Fluvastatin sodium, a hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitor (i.e., statin), is an antilipemic agent.1, 4, 5
Reduction in Risk of Cardiovascular Effects
Reducing Progression of Coronary Atherosclerosis (Secondary Prevention)
Fluvastatin is used as an adjunct to diet and lifestyle modifications in adults with clinical evidence of coronary heart disease (CHD) to reduce the risk of undergoing coronary revascularization procedures and slow the progression of coronary atherosclerosis.1, 72, 400
Efficacy and safety of fluvastatin for this use were established in a randomized, double-blind, placebo-controlled study (Lescol Intervention Prevention Study [LIPS]) in 1677 patients with stable or unstable angina or silent ischemia who had undergone a first percutaneous coronary intervention (PCI).1, 72 Fluvastatin immediate-release capsules (40 mg twice daily), initiated within a mean of 3 days following PCI and continued for a median of 3.9 years, resulted in a 22% reduction in the relative risk and a 5.3% reduction in the absolute risk of fatal or nonfatal major adverse cardiac events (e.g., cardiac death, nonfatal MI, new or repeat PCI or coronary artery bypass grafting [CABG] procedure).1, 71, 72 Reduction in the risk of adverse cardiac events also was observed in geriatric patients (older than 65 years of age).1, 72 Revascularization procedures (repeat PCI or CABG) involving the originally instrumented site comprised most of the initial recurrent adverse cardiac events; these procedures were performed in 143 or 171 patients receiving fluvastatin or placebo, respectively, within the first 6 months following the initial procedure.1, 72 Treatment with fluvastatin also was associated with a 32% reduction in the risk of late revascularization procedures (i.e., PCI or CABG occurring at the original site more than 6 months following the initial procedure, or at another site).1, 72
In another randomized, double-blind, placebo-controlled study (Fluvastatin Angiographic Restenosis [FLARE]) in patients with symptomatic or ischemia-producing coronary lesions who required balloon angioplasty, therapy with fluvastatin (40 mg twice daily) was associated with a lower incidence of death and nonfatal MI (1.4% in fluvastatin-treated patients versus 4% in placebo-treated patients).53
Efficacy and safety of fluvastatin in slowing the progression of coronary atherosclerosis were established in a placebo-controlled trial in men and women with angiographically documented CHD and mildly to moderately elevated serum low-density lipoprotein (LDL)-cholesterol concentrations; the study found that progression of coronary atherosclerosis was slowed in patients treated with fluvastatin immediate-release capsules 40 mg per day as measured by within-patient, per-lesion changes in minimum lumen diameter of qualifying lesions (primary end point), percent diameter stenosis, and the formation of new lesions over the 2.5-year follow-up period.1, 33, 34, 72
Beneficial effects of fluvastatin on angiographic progression of coronary atherosclerosis (change in minimum lumen diameter) were independent of patient gender and consistent across a range of baseline LDL-cholesterol concentrations.1, 33, 34, 72 However, changes in minimum lumen diameter were greater among patients with low baseline high-density lipoprotein (HDL)-cholesterol (i.e., less than 35 mg/dL) than in those with normal to high HDL-cholesterol concentrations (i.e., 35 mg/dL or greater).52 In addition, fluvastatin-treated patients with low baseline HDL-cholesterol concentrations had improved event-free survival, as evidenced by a lower rate of time to first clinical event (i.e., percutaneous transluminal coronary angioplasty [PTCA], CABG, definite or probable MI, unstable angina requiring hospitalization, or death of any cause) compared with no benefit among patients with normal or high HDL-cholesterol concentrations.52
Fluvastatin also has been used for primary prevention† of atherosclerotic cardiovascular disease (ASCVD).400 The potential benefits of fluvastatin in patients with chronic kidney disease, a population at high risk of cardiovascular disease, were evaluated in the Assessment of Lescol in Renal Transplantation (ALERT) study, a randomized, double-blind, placebo-controlled study that was conducted in approximately 2100 renal transplant patients.388 Results of the study showed no substantial effect of fluvastatin on the primary end point of major adverse cardiac events (defined as cardiac death, nonfatal MI, or coronary intervention procedure) compared with placebo, although fluvastatin appeared to reduce the risk of cardiac death and nonfatal MI.388
The 2018 American Heart Association (AHA)/American College of Cardiology (ACC) cholesterol management guideline emphasizes lifestyle modification as the foundation of ASCVD risk reduction.400 If pharmacologic therapy is needed, hydroxymethyl-glutaryl-CoA (HMG-CoA) reductase inhibitor (statin) therapy is recommended.400 Statins are considered the first-line drugs of choice for reducing LDL-cholesterol, the lipoprotein fraction found to be a major cause of clinical ASCVD.400, 401, 402 There is extensive evidence demonstrating that statins can substantially reduce LDL-cholesterol concentrations and associated risk of ASCVD when used for secondary prevention or primary prevention in high-risk patients.336, 337, 338, 400, 401, 402 Because the relative risk reduction is correlated with the degree of LDL lowering, the maximum tolerated statin intensity should be used to achieve optimum ASCVD benefits.400, 401, 402
When considering whether to initiate statin therapy for primary prevention, the 2018 AHA/ACC cholesterol management guideline recommends a shared decision-making approach between the patient and clinician.400 The guideline recommends consideration of statin therapy in certain high-risk groups such as adults 20-75 years of age with LDL-cholesterol levels ≥190 mg/dL, adults 40-75 years of age with diabetes mellitus, adults 40-75 years of age without diabetes mellitus but with LDL-cholesterol levels ≥70 mg/dL and an estimated 10-year ASCVD risk ≥7.5%, and adults 40-75 years of age with chronic kidney disease (not treated with dialysis or transplantation) and LDL-cholesterol concentrations of 70-189 mg/dL who have a 10-year ASCVD risk ≥7.5%.400, 401
The guideline states that patients with clinical ASCVD (defined as those with acute coronary syndromes [ACS], history of MI, stable or unstable angina or coronary or other arterial revascularization, stroke, transient ischemic attack [TIA], or peripheral artery disease [PAD], including those with aortic aneurysm) should be treated with a statin in conjunction with lifestyle modification to reduce LDL-cholesterol concentrations.400 Because patients >75 years of age may have a higher risk of adverse effects and lower adherence to therapy, the expected benefits versus adverse effects should be considered before initiating statin therapy in this population.400 The maximum tolerated intensity of a statin should be used to achieve optimum ASCVD benefits.400 AHA/ACC recommends the use of high-intensity statin therapy (defined as reducing LDL-cholesterol concentrations by at least 50%).400 If high-intensity statin therapy is not possible (e.g., because of a contraindication or intolerable adverse effect), moderate-intensity statin therapy (defined as reducing LDL-cholesterol concentrations by 30-49%) may be used.400
The appropriate intensity of a statin should be used to reduce the risk of ASCVD.400 Based on the average LDL-cholesterol response observed with specific statins and dosages used in the randomized controlled studies evaluated by the AHA/ACC guideline panel, immediate-release fluvastatin 40 mg twice daily (or extended-release fluvastatin 80 mg daily) is considered to be a moderate-intensity statin (producing approximate LDL-cholesterol reductions of 30-49%).400
Combination Antilipemic Therapy
The addition of a nonstatin drug (e.g., ezetimibe, PCSK9 inhibitor) to statin therapy may be useful in certain high-risk patients who experience an inadequate reduction in LDL-cholesterol concentrations despite maximally tolerated statin therapy (e.g., <50% reduction in LDL-cholesterol or LDL-cholesterol concentration ≥55 mg/dL or non-HDL-cholesterol ≥85 mg/dL).400, 403 If combination therapy is necessary, selection of the nonstatin drug should be based on the risk and benefit profile (i.e., reduction in ASCVD risk outweighs the drug's potential for adverse effects and drug interactions) and patient preferences.400, 403
A 2022 consensus decision pathway published by ACC addresses the use of nonstatin therapies for primary or secondary prevention of ASCVD.403 In patients with primary hypercholesterolemia without ASCVD who require additional LDL-lowering therapy despite maximal statin therapy, ezetimibe and/or a PCSK9 monoclonal antibody (mAb) inhibitor are considered preferred initial nonstatin therapies due to demonstrated benefits in cardiovascular outcomes.403 If therapeutic goals are not achieved, other nonstatin therapies (e.g., inclisiran, bempedoic acid, evinacumab, lomitapide) may be considered.403
In patients receiving statin therapy as secondary prevention who are at very high risk of ASCVD and require additional LDL-lowering therapy despite maximal statin therapy, ezetimibe and/or a PCSK9 inhibitor are considered preferred initial nonstatin therapies.403 In patients receiving statin therapy as secondary prevention who are not at very high risk of ASCVD, ezetimibe is considered the preferred initial nonstatin therapy, followed by addition or replacement with a PCSK9 inhibitor if additional LDL-lowering therapy is needed.403 If therapeutic goals are not achieved in the secondary prevention setting, inclisiran (in place of a PCSK9 inhibitor) or bempedoic acid may be considered.403
A 2022 scientific statement published by the National Lipid Association (NLA) addresses the use of nonstatin therapies for ASCVD risk reduction in patients with statin intolerance.406 Nonstatin LDL-lowering therapy may be considered in patients with complete or partial statin intolerance, including during the course of attempting to identify a tolerable alternate statin regimen in patients with high or very high ASCVD risk.406 When nonstatin therapies are used, agents that have demonstrated cardiovascular outcome benefit in randomized trials are preferred.406
Primary Hypercholesterolemia or Mixed Dyslipidemia
Fluvastatin is used as an adjunct to nondrug therapies (e.g., dietary management) in adults to decrease elevated serum total and LDL-cholesterol, apolipoprotein B (apo B), and triglyceride concentrations, and to increase HDL-cholesterol concentrations in the treatment of primary hypercholesterolemia (heterozygous familial and nonfamilial) or mixed dyslipidemia (Fredrickson type IIa or IIb).1, 72
Fluvastatin immediate-release capsules are specifically labeled for the reduction of elevated total-cholesterol, LDL-cholesterol, apo B, and triglycerides, and to increase HDL-cholesterol in patents with primary hypercholesterolemia and mixed dyslipidemia (Fredrickson types IIa and IIb).1 Fluvastatin extended-release tablets are specifically labeled for the reduction of elevated LDL-cholesterol in adults with primary hyperlidipemia.72 The manufacturer of the immediate-release preparation states that the drug has not been studied in conditions where the major abnormality is elevation of chylomicrons, very-low-density lipoproteins (VLDLs), or intermediate-density lipoproteins (IDLs) (i.e., hyperlipoproteinemia Types I, III, IV, or V).1
Reductions in total and LDL-cholesterol produced by usual dosages of fluvastatin substantially exceed those of placebo but appear to be less than those produced by monotherapy with usual dosages of other antilipemic agents.1, 31, 32, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 51, 72 Mean reductions in total cholesterol, LDL-cholesterol, apo B, and triglyceride concentrations of 13-27, 17-36, 18-28, and 7-18%, respectively, have been reported in controlled studies in patients with primary hypercholesterolemia or mixed dyslipidemia who received 20-80 mg of fluvastatin daily for at least 6 weeks.1, 28, 31, 32, 35, 36, 37, 38, 39, 60 Modest and variable increases in HDL-cholesterol concentrations (2-10%) also were observed in these patients.1, 31, 32, 35, 36, 60 In a subgroup of patients with primary mixed dyslipidemia (defined as baseline triglyceride concentrations of at least 200 mg/dL), therapy with immediate-release fluvastatin was associated with 16-27, 22-35, 18-28, and 17-23% reductions in total cholesterol, LDL-cholesterol, apo B, and triglyceride concentrations, respectively, and 6-9% increases in HDL-cholesterol concentrations.1
Effects on various lipoprotein fractions appear to be similar in patients receiving an equivalent daily dosage (80 mg) of extended-release tablets or immediate-release capsules.1, 72 Mean reductions in total cholesterol, LDL-cholesterol, apo B, and triglyceride concentrations of 25, 35, 27, and 19%, respectively, and mean increases in HDL-cholesterol concentrations of 7% have been reported in patients receiving the extended-release formulation for at least 4 weeks.72 In a subgroup of patients with primary mixed dyslipidemia (defined as triglyceride concentrations of at least 200 mg/dL), therapy with extended-release fluvastatin was associated with 25, 33, 27, and 25% reductions in total cholesterol, LDL-cholesterol, apo B, and triglyceride concentrations, respectively, and 11% increases in HDL-cholesterol concentrations.72
Reductions in total and LDL-cholesterol concentrations produced by usual dosages of fluvastatin appear to be smaller than those produced by monotherapy with other statins.40, 41, 42, 43, 44, 51 In a randomized, multicenter, parallel-group study comparing the efficacy of various statins (e.g., atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin), patients with hypercholesterolemia who received fluvastatin 20-40 mg daily had similar or smaller reductions in total and LDL-cholesterol concentrations (13-19 and 17-23%, respectively) than those receiving atorvastatin 10-80 mg daily (28-42 and 38-54%, respectively), lovastatin 20-80 mg daily (21-36 and 29-48%, respectively), pravastatin 10-40 mg daily (13-24 and 19-34%, respectively), and simvastatin 10-40 mg daily (21-30 and 28-41%, respectively).40
Fluvastatin (40 mg daily) reportedly produces smaller reductions in total and LDL-cholesterol concentrations than cholestyramine (16 g daily), with reductions of 22 and 28%, respectively, in fluvastatin-treated patients versus 25 and 35%, respectively, in cholestyramine-treated patients.67 However, treatment with cholestyramine was associated with a 12% increase in triglyceride concentrations compared with an 11% decrease in fluvastatin-treated patients.67 Limited data from comparative studies suggest that fluvastatin has efficacy similar to or greater than that of fibric acid derivatives in reducing total and LDL-cholesterol concentrations in patients with primary hypercholesterolemia.47 In a 12-week, open-label study comparing fluvastatin (40 mg daily) with bezafibrate (400 mg daily) (currently not commercially available in the US), patients with primary types IIa and IIb hypercholesterolemia who received fluvastatin therapy had greater reductions in total and LDL-cholesterol concentrations than those treated with bezafibrate (27 and 45% versus 8 and 4%, respectively).47 Reductions in triglyceride concentrations (26%) reportedly were similar with the 2 treatments.47
The combination of fluvastatin and other antilipemic agents (e.g., bile acid sequestrants, niacin, fibric acid derivatives) generally results in additive antilipemic effects; however, the risk of myopathy and rhabdomyolysis may be increased with some combinations.12, 45, 46, 48, 49, 72 The addition of a bile acid sequestrant to fluvastatin therapy further reduced LDL-cholesterol by 9-12%, resulting in overall LDL-cholesterol reductions of 27-47% in patients receiving fluvastatin 10-40 mg daily and cholestyramine 4-16 g daily.45, 46, 66 The combination of fluvastatin (20 mg daily) and niacin (3 g daily) for 9 weeks in hypercholesterolemic patients further reduced total and LDL-cholesterol concentrations by 12 and 19%, respectively.48 In addition, such combined therapy also reduced triglyceride concentrations by an additional 18% and increased HDL-cholesterol concentrations by 23%.48 In several double-blind studies in a limited number of hypercholesterolemic patients, the combination of fluvastatin (40 mg daily) and fibric acid derivatives (i.e., gemfibrozil 600 mg twice daily or bezafibrate [not commercially available in the US] 400 mg daily) resulted in greater reductions in total cholesterol, LDL-cholesterol, and triglyceride concentrations compared with those achieved with fluvastatin monotherapy.12, 25, 26, 49 Triple-drug therapy with fluvastatin, cholestyramine, and a fibric acid derivative in patients with severe heterozygous familial hypercholesterolemia has produced further sustained reductions in LDL-cholesterol concentrations compared with those produced by combinations of any 2 of these drugs.50
Adolescent Patients with Heterozygous Familial Hypercholesterolemia
Fluvastatin also is used as an adjunct to dietary therapy to decrease elevated serum total cholesterol, LDL-cholesterol, and apo B concentrations in the management of heterozygous familial hypercholesterolemia in boys and girls (who are at least 1 year postmenarchal) 10-16 years of age who, despite an adequate trial of dietary management, have a serum LDL-cholesterol concentration ≥190 mg/dL or a serum LDL-cholesterol concentration ≥160 mg/dL and either a family history of premature cardiovascular disease or 2 or more other cardiovascular disease risk factors.1, 72
Efficacy and safety of immediate-release fluvastatin for this use have been evaluated in 2 open-label, uncontrolled, dose-titration studies.1, 72 In these studies, pediatric patients (9-16 years of age) with heterozygous familial hypercholesterolemia treated with fluvastatin 20-80 mg daily for approximately 2 years had 21-22% reductions in total cholesterol and 27-28% reductions in LDL-cholesterol concentrations.1, 72 Approximately 83-89% of patients received the maximum dosage of 80 mg daily.1, 72 At the end of the study, 26-30% of patients achieved a target LDL-cholesterol goal of less than 130 mg/dL.1 The long-term efficacy of fluvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established.1
Elevated serum cholesterol, especially the LDL-cholesterol fraction, is a major cause of clinical ASCVD; other major risk factors include cigarette smoking, hypertension, diabetes, age, heterozygous familial hypercholesterolemia, chronic kidney disease (eGFR 15-59 mL/minute per 1.73m2), history of heart failure, and other lipoprotein abnormalities.400, 403 Therefore, the goal of antilipemic therapy in patients with hyperlipidemia is to reduce the risk of ASCVD.400 Clinical studies have demonstrated that immediate-release fluvastatin 20-40 mg daily is considered to be a low-intensity statin producing approximate LDL-cholesterol reductions of <30% when used alone and immediate-release fluvastatin 40 mg twice daily or extended-release fluvastatin 80 mg daily is considered to be a moderate-intensity statin producing approximate LDL-cholesterol reductions of 30-49% when used alone.118, 119, 400
The 2018 AHA/ACC cholesterol management guideline emphasizes lifestyle modification as the foundation of ASCVD risk reduction.400 If pharmacologic therapy is needed, statin therapy is recommended as a first-line therapy.400
When considering whether to initiate statin therapy for dyslipidemia in the setting of primary prevention, the 2018 AHA/ACC cholesterol management guideline recommends a shared decision-making approach between the patient and clinician.400 The guideline recommends consideration of statin therapy in certain high-risk groups such as adults 20-75 years of age with LDL-cholesterol levels ≥190 mg/dL, adults 40-75 years of age with diabetes mellitus, adults 40-75 years of age without diabetes mellitus but with LDL-cholesterol levels ≥70 mg/dL and an estimated 10-year ASCVD risk ≥7.5%, and adults 40-75 years of age with chronic kidney disease (not treated with dialysis or transplantation) and LDL-cholesterol concentrations of 70-189 mg/dL who have a 10-year ASCVD risk of 7.5% or higher.400, 401
There is extensive evidence demonstrating that statins can substantially reduce LDL-cholesterol concentrations and associated risk of ASCVD when used for such patients.336, 337, 338, 400, 401, 402, 403 Because the relative risk reduction is correlated with the degree of LDL lowering, the maximum tolerated statin intensity should be used to achieve optimum ASCVD benefits.400, 401, 402
Combination Antilipemic Therapy
An ACC expert committee update on nonstatin drug therapies recommends that adults without clinical ASCVD with baseline LDL-cholesterol concentrations ≥190 mg/dL not due to secondary causes may be considered for ezetimibe and/or a PCSK9 mAb inhibitor if they have not met certain thresholds of LDL-cholesterol reduction on maximally tolerated statin therapy for primary prevention (e.g., at least 50% reduction in LDL-cholesterol with an LDL-cholesterol <100 mg/dL or a non-HDL-cholesterol concentration <130 mg/dL).403 Individuals with LDL-cholesterol concentrations >190 mg/dL are more likely to have genetic disorders associated with hypercholesterolemia, such as heterozygous familial hypercholesterolemia or homozygous familial hypercholesterolemia.403 Current treatments for patients with heterozygous familial hypercholesterolemia include lifestyle modifications (e.g., low-fat diet, maintenance of a healthy body weight, smoking cessation), first-line treatment with statins, and, if necessary, combination therapy with other lipid-lowering medications (e.g., bile acid sequestrants, ezetimibe, PCSK9 inhibitors, bempedoic acid, inclisiran).403
Patients with moderate or severe hypertriglyceridemia (fasting or non-fasting triglyceride levels 175-499 mg/dL or fasting levels ≥500 mg/dL, respectively) generally are at increased risk of ASCVD and pancreatitis especially in patients with fasting levels ≥500 mg/dL.400, 403 The AHA/ACC cholesterol management guideline recommends assessment and modification of lifestyle (obesity and metabolic syndrome), secondary disorders (e.g., diabetes mellitus, chronic liver or kidney disease and/or nephrotic syndrome, hypothyroidism), and medications that increase triglycerides.400 Initiation or intensification of statin therapy may be considered in adults 40-75 years of age with moderate or severe hypertriglyceridemia and 10-year ASCVD risk of ≥7.5%.400 Experts state statins alone cannot prevent increasing levels of triglycerides in the face of secondary causes from triggering acute hypertriglyceridemic pancreatitis.400
In addition to early identification of children with familial hypercholesterolemia, dietary (e.g., caloric restriction, Mediterranean-style diet) and lifestyle modification (e.g., physical activity) are prioritized for the management of hypercholesterolemia in children and adolescents.400, 404 Evidence from randomized controlled trials coupled with the increased risk of cardiovascular disease in untreated severe hypercholesterolemia, support the use of statins in children and adolescents at ages ≥10 years who have familial hypercholesterolemia.400
In children and adolescents ≥10 years of age with an LDL-cholesterol level persistently ≥190 mg/dL or ≥160 mg/dL with a clinical presentation consistent with familial hypercholesterolemia and who do not respond adequately with 3-6 months of lifestyle therapy, experts state it is reasonable to initiate statin therapy.400 Treatment intensity should be based on the severity of the hypercholesterolemia and should incorporate patient/family preference; some experts recommend initiation at the lowest recommended dose and up-titration according to LDL-cholesterol lowering response and tolerability.400, 404 These experts recommend a target LDL-cholesterol level <130 mg/dL or ≥50% reduction from pre-treatment levels, particularly in those with high-risk conditions or other major risk factors; combination therapy with other lipid-lowering medications (e.g., bile acid sequestrants, ezetimibe) may be required.404
Fluvastatin is administered orally (as immediate-release capsules or extended-release tablets) without regard to meals.1, 72
Fluvastatin immediate-release capsules are administered orally once (in the evening) or twice daily.1 The capsules should not be opened.1 Do not administer two 40 mg immediate-release capsules at once.1
Fluvastatin extended-release tablets are administered orally as a single dose at any time of day.1, 72 The extended-release tablets should not be broken, crushed, or chewed prior to administration.1, 72
If a dose of immediate-release fluvastatin is missed, the missed dose may be administered as soon as possible.1 If it has been more than 12 hours since the last dose, do not administer until the next scheduled dose is due; do not administer 2 doses at the same time.1
Store immediate-release capsules at 20-25°C and protect from light.1 Store extended-release tablets at 20-25°C (excursions permitted to 15-30°C) and protect from light.72
Dosage of fluvastatin sodium is expressed in terms of fluvastatin and must be carefully adjusted according to individual requirements (i.e., percent reduction in LDL-cholesterol concentrations) and response.1, 72, 400
Reduction in the Risk of Cardiovascular Events
Immediate-release capsules: For the reduction in risk of cardiovascular events in adults, the usual recommended starting dosage of fluvastatin is 40 mg once daily in the evening or 40 mg twice daily.1 The recommended dosing range of fluvastatin immediate-release is 20-80 mg per day.1
Extended-release tablets: Fluvastatin extended-release is only available as an 80 mg tablet; the dosage cannot be titrated.72 The recommended dosage of fluvastatin (as extended-release tablets) in adults is 80 mg once daily.72 For patients that require a high-intensity statin or are unable to achieve their LDL-cholesterol goal receiving fluvastatin extended-release 80 mg daily, an alternative LDL-cholesterol lowering treatment is recommended.72
The AHA/ACC cholesterol management guideline states that the appropriate intensity of statin therapy should be used to reduce ASCVD risk.400 The guideline recommends use of high-intensity statin therapy (defined as reducing LDL-cholesterol concentrations by at least 50%); if high-intensity statin therapy is not possible (e.g., because of a contraindication or intolerable adverse effect), moderate-intensity statin therapy (defined as reducing LDL-cholesterol concentrations by 30-49%) should be used.400 The AHA/ACC guideline panel considers fluvastatin 40 mg twice daily (or extended-release fluvastatin 80 mg daily) to be a moderate-intensity statin.400
Immediate-release capsules: Therapy with fluvastatin generally is initiated with a dosage of 20 mg daily (as immediate-release capsules) in adults who require reductions in LDL-cholesterol of less than 25%.1 In patients who require larger reductions in LDL-cholesterol concentrations (i.e., 25% or more) or in patients with primary hypercholesterolemia or mixed dyslipidemia, fluvastatin should be initiated at a dosage of 40 mg daily in the evening or 40 mg twice daily (as immediate-release capsules); administration of two 40-mg immediate-release capsules at one time should be avoided.1 Dosage should be increased at intervals of no less than 4 weeks until the desired effect on lipoprotein concentrations is observed or a maximum dosage of 80 mg daily is reached.1 The usual maintenance dosage of fluvastatin in adults is 20-80 mg daily.1
Extended-release tablets: The recommended dosage of fluvastatin (as extended-release tablets) in adults is 80 mg once daily.72
Immediate-release capsules: The recommended initial dosage of fluvastatin for the treatment of heterozygous familial hypercholesterolemia in boys and postmenarchal girls 10-16 years of age is 20 mg once daily.1 Dosage should be increased at 6-week intervals until the desired effect on lipoprotein concentrations is observed or a maximum dosage of 80 mg daily (administered as 40 mg twice daily as immediate-release capsules or 80 mg once daily as extended-release tablets) is reached.1, 72
Extended-release fluvastatin tablets cannot be used for dosage initiation in pediatric patients, but may be used once the patient reaches a dosage of 80 mg daily after titration with the immediate-release capsules.72
Dosage Modifications for Concomitant Therapy
In patients receiving cyclosporine or fluconazole, the manufacturer recommends that fluvastatin dosage not exceed 20 mg twice daily.1
The manufacturer makes no specific dosage recommendations for patients with hepatic impairment.1, 72 Use of fluvastatin is contraindicated in patients with active liver disease or unexplained, persistent increases in serum aminotransferase concentrations.1, 72
The manufacturer states that dosage modification in patients with mild to moderate renal impairment is not necessary.1, 72 Fluvastatin, at dosages exceeding 40 mg daily, has not been studied in patients with severe renal impairment; caution is advised when administering higher dosages of the drug to such patients.1, 72
Select dosage with caution in geriatric patients, considering the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy.1, 72
Pharmacogenomic Considerations in Dosing
Patients with solute carrier organic anion transporter (SLCO) 1B1 decreased or possible decreased function phenotypes will have increased fluvastatin exposure compared to those with normal function, which may translate to an increased risk of statin-associated musculoskeletal symptoms if dosage exceeds 40 mg daily.500 In such patients, initiate fluvastatin at ≤40 mg per day and adjust dosage based on disease-specific guidelines.500 If the patient is tolerating a dosage of 40 mg daily, but a higher potency is needed, consider a higher dose (>40 mg), an alternative statin, or combination therapy (i.e., fluvastatin plus a nonstatin guideline directed medical therapy).500
Patients with cytochrome P-450 (CYP) 2C9 intermediate metabolizer phenotypes will have increased fluvastatin exposure compared to patients with CYP2C9 normal metabolizer phenotype, which may translate to an increased risk of statin-associated musculoskeletal symptoms.500 In such patients, initiate fluvastatin at ≤40 mg per day and adjust dosage based on disease-specific guidelines.500 If a dosage higher than 40 mg per day is needed, consider an alternative statin or combination therapy (i.e., fluvastatin plus a nonstatin guideline directed medical therapy).500
Patients with CYP2C9 poor metabolizer phenotypes will have increased fluvastatin exposure compared to patients with CYP2C9 normal and intermediate metabolizer phenotype, which may translate to an increased risk of statin-associated musculoskeletal symptoms.500 In such patients, initiate fluvastatin at ≤20 mg per day and adjust dosage based on disease-specific guidelines.500 If a dosage higher than 20 mg per day is needed, consider an alternative statin, or combination therapy (i.e., fluvastatin plus a nonstatin guideline directed medical therapy).500
In patients with combined phenotypes of SLCO1B1 decreased or possible decreased function and CYP2C9 intermediate metabolizer, consider initiating fluvastatin at ≤20 mg per day and adjust dosage based on disease-specific guidelines.500 If a dosage higher than 20 mg per day is needed, consider an alternative statin, or combination therapy (i.e., fluvastatin plus a nonstatin guideline directed medical therapy).500
In patients with combined phenotypes of SLCO1B1 decreased or possible decreased function and CYP2C9 poor metabolizer, or SLCO1B1 poor function and CYP2C9 intermediate or poor metabolizer, consider an alternative statin.500
Myopathy manifested as muscle pain, tenderness, or weakness associated with elevated creatine kinase and rhabdomyolysis with acute renal injury secondary to myoglobinuria have been reported in patients receiving statins, including extended-release fluvastatin; rare fatalities have occurred.1, 72 Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine kinase (CK) values to greater than 10 times the upper limit of normal (ULN), occurred in <0.1% of patients in fluvastatin clinical trials.1, 72
Predisposing factors for myopathy and/or rhabdomyolysis include advanced age (≥65 years of age), concomitant use of statins with certain other drugs (e.g., cyclosporine, fluconazole, erythromycin, and other lipid-lowering drugs), and those with renal impairment or uncontrolled hypothyroidism.1, 72 Avoid concomitant use of extended-release fluvastatin with gemfibrozil, cyclosporine, and fluconazole.72 When used concomitantly with extended-release fluvastatin, lipid modifying doses (≥1 g/day) of niacin, fibrates, and colchicine may also increase the risk of myopathy and rhabdomyolysis.72
AHA/ACC cholesterol management guideline recommends measurement of CK levels in patients with severe statin-associated muscle symptoms; however, routine monitoring is not useful.400
Fluvastatin should be discontinued if CK concentrations become markedly elevated or if myopathy is diagnosed or suspected.1, 72 Fluvastatin therapy should be temporarily withheld in any patient experiencing an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., sepsis, shock or hypotension, severe hypovolemia, major surgery, trauma, severe metabolic, endocrine, or electrolyte disorders, or uncontrolled seizures).1, 72
Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CK.1 Advise patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing fluvastatin.1, 72
Immune-Mediated Necrotizing Myopathy
Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, has been reported rarely in patients receiving statins, including reports of recurrence when the same or a different statin was administered.1, 72 The condition is characterized by proximal muscle weakness and elevated CK concentrations that persist despite discontinuance of statin therapy, positive anti-HMG CoA reductase antibody, muscle biopsy showing necrotizing myopathy, and improvement following therapy with immunosuppressive agents.1, 72 Additional neuromuscular and serologic testing may be necessary.1, 72
Discontinue fluvastatin if IMNM is suspected.72 The risk of IMNM should be considered carefully prior to initiating therapy with another statin, and patients should be monitored for signs and symptoms.1
Increases in serum aminotransferase (i.e., AST, ALT) concentrations have been reported in patients receiving statins, including fluvastatin.1, 72 In most cases, the elevations appeared soon after initiation, were transient, were not accompanied by symptoms, and resolved or improved on continued therapy or after a brief interruption in therapy.1, 72 Persistent increases to >3 times the ULN in serum aminotransferases have occurred in approximately 1.1% of patients receiving fluvastatin in clinical trials.1, 72 Marked persistent increases of hepatic aminotransferases have also occurred with fluvastatin.72 Persistent aminotransferase elevations (>3 times the ULN on 2 consecutive weekly measurements) are more common at higher dosages (40 or 80 mg daily).1 Most cases occurred within 12 weeks of therapy.1
Liver enzyme tests should be performed prior to initiation of fluvastatin therapy and repeated as clinically indicated.1, 72 Serious statin-related liver injury is rare and unpredictable in individual patients, and routine periodic monitoring of liver enzymes does not appear to be effective in detecting or preventing serious statin-related liver injury.200 The AHA/ACC cholesterol management guideline states that, during statin therapy, it is reasonable to obtain liver function tests in adults experiencing symptoms of hepatotoxicity (e.g., unusual fatigue or weakness, loss of appetite, abdominal pain, dark colored urine, yellowing of the skin or sclera); however, routine monitoring is not recommended.400
In very rare cases, possibly drug-related hepatitis was observed that resolved upon fluvastatin discontinuation.1 There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including fluvastatin.1, 72 If serious liver injury with clinical manifestations and/or hyperbilirubinemia or jaundice occurs, fluvastatin therapy should be promptly discontinued.1, 72 If an alternate etiology is not found, fluvastatin therapy should not be restarted.1
Fluvastatin should be used with caution in patients who consume substantial amounts of alcohol and/or have a history of liver disease.1, 72 The drug is contraindicated in patients with active liver disease (acute failure or decompensated cirrhosis), including unexplained, persistent elevations in serum aminotransferase concentrations.1, 72
Increases in glycosylated hemoglobin (hemoglobin A1c [HbA1c]) and fasting serum glucose concentrations have been reported in patients receiving statins, including fluvastatin.1, 72, 200
Data from meta-analyses and clinical trials with other statins indicate that statin therapy may increase the risk of developing diabetes mellitus.200 AHA/ACC cholesterol management guideline states that patients receiving statin therapy should be evaluated for new-onset diabetes mellitus but because the benefits of statin therapy outweigh the risks of new-onset diabetes, the possibility of this adverse effect should not be a contraindication to statin therapy or a reason for discontinuance of therapy.400
Statins interfere with cholesterol synthesis and theoretically may blunt adrenal or gonadal steroid hormone production.1 Fluvastatin had no effect on nonstimulated cortisol concentrations, adrenal response to corticotropin (adrenocorticotropic hormone, ACTH) stimulation, or thyroid metabolism.1 Small declines in total serum testosterone concentrations were reported in men treated with fluvastatin, but no commensurate elevation in luteinizing hormone (LH) concentrations, and no effect on follicular stimulating hormone (FSH) concentrations were observed.1 Data are insufficient to determine an effect on female sex hormones, due to the limited number of premenopausal females studied to date.1
Patients treated with fluvastatin who develop clinical evidence of endocrine dysfunction should be evaluated appropriately.1 Caution should be exercised if fluvastatin is used concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones (e.g., ketoconazole, spironolactone, cimetidine).1
All statins were previously contraindicated in pregnant women because the fetal risk with these drugs was thought to outweigh any possible benefit.405 This determination was based on several factors including safety signals from animal data.405 Fluvastatin produced delays in skeletal development in rats at doses of 12 mg/kg daily and in rabbits at doses of 10 mg/kg daily (approximately 2 and 5 times, respectively, the human exposure after a 40-mg dose based on mg/m2 surface area).72 Malaligned thoracic vertebrae were observed in rats at 36 mg/kg, a dose that produced maternal toxicity.72 Maternal mortality at or near term and postpartum, as well as fetal and neonatal lethality, were observed in female rats receiving fluvastatin 12 and 24 mg/kg daily during the third trimester of pregnancy.72
In addition, congenital anomalies including severe CNS defects and unilateral limb deficiencies were reported in a case series of pregnant women who were exposed to a lipophilic statin during the first trimester.400 Because statins decrease synthesis of cholesterol and possibly other products of the cholesterol biosynthetic pathway, there is also a concern that these drugs can potentially cause fetal harm.405 More recent data from case series and observational cohort studies have not shown evidence of an increased risk of major birth defects with statin use during pregnancy, and this was observed after controlling for potential confounders such as maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use.405 The overall evidence from animal studies suggests limited potential for statins to cause malformations or other adverse fetal effects.405 While an increased risk of miscarriage has been reported in pregnant women exposed to statins, it is not clear whether this effect is related to the drugs or to other confounding factors.400, 405 FDA conducted a comprehensive review of all available clinical and nonclinical data related to statin use in pregnant women and concluded that the totality of evidence suggests limited potential for statins to cause malformations and other adverse embryofetal effects.405 Because statins may prevent serious or potentially fatal cardiovascular events in certain high-risk patients who are pregnant, FDA has requested that the contraindication in pregnant women be removed from the prescribing information for all statins.405 While FDA still advises that most pregnant patients discontinue statins because of the possibility of fetal harm, there may be some patients (e.g., those with homozygous familial hypercholesterolemia or established cardiovascular disease) in whom continued therapy may be beneficial; therefore, decisions should be individualized based on the patient's risks versus benefits.400, 402, 405 Patients who become pregnant or suspect that they are pregnant while receiving a statin should notify their clinician who can advise them on the appropriate course of action.405
Fluvastatin is distributed into milk in animals, with a milk-to-plasma ratio of 2:1.1, 72 Because of the potential for serious adverse reactions from fluvastatin in nursing infants, the drug is contraindicated in nursing women; women who require fluvastatin therapy should not breast-feed their infants.1 Many patients can stop statin therapy temporarily until breast-feeding is complete; patients who require ongoing statin treatment should not breast-feed and should use alternatives such as infant formula.400, 402, 405
Females and Males of Reproductive Potential
Fluvastatin did not affect fertility or reproductive performance in female rats receiving up to 6 mg/kg daily or in male rats receiving up to 20 mg/kg daily.1, 72 Seminal vesicles and testes were small in hamsters treated for 3 months at 20 mg/kg daily (approximately 3 times the 40-mg human daily dose based on surface area, mg/m2).1, 72 There was tubular degeneration and aspermatogenesis in testes as well as vesiculitis of seminal vesicles.1, 72 Vesiculitis of seminal vesicles and edema of the testes were also seen in rats treated for 2 years at 18 mg/kg daily (approximately 4 times the human peak plasma concentration achieved with a 40-mg daily dose).1, 72
Small declines in total serum testosterone concentrations were reported in men treated with fluvastatin, but no commensurate elevation in LH concentrations, and no effect on FSH concentrations were observed.1 Data are insufficient to determine an effect on female sex hormones, due to the limited number of premenopausal females studied to date.1
AHA/ACC cholesterol management guideline recommends women (including adolescents) of childbearing age who are sexually active should be counseled to use a reliable form of contraception.1, 400
Safety and effectiveness of fluvastatin in pediatric patients ≥10 years of age (adolescent boys and girls at least one year post-menarche) with heterozygous familial hypercholesterolemia (HeFH) have been established in open-label, uncontrolled studies of 2 years' duration.1, 72 The most common adverse effects observed were influenza and infections.1 There were no detectable effects on growth or sexual maturation in boys or on duration of menstrual cycle in girls.1, 72 The manufacturer states that pediatric patients receiving fluvastatin in adolescence should be re-evaluated in adulthood, with appropriate adjustments in the antilipemic regimen, to achieve adult treatment goals.1 Adolescent girls should be advised to use appropriate contraceptive methods during fluvastatin therapy.1 Safety and efficacy of fluvastatin have not been evaluated in children <10 years of age with HeFH or in children with other types of hyperlipidemia.72 However, experts state that statins may be considered in patients as young as 8 years of age in the presence of concerning family history, extremely elevated LDL-cholesterol level, or elevated lipoprotein (a), in the context of informed shared decision-making and counseling with the patient and family.400
Pharmacokinetic data in the pediatric population are not available.1, 72
Fluvastatin generally is well tolerated in geriatric patients.6 Fluvastatin exposures were not substantially different between geriatric patients (65 years of age or older) and younger patients.1, 72 However, because advanced age is a predisposing factor for myopathy, fluvastatin should be used with caution in geriatric patients.1, 72
Because patients older than 75 years of age may have a higher risk of adverse effects and lower adherence to therapy, the expected benefits versus adverse effects should be considered before initiating statin therapy in this population.400
Fluvastatin plasma levels are not significantly different in patients > 65 years of age compared to patients 21-49 years of age.1, 72
In patients with hepatic impairment due to liver cirrhosis, fluvastatin AUC and peak plasma concentration increased approximately 2.5-fold compared to healthy subjects after administration of a single 40-mg dose.1 The enantiomer ratios of the 2 isomers of fluvastatin in hepatic impairment patients were comparable to those observed in healthy subjects.1, 72
Fluvastatin should be used with caution in patients who consume substantial amounts of alcohol and/or have a history of liver disease.1, 72 The drug is contraindicated in patients with active liver disease (acute failure or decompensated cirrhosis), including unexplained, persistent elevations in serum aminotransferase concentrations.1, 72
In patients with moderate to severe renal impairment (creatinine clearance 10-40 mL/minute), AUC and peak plasma concentration increased approximately 1.2 fold after administration of a single dose of 40 mg fluvastatin compared to healthy volunteers.1, 72 In patients with end-stage renal disease on hemodialysis, the AUC increased by approximately 1.5 fold.1, 72 Fluvastatin extended-release preparation has not been evaluated in patients with renal impairment; however, systemic exposures after administration of the extended-release preparation are lower than after the 40 mg immediate-release capsule.1, 72
The manufacturer states that dosage modification in patients with mild to moderate renal impairment is not necessary.1, 72 Fluvastatin, at dosages exceeding 40 mg daily, has not been studied in patients with severe renal impairment; caution is advised when administering higher dosages of the drug to such patients.1, 72 Monitor all patients with renal impairment for the development of myopathy.72
Pharmacogenomic Considerations
Genetic variation in the solute carrier organic anion transporter (SLCO) family member (SLCO1B1), ABCG2 (also known as breast cancer resistance protein [BCRP]), and cytochrome P-450 (CYP) 2C9 genes alter systemic exposure to statins (i.e., lovastatin, simvastatin, rosuvastatin, pravastatin, pitavastatin, atorvastatin, fluvastatin), which can increase the risk for statin-associated musculoskeletal symptoms.500 SLCO1B1 encodes a transporter (SLCO1B1; alternative names include organic ion transporter protein [OATP] 1B1 or OATP-C) that facilitates the hepatic uptake of all statins.500 ABCG2 encodes an efflux transporter (BCRP) that modulates the absorption and disposition of rosuvastatin and atorvastatin; CYP2C9 encodes a phase I drug metabolizing enzyme responsible for the oxidation of some statins (e.g., fluvastatin).500
In patients with phenotypes that result in increased statin exposure, the potential for other patient-specific issues that may increase statin exposure (e.g., renal and hepatic function, drug-drug interactions) must also be considered.500 Experts state that given the balance of statin-associated musculoskeletal symptoms risk versus known cardiovascular disease benefit, for patients who are candidates for new statin therapy, pharmacogenetic test results may provide additional useful information.500
Pharmacogenetic test results may be used as the basis for changing to another statin type or dose for patients currently prescribed statin therapy, depending on how long the patient has been tolerating the statin.500 Experts state statin therapy should neither be discontinued nor avoided based on SLCO1B1, ABCG2, or CYP2C9 genotype results for patients with an indication for statin therapy, especially if the statin therapy is based on the shared decision making between patient and provider.500
Patients with SLCO1B1 decreased or possible decreased function phenotypes or poor function phenotypes will have increased fluvastatin exposure, which may translate to an increased risk of statin-associated musculoskeletal symptoms if the dosage exceeds 40 mg per day.500
Patients with CYP2C9 intermediate metabolizer (activity score 1 and 1.5) or poor metabolizer (activity score 0.5 and 0) phenotypes will have increased fluvastatin exposure, which may translate to an increased risk of statin-associated musculoskeletal symptoms.500
Limited data suggest that patients with combined SLCO1B1 (decreased or possible decreased or poor function) and CYP2C9 intermediate or poor metabolizer phenotypes will have increased fluvastatin exposure, which may translate to an increased risk of statin-associated musculoskeletal symptoms.500 Patients with such phenotypes may require lower initial doses, combination therapy (i.e., fluvastatin plus a nonstatin guideline directed medical therapy), or an alternative statin to achieve therapeutic goals without increasing the risk of myopathy.500
Adverse effects reported in ≥2% of patients, and greater than placebo, receiving immediate-release fluvastatin include headache, dyspepsia, myalgia, abdominal pain, and nausea.1
Adverse effects reported in ≥2.5% of patients, and greater than placebo, receiving extended-release fluvastatin include influenza-like symptoms, sinusitis, dyspepsia, urinary tract infection, bronchitis, and nausea.72
Fluvastatin is metabolized principally by cytochrome P450 isoenzyme (CYP) 2C9 (approximately 75%); CYP2C8 and CYP3A4 (approximately 5 and 20%, respectively) also contribute to fluvastatin metabolism.1, 72, 339 Fluvastatin is also a CYP2C9 inhibitor.339
Fluvastatin is a substrate of organic anion transporter protein (OATP) 1B1, 1B3, and 2B1.339, 501, 502
Drug interaction studies have not been performed with extended-release fluvastatin.72
Drugs Affecting or Affected by Hepatic Microsomal Enzymes
CYP2C9 inhibitors: Concomitant administration of fluvastatin with a CYP2C9 inhibitor (e.g., fluconazole) results in decreased fluvastatin clearance and increased AUC.1, 72, 339
CYP2C9 inducers: Concomitant administration of fluvastatin with a CYP2C9 inducer (e.g., rifampin) results in increased fluvastatin clearance and decreased AUC.1, 72, 339, 502
CYP substrates: Concomitant administration of fluvastatin with a CYP2C9 substrate (e.g., phenytoin, warfarin) results in increased exposure and possible increased pharmacodynamic effects of such substrates.1, 72, 339, 502
Drugs Affecting or Affected by Transport Systems
Concomitant administration of fluvastatin with drugs inhibiting OATP1B1, 1B3, or 2B1 may increase drug exposure and increase the risk of statin-induced toxicity (e.g., myopathy).501, 502
Drugs Affecting Gastric Acidity
Concomitant administration of fluvastatin with histamine H2-receptor antagonists (e.g., cimetidine) and proton-pump inhibitors (e.g., omeprazole) may result in decreased fluvastatin clearance and increased plasma concentrations.1, 72 Concomitant administration of fluvastatin 20 mg on day 6 of cimetidine 400 mg twice daily resulted in a 30 and 40% increase in fluvastatin AUC and peak plasma concentration, respectively.1, 72 Concomitant administration of fluvastatin 20 mg on day 6 of omeprazole 40 mg daily resulted in a 20 and 37% increase in fluvastatin AUC and peak plasma concentration, respectively.1, 72
Concomitant administration of fluvastatin with other lipid-lowering drugs (e.g., gemfibrozil, other fibrates) may increase the risk of myopathy and/or rhabdomyolysis.1, 72, 339 Avoid the combined use of gemfibrozil and fluvastatin.1, 72 The manufacturers state caution should be used if fluvastatin is administered with other fibrates or niacin (dosage ≥1 g/day), although some experts state the combination may be used.1, 72, 339 Experts state it is safer to use fenofibrate than gemfibrozil because of a lower risk of severe myopathy.400 The benefit of further alterations in lipid levels by the combined use of fluvastatin with other fibrates or niacin should be carefully weighed against the potential risks of these combinations.72 If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration.72
Concomitant administration of fluvastatin 40 mg twice daily for 14 days with glyburide 5-20 mg once daily for 22 days resulted in a 51 and 44% increase in fluvastatin AUC and peak plasma concentration, respectively.1, 72 Concomitant administration of fluvastatin 40 mg twice daily for 21 days with glyburide 5-20 mg once daily for 22 days resulted in a 70 and 50% increase in glyburide AUC and peak plasma concentration, respectively; this difference is considered clinically significant.1, 72 Monitor blood glucose levels appropriately (i.e., when fluvastatin is initiated in a patient also taking glyburide).1, 72
At therapeutic concentrations, the protein binding of fluvastatin is not affected by glyburide.1, 72
Azole antifungal drugs (e.g., itraconazole, ketoconazole, posaconazole, voriconazole) are CYP2C9 and CYP3A4 inhibitors.339, 501
Concomitant administration of fluvastatin 40 mg daily with fluconazole 400 mg on day 1 and 1200 mg twice daily for days 2-4 resulted in a 84 and 44% increase in fluvastatin AUC and peak plasma concentration, respectively; this difference is considered clinically significant.1, 72 In patients taking concomitant fluconazole and immediate-release fluvastatin, limit the fluvastatin dosage to 20 mg twice daily.1 Avoid concomitant use of fluconazole and extended-release fluvastatin due to the increased risk of myopathy and rhabdomyolysis.72
No pharmacokinetic changes observed with concomitant administration of immediate-release fluvastatin with itraconazole.1, 72
Concomitant administration of fluvastatin 20 mg once daily administered 4 hours after a meal with cholestyramine 8 g once daily resulted in a 51 and 83% decrease in fluvastatin AUC and peak plasma concentration, respectively.1, 72
Concomitant administration of extended-release fluvastatin 80 mg once daily administered for 19 days with clopidogrel 300 mg loading dose on day 10 followed by 75 mg once daily on days 11-19 resulted in a 2% decrease in fluvastatin AUC and a 27% increase in fluvastatin peak plasma concentration.1, 72
Cases of myopathy, including rhabdomyolysis, have been reported when fluvastatin was used concomitantly with colchicine.1, 72 The manufacturers state caution should be used when prescribing fluvastatin with colchicine, although some experts state the combination is reasonable when clinically indicated and while closely monitoring patients for signs and symptoms of myopathy.1, 72, 339, 502
The benefit of the combined use of extended-release fluvastatin with colchicine should be carefully weighed against the increased risk of myopathy and rhabdomyolysis.72 If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration.72
Concomitant use of fluvastatin and cyclosporine can increase fluvastatin exposure and risk of myopathy and rhabdomyolysis.1, 72, 339 When fluvastatin 20 mg daily for 14 weeks was administered concomitantly with a stable dosage of twice daily cyclosporine, fluvastatin AUC and peak plasma concentration increased 90 and 30%, respectively; this difference is considered clinically significant.1, 72
If concomitant fluvastatin and cyclosporine are used, the manufacturers state the dosage of immediate-release fluvastatin should be limited to 20 mg twice daily and concomitant use of extended-release fluvastatin should be avoided.1, 72
Concomitant administration of fluvastatin 40 mg once daily for 8 days with diclofenac 25 mg once daily resulted in a 50 and 80% increase in fluvastatin AUC and peak plasma concentration, respectively.1, 72 Concomitant administration of fluvastatin 40 mg once daily for 8 days with diclofenac 25 mg once daily resulted in a 25 and 60% increase in diclofenac AUC and peak plasma concentration, respectively.1, 72
Concomitant administration of fluvastatin 40 mg once daily with digoxin 0.1-0.5 mg once daily for 3 weeks resulted in an 11% increase in fluvastatin peak plasma concentration, but no change in AUC.1, 72
Concomitant use of fluvastatin with efavirenz may result in increased fluvastatin exposure.503 Experts state fluvastatin dose adjustments may be necessary; monitor for fluvastatin toxicity.503
Concomitant administration of fluvastatin with erythromycin may increase the risk of myopathy.1, 72, 502 No pharmacokinetic changes observed with concomitant administration of fluvastatin immediate-release with erythromycin.1, 72
Concomitant use of fluvastatin with etravirine may result in increased fluvastatin exposure.503 Experts state fluvastatin dose adjustments may be necessary; to monitor for fluvastatin toxicity.503
Concomitant administration of fluvastatin 40 mg twice daily for 5 days with phenytoin 300 mg once daily resulted in a 40 and 27% increase in fluvastatin AUC and peak plasma concentration, respectively.1, 72 Concomitant administration of fluvastatin 40 mg twice daily for for 5 days with phenytoin 300 mg once daily resulted in a 20 and 5% increase in phenytoin AUC and peak plasma concentration, respectively; this difference is considered clinically significant.1, 72 Monitor plasma phenytoin levels appropriately (i.e., when fluvastatin is initiated or dosage is adjusted).1, 72
Concomitant administration of fluvastatin 40 mg once daily with propranolol 40 mg twice daily for 3.5 days resulted in a 5% decrease in fluvastatin AUC, but no change in peak plasma concentration.1, 72
Concomitant administration of fluvastatin 20 mg once daily with rifampicin 600 mg once daily for 6 days resulted in a 53 and 42% decrease in fluvastatin AUC and peak plasma concentration, respectively.1, 72
There are postmarketing reports of clinically evident bleeding and/or increased prothrombin time (PT) and international normalized ratio (INR) in patients taking concomitant statins and warfarin.1, 72, 339
Concomitant administration of fluvastatin 40 mg daily for 8 days with warfarin 30 mg once daily resulted in a 30 and 67% increase in fluvastatin AUC and peak plasma concentration, respectively.1, 72
Concomitant administration of fluvastatin 40 mg daily for 8 days with warfarin 30 mg once daily resulted in a 7 and 10% increase in S-warfarin AUC and peak plasma concentration, respectively; R-warfarin peak plasma concentration also increased 6%, but there was no change in R-warfarin AUC.1, 72
At therapeutic concentrations, the protein binding of fluvastatin is not affected by warfarin.1, 72
PT/INR should be monitored when fluvastatin is initiated or dosage is adjusted in patients receiving warfarin; thereafter, PT/INR can be monitored at usually recommended intervals.1, 72, 339, 502
Fluvastatin is a competitive inhibitor of 3-hydroxymethylglutaryl-CoA (HMG-CoA) reductase, an enzyme that catalyzes the conversion of HMG-CoA to mevalonate (an early and rate-limiting step in cholesterol biosynthesis).1, 72, 501 Fluvastatin is pharmacologically related to other statins (e.g., atorvastatin, lovastatin, pravastatin, simvastatin, pitavastatin, rosuvastatin).4, 5, 501 Fluvastatin, like atorvastatin, is a synthetic compound that differs structurally from mevinic acid-derivative statins (e.g., lovastatin, pravastatin, simvastatin) and is not fungus-derived.4, 5, 56, 62
Unlike the lactone prodrugs lovastatin and simvastatin, fluvastatin exists as an active hydroxy acid and does not require hydrolysis in vivo.56, 61, 62 The fluorophenyl indole moiety of fluvastatin is similar structurally to HMG-CoA and competes with this compound for HMG-CoA reductase.11, 501
Fluvastatin reduces elevated low-density lipotrotein (LDL)-cholesterol concentrations.1, 72 Therapeutic response is expected within 4 weeks.1, 72 The mechanism of the LDL-lowering effect may involve both reduction of very low-density lipoprotein (VLDL) concentration, and induction of the LDL receptor, leading to reduced production and/or increased catabolism of LDL-cholesterol.1, 72, 501 Triglyceride and apolipoprotein B may decrease and high-density lipoptotein (HDL)-cholesterol concentrations may increase during treatment with fluvastatin.1, 72, 501 Other favorable effects of statins (pleiotropic effects) include an antiproliferative influence on smooth muscle cells, reconstruction of endothelial activity, antioxidant, antithrombotic, anticancer, and anti-inflammatory effects.501
Fluvastatin is lipophilic and has variable absolute bioavailability (24%, range 9-50%).1 Peak plasma concentrations are reached in less than 1 hour following administration of a 10-mg dose (immediate-release preparation).1 At steady state, administration of immediate-release fluvastatin with the evening meal results in a 50% decrease in peak plasma concentration, 11% decrease in AUC, and a more than 2-fold increase in time to peak plasma concentration as compared to administration 4 hours after the evening meal; no significant differences in the lipid-lowering effects were observed.1 After single or multiple doses above 20 mg, immediate-release fluvastatin exhibits saturable first-pass metabolism resulting in more than dose proportional plasma fluvastatin concentrations.1
The mean relative bioavailability of the extended-release preparation is approximately 29% (range, 9-66%) compared to the fluvastatin immediate-release preparation administered under fasting conditions; peak concentration is reached in approximately 3 hours under fasting conditions or 2.5 hours after a low-fat meal.72 Administration with a high-fat meal delayed absorption (time to peak concentration 6 hours) and increased bioavailability of the extended-release preparation by approximately 50%.72 However, the maximum concentration following administration of the extended-release preparation after a high-fat meal is less than the peak concentration following a single dose or twice daily dose of immediate-release fluvastatin 40 mg.72
Fluvastatin has 2 enantiomers; both enantiomers are metabolized in a similar manner.1, 72 Fluvastatin is metabolized in the liver, primarily via hydroxylation to metabolites that have some pharmacologic activity, but do not circulate in the blood.1, 72 Fluvastatin is metabolized principally by cytochrome P-450 (CYP) 2C9 (approximately 75%) and to a lesser extent by CYP2C8 and CYP3A4 (approximately 5 and 20%, respectively).1, 72 Fluvastatin is 98% bound to plasma proteins and is primarily (about 90%) excreted in the feces as metabolites, with less than 2% present as unchanged drug; approximately 5% of a radiolabeled oral dose is recovered in urine.1, 72 The elimination half-life of immediate-release and extended-release fluvastatin is approximately 3 and 3-5 hours, respectively.1, 72, 128 The AUC of fluvastatin is approximately 30% higher in females 21-49 years of age compared to males of the same age group; adjusting for body weight decreases the magnitude of the observed differences.1, 72 There were no significant differences in fluvastatin exposures between males and females in other age groups.1, 72 Fluvastatin AUC increases 67% and 77% for women compared to men under fasted and high-fat meal conditions, respectively, following administration of the extended-release preparation.1, 72 .1, 72
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 20 mg (of fluvastatin)* | Fluvastatin Sodium Capsules | |
Sandoz | ||||
40 mg (of fluvastatin)* | Fluvastatin Sodium Capsules | |||
Lescol® | Sandoz | |||
Tablets, extended-release | 80 mg (of fluvastatin)* | Fluvastatin Sodium Extended-Release Tablets | ||
Lescol® XL | Sandoz |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Only references cited for selected revisions after 1984 are available electronically.
1. Teva Pharmaceuticals. Fluvastatin sodium capsules prescribing information. Parsippany, NJ: 2020 Aug
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