Fluvastatin

Pronunciation

(FLOO va sta tin)

U.S. Brand Names

Lescol®; Lescol® XL

Generic Available

Canadian Brand Names

Lescol®

Use

To be used as a component of multiple risk factor intervention in patients at risk for atherosclerosis vascular disease due to hypercholesterolemia

Adjunct to dietary therapy to reduce elevated total cholesterol (total-C), LDL-C, triglyceride, and apolipoprotein B (apo-B) levels and to increase HDL-C in primary hypercholesterolemia and mixed dyslipidemia (Fredrickson types IIa and IIb); to slow the progression of coronary atherosclerosis in patients with coronary heart disease; reduce risk of coronary revascularization procedures in patients with coronary heart disease

Pregnancy Risk Factor

Pregnancy Implications

Animal studies have shown delays in fetal skeletal development and fetal, neonatal, and maternal mortality. Congenital anomalies following use of other HMG-CoA reductase inhibitors in humans have been reported (rare). Use in women of childbearing potential only if they are highly unlikely to conceive; discontinue if pregnancy occurs.

Lactation

Enters breast milk/contraindicated

Contraindications

Hypersensitivity to fluvastatin or any component of the formulation; active liver disease; unexplained persistent elevations of serum transaminases; pregnancy; breast-feeding

Warnings/Precautions

Secondary causes of hyperlipidemia should be ruled out prior to therapy. Liver function must be monitored by periodic laboratory assessment. Rhabdomyolysis with acute renal failure has occurred with fluvastatin and other HMG-CoA reductase inhibitors. Risk may be increased with concurrent use of other drugs which may cause rhabdomyolysis (including gemfibrozil, fibric acid derivatives, or niacin at doses

1 g/day). Temporarily discontinue in any patient experiencing an acute or serious condition predisposing to renal failure secondary to rhabdomyolysis. Use caution in patients with previous liver disease or heavy ethanol use. Treatment in patients <18 years of age is not recommended.

Adverse Reactions

As reported with fluvastatin capsules; in general, adverse reactions reported with fluvastatin extended release tablet were similar, but the incidence was less.

1% to 10%:

Central nervous system: Headache (9%), fatigue (3%), insomnia (3%)

Gastrointestinal: Dyspepsia (8%), diarrhea (5%), abdominal pain (5%), nausea (3%)

Genitourinary: Urinary tract infection (2%)

Neuromuscular & skeletal: Myalgia (5%)

Respiratory: Sinusitis (3%), bronchitis (2%)

<1% including additional class-related events (not necessarily reported with fluvastatin therapy) and postmarketing case reports: Alkaline phosphatase increased, alopecia, alteration in taste, anaphylaxis, angioedema, anorexia, anxiety, arthralgia, arthritis, blurred vision, cataracts, chills, cholestatic jaundice, cirrhosis, CPK increased (>10x normal), depression, dermatomyositis, dizziness, dryness of skin/mucous membranes, dyspnea, eosinophilia, erectile dysfunction, erythema multiforme, ESR increased, extraocular muscle movement impaired, facial paresis, fatty liver, fever, flushing, fulminant hepatic necrosis, GGT increased, gynecomastia, hemolytic anemia, hepatitis, hepatoma, hyperbilirubinemia, hypersensitivity reaction, impotence, leukopenia, libido decreased, malaise, memory loss, muscle cramps, myopathy, nail changes, nodules, ophthalmoplegia, pancreatitis, paresthesia, peripheral nerve palsy, peripheral neuropathy, photosensitivity, polymyalgia, positive ANA, pruritus, psychic disturbance, purpura, rash, renal failure (secondary to rhabdomyolysis), rhabdomyolysis, rheumatica, skin discoloration, Stevens-Johnson syndrome, systemic lupus erythematosus-like syndrome, thrombocytopenia, thyroid dysfunction, toxic epidermal necrolysis, transaminases increased, tremor, urticaria, vasculitis, vertigo, vomiting

Overdosage/Toxicology

GI complaints and elevated SGOT and SGPT have been reported following large doses of the extended release tablets. In case of overdose, supportive measure should be instituted, as required; dialyzability is not known.

Drug Interactions

Substrate (minor) of CYP2C8/9, 2D6, 3A4; Inhibits CYP1A2 (weak), 2C8/9 (moderate), 2D6 (weak), 3A4 (weak)

Cholestyramine: Cholestyramine may decrease the absorption of fluvastatin. Separate administration times by at least 4 hours. Cholestyramine may increase the therapeutic effects of fluvastatin.

Cimetidine: Cimetidine may increase serum concentrations of fluvastatin

Clofibrate: Clofibrate may increase the risk of myopathy and rhabdomyolysis

Colestipol: Colestipol may increase the therapeutic effects of fluvastatin

CYP2C8/9 substrates: Fluvastatin may increase the levels/effects of CYP2C8/9 substrates. Example substrates include amiodarone, fluoxetine, glimepiride, glipizide, nateglinide, phenytoin, pioglitazone, rosiglitazone, sertraline, and warfarin.

Diclofenac: Fluvastatin may increase the Cmax and AUC of diclofenac when given together

Digoxin: Fluvastatin may increase Cmax and decrease clearance of digoxin. Monitor serum digoxin concentrations.

Fenofibrate: Fenofibrate may increase the risk of myopathy and rhabdomyolysis

Gemfibrozil: Gemfibrozil may increase the risk of myopathy and rhabdomyolysis

Glyburide: Cmax and AUC of both fluvastatin and glyburide may increase; half-life of glyburide may also increase; monitor

Omeprazole: Omeprazole may increase serum concentrations of fluvastatin

Phenytoin: Cmax and AUC of both phenytoin and fluvastatin may be increased when given together; monitor phenytoin when fluvastatin is initiated, modified, or discontinued

Ranitidine: Ranitidine may increase serum concentrations of fluvastatin

Rifampin: Rifampin may decrease serum concentrations of fluvastatin

Ritonavir: Ritonavir may increase serum concentrations of fluvastatin

Warfarin: Fluvastatin may increase hypoprothrombinemic effects of warfarin; monitor INR closely when fluvastatin is initiated, modified, or discontinued

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid excessive ethanol consumption (due to potential hepatic effects).

Food: Reduces rate but not the extent of absorption.

Stability

Store at 25°C (77°F); protect from light

Mechanism of Action

Acts by competitively inhibiting 3-hydroxyl-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the reduction of HMG-CoA to mevalonate; this is an early rate-limiting step in cholesterol biosynthesis. HDL is increased while total, LDL and VLDL cholesterols, apolipoprotein B, and plasma triglycerides are decreased.

Pharmacodynamics/Kinetics

Distribution: Vd: 0.35 L/kg

Protein binding: >98%

Metabolism: To inactive and active metabolites [oxidative metabolism via CYP2C9 (75%), 2C8 (~5%), and 3A4 (~20%) isoenzymes]; active forms do not circulate systemically; extensive first-pass hepatic extraction

Bioavailability: Absolute: Capsule: 24%; Extended release tablet: 29%

Half-life elimination: Capsule: <3 hours; Extended release tablet: 9 hours

Excretion: Feces (90%): urine (5%)

Dosage

Adults: Oral:

Patients requiring 25% decrease in LDL-C: 40 mg capsule or 80 mg extended release tablet once daily in the evening; may also use 40 mg capsule twice daily

Patients requiring <25% decrease in LDL-C: 20 mg capsule once daily in the evening

Note: Dosing range: 20-80 mg/day; adjust dose based on response to therapy; maximum response occurs within 4-6 weeks

Dosage adjustment in renal impairment: Less than 6% excreted renally; no dosage adjustment needed with mild to moderate renal impairment; use with caution in severe impairment

Dosage adjustment in hepatic impairment: Levels may accumulate in patients with liver disease (increased AUC and Cmax); use caution with severe hepatic impairment or heavy ethanol ingestion; contraindicated in active liver disease or unexplained transaminase elevations; decrease dose and monitor effects carefully in patients with hepatic insufficiency

Elderly: No dosage adjustment necessary based on age

Administration

Patient should be placed on a standard cholesterol-lowering diet before and during treatment; fluvastatin may be taken without regard to meals; adjust dosage as needed in response to periodic lipid determinations during the first 4 weeks after a dosage change; lipid-lowering effects are additive when fluvastatin is combined with a bile-acid binding resin or niacin, however, it must be administered at least 2 hours following these drugs.

Monitoring Parameters

Obtain baseline LFTs and total cholesterol profile; repeat tests at 12 weeks after initiation of therapy or elevation in dose, and periodically thereafter. Monitor LDL-C at intervals no less than 4 weeks.

Dietary Considerations

Before initiation of therapy, patients should be placed on a standard cholesterol-lowering diet for 3-6 months and the diet should be continued during drug therapy. May be taken without regard to meals.

Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. Take as directed, with or without food. Follow diet and exercise regimen as prescribed. You may experience nausea or dyspepsia (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); diarrhea (buttermilk, boiled milk, or yogurt may help); or headache (consult prescriber for approved analgesic). Report muscle pain or cramping; tremor; or CNS changes (eg, memory loss, depression, personality changes; numbness, weakness, tingling or pain in extremities). Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant. Consult prescriber for instruction on appropriate contraceptive measures. This drug may cause severe fetal defects. Do not donate blood during or for 1 month following therapy (same reason). Do not breast-feed.

Anesthesia and Critical Care Concerns/Other Considerations

Statin therapy should be held temporarily in patients with conditions (ie, sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine or electrolyte disorders; uncontrolled seizures) that predispose them to acute renal failure secondary to rhabdomyolysis.

Myopathy: Currently marketed HMG-CoA reductase inhibitors appear to have a similar potential for causing myopathy. Incidence of severe myopathy is about 0.08% to 0.09%. The factors that increase risk include advanced age (especially >80 years of age), women more frequently than men, small body frame, frailty, multisystem disease (eg, chronic renal insufficiency especially due to diabetes), multiple medications, perioperative periods (higher risk when continued during hospitalization for major surgery), drug interactions (use with caution or avoid). The combination of a HMG-CoA reductase inhibitor plus nicotinic acid seems to carry a lower risk of myopathy than does a HMG-CoA reductase inhibitor plus a fibrate. Other medications, when used concurrently, may enhance the risk of myopathy associated with statins; these include drugs that inhibit CYP3A4 isoenzymes (lovastatin, simvastatin, atorvastatin) or CYP2C9 isoenzymes (fluvastatin). HMG-CoA reductase inhibitors may exacerbate exercise-induced skeletal muscle injury. Many experts favor getting a baseline creatine kinase (CK) measurement before initiating therapy (asymptomatic CK elevations are common). Obtain a CK measurement if patient complains of muscle soreness, tenderness, or pain.

Cardiovascular Considerations

HMG-CoA reductase inhibitors are effective in primary and secondary prevention of cardiovascular events in patients with hyperlipidemia. For primary prevention, a patient's major risk factors (cigarette smoking, hypertension or currently taking antihypertensives, low HDL-C, family history, age, gender) should be evaluated. Patients with multiple risk factors (

2) require more intensive therapy guided by the calculation of a 10-year absolute CHD risk (ie, the percent probability of having a CHD event in next 10 years). An individual's 10-year absolute CHD risk can be calculated at www.med-decisions.com/cvtool/phys/phys.html (last accessed July 3, 2003). LDL cholesterol goals, therapeutic lifestyle changes, and drug therapy are determined based upon a patient's risk factor profile.

Primary prevention trials show that cholesterol-lowering drugs reduce the risk of major coronary events, coronary death, and cerebrovascular events even in the first 6-12 months of use. The WOSCOP trial suggested a trend towards enhanced survival using pravastatin in their patients (mean LDL-cholesterol of 192 mg/dL and no history of MI). In a recent trial (ASCOT-LLA), patients with HTN and at least 3 other risk factors defined by the authors benefited in reducing nonfatal CV events with the use of statins; however, no significant difference in CV mortality or overall mortality was observed. These patients had a total cholesterol below 250 mg/dL before treatment.

Secondary prevention trials indicate that "statin" therapy reduces mortality, major coronary events, coronary artery procedures, and stroke. The Heart Protection Study proved that lowering serum cholesterol levels reduces the rate of major vascular events among high-risk individuals with documented vascular disease (CHD, cerebrovascular, peripheral vascular) or diabetes regardless of initial cholesterol concentrations.

HMG-CoA reductase inhibitors decrease levels of high-sensitivity C-reactive protein (hs-CRP). They also possess pleiotropic properties including improved endothelial function, reduced inflammation at the site of the coronary plaque, inhibition of platelet aggregation, and anticoagulant effects. These nonlipid effects may be beneficial when HMG-CoA reductase inhibitors are introduced early in the management of acute coronary syndromes (de Denus S, Spinler SA, 2002).

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

May cause dizziness, insomnia, or drowsiness

Mental Health: Effects on Psychiatric Treatment

None reported

Dosage Forms

Capsule (Lescol®): 20 mg, 40 mg

Tablet, extended release (Lescol® XL): 80 mg

References

de Denus S and Spinler SA, "Early Statin Therapy for Acute Coronary Syndromes," Ann Pharmacother , 2002, 36(11):1749-58.

"Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III)," JAMA , 2001, 285(19):2486-97.

Fonarow GC, French WJ, Parsons LS, et al, "Use of Lipid-Lowering Medications at Discharge in Patients With Acute Myocardial Infarction: Data From the National Registry of Myocardial Infarction 3," Circulation , 2001, 103(1):38-44.

Koren MJ, Smith DG, Hunninghake DB, et al, "The Cost of Reaching National Cholesterol Education Program (NCEP) Goals in Hypercholesterolaemic Patients. A Comparison of Atorvastatin, Simvastatin, Lovastatin and Fluvastatin," Pharmacoeconomics , 1998, 14(1):59-70.

"MRC/BHF Heart Protection Study of Cholesterol Lowering With Simvastatin in 20,536 High-Risk Individuals: A Randomised Placebo-Controlled Trial. Heart Protection Study Collaborative Group," Lancet , 2002, 360(9326):7-22.

Pasternak RC, Smith SC Jr, Bairey-Merz CN, et al, "ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins," Stroke , 2002, 33(9):2337-41. Available at: http://www.acc.org/clinical/alerts/statins_june02.htm. Accessed June 18, 2003.

Pearson TA, Mensah GA, Alexander RW, et al, "Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: A Statement for Healthcare Professionals From the Centers for Disease Control and Prevention and the American Heart Association," Circulation , 2003, 107(3):499-511.

Phillips BG, Yim JM, Brown EJ Jr, et al, "Pharmacologic Profile of Survivors of Acute Myocardial Infarction at United States Academic Hospitals," Am Heart J , 1996, 131(5):872-8.

Sever PS, Dahlof B, Poulter NR, et al, "Prevention of Coronary and Stroke Events With Atorvastatin in Hypertensive Patients Who Have Average or Lower-Than-Average Cholesterol Concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial - Lipid Lowering Arm (ASCOT-LLA): A Multicentre Randomised Controlled Trial," Lancet , 2003, 361(9364):1149-58.

Shepherd J, Cobbe SM, Ford I, et al, "Prevention of Coronary Heart Disease With Pravastatin in Men With Hypercholesterolemia. West of Scotland Coronary Prevention Study Group," N Engl J Med , 1995, 333(20):1301-7.

International Brand Names

Canef® (DK, FI, MX, NL, NO, PT, SE); Cardiol® (PT); Cranoc® (DE); Digaril® (ES); Fractal® (FR); Lescol® (AR, AT, AU, BE, BG, CA, CH, CO, CR, CZ, DK, DO, EC, ES, FI, FR, GB, GT, HN, HR, HU, ID, IE, IL, IT, MX, NL, NO, NZ, PA, PL, PT, RO, RU, SE, SG, SI, SV, TH, TR, YU, ZA); Leucol® (CL); Lipaxan® (IT); Lochol® (HU, JP); Locol® (DE); Lymetel® (ES); Primesin® (IT); Vaditon® (ES); Vastin® (AU)

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