Mevacor Information
Mevacor (Lovastatin) Description
Mevacor (Lovastatin) is a cholesterol lowering agent isolated from a strain of . 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 [1-[1α(*),3α,7β,8β(2*,4*), 8aβ]]-1,2,3,7, 8,8a‑hexahydro-3,7‑dimethyl-8-[2‑(tetrahydro-4-hydroxy-6-oxo-2-pyran-2‑yl)ethyl]-1-naphthalenyl 2-methylbutanoate. The empirical formula of lovastatin is CHO and its molecular weight is 404.55. Its structural formula is:
Lovastatin is a white, nonhygroscopic crystalline powder that is insoluble in water and sparingly soluble in ethanol, methanol, and acetonitrile.
Tablets Mevacor (Lovastatin) 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 (Lovastatin) 20 mg also contain FD&C Blue 2 aluminum lake. Tablets Mevacor (Lovastatin) 40 mg also contain D&C Yellow 10 aluminum lake and FD&C Blue 2 aluminum lake.
Mevacor (Lovastatin) Clinical Pharmacology
The involvement of low-density lipoprotein cholesterol (LDL‑C) in atherogenesis has been well-documented in clinical and pathological studies, as well as in many animal experiments. Epidemiological and clinical studies have established that high LDL‑C and low high-density lipoprotein cholesterol (HDL‑C) are both associated with coronary heart disease. However, the risk of developing coronary heart disease is continuous and graded over the range of cholesterol levels and many coronary events do occur in patients with total cholesterol (total‑C) and LDL‑C in the lower end of this range.
Mevacor (Lovastatin) has been shown to reduce both normal and elevated LDL‑C concentrations. LDL is formed from very low-density lipoprotein (VLDL) and is catabolized predominantly by the high affinity LDL receptor. The mechanism of the LDL-lowering effect of Mevacor (Lovastatin) may involve both reduction of VLDL‑C concentration, and induction of the LDL receptor, leading to reduced production and/or increased catabolism of LDL‑C. Apolipoprotein B also falls substantially during treatment with Mevacor (Lovastatin) . Since each LDL particle contains one molecule of apolipoprotein B, and since little apolipoprotein B is found in other lipoproteins, this strongly suggests that Mevacor (Lovastatin) does not merely cause cholesterol to be lost from LDL, but also reduces the concentration of circulating LDL particles. In addition, Mevacor (Lovastatin) can produce increases of variable magnitude in HDL‑C, and modestly reduces VLDL‑C and plasma triglycerides (TG) (see Tables I-III under ). The effects of Mevacor (Lovastatin) on Lp(a), fibrinogen, and certain other independent biochemical risk markers for coronary heart disease are unknown.
Mevacor (Lovastatin) is a specific inhibitor of HMG‑CoA reductase, the enzyme which catalyzes the conversion of HMG‑CoA to mevalonate. The conversion of HMG‑CoA to mevalonate is an early step in the biosynthetic pathway for cholesterol.
Mevacor (Lovastatin) Indications And Usage
Therapy with Mevacor (Lovastatin) should be a component of multiple risk factor intervention in those individuals with dyslipidemia at risk for atherosclerotic vascular disease. Mevacor (Lovastatin) 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.
In individuals without symptomatic cardiovascular disease, average to moderately elevated total‑C and LDL‑C, and below average HDL‑C, Mevacor (Lovastatin) is indicated to reduce the risk of:
- Myocardial infarction- Unstable angina- Coronary revascularization procedures
(See .)
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 (
LDL-C = total-C – [0.2 x (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 (Lovastatin) is not indicated.
The National Cholesterol Education Program (NCEP) Treatment Guidelines are summarized below:
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 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 (Lovastatin) 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).
The NCEP classification of cholesterol levels in pediatric patients with a familial history of hypercholesterolemia or premature cardiovascular disease is summarized below:
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.
Mevacor (Lovastatin) Contraindications
Hypersensitivity to any component of this medication.
Active liver disease or unexplained persistent elevations of serum transaminases (see ).
Mevacor (Lovastatin) Warnings
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.
As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose related.
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.
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.
The risk of myopathy/rhabdomyolysis is increased by concomitant use of lovastatin with the following:
The use of lovastatin concomitantly with the potent CYP3A4 inhibitors itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, or large quantities of grapefruit juice (>1 quart daily) should be avoided.
Prescribing recommendations for interacting agents are summarized in Table VI (see also ; ; ).
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).
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 (Lovastatin) and placebo groups (18 [0.6%] vs. 11 [0.3%]). The starting dose of Mevacor (Lovastatin) was 20 mg/day; 50% of the Mevacor (Lovastatin) treated participants were titrated to 40 mg/day at Week 18. Of the 18 participants on Mevacor (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 Mevacor (Lovastatin) group (n=3,304) and 4 (0.1%) in the placebo group (n=3,301).
It is recommended that liver function tests be performed prior to initiation of therapy in patients with a history of liver disease, or when otherwise clinically indicated. It is recommended that liver function tests be performed in all patients prior to use of 40 mg or more daily and thereafter when clinically indicated. Patients who develop increased transaminase levels should be monitored with a second liver function evaluation to confirm the finding and be followed thereafter with frequent liver function tests until the abnormality(ies) returns to normal. Should an increase in AST or ALT of three times the upper limit of normal or greater persist, withdrawal of therapy with Mevacor (Lovastatin) is recommended.
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.
As with other lipid-lowering agents, moderate (less than three times the upper limit of normal) elevations of serum transaminases have been reported following therapy with Mevacor (Lovastatin) (see ). These changes appeared soon after initiation of therapy with Mevacor (Lovastatin) , were often transient, were not accompanied by any symptoms and interruption of treatment was not required.
Mevacor (Lovastatin) Precautions
Patients should be advised about substances they should not take concomitantly with lovastatin and be advised to report promptly unexplained muscle pain, tenderness, or weakness (see list below and ). Patients should also be advised to inform other physicians prescribing a new medication that they are taking Mevacor (Lovastatin) .
Lovastatin produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a dose that produced mean plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose (as measured by total enzyme inhibitory activity). Vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis were also seen in dogs treated for 14 weeks at 180 mg/kg/day, a dose which resulted in a mean plasma drug level (C) similar to that seen with the 60 mg/kg/day dose.
CNS vascular lesions, characterized by perivascular hemorrhage and edema, mononuclear cell infiltration of perivascular spaces, perivascular fibrin deposits and necrosis of small vessels, were seen in dogs treated with lovastatin at a dose of 180 mg/kg/day, a dose which produced plasma drug levels (C) which were about 30 times higher than the mean values in humans taking 80 mg/day.
Similar optic nerve and CNS vascular lesions have been observed with other drugs of this class.
Cataracts were seen in dogs treated for 11 and 28 weeks at 180 mg/kg/day and 1 year at 60 mg/kg/day.
In a 21-month carcinogenic study in mice, there was a statistically significant increase in the incidence of hepatocellular carcinomas and adenomas in both males and females at 500 mg/kg/day. This dose produced a total plasma drug exposure 3 to 4 times that of humans given the highest recommended dose of lovastatin (drug exposure was measured as total HMG‑CoA reductase inhibitory activity in extracted plasma). Tumor increases were not seen at 20 and 100 mg/kg/day, doses that produced drug exposures of 0.3 to 2 times that of humans at the 80 mg/day dose. A statistically significant increase in pulmonary adenomas was seen in female mice at approximately 4 times the human drug exposure. (Although mice were given 300 times the human dose [HD] on a mg/kg body weight basis, plasma levels of total inhibitory activity were only 4 times higher in mice than in humans given 80 mg of Mevacor (Lovastatin) .)
There was an increase in incidence of papilloma in the non-glandular mucosa of the stomach of mice beginning at exposures of 1 to 2 times that of humans. The glandular mucosa was not affected. The human stomach contains only glandular mucosa.
In a 24‑month carcinogenicity study in rats, there was a positive dose response relationship for hepatocellular carcinogenicity in males at drug exposures between 2-7 times that of human exposure at 80 mg/day (doses in rats were 5, 30 and 180 mg/kg/day).
An increased incidence of thyroid neoplasms in rats appears to be a response that has been seen with other HMG‑CoA reductase inhibitors.
A chemically similar drug in this class was administered to mice for 72 weeks at 25, 100, and 400 mg/kg body weight, which resulted in mean serum drug levels approximately 3, 15, and 33 times higher than the mean human serum drug concentration (as total inhibitory activity) after a 40 mg oral dose. Liver carcinomas were significantly increased in high dose females and mid- and high dose males, with a maximum incidence of 90 percent in males. The incidence of adenomas of the liver was significantly increased in mid- and high dose females. Drug treatment also significantly increased the incidence of lung adenomas in mid- and high dose males and females. Adenomas of the Harderian gland (a gland of the eye of rodents) were significantly higher in high dose mice than in controls.
No evidence of mutagenicity was observed in a microbial mutagen test using mutant strains of with or without rat or mouse liver metabolic activation. In addition, no evidence of damage to genetic material was noted in an alkaline elution assay using rat or mouse hepatocytes, a V‑79 mammalian cell forward mutation study, an chromosome aberration study in CHO cells, or an chromosomal aberration assay in mouse bone marrow.
Drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell formation were seen in dogs starting at 20 mg/kg/day. Similar findings were seen with another drug in this class. No drug-related effects on fertility were found in studies with lovastatin in rats. However, in studies with a similar drug in this class, there was decreased fertility in male rats treated for 34 weeks at 25 mg/kg body weight, although this effect was not observed in a subsequent fertility study when this same dose was administered for 11 weeks (the entire cycle of spermatogenesis, including epididymal maturation). In rats treated with this same reductase inhibitor at 180 mg/kg/day, seminiferous tubule degeneration (necrosis and loss of spermatogenic epithelium) was observed. No microscopic changes were observed in the testes from rats of either study. The clinical significance of these findings is unclear.
Mevacor (Lovastatin) Adverse Reactions
Mevacor (Lovastatin) is generally well tolerated; adverse reactions usually have been mild and transient.
In Phase III controlled clinical studies involving 613 patients treated with Mevacor (Lovastatin) , the adverse experience profile was similar to that shown below for the 8,245‑patient EXCEL study (see ).
Persistent increases of serum transaminases have been noted (see ). About 11% of patients had elevations of CK levels of at least twice the normal value on one or more occasions. The corresponding values for the control agent cholestyramine was 9 percent. This was attributable to the noncardiac fraction of CK. Large increases in CK have sometimes been reported (see ).
Mevacor (Lovastatin) was compared to placebo in 8,245 patients with hypercholesterolemia (total-C 240-300 mg//dL [6.2-7.8 mmol/L]) in the randomized, double-blind, parallel, 48 week EXCEL study. Clinical adverse experiences reported as possibly, probably or definitely drug-related in ≥1% in any treatment group are shown in the table below. For no event was the incidence on drug and placebo statistically different.
Other clinical adverse experiences reported as possibly, probably or definitely drug-related in 0.5 to 1.0 percent of patients in any drug-treated group are listed below. In all these cases the incidence on drug and placebo was not statistically different. : chest pain; : acid regurgitation, dry mouth, vomiting; leg pain, shoulder pain, arthralgia; : insomnia, paresthesia; : alopecia, pruritus; : eye irritation.
In the EXCEL study (see ), 4.6% of the patients treated up to 48 weeks were discontinued due to clinical or laboratory adverse experiences which were rated by the investigator as possibly, probably or definitely related to therapy with Mevacor (Lovastatin) . The value for the placebo group was 2.5%.
In controlled clinical studies in which lovastatin was administered concomitantly with cholestyramine, no adverse reactions peculiar to this concomitant treatment were observed. The adverse reactions that occurred were limited to those reported previously with lovastatin or cholestyramine. Other lipid-lowering agents were not administered concomitantly with lovastatin during controlled clinical studies. Preliminary data suggests that the addition of gemfibrozil to therapy with lovastatin is not associated with greater reduction in LDL‑C than that achieved with lovastatin alone. In uncontrolled clinical studies, most of the patients who have developed myopathy were receiving concomitant therapy with cyclosporine, gemfibrozil or niacin (nicotinic acid). The combined use of lovastatin at doses exceeding 20 mg/day with cyclosporine, gemfibrozil, other fibrates or lipid-lowering doses (≥1 g/day) of niacin should be avoided (see ).
The following effects have been reported with drugs in this class. Not all the effects listed below have necessarily been associated with lovastatin therapy.
Skeletal:
Neurological:
Hypersensitivity Reactions:
Gastrointestinal:
Skin:
Reproductive:
Eye:
Laboratory Abnormalities:
Mevacor (Lovastatin) Overdosage
After oral administration of Mevacor (Lovastatin) to mice, the median lethal dose observed was >15 g/m.
Five healthy human volunteers have received up to 200 mg of lovastatin as a single dose without clinically significant adverse experiences. A few cases of accidental overdosage have been reported; no patients had any specific symptoms, and all patients recovered without sequelae. The maximum dose taken was 5-6 g.
Until further experience is obtained, no specific treatment of overdosage with Mevacor (Lovastatin) can be recommended.
The dialyzability of lovastatin and its metabolites in man is not known at present.
Mevacor (Lovastatin) Dosage And Administration
The patient should be placed on a standard cholesterol-lowering diet before receiving Mevacor (Lovastatin) and should continue on this diet during treatment with Mevacor (Lovastatin) (see for details on dietary therapy). Mevacor (Lovastatin) should be given with meals.
The usual recommended starting dose is 20 mg once a day given with the evening meal. The recommended dosing range of lovastatin is 10-80 mg/day in single or two divided doses; the maximum recommended dose is 80 mg/day. Doses should be individualized according to the recommended goal of therapy (see and ). Patients requiring reductions in LDL‑C of 20% or more to achieve their goal (see ) should be started on 20 mg/day of Mevacor (Lovastatin) . A starting dose of 10 mg of lovastatin may be considered for patients requiring smaller reductions. Adjustments should be made at intervals of 4 weeks or more. The 10 mg dosage is provided for information purposes only. Although lovastatin tablets 10 mg are available in the marketplace, Mevacor (Lovastatin) is no longer marketed in the 10 mg strength.
Cholesterol levels should be monitored periodically and consideration should be given to reducing the dosage of Mevacor (Lovastatin) if cholesterol levels fall significantly below the targeted range.
Mevacor (Lovastatin) How Supplied
No. 8123 — Tablets Mevacor (Lovastatin) 20 mg are blue, octagonal tablets, coded MSD 731 on one side and plain on the other. They are supplied as follows:
No. 8124 — Tablets Mevacor (Lovastatin) 40 mg are green, octagonal tablets, coded MSD 732 on one side and plain on the other. They are supplied as follows:
Mevacor (Lovastatin) This Is A Representative Sample Of The Packaging. Please See How Supplied Section For A Complete List Of Available Packaging. Principal Display Panel - Bottle Label Mg
Mevacor (Lovastatin) 20 mg(Lovastatin)
Manuf. for: Merck Sharp & Dohme Corp., a subsidiary ofMERCK & CO., INC.Whitehouse Station, NJ 08889, USA
By:Mylan Pharmaceuticals Inc.Morgantown, WV 26505, USA
Lovastatin (active ingred.) Made in IndiaFormulated in USA
Each tablet contains 20 mg of lovastatin.
60 Tablets
NDC 0006-0731-61
Store at 20-25°C (68-77°F).[See USP Controlled Room Temperature.] Protect from light.
USUAL ADULT DOSAGE: See accompanying circular.
Rx only
8123 (USA)
86084/161209
9874703
USA 014-871-01
Mevacor (Lovastatin) Principal Display Panel - Bottle Label Mg
Mevacor (Lovastatin) 40 mg(Lovastatin)
Manuf. for: Merck Sharp & Dohme Corp., a subsidiary ofMERCK & CO., INC.Whitehouse Station, NJ 08889, USA
By:Mylan Pharmaceuticals Inc.Morgantown, WV 26505, USA
Lovastatin (active ingred.) Made in IndiaFormulated in USA
Each tablet contains 40 mg of lovastatin.
60 Tablets
NDC 0006-0732-61
Store at 20-25°C (68-77°F).[See USP Controlled Room Temperature.] Protect from light.
USUAL ADULT DOSAGE: See accompanying circular.
Rx only
8124 (USA)
86083/161209
9874803
USA 014-873-01
