at the original site > 6 months after the initial procedure, or at another site).

Figure 2. Fluvastatin Capsules Intervention Prevention Study–- Primary and Secondary Endpoints In the Lipoprotein and Coronary Atherosclerosis Study (LCAS), the effect of fluvastatin capsule therapy on coronary atherosclerosis was assessed by quantitative coronary angiography (QCA) in patients with CAD and mild to moderate hypercholesterolemia (baseline LDL-C range 115 to 190 mg/dL). In this randomized double-blind, placebo-controlled trial, 429 patients were treated with conventional measures (Step 1, AHA Diet) and either fluvastatin 40 mg/day or placebo.

In order to provide treatment to patients receiving placebo with LDL-C levels ≥160 mg/dL at baseline, adjunctive therapy with cholestyramine was added after Week 12 to all patients in the study with baseline LDL-C values of ≥ 160 mg/dL, which were present in 25% of the study population. Quantitative coronary angiograms were evaluated at baseline and 2.5 years in 340 (79%) angiographic evaluable patients. Compared to placebo, fluvastatin capsules significantly slowed the progression of coronary atherosclerosis as measured by within-patient per-lesion change in minimum lumen diameter (MLD), the primary endpoint (Figure 3 below), percent diameter stenosis (Figure 4), and the formation of new lesions (13% of all fluvastatin patients versus 22% of all placebo patients).

A significant difference in favor of fluvastatin capsules was found between all fluvastatin and all placebo patients in the distribution among the three categories of definite progression, definite regression, and mixed or no change. Beneficial angiographic results (change in MLD) were independent of patients’ gender and consistent across a range of baseline LDL-C levels. Figure 3.

Change in Minimum Lumen Diameter (mm) Figure 4. Change in % Diameter Stenosis Primary Hyperlipidemia in Adults Fluvastatin sodium extended-release tablets have been studied in five controlled trials of adult patients with primary… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility In a 2-year carcinogenicity study in rats at doses of 6, 9, and 18 to 24 (escalated after 1 year) mg/kg/day, there was an increased incidence of thyroid follicular cell adenomas and carcinomas in males treated with 18 to 4 mg/kg/day. Additionally, a low incidence of forestomach squamous papillomas and one forestomach carcinoma were observed at the 18 to 24 mg/kg/day dose, likely due to prolonged direct contact exposure rather than a systemic effect. This dose represents a plasma AUC exposure approximately 26 to 35 times the mean human plasma drug concentration after a 40 mg oral dose.

A carcinogenicity study conducted in mice at doses of 0.3, 15 and 30 mg/kg/day revealed a statistically significant increase in forestomach squamous cell papillomas in females at 15 mg/kg/day and in males and females at 30 mg/kg/day. These doses represent plasma AUC exposures approximately 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 fertility study in rats with daily doses up to 6 mg/kg/day for females and 20 mg/kg/day for males, fluvastatin sodium had no adverse effects on the fertility or reproductive performance. Hamsters treated for 3 months at 20 mg/kg/day (approximately three times the 40 mg human daily dose based on body surface area, mg/m 2 ) showed small seminal vesicles and testes, along with tubular degeneration and aspermatogenesis in the testes and vesiculitis in the seminal vesicles.

Rats treated for 2 years at 18 mg/kg/day (approximately four times human exposure based on body surface area) exhibited vesiculitis in the seminal vesicles and edema in the testes.