Mevacor

Clinically evident bleeding and/or increased prothrombin time have been reported occasionally in patients taking coumarin anticoagulants concomitantly with lovastatin. It is recommended that in patients taking anticoagulants, prothrombin time be determined before starting lovastatin and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at intervals usually recommended for patients on coumarin anticoagulants. If the dose of lovastatin is changed, the same procedure should be repeated. Lovastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.

Hyperkalemia associated with myositis (myalgia and elevated CK) has been reported in the case of a single patient with insulin-dependent diabetes mellitus and mild renal insufficiency who received MEVACOR concomitantly with an angiotensin-converting enzyme inhibitor (lisinopril).

The risk of myopathy/rhabdomyolysis is increased when verapamil is used concomitantly with higher doses of a closely related member of the HMG-CoA reductase inhibitor class (see Warnings and Precautions, Myopathy/Rhabdomyolysis Caused by Drug Interactions).

Preliminary evidence suggests that the cholesterol lowering effects of MEVACOR and the bile acid sequestrant, cholestyramine, are additive.

When MEVACOR is used concurrently with cholestyramine or any other resin, an interval of at least two hours should be maintained between the two drugs, since the absorption of MEVACOR may be impaired by the resin.

The risk of myopathy/rhabdomyolysis is increased by concomitant administration of cyclosporine or danazol particularly with higher doses of lovastatin (see Warnings and Precautions, Myopathy/Rhabdomyolysis).

In patients with hypercholesterolemia, concomitant administration of lovastatin and digoxin had no effect on digoxin plasma concentrations.

Grapefruit juice contains one or more components that inhibit CYP3A4 and can increase the plasma levels of drugs metabolized by CYP3A4. The effect of typical consumption (one 250 mL glass daily) is minimal (34% increase in active plasma HMG-CoA reductase inhibitory activity as measured by the area under the concentration-time curve) and of no clinical relevance. However, very large quantities (over 1 liter daily) significantly increase the plasma levels of HMG-CoA reductase inhibitory activity during lovastatin therapy and should be avoided (see Warnings and Precautions, Myopathy/Rhabdomyolysis Caused by Drug Interactions).

See Warnings and Precautions, Measures to reduce the risk of myopathy/rhabdomyolysis caused by drug interactions.

Lovastatin may elevate creatine phosphokinase and transaminase levels (see Adverse Reactions, Laboratory Tests). In the differential diagnosis of chest pain in a patient on therapy with MEVACOR, cardiac and non cardiac fractions of these enzymes should be determined.

These drugs increase the risk of myopathy when given concomitantly with lovastatin, probably because they can produce myopathy when given alone (see Warnings and Precautions, Myopathy/Rhabdomyolysis Caused by Drug Interactions). There is no evidence to suggest that these agents affect the pharmacokinetics of lovastatin.

Myopathy, including rhabdomyolysis, has occurred in patients who were receiving coadministration of MEVACOR with fibric acid derivatives or niacin, particularly in subjects with pre-existing renal insufficiency (see Warnings and Precautions, Myopathy/Rhabdomyolysis Caused by Drug Interactions).

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 (see Warnings and Precautions, Myopathy/Rhabdomyolysis Caused by Drug Interactions).

In healthy volunteers, the coadministration of propranolol and lovastatin resulted in a slight decrease of the AUC of lovastatin and its metabolites as well as in a significant decrease of the C_max for the lovastatin metabolites.

However there was no clinically relevant interaction reported in patients who have been receiving MEVACOR concomitantly with beta adrenergic blocking agents.

Although specific interaction studies were not performed, in clinical studies, MEVACOR was used concomitantly with a number of diuretics and nonsteroidal anti inflammatory drugs (NSAIDs), hypoglycemic drugs (chlorpropamide, glipizide, glyburide, insulin), without evidence, to date, of clinically significant adverse interactions.

Combined drug therapy should be approached with caution as information from controlled studies is limited. Based on post-marketing surveillance, gemfibrozil, other fibrates and lipid lowering doses of niacin (nicotinic acid) may increase the risk of myopathy when given concomitantly with HMG-CoA reductase inhibitors, probably because they can produce myopathy when given alone (see below and Warnings and Precautions, Muscle Effects). Therefore, combined drug therapy should be approached with caution.

Lovastatin has no CYP3A4 inhibitory activity; therefore, it is not expected to affect the plasma levels of other drugs metabolized by CYP3A4. However, lovastatin itself is a substrate for CYP3A4. Potent inhibitors of CYP3A4 increase the risk of myopathy by increasing the plasma levels of HMG CoA reductase inhibitory activity during lovastatin therapy. These inhibitors include itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, and nefazodone (see Warnings and Precautions, Myopathy/Rhabdomyolysis Caused by Drug Interactions).

Patients on fusidic acid (oral or IV) treated concomitantly with lovastatin may have an increased risk of myopathy/rhabdomyolysis (see Warnings and Precautions, Muscle Effects, Other drugs). No clinical data is available regarding drug interaction between fusidic acid and lovastatin.

Patients should be placed on a standard cholesterol-lowering diet before receiving MEVACOR and should continue on this diet during treatment with MEVACOR. If appropriate, a program of weight control and physical exercise should be implemented.

If a tablet is missed at its usual time, it should be taken as soon as possible. But, if it is too close to the time of the next dose: only the prescribed dose should be taken at the appointed time. A double dose should not be taken.

insomnia, paresthesia.

acid regurgitation, dry mouth, vomiting.

The following adverse events have also been reported during post-marketing experience with MEVACOR, regardless of causality assessment: hepatitis, cholestatic jaundice, vomiting, anorexia, paresthesia, peripheral neuropathy, psychiatric disturbances including anxiety, alopecia, erythema multiforme, including Stevens-Johnson syndrome and toxic epidermal necrolysis.

Gynecomastia has been reported following treatment with other HMG-CoA reductase inhibitors.

An apparent hypersensitivity syndrome has been reported rarely which has included one or more of the following features: anaphylaxis, angioedema, lupus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, thrombocytopenia, leukopenia, eosinophilia, hemolytic anemia, positive ANA, ESR increase, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, flushing, chills, dyspnea and malaise.

Visual evoked response, nerve conduction measurements and electromyography in over 30 patients showed no evidence of neurotoxic effects of lovastatin.

leg pain, shoulder pain, arthralgia.

See Warnings and Precautions.

eye irritation.

No significant difference was found among the different treatment groups including placebo in the incidence of serious clinical adverse experiences including death due to CHD, nonfatal myocardial infarction, cancer, and deaths due to all causes. This study was not designed or powered to evaluate the incidence of these serious clinical adverse experiences. The EXCEL study included a minority of patients at risk of or with coronary artery disease; however, its findings cannot be extrapolated in this respect to other segments of the high-risk population.

alopecia, pruritus.

Marked persistent increases of serum transaminases have been noted (see Warnings and Precautions, Myopathy/Rhabdomyolysis).

Other liver function test abnormalities including elevated alkaline phosphatase and bilirubin have been reported. In the EXCEL study, 7.3% of the patients on lovastatin had elevations of CK levels of at least twice the normal value on one or more occasions compared to 6.2% on placebo.

The EXCEL study, however, excluded patients with factors known to be associated with an increased risk of myopathy (see Warnings and Precautions, Myopathy/Rhabdomyolysis and Drug Interactions, Drug-Laboratory Test Interactions).

chest pain.

Other clinical adverse reactions reported as possibly, probably or definitely drug related in 0.5 to 1.0% of patients in any drug treated group are listed below. In all these cases the incidence with drug or placebo was not statistically different.

MEVACOR was also found to slow the progression of coronary atherosclerosis in patients with coronary heart disease as part of a treatment strategy to lower total and LDL-C to the desired levels. In two trials including this type of patient, i.e. in a secondary prevention intervention, MEVACOR monotherapy was shown to slow the progression of coronary atherosclerosis as evaluated by computerized quantitative coronary angiography (QCA). This effect, however, was not accompanied by an improvement in the clinical endpoints (death, fatal/nonfatal myocardial infarction, hospitalization for unstable angina, and coronary revascularization procedure [PTCA and CABG]) within the 2-2½ years' trial period. These trials, however, were not designed to demonstrate a reduction in the risk of coronary morbidity and mortality.

The effect of lovastatin on the progression of atherosclerosis in the coronary arteries has been corroborated by similar findings in carotid vasculature. In the Asymptomatic Carotid Artery Progression Study (ACAPS) which included hyperlipidemic patients with early asymptomatic carotid lesions and without known coronary artery disease, the effect of therapy with lovastatin on carotid atherosclerosis was assessed by B-mode ultrasonography. There was a significant regression of carotid lesions in patients receiving lovastatin alone compared to those receiving placebo alone. The predictive value of changes in the carotid vasculature for stroke has not yet been established. In the lovastatin group there was a significant reduction in the number of patients with major cardiovascular events relative to the placebo group (5 vs 14) and a significant reduction in all-cause mortality (1 vs 8) however, it was not powered to demonstrate a reduction in the risk of coronary morbidity and mortality. This trial should be viewed as supportive and complementary to the others mentioned above.

MEVACOR (lovastatin tablets) is indicated as an adjunct to diet, at least equivalent to the American Heart Association (AHA) Step 1 diet, for the reduction of elevated total and Low Density Lipoprotein Cholesterol (LDL-C) levels in patients with primary hypercholesterolemia (Types IIa and IIb), (a disorder of lipid metabolism characterized by elevated serum cholesterol levels in association with normal triglyceride levels (Type IIa) or with increased triglyceride levels [Type IIb]) when the response to diet and other nonpharmacological measures alone has been inadequate.

After establishing that the elevation in plasma lipids represents a primary disorder not due to secondary conditions such as poorly controlled diabetes mellitus, hypothyroidism, the nephrotic syndrome, liver disease, or dysproteinemias, prospective patient should have an elevated LDL-C level as the cause for an elevated total serum cholesterol. This may be particularly relevant for patients with total triglycerides (TG) over 4.52 mmol/L (400 mg/dL) or with markedly elevated High Density Lipoprotein Cholesterol (HDL-C) values, where non-LDL lipoprotein fractions may contribute significantly to total cholesterol levels without apparent increase in cardiovascular risk. In general, LDL-C may be estimated according to the following equations:

LDL-C (mmol/L) = Total cholesterol − [(0.37×triglycerides) + HDL-C]

LDL-C (mg/dL) = Total cholesterol − [(0.16×triglycerides) + HDL-C]

When total triglycerides are greater than 4.52 mmol/L (400 mg/dL) this equation is not applicable. In such patients, LDL-C may be obtained by ultracentrifugation.

Each green-colored, octagon-shaped, flat, bevelled-edge tablet, engraved with MSD 732 on one side and plain on the other side, contains: lovastatin 40 mg. Nonmedicinal ingredients: butylated hydroxyanisole, indigotine and Quinoline yellow both on alumina substratum, lactose, magnesium stearate, microcrystalline cellulose and pregelatinized starch. Blister packages of 28.

Each light blue-colored, octagon-shaped, flat, bevelled-edge tablet, engraved with MSD 731 on one side and plain on the other side, contains: lovastatin 20 mg. Nonmedicinal ingredients: butylated hydroxyanisole, indigotine on alumina, lactose, magnesium stearate, microcrystalline cellulose and pregelatinized starch. Blister packages of 28.

Because MEVACOR does not undergo significant renal excretion, modification of dosage should not be necessary in patients with moderate renal insufficiency.

In patients with severe renal insufficiency (creatinine clearance <0.5 mL/s [30 mL/min]), dosages above 20 mg/day should be carefully considered and, if deemed necessary, implemented cautiously (see Warnings and Precautions, Myopathy/Rhabdomyolysis).

Effects on skeletal muscle such as myalgia, myopathy and, rarely, rhabdomyolysis have been reported in patients treated with MEVACOR.

Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria, have been reported with MEVACOR and with other HMG-CoA reductase inhibitors.

Myopathy, defined as muscle pain or muscle weakness in conjunction with increases in creatine phosphokinase (CK) values to greater than ten times the upper limit of normal (ULN), should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or a marked elevation of CK. Patients should be advised to report promptly any unexplained muscle pain, tenderness or weakness, particularly if associated with malaise or fever. Patients who develop any signs or symptoms suggestive of myopathy should have their CK levels measured. MEVACOR therapy should be immediately discontinued if markedly elevated CK levels are measured or myopathy is diagnosed or suspected. 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 with dosage and by high levels of HMG-CoA reductase inhibitory activity in plasma.

General measures: 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. Lovastatin therapy should be discontinued immediately if myopathy is diagnosed or suspected. The presence of these symptoms, and/or a CK level >10 times the upper limit of normal indicates myopathy. In most cases, when patients were promptly discontinued from treatment, muscle symptoms and CK increases resolved. 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. Therapy with lovastatin should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.

Potent inhibitors of CYP3A4, e.g., the antifungal azoles itraconazole, and ketoconazole, the antibiotics erythromycin, clarithromycin and telithromycin, the HIV protease inhibitors, or the antidepressant nefazodone, particularly with higher doses of lovastatin (see Drug Interactions, Cytochrome P-450 Inhibitors (CYP3A4).

HMG-CoA reductase inhibitors interfere with cholesterol synthesis and as such might theoretically blunt adrenal and/or gonadal steroid production. Clinical studies with lovastatin have shown that this agent does not reduce plasma cortisol concentration or impair adrenal reserve, and does not reduce basal plasma testosterone concentration. However, the effects of HMG-CoA reductase inhibitors on male fertility have not been studied in an adequate number of patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown.

Patients treated with lovastatin who develop clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should be exercised if an HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is administered to patients receiving other drugs (e.g. ketoconazole, spironolactone, or cimetidine) that may decrease the levels of endogenous steroid hormones (see Drug Interactions, Cytochrome P-450 Inhibitors (CYP3A4).

Current long-term data from clinical trials do not indicate an adverse effect of lovastatin on the human lens.

Limited experience is available in children. However, safety and effectiveness in children have not been established.

MEVACOR is contraindicated during pregnancy.

Safety in pregnant women has not been established. No controlled clinical trials with lovastatin have been conducted in pregnant women. Rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors have been received. However, in an analysis of approximately 200 prospectively followed pregnancies exposed during the first trimester to MEVACOR or another closely related HMG-CoA reductase inhibitor, the incidence of congenital anomalies was comparable to that seen in the general population. This number of pregnancies was statistically sufficient to exclude a 2.5-fold or greater increase in congenital anomalies over the background incidence.

Atherosclerosis is a chronic process, and ordinarily, discontinuation of lipid-lowering drugs during pregnancy should have little impact on the long-term risk associated with primary hypercholesterolemia. Although there is no evidence that the incidence of congenital anomalies in offspring of patients taking MEVACOR or another closely related HMG-CoA reductase inhibitor differs from that observed in the general population, maternal treatment with MEVACOR may reduce the fetal levels of mevalonate which is a precursor of cholesterol biosynthesis. For these reasons, MEVACOR should not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with MEVACOR should be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant. (See Contraindications.)

In the initial controlled clinical trials performed in 695 patients, marked persistent increases (to more than 3 times the upper limit of normal) in serum transaminases occurred in 1.6% of adult patients who received MEVACOR for at least one year (see Adverse Reactions, Laboratory Tests). When the drug was interrupted or discontinued in these patients, the transaminase levels fell slowly to pretreatment levels. The increases usually appeared 3 to 12 months after the start of therapy with MEVACOR. In most cases they were not associated with jaundice or other clinical signs or symptoms (see Drug Interactions and Adverse Reactions, Post-Market Adverse Drug Reactions).

In the 48-week EXCEL study performed in 8245 patients suffering from moderate hypercholesterolemia, the incidence of marked (more than 3 times the upper limit of normal) increases in serum transaminases on successive testing was 0.1% in patients receiving a placebo and 0.1% at 20 mg/day, 0.9% at 40 mg/day and 1.5% at 80 mg/day in patients administered lovastatin.

It is recommended that liver function tests be performed at baseline and periodically thereafter in all patients. Particular attention should be paid to patients who develop elevated serum transaminase levels and in patients in whom the dose is increased to 40 mg/day or more. In these patients, measurements should be repeated promptly and then performed more frequently.

If the transaminase levels show evidence of progression, particularly if they rise to three times the upper limit of normal and are persistent, the drug should be discontinued.

MEVACOR, as well as other HMG-CoA reductase inhibitors, 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 serum transaminase elevations are contraindications to the use of MEVACOR; if such condition develops during therapy, the drug should be discontinued.

Moderate elevations of serum transaminases (less than three times the upper limit of normal) have been reported following therapy with MEVACOR (see Adverse Reactions). These changes were not specific to MEVACOR and were also observed with comparative lipid metabolism regulators. They generally appeared within the first 3 months after initiation of therapy, were often transient and were not accompanied by any other symptoms. They did not necessitate interruption of treatment.

MEVACOR is not effective or is less effective in patients with rare homozygous familial hypercholesterolemia.

Lipid-lowering drugs that can cause myopathy when given alone: Gemfibrozil, other fibrates, or lipid-lowering doses (≥1 g/day) of niacin, particularly with higher doses of lovastatin (see Drug Interactions, Gemfibrozil and Other Fibrates, Lipid-Lowering Doses (≥1 g/day) of Niacin (nicotinic acid).

The risk of myopathy/rhabdomyolysis is dose related. In a clinical study Expanded Clinical Evaluation of Lovastatin (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.

Before instituting therapy with MEVACOR, an attempt should be made to control hypercholesterolemia with appropriate diet, exercise, weight reduction in overweight and obese patients, and to treat other underlying medical problems (see Indications and Clinical Use). The patient should be advised to inform subsequent physicians of the prior use of MEVACOR or any other lipid metabolism regulator.

The effects of lovastatin induced changes in lipoprotein levels, including reduction of serum cholesterol, on cardiovascular morbidity or mortality or total mortality has not been established.

The use of HMG-CoA reductase inhibitors has been associated with severe myopathy, including rhabdomyolysis, which may be more frequent when they are co-administered with drugs that inhibit the cytochrome P-450 enzyme system. Lovastatin is metabolized by the cytochrome P-450 isoform 3A4 and as such may interact with agents which inhibit this enzyme (see Warnings and Precautions, Myopathy/Rhabdomyolysis and Drug Interactions, Cytochrome P-450 Inhibitors (CYP3A4).

MEVACOR, as with other HMG-CoA reductase inhibitors, should be prescribed with caution in patients with pre-disposing factors for myopathy/rhabdomyolysis. Such factors include: personal or family history of hereditary muscular disorders; previous history of muscle toxicity with another HMG-CoA reductase inhibitor; concomitant use of a fibrate or niacin; hypothyroidism; alcohol abuse; excessive physical exercise; age >70 years; renal impairment; hepatic impairment; diabetes with hepatic fatty change; surgery and trauma; frailty; situations where an increase in plasma levels of active ingredient may occur (see Drug Interactions, Drug-Drug Interactions).

MEVACOR therapy should be temporarily withheld or discontinued in any patient with an acute serious condition suggestive of myopathy or predisposing to the development of rhabdomyolysis (e.g. sepsis, hypotension, major surgery, trauma, severe metabolic endocrine and electrolyte disorders, or uncontrolled seizures).

In patients over 60 years, efficacy appeared similar to that seen in the population as a whole, with no apparent increase in the frequency of clinical or laboratory adverse findings.

Elderly patients may be more susceptible to myopathy (see Warnings and Precautions, Muscle Effects, Pre-disposing Factors for Myopathy/Rhabdomyolysis).

A significant decrease in plasma CoQ₁₀ levels in patients treated with MEVACOR and other statins has been observed in short-term clinical trials. The clinical significance of a potential long-term statin-induced deficiency of CoQ₁₀ has not yet been established.

To date, hypersensitivity syndrome has not been described. In a few instances eosinophilia and skin eruptions appear to be associated with lovastatin treatment. If hypersensitivity is suspected, MEVACOR should be discontinued.

Higher dosages (80 mg/day) required for some patients with severe hypercholesterolemia are associated with increased plasma levels of lovastatin.

Caution should be exercised in such patients who are also significantly renally impaired, elderly or are concomitantly administered P-450 inhibitors (see Warnings and Precautions, Myopathy/Rhabdomyolysis and Drug Interactions).

In some patients the beneficial effect of lowered total cholesterol and LDL-C levels may be partly blunted by a concomitant increase in the Lp(a) levels. Until further experience is obtained from controlled clinical trials, it is suggested, where feasible, that Lp(a) measurements be carried out in patients placed on therapy with MEVACOR.

It is not known whether MEVACOR is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from MEVACOR, women taking MEVACOR should not nurse their infant (see Contraindications).

Lovastatin has complex pharmacokinetic characteristics.

MEVACOR is a cholesterol lowering agent isolated from a strain of A. terreus. After oral ingestion, lovastatin, which is an inactive lactone, is hydrolyzed to the corresponding β-hydroxy acid form. This principal metabolite is a specific 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 reduces cholesterol production by the liver and induces some changes in cholesterol transport and disposition in the blood and tissues. The mechanism(s) of this effect is believed to involve both reduction of the synthesis of Low Density Lipoprotein (LDL), and an increase in LDL catabolism as a result of induction of the hepatic LDL receptors.

Lovastatin is metabolized by the microsomal hepatic enzyme system (Cytochrome P-450 isoform 3A4 system). The major active metabolites present in human plasma are the β-hydroxy acid of lovastatin, its 6'-hydroxy, 6'-hydroxymethyl, and 6'-exomethylene derivatives.