MEVACOR is generally well tolerated; adverse reactions usually have been mild and transient.

Phase III Clinical Studies

In Phase III controlled clinical studies involving 613 patients treated with MEVACOR, the adverse experience profile was similar to that shown below for the 8,245-patient EXCEL study (see Expanded Clinical Evaluation of Lovastatin [EXCEL] Study).

Persistent increases of serum transaminases have been noted (see WARNINGS, Liver Dysfunction). 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 WARNINGS, Myopathy/Rhabdomyolysis).

Expanded Clinical Evaluation of Lovastatin (EXCEL) Study

MEVACOR 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. Body as a Whole: chest pain; Gastrointestinal: acid regurgitation, dry mouth, vomiting; Musculoskeletal: leg pain, shoulder pain, arthralgia; Nervous System/Psychiatric: insomnia, paresthesia; Skin: alopecia, pruritus; Special Senses: eye irritation.

In the EXCEL study (see CLINICAL PHARMACOLOGY, Clinical Studies), 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. The value for the placebo group was 2.5%.

Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)

In AFCAPS/TexCAPS (see CLINICAL PHARMACOLOGY, ADVERSE REACTIONS, Expanded Clinical Evaluation of Lovastatin (EXCEL) Study).

Concomitant Therapy

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 WARNINGS, Myopathy/Rhabdomyolysis).

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: muscle cramps, myalgia, myopathy, rhabdomyolysis, arthralgias.

Neurological: dysfunction of certain cranial nerves (including alteration of taste, impairment of extra-ocular movement, facial paresis), tremor, dizziness, vertigo, memory loss, paresthesia, peripheral neuropathy, peripheral nerve palsy, psychic disturbances, anxiety, insomnia, depression.

Hypersensitivity Reactions: An apparent hypersensitivity syndrome has been reported rarely which has included one or more of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome.

Gastrointestinal: pancreatitis, hepatitis, including chronic active hepatitis, cholestatic jaundice, fatty change in liver; and rarely, cirrhosis, fulminant hepatic necrosis, and hepatoma; anorexia, vomiting.

Skin: alopecia, pruritus. A variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails) have been reported.

Reproductive: gynecomastia, loss of libido, erectile dysfunction.

Eye: progression of cataracts (lens opacities), ophthalmoplegia.

Laboratory Abnormalities: elevated transaminases, alkaline phosphatase, γ -glutamyl transpeptidase, and bilirubin; thyroid function abnormalities.

Adolescent Patients (ages 10-17 years)

In a 48-week controlled study in adolescent boys with heFH (n=132) and a 24-week controlled study in girls who were at least 1 year post-menarche with heFH (n=54), the safety and tolerability profile of the groups treated with MEVACOR (10 to 40 mg daily) was generally similar to that of the groups treated with placebo (see CLINICAL PHARMACOLOGY, PRECAUTIONS, Pediatric Use).

CYP3A4 Interactions

Lovastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity; therefore it is not expected to affect the plasma concentrations of other drugs metabolized by CYP3A4. Potent inhibitors of CYP3A4 (below) increase the risk of myopathy by reducing the elimination of lovastatin.

See WARNINGS, Myopathy/Rhabdomyolysis, and CLINICAL PHARMACOLOGY, Pharmacokinetics.

Itraconazole
Ketoconazole
Erythromycin
Clarithromycin
Telithromycin
HIV protease inhibitors
Nefazodone
Large quantities of grapefruit juice (> 1 quart daily)

Interactions with lipid-lowering drugs that can cause myopathy when given alone

The risk of myopathy is also increased by the following lipid-lowering drugs that are not potent CYP3A4 inhibitors, but which can cause myopathy when given alone.

See WARNINGS, Myopathy/Rhabdomyolysis.
Gemfibrozil
Other fibrates
Niacin (nicotinic acid) (≥ 1 g/day)

Other drug interactions

Cyclosporine or Danazol: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of cyclosporine or danazol particularly with higher doses of lovastatin (see WARNINGS, Myopathy/Rhabdomyolysis; CLINICAL PHARMACOLOGY, Pharmacokinetics).

Amiodarone or Verapamil: The risk of myopathy/rhabdomyolysis is increased when either amiodarone or verapamil is used concomitantly with a closely related member of the HMG-CoA reductase inhibitor class (see WARNINGS, Myopathy/Rhabdomyolysis).

Coumarin Anticoagulants: In a small clinical trial in which lovastatin was administered to warfarin treated patients, no effect on prothrombin time was detected. However, another HMG-CoA reductase inhibitor has been found to produce a less than two-second increase in prothrombin time in healthy volunteers receiving low doses of warfarin. Also, bleeding and/or increased prothrombin time have been reported in a few 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 insure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the 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.

Propranolol: In normal volunteers, there was no clinically significant pharmacokinetic or pharmacodynamic interaction with concomitant administration of single doses of lovastatin and propranolol.

Digoxin: In patients with hypercholesterolemia, concomitant administration of lovastatin and digoxin resulted in no effect on digoxin plasma concentrations.

Oral Hypoglycemic Agents: In pharmacokinetic studies of MEVACOR in hypercholesterolemic non-insulin dependent diabetic patients, there was no drug interaction with glipizide or with chlorpropamide (see CLINICAL PHARMACOLOGY, Clinical Studies).

Endocrine Function

HMG-CoA reductase inhibitors interfere with cholesterol synthesis and as such might theoretically blunt adrenal and/or gonadal steroid production. Results of clinical trials with drugs in this class have been inconsistent with regard to drug effects on basal and reserve steroid levels. However, clinical studies have shown that lovastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve, and does not reduce basal plasma testosterone concentration. Another HMG-CoA reductase inhibitor has been shown to reduce the plasma testosterone response to HCG. In the same study, the mean testosterone response to HCG was slightly but not significantly reduced after treatment with lovastatin 40 mg daily for 16 weeks in 21 men. The effects of HMG-CoA reductase inhibitors on male fertility have not been studied in adequate numbers of male patients. The effects, if any, on the pituitary-gonadal axis in pre-menopausal women are unknown. Patients treated with lovastatin who develop clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should also be exercised if an HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is administered to patients also receiving other drugs (e.g., ketoconazole, spironolactone, cimetidine) that may decrease the levels or activity of endogenous steroid hormones.

CNS Toxicity

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 (Cmax) 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 (Cmax) 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.

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