LESCOL®
Novartis Pharmaceuticals
Fluvastatin Sodium
Lipid Metabolism Regulator
Action And Clinical Pharmacology: Fluvastatin is a fully synthetic HMG-CoA reductase inhibitor and is hydrophilic. Fluvastatin is a racemate of two erythro enantiomers of which one exerts the pharmacological activity.
Fluvastatin 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 ultimate result of these mechanisms is a reduction of the plasma total cholesterol (total-C) and low density lipoprotein cholesterol (LDL-C) concentrations.
Epidemiologic and clinical studies have associated the risk of coronary artery disease (CAD) with elevated levels of Total-C, LDL-C and decreased levels of HDL-C. These abnormalities of lipoprotein metabolism are considered as major contributors to the development of the disease. Other factors, e.g., interactions between lipids/lipoproteins and endothelium, platelets and macrophages, have also been incriminated in the development of human atherosclerosis and of its complications.
Fluvastatin is rapidly and completely (98%) absorbed following oral administration to fasted volunteers. The drug is also completely absorbed, even when administered up to 4 hours postprandial, but at a reduced rate.
Fluvastatin is targeted to, and sequestered by the liver. Therefore, absolute bioavailability based on systemic blood concentrations is about 25%. At doses above 20 mg, given in the fasted state, absolute bioavailability can be dose dependent. Fluvastatin has a volume of distribution of approximately 30 L. More than 98% of the circulating drug is bound to plasma albumin.
Following administration of -fluvastatin to healthy volunteers, excretion of radioactivity was about 5% in the urine and 90% in the feces. Fluvastatin accounted for less than 2% of the total radioactivity excreted. The beta elimination half-life for fluvastatin is 1.2 hours.
Fluvastatin is predominantly metabolized by the hepatic microsomal CYP2C9 subclass of the P450 cytochromes. It is not metabolized to a significant extent by other cytochrome subclasses, including CYP3A4.
Pharmacokinetics: Fluvastatin is not a pro-drug. It is absorbed rapidly and completely (98%) following oral administration to fasted volunteers. The drug is also completely absorbed, even when administered up to 4 hours postprandial, but at a reduced rate (Cmax is reduced by 40 to 70%). Fluvastatin is targeted to, and sequestered by the liver; therefore, absolute bioavailability based on systemic blood concentrations is about 25%. At doses above 20 mg given in the fasted state, absolute bioavailability can be dose dependent. Dose-normalized values at 40 mg were 20 to 40% higher than at 20 mg in the fasted state. The volume of distribution (VDss) for the drug is calculated to be approximately 30 L. More than 98% of the circulating drug is bound to plasma albumin, and this binding is unaffected by drug concentration.
Fluvastatin is predominantly metabolized by the hepatic microsomal CYP2C9 subclass of the P450 cytochromes. It is not metabolized to a significant extent by other cytochrome subclasses, including CYP3A4. Interactions between fluvastatin and drugs metabolized by the CYP2C9 or CYP3A4 subclasses of the P450 cytochromes may occur in some patients.
Following administration of -fluvastatin to healthy volunteers, excretion of radioactivity was about 5% in the urine and 90% in the feces, and fluvastatin accounted for less than 2% of the total radioactivity excreted. The plasma clearance for fluvastatin in man is calculated to be approximately 40 L/hour. Steady-state plasma concentrations show no evidence of fluvastatin accumulation following administration of up to 80 mg daily for 25 days. 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 or 40 mg dose. This increase in systemic exposure may result from saturation of uptake and sequestration of fluvastatin by the liver when fluvastatin is administered under fasting conditions. After single (or multiple) 20 and 40 mg (40 and 80 mg/day) oral doses of fluvastatin, no differences in the fluvastatin elimination half-life are observed. The beta elimination half-life for fluvastatin is 1.2 hours (range of 0.53 to 3.1 hours).
The extent of absorption of fluvastatin 20 mg capsules is equivalent to that of a solution of fluvastatin except that the time to peak under fasted conditions is about 0.7 hours following administration of the capsule compared to about 0.4 hours for the solution. Following ingestion of a single 20 mg fluvastatin capsule under fasted conditions, measurable plasma concentrations of fluvastatin appear systemically within 10 minutes after dosing and reach a peak of 147 ± 86 ng/mL at 0.66 ± 0.3 hours. Fluvastatin, like the other HMG-CoA reductase inhibitors, has variable bioavailability. The coefficient of variation (based on the inter-subject variability) was 47 to 57% for AUC, and 58 to 69% for Cmax.
Results from an overnight pharmacokinetic evaluation following steady-state (15 weeks) administration of fluvastatin with the evening meal or 4 hours after the evening meal, showed no significant difference in AUC and no apparent difference in the lipid-lowering effects between the two treatment groups. The administration of fluvastatin with the evening meal resulted in a 2-fold decrease in Cmax and more than a 2-fold increase in tmax as compared to patients receiving the drug 4 hours after the evening meal.
The effects of gender and age on the pharmacokinetics of fluvastatin were evaluated in 4 patient subgroups; young and elderly, males and females. All patients were administered 20 mg fluvastatin daily, at least 2 hours after the evening meal, for 21 days. Overnight pharmacokinetic evaluations indicate that for the general patient population, plasma concentrations of fluvastatin do not significantly vary either as a function of age or gender.
In a single-dose study the kinetics of fluvastatin in subjects with cirrhosis (n=11) and in healthy age- and sex-matched subjects (n=11) were compared. The mean AUC and Cmax parameters were about 2.5 times higher in the subjects with hepatic insufficiency. There was a 28% decrease in plasma clearance and a 31% smaller volume of distribution. No apparent difference was observed in the plasma elimination half-lives for the two groups.
In a study conducted in 14 healthy volunteers, coadministration of diclofenac 25 mg/day and fluvastatin 40 mg/day for 8 days resulted in a significant increase in the fluvastatin AUC(0-9) and Cmax on day 8 when compared to baseline (54 and 77%, respectively). Diclofenac Cmax and AUC were increased (60 and 25%, respectively) and oral clearance decreased by 16% on day 8 when compared to baseline.
In a study conducted in 19 stable renal transplant patients with hypercholesterolemia receiving cyclosporine A concomitantly with fluvastatin 20 mg/day, the AUC for fluvastatin was increased by 1.9 times (94%) compared to that of control subjects from another study who had received the same dose of fluvastatin. The Cmax was increased by 30% but the Tmax remained unchanged. Published data show that plasma trough concentrations of cyclosporine A are not significantly changed during coadministration with fluvastatin 20 mg/day. In patients receiving cyclosporine A in combination with fluvastatin, liver enzymes and CK levels should be carefully monitored and the dose of fluvastatin adjusted, if necessary. At present, no data are with doses above 40 mg/day.
Biotransformation pathways for fluvastatin include: a) hydroxylation of the indole ring at the 5- and 6-positions; b) N-dealkylation; and c) beta-oxidation. The major circulating blood components are fluvastatin and the pharmacologically inactive N-desisopropyl-propionic acid metabolite. The hydroxylated metabolites have pharmacological activity but do not circulate systemically. Both enantiomers of fluvastatin are metabolized in a similar manner resulting in only minor differences in systemic exposure.
Indications And Clinical Uses: Therapy with lipid-altering agents should be considered a component of multiple risk factor intervention in those individuals at increased risk for atherosclerosis vascular disease due to hypercholesterolemia. Fluvastatin should be used in addition to a diet restricted in saturated fat and cholesterol when the response to diet and other nonpharmacological measures alone has been inadequate.
Hypercholesterolemia: The therapeutic indication for fluvastatin is as an adjunct to diet (at least equivalent to the American Heart Association (AHA) Step 1 Diet) in the treatment of elevated total cholesterol (total-C) and LDL-C levels in patients with primary hypercholesterolemia (Type IIa and IIb) whose response to dietary restriction of saturated fat and cholesterol and other nonpharmacological measures has not been adequate.
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, a lipid profile should be performed to measure total-C, HDL-C and TG.
LDL-C (mmol/L)=total-C-HDL-C-0.37 TG. For TG levels >4.52 mmol/L (>400 mg/dL), 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, as with other HMG-CoA reductase inhibitors, fluvastatin is not indicated.
Since the goal of treatment is to lower LDL-C, LDL-C levels should 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.
Fluvastatin has not been studied in conditions where the major abnormality is elevation of chylomicrons, VLDL, or IDL (i.e., hyperlipoproteinemia Types I, III, IV or V).
Coronary Heart Disease: Fluvastatin was also found to reduce the rate of progression of atherosclerosis in patients with coronary artery disease and mild to moderate elevations of cholesterol as part of a treatment strategy to lower total and LDL cholesterol to target levels. In a placebo controlled trial including such patients*, fluvastatin monotherapy reduced the rate of progression of atherosclerosis as evaluated by quantitative coronary angiography (QCA). This effect however was not accompanied by a statistically significant improvement in the clinical endpoints (new occurrence or worsening of angina, coronary revascularization procedures [PTCA] or CABG surgery, myocardial infarction [MI] and total mortality) within the 2.5 years of treatment. This trial, however, was not designed to demonstrate a reduction in the risk of coronary morbidity and mortality.
*Lipoprotein and Coronary Atherosclerosis Study (LCAS).
Contra-Indications: Hypersensitivity to any component of this medication. Fluvastatin is contraindicated in patients with active liver disease or unexplained, persistent clinically relevant elevations in serum transaminases (see Warnings).
Pregnancy and Lactation: As with other drugs of this class, fluvastatin is contraindicated during pregnancy and in nursing mothers (see Precautions).
Manufacturers’ Warnings In Clinical States: Pharmacokinetic Interactions : The use of HMG-CoA reductase inhibitors has been associated with rhabdomyolysis, which may be more frequent when they are coadministered with drugs that inhibit the same cytochrome P450 isoenzyme system (CYP 3A4, CYP 2C9 or CYP 2D6). The various HMG-CoA reductase inhibitors differ with respect to the P450 isoenzyme involved in their metabolism. Fluvastatin is predominantly metabolized by the CYP2C9 subclass of the P450 cytochromes. It is not metabolized to a significant extent by other cytochrome subclasses, including CYP3A4 (see Warnings, Muscle Effects and Precautions, Drug Interactions).
Hepatic Effects: Biochemical abnormalities of liver function have been associated with HMG-CoA reductase inhibitors and other lipid-lowering agents.
Overall, 25 of 2 373 patients (1.1 %) treated with fluvastatin in worldwide controlled clinical trials developed marked persistent elevations (to more than 3 times the upper limit of normal) in transaminase levels requiring discontinuation of treatment in 14 (0.6%) patients. The incidence of such elevations varied from 0.9% at 20 mg/day to 1.9% at 80 mg/day.
In all clinical trials (controlled and uncontrolled), ranging from 28 to 71.2 weeks of exposure, 33 of 2 969 (1.1%) patients had persistent transaminase elevations requiring discontinuation of treatment in 19 (0.6%) patients. In the majority of patients, these abnormal biochemical findings were asymptomatic.
It is recommended that liver function tests be performed at baseline and 12 weeks after initiation of treatment as well as after an increase in the dose, and periodically thereafter (i.e. semi-annually). Particular attention should be paid to patients who develop elevated serum transaminase levels, and in these patients, measurements should be repeated promptly and then performed more frequently.
If the transaminase levels show evidence of progression, particularly if they rise to 3 times the upper limit of normal and are persistent, the drug should be discontinued.
Fluvastatin should be used with caution in patients who consume substantial quantities of alcohol (>14 drinks/week) and/or have a past history of liver disease. Active liver disease or unexplained transaminase elevations are contraindications to the use of fluvastatin; if such condition develops during therapy, the drug should be discontinued.
Muscle Effects: CPK: Transient elevations of creatine phosphokinase (CPK) levels have been seen in fluvastatin-treated patients but have usually been of no clinical significance.
Myalgia and muscle cramps have also been associated with fluvastatin therapy.
Myopathy has been reported in isolated cases with fluvastatin. Two cases were in patients receiving placebo. The incidence of myopathy in fluvastatin-treated patients compares favorably with that in placebo. Rhabdomyolysis with renal dysfunction secondary to myoglobinuria has been reported with other drugs of this class. Rhabdomyolysis has been reported in isolated cases with fluvastatin (see Precautions, Drug Interactions and Cytochrome P450).
Myopathy should be considered in patients with diffuse myalgias, muscle tenderness or weakness and/or marked elevations of creatinine phosphokinase (10 times the upper limit of normal).
An increased risk of myopathy has been reported with HMG-CoA reductase inhibitors when administered concomitantly with immunosuppressive drugs, including cyclosporine, gemfibrozil, erythromycin, or niacin at lipid lowering doses.
Therefore, the benefits and risks of using HMG-CoA reductase inhibitors concomitantly with immunosuppressive drugs, erythromycin, or other drugs metabolized by the P450 enzyme system, fibrates or lipid-lowering doses of niacin should be carefully considered (see Pharmacokinetic Interactions and Precautions, Drug Interactions and Cytochrome P450).
There is limited experience to date with the use of fluvastatin together with cyclosporine. In a study conducted in 19 stable renal transplant patients receiving cyclosporine A concomitantly with fluvastatin 20 mg/day, the AUC for fluvastatin was increased by 1.9 times (94%). Published data indicate that the trough concentration of cyclosporine A was not changed (see Pharmacology, Pharmacokinetics). At present, since no data with doses above 40 mg/day are available, this dosage should not be exceeded in patients receiving cyclosporine A.
Myopathy has not been observed in clinical trials involving small numbers of patients who were treated with fluvastatin together with niacin at lipid lowering doses.
The use of fibrates alone or in combination with HMG-CoA reductase inhibitors has been occasionally associated with myopathy. In short-term studies involving a small number of patients, myopathy was not reported during administration of benzafibrate and fluvastatin at doses of 40 and 60 mg/day. To date, the 80 mg/day dose has not been evaluated with bezafibrate.
Interruption of therapy with fluvastatin should be considered in any patient with an acute serious condition suggestive of myopathy or having a risk factor predisposing to the development of renal failure or rhabdomyolysis, such as severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine or electrolyte disorders and uncontrolled seizures.
Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.
Precautions: The effect of fluvastatin-induced changes in lipoprotein levels, including reduction of serum cholesterol, on cardiovascular morbidity and mortality, or total mortality has not been established.
General: Before instituting therapy with fluvastatin, an attempt should be made to control hypercholesterolemia with appropriate diet, exercise, weight reduction in overweight and obese patients, and to treat other underlying medical problems (see Indications). The patient should be advised to inform subsequent physicians of the prior use of fluvastatin or any other lipid metabolism regulator.
Homozygous Familial Hypercholesterolemia: Fluvastatin has not been evaluated in patients with rare homozygous familial hypercholesterolemia. HMG-CoA reductase inhibitors are less or not effective in this subgroup of hypercholesterolemic patients.
Effect on Lipoprotein(A) [Lp(a)]: In some patients the beneficial effect of lowered total cholesterol and LDL cholesterol levels may be partly blunted by a concomitant increase in the Lp(a) levels. Until further experience is obtained from controlled clinical trials, it is suggested, where feasible, that Lp(a) measurements be carried out in patients placed on therapy with fluvastatin.
Effect on CoQ10 Levels (Ubiquinone): A significant decrease in plasma CoQ10 levels in patients treated with fluvastatin and other statins has been observed in short-term clinical trials. The clinical significance of a potential long-term statin-induced deficiency of CoQ10 has not yet been established. It has been reported that a decrease in myocardial ubiquinone levels could lead to impaired cardiac function in patients with borderline congestive heart failure.
Renal Impairment: Because fluvastatin does not undergo significant renal excretion, modification of dosage should not be necessary in patients with mild to moderate renal impairment (creatinine clearance >30 mL/min).
As there is no experience with fluvastatin in patients with severe renal insufficiency (creatinine > 260 mol/L, i.e., creatinine clearance
Endocrine Function: HMG-CoA reductase inhibitors interfere with cholesterol synthesis and as such could theoretically blunt adrenal and/or gonadal steroid production.
Fluvastatin exhibited no effect upon non-stimulated cortisol levels, FSH (males only) or thyroid metabolism as assessed by TSH. Small declines in total testosterone have been noted in treated groups, but no commensurate elevation in LH occurred. However, the effects of HMG-CoA reductase inhibitors on male fertility have not been studied in an adequate number of patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown.
Patients treated with fluvastatin 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.
Effect on Lens: Current data from long-term clinical trials do not indicate an adverse effect of fluvastatin on the human lens.
Pregnancy: Fluvastatin is contraindicated during pregnancy (see Contraindications).
Data on the use of fluvastatin in pregnant women is limited. A few reports have been received of congenital anomalies in infants whose mothers were treated during a critical period of pregnancy with other HMG-CoA reductase inhibitors. During the clinical progam, a total of 5 women who were receiving fluvastatin became pregnant and were discontinued from the studies. Of these 5 women, 3 gave birth to healthy babies, one experienced an ectopic pregnancy which was attributed to a severely scarred fallopian tube; and one spontaneously aborted.
Atherosclerosis is a chronic process and discontinuation of lipid metabolism regulators 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.
Fluvastatin should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards. 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 (see Contraindications).
Lactation: It is not known whether fluvastatin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from fluvastatin, women receiving fluvastatin should not breast-feed (see Contraindications).
Children: Limited experience with the use of other HMG-CoA reductase inhibitors is available in children. Safety and effectiveness of fluvastatin in children have not been established.
Geriatrics: The effect of age on the pharmacokinetics of fluvastatin was evaluated. Results indicate that for the general patient population plasma concentrations of fluvastatin do not vary either as a function of age or gender (see Pharmacology, Pharmacokinetics).
Drug Interactions: Concomitant Therapy With Other Lipid Metabolism Regulators: Combined drug therapy should be approached with caution as information from controlled studies is limited.
A drug interactive effect (pharmacokinetic and/or clinical) has been shown for the following drugs in combination with fluvastatin.
Cholestyramine: The cholesterol-lowering effects of fluvastatin and the bile acid sequestrant, cholestyramine, are additive.
Administration of fluvastatin concomitantly 2 to 4 hours after cholestyramine, results in fluvastatin decreases of more than 50% for the fluvastatin AUC and 50 to 80% for the fluvastatin Cmax. However, administration of fluvastatin 4 hours after cholestyramine resulted in a clinically significant additive effect in reducing total-C and LDL-C compared with that achieved with either component drug (see Dosage).
Gemfibrozil/Fenofibrate/Niacin: Myopathy, including rhabdomyolysis, has occurred in patients who were receiving co-administration of HMG-CoA reductase inhibitors with fibric acid derivatives and niacin (in lipid lowering doses), particularly in subjects with pre-existing renal insufficiency (see Warnings, Muscle Effects). Fluvastatin has been safely administered concomitantly with nicotinic acid, gemfibrozil and bezafibrate in clinical studies. In short-term studies involving a small number of patients, myopathy was not reported during administration of bezafibrate and fluvastatin at doses of 40 and 60 mg/day. To date, the 80 mg/day dose has not been evaluated with bezafibrate.
Other Concomitant Therapy: Cimetidine/Ranitidine/Omeprazole: Concomitant administration of fluvastatin with cimetidine, ranitidine and omeprazole results in a significant increase in the fluvastatin Cmax (43, 70 and 50%, respectively) and AUC (24 to 33%), with an 18 to 23% decrease in apparent oral plasma clearance (Cl/F).
Digoxin: In a crossover study involving 18 patients chronically receiving digoxin, concomitant administration of a single 40 mg dose of fluvastatin had no effect on digoxin AUC and small but clinically insignificant increases in the digoxin Cmax and urinary clearance were noted.
Rifampin: Administration of fluvastatin to subjects pretreated with rifampin results in significant reduction in Cmax (59%) and AUC (51%) of fluvastatin, with a large increase (95%) in plasma clearance.
Antipyrine: Administration of fluvastatin does not influence the metabolism and excretion of antipyrine, either by induction or inhibition.
Beta-adrenergic Blocking Drugs: Concomitant administration of propranolol has no effect on the bioavailability of fluvastatin sodium.
Warfarin: In vitro protein binding studies demonstrated no interaction at therapeutic concentrations. In a drug interaction study, the concomitant use of fluvastatin and warfarin did not alter the plasma levels and prothrombin times compared to warfarin alone. However, since other drugs of this class have been shown to enhance the anticoagulant effect of warfarin, caution is advised when administering warfarin concomitantly with fluvastatin.
Cytochrome P450: Fluvastatin is predominantly metabolized by the hepatic microsomal CYP2C9 subclass of the P450 cytochromes. It is not metabolized to a significant extent by other cytochrome subclasses, including CYP3A4. The clearance of drugs which are also CYP2C9 substrates may decrease when coadministered with fluvastatin. However, for those CYP2C9-metabolized drugs which have been studied directly, including diclofenac, tolbutamide, and warfarin, the effect on clearance is small and no clinically significant drug interactions of fluvastatin with other CYP2C9 substrates have been demonstrated. Caution should nevertheless be exercised with concomitant use of drugs metabolized by the CYP2C9 subclass of the P450 cytochromes such as phenytoin, oral anticoagulants (e.g., warfarin), oral hypoglycemic agents (e.g., tolbutamide, chlorpropamide) and NSAIDs (e.g., diclofenac) (see Warnings, Muscle Effects).
In addition, since fluvastatin demonstrates a moderate affinity for the CYP 3A4 isoenzyme, drugs or common agents such as grapefruit juice that inhibit this enzyme (immunosuppressants, azole-type antifungal agents, macrolide antibiotics or antidepressants) may represent a potential, at least in some patients, for drug interactions when combined with fluvastatin (see Warnings, Pharmacokinetics Interactions and Muscle Effects).
Patients with Severe Hypercholesterolemia: Higher dosages (80 mg/day) required for some patients with severe hypercholesterolemia are associated with increased plasma levels of fluvastatin. Caution should be exercised in such patients who are also significantly renally impaired, elderly, or are also concomitantly being administered digoxin, or CYP 450 inhibitors (See Warnings, Pharmacokinetic Interactions and Muscle Effects and Precautions, Drug Interactions).
Although specific interaction studies were not performed with all drugs listed below, in clinical studies, fluvastatin was used concomitantly with angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, calcium-channel blockers, oral sulphonylureas, antacids, diuretics and NSAIDs without evidence to date of clinically significant interactions.
Immunosuppressive Drugs, Erythromycin: See Warnings, Muscle Effects.
Laboratory Interactions : The HMG-CoA reductase inhibitors may cause elevation of creatinine phosphokinase and transaminase levels (see Warnings). In the differential diagnosis of chest pain in a patient on fluvastatin, cardiac and noncardiac fractions of these enzymes should be determined.
Adverse Reactions: In all clinical studies (controlled and uncontrolled), 1% (32/2 969) of fluvastatin patients were discontinued due to adverse experiences attributed to study drug (mean exposure of approximately 16 months ranging in duration from 1 to more than 36 months). This results, in controlled studies, in an exposure adjusted incidence of 0.8 % per patient year in fluvastatin patients compared to an incidence of 1.1 % in placebo patients. Adverse events were usually mild and transient. Clinical adverse reactions of positive or uncertain relationship to study medication occuring at a frequency ³ 1 % in controlled clinical trials with fluvastatin
Other clinical adverse reactions of positive or uncertain relationship to study medication occuring in 0.5 to 1.0% of patients receiving 20 to 80 mg fluvastatin monotherapy in controlled clinical trials (N=2 326) are listed below:
Gastrointestinal: vomiting, gastritis.
Musculoskeletal: arthritis.
CNS: conjunctivitis, paresthesia.
Respiratory: rhinitis.
Integumentary: pruritus.
Miscellaneous: leg pain, influenza-like symptoms, allergy.
The following effects have been reported with drugs of this class: Skeletal: myopathy, rhabdomyolysis (see Warnings), muscle cramping/pain.
Neurological: paresthesia, peripheral neuropathy, psychiatric disturbances/anxiety.
Hypersensitivity Reactions: An apparent hypersensitivity syndrome has been reported rarely with other HMG-CoA reductase inhibitors and has included one or more of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatica, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive antinuclear antibody (ANA), erythrocytes sedimentation rate (ESR) increase, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiform, including Stevens-Johnson syndrome.
Gastrointestinal: hepatitis, cholestatic jaundice, anorexia, vomiting.
Skin: alopecia.
Miscellaneous: asthenia, sweating, hot flushes.
Symptoms And Treatment Of Overdose: Symptoms: The maximum single oral dose of fluvastatin received by healthy volunteers was 60 mg. No clinically significant adverse experiences were seen at this dose. There has been a single report of two children, one 2 year old and the other 3 years of age, either of whom may have possibly ingested fluvastatin. The maximum amount of fluvastatin ingested was 80 mg (4´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.
Treatment: Should an accidental overdose occur, administration of activated charcoal is recommended. In the case of very recent oral intake, gastric lavage may be considered.
Treatment should be symptomatic. The dialyzability of fluvastatin and its metabolites in man is not known at present.
Dosage And Administration: Prior to initiating fluvastatin, the patient should be placed on a standard cholesterol-lowering diet (at least equivalent to the American Heart Association (AHA) Step 1 Diet), which should be continued during treatment. If appropriate, a program of weight control and physical exercise should be implemented.
The recommended starting dose is 20 mg once daily to be taken in the evening or at bedtime. The recommended dosing range is 20 to 80 mg/day. The daily dose regimen of 80 mg should be administered in divided doses, i.e., 40 mg b.i.d. Fluvastatin should be taken with or after meals. Since the maximal reductions in LDL-C are seen within 4 weeks of administration of a given dose, periodic lipid determinations should be performed with dosage adjusted to a maximum of 40 mg twice a day, according to the patient’s response.
The therapeutic effect of fluvastatin is maintained with prolonged administration.
Cholesterol levels should be monitored periodically and consideration should be given to reducing the dosage of fluvastatin if cholesterol levels fall below the targeted range, such as that recommended by the Second Report of the U.S. National Cholesterol Education Program (NCEP).
Severe Hypercholesterolemia: In patients with severe hypercholesterolemia, higher dosages (80 mg/day) may be required (see Warnings, Pharmacokinetic Interactions and Muscle Effects and Precautions, Drug Interactions).
Concomitant Therapy: (see Precautions).
Patients with Renal Insufficiency: (see Precautions).
Availability And Storage: 20 mg: Each brown opaque cap and light brown opaque body gelatin capsule contains: fluvastatin 20 mg (from fluvastatin sodium 21.06 mg).
Printed twice and “20” in white ink on the cap; “Lescol” and product logo in red ink on the body. Nonmedicinal ingredients: calcium carbonate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, sodium bicarbonate and talc. Capsule shell and printing ink: ammonium hydroxide, benzyl alcohol, n-butyl alcohol, butylparaben, carboxymethylcellulose sodium, edetate calcium disodium, ethyl alcohol, gelatin, iron oxide black, iron oxide red, iron oxide yellow, isopropyl alcohol, methylparaben, polyvinylpyrrolidone, propylene glycol, propylparaben, shellac, silicon dioxide, sodium hydroxide, sodium laurel sulfate, sodium propionate and titanium dioxide. Bottles of 100.
40 mg: Each brown opaque cap and gold opaque body gelatin capsule contains: fluvastatin 40 mg (from fluvastatin sodium 42.12 mg).
Printed twice and “40” in white ink on the cap; “Lescol” and product logo in red ink on the body. Nonmedicinal ingredients: calcium carbonate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, sodium bicarbonate and talc. Capsule shell and printing ink: ammonium hydroxide, benzyl alcohol, n-butyl alcohol, butylparaben, carboxymethylcellulose sodium, edetate calcium disodium, ethyl alcohol, gelatin, iron oxide black, iron oxide red, iron oxide yellow, isopropyl alcohol, methylparaben, polyvinylpyrrolidone, propylene glycol, propylparaben, shellac, silicon dioxide, sodium hydroxide, sodium laurel sulfate, sodium propionate and titanium dioxide. Bottles of 100.
Store between 15 and 30°C in a tight container. Protect from light and humidity.
LESCOL® Novartis Pharmaceuticals Fluvastatin Sodium Lipid Metabolism Regulator
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