Lescol Information
Lescol (Fluvastatin sodium) Description
Lescol (Fluvastatin sodium) (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 [*,*-()]-(±)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1-indol-2-yl]-3,5-dihydroxy-6-heptenoic acid, monosodium
salt. The empirical formula of fluvastatin sodium is CHFNO•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 (Fluvastatin sodium) is supplied as capsules
containing fluvastatin sodium, equivalent to 20 mg or 40 mg of fluvastatin, for
oral administration. Lescol (Fluvastatin sodium) XL (fluvastatin sodium) is
supplied as extended-release tablets containing fluvastatin sodium, equivalent
to 80 mg of fluvastatin, for oral administration.
Lescol (Fluvastatin sodium) 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 (Fluvastatin sodium) 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 (Fluvastatin sodium) or Lescol (Fluvastatin sodium) XL induced changes in lipoprotein levels, including
reduction of serum cholesterol, on cardiovascular mortality has not been
determined.
Lescol (Fluvastatin sodium) 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.
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 and more than
two-fold increase in t 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 (Fluvastatin sodium) 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 (Fluvastatin sodium) immediate-release capsule administered under fasting conditions.
Administration of a high-fat meal delayed the absorption (T: 6H) and increased the bioavailability of the XL tablet by
approximately 50%. Once Lescol (Fluvastatin sodium) 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 (Fluvastatin sodium) capsule. Overall variability in the
pharmacokinetics of Lescol (Fluvastatin sodium) XL is large (42%-64% CV for C and AUC), and especially so after a high-fat meal (63%-89%
for C and AUC). Intrasubject variability in the
pharmacokinetics of Lescol (Fluvastatin sodium) XL under fasting conditions (about 25% for C and AUC) tends to be much smaller as compared to the
overall variability. Multiple peaks in plasma fluvastatin concentrations have
been observed after Lescol (Fluvastatin sodium) XL administration.
Fluvastatin is 98% bound to plasma proteins. The mean volume of
distribution (VD) 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.
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).
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 (Fluvastatin sodium) XL tablet for 7 days, systemic exposure to
fluvastatin is increased (20%-30%) compared to a single dose of the 80 mg Lescol (Fluvastatin sodium)
XL tablet. Terminal half-life of Lescol (Fluvastatin sodium) 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:
No significant (<6%) renal excretion of fluvastatin occurs in
humans.
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 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.
Plasma levels of fluvastatin are not affected by age.
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 (Fluvastatin sodium) XL,
there are 67% and 77% increases in systemic availability for women over men
under fasted and high- fat meal conditions.
Pharmacokinetic data in the pediatric population are not
available.
Lescol (Fluvastatin sodium) Clinical Studies
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 (Fluvastatin sodium) treatment produced dose-related reductions in Apo B and in
triglycerides and increases in HDL-C. The median (25,
75 percentile) percent changes from baseline in HDL-C
after 12 weeks of treatment with Lescol (Fluvastatin sodium) 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 (Fluvastatin sodium) also produced
significant decreases in Total-C, LDL-C, TG and Apo B and variable increases in
HDL-C. The median (25, 75
percentile) percent changes from baseline in HDL-C after 12 weeks of treatment
with Lescol (Fluvastatin sodium) 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 (Fluvastatin sodium) XL (fluvastatin sodium) Extended-Release
Tablets have been studied in five controlled studies of patients with Type IIa
or IIb hyperlipoproteinemia. Lescol (Fluvastatin sodium) XL was administered to over 900 patients in
trials from 4 to 26 weeks in duration. In the three largest of these studies,
Lescol (Fluvastatin sodium) 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 and 75 percentile)
percent changes from baseline in HDL-C for Lescol (Fluvastatin sodium) XL were +7(+0,+15) after 24
weeks of treatment.
In patients with primary mixed dyslipidemia (Fredrickson Type IIb) as
defined by baseline plasma triglycerides levels 200 mg/dL, Lescol (Fluvastatin sodium) XL 80 mg
produced a median reduction in triglycerides of 25%. In these patients, Lescol (Fluvastatin sodium)
XL 80 mg produced median (25 and 75 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.
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 (Fluvastatin sodium)
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 (Fluvastatin sodium) capsules 20 mg
daily with dose adjustments every 6 weeks to 40 mg daily then 80 mg daily
(Lescol (Fluvastatin sodium) 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 (Fluvastatin sodium) 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 (Fluvastatin sodium) 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 (Fluvastatin sodium) or Lescol (Fluvastatin sodium) XL
therapy in childhood to reduce morbidity and mortality in adulthood has not been
established.
In the Lescol (Fluvastatin sodium) Intervention Prevention Study, the effect of Lescol (Fluvastatin sodium)
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 (Fluvastatin sodium) 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 (Fluvastatin sodium) significantly reduced the risk of recurrent cardiac events
(Figure 1) by 22% (p=0.013, 181 patients in the Lescol (Fluvastatin sodium) 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 (Fluvastatin sodium)
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 (Fluvastatin sodium) 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 (Fluvastatin sodium) 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 (Fluvastatin sodium) ® Intervention Prevention Study
- Primary and Secondary Endpoints
In the Lipoprotein and Coronary Atherosclerosis Study (LCAS), the
effect of Lescol (Fluvastatin sodium) 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 (Fluvastatin sodium) 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 (Fluvastatin sodium) significantly slowed the progression of coronary
atherosclerosis. Compared to placebo, Lescol (Fluvastatin sodium) 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 (Fluvastatin sodium) 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.
Lescol (Fluvastatin sodium) Indications And Usage
Therapy with lipid-altering agents should be used in addition to
a diet restricted in saturated fat and cholesterol (see National Cholesterol
Education Program [NCEP] Treatment Guidelines, below).
Lescol (Fluvastatin sodium) and
Lescol (Fluvastatin sodium) XL (fluvastatin sodium) are indicated to reduce
elevated total cholesterol (Total-C), LDL-C, TG and Apo B levels, and to
increase HDL-C in patients with primary hypercholesterolemia and mixed
dyslipidemia (Fredrickson Type IIa and IIb) whose response to dietary
restriction of saturated fat and cholesterol and other nonpharmacological
measures has not been adequate.
Lescol (Fluvastatin sodium) and Lescol (Fluvastatin sodium) XL are indicated as an adjunct to diet to
reduce Total-C, LDL-C, and Apo B levels in adolescent boys and girls who are at
least one year post-menarche, 10-16 years of age, with heterozygous familial
hypercholesterolemia whose response to dietary restriction has not been adequate
and the following findings are present:
Therapy with lipid-altering agents should be considered only after
secondary causes for hyperlipidemia such as poorly controlled diabetes mellitus,
hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver disease,
other medication, or alcoholism, have been excluded. Prior to initiation of
fluvastatin sodium, a lipid profile should be performed to measure Total-C,
HDL-C and TG. For patients with TG <400 mg/dL (<4.5 mmol/L), LDL-C can be
estimated using the following equation:
LDL-C = Total-C - HDL-C - 1/5 TG
For TG levels >400 mg/dL (>4.5 mmol/L), this equation is less
accurate and LDL-C concentrations should be determined by ultracentrifugation.
In many hypertriglyceridemic patients LDL-C may be low or normal despite
elevated Total-C. In such cases, Lescol (Fluvastatin sodium) is not indicated.
Lipid determinations should be performed at intervals of no less than 4
weeks and dosage adjusted according to the patient’s response to therapy.
The National Cholesterol Education Program (NCEP) Treatment Guidelines
are summarized below:
After the LDL-C goal has been achieved, if the TG is still 200 mg/dL,
non-HDL-C (Total-C minus HDL-C) becomes a secondary target of therapy. Non-HDL-C
goals are set 30 mg/dL higher than LDL-C goals for each risk category.
At the time of hospitalization for an acute coronary event,
consideration can be given to initiating drug therapy at discharge if the LDL-C
level is 130 mg/dL (NCEP-ATP II).
Since the goal of treatment is to lower LDL-C, the NCEP recommends that
the LDL-C levels be used to initiate and assess treatment response. Only if
LDL-C levels are not available, should the Total-C be used to monitor therapy.
Neither Lescol (Fluvastatin sodium) nor Lescol (Fluvastatin sodium) XL have been studied in conditions where the
major abnormality is elevation of chylomicrons, VLDL, or IDL (i.e.,
hyperlipoproteinemia Types I, III, IV, or V).
The NCEP classification of cholesterol levels in pediatric patients
with a familial history of hypercholesterolemia or premature cardiovascular
disease is summarized below:
Children treated with fluvastatin in adolescence should be re-evaluated
in adulthood and appropriate changes made to their cholesterol-lowering regimen
to achieve adult treatment goals.
In patients with coronary heart disease, Lescol (Fluvastatin sodium) and Lescol (Fluvastatin sodium) XL are
indicated to reduce the risk of undergoing coronary revascularization
procedures.
Lescol (Fluvastatin sodium) and Lescol (Fluvastatin sodium) XL are also indicated to slow the progression
of coronary atherosclerosis in patients with coronary heart disease as part of a
treatment strategy to lower total and LDL cholesterol to target levels.
Lescol (Fluvastatin sodium) Contraindications
Hypersensitivity to any component of this medication. Lescol (Fluvastatin sodium) and Lescol (Fluvastatin sodium) XL
(fluvastatin sodium) are contraindicated in patients with active liver disease
or unexplained, persistent elevations in serum transaminases (see WARNINGS.
Atherosclerosis is a chronic process and discontinuation of
lipid-lowering drugs during pregnancy should have little impact on the outcome
of long-term therapy of primary hypercholesterolemia. Cholesterol and other
products of cholesterol biosynthesis are essential components for fetal
development (including synthesis of steroids and cell membranes). Since HMG-CoA
reductase inhibitors decrease cholesterol synthesis and possibly the synthesis
of other biologically active substances derived from cholesterol, they may cause
fetal harm when administered to pregnant women. Therefore, HMG-CoA reductase
inhibitors are contraindicated during pregnancy and in nursing mothers. If the patient becomes pregnant while
taking this class of drug, therapy should be discontinued and the patient
apprised of the potential hazard to the fetus.
Lescol (Fluvastatin sodium) Warnings
Biochemical abnormalities of liver function have been associated
with HMG-CoA reductase inhibitors and other lipid-lowering agents. Approximately
1.1% of patients treated with Lescol (Fluvastatin sodium) (fluvastatin
sodium) capsules in worldwide trials developed dose-related, persistent
elevations of transaminase levels to more than 3 times the upper limit of
normal. Fourteen of these patients (0.6%) were discontinued from therapy. In all
clinical trials, a total of 33/2969 patients (1.1%) had persistent transaminase
elevations with an average fluvastatin exposure of approximately 71.2 weeks; 19
of these patients (0.6%) were discontinued. The majority of patients with these
abnormal biochemical findings were asymptomatic.
In a pooled analysis of all placebo-controlled studies in which Lescol (Fluvastatin sodium)
capsules were used, persistent transaminase elevations (>3 times the upper
limit of normal [ULN] on two consecutive weekly measurements) occurred in 0.2%,
1.5%, and 2.7% of patients treated with 20, 40, and 80 mg (titrated to 40 mg
twice daily) Lescol (Fluvastatin sodium) capsules, respectively. Ninety-one percent of the cases of
persistent liver function test abnormalities (20 of 22 patients) occurred within
12 weeks of therapy and in all patients with persistent liver function test
abnormalities there was an abnormal liver function test present at baseline or
by Week 8.
In the pooled analysis of the 24-week controlled trials, persistent
transaminase elevation occurred in 1.9%, 1.8% and 4.9% of patients treated with
Lescol (Fluvastatin sodium) XL (fluvastatin sodium) 80 mg, Lescol (Fluvastatin sodium) 40 mg and
Lescol (Fluvastatin sodium) 40 mg twice daily, respectively. In 13 of 16 patients treated with Lescol (Fluvastatin sodium)
XL the abnormality occurred within 12 weeks of initiation of treatment with
Lescol (Fluvastatin sodium) XL 80 mg.
Active liver disease or unexplained transaminase elevations are
contraindications to the use of Lescol (Fluvastatin sodium) and Lescol (Fluvastatin sodium) XL (see CONTRAINDICATIONS).
Caution should be exercised when fluvastatin sodium is administered to patients
with a history of liver disease or heavy alcohol ingestion (see CLINICAL
PHARMACOLOGY: Pharmacokinetics/Metabolism. Such
patients should be closely monitored.
The risk of myopathy and/or rhabdomyolysis during treatment with
HMG-CoA reductase inhibitors has been reported to be increased if therapy with
either cyclosporine, gemfibrozil, erythromycin, or niacin is administered
concurrently. Isolated cases of myopathy have been reported during
post-marketing experience with concomitant administration of fluvastatin and
colchicine. No information is available on the pharmacokinetic interaction
between fluvastatin and colchicine. However, myotoxicity, including muscle pain
and weakness and rhabdomyloysis, have been reported anecdotally with concomitant
administration of colchicine.
Myopathy was not observed in a clinical trial in 74 patients involving
patients who were treated with fluvastatin sodium together with niacin.
Uncomplicated myalgia has been observed infrequently in patients
treated with Lescol (Fluvastatin sodium) at rates indistinguishable from placebo.
The use of fibrates alone may occasionally be associated with myopathy.
The combined use of HMG-CoA reductase inhibitors and fibrates should generally
be avoided.
Lescol (Fluvastatin sodium) Precautions
Before instituting therapy with Lescol (Fluvastatin sodium)
(fluvastatin sodium) or Lescol (Fluvastatin sodium) XL (fluvastatin sodium),
an attempt should be made to control hypercholesterolemia with appropriate diet,
exercise, and weight reduction in obese patients, and to treat other underlying
medical problems (see INDICATIONS AND USAGE).
The HMG-CoA reductase inhibitors may cause elevation of creatine
phosphokinase and transaminase levels (see WARNINGS and ADVERSE REACTIONS). This
should be considered in the differential diagnosis of chest pain in a patient on
therapy with fluvastatin sodium.
HMG-CoA reductase inhibitors are reported to be less effective in
patients with rare homozygous familial hypercholesterolemia, possibly because
these patients have few functional LDL receptors.
Women should be informed that if they become pregnant while receiving
Lescol (Fluvastatin sodium) or Lescol (Fluvastatin sodium) XL the drug should be discontinued immediately to avoid
possible harmful effects on a developing fetus from a relative deficit of
cholesterol and biological products derived from cholesterol. In addition,
Lescol (Fluvastatin sodium) or Lescol (Fluvastatin sodium) XL should not be taken during nursing. (See CONTRAINDICATIONS.)
The below listed drug interaction information is derived from
studies using immediate- release fluvastatin. Similar studies have not been
conducted using the Lescol (Fluvastatin sodium) XL tablet.
(See WARNINGS: Skeletal Muscle).
In vitro data indicate that fluvastatin metabolism involves multiple
Cytochrome P450 (CYP) isozymes. CYP2C9 isoenzyme is primarily involved in the
metabolism of fluvastatin (~75%), while CYP2C8 and CYP3A4 isoenzymes are
involved to a much less extent, i.e., ~5% and ~20%, respectively. If one pathway
is inhibited in the elimination process of fluvastatin other pathways may
compensate.
In vivo drug interaction studies with CYP3A4 inhibitors/substrates such
as cyclosporine, erythromycin, and itraconazole result in minimal changes in the
pharmacokinetics of fluvastatin, confirming less involvement of CYP3A4 isozyme.
Concomitant administration of fluvastatin and phenytoin increased the levels of
phenytoin and fluvastatin, suggesting predominant involvement of CYP2C9 in
fluvastatin metabolism.
Concomitant administration of immediate- release fluvastatin
sodium with niacin or propranolol has no effect on the bioavailability of
fluvastatin sodium.
Administration of immediate- release fluvastatin sodium
concomitantly with, or up to 4 hours after cholestyramine, results in
fluvastatin decreases of more than 50% for AUC and 50%-80% for C. However, administration of immediate- release fluvastatin
sodium 4 hours after cholestyramine resulted in a clinically significant
additive effect compared with that achieved with either component drug.
Plasma cyclosporine levels remain unchanged when fluvastatin (20
mg daily) was administered concurrently in renal transplant recipients on stable
cyclosporine regimens. Fluvastatin AUC increased 1.9- fold, and C increased 1.3- fold compared to historical controls.
In a crossover study involving 18 patients chronically receiving
digoxin, a single 40 mg dose of immediate- release fluvastatin had no effect on
digoxin AUC, but had an 11% increase in digoxin C and
small increase in digoxin urinary clearance.
Erythromycin (500 mg, single dose) did not affect steady-state
plasma levels of fluvastatin (40 mg daily).
Administration of fluvastatin 40 mg single dose to healthy
volunteers pre-treated with fluconazole for 4 days results in an increase of
fluvastatin C (44%) and AUC (84%). Based on this data,
caution should be exercised when fluvastatin is co-administered with
fluconazole.
Concomitant administration of fluvastatin (40 mg) and
itraconazole (100 mg daily x 4 days) does not affect plasma itraconazole or
fluvastatin levels.
There is no change in either fluvastatin (20 mg twice daily) or
gemfibrozil (600 mg twice daily) plasma levels when these drugs are
co-administered.
Single morning dose administration of phenytoin (300 mg extended
release) increased mean steady-state fluvastatin (40 mg) C by 27% and AUC by 40% whereas fluvastatin increased the
mean phenytoin C by 5% and AUC by 20%. Patients on
phenytoin should continue to be monitored appropriately when fluvastatin therapy
is initiated or when the fluvastatin dosage is changed.
Concurrent administration of fluvastatin (40 mg) increased the
mean C and AUC of diclofenac by 60% and 25%
respectively.
In healthy volunteers, concurrent administration of either single
or multiple daily doses of fluvastatin sodium (40 mg) with tolbutamide (1 g) did
not affect the plasma levels of either drug to a clinically significant
extent.
In glibenclamide-treated NIDDM patients (n=32), administration of
fluvastatin (40 mg twice daily for 14 days) increased the mean C, AUC, and t of glibenclamide
approximately 50%, 69% and 121%, respectively. Glibenclamide (5-20 mg daily)
increased the mean C and AUC of fluvastatin by 44% and
51%, respectively. In this study there were no changes in glucose, insulin and
C-peptide levels. However, patients on concomitant therapy with glibenclamide
(glyburide) and fluvastatin should continue to be monitored appropriately when
their fluvastatin dose is increased to 40 mg twice daily.
Concomitant administration of fluvastatin with losartan has no
effect on the bioavailability of either losartan or its active metabolite.
Concomitant administration of immediate- release fluvastatin
sodium with cimetidine, ranitidine and omeprazole results in a significant
increase in the fluvastatin C (43%, 70% and 50%,
respectively) and AUC (24%-33%), with an 18%-23% decrease in plasma clearance.
Administration of immediate- release fluvastatin sodium to
subjects pretreated with rifampicin results in significant reduction in C (59%) and AUC (51%), with a large increase (95%) in plasma
clearance.
In vitro protein binding studies demonstrated no interaction at
therapeutic concentrations. Concomitant administration of a single dose of
warfarin (30 mg) in young healthy males receiving immediate- release fluvastatin
sodium (40 mg/day x 8 days) resulted in no elevation of racemic warfarin
concentration. There was also no effect on prothrombin complex activity when
compared to concomitant administration of placebo and warfarin. However,
bleeding and/or increased prothrombin times have been reported in patients
taking coumarin anticoagulants concomitantly with other HMG-CoA reductase
inhibitors. Therefore, patients receiving warfarin-type anticoagulants should
have their prothrombin times closely monitored when fluvastatin sodium is
initiated or the dosage of fluvastatin sodium is changed.
HMG-CoA reductase inhibitors interfere with cholesterol synthesis
and lower circulating cholesterol levels and, as such, might theoretically blunt
adrenal or gonadal steroid hormone production.
Fluvastatin exhibited no effect upon non-stimulated cortisol levels and
demonstrated no effect upon thyroid metabolism as assessed by TSH. Small
declines in total testosterone have been noted in treated groups, but no
commensurate elevation in LH occurred, suggesting that the observation was not
due to a direct effect upon testosterone production. No effect upon FSH in males
was noted. Due to the limited number of premenopausal females studied to date,
no conclusions regarding the effect of fluvastatin upon female sex hormones may
be made.
Two clinical studies in patients receiving fluvastatin at doses up to
80 mg daily for periods of 24 to 28 weeks demonstrated no effect of treatment
upon the adrenal response to ACTH stimulation. A clinical study evaluated the
effect of fluvastatin at doses up to 80 mg daily for 28 weeks upon the gonadal
response to HCG stimulation. Although the mean total testosterone response was
significantly reduced (p<0.05) relative to baseline in the 80 mg group, it
was not significant in comparison to the changes noted in groups receiving
either 40 mg of fluvastatin or placebo.
Patients treated with fluvastatin 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 receiving other drugs (e.g.,
ketoconazole, spironolactone, or cimetidine) that may decrease the levels of
endogenous steroid hormones.
CNS effects, as evidenced by decreased activity, ataxia, loss of
righting reflex, and ptosis were seen in the following animal studies: the
18-month mouse carcinogenicity study at 50 mg/kg/day, the 6-month dog study at
36 mg/kg/day, the 6-month hamster study at 40 mg/kg/day, and in acute, high-dose
studies in rats and hamsters (50 mg/kg), rabbits (300 mg/kg) and mice (1500
mg/kg). CNS toxicity in the acute high-dose studies was characterized (in mice)
by conspicuous vacuolation in the ventral white columns of the spinal cord at a
dose of 5000 mg/kg and (in rat) by edema with separation of myelinated fibers of
the ventral spinal tracts and sciatic nerve at a dose of 1500 mg/kg. CNS
toxicity, characterized by periaxonal vacuolation, was observed in the medulla
of dogs that died after treatment for 5 weeks with 48 mg/kg/day; this finding
was not observed in the remaining dogs when the dose level was lowered to 36
mg/kg/day. CNS vascular lesions, characterized by perivascular hemorrhages,
edema, and mononuclear cell infiltration of perivascular spaces, have been
observed in dogs treated with other members of this class. No CNS lesions have
been observed after chronic treatment for up to 2 years with fluvastatin in the
mouse (at doses up to 350 mg/kg/day), rat (up to 24 mg/kg/day), or dog (up to 16
mg/kg/day).
Prominent bilateral posterior Y suture lines in the ocular lens were
seen in dogs after treatment with 1, 8, and 16 mg/kg/day for 2 years.
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
or ; 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 mutagenicity in vivo in either a
rat 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 milligram human daily dose
based on surface area, mg/m). 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
C achieved with a 40 milligram daily dose).
See CONTRAINDICATIONS.
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/m 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. Therefore, the
maternal and neonatal lethality observed with fluvastatin sodium reflect its
exaggerated pharmacologic effect during pregnancy. There are no data with
fluvastatin sodium in pregnant women. However, rare reports of congenital
anomalies have been received following intrauterine exposure to other HMG-CoA
reductase inhibitors. There has been one report of severe congenital bony
deformity, tracheo-esophageal fistula, and anal atresia (VATER association) in a
baby born to a woman who took another HMG-CoA reductase inhibitor with
dextroamphetamine sulfate during the first trimester of pregnancy. If a woman becomes pregnant while
taking Lescol (Fluvastatin sodium) or Lescol (Fluvastatin sodium) XL, the drug should be discontinued and the patient
advised again as to the potential hazards to the fetus.
Based on preclinical data, drug is present in breast milk in a
2:1 ratio (milk:plasma). Because of the potential for serious adverse reactions
in nursing infants, nursing women should not take Lescol (Fluvastatin sodium) or Lescol (Fluvastatin sodium) XL (see
CONTRAINDICATIONS).
The safety and efficacy of Lescol (Fluvastatin sodium) and Lescol (Fluvastatin sodium) XL in children and
adolescent patients 9-16 years of age with heterozygous familial
hypercholesterolemia have been evaluated in open-label, uncontrolled clinical
trials of 2 years' duration. The most common adverse events observed were
influenza and infections. In these limited uncontrolled studies, there was no
detectable effect on growth or sexual maturation in the adolescent boys or on
menstrual cycle length in girls. See CLINICAL STUDIES: Heterozygous Familial
Hypercholesterolemia in Pediatric Patients; ADVERSE REACTIONS: Pediatric
Patients (9-16 years of age); and DOSAGE AND ADMINISTRATION: Heterozygous
Familial Hypercholesterolemia in Pediatric Patients. Adolescent females should
be counseled on appropriate contraceptive methods while on fluvastatin therapy
see CONTRAINDICATIONS: Pregnancy and Lactation
The effect of age on the pharmacokinetics of immediate- release
fluvastatin sodium was evaluated. Results indicate that for the general patient
population plasma concentrations of fluvastatin sodium do not vary as a function
of age(See also CLINICAL PHARMACOLOGY:
Pharmacokinetics/Metabolism.)Elderly patients (65
years of age) demonstrated a greater treatment response in respect to LDL-C,
Total-C and LDL/HDL ratio than patients <65 years of age.
Lescol (Fluvastatin sodium) Adverse Reactions
In all clinical studies of Lescol (Fluvastatin sodium)
(fluvastatin sodium), 1.0% (32/2969) of fluvastatin-treated patients were
discontinued due to adverse experiences attributed to study drug (mean exposure
approximately 16 months ranging in duration from 1 to >36 months). This
results in an exposure adjusted rate of 0.8% (32/4051) per patient year in
fluvastatin patients in controlled studies compared to an incidence of 1.1%
(4/355) in placebo patients. Adverse reactions have usually been of mild to
moderate severity.
In controlled clinical studies, 3.9% (36/912) of patients treated with
Lescol (Fluvastatin sodium) XL (fluvastatin sodium) 80 mg discontinued due to
adverse events (causality not determined).
Clinically relevant adverse experiences occurring in the Lescol (Fluvastatin sodium) and
Lescol (Fluvastatin sodium) XL controlled studies with a frequency >2%, regardless of causality,
include the following:
The following effects have been reported with drugs in this class. Not
all the effects listed below have necessarily been associated with fluvastatin
sodium therapy.
In two open-label, uncontrolled studies, 114 patients (66 boys
and 48 girls) with heterozygous familial hypercholesterolemia, 9-16 years of
age, were treated for 2 years with fluvastatin sodium administered as Lescol (Fluvastatin sodium)
capsules 20 mg- 40 mg bid or Lescol (Fluvastatin sodium) XL 80 mg extended-release tablets. The most
common adverse events observed were influenza and infections. (See CLINICAL
STUDIES: Heterozygous Familial Hyercholesterolemia in Pediatric Patients and
PRECAUTIONS: Pediatric Use.
Fluvastatin sodium has been administered concurrently with
cholestyramine and nicotinic acid. No adverse reactions unique to the
combination or in addition to those previously reported for this class of drugs
alone have been reported. Myopathy and rhabdomyolysis (with or without acute
renal failure) have been reported when another HMG-CoA reductase inhibitor was
used in combination with immunosuppressive drugs, gemfibrozil, erythromycin, or
lipid-lowering doses of nicotinic acid. Concomitant therapy with HMG-CoA
reductase inhibitors and these agents is generally not recommended. (See
WARNINGS: Skeletal Muscle.)
Lescol (Fluvastatin sodium) Overdosage
The approximate oral LD is greater than
2 g/kg in mice and greater than 0.7 g/kg in rats.
The maximum single oral dose of Lescol (Fluvastatin sodium)
(fluvastatin sodium) capsules received by healthy volunteers was 80 mg. No
clinically significant adverse experiences were seen at this dose. The maximum
dose administered with an extended-release formulation was 640 mg for two weeks.
This dose was not well tolerated and produced a variety of GI complaints and an
increase in transaminase values (i.e., SGOT and SGPT).
There has been a single report of 2 children, one 2 years old and the
other 3 years of age, either of whom may have possibly ingested fluvastatin
sodium. The maximum amount of fluvastatin sodium that could have been ingested
was 80 mg (4 x 20 mg capsules). Vomiting was induced by ipecac in both children
and no capsules were noted in their emesis. Neither child experienced any
adverse symptoms and both recovered from the incident without problems.
Should an accidental overdose occur, treat symptomatically and
institute supportive measures as required. The dialyzability of fluvastatin
sodium and of its metabolites in humans is not known at present.
Information about the treatment of overdose can often be obtained from
a certified Regional Poison Control Center. Telephone numbers of certified
Regional Poison Control Centers are listed in the Physicians’ Desk
Reference.*
Lescol (Fluvastatin sodium) Dosage And Administration
The patient should be placed on a standard cholesterol-lowering
diet before receiving Lescol (Fluvastatin sodium) or
Lescol (Fluvastatin sodium) XL (fluvastatin sodium) and should continue on
this diet during treatment with Lescol (Fluvastatin sodium) or Lescol (Fluvastatin sodium) XL. (See NCEP Treatment
Guidelines for details on dietary therapy.)
For patients requiring LDL-C reduction to a goal of ≥25%, the
recommended starting dose is 40 mg as one capsule in the evening, 80 mg as one
Lescol (Fluvastatin sodium) XL tablet administered as a single dose at any time of the day or 80 mg
in divided doses of the 40 mg capsule given twice daily. For patients requiring
LDL-C reduction to a goal of <25% a starting dose of 20 mg may be used. The
recommended dosing range is 20-80 mg/day. Lescol (Fluvastatin sodium) or Lescol (Fluvastatin sodium) XL may be taken
without regard to meals, since there are no apparent differences in the
lipid-lowering effects of fluvastatin sodium administered with the evening meal
or 4 hours after the evening meal. Do not break, crush or chew Lescol (Fluvastatin sodium) XL
tablets or open Lescol (Fluvastatin sodium) capsules prior to administration.
Since the maximal reductions in LDL-C of a given dose are seen within 4
weeks, periodic lipid determinations should be performed and dosage adjustment
made according to the patient’s response to therapy and established treatment
guidelines. The therapeutic effect of Lescol (Fluvastatin sodium) or Lescol (Fluvastatin sodium) XL is maintained with
prolonged administration.
The recommended starting dose is one 20 mg Lescol (Fluvastatin sodium) capsule. Dose
adjustments, up to a maximum daily dose administered either as Lescol (Fluvastatin sodium) capsules
40 mg twice daily or one Lescol (Fluvastatin sodium) XL 80 mg tablet once daily, should be made at
6 week intervals. Doses should be individualized according to the goal of
therapy (see NCEP Pediatric Panel Guidelines and INDICATIONS AND USAGE.).
Lipid-lowering effects on total cholesterol and LDL cholesterol
are additive when immediate release Lescol (Fluvastatin sodium) is combined with a bile-acid binding
resin or niacin. When administering a bile-acid resin (e.g., cholestyramine) and
fluvastatin sodium, Lescol (Fluvastatin sodium) should be administered at bedtime, at least 2 hours
following the resin to avoid a significant interaction due to drug binding to
resin. (See also ADVERSE REACTIONS: Concomitant Therapy.)
Since fluvastatin sodium is cleared hepatically with less than 6%
of the administered dose excreted into the urine, dose adjustments for mild to
moderate renal impairment are not necessary. Fluvastatin has not been studied at
doses greater than 40 mg in patients with severe renal impairment; therefore
caution should be exercised when treating such patients at higher doses.
Lescol (Fluvastatin sodium) How Supplied
Brown and light brown imprinted twice with " " and “20” on one half and “Lescol (Fluvastatin sodium) ” and the Lescol (Fluvastatin sodium)
(fluvastatin sodium) logo twice on the other half of the capsule.
Brown and gold imprinted twice with " " and “40” on one half and “Lescol (Fluvastatin sodium) ” and the Lescol (Fluvastatin sodium)
(fluvastatin sodium) logo twice on the other half of the capsule.
Store at 25ºC (77ºF); excursions permitted to 15 -30ºC (59 -86ºF)
[see USP Controlled Room Temperature]. Dispense in a tight container. Protect
from light.
Lescol (Fluvastatin sodium) References
1. National Cholesterol Education Program (NCEP):
Highlights of the Report of the Expert Panel on Blood Cholesterol Levels in
Children and Adolescents. .
89(3):495-501.1992.
REV: OCTOBER 2006 T2006-97
Lescol (Fluvastatin sodium)
Lescol (Fluvastatin sodium) Principal Display Panel
Rx Only
Lescol (Fluvastatin sodium) ® (fluvastatin sodium) capsules
equivalent to 20 mg fluvastatin
Rx Only
Lescol (Fluvastatin sodium) ® (fluvastatin sodium) capsules
equivalent to 40 mg fluvastatin
