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Lovastatin


Pronunciation

 (LOE va sta tin)


U.S. Brand Names

 Altocor™ [DSC]; Altoprev™; Mevacor®


Synonyms

 Mevinolin; Monacolin K


Generic Available

 Yes: Immediate release tablet


Canadian Brand Names

 Apo-Lovastatin®; Gen-Lovastatin; Mevacor®; Novo-Lovastatin; Nu-Lovastatin; PMS-Lovastatin; ratio-Lovastatin


Use

Adjunct to dietary therapy to decrease elevated serum total and LDL-cholesterol concentrations in primary hypercholesterolemia

Primary prevention of coronary artery disease (patients without symptomatic disease with average to moderately elevated total and LDL-cholesterol and below average HDL-cholesterol); slow progression of coronary atherosclerosis in patients with coronary heart disease

Adjunct to dietary therapy in adolescent patients (10-17 years of age, females >1 year postmenarche) with heterozygous familial hypercholesterolemia having LDL >189 mg/dL, or LDL >160 mg/dL with positive family history of premature cardiovascular disease (CVD), or LDL >160 mg/dL with the presence of at least two other CVD risk factors


Pregnancy Risk Factor

 X


Pregnancy Implications

 Safety and efficacy have not been established for use during pregnancy (treatment should be discontinued if pregnancy is recognized). Administer to women of childbearing potential only if conception is unlikely; females should be counseled on appropriate contraceptive methods.


Lactation

 Excretion unknown/contraindicated


Contraindications

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


Warnings/Precautions

 Liver function must be monitored by periodic laboratory assessment. Rhabdomyolysis with acute renal failure has occurred. Risk is dose-related and is increased with concurrent use of lipid-lowering agents which may cause rhabdomyolysis (gemfibrozil, fibric acid derivatives, or niacin at doses 1 g/day) or during concurrent use with potent CYP3A4 inhibitors (including amiodarone, clarithromycin, cyclosporine, erythromycin, itraconazole, ketoconazole, nefazodone, grapefruit juice in large quantities, verapamil, or protease inhibitors such as indinavir, nelfinavir, or ritonavir). Weigh the risk versus benefit when combining any of these drugs with lovastatin. Temporarily discontinue in any patient experiencing an acute or serious condition predisposing to renal failure secondary to rhabdomyolysis. Use with caution in patients who consume large amounts of ethanol or have a history of liver disease. Safety and efficacy of the immediate release tablet have not been evaluated in prepubertal patients, patients <10 years of age, or doses >40 mg/day in appropriately-selected adolescents; extended release tablets have not been studied in patients <20 years of age.


Adverse Reactions

 Percentages as reported with immediate release tablets; similar adverse reactions seen with extended release tablets.

>10%: Neuromuscular & skeletal: CPK increased (>2x normal) (11%)

1% to 10%:

Central nervous system: Headache (2% to 3%), dizziness (0.5% to 1%)

Dermatologic: Rash (0.8% to 1%)

Gastrointestinal: Abdominal pain (2% to 3%), constipation (2% to 4%), diarrhea (2% to 3%), dyspepsia (1% to 2%), flatulence (4% to 5%), nausea (2% to 3%)

Neuromuscular & skeletal: Myalgia (2% to 3%), weakness (1% to 2%), muscle cramps (0.6% to 1%)

Ocular: Blurred vision (0.8% to 1%)

<1% (Limited to important or life-threatening): Chest pain, acid regurgitation, xerostomia, vomiting, leg pain, arthralgia, insomnia, paresthesia, alopecia, pruritus, eye irritation, dermatomyositis

Additional class-related events or case reports (not necessarily reported with lovastatin therapy): Alkaline phosphatase increased, alopecia, alteration in taste, anaphylaxis, angioedema, anorexia, anxiety, arthritis, cataracts, chills, cholestatic jaundice, cirrhosis, CPK increased (>10x normal), depression, dryness of skin/mucous membranes, dyspnea, eosinophilia, erectile dysfunction, erythema multiforme, ESR increased, facial paresis, fatty liver, fever, flushing, fulminant hepatic necrosis, GGT increased, gynecomastia, hemolytic anemia, hepatitis, hepatoma, hyperbilirubinemia, hypersensitivity reaction, impaired extraocular muscle movement, impotence, leukopenia, libido decreased, malaise, memory loss, myopathy, nail changes, nodules, ophthalmoplegia, pancreatitis, paresthesia, peripheral nerve palsy, peripheral neuropathy, photosensitivity, polymyalgia rheumatica, positive ANA, pruritus, psychic disturbance, purpura, rash, renal failure (secondary to rhabdomyolysis), rhabdomyolysis, 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

 Few adverse events have been reported. Treatment is symptomatic.


Drug Interactions

 Substrate of CYP3A4 (major); Inhibits CYP2C8/9 (weak), 2D6 (weak), 3A4 (weak)

Amiodarone: Inhibits metabolism of lovastatin and may increase lovastatin-induced myopathy and rhabdomyolysis. Concurrent use is not recommended, but if unavoidable, dose of lovastatin should be limited.

Antacids: Plasma concentrations may be decreased when given with magnesium-aluminum hydroxide containing antacids (reported with atorvastatin and pravastatin). Clinical efficacy is not altered, no dosage adjustment is necessary

Cholestyramine reduces absorption of several HMG-CoA reductase inhibitors. Separate administration times by at least 4 hours.

Cholestyramine and colestipol (bile acid sequestrants): Cholesterol-lowering effects are additive.

Clofibrate and fenofibrate may increase the risk of myopathy and rhabdomyolysis; limit dose of lovastatin

Cyclosporine: Concurrent use may increase risk of myopathy; limit dose of lovastatin

CYP3A4 inhibitors: May increase the levels/effects of lovastatin. Example inhibitors include azole antifungals, ciprofloxacin, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, and verapamil.

Gemfibrozil: Increased risk of myopathy and rhabdomyolysis; limit dose of lovastatin

Grapefruit juice may inhibit metabolism of lovastatin via CYP3A4; avoid high dietary intakes of grapefruit juice.

Isradipine may decrease lovastatin blood levels.

Niacin (at higher dosages 1 g/day) may increase risk of myopathy and rhabdomyolysis; limit dose of lovastatin

Protease inhibitors: Concurrent use increases the risk of myopathy and rhabdomyolysis; concurrent use should be avoided.

Verapamil: Inhibits metabolism of lovastatin and may increase lovastatin-induced myopathy and rhabdomyolysis. Concurrent use is not recommended, but if unavoidable, dose of lovastatin should be limited.

Warfarin effect (hypoprothrombinemic response) may be increased; monitor INR closely when lovastatin is initiated or discontinued.


Ethanol/Nutrition/Herb Interactions

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

Food: The therapeutic effect of lovastatin may be decreased if taken with food. Lovastatin serum concentrations may be increased if taken with grapefruit juice; avoid concurrent intake of large quantities (>1 quart/day).

Herb/Nutraceutical: St John's wort may decrease lovastatin levels.


Stability

Tablet, immediate release: Store between 5°C to 30°C (41°F to 86°F); protect from light

Tablet, extended release: Store between 20°C to 25°C (68°F to 77°F); avoid excessive heat and humidity


Mechanism of Action

 Lovastatin acts by competitively inhibiting 3-hydroxyl-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the rate-limiting step in cholesterol biosynthesis


Pharmacodynamics/Kinetics

Onset of action: LDL-cholesterol reductions: 3 days

Absorption: 30%; increased with extended release tablets

Protein binding: 95%

Metabolism: Hepatic; extensive first-pass effect; hydrolyzed to B-hydroxy acid (active)

Bioavailability: Increased with extended release tablets

Half-life elimination: 1.1-1.7 hours

Time to peak, serum: 2-4 hours

Excretion: Feces (~80% to 85%); urine (10%)


Dosage

 Oral:

Adolescents 10-17 years: Immediate release tablet:

LDL reduction <20%: Initial: 10 mg/day with evening meal

LDL reduction 20%: Initial: 20 mg/day with evening meal

Usual range: 10-40 mg with evening meal, then adjust dose at 4-week intervals

Adults: Initial: 20 mg with evening meal, then adjust at 4-week intervals; maximum dose: 80 mg/day immediate release tablet or 60 mg/day extended release tablet

Dosage modification/limits based on concurrent therapy:

Cyclosporine and other immunosuppressant drugs: Initial dose: 10 mg/day with a maximum recommended dose of 20 mg/day

Concurrent therapy with fibrates and/or lipid-lowering doses of niacin (>1 g/day): Maximum recommended dose: 20 mg/day. Concurrent use with fibrates should be avoided unless risk to benefit favors use.

Concurrent therapy with amiodarone or verapamil: Maximum recommended dose: 40 mg/day of regular release or 20 mg/day with extended release.

Dosage adjustment in renal impairment: Clcr<30 mL/minute: Use doses >20 mg/day with caution.


Administration

 Administer with meals. Do not crush or chew extended release tablets.


Monitoring Parameters

 Obtain baseline LFTs and total cholesterol profile. LFTs should be performed before initiation of therapy, at 6- and 12 weeks after initiation or first dose, and periodically thereafter.


Reference Range

 NCEP classification of pediatric patients with familial history of hypercholesterolemia or premature CVD: Acceptable total cholesterol: <170 mg/dL, LDL: <110 mg/dL


Test Interactions

 Increased liver transaminases (S), altered thyroid function tests


Dietary Considerations

 Before initiation of therapy, patients should be placed on a standard cholesterol-lowering diet for 6 weeks and the diet should be continued during drug therapy. Avoid intake of large quantities of grapefruit juice ( 1 quart/day); may increase toxicity.


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 food at evening meal. Follow diet and exercise regimen as prescribed. You will have periodic blood tests to assess effectiveness. 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 (see prescriber for analgesic). Report muscle pain or cramping; tremor; 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 appropriate barrier contraceptive measures to use during and for 1 month following therapy. This drug may cause severe fetal defects. Do not donate blood during or for 1 month following therapy. Do not breast-feed.


Nursing Implications

 Urge patient to adhere to cholesterol-lowering diet


Anesthesia and Critical Care Concerns/Other Considerations

 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), gender (occurs in 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) , and drug interactions (use with caution or avoid).


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).

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.


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


Mental Health: Effects on Psychiatric Treatment

 None reported


Dosage Forms

Tablet: 10 mg, 20 mg, 40 mg

Mevacor®: 10 mg [DSC], 20 mg, 40 mg

Tablet, extended release (Altocor™ [DSC], Altoprev™): 10 mg, 20 mg, 40 mg, 60 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.

Grundy SM, Cleeman JI, Merz CN, "Implications of Recent Clinical Trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines," Arterioscler Thromb Vasc Biol , 2004, 24(8):E149-61.

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.

"National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents," Pediatrics , 1992, 89(3):495-501.

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

 Anlostin® (PL); Apo-Lova® (PL); Apo-Lovastatin® (CA, CZ, SG); Artein® (HR, SI); Aterkey® (ES); Aztatin® (BD); Belvas® (ID); Cholestra® (ID); Colesvir® (ES); Colevix® (CL); Elstatin® (SG); Flozul® (PT); Gen-Lovastatin (CA); Hexaltina® (DO); Hipolip® (YU); Hiposterol® (CL); Hipovastin® (AR); Holetar® (CZ, HR, RU, SI); Lipopres® (BG); Liposcler® (ES); Lipovas® (ID); Liprox® (PL); Lipus® (PT); Lispor® (CL); Lofacol® (ID); Lostatin® (SG); Lotyn® (ID); Lovabeta® (DE); Lovacodan® (DK); Lovacol® (CL, FI); Lovadura® (DE); Lovagamma® (DE); LovaHEXAL® (DE); Lovakor® (TR); Lovalip® (CL, IL); Lovarem® (CY); Lovasin® (EC); Lovastatin 1 A Pharma® (DE); Lovastatina Alacan® (ES); Lovastatina Aphar® (ES); Lovastatina Bexal® (ES); Lovastatin AbZ® (DE); Lovastatina Centrum® (ES); Lovastatina Chemo Techni® (ES); Lovastatina Cinfa® (ES); Lovastatina® (CL); Lovastatina Combino Pharm® (ES); Lovastatina Geminis® (ES); Lovastatina Genfar® (EC); Lovastatina Grapa® (ES); Lovastatina Kern® (ES); Lovastatina Lareq® (ES); Lovastatina Lasa® (ES); Lovastatin AL® (DE); Lovastatin Alternova® (DK); Lovastatina Mabo® (ES); Lovastatina Mepha® (PT); Lovastatina Merck® (ES); Lovastatina MK® (CO); Lovastatina Normon® (ES); Lovastatina Pliva® (ES); Lovastatin® (AR); Lovastatina Ratio® (DO); Lovastatina Tamarang® (ES); Lovastatina Universal® (ES); Lovastatina Vir® (ES); Lovastatin AZU® (DE); Lovastatin Heumann® (DE); Lovastatin Hexal® (AT); Lovastatin-ISIS® (DE); Lovastatin-ratiopharm® (DE, DK); Lovastatin-saar® (DE); Lovastatin Stada® (DE); Lovastatin-Teva® (DE); Lovastatinum® (PL); Lovastatin UNP® (DK); Lovastatin von ct® (DE); Lovasterol® (CO, PL); Lovastin® (PL); Lova TAD® (DE); Lovatin® (BD); Lovatrol® (ID); Lovax® (BR); Medostatin® (CZ, RO, RU, SG); Medovascin® (GR); Mevacor® (AT, BR, CA, CL, CZ, DK, ES, FI, HK, HU, LU, MX, NO, PL, RO, RU, YU); Mevasterol® (ES); Mevinacor® (DE, PT); Mevlor® (AR, PT); Minor® (BR); Nergadan® (ES); Novo-Lovastatin (CA); Nu-Lovastatin (CA); Paschol® (ID); PMS-Lovastatin (CA); Pro-Hdl® (IN); ratio-Lovastatin (CA); Reducol® (BR); Rovacor® (IN, RU, SG); Sanelor® (CL); Sivlor® (AR); Taucor® (ES); Tecnolip® (PT)


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