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LESCOL XL
Overview
What is LESCOL XL?
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 [*,*-()]-(±)-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 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:
Inactive Ingredients in capsules:
Capsules may also include:
Inactive Ingredients in extended-release
tablets:
What does LESCOL XL look like?
What are the available doses of LESCOL XL?
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What should I talk to my health care provider before I take LESCOL XL?
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How should I use LESCOL XL?
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 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 and Lescol 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 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.
C = cholesterol, TG = triglycerides, LDL = low density
lipoprotein, VLDL = very low density lipoprotein,
IDL = intermediate density lipoprotein
Neither Lescol nor Lescol 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 and Lescol XL are
indicated to reduce the risk of undergoing coronary revascularization
procedures.
Lescol and Lescol 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.
The patient should be placed on a standard cholesterol-lowering
diet before receiving Lescol (fluvastatin sodium) or
Lescol XL (fluvastatin sodium) and should continue on
this diet during treatment with Lescol or Lescol 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 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 or Lescol 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 XL
tablets or open Lescol 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 or Lescol XL is maintained with
prolonged administration.
The recommended starting dose is one 20 mg Lescol capsule. Dose
adjustments, up to a maximum daily dose administered either as Lescol capsules
40 mg twice daily or one Lescol 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 is combined with a bile-acid binding
resin or niacin. When administering a bile-acid resin (e.g., cholestyramine) and
fluvastatin sodium, Lescol 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.
What interacts with LESCOL XL?
Hypersensitivity to any component of this medication. Lescol (fluvastatin sodium) and Lescol 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.
What are the warnings of LESCOL XL?
Patients should avoid alcoholic beverages while taking the drug. Due to its potential anticholinergic action, this drug should be used with caution in patients with asthma, glaucoma, or enlargement of the prostate gland. Do not give to children under 12 years of age unless directed by a doctor.
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) 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
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 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 XL (fluvastatin sodium) 80 mg, Lescol 40 mg and
Lescol 40 mg twice daily, respectively. In 13 of 16 patients treated with Lescol
XL the abnormality occurred within 12 weeks of initiation of treatment with
Lescol XL 80 mg.
It is recommended that liver function tests be
performed before the initiation of therapy and at 12 weeks following initiation
of treatment or elevation in dose.
Active liver disease or unexplained transaminase elevations are
contraindications to the use of Lescol and Lescol 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.
Rhabdomyolysis with renal dysfunction secondary
to myoglobinuria has been reported with fluvastatin and with other drugs in this
class.
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 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.
What are the precautions of LESCOL XL?
Before instituting therapy with Lescol
(fluvastatin sodium) or Lescol 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.
Patients should be advised to report promptly
unexplained muscle pain, tenderness or weakness, particularly if accompanied by
malaise or fever.
Women should be informed that if they become pregnant while receiving
Lescol or Lescol 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 or Lescol 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 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 or Lescol 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 or Lescol XL (see
CONTRAINDICATIONS).
The safety and efficacy of Lescol and Lescol 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.
What are the side effects of LESCOL XL?
In all clinical studies of Lescol
(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 XL (fluvastatin sodium) 80 mg discontinued due to
adverse events (causality not determined).
Clinically relevant adverse experiences occurring in the Lescol and
Lescol XL controlled studies with a frequency >2%, regardless of causality,
include the following:
Array
Array
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.
Skeletal:
Neurological:
Hypersensitivity Reactions:
Gastrointestinal:
Skin:
Reproductive:
Eye:
Laboratory Abnormalities:
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
capsules 20 mg- 40 mg bid or Lescol 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 | Array | (%) | Placebo | Array | (%) | Lescol | Array | XL | Array | Array | |||
| Adverse Event | (N=2326) | (N=960) | (N = 912) | ||||||||||
| Musculoskeletal | |||||||||||||
| Myalgia | 5.0 | 4.5 | 3.8 | ||||||||||
| Arthritis | 2.1 | 2.0 | 1.3 | ||||||||||
| Arthropathy | NA | NA | 3.2 | ||||||||||
| Respiratory | |||||||||||||
| Sinusitis | 2.6 | 1.9 | 3.5 | ||||||||||
| Bronchitis | 1.8 | 1.0 | 2.6 | ||||||||||
| Gastrointestinal | |||||||||||||
| Dyspepsia | 7.9 | 3.2 | 3.5 | ||||||||||
| Diarrhea | 4.9 | 4.2 | 3.3 | ||||||||||
| Abdominal Pain | 4.9 | 3.8 | 3.7 | ||||||||||
| Nausea | 3.2 | 2.0 | 2.5 | ||||||||||
| Flatulence | 2.6 | 2.5 | 1.4 | ||||||||||
| Psychiatric Disorders | |||||||||||||
| Insomnia | 2.7 | 1.4 | 0.8 | ||||||||||
| Genitourinary | |||||||||||||
| Urinary Tract Infection | 1.6 | 1.1 | 2.7 | ||||||||||
| Miscellaneous | |||||||||||||
| Headache | 8.9 | 7.8 | 4.7 | ||||||||||
| Influenza-Like Symptoms | 5.1 | 5.7 | 7.1 | ||||||||||
| Accidental Trauma | 5.1 | 4.8 | 4.2 | ||||||||||
| Fatigue | 2.7 | 2.3 | 1.6 | ||||||||||
| Allergy | 2.3 | 2.2 | 1.0 |
What should I look out for while using LESCOL XL?
Hypersensitivity to any component of this medication. Lescol (fluvastatin sodium) and Lescol 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.
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) 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
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 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 XL (fluvastatin sodium) 80 mg, Lescol 40 mg and
Lescol 40 mg twice daily, respectively. In 13 of 16 patients treated with Lescol
XL the abnormality occurred within 12 weeks of initiation of treatment with
Lescol XL 80 mg.
It is recommended that liver function tests be
performed before the initiation of therapy and at 12 weeks following initiation
of treatment or elevation in dose.
Active liver disease or unexplained transaminase elevations are
contraindications to the use of Lescol and Lescol 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.
Rhabdomyolysis with renal dysfunction secondary
to myoglobinuria has been reported with fluvastatin and with other drugs in this
class.
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 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.
What might happen if I take too much LESCOL XL?
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) 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.*
How should I store and handle LESCOL XL?
ArrayYellow, round, slightly biconvex film-coated tablet with beveled edges debossed with “Lescol XL” on one side and “80” on the other.Store at 25ºC (77ºF); excursions permitted to 15 -30ºC (59 -86ºF) [see USP Controlled Room Temperature]. Dispense in a tight container. Protect from light.Yellow, round, slightly biconvex film-coated tablet with beveled edges debossed with “Lescol XL” on one side and “80” on the other.Store at 25ºC (77ºF); excursions permitted to 15 -30ºC (59 -86ºF) [see USP Controlled Room Temperature]. Dispense in a tight container. Protect from light.
Clinical Information
Chemical Structure
No Image foundClinical 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.
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.
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 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: 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 and AUC), and especially so after a high-fat meal (63%-89%
for C and AUC). Intrasubject variability in the
pharmacokinetics of Lescol 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 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 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:
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 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.
Non-Clinical Toxicology
Hypersensitivity to any component of this medication. Lescol (fluvastatin sodium) and Lescol 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.
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) 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 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 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 XL (fluvastatin sodium) 80 mg, Lescol 40 mg and Lescol 40 mg twice daily, respectively. In 13 of 16 patients treated with Lescol XL the abnormality occurred within 12 weeks of initiation of treatment with Lescol XL 80 mg.
It is recommended that liver function tests be performed before the initiation of therapy and at 12 weeks following initiation of treatment or elevation in dose.
Active liver disease or unexplained transaminase elevations are contraindications to the use of Lescol and Lescol 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.
Rhabdomyolysis with renal dysfunction secondary to myoglobinuria has been reported with fluvastatin and with other drugs in this class.
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 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.
Preliminary evidence suggests that cimetidine inhibits mebendazole metabolism and may result in an increase in plasma concentrations of mebendazole.
Before instituting therapy with Lescol (fluvastatin sodium) or Lescol 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.
Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.
Women should be informed that if they become pregnant while receiving Lescol or Lescol 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 or Lescol 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 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 or Lescol 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 or Lescol XL (see CONTRAINDICATIONS).
The safety and efficacy of Lescol and Lescol 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.
In all clinical studies of Lescol (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 XL (fluvastatin sodium) 80 mg discontinued due to adverse events (causality not determined).
Clinically relevant adverse experiences occurring in the Lescol and Lescol 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.
Skeletal:
Neurological:
Hypersensitivity Reactions:
Gastrointestinal:
Skin:
Reproductive:
Eye:
Laboratory Abnormalities:
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 capsules 20 mg- 40 mg bid or Lescol 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.)
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
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