lovastatin 40 mg tablet

Uses

Prevention of Cardiovascular Events

The American College of Cardiology (ACC)/American Heart Association (AHA) cholesterol management guideline recommends statins as first-line therapy for prevention of atherosclerotic cardiovascular disease (ASCVD) in adults. There is extensive evidence demonstrating that statins can substantially reduce ASCVD risk when used for secondary prevention or primary prevention (in high-risk patients). Because the relative reduction in ASCVD risk is correlated with the degree of low-density lipoprotein (LDL)-cholesterol lowering, the maximum tolerated statin intensity should be used to achieve optimum ASCVD benefits. According to the ACC/AHA guidelines, lovastatin may be used for primary or secondary prevention in adults when moderate-intensity statin therapy is indicated.(See Prevention of Cardiovascular Events under Dosage and Administration: Dosage.) Nonstatin therapies do not provide acceptable ASCVD risk reduction benefits compared to their potential for adverse effects in the routine prevention of ASCVD. For additional details on prevention of ASCVD, and also consult the most recent ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults (available at http://www.cardiosource.org or http://my.americanheart.org).

Primary Prevention

Lovastatin is used as an adjunct to nondrug therapies (i.e., lifestyle modifications) in patients without symptomatic cardiovascular disease who have normal or moderate elevations of total and LDL-cholesterol and below-average high-density lipoprotein (HDL)-cholesterol concentrations to reduce the risk of myocardial infarction (MI) or unstable angina and to reduce the risk of undergoing coronary revascularization procedures.

The ACC/AHA cholesterol management guideline recommends statins as first-line therapy for primary prevention in patients 21 years of age and older without clinical ASCVD who have primary, severe elevations in LDL-cholesterol concentration (190 mg/dL or greater); patients 40-75 years of age with type 1 or 2 diabetes mellitus; and patients 40-75 years of age with LDL-cholesterol concentrations of 70-189 mg/dL and an estimated 10-year ASCVD risk of 7.5% or higher. Before initiating statin therapy for primary prevention in patients without clinical ASCVD or diabetes mellitus, it is reasonable for clinicians and patients to discuss the potential for ASCVD risk reduction benefits, adverse effects, and drug interactions, as well as patient preferences for treatment.

In a randomized, double-blind, placebo-controlled study (Air Force/Texas Coronary Atherosclerosis Prevention Study [AFCAPS/TexCAPS]) in patients who had total and LDL-cholesterol concentrations averaging 221 and 150 mg/dL, respectively, and HDL-cholesterol concentrations averaging 36 mg/dL (men) or 40 mg/dL (women), lovastatin therapy (20-40 mg daily) reduced the incidence of a first acute major event (i.e., primary end point defined as fatal or nonfatal MI, unstable angina, or sudden cardiac death) by 37% after an average follow-up period of 5.2 years. Lovastatin therapy also produced benefit in terms of secondary end points, including a 33% reduction in coronary revascularization procedures, a 32% reduction in unstable angina, a 40% reduction in the incidence of fatal or nonfatal MI, and a 25% reduction in cardiovascular (e.g., atherosclerotic) events.

Reducing Progression of Coronary Atherosclerosis

Lovastatin is used as an adjunct to nondrug therapies (e.g., dietary management) in patients with coronary heart disease (CHD) to slow the progression of coronary atherosclerosis as part of a treatment strategy to lower total and LDL-cholesterol concentrations to target levels.

Lovastatin has been shown to slow the progression of atherosclerosis in both coronary and carotid arteries by reducing intimal-medial wall thickness. In several double-blind, placebo-controlled studies (e.g., Canadian Coronary Atherosclerosis Intervention Trial [CCAIT], Monitored Atherosclerosis Regression Study [MARS], Familial Atherosclerosis Treatment Study [FATS]) in men and women with or without documented CHD and elevated lipoprotein concentrations, progression of atherosclerosis at 2-3 years (measured as the mean per-patient changes from baseline in mean and minimal coronary artery lumen diameters, percent diameter stenosis, and formation of new lesions) was reduced in patients who received recommended daily dosages of lovastatin.

Treatment with lovastatin has been shown to reduce the rate of progression of atherosclerosis in the carotid arteries. In the MARS and the Asymptomatic Carotid Artery Progression Studies (ACAPS), hypercholesterolemic patients with or without CHD who received recommended daily dosages of lovastatin for a median of 2-4 years showed less progression of atherosclerosis (as determined by B-mode ultrasound quantification of carotid artery intimal-medial thickness [IMT]) compared with those receiving placebo. In addition, treatment with lovastatin also was associated with a reduction in the risk of major cardiovascular events and all-cause mortality.

Intensity of Statin Therapy

The ACC/AHA cholesterol management guideline states that the appropriate intensity of a statin should be used to reduce the risk of ASCVD in patients most likely to benefit. Based on the average LDL-cholesterol response observed with specific statins and dosages used in the randomized controlled studies evaluated by the guideline expert panel, ACC/AHA considers lovastatin 20 mg daily to be a low-intensity statin (producing approximate LDL-cholesterol reductions of less than 30%) and lovastatin 40 mg daily to be a moderate-intensity statin (producing approximate LDL-cholesterol reductions of 30% to less than 50%). Individual patient response may vary in clinical practice.

Combination Antilipemic Therapy

The ACC/AHA cholesterol management guideline states that nonstatin drugs may be useful adjuncts to statin therapy in certain high-risk patients (e.g., patients with ASCVD, LDL-cholesterol concentrations of at least 190 mg/dL, or diabetes mellitus) who have a less-than-anticipated response to statins, are unable to tolerate a less-than-recommended intensity of a statin, or are completely intolerant to statin therapy, particularly if there is evidence from randomized controlled studies suggesting that the addition of the nonstatin drug further reduces ASCVD events. If combination therapy is necessary, selection of the nonstatin drug should be based on the risk and benefit profile (i.e., reduction in ASCVD risk outweighs the drug's potential for adverse effects and drug interactions) and patient preferences.

Dyslipidemias

Primary Hypercholesterolemia or Mixed Dyslipidemia

Lovastatin is used as an adjunct to nondrug therapies (e.g., dietary management) in adults to decrease elevated serum total and LDL-cholesterol, apolipoprotein B (apo B), and triglyceride concentrations, and to increase HDL-cholesterol concentrations in the treatment of primary hypercholesterolemia, including heterozygous familial hypercholesterolemia and other primary causes of hypercholesterolemia (e.g., polygenic hypercholesterolemia). Lovastatin as conventional (immediate-release) tablets also is used as an adjunct to dietary therapy to reduce elevated serum total cholesterol, LDL-cholesterol, and apo B concentrations in the treatment of heterozygous familial hypercholesterolemia in boys and girls (who are at least 1 year postmenarchal) 10-17 years of age who, despite an adequate trial of dietary management, have a serum LDL-cholesterol concentration of 190 mg/dL or greater or a serum LDL-cholesterol concentration exceeding 160 mg/dL and either a family history of premature cardiovascular disease or 2 or more other cardiovascular risk factors. Statins such as lovastatin also are used in combination with fenofibrate to decrease triglyceride concentrations and increase HDL-cholesterol concentrations in patients with mixed dyslipidemia and CHD or CHD risk equivalents who are receiving optimal statin therapy; however, no additional benefit on cardiovascular morbidity and mortality has been demonstrated with such combination therapy beyond that already established with statin monotherapy.

Although lovastatin also has been used to reduce elevated LDL-cholesterol concentrations in patients with combined hypercholesterolemia and hypertriglyceridemia caused by genotypic familial combined hyperlipidemia, the drug has not been studied in conditions where the major abnormality is elevation of chylomicrons, very-low-density lipoproteins (VLDLs), or intermediate-density lipoproteins (IDLs).

Nondrug therapies and measures specific for the type of dyslipidemia (therapeutic lifestyle changes) are the initial treatments of choice, including dietary management (e.g., restriction of total and saturated fat and cholesterol intake, addition of plant stanols/sterols and viscous fiber to diet), weight control, an appropriate program of physical activity, and management of potentially contributory disease (e.g., hypothyroidism). Drug therapy is not a substitute for but an adjunct to these nondrug therapies and measures, which should be continued when drug therapy is initiated.

Reductions in total and LDL-cholesterol produced by usual dosages of lovastatin substantially exceed those of placebo and appear to be similar to or greater than those produced by monotherapy with usual dosages of certain other antilipemic agents. Mean reductions in total cholesterol concentrations of 13-34%, LDL-cholesterol concentrations of 17-48%, and triglyceride concentrations of 6-27% have been observed in controlled and uncontrolled studies in patients with heterozygous familial hypercholesterolemia or other forms of primary hypercholesterolemia who received 10-80 mg of lovastatin daily. Modest and variable increases in HDL-cholesterol concentrations (1-10%) also were observed in these patients. In 2 multicenter, placebo-controlled studies, 89% of patients with heterozygous familial hypercholesterolemia or 97% of patients with other forms of primary hypercholesterolemia who received lovastatin 40 mg twice daily and dietary management had reductions in LDL-cholesterol of at least 20%, while 61 or 51% of such patients had LDL-cholesterol reductions of at least 40%; reductions in LDL-cholesterol averaged 39% in both groups of patients.

Reductions in total and LDL-cholesterol concentrations produced by usual dosages of lovastatin generally appear to be similar to or greater than those produced by monotherapy with usual dosages of some statins (e.g., fluvastatin, pravastatin, simvastatin) but less than those produced by usual dosages of atorvastatin and rosuvastatin. In a randomized, multicenter, parallel-group study comparing the efficacy of various statins, patients with hypercholesterolemia who received lovastatin 20-80 mg daily experienced similar or greater reductions in total and LDL-cholesterol concentrations (21-36 and 29-48%, respectively) than those receiving fluvastatin 20-40 mg daily (13-19 and 17-23%, respectively), pravastatin 10-40 mg daily (13-24 and 19-34%, respectively), or simvastatin 10-40 mg daily (21-30 and 28-41%, respectively). However, atorvastatin dosages of 10-80 mg daily produced greater reductions in total and LDL-cholesterol concentrations (28-42 and 38-54%, respectively) than lovastatin. Maximum reductions in LDL-cholesterol concentrations with lovastatin reportedly average about 35-40% at maximum recommended dosages (80 mg daily in 1 or 2 divided doses).(See Intensity of Statin Therapy under Uses: Prevention of Cardiovascular Events.)

Limited data from comparative studies suggest that reductions in total and LDL-cholesterol concentrations produced by lovastatin are similar to or greater than those produced by certain other antilipemic agents (i.e., bile acid sequestrants, niacin, fibric acid derivatives). Lovastatin 40-80 mg daily reportedly has produced greater reductions in total cholesterol than cholestyramine 12-24 g daily. HDL-cholesterol increases produced by lovastatin are similar to or greater than those reported with usual cholestyramine dosages. Lovastatin appears to produce greater reductions in total and LDL-cholesterol than niacin or fibric acid derivatives (i.e., fenofibrate, gemfibrozil) in reducing total and LDL-cholesterol concentrations but is less effective than these agents in reducing triglycerides or increasing HDL-cholesterol concentrations. In several comparative studies in patients with primary hypercholesterolemia or familial combined hyperlipidemia, therapy with lovastatin (20-40 mg daily) reduced total and LDL-cholesterol concentrations by 17-23 and 21-28%, respectively, while total and LDL-cholesterol reductions averaged 6 and 5%, respectively, with niacin; 9 and 2%, respectively, with gemfibrozil; and 13 and 12%, respectively, with fenofibrate. Reductions in triglycerides and increases in HDL-cholesterol concentrations generally were less pronounced among patients treated with lovastatin (8-25% reduction and 6-13% increase) than in those receiving niacin (22% reduction and 18% increase), gemfibrozil (48% reduction and 18% decrease), or fenofibrate (42% reduction and 22% increase).

When lovastatin monotherapy combined with dietary management does not reduce LDL-cholesterol concentrations to optimal levels in patients with dyslipidemia, combination drug therapy may be required. Although combined therapy with lovastatin and another antilipemic agent generally results in cholesterol reductions exceeding those achieved with either therapy alone, the risk of myopathy and rhabdomyolysis may be increased with such concomitant use. Therapy with lovastatin (20-40 mg daily) in fixed combination with extended-release niacin (1-2 g daily) (no longer commercially available in the US) reduced LDL-cholesterol or triglyceride concentrations by 30-42 or 32-44%, respectively, and increased HDL-cholesterol concentrations by 20-30%. Limited data indicate that concomitant therapy with gemfibrozil and lovastatin may be superior to that with gemfibrozil and a bile acid sequestrant in patients with familial combined hyperlipidemia, in part because the bile acid sequestrant appears to lessen the favorable effects of gemfibrozil on HDL- and VLDL-cholesterol and total triglycerides. Lovastatin has been used concomitantly with the bile acid sequestrants colestipol or cholestyramine in a limited number of patients with heterozygous familial hypercholesterolemia or other forms of primary hypercholesterolemia. The addition of a bile acid sequestrant to lovastatin therapy further reduced LDL-cholesterol by 19-26%, resulting in overall LDL-cholesterol reductions of 46-60% in patients receiving lovastatin 40-80 mg daily and either colestipol hydrochloride 10-20 g daily or cholestyramine 4-24 g daily. Triple-drug therapy with lovastatin, niacin, and a bile acid sequestrant in patients with severe heterozygous familial hypercholesterolemia or other forms of severe primary hypercholesterolemia has produced further sustained reductions in LDL-cholesterol compared with those produced by combinations of any two of these drugs, and some clinicians have suggested that niacin may be more effective than a fibric acid derivative (e.g., gemfibrozil) in a three-drug regimen in patients whose cholesterol concentrations are controlled inadequately by the combination of a statin and a bile acid sequestrant. However, because of the increased risk of adverse muscular effects with combination therapy, some antilipemic drug combinations should be avoided or used with caution.

Other Uses

Lovastatin has reduced total and LDL-cholesterol concentrations in a few patients with familial dysbetalipoproteinemia or with hypercholesterolemia associated with or exacerbated by diabetes mellitus (diabetic dyslipidemia), cardiac or renal transplantation, nephrotic syndrome (nephrotic hyperlipidemia), or distal ileal bypass surgery. The drug also has been used to lower total cholesterol, LDL-cholesterol, and/or apolipoprotein B in a limited number of patients with hypoalphalipoproteinemia or in those with mild endogenous (primary) hypertriglyceridemia and borderline elevated total cholesterol, decreased HDL-cholesterol, and elevated apolipoprotein B (type IV hyperlipoproteinemia with elevated total apo B). Additional studies are necessary to determine the role, if any, of lovastatin therapy in patients with these disorders.

For additional information on these and other uses of lovastatin or other statins, see General Principles of Antilipemic Therapy and see Uses in the HMG-CoA Reductase Inhibitors General Statement 24:06.08.

Dosage and Administration

Administration

Lovastatin is administered orally in the evening or at bedtime. Lovastatin conventional tablets should be administered with the evening meal. Lovastatin extended-release tablets should be taken in the evening at bedtime.

Patients should be placed on a standard cholesterol-lowering diet before initiation of lovastatin therapy and should remain on this diet during treatment with the drug. For recommendations on dietary and other nondrug therapies (i.e., lifestyle modifications), consult the most recent American Heart Association (AHA)/American College of Cardiology (ACC) Guideline on Lifestyle Management to Reduce Cardiovascular Risk (available at http://www.cardiosource.org or http://my.americanheart.org).

Because administration of lovastatin with grapefruit juice has resulted in substantial increases in plasma concentrations of the antilipemic agent, the manufacturers and some clinicians recommend that concomitant administration of lovastatin with grapefruit juice should be avoided. However, the extent of this interaction may be influenced by the quantity and timing of grapefruit juice consumption, and other clinicians suggest that small amounts of grapefruit juice (e.g., 240 mL) may be acceptable and may even be used to therapeutic advantage.

Dosage

Dosage of lovastatin must be carefully adjusted according to individual requirements and response. Dosage should be increased at intervals of no less than 4 weeks until the desired effect on lipoprotein concentrations is observed; reduction of lovastatin dosage should be considered in patients whose serum cholesterol concentrations fall below the desired target range. The manufacturer recommends that serum lipoprotein concentrations be determined periodically during lovastatin therapy. The ACC/AHA cholesterol management guideline states that lipoprotein concentrations should be determined within 4-12 weeks following initiation of statin therapy (to determine the patient's response to therapy and adherence) and monitored every 3-12 months thereafter as clinically indicated.

Prevention of Cardiovascular Events

The ACC/AHA cholesterol management guideline states that the appropriate intensity of statin therapy should be used to reduce atherosclerotic cardiovascular disease (ASCVD) risk in patients most likely to benefit. Giving a maximally tolerated statin intensity should be emphasized over giving lower statin dosages and adding nonstatin drugs to address low high-density lipoprotein (HDL)-cholesterol or high triglyceride concentrations, a strategy that has not yet been shown to reduce ASCVD risk.

Primary Prevention

For primary prevention of cardiovascular disease in patients 21 years of age and older without clinical ASCVD who have primary, severe elevations in low-density lipoprotein (LDL)-cholesterol concentration (190 mg/dL or greater), the ACC/AHA cholesterol management guideline recommends that high-intensity statin therapy (i.e., with atorvastatin or rosuvastatin) be initiated unless contraindicated. ( or .)

For primary prevention of cardiovascular disease in patients 40-75 years of age with type 1 or 2 diabetes mellitus and LDL-cholesterol concentrations of 70-189 mg/dL, the ACC/AHA cholesterol management guideline recommends that moderate-intensity statin therapy (e.g., lovastatin 40 mg once daily) be initiated or continued. In those with an estimated 10-year ASCVD risk of 7.5% or higher, it is reasonable to consider high-intensity statin therapy (i.e., with atorvastatin or rosuvastatin) unless contraindicated. In patients with diabetes mellitus who are younger than 40 or older than 75 years of age, it is reasonable to evaluate the potential benefits, adverse effects, drug interactions, and patient preferences when deciding to initiate, continue, or intensify statin therapy.

For primary prevention of cardiovascular disease in patients 40-75 years of age without clinical ASCVD or diabetes mellitus who have LDL-cholesterol concentrations of 70-189 mg/dL and an estimated 10-year ASCVD risk of 7.5% or higher, the ACC/AHA cholesterol management guideline recommends that moderate- (e.g., lovastatin 40 mg once daily) to high-intensity statin therapy (i.e., with atorvastatin or rosuvastatin) be initiated or continued. In those with an estimated 10-year ASCVD risk of 5 to less than 7.5%, it is reasonable to offer treatment with moderate-intensity statin therapy. Before initiating statin therapy for primary prevention of ASCVD in patients 40-75 years of age without clinical ASCVD or diabetes mellitus who have LDL-cholesterol concentrations of 70-189 mg/dL, it is reasonable for clinicians and patients to discuss the potential benefits, adverse effects, drug interactions, and patient preferences for such therapy.

Secondary Prevention

For secondary prevention of cardiovascular disease in patients 21-75 years of age with clinical ASCVD, the ACC/AHA cholesterol management guideline recommends that high-intensity statin therapy (i.e., with atorvastatin or rosuvastatin) be initiated or continued unless contraindicated. ( or .) In patients 21-75 years of age with clinical ASCVD who are at increased risk for developing statin-associated adverse effects or in whom high-intensity statin therapy is inappropriate or contraindicated, moderate-intensity statin therapy (e.g., lovastatin 40 mg once daily) should be given if tolerated. In patients older than 75 years of age with clinical ASCVD, use of statin therapy should be individualized based on the potential benefits, adverse effects, drug interactions, and patient preferences; it is reasonable to consider initiating or continuing moderate-intensity statin therapy in such patients if tolerated.

Dyslipidemias

Immediate-Release Tablets

The usual initial dosage of lovastatin as conventional tablets in adults is 20 mg once daily given with the evening meal. The manufacturer states that patients requiring reductions in LDL-cholesterol of 20% or greater should receive an initial lovastatin dosage of 20 mg daily; a dosage of 10 mg daily may be considered for patients requiring smaller reductions in LDL-cholesterol concentration. The recommended dosage range of lovastatin as conventional tablets in adults is 10-80 mg daily given a single dose or in 2 divided doses. The maximum recommended dosage of lovastatin is 80 mg daily. Twice-daily dosing of lovastatin has been used in most clinical studies in patients with heterozygous familial hypercholesterolemia and appears to be slightly but consistently more effective than once-daily dosing; however, once-daily dosing may be acceptable for patients in whom dosing convenience is considered important for compliance, particularly if only moderate degrees of hypercholesterolemia are present. When given as a single daily dose, lovastatin appears to be more effective when administered in the evening, possibly because cholesterol synthesis occurs mainly at night.

The recommended dosage range of lovastatin as conventional tablets for the management of heterozygous familial hypercholesterolemia in children 10-17 years of age is 10-40 mg daily. The manufacturer states that patients requiring reductions in LDL-cholesterol of 20% or greater should receive an initial lovastatin dosage of 20 mg daily; a dosage of 10 mg daily may be considered for patients requiring smaller reductions in LDL-cholesterol concentration. The maximum recommended dosage of lovastatin in children 10-17 years of age is 40 mg daily.

Extended-Release Tablets

The recommended dosage of lovastatin as extended-release tablets in adults ranges from 20 to 60 mg once daily.

In geriatric patients (65 years of age or older), the usual initial dosage of lovastatin as extended-release tablets is 20 mg once daily at bedtime. Higher dosages should be used only after careful consideration of the potential risks and benefits.(See Cautions: Geriatric Precautions.)

Concomitant Therapy

Because of an increased risk of myopathy/rhabdomyolysis, concomitant use of lovastatin with potent inhibitors of cytochrome P-450 (CYP) isoenzyme 3A4 (CYP3A4) (e.g., clarithromycin, cobicistat-containing preparations, erythromycin, HIV protease inhibitors, itraconazole, ketoconazole, nefazodone, posaconazole, telithromycin, voriconazole) is contraindicated. Concomitant use of lovastatin with cyclosporine or gemfibrozil should be avoided. In patients receiving danazol, diltiazem, dronedarone, or verapamil concomitantly with lovastatin, dosage of lovastatin should be initiated at 10 mg daily and should not exceed 20 mg daily. In patients receiving amiodarone concomitantly with lovastatin, dosage of lovastatin should not exceed 40 mg daily. In patients receiving ranolazine concomitantly with lovastatin, dosage adjustment of lovastatin may be considered.

In clinical studies in a limited number of patients, lovastatin dosages of 40-80 mg daily combined with colestipol hydrochloride dosages of 10-20 g daily or cholestyramine dosages of 4-24 g daily have resulted in additive or synergistic effects in reducing serum total and/or LDL-cholesterol concentrations.

Dosage Modification

The ACC/AHA cholesterol management guideline states that decreasing the statin dosage in adults may be considered when LDL-cholesterol concentrations are less than 40 mg/dL on 2 consecutive measurements; however, there are no data to suggest that LDL-cholesterol concentrations below 40 mg/dL would increase the risk of adverse effects.

Dosage in Renal and Hepatic Impairment

Although lovastatin is only minimally excreted in urine, the manufacturer states that the drug should be used with caution in patients with severe renal impairment (creatinine clearance less than 30 mL/minute); dosage increases above 20 mg daily should be carefully considered and, if deemed necessary, implemented with extreme caution. The manufacturer of the extended-release lovastatin preparation states that dosage increases above 20 mg daily should only be considered in patients with severe renal impairment if the expected benefits exceed the increased risk of myopathy and rhabdomyolysis.

Because the pharmacokinetics of lovastatin have not been studied in patients with hepatic dysfunction, the drug should be used with caution in patients who consume substantial amounts of alcohol and/or have a history of liver disease. Use of lovastatin is contraindicated in patients with active liver disease or unexplained, persistent elevations in serum aminotransferase concentrations.

Cautions

Lovastatin shares the toxic potentials of other statins, and the usual cautions, precautions, and contraindications associated with these drugs should be observed. Patients should be fully advised about the risks, especially rhabdomyolysis, associated with statin therapy alone or combined with other drugs. and also

Precautions and Contraindications

Lovastatin is contraindicated in patients with hypersensitivity to any component of the formulation; in patients with active liver disease or unexplained, persistent elevations of serum transaminases; in patients receiving concomitant therapy with potent inhibitors of cytochrome P-450 (CYP) isoenzyme 3A4 (CYP3A4) (e.g., clarithromycin, cobicistat-containing preparations, erythromycin, HIV protease inhibitors, itraconazole, ketoconazole, nefazodone, posaconazole, telithromycin, voriconazole); in pregnant or lactating women; and in women of childbearing age (unless these patients are unlikely to conceive).

Pediatric Precautions

In several randomized, double-blind, placebo-controlled studies in boys and postmenarchal girls 10-17 years of age with heterozygous familial hypercholesterolemia, the adverse effect profile of lovastatin (10-40 mg daily for at least 24 weeks) as conventional tablets generally was similar to that of placebo; dosages exceeding 40 mg daily have not been evaluated in this population. There were no detectable adverse effects on growth or sexual maturation in adolescent boys or on duration of menstrual cycle in girls. If therapy with lovastatin is considered, the manufacturer states that adolescent girls should be advised to use effective and appropriate contraceptive methods during therapy to reduce the likelihood of unintended pregnancy.(See Cautions: Pregnancy, Fertility, and Lactation.) Safety and efficacy of lovastatin have not been evaluated in prepubertal children or in children younger than 10 years of age.

Safety and efficacy of lovastatin as extended-release tablets have not been established in children or adolescents younger than 20 years of age. Therefore, the manufacturer states that this preparation should not be used in this population.

For additional information on the use of statins in pediatric patients, .

Geriatric Precautions

Results of a pharmacokinetic study in a limited number of patients receiving lovastatin (80 mg daily) as conventional tablets indicate that mean plasma levels of HMG-CoA reductase inhibitory activity are approximately 45% higher in geriatric patients (70-78 years of age) than in younger adults (18-30 years of age). However, data from clinical studies and other reported clinical experience employing various preparations of lovastatin suggest that safety and efficacy of the drug in geriatric patients appear to be similar to those in younger adults. Although dosage adjustment based on age-related pharmacokinetic differences does not appear to be necessary for geriatric patients, greater sensitivity in some older patients cannot be ruled out. Because advanced age (65 years of age or older) is a predisposing factor for myopathy, including rhabdomyolysis, the manufacturer states that lovastatin should be prescribed with caution in this population. Lower initial dosages of extended-release lovastatin are recommended in geriatric patients.(See Extended-Release Tablets under Dosage: Dyslipidemias, in Dosage and Administration.)

The ACC/AHA cholesterol management guideline states that initiation of statin therapy for primary prevention of atherosclerotic cardiovascular disease (ASCVD) in patients older than 75 years of age requires consideration of additional factors, including increasing comorbidities, safety considerations, and priorities of care. Therefore, the potential for an ASCVD risk reduction benefit, adverse effects, and drug interactions, along with patient preferences, must be considered before initiating statin therapy in patients older than 75 years of age.

Mutagenicity and Carcinogenicity

Lovastatin did not exhibit mutagenic potential in in vitro mammalian cell systems (rat or mouse hepatocytes, V-79 cell forward mutation study), in vitro (Chinese hamster ovary cell) or in vivo (mouse bone marrow) chromosomal aberration studies, or microbial (Ames test) systems with or without metabolic activation. There is some in vitro evidence, however, that inhibition of HMG-CoA reductase can inhibit DNA synthesis during the S phase of the cell life cycle; this inhibition appears to result from depletion of mevalonic acid and is independent of its conversion to cholesterol.

An increased incidence of hepatocellular carcinoma and adenoma was observed after 21 months in mice given oral lovastatin 500 mg/kg daily resulting in plasma concentrations up to 3-4 times the estimated human exposure; similar changes were not observed at oral dosages of 20 or 100 mg/kg daily resulting in plasma concentrations up to 0.3-2 times the estimated human exposure. An increased incidence of pulmonary adenomas also was observed in female mice receiving oral lovastatin 500 mg/kg daily (resulting in plasma concentrations up to 4 times the estimated human exposure), but the relationship of these adenomas to administration of the drug is not known since the incidence of these tumors was within the range of that found in untreated animals in studies of similar duration. Similar changes were not observed in female mice given oral dosages of 20 or 100 mg/kg daily or in male mice at any dosage.

In mice given oral lovastatin dosages of 100 or 500 mg/kg daily, an increase in the incidence of papilloma in the nonglandular mucosa of the stomach was observed. There is a strong association between the development of papilloma and hyperplasia of squamous epithelium (acanthosis) in this region of the stomach; such acanthosis in these rodents appears to be related to inhibition of HMG-CoA reductase in this nonglandular tissue. Since the glandular mucosa of the stomach in these rodents was not affected and the human stomach contains only glandular mucosa, the importance of this finding to humans is unclear. Also, although similar squamous epithelium is found in the esophagus and anorectal junction of the mouse and rat, no evidence of similar drug-induced hyperplasia was observed in these tissues in studies of up to 21 months in mice given oral lovastatin dosages up to 500 mg/kg daily or of up to 24 months in rats given 180 mg/kg daily (112 times the maximum recommended human dosage).

In a 24-month study in rats, hepatocellular carcinogenicity showed a positive relationship to lovastatin dosage in males, but the incidence of hepatocellular carcinogenicity in this study was similar to that observed spontaneously in this strain of rat.

An increased incidence of thyroid neoplasms has been observed in rats given statins, including lovastatin.

The relevance has not been established, but mevastatin (compactin, not commercially available) has been shown to enhance adhesion of metastatic melanoma cells to epithelial cells in vitro.

Pregnancy, Fertility, and Lactation

Pregnancy

Safety of lovastatin in pregnant women has not been established. Lovastatin should be discontinued as soon as pregnancy is recognized. Currently, most experts recommend that dyslipidemias in pregnant women be managed with dietary measures; consultation with a lipid specialist is recommended for pregnant women with severe forms of dyslipidemia.

Lovastatin has produced skeletal malformations in offspring of pregnant mice and rats receiving dosages of 80 mg/kg daily during gestation (7 times the human dose based on body surface area and 5 times the human exposure based on area under the plasma concentration-time curve [AUC], respectively). Administration of the active β,δ-dihydroxyacid form of lovastatin (mevinolinic acid) at 60 mg/kg daily produced similar skeletal malformations; these teratogenic effects were markedly or completely suppressed by concomitant administration of the inhibited product mevalonic acid but not by cholesterol coadministration. No evidence of malformations was observed when pregnant rabbits were given 5 mg/kg daily (equivalent to a human dose of 80 mg daily based on body surface area) or a maternally toxic dose of 15 mg/kg daily (3 times the human dose of 80 mg daily based on body surface area).

Cholesterol and other products of the cholesterol biosynthetic pathway are essential for fetal development, including synthesis of steroids and cell membranes. Because of the ability of statins such as lovastatin to decrease the synthesis of cholesterol and possibly other products of the cholesterol biosynthetic pathway, lovastatin may cause fetal harm when administered to pregnant women. Rarely, congenital anomalies have been reported clinically following intrauterine exposure to statins. In an analysis of more than 200 prospectively followed pregnancies exposed during the first trimester to lovastatin or another closely related statin, the incidence of congenital anomalies was comparable to that seen in the general population; this number of pregnancies was sufficient to exclude a threefold or greater increase in congenital anomalies over the background incidence.

Lovastatin is contraindicated in women who are or may become pregnant. The drug should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazard. If the patient becomes pregnant while receiving lovastatin, the drug should be discontinued immediately and the patient informed of the potential hazard to the fetus.

Fertility

Although the manufacturer states that reproduction studies in rats receiving lovastatin have not revealed evidence of impaired fertility, an increase in the rate of spontaneous testicular degeneration (i.e., testicular atrophy, decreased spermatogenesis, spermatocytic degeneration, and giant cell formation) was observed in dogs given oral lovastatin 20 mg/kg daily (12.5 times the maximum recommended human dosage) in a 1-year study; however, this effect was poorly reproducible and appeared to be unrelated to dosage. In a study in patients with type II hyperlipoproteinemia receiving oral lovastatin 40 mg daily for 4 months, there was a small but statistically significant reduction in sperm motility compared with that observed during dietary management alone but not compared with neomycin therapy. No alterations in sperm morphology or testicular dimensions or of biochemical indices of gonadal function (serum concentrations of testosterone, luteinizing hormone, follicle-stimulating hormone, prolactin) have been found in patients receiving lovastatin in clinical studies. However, at least one case of hypospermia, which resolved following discontinuance of lovastatin, has been reported.

Lactation

It is not known whether lovastatin is distributed into human milk; however, other statins are distributed into human milk. Because of the potential for serious adverse reactions from lovastatin in nursing infants, the drug is contraindicated in nursing women; women who require lovastatin therapy should not breast-feed their infants.