Lovastatin (Page 3 of 7)

CONTRAINDICATIONS

Hypersensitivity to any component of this medication.

Active liver disease or unexplained persistent elevations of serum transaminases (see WARNINGS).

Concomitant administration with strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and cobicistat-containing products) (see WARNINGS, Myopathy/Rhabdomyolysis).

Pregnancy and lactation (see PRECAUTIONS, Pregnancy and Nursing Mothers). Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. Moreover, cholesterol and other products of the cholesterol biosynthesis pathway are essential components for fetal development, including synthesis of steroids and cell membranes. Because of the ability of inhibitors of HMG-CoA reductase such as lovastatin to decrease the synthesis of cholesterol and possibly other products of the cholesterol biosynthesis pathway, lovastatin is contraindicated during pregnancy and in nursing mothers. Lovastatin should be administered to women of childbearing age only when such patients are highly unlikely to conceive. If the patient becomes pregnant while taking this drug, lovastatin should be discontinued immediately and the patient should be apprised of the potential hazard to the fetus (see PRECAUTIONS, Pregnancy).

WARNINGS

Myopathy/Rhabdomyolysis Lovastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma.

The risk of myopathy/rhabdomyolysis is dose related. In a clinical study (EXCEL) in which patients were carefully monitored and some interacting drugs were excluded, there was one case of myopathy among 4933 patients randomized to lovastatin 20 to 40 mg daily for 48 weeks, and 4 among 1649 patients randomized to 80 mg daily.

There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. .

All patients starting therapy with lovastatin, or whose dose of lovastatin is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing lovastatin. Lovastatin therapy should be discontinued immediately if myopathy is diagnosed or suspected. In most cases, muscle symptoms and CK increases resolved when treatment was promptly discontinued. Periodic CK determinations may be considered in patients starting therapy with lovastatin or whose dose is being increased, but there is no assurance that such monitoring will prevent myopathy.

Many of the patients who have developed rhabdomyolysis on therapy with lovastatin have had complicated medical histories, including renal insufficiency usually as a consequence of long-standing diabetes mellitus. Such patients merit closer monitoring. Lovastatin therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Lovastatin therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.

The risk of myopathy/rhabdomyolysis is increased by concomitant use of lovastatin with the following:

Strong inhibitors of CYP3A4: Lovastatin, like several other inhibitors of HMG-CoA reductase, is a substrate of cytochrome P450 3A4 (CYP3A4). Certain drugs which inhibit this metabolic pathway can raise the plasma levels of lovastatin and may increase the risk of myopathy. These include itraconazole, ketoconazole, posaconazole, voriconazole, the macrolide antibiotics erythromycin and clarithromycin, the ketolide antibiotic telithromycin, HIV protease inhibitors, boceprevir, telaprevir, the antidepressant nefazodone, or cobicistat-containing products. Combination of these drugs with lovastatin is contraindicated. If short-term treatment with strong CYP3A4 inhibitors is unavoidable, therapy with lovastatin should be suspended during the course of treatment (see CONTRAINDICATIONS; PRECAUTIONS, Drug Interactions).

Gemfibrozil: The combined use of lovastatin with gemfibrozil should be avoided.

Other lipid-lowering drugs (other fibrates or greater than or equal to 1 g/day of niacin): Caution should be used when prescribing other fibrates or lipid-lowering doses (greater than or equal to 1 g/day) of niacin with lovastatin, as these agents can cause myopathy when given alone. The benefit of further alterations in lipid levels by the combined use of lovastatin with other fibrates or niacin should be carefully weighed against the potential risks of these combinations.

Cyclosporine: The use of lovastatin with cyclosporine should be avoided.

Danazol, diltiazem, dronedarone or verapamil with higher doses of lovastatin: The dose of lovastatin should not exceed 20 mg daily in patients receiving concomitant medication with danazol, diltiazem, dronedarone, or verapamil. The benefits of the use of lovastatin in patients receiving danazol, diltiazem, dronedarone, or verapamil should be carefully weighed against the risks of these combinations.

Amiodarone: The dose of lovastatin should not exceed 40 mg daily in patients receiving concomitant medication with amiodarone. The combined use of lovastatin at doses higher than 40 mg daily with amiodarone should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy. The risk of myopathy/rhabdomyolysis is increased when amiodarone is used concomitantly with higher doses of a closely related member of the HMG-CoA reductase inhibitor class.

Colchicine: Cases of myopathy, including rhabdomyolysis, have been reported with lovastatin coadministered with colchicine, and caution should be exercised when prescribing lovastatin with colchicine (see PRECAUTIONS, Drug Interactions).

Ranolazine: The risk of myopathy, including rhabdomyolysis, may be increased by concomitant administration of ranolazine. Dose adjustment of lovastatin may be considered during co-administration with ranolazine.

Prescribing recommendations for interacting agents are summarized in Table VII (see also CLINICAL PHARMACOLOGY, Pharmacokinetics; PRECAUTIONS, Drug Interactions; DOSAGE AND ADMINISTRATION).

Table VII
Drug Interactions Associated with Increased
Risk of Myopathy/Rhabdomyolysis
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors, e.g.: Contraindicated with lovastatin
Ketoconazole
Itraconazole
Posaconazole
Voriconazole
Erythromycin
Clarithromycin
Telithromycin
HIV protease inhibitors
Boceprevir
Telaprevir
Nefazodone
Cobicistat-containing products
Gemfibrozil Avoid with lovastatin
Cyclosporine
Danazol Do not exceed 20 mg lovastatin daily
Diltiazem
Dronedarone
Verapamil
Amiodarone Do not exceed 40 mg lovastatin daily
Grapefruit juice Avoid grapefruit juice

Liver Dysfunction
Persistent increases (to more than 3 times the upper limit of normal) in serum transaminases occurred in 1.9% of adult patients who received lovastatin for at least one year in early clinical trials (see ADVERSE REACTIONS). When the drug was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pretreatment levels. The increases usually appeared 3 to 12 months after the start of therapy with lovastatin, and were not associated with jaundice or other clinical signs or symptoms. There was no evidence of hypersensitivity. In the EXCEL study (see CLINICAL PHARMACOLOGY, Clinical Studies), the incidence of persistent increases in serum transaminases over 48 weeks was 0.1% for placebo, 0.1% at 20 mg/day, 0.9% at 40 mg/day, and 1.5% at 80 mg/day in patients on lovastatin. However, in post-marketing experience with lovastatin, symptomatic liver disease has been reported rarely at all dosages (see ADVERSE REACTIONS).

In AFCAPS/TexCAPS, the number of participants with consecutive elevations of either alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (greater than 3 times the upper limit of normal), over a median of 5.1 years of follow-up, was not significantly different between the lovastatin and placebo groups (18 [0.6%] vs. 11 [0.3%]). The starting dose of lovastatin was 20 mg/day; 50% of the lovastatin treated participants were titrated to 40 mg/day at Week 18. Of the 18 participants on lovastatin with consecutive elevations of either ALT or AST, 11 (0.7%) elevations occurred in participants taking 20 mg/day, while 7 (0.4%) elevations occurred in participants titrated to 40 mg/day. Elevated transaminases resulted in discontinuation of 6 (0.2%) participants from therapy in the lovastatin group (n=3,304) and 4 (0.1%) in the placebo group (n=3,301).

It is recommended that liver enzyme tests be obtained prior to initiating therapy with lovastatin and repeated as clinically indicated.

There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including lovastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with lovastatin, promptly interrupt therapy. If an alternate etiology is not found do not restart lovastatin.

The drug should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver disease or unexplained transaminase elevations are contraindications to the use of lovastatin.

Moderate (less than three times the upper limit of normal) elevations of serum transaminases have been reported following therapy with lovastatin (see ADVERSE REACTIONS). These changes appeared soon after initiation of therapy with lovastatin, were often transient, were not accompanied by any symptoms and interruption of treatment was not required.

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