Lescol (Fluvastatin Sodium) - Description and Clinical Pharmacology

Lescol ^®                                                   

(fluvastatin sodium)                                         

Capsules

Lescol ^®   XL

(fluvastatin sodium)

Extended-Release Tablets

Rx only

^{Prescribing Information}

DESCRIPTION

Lescol^® (fluvastatin sodium), is a water-soluble cholesterol lowering agent which acts through the inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase.

      Fluvastatin sodium is [ R *, S *-(E)]-(±)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1 H -indol-2-yl]-3,5-dihydroxy-6-heptenoic acid, monosodium salt. The empirical formula of fluvastatin sodium is C₂₄H₂₅FNO₄•Na, its molecular weight is 433.46 and its structural formula is:

      This molecular entity is the first entirely synthetic HMG-CoA reductase inhibitor, and is in part structurally distinct from the fungal derivatives of this therapeutic class.

      Fluvastatin sodium is a white to pale yellow, hygroscopic powder soluble in water, ethanol and methanol. Lescol is supplied as capsules containing fluvastatin sodium, equivalent to 20 mg or 40 mg of fluvastatin, for oral administration. Lescol^® XL (fluvastatin sodium) is supplied as extended-release tablets containing fluvastatin sodium, equivalent to 80 mg of fluvastatin, for oral administration.

Active Ingredient: fluvastatin sodium

Inactive Ingredients in capsules: gelatin, magnesium stearate, microcrystalline cellulose, pregelatinized starch (corn), red iron oxide, sodium lauryl sulfate, talc, titanium dioxide, yellow iron oxide, and other ingredients.

Capsules may also include: benzyl alcohol, black iron oxide, butylparaben, carboxymethylcellulose sodium, edetate calcium disodium, methylparaben, propylparaben, silicon dioxide and sodium propionate.

Inactive Ingredients in extended-release tablets: microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, potassium bicarbonate, povidone, magnesium stearate, yellow iron oxide, titanium dioxide and polyethylene glycol 8000.

CLINICAL PHARMACOLOGY

A variety of clinical studies have demonstrated that elevated levels of total cholesterol (Total-C), low density lipoprotein cholesterol (LDL-C), triglycerides (TG) and apolipoprotein B (a membrane transport complex for LDL-C) promote human atherosclerosis. Similarly, decreased levels of HDL-cholesterol (HDL-C) and its transport complex, apolipoprotein A, are associated with the development of atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the level of Total-C and LDL-C and inversely with the level of HDL-C.

      Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, IDL and remnants, can also promote atherosclerosis. Elevated plasma triglycerides are frequently found in a triad with low HDL-C levels and small LDL particles, as well as in association with non-lipid metabolic risk factors for coronary heart disease. As such, total plasma TG has not consistently been shown to be an independent risk factor for CHD. Furthermore, the independent effect of raising HDL or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.

      In patients with hypercholesterolemia and mixed dyslipidemia, treatment with Lescol^® (fluvastatin sodium) or Lescol^® XL (fluvastatin sodium) reduced Total-C, LDL-C, apolipoprotein B, and triglycerides while producing an increase in HDL-C. Increases in HDL-C are greater in patients with low HDL-C (<35 mg/dL). Neither agent had a consistent effect on either Lp(a) or fibrinogen. The effect of Lescol or Lescol XL induced changes in lipoprotein levels, including reduction of serum cholesterol, on cardiovascular mortality has not been determined.

Mechanism of Action

Lescol is a competitive inhibitor of HMG-CoA reductase, which is responsible for the conversion of 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.

Pharmacokinetics/Metabolism

Oral Absorption

Fluvastatin is absorbed rapidly and completely following oral administration of the capsule, with peak concentrations reached in less than 1 hour. Following administration of a 10 mg dose, the absolute bioavailability is 24% (range 9%-50%). Administration with food reduces the rate but not the extent of absorption. At steady state, administration of fluvastatin with the evening meal results in a two-fold decrease in C_max and more than two-fold increase in t_max as compared to administration 4 hours after the evening meal. No significant differences in extent of absorption or 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 higher than expected plasma fluvastatin concentrations.

      Fluvastatin has two optical enantiomers, an active 3R,5S and an inactive 3S,5R form. In vivo studies showed that stereo-selective hepatic binding of the active form occurs during the first pass resulting in a difference in the peak levels of the two enantiomers, with the active to inactive peak concentration ratio being about 0.7. The approximate ratio of the active to inactive approaches unity after the peak is seen and thereafter the two enantiomers decline with the same half-life. After an intravenous administration, bypassing the first-pass, metabolism, the ratios of the enantiomers in plasma were similar throughout the concentration-time profiles.

      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%-66%) compared to that of the Lescol 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 XL tablet by approximately 50%. Once Lescol XL begins to be absorbed, fluvastatin concentrations rise rapidly. The maximum concentration seen after a high-fat meal is much less than the peak concentration following a single dose or twice daily dose of the 40 mg Lescol capsule. Overall variability in the pharmacokinetics of Lescol XL is large (42%-64% CV for C_max and AUC), and especially so after a high-fat meal (63%-89% for C_max and AUC). Intrasubject variability in the pharmacokinetics of Lescol XL under fasting conditions (about 25% for C_max and AUC) tends to be much smaller as compared to the overall variability. Multiple peaks in plasma fluvastatin concentrations have been observed after Lescol XL administration.

Distribution

Fluvastatin is 98% bound to plasma proteins. The mean volume of distribution (VD_ss) is estimated at 0.35 L/kg. The parent drug is targeted to the liver and no active metabolites are present systemically. At therapeutic concentrations, the protein binding of fluvastatin is not affected by warfarin, salicylic acid and glyburide.

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. Both enantiomers of fluvastatin are metabolized in a similar manner.

      In vitro studies demonstrated that fluvastatin undergoes oxidative metabolism, predominantly via 2C9 isozyme systems (75%). Other isozymes that contribute to fluvastatin metabolism are 2C8 (~5%) and 3A4 (~20 %). (See PRECAUTIONS: Drug Interactions Section).

Elimination

Fluvastatin is primarily (about 90%) eliminated in the feces as metabolites, with less than 2% present as unchanged drug. Urinary recovery is about 5%. After a radiolabeled dose of fluvastatin, the clearance was 0.8 L/h/kg. Following multiple oral doses of radiolabeled compound, there was no accumulation of fluvastatin; however, there was a 2.3- fold accumulation of total radioactivity.

      Steady-state plasma concentrations show no evidence of accumulation of fluvastatin following immediate release capsule administration of up to 80 mg daily, as evidenced by a beta-elimination half-life of less than 3 hours. However, under conditions of maximum rate of absorption (i.e., fasting) systemic exposure to fluvastatin is increased 33% to 53% compared to a single 20 mg or 40 mg dose of the immediate- release capsule. Following once daily administration of the 80 mg Lescol XL tablet for 7 days, systemic exposure to fluvastatin is increased (20%-30%) compared to a single dose of the 80 mg Lescol XL tablet. Terminal half-life of Lescol XL was about 9 hours as a result of the slow-release formulation.

      Single-dose and steady-state pharmacokinetic parameters in 33 subjects with hypercholesterolemia for the capsules and in 35 healthy subjects for the extended-release tablets are summarized below:

Table 1 Single-Dose and Steady-State Pharmacokinetic Parameters

		C max   (ng/mL) mean±SD (range)	AUC (ng·h/mL) mean±SD (range)	t max   (hr) mean±SD (range)	CL/F (L/hr) mean±SD (range)	t 1/2 (hr) mean±SD (range)
Capsules
	20 mg single dose (n=17)	166±106	207±65	0.9±0.4	107±38.1	2.5±1.7
		(48.9-517)	(111-288)	(0.5-2.0)	(69.5-181)	(0.5-6.6)
	20 mg twice daily (n=17)	200±86	275±111	1.2±0.9	87.8±45	2.8±1.7
		(71.8-366)	(91.6-467)	(0.5-4.0)	(42.8-218)	(0.9-6.0)
	40 mg single dose (n=16)	273±189	456±259	1.2±0.7	108±44.7	2.7±1.3
		(72.8-812)	(207-1221)	(0.75-3.0)	(32.8-193)	(0.8-5.9)
	40 mg twice daily (n=16)	432±236	697±275	1.2±0.6	64.2±21.1	2.7±1.3
		(119-990)	(359-1559)	(0.5-2.5)	(25.7-111)	(0.7-5.0)
Extended-Release Tablets 80 mg single dose (n=24)
	80 mg single dose, fasting (n=24)	126±53	579±341	3.2± 2.6	-	-
		(37-242)	(144-1760)	(1-12)
	80 mg single dose, fed state high- fat meal (n=-24)	183±163	861±632	6	-	-
		(21-733)	(199-3132)	(2-24)
Extended-Release Tablets 80 mg following 7 days dosing (steady-state) (n=11)
	80 mg once daily, fasting (n=11)	102±42	630±326	2.6±0.91	-	-
		(43.9-181)	(247-1406)	(1.5-4)

Special Populations

Renal Insufficiency:

No significant (<6%) renal excretion of fluvastatin occurs in humans.

Hepatic Insufficiency:

Fluvastatin is subject to saturable first-pass metabolism/sequestration by the liver and is eliminated primarily via the biliary route. Therefore, the potential exists for drug accumulation in patients with hepatic insufficiency. Caution should therefore be exercised when fluvastatin sodium is administered to patients with a history of liver disease or heavy alcohol ingestion (see WARNINGS).

      Fluvastatin AUC and C_max values increased by about 2.5- fold in hepatic insufficiency patients. This result was attributed to the decreased presystemic metabolism due to hepatic dysfunction. The enantiomer ratios of the two isomers of fluvastatin in hepatic insufficiency patients were comparable to those observed in healthy subjects.

Age:

Plasma levels of fluvastatin are not affected by age.

Gender:

Women tend to have slightly higher (but statistically insignificant) fluvastatin concentrations than men for the immediate- release capsule. This is most likely due to body weight differences, as adjusting for body weight decreases the magnitude of the differences seen. For Lescol XL, there are 67% and 77% increases in systemic availability for women over men under fasted and high- fat meal conditions.

Pediatric:

Pharmacokinetic data in the pediatric population are not available. 

CLINICAL STUDIES

Hypercholesterolemia (heterozygous familial and nonfamilial) and Mixed Dyslipidemia

In 12 placebo-controlled studies in patients with Type IIa or IIb hyperlipoproteinemia, Lescol^® (fluvastatin sodium) alone was administered to 1621 patients in daily dose regimens of 20 mg, 40 mg, and 80 mg (40 mg twice daily) for at least 6 weeks duration. After 24 weeks of treatment, daily doses of 20 mg, 40 mg, and 80 mg (40 mg twice daily) resulted in median LDL-C reductions of 22% (n=747), 25% (n=748) and 36% (n=257), respectively. Lescol treatment produced dose-related reductions in Apo B and in triglycerides and increases in HDL-C. The median (25^th, 75^th percentile) percent changes from baseline in HDL-C after 12 weeks of treatment with Lescol at daily doses of 20 mg, 40 mg and 80 mg (40 mg twice daily) were +2 (-4,+10), +5 (-2,+12), and +4 (-3,+12), respectively. In a subgroup of patients with primary mixed dyslipidemia, defined as baseline TG levels ≥200 mg/dL, treatment with Lescol also produced significant decreases in Total-C, LDL-C, TG and Apo B and variable increases in HDL-C. The median (25^th, 75^th percentile) percent changes from baseline in HDL-C after 12 weeks of treatment with Lescol at daily doses of 20 mg, 40 mg and 80 mg (40 mg twice daily) in this population were +4 (-2,+12), +8 (+1,+15), and +4 (-3,+13), respectively.

      In a long-term open-label free titration study, after 96 weeks LDL-C decreases of 25% (20 mg, n=68), 31% (40 mg, n=298) and 34% (80 mg, n=209) were seen. No consistent effect on Lp(a) was observed.

      Lescol^® XL (fluvastatin sodium) Extended-Release Tablets have been studied in five controlled studies of patients with Type IIa or IIb hyperlipoproteinemia. 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. Therapeutic response is well established within two weeks, and a maximum response is achieved within four weeks. After four weeks of therapy, the median decrease in LDL-C was 38% and at Week 24 endpoint the median LDL-C decrease was 35%. Significant increases in HDL-C were also observed. The median (25^th and 75^th percentile) percent changes from baseline in HDL-C for Lescol XL were +7(+0,+15) after 24 weeks of treatment.

Table 2 Median Percent Change in Lipid Parameters from Baseline to Week 24 Endpoint All Placebo-Controlled Studies (Lescol^®) and Active Controlled Trials (Lescol^® XL)

	Total Chol.		TG		LDL		Apo B		HDL
Dose	N	% ∆	N	% ∆	N	% ∆	N	% ∆	N	% ∆
All Patients
Lescol 20 mg1	747	-17	747	-12	747	-22	114	-19	747	+3
Lescol 40 mg1	748	-19	748	-14	748	-25	125	-18	748	+4
Lescol 40 mg twice daily1	257	-27	257	-18	257	-36	232	-28	257	+6
Lescol XL 80 mg2	750	-25	750	-19	748	-35	745	-27	750	+7
Baseline TG ≥200 mg/dL
Lescol 20 mg1	148	-16	148	-17	148	-22	23	-19	148	+6
Lescol 40 mg1	179	-18	179	-20	179	-24	47	-18	179	+7
Lescol 40 mg twice daily1	76	-27	76	-23	76	-35	69	-28	76	+9
Lescol XL 80 mg2	239	-25	239	-25	237	-33	235	-27	239	+11

^{1 Data for Lescol from 12 placebo- controlled trials}

^{2 Data for Lescol XL 80 mg tablet from three 24- week controlled trials}

      In patients with primary mixed dyslipidemia (Fredrickson Type IIb) as defined by baseline plasma triglycerides levels ≥200 mg/dL, Lescol XL 80 mg produced a median reduction in triglycerides of 25%. In these patients, Lescol XL 80 mg produced median (25^th and 75^th percentile) percent change from baseline in HDL-C of +11(+3,+20). Significant decreases in Total-C, LDL-C, and Apo B were also achieved. In these studies, patients with triglycerides >400 mg/dL were excluded.

Heterozygous Familial Hypercholesterolemia in Pediatric Patients

Fluvastatin sodium was studied in two open-label, uncontrolled, dose-titration studies which enrolled pediatric patients with heterozygous familial hypercholesterolemia. The first study enrolled 29 pre-pubertal boys, 9-12 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 Lescol capsules 20 mg daily with dose adjustments every 6 weeks to 40 mg daily then 80 mg daily (40 mg bid) to achieve an LDL-C goal of 96.7 to 123.7 mg/dL. Endpoint analyses were performed at Year 2. 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 Lescol 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.

      In the first study, Lescol 20 mg to 80 mg daily doses 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). In the second study, Lescol 20 mg to 80 mg daily doses decreased plasma levels of Total-C and LDL-C by 22% and 28%, respectively. The mean achieved LDL-C was 159 mg/dL (range: 90-295 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 Lescol or Lescol XL therapy in childhood to reduce morbidity and mortality in adulthood has not been established.

Reduction in the Risk of Recurrent Cardiac Events

In the Lescol Intervention Prevention Study, the effect of Lescol 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 coronary heart disease 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 Lescol 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. At baseline patients had total cholesterol between 100 and 367 mg/dL (mean 201 mg/dL), LDL-C between 42 and 243 mg/dL (mean 132 mg/dL), triglycerides between 15 and 270 mg/dL (mean 70 mg/dL) and HDL-C between 8 and 174 mg/dL (mean 39 mg/dL).

      Lescol significantly reduced the risk of recurrent cardiac events (Figure 1) by 22% (p=0.013, 181 patients in the Lescol group vs. 222 patients in the placebo group). Revascularization procedures comprised the majority of the initial recurrent cardiac events (143 revascularization procedures in the Lescol 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 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 Lescol 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

Atherosclerosis

In the Lipoprotein and Coronary Atherosclerosis Study (LCAS), the effect of Lescol therapy on coronary atherosclerosis was assessed by quantitative coronary angiography (QCA) in patients with coronary artery disease 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 Lescol 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. These baseline levels 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.

      Lescol significantly slowed the progression of coronary atherosclerosis. Compared to placebo, Lescol significantly slowed the progression of lesions as measured by within-patient per-lesion change in minimum lumen diameter (MLD), the primary endpoint (see 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). Additionally, a significant difference in favor of Lescol 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.