indication

For the treatment of hypercholesterolemia.

pharmacology

Simvastatin, the methylated form of lovastatin, is an oral antilipemic agent which inhibits HMG-CoA reductase. simvastatin is used in the treatment of primary hypercholesterolemia and is effective in reducing total and LDL-cholesterol as well as plasma triglycerides and apolipoprotein B.

mechanism of action

The 6-membered lactone ring of simvastatin is hydrolyzed in vivo to generate the beta,delta-dihydroxy acid, an active metabolite structurally similar to HMG-CoA (hydroxymethylglutaryl CoA). Once hydrolyzed, simvastatin competes with HMG-CoA for HMG-CoA reductase, a hepatic microsomal enzyme. Interference with the activity of this enzyme reduces the quantity of mevalonic acid, a precursor of cholesterol.

biotransformation

Hepatic, simvastatin is a substrate for CYP3A4.

absorption

Absorption of simvastatin, estimated relative to an intravenous reference dose, in each of two animal species tested, averaged about 85% of an oral dose. In animal studies, after oral dosing, simvastatin achieved substantially higher concentrations in the liver than in non-target tissues.

half life

3 hours

route of elimination

Following an oral dose of 14C-labeled simvastatin in man, 13% of the dose was excreted in urine and 60% in feces.

drug interactions

Amiodarone: Increased risk of rhabdomyolysis

Amprenavir: Amprenavir may increase the effect and toxicity of simvastatin. Concomitant therapy is contraindicated.

Atazanavir: Increased risk of myopathy/rhabdomyolysis

Bosentan: Bosentan may decrease the serum concentration of simvastatin by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of simvastatin if bosentan is initiated, discontinued or dose changed.

Carbamazepine: Carbamazepine, a p-glycoprotein inducer, may decrease the effect of simvastatin by increasing its efflux. Monitor for changes in the therapeutic and adverse effects of simvastatin if carbamazepine is initiated, discontinued or dose changed.

Clarithromycin: The macrolide, clarithromycin, may increase the toxicity of the statin, simvastatin.

Colchicine: Increased risk of rhabdomyolysis with this combination

Cyclosporine: Possible myopathy and rhabdomyolysis

Delavirdine: Delavirdine, a strong CYP3A4 inhibitor, may increase the serum concentration of simvastatin by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of simvastatin if delavirdine is initiated, discontinued or dose changed.

Diltiazem: Diltiazem may increase the serum concentration of simvastatin. Simvastatin may increase the serum concentration of diltiazem. Monitor for changes in the therapeutic and adverse effects of both agents if concomitant therapy is initiated, discontinued or if doses are changed.

Efavirenz: Efavirenz may decrease the serum concentration of simvastatin. Monitor for changes in the therapeutic and adverse effects of simvastatin if efavirenz is initiated, discontinued or dose changed.

Erythromycin: The macrolide, erythromycin, may increase the toxicity of the statin, simvastatin.

Fenofibrate: Increased risk of myopathy/rhabdomyolysis

Fluconazole: Increased risk of myopathy/rhabdomyolysis

Fosamprenavir: Fosamprenavir, a strong CYP3A4 inhibitor, may increase the serum concentration of simvastatin by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of simvastatin if fosamprenavir is initiated, discontinued or dose changed.

Fusidic Acid: Increased risk of myopathy/rhabdomyolysis

Gemfibrozil: Increased risk of myopathy/rhabdomyolysis

Imatinib: Imatinib, a strong CYP3A4 inhibitor, may increase the effect and toxicity of simvastatin by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of simvastatin if imatinib is initiated, discontinued or dose changed.

Itraconazole: Increased risk of myopathy/rhabdomyolysis

Ketoconazole: Increased risk of myopathy/rhabdomyolysis

Nefazodone: Nefazodone may increase the effect and toxicity of simvastatin. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of simvastatin if nefazodone is initiated, discontinued or dose changed.

Nelfinavir: Nelfinavir may increase the effect and toxicity of simvastatin. Concomitant therapy should be avoided.

Nevirapine: The strong CYP3A4 inducer, nevirapine, may decrase the effect of simvastatin by increasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of simvastatin if nevirapine is initiated, discontinued or dose changed.

Quinupristin: This combination presents an increased risk of toxicity

Ranolazine: Ranolazine may increase the serum concentration of simvastatin. Monitor for changes in the therapeutic and adverse effects of simvastatin if ranolazine is initiated, discontinued or dose changed.

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

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

Telithromycin: Telithromycin may increase the adverse effects of simvastatin by decreasing its metabolism. Concomitant therapy should be avoided.

Ticagrelor: Patients receiving more than 40 mg per day of simvastatin may be at increased risk of statin-related adverse effects.

Tipranavir: Tipranavir, co-administered with Ritonavir, may increase the plasma concentration of Simvastatin. Concomitant therapy is contraindicated.

Verapamil: Verapamil, a moderate CYP3A4 inhibitor, may increase the serum concentration of Simvastatin by decreasing its metabolism. Avoid concurrent use if possible or reduce Simvastatin dose during concomitant therapy. Monitor for changes in the therapeutic/adverse effects of Simvastatin if Verapamil is initiated, discontinued or dose changed.

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of simvastatin by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of simvastain if voriconazole is initiated, discontinued or dose changed.