indication

To be used as an adjunct to dietary therapy to prevent cardiovascular events. May be used as secondary prevention in patients with coronary heart disease (CHD) to reduce the risk of requiring coronary revascularization procedures, for reducing progression of coronary atherosclerosis in hypercholesterolemic patients with CHD, and for the treatment of primary hypercholesterolemia and mixed dyslidipidemia.

pharmacology

Fluvastatin, the first synthetically-derived HMG-CoA reductase inhibitor, is a hydrophilic, acidic, antilipemic agent used to lower cholesterol and triglyceride levels associated with primary hypercholesterolemia and mixed dyslipidemia (Fredrickson types IIa and IIb), to slow the progression of coronary atherosclerosis in patients with CHD and as secondary prevention therapy in patients with CHD to reduce the risk of requiring coronary revascularization procedures. Although similar to lovastatin, simvastatin, and pravastatin, fluvastatin has a shorter half-life, no active metabolites, extensive protein binding, and minimal CSF penetration. Fluvastatin acts primarily in the liver. It is prepared as a racemate of two erythro enantiomers of which the 3R,5S enantiomer exerts the pharmacologic effect.

mechanism of action

Fluvastatin selectively and competitively inhibits the hepatic enzyme hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase. HMG-CoA reductase is responsible for converting HMG-CoA to mevalonate, the rate-limiting step in cholesterol biosynthesis. Inhibition results in a decrease in hepatic cholesterol levels which stimulates the synthesis of LDL receptors and increases hepatic uptake of LDL cholesterol. The end result is decreased levels of plasma total and LDL cholesterol.

toxicity

Generally well-tolerated. May cause GI upset (diarrhea, nausea, constipation, gas, abdominal pain), myotoxicity (mypothy, myositis, rhabdomyolysis), and hepatotoxicity.

biotransformation

Undergoes hepatic metabolism primarily via hydroxylation of the indole ring at the 5- and 6-positions to 5-hydroxy fluvastatin and 6-hydroxy fluvastatin, respectively. N-dealkylation to N-desisopropyl fluvastatin and beta-oxidation of the side chain also occurs. Metabolized primarily by the CYP2C9 isozyme system (75%), and to a lesser extent by CYP3A4 (~20%) and CYP2C8 (~5%). Hydroxylated metabolites retain some pharmcological activity, but are present as conjugates (glucuronides and sulfates) in the blood and are rapidly eliminated via bile into feces.

absorption

Rapidly and almost completely absorbed (> 90%), but undergoes extensive first pass metabolism. Bioavailability is 24% (range 9-50%).

half life

1-3 hours

route of elimination

Fluvastatin is metabolized in the liver, primarily via hydroxylation of the indole ring at the 5- and 6-positions. In vitro studies demonstrated that fluvastatin undergoes oxidative metabolism, predominantly via 2C9 isozyme systems (75%). No significant (<6%) renal excretion of fluvastatin occurs in humans.

drug interactions

Acenocoumarol: Fluvastatin may increase the anticoagulant effect of acenocoumarol. Monitor for changes in the therapeutic and adverse effects of acenocoumarol if fluvastatin is initiated, discontinued or dose changed.

Anisindione: Fluvastatin may increase the anticoagulant effect of anisindione. Monitor for changes in the therapeutic and adverse effects of anisindione if fluvastatin if initiated, discontinued or dose changed.

Bezafibrate: Increased risk of myopathy/rhabdomyolysis

Cholestyramine: Increased/decreased effect according to spacing

Colchicine: Increased risk of rhabdomyolysis with this combination

Colestipol: Increased/decreased effect according to spacing

Cyclosporine: Possible myopathy and rhabdomyolysis

Dicumarol: Fluvastatin may increase the anticoagulant effect of dicumarol. Monitor for changes in the therapeutic and adverse effects of dicumarol if fluvastatin if initiated, discontinued or dose changed.

Fenofibrate: Increased risk of myopathy/rhabdomyolysis

Fluconazole: Fluconazole may increase the serum concentration of fluvastatin by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of fluvastatin if fluconazole is initiated, discontinued or dose changed.

Gemfibrozil: Increased risk of myopathy/rhabdomyolysis

Rifabutin: Rifabutin may decrease the effect of fluvastatin by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of fluvastatin if rifabutin is initiated, discontinued or dose changed.

Rifampin: Rifampin may decrease the effect of fluvastatin by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of fluvastatin if rifampin is initiated, discontinued or dose changed.

Warfarin: Fluvastatin may increase the anticoagulant effect of warfarin. Monitor for changes in the therapeutic and adverse effects of warfarin if fluvastatin is initiated, discontinued or dose changed.