Mevacor

Mevacor

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Side Effects & Adverse Reactions

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 20-40 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; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.

All patients starting therapy with MEVACOR, or whose dose of MEVACOR 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 MEVACOR. MEVACOR 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 MEVACOR 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. MEVACOR therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. MEVACOR 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 ≥1 g/day of niacin): Caution should be used when prescribing other fibrates or lipid-lowering doses (≥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.:
Ketoconazole
Itraconazole
Posaconazole
Voriconazole
Erythromycin
Clarithromycin
Telithromycin
HIV protease inhibitors
Boceprevir
Telaprevir
Nefazodone
Cobicistat-containing products
Contraindicated with lovastatin
Gemfibrozil
Cyclosporine
Avoid with lovastatin

Danazol
Diltiazem
Dronedarone
Verapamil

Do not exceed 20 mg lovastatin daily
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 MEVACOR, 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) (> 3 times the upper limit of normal), over a median of 5.1 years of follow-up, was not significantly different between the MEVACOR and placebo groups (18 [0.6%] vs. 11 [0.3%]). The starting dose of MEVACOR was 20 mg/day; 50% of the MEVACOR treated participants were titrated to 40 mg/day at Week 18. Of the 18 participants on MEVACOR 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 MEVACOR 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 MEVACOR 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 MEVACOR, promptly interrupt therapy. If an alternate etiology is not found do not restart MEVACOR.

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 MEVACOR (see ADVERSE REACTIONS). These changes appeared soon after initiation of therapy with MEVACOR, were often transient, were not accompanied by any symptoms and interruption of treatment was not required.

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Uses

Therapy with MEVACOR should be a component of multiple risk factor intervention in those individuals with dyslipidemia at risk for atherosclerotic vascular disease. MEVACOR should be used in addition to a diet restricted in saturated fat and cholesterol as part of a treatment strategy to lower total‑C and LDL‑C to target levels when the response to diet and other nonpharmacological measures alone has been inadequate to reduce risk.

Primary Prevention of Coronary Heart Disease

In individuals without symptomatic cardiovascular disease, average to moderately elevated total‑C and LDL‑C, and below average HDL‑C, MEVACOR is indicated to reduce the risk of:

- Myocardial infarction
- Unstable angina
- Coronary revascularization procedures

(See CLINICAL PHARMACOLOGY, Clinical Studies.)

Coronary Heart Disease

MEVACOR is indicated to slow the progression of coronary atherosclerosis in patients with coronary heart disease as part of a treatment strategy to lower total‑C and LDL‑C to target levels.

Hypercholesterolemia

Therapy with lipid-altering agents should be a component of multiple risk factor intervention in those individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. MEVACOR is indicated as an adjunct to diet for the reduction of elevated total‑C and LDL‑C levels in patients with primary hypercholesterolemia (Types IIa and IIb2), when the response to diet restricted in saturated fat and cholesterol and to other nonpharmacological measures alone has been inadequate.

2

Classification of Hyperlipoproteinemias

Lipoproteins Lipid Elevations
Type elevated major minor
IDL = intermediate-density lipoprotein.
I chylomicrons TG ↑→C
IIa LDL C
IIb LDL, VLDL C TG
III (rare) IDL C/TG
IV VLDL TG ↑→C
V (rare) chylomicrons, VLDL TG ↑→C
Adolescent Patients with Heterozygous Familial Hypercholesterolemia

MEVACOR is indicated as an adjunct to diet to reduce total‑C, LDL‑C and apolipoprotein B levels in adolescent boys and girls who are at least one year post-menarche, 10-17 years of age, with heFH if after an adequate trial of diet therapy the following findings are present:

  1. LDL-C remains >189 mg/dL or
  2. LDL-C remains >160 mg/dL and:
    • there is a positive family history of premature cardiovascular disease or
    • two or more other CVD risk factors are present in the adolescent patient
General Recommendations

Prior to initiating therapy with lovastatin, secondary causes for hypercholesterolemia (e.g., poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver disease, other drug therapy, alcoholism) should be excluded, and a lipid profile performed to measure total‑C, HDL‑C, and TG. For patients with TG less than 400 mg/dL (<4.5 mmol/L), LDL‑C can be estimated using the following equation:

LDL-C = total-C – [0.2 × (TG) + HDL-C]

For TG levels >400 mg/dL (>4.5 mmol/L), this equation is less accurate and LDL‑C concentrations should be determined by ultracentrifugation. In hypertriglyceridemic patients, LDL‑C may be low or normal despite elevated total‑C. In such cases, MEVACOR is not indicated.

The National Cholesterol Education Program (NCEP) Treatment Guidelines are summarized below:

NCEP Treatment Guidelines: LDL‑C Goals and Cutpoints for Therapeutic Lifestyle Changes and Drug Therapy in Different Risk Categories
Risk Category LDL Goal (mg/dL) LDL Level at Which to
Initiate Therapeutic Lifestyle Changes
(mg/dL)
LDL Level at Which to
Consider Drug Therapy
(mg/dL)
*
CHD, coronary heart disease
Some authorities recommend use of LDL-lowering drugs in this category if an LDL‑C level of <100 mg/dL cannot be achieved by therapeutic lifestyle changes. Others prefer use of drugs that primarily modify triglycerides and HDL‑C, e.g., nicotinic acid or fibrate. Clinical judgment also may call for deferring drug therapy in this subcategory.
Almost all people with 0–1 risk factor have a 10-year risk<10%; thus, 10-year risk assessment in people with 0–1 risk factor is not necessary.
CHD* or CHD risk equivalents
(10-year risk >20%)

<100 ≥100 ≥130
(100–129: drug optional)†
2+ Risk factors
(10 year risk ≤20%)

<130 ≥130 10-year risk 10–20%: ≥130
10-year risk <10%: ≥ 160
0–1 Risk factor‡ <160 ≥160 ≥190
(160–189: LDL-lowering drug optional)

After the LDL‑C goal has been achieved, if the TG is still ≥200 mg/dL, non-HDL‑C (total‑C minus HDL‑C) becomes a secondary target of therapy. Non-HDL‑C goals are set 30 mg/dL higher than LDL‑C goals for each risk category.

At the time of hospitalization for an acute coronary event, consideration can be given to initiating drug therapy at discharge if the LDL‑C is ≥130 mg/dL (see NCEP Guidelines above).

Since the goal of treatment is to lower LDL‑C, the NCEP recommends that LDL‑C levels be used to initiate and assess treatment response. Only if LDL‑C levels are not available, should the total‑C be used to monitor therapy.

Although MEVACOR may be useful to reduce elevated LDL‑C levels in patients with combined hypercholesterolemia and hypertriglyceridemia where hypercholesterolemia is the major abnormality (Type IIb hyperlipoproteinemia), it has not been studied in conditions where the major abnormality is elevation of chylomicrons, VLDL or IDL (i.e., hyperlipoproteinemia types I, III, IV, or V).2

The NCEP classification of cholesterol levels in pediatric patients with a familial history of hypercholesterolemia or premature cardiovascular disease is summarized below:

    Category Total-C (mg/dL) LDL-C (mg/dL)
    Acceptable <170 <110
    Borderline 170–199 110–129
    High ≥200 ≥130

Children treated with lovastatin in adolescence should be re-evaluated in adulthood and appropriate changes made to their cholesterol-lowering regimen to achieve adult goals for LDL‑C.

History

There is currently no drug history available for this drug.

Other Information

MEVACOR® (Lovastatin) is a cholesterol lowering agent isolated from a strain of Aspergillus terreus. After oral ingestion, lovastatin, which is an inactive lactone, is hydrolyzed to the corresponding β‑hydroxyacid form. This is a principal metabolite and an inhibitor of 3‑hydroxy-3‑methylglutaryl-coenzyme A (HMG‑CoA) reductase. This enzyme catalyzes the conversion of HMG‑CoA to mevalonate, which is an early and rate limiting step in the biosynthesis of cholesterol.

Lovastatin is [1S-[1α(R*),3α,7β,8β(2S*,4S*), 8aβ]]-1,2,3,7, 8,8a‑hexahydro-3,7‑dimethyl-8-[2‑(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2‑yl)ethyl]-1-naphthalenyl 2-methylbutanoate. The empirical formula of lovastatin is C24H36O5 and its molecular weight is 404.55. Its structural formula is:

image of lovastatin chemical structure

Lovastatin is a white, nonhygroscopic crystalline powder that is insoluble in water and sparingly soluble in ethanol, methanol, and acetonitrile.

Tablets MEVACOR are supplied as 20 mg and 40 mg tablets for oral administration. In addition to the active ingredient lovastatin, each tablet contains the following inactive ingredients: cellulose, lactose, magnesium stearate, and starch. Butylated hydroxyanisole (BHA) is added as a preservative. Tablets MEVACOR 20 mg also contain FD&C Blue 2 aluminum lake. Tablets MEVACOR 40 mg also contain D&C Yellow 10 aluminum lake and FD&C Blue 2 aluminum lake.

Mevacor Manufacturers


  • Merck Sharp & Dohme Corp.
    Mevacor (Lovastatin) Tablet [Merck Sharp & Dohme Corp.]

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