Source: FDA, National Drug Code (US) Revision Year: 2020
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 sterols, including cholesterol. The inhibition of cholesterol biosynthesis reduces the cholesterol in hepatic cells, which stimulates the synthesis of LDL receptors and thereby increases the uptake of LDL particles. The end result of these biochemical processes is a reduction of the plasma cholesterol concentration.
Following oral administration of the capsule, fluvastatin reaches peak concentrations in less than 1 hour. The absolute bioavailability is 24% (range 9% to 50%) after administration of a 10 mg dose.
At steady state, administration of fluvastatin with the evening meal results in a 50% decrease in Cmax, an 11% decrease in AUC, and a more than 2-fold increase in Tmax as compared to administration 4 hours after the evening meal. No significant differences in the lipid-lowering effects were observed between the two administrations. After single or multiple doses above 20 mg, fluvastatin exhibits saturable first-pass metabolism resulting in more than dose proportional plasma fluvastatin concentrations.
Fluvastatin administered as LESCOL XL 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 XL 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 (Tmax 6h) and increased the bioavailability of the XL tablet by approximately 50%. However, the maximum concentration of LESCOL XL 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.
Fluvastatin is 98% bound to plasma proteins. The mean volume of distribution (VDss) is estimated at 0.35 L/kg. At therapeutic concentrations, the protein binding of fluvastatin is not affected by warfarin, salicylic acid and glyburide.
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.
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 (t1/2) of fluvastatin is approximately 3 hours.
In patients with moderate to severe renal impairment (CLCr 10 to 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. LESCOL XL was not evaluated in patients with renal impairment. However, systemic exposures after administration of LESCOL XL are lower than after the 40 mg immediate release capsule.
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. The enantiomer ratios of the two isomers of fluvastatin in hepatic impairment patients were comparable to those observed in healthy subjects.
Plasma levels of fluvastatin are not significantly different in patients age > 65 years compared to patients age 21 to 49 years.
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 to 49 years), where there was an approximate 30% increase in AUC in females. Adjusting for body weight decreases the magnitude of the differences seen. For LESCOL XL, the AUC increases 67% and 77% for women compared to men under fasted and high- fat meal fed conditions, respectively.
Pharmacokinetic data in the pediatric population are not available.
Data from drug-drug interactions studies involving coadministration of gemfibrozil, niacin, itraconazole, erythromycin, tolbutamide or clopidogrel indicate that the PK disposition of fluvastatin is not significantly altered when fluvastatin is coadministered with any of these drugs.
The below listed drug interaction information is derived from studies using fluvastatin capsules. Similar studies have not been conducted using the LESCOL XL tablet.
Table 3. Effect of Coadministered Drugs on Fluvastatin Systemic Exposure:
| Coadministered Drug and Dosing Regimen | Fluvastatin | ||
|---|---|---|---|
| Dose (mg)* | Change in AUC** | Change in Cmax** | |
| Cyclosporine – stable dose (twice daily)† | 20 mg QD for 14 weeks | ↑ 90% | ↑ 30% |
| Fluconazole 400 mg QD Day 1, 200 mg b.i.d. Day 2-4† | 40 mg QD | ↑ 84% | ↑ 44% |
| Cholestyramine 8 g QD | 20 mg QD administered 4 hrs after a meal plus cholestyramine | ↓ 51% | ↓ 83% |
| Rifampicin 600 mg QD for 6 days | 20 mg QD | ↓ 53% | ↓ 42% |
| Cimetidine 400 mg twice daily for 5 days, QD on Day 6 | 20 mg QD | ↑ 30% | ↑ 40% |
| Ranitidine 150 mg twice daily for 5 days, QD on Day 6 | 20 mg QD | ↑ 10% | ↑ 50% |
| Omeprazole 40 mg QD for 6 days | 20 mg QD | ↑ 20% | ↑ 37% |
| Phenytoin 300 mg QD | 40 mg twice daily for 5 days | ↑ 40% | ↑ 27% |
| Propranolol 40 mg twice daily for 3.5 days | 40 mg QD | ↓ 5% | No change |
| Digoxin 0.1–0.5 mg QD for 3 weeks | 40 mg QD | No change | ↑ 11% |
| Diclofenac 25 mg QD | 40 mg QD for 8 days | ↑ 50% | ↑ 80% |
| Glyburide 5–20 mg QD for 22 days | 40 mg twice daily for 14 days | ↑ 51% | ↑ 44% |
| Warfarin 30 mg QD | 40 mg QD for 8 days | ↑ 30% | ↑ 67% |
| Clopidogrel 300 mg loading dose on Day 10, 75 mg QD on Days 11-19 | 80 mg XL QD for 19 days | ↓ 2% | ↑ 27% |
* Single dose unless otherwise noted.
** Mean ratio (with/without coadministered drug and no change = 1-fold) or % change (with/without coadministered drug and no change = 0%); symbols of ↑ and ↓ indicate the exposure increase and decrease, respectively.
† Considered clinically significant [see Dosage and Administration (2) and Drug Interactions (7)].
Data from drug-drug interaction studies involving fluvastatin and coadministration of either gemfibrozil, tolbutamide or losartan indicate that the PK disposition of either gemfibrozil, tolbutamide or losartan is not significantly altered when coadministered with fluvastatin.
Table 4. Effect of Fluvastatin Coadministration on Systemic Exposure of Other Drugs:
| Fluvastatin Dosage Regimen | Coadministered Drug | ||
|---|---|---|---|
| Name and Dose (mg)* | Change in AUC** | Change in Cmax** | |
| 40 mg QD for 5 days | Phenytoin 300 mg QD† | ↑ 20% | ↑ 5% |
| 40 mg twice daily for 21 days | Glyburide 5–20 mg QD for 22 days† | ↑ 70% | ↑ 50% |
| 40 mg QD for 8 days | Diclofenac 25 mg QD | ↑ 25% | ↑ 60% |
| 40 mg QD for 8 days | Warfarin 30 mg QD | S-warfarin: ↑ 7% | S-warfarin: ↑ 10% |
| R-warfarin: no change | R-warfarin: ↑ 6% | ||
* Single dose unless otherwise noted.**Mean ratio (with/without coadministered drug and no change = 1-fold) or % change (with/without coadministered drug and no change = 0%); symbols of ↑ and ↓ indicate the exposure increase and decrease, respectively.
† Considered clinically significant [see Dosage and Administration (2) and Drug Interactions (7)].
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.
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):
| Total Chol | TG | LDL | Apo B | HDL | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Dose | N | % ∆ | N | % ∆ | N | % ∆ | N | % ∆ | N | % ∆ |
| All Patients | ||||||||||
| LESCOL XL 80 mg* | 750 | -25 | 750 | -19 | 748 | -35 | 745 | -27 | 750 | +7 |
| Baseline TG ≥200 mg/dL | ||||||||||
| LESCOL XL 80 mg* | 239 | -25 | 239 | -25 | 237 | -33 | 235 | -27 | 239 | +11 |
* Data for LESCOL XL 80 mg tablet from three 24-week controlled trials.
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.
In the LESCOL 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 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 study, 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% Caucasian, 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 Revas cularization Procedure) (ITT Population):
Outcome data for the LESCOL 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. LESCOL 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 115-190 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:
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