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Side Effects & Adverse Reactions
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. Patients who develop transaminase elevations or signs and symptoms of liver disease should be monitored to confirm the finding and should be followed thereafter with frequent liver function tests until the levels return to normal. Should an increase in AST or ALT of three times the upper limit of normal or greater persist (found on two consecutive occasions) withdrawal of fluvastatin sodium therapy is recommended.
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.Skeletal Muscle
Rhabdomyolysis with renal dysfunction secondary to myoglobinuria has been reported with fluvastatin and with other drugs in this class. Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values to greater than 10 times the upper limit of normal, has been reported.
Myopathy should be considered in any patients with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. Fluvastatin sodium therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Fluvastatin sodium therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.
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.
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FDA Safety Alerts
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There is currently no manufacturer warning information available for this drug.
FDA Labeling Changes
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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).Hypercholesterolemia (heterozygous familial and nonfamilial) and Mixed Dyslipidemia
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.Heterozygous Familial Hypercholesterolemia in Pediatric Patients
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:
- LDL-C remains > 190 mg/dL or
- LDL-C remains > 160 mg/dL and:
- there is a positive family history of premature cardiovascular disease or
- two or more other cardiovascular disease risk factors are present.
- there is a positive family history of premature cardiovascular disease or
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:
|Risk Category||LDL Goal |
|LDL Level at Which to |
|LDL Level at Which to Consider |
|CHD† or CHD risk |
(10-year risk >20%)
(100-129: drug optional)††
|2+ Risk factors |
(10-year risk <20%)
|<130||>130||10-year risk 10%-20%: >130 |
10-year risk <10%: >160
|0-1 Risk factor†††||<160||>160||>190 |
† CHD, coronary heart disease
†† Some authorities recommend use of LDL-lowering drugs in this category if an LDL-C level of <100mg/dL cannot be achieved by therapeutic lifestyle changes. Others prefer use of drugs that primarily modify triglycerides and HDL-C, e.g., nicotinic acid or fibrate. Clinical judgement also may call for deferring drug therapy in this subcategory.
††† Almost all people with 0-1 risk factor have 10-year risk <10%; thus, 10-year risk assessment in people with 0-1 risk factor is not necessary.
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.
| || ||Lipid Elevations|
|V (rare)||Chylomicrons, VLDL||TG||↑→C|
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:
|Category||Total-C (mg/dL)||LDL-C (mg/dL)|
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.Secondary Prevention of Coronary Events
In patients with coronary heart disease, Lescol and Lescol XL are indicated to reduce the risk of undergoing coronary revascularization procedures.Atherosclerosis
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.
There is currently no drug history available for this drug.
Lescol® (fluvastatin sodium), is a water-soluble cholesterol lowering agent which acts through the inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase.
Fluvastatin sodium is [R*,S*-(E)]-(±)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoic acid, monosodium salt. The empirical formula of fluvastatin sodium is C24H25FNO4•Na, its molecular weight is 433.46 and its structural formula is:
This molecular entity is the first entirely synthetic HMG-CoA reductase inhibitor, and is in part structurally distinct from the fungal derivatives of this therapeutic class.
Fluvastatin sodium is a white to pale yellow, hygroscopic powder soluble in water, ethanol and methanol. Lescol is supplied as capsules containing fluvastatin sodium, equivalent to 20 mg or 40 mg of fluvastatin, for oral administration. Lescol® XL (fluvastatin sodium) is supplied as extended-release tablets containing fluvastatin sodium, equivalent to 80 mg of fluvastatin, for oral administration.
Active Ingredient: fluvastatin sodium
Inactive Ingredients in capsules: gelatin, magnesium stearate, microcrystalline cellulose, pregelatinized starch (corn), red iron oxide, sodium lauryl sulfate, talc, titanium dioxide, yellow iron oxide, and other ingredients.
Capsules may also include: benzyl alcohol, black iron oxide, butylparaben, carboxymethylcellulose sodium, edetate calcium disodium, methylparaben, propylparaben, silicon dioxide and sodium propionate.
Inactive Ingredients in extended-release tablets: microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, potassium bicarbonate, povidone, magnesium stearate, yellow iron oxide, titanium dioxide and polyethylene glycol 8000.