indication

For management as an adjunct to diet to reduce elevated total-C, LDL-C, apo B, and TG levels in patients with primary hypercholesterolemia and mixed dyslipidemia. For primary prevention of coronary heart disease and to slow progression of coronary atherosclerosis in patients with coronary heart disease.

pharmacology

The primary cause of cardiovascular disease is atherosclerotic plaque formation. Sustained elevations of cholesterol in the blood increase the risk of cardiovascular disease. Lovastatin lowers hepatic cholesterol synthesis by competitively inhibiting HMG-CoA reductase, the enzyme that catalyzes the rate-limiting step in the cholesterol biosynthesis pathway via the mevalonic acid pathway. Decreased hepatic cholesterol levels causes increased uptake of low density lipoprotein (LDL) cholesterol and reduces cholesterol levels in the circulation. At therapeutic doses, lovastatin decreases serum LDL cholesterol by 29-32%, increases high density lipoprotein (HDL) cholesterol by 4.6-7.3%, and decrease triglyceride levels by 2-12%. HDL cholesterol is thought to confer protective effects against CV disease, whereas high LDL and triglyceride levels are associated with higher risk of disease.

mechanism of action

Lovastatin is structurally similar to the HMG, a substituent of the endogenous substrate of HMG-CoA reductase. Lovastatin is a prodrug that is activated in vivo via hydrolysis of the lactone ring. The hydrolyzed lactone ring mimics the tetrahedral intermediate produced by the reductase allowing the agent to bind with 20,000 times greater affinity than its natural substrate. The bicyclic portion of lovastatin binds to the coenzyme A portion of the active site.

toxicity

LD₅₀>1000 mg/kg (orally in mice)

biotransformation

Undergoes first pass hydrolysis to active metabolites β-hydroxyacid and 6'-hydroxy dervative.

absorption

< 5%. Time to peak serum concentration is 2-4 hours.

half life

5.3 hours

route of elimination

Lovastatin undergoes extensive first-pass extraction in the liver, its primary site of action, with subsequent excretion of drug equivalents in the bile. 83% of the orally administered dose is excreted in bile and 10% is excreted in urine.

drug interactions

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

Amprenavir: Amprenavir may increase the serum concentration of the lovastatin. Concomitant therapy is contraindicated.

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

Atazanavir: Atazanavir may increase the effect and toxicity of lovastatin. Concomitant therapy is contraindicated.

Azithromycin: The macrolide antibiotic, azithromycin, may increase the serum concentration of lovastatin by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of lovastatin if azithromycin is initiated, discontinued or dose changed.

Bezafibrate: Increased risk of myopathy/rhabdomyolysis

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

Carbamazepine: Carbamazepine, a p-glycoprotein inducer and strong CYP3A4 inducer, may decrease the effect of lovastatin by increasing its efflux and metabolism. Monitor for changes in the therapeutic and adverse effects of lovastatin if carbamazepine is initiated, discontinued or dose changed.

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

Colchicine: Increased risk of rhabdomyolysis with this combination

Cyclosporine: Possible myopathy and rhabdomyolysis

Danazol: Risk of severe myopathy/rhabdomyolysis with this combination

Darunavir: Darunavir may increase the effect and toxicity of lovastatin. Concomitant therapy is contraindicated.

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

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

Diltiazem: Diltiazem may increase the serum concentration of lovastatin. Lovastatin 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 lovastatin by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of lovastatin if efavirenz is initiated, discontinued or dose changed.

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

Fenofibrate: Increased risk of myopathy/rhabdomyolysis

Fluconazole: Increased risk of myopathy/rhabdomyolysis

Fosamprenavir: Fosamprenavir, a strong CYP3A4 inhibitor, may increase the effect and toxicity of lovastatin by decreasing its metabolism. Concomitant therapy is contraindicated.

Gemfibrozil: Increased risk of myopathy/rhabdomyolysis

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

Indinavir: Indinavir may increase the effect and toxicity of lovastatin. Concomitant therapy is contraindicated.

Itraconazole: Increased risk of myopathy/rhabdomyolysis

Josamycin: The macrolide, josamycin, may increase the toxicity of the statin, lovastatin.

Ketoconazole: Increased risk of myopathy/rhabdomyolysis

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

Nelfinavir: Nelfinavir may increase the effect and toxicity of lovastatin. Concomitant therapy is contraindicated.

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

Niacin: Risk of severe myopathy/rhabdomyolysis with this combination

Quinupristin: This combination presents an increased risk of toxicity

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

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

Ritonavir: Ritonavir may increase the effect and toxicity of lovastatin. Concomitant therapy is contraindicated.

Saquinavir: Saquinavir may increase the effect and toxicity of lovastatin. Concomitant therapy is contraindicated.

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

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

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

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

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

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