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fluvastatin sodium 40 mg cap generic lescol

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Uses

Prevention of Cardiovascular Events

The American College of Cardiology (ACC)/American Heart Association (AHA) cholesterol management guideline recommends statins as first-line therapy for prevention of atherosclerotic cardiovascular disease (ASCVD) in adults. There is extensive evidence demonstrating that statins can substantially reduce ASCVD risk when used for secondary prevention or primary prevention (in high-risk patients). Because the relative reduction in ASCVD risk is correlated with the degree of low-density lipoprotein (LDL)-cholesterol lowering, the maximum tolerated statin intensity should be used to achieve optimum ASCVD benefits. According to the ACC/AHA guidelines, fluvastatin may be used for primary or secondary prevention in adults when moderate-intensity statin therapy is indicated.(See Prevention of Cardiovascular Events under Dosage and Administration: Dosage.) Nonstatin therapies do not provide acceptable ASCVD risk reduction benefits compared to their potential for adverse effects in the routine prevention of ASCVD. For additional details on prevention of ASCVD, and also consult the most recent ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults (available at http://www.cardiosource.org or http://my.americanheart.org).

Secondary Prevention

Fluvastatin is used as an adjunct to nondrug therapies (i.e., lifestyle modifications) in patients with clinical evidence of coronary heart disease (CHD) to reduce the risk of undergoing coronary revascularization procedures.

The ACC/AHA cholesterol management guideline recommends statins as first-line therapy for secondary prevention in patients 21-75 years of age who have clinical ASCVD (i.e., acute coronary syndromes, history of myocardial infarction [MI], stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack [TIA], or peripheral arterial disease presumed to be of atherosclerotic origin) unless contraindicated.

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) therapy with fluvastatin (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). Reduction in the risk of adverse cardiac events also was observed in geriatric patients (older than 65 years of age). 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. 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).

In another randomized, double-blind, placebo-controlled study (Fluvastatin Angiographic Restenosis [FLARE] study) 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).

Reducing Progression of Coronary Atherosclerosis

Fluvastatin is used as an adjunct to nondrug therapies (e.g., dietary management) to slow the progression of coronary atherosclerosis in hypercholesterolemic patients with CHD. In a placebo-controlled trial in men and women with angiographically documented CHD and mildly to moderately elevated serum LDL-cholesterol concentrations, progression of coronary atherosclerosis was slowed in patients treated with fluvastatin 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.

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. 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). 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.

Intensity of Statin Therapy

The ACC/AHA cholesterol management guideline states that the appropriate intensity of a statin should be used to reduce the risk of ASCVD in patients most likely to benefit. Based on the average LDL-cholesterol response observed with specific statins and dosages used in the randomized controlled studies evaluated by the guideline expert panel, ACC/AHA considers fluvastatin 20-40 mg daily to be a low-intensity statin (producing approximate LDL-cholesterol reductions of less than 30%) and fluvastatin 80 mg daily to be a moderate-intensity statin (producing approximate LDL-cholesterol reductions of 30% to less than 50%). Individual patient response may vary in clinical practice.

Combination Antilipemic Therapy

The ACC/AHA cholesterol management guideline states that nonstatin drugs may be useful adjuncts to statin therapy in certain high-risk patients (e.g., patients with ASCVD, LDL-cholesterol concentrations of at least 190 mg/dL, or diabetes mellitus) who have a less-than-anticipated response to statins, are unable to tolerate a less-than-recommended intensity of a statin, or are completely intolerant to statin therapy, particularly if there is evidence from randomized controlled studies suggesting that the addition of the nonstatin drug further reduces ASCVD events. 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.

Patients with Chronic Kidney Disease

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. 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.

Dyslipidemias

Primary Hypercholesterolemia or Mixed Dyslipidemia

Fluvastatin is used as an adjunct to nondrug therapies (e.g., dietary management) 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). 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 of 190 mg/dL or greater or a serum LDL-cholesterol concentration of 160 mg/dL or greater and either a family history of premature cardiovascular disease or 2 or more other cardiovascular risk factors. Statins such as fluvastatin also are used in combination with fenofibrate to decrease triglyceride concentrations and increase HDL-cholesterol concentrations in patients with mixed dyslipidemia and CHD (or CHD risk equivalents) who are receiving optimal statin therapy; however, no additional benefit on cardiovascular morbidity and mortality has been demonstrated with such combination therapy beyond that already established with statin monotherapy.

Nondrug therapies and measures specific for the type of dyslipidemia (therapeutic lifestyle changes) are the initial treatments of choice, including dietary management (e.g., restriction of total and saturated fat and cholesterol intake, addition of plant stanols/sterols and viscous fiber to diet), weight control, an appropriate program of physical activity, and management of potentially contributory disease. Drug therapy is not a substitute for but an adjunct to these nondrug therapies and measures, which should be continued when drug therapy is initiated.

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. Mean reductions in total cholesterol, LDL-cholesterol, apolipoprotein B (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. Modest and variable increases in HDL-cholesterol concentrations (2-10%) also were observed in these patients. In a subgroup of patients with primary mixed dyslipidemia (defined as baseline triglyceride concentrations of at least 200 mg/dL), therapy with 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. In a long-term (98-week), open label, dose-titration study, LDL-cholesterol reductions of 25, 31, and 34% were observed with 20, 40, and 80 mg, respectively, of fluvastatin.

Effects on various lipoprotein fractions appear to be similar in patients receiving an equivalent daily dosage (80 mg) of extended-release tablets or conventional capsules. 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. 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.

Safety and efficacy of fluvastatin in pediatric patients have been evaluated in 2 open-label, uncontrolled, dose-titration studies. 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. Approximately 83-89% of patients received the maximum dosage of 80 mg daily. At the end of the study, 26-30% of patients achieved a target LDL-cholesterol goal of less than 130 mg/dL. The long-term efficacy of fluvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established. For additional details on management of dyslipidemias in pediatric patients, and also consult the most recent Integrated Guideline for Cardiovascular Health and Risk Reduction in Children and Adolescents (available at http://www.nhlbi.nih.gov).

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. 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).

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. However, treatment with cholestyramine was associated with a 12% increase in triglyceride concentrations compared with an 11% decrease in fluvastatin-treated patients. 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. 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). Reductions in triglyceride concentrations (26%) reportedly were similar with the 2 treatments.

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 antilipemic combinations.(See Combination Antilipemic Therapy under Uses: Prevention of Cardiovascular Events.) 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. 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. In addition, such combined therapy also reduced triglyceride concentrations by an additional 18% and increased HDL-cholesterol concentrations by 23%. 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. 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. The increased risk of adverse muscular effects should be considered when fluvastatin is used in combination with some antilipemic agents (e.g., fibric acid derivatives or niacin at lipid-modifying dosages [at least 1 g daily]).

Other Uses

Fluvastatin has reduced total and LDL-cholesterol concentrations in a few patients with hypercholesterolemia associated with or exacerbated by diabetes mellitus (diabetic dyslipidemia), renal insufficiency, cardiac or renal transplantation, or nephrotic syndrome (nephrotic hyperlipidemia). Fluvastatin also has been shown to decrease proteinuria in patients with immunoglobulin A nephropathy. Additional studies are necessary to determine the role, if any, of fluvastatin therapy in patients with these disorders.

For additional information on the role of fluvastatin or other statins in the treatment of lipoprotein disorders, prevention of cardiovascular events, or other uses, see General Principles of Antilipemic Therapy and see Uses in the HMG-CoA Reductase Inhibitors General Statement 24:06.08.

Dosage and Administration

Administration

Fluvastatin sodium conventional capsules are administered orally once (in the evening) or twice daily. Fluvastatin sodium extended-release tablets are administered orally as a single dose at any time of day. Fluvastatin may be taken without regard to meals. Conventional capsules should not be opened, and extended-release tablets should not be broken, crushed, or chewed prior to administration. Patients should be placed on a standard cholesterol-lowering diet before initiation of fluvastatin therapy and should remain on this diet during treatment with the drug. For recommendations on dietary and other nondrug therapies (i.e., lifestyle modifications), consult the most recent American Heart Association (AHA)/American College of Cardiology (ACC) Guideline on Lifestyle Management to Reduce Cardiovascular Risk (available at http://www.cardiosource.org or http://my.americanheart.org).

Dosage

Dosage of fluvastatin sodium is expressed in terms of fluvastatin and must be carefully adjusted according to individual requirements (i.e., percent reduction in low-density lipoprotein [LDL]-cholesterol concentrations) and response. The manufacturer states that serum lipoprotein concentrations should be determined periodically during fluvastatin therapy. The ACC/AHA guideline for management of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults states that lipoprotein concentrations should be determined within 4-12 weeks following initiation of statin therapy (to determine the patient's response to therapy and adherence) and monitored every 3-12 months thereafter as clinically indicated.

Adherence to lifestyle modifications and to statin therapy are required for atherosclerotic cardiovascular disease (ASCVD) risk reduction and, thus, should be reinforced periodically.

Prevention of Cardiovascular Events

The ACC/AHA cholesterol management guideline states that the appropriate intensity of statin therapy should be used to reduce ASCVD risk in patients most likely to benefit. Giving a maximally tolerated statin intensity should be emphasized over giving lower statin dosages and adding nonstatin drugs to address low HDL-cholesterol or high triglyceride concentrations, a strategy that has not yet been shown to reduce ASCVD risk. It should be noted that although fluvastatin dosages of 20-40 mg once daily (as conventional capsules) or 80 mg once daily (as extended-release tablets) are FDA-labeled dosages of fluvastatin, these dosages were not evaluated in randomized controlled studies reviewed by the ACC/AHA expert panel.

Primary Prevention

For primary prevention of cardiovascular disease in patients 21 years of age and older without clinical ASCVD who have primary, severe elevations in low-density lipoprotein (LDL)-cholesterol concentration (190 mg/dL or greater), the ACC/AHA cholesterol management guideline recommends that high-intensity statin therapy (i.e., with atorvastatin or rosuvastatin) be initiated unless contraindicated. ( or .)

For primary prevention of cardiovascular disease in patients 40-75 years of age with type 1 or 2 diabetes mellitus and LDL-cholesterol concentrations of 70-189 mg/dL, the ACC/AHA cholesterol management guideline recommends that moderate-intensity statin therapy (e.g., fluvastatin 40 mg twice daily [as conventional capsules], fluvastatin 80 mg once daily [as extended-release tablets]) be initiated or continued. In those with an estimated 10-year ASCVD risk of 7.5% or higher, it is reasonable to consider high-intensity statin therapy (i.e., with atorvastatin or rosuvastatin) unless contraindicated. In patients with diabetes mellitus who are younger than 40 or older than 75 years of age, it is reasonable to evaluate the potential benefits, adverse effects, drug interactions, and patient preferences when deciding to initiate, continue, or intensify statin therapy.

For primary prevention of cardiovascular disease in patients 40-75 years of age without clinical ASCVD or diabetes mellitus who have LDL-cholesterol concentrations of 70-189 mg/dL and an estimated 10-year ASCVD risk of 7.5% or higher, the ACC/AHA cholesterol management guideline recommends that moderate- (e.g., fluvastatin 40 mg twice daily [as conventional capsules], fluvastatin 80 mg once daily [as extended-release tablets]) to high-intensity statin therapy (i.e., with atorvastatin or rosuvastatin) be initiated or continued. In those with an estimated 10-year ASCVD risk of 5 to less than 7.5%, it is reasonable to offer treatment with moderate-intensity statin therapy. Before initiating statin therapy for primary prevention of ASCVD in patients 40-75 years of age without clinical ASCVD or diabetes mellitus who have LDL-cholesterol concentrations of 70-189 mg/dL, it is reasonable for clinicians and patients to discuss the potential benefits, adverse effects, drug interactions, and patient preferences for such therapy.

Secondary Prevention

For secondary prevention of cardiovascular disease in patients 21-75 years of age with clinical ASCVD, the ACC/AHA cholesterol management guideline recommends that high-intensity statin therapy (i.e., with atorvastatin or rosuvastatin) be initiated or continued unless contraindicated. ( or .) In patients 21-75 years of age with clinical ASCVD who are at increased risk for developing statin-associated adverse effects or in whom high-intensity statin therapy is inappropriate or contraindicated, moderate-intensity statin therapy (e.g., fluvastatin 40 mg twice daily [as conventional capsules], fluvastatin 80 mg once daily [as extended-release tablets]) should be given if tolerated. In patients older than 75 years of age with clinical ASCVD, use of statin therapy should be individualized based on the potential benefits, adverse effects, drug interactions, and patient preferences; it is reasonable to consider initiating or continuing moderate-intensity statin therapy in such patients if tolerated.

Dyslipidemias

Therapy with fluvastatin generally is initiated with a dosage of 20 mg daily as conventional capsules in adults who require reductions in LDL-cholesterol of less than 25%. 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 (as conventional capsules), 40 mg twice daily (as conventional capsules), or 80 mg once daily at any time of day (as extended-release tablets); administration of two 40-mg conventional capsules at one time should be avoided. 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. The usual maintenance dosage of fluvastatin in adults is 20-80 mg daily.

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. 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 conventional capsules or 80 mg once daily as extended-release tablets) is reached.

The cholesterol-lowering effects of fluvastatin and bile acid sequestrants (e.g., cholestyramine) are additive or synergistic. The manufacturer recommends that fluvastatin be administered at least 2 hours after a bile acid sequestrant when these drugs are used concomitantly.

Concomitant use of fluvastatin with cyclosporine has resulted in increased fluvastatin concentrations and may increase the risk of myopathy or rhabdomyolysis. Concomitant use of fluvastatin with fluconazole also has resulted in increased fluvastatin concentrations. Therefore, if fluvastatin is used concomitantly with cyclosporine or fluconazole, the manufacturer recommends that fluvastatin dosage not exceed 20 mg twice daily.

Dosage Modification

The ACC/AHA cholesterol management guideline states that decreasing the statin dosage in adults may be considered when LDL-cholesterol concentrations are less than 40 mg/dL on 2 consecutive measurements; however, there are no data to suggest that LDL-cholesterol concentrations below 40 mg/dL would increase the risk of adverse effects.

Dosage in Renal and Hepatic Impairment

Because only minimal amounts of fluvastatin (approximately 5%) are excreted in urine, the manufacturer states that dosage modification in patients with mild to moderate renal impairment is not necessary. 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.

Since fluvastatin is metabolized predominantly in the liver and potentially may accumulate in the plasma of patients with hepatic impairment, the drug should be used with caution in patients who consume substantial amounts of alcohol and/or have a history of liver disease, and such patients should be monitored closely while receiving fluvastatin therapy. Use of fluvastatin is contraindicated in patients with active liver disease or unexplained, persistent increases in serum aminotransferase concentrations.

Cautions

Fluvastatin shares the toxic potentials of other statins, and the usual cautions, precautions, and contraindications associated with these agents should be observed.

Patients should be fully advised about the risks, especially rhabdomyolysis, associated with statin therapy alone or combined with other drugs. and also

Pediatric Precautions

Safety and efficacy of fluvastatin in pediatric patients 9-16 years of age have been evaluated in open-label, uncontrolled studies of 2 years' duration. The most common adverse effects observed were influenza and infections. There were no detectable effects on growth or sexual maturation in boys or on duration of menstrual cycle in girls. 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. Adolescent girls should be advised to use appropriate contraceptive methods during fluvastatin therapy. For additional information on the use of statins in pediatric patients, .

Geriatric Precautions

Fluvastatin generally is well tolerated in geriatric patients. Fluvastatin exposures were not substantially different between geriatric patients (65 years of age or older) and younger patients. However, because advanced age (65 years of age or older) is a predisposing factor for myopathy, fluvastatin should be used with caution in geriatric patients. The greater frequency of decreased hepatic and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered when assessing the potential benefit of antilipemic therapy. The American College of Cardiology (ACC)/American Heart Association (AHA) cholesterol management guideline states that initiation of statin therapy for primary prevention of atherosclerotic cardiovascular disease (ASCVD) in patients older than 75 years of age requires consideration of additional factors, including increasing comorbidities, safety considerations, and priorities of care. Therefore, the potential for an ASCVD risk reduction benefit, adverse effects, and drug interactions, along with patient preferences, must be considered before initiating statin therapy in patients older than 75 years of age.

Mutagenicity and Carcinogenicity

Fluvastatin did not exhibit mutagenic potential in vitro with or without rat liver metabolic activation in microbial mutagen tests using mutant strains of Salmonella typhimurium or Escherichia coli, the malignant transformation assay in BALB/3T3 cells, unscheduled DNA synthesis in rat primary hepatocytes, chromosomal aberrations in V79 Chinese Hamster cells, or HGPRT V79 Chinese Hamster cells. Fluvastatin also did not exhibit mutagenic potential in vivo in either a rat or mouse micronucleus test.

A 2-year carcinogenicity study was performed in rats using fluvastatin dosages of 6, 9, and 18-24 (dose was escalated after 1 year) mg/kg daily (approximately 9, 13, and 26-35 times, respectively, the mean plasma drug concentrations in humans after a 40-mg dose). A low incidence of forestomach squamous papillomas and one carcinoma of the forestomach secondary to prolonged hyperplasia induced by direct contact exposure to fluvastatin rather than a systemic effect of the drug was observed at a dosage of 24 mg/kg daily. An increased incidence of thyroid follicular cell adenomas and carcinomas was observed in male rats at dosages of 18-24 mg/kg daily (dosage escalation after 1 year). The increased incidence of thyroid follicular cell neoplasm in male rats receiving fluvastatin appears to be consistent with species-specific findings with other statins. Unlike with other statins, no hepatic adenomas or carcinomas were observed in rats receiving fluvastatin.

In a carcinogenicity study in mice receiving fluvastatin 0.3, 15, and 30 mg/kg daily (approximately 0.05, 2, and 7 times, respectively, the mean plasma drug concentrations in humans after a 40-mg dose), a substantial increase in forestomach squamous cell papillomas was observed in male and female mice at a dosage of 30 mg/kg daily and in female mice at a dosage of 15 mg/kg daily.

Pregnancy, Fertility, and Lactation

Pregnancy

There are no adequate and well-controlled studies using fluvastatin in pregnant women. Since atherosclerosis is a chronic process, discontinuance of antilipemic agents during pregnancy generally should not have a substantial effect on the outcome of long-term therapy for primary hypercholesterolemia. Currently, most experts recommend that dyslipidemias in pregnant women be managed with dietary measures; consultation with a lipid specialist is recommended for pregnant women with severe forms of dyslipidemia.

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 or 5 times, respectively, human exposure after a 40-mg dose based on mg/m surface area). Malaligned thoracic vertebrae were seen in rats at 36 mg/kg, a dose that produced maternal toxicity. 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. No effects on the dam or fetus occurred in rats receiving 2 mg/kg daily. An additional study at 2, 6, 12, and 24 mg/kg daily confirmed the findings of the initial study. In a modified segment III study in rats receiving fluvastatin 12 and 24 mg/kg daily with or without concurrent supplementation of mevalonic acid, supplementation of mevalonic acid completely prevented maternal and neonatal mortality but, at the 24-mg/kg dosage of fluvastatin, did not prevent low pup body weights on days 0 and 7 postpartum.

Cholesterol and other products of the cholesterol biosynthetic pathway are essential for fetal development, including synthesis of steroids and cell membranes. Because of the ability of statins such as fluvastatin to decrease the synthesis of cholesterol and possibly other products of the cholesterol biosynthetic pathway, fluvastatin may cause fetal harm when administered to pregnant women. Rarely, congenital anomalies have been reported following intrauterine exposure to other statins. Therefore, fluvastatin is contraindicated in women who are or may become pregnant. 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 receiving fluvastatin, the drug should be discontinued and the patient informed of the potential hazard to the fetus.

Fertility

Fluvastatin did not affect fertility or reproductive performance in female rats receiving 0.6, 2, or 6 mg/kg daily or in male rats receiving 2, 10, or 20 mg/kg daily. 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/m). There was tubular degeneration and aspermatogenesis in testes as well as vesiculitis of seminal vesicles. Vesiculitis of seminal vesicles and edema of the testes were also seen in rats treated for 2 years at 18 mg/kg daily (approximately 4 times the human peak plasma concentration achieved with a 40-mg daily dose).

Lactation

Fluvastatin is distributed into milk in animals, with a milk-to-plasma ratio of 2:1. 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.

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