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ALTOPREV® (lovastatin extended-release tablets)

ALTOPREV® (lovastatin extended-release tablets) Clinical Studies

In clinical studies with ALTOPREV® (lovastatin extended-release tablets) , adverse reactions have generally been mild and transient. In controlled studies with 467 patients who received ALTOPREV® (lovastatin extended-release tablets) , < 3% of patients were discontinued due to adverse experiences attributable to ALTOPREV (lovastatin extended-release tablets) ® . This was similar to the discontinuation rate in the placebo and lovastatin immediate-release treatment groups. Pooled results from clinical studies with ALTOPREV® (lovastatin extended-release tablets) show that the most frequently reported adverse reactions in the ALTOPREV® (lovastatin extended-release tablets) group were infection, headache and accidental injury. Similar incidences of these adverse reactions were seen in the lovastatin and placebo groups. The most frequent adverse events thought to be related to ALTOPREV® (lovastatin extended-release tablets) were nausea, abdominal pain, insomnia, dyspepsia, headache, asthenia, and myalgia. In controlled trials (e.g., vs. placebo and vs. lovastatin immediate-release), clinical adverse experiences reported as 5% in any treatment group are shown in Table VII below.

Table VII: Pooled Controlled Studies TESS by Body System and COSTART Term, Most Common (5% in Any Group)

Lovastatin Immediate-Release

Lovastatin Immediate-Release Phase III Clinical Studies

In Phase III controlled clinical studies involving 613patients treated with lovas-tatin immediate-release, 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%. 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

Lovastatin immediate-release 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.

Table VIII : Clinical Adverse Events Reported as Possibly, Probably or Definitely Drug-Related in ≥ 1% in Any Treatment Group in the EXCEL Study

Other clinical adverse experiences 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 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 48weeks were discontinued due to clinical or laboratory adverse experiences which were rated by the investigator as possibly, probably or definitely related to therapy with lovastatin immediate-release. The value for the placebo group was 2.5%.

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

In AFCAPS/TexCAPS (see CLINICAL PHARMACOLOGY, Clinical Studies) involving 6,605 participants treated with 20-40 mg/day of lovastatin immediate-release (n=3,304) or placebo (n=3,301), the safety and tolerability profile of the group treated with lovastatin immediate-release was comparable to that of the group treated with placebo during a median of 5.1 years of follow-up. The adverse experiences reported in AFCAPS/TexCAPS were similar to those reported in EXCEL [see ADVERSE REACTIONS, Expanded Clinical Evaluation of Lovastatin (EXCEL) Study].

Concomitant Therapy

In controlled clinical studies in which lovastatin immediate-release 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) (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: ana-phylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukope-nia, 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.

Drug interaction studies have not been performed with ALTOPREV® (lovastatin extended-release tablets) . The types, frequencies and magnitude of drug interactions that may be encountered when ALTOPREV® (lovastatin extended-release tablets) is administered with other drugs may differ from the drug interactions encountered with the lovastatin immediate-release formulation. In addition, as the drug exposure with ALTOPREV® 60 mg is greater than that with lovastatin immediate-release 80 mg (maximum recommended dose), the severity and magnitude of drug interactions that may be encountered with ALTOPREV® (lovastatin extended-release tablets) 60 mg are not known. It is therefore recommended that the following precautions and recommendations for the concomitant administration of lovastatin immediate-release with other drugs be interpreted with caution, and that the monitoring of the pharmacologic effects of ALTOPREV® (lovastatin extended-release tablets) and/or other concomitantly administered drugs be undertaken where appropriate.

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
HIV protease inhibitors
Nefazodone
Cyclosporine
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

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 seconds increase in prothrombin time in healthy volunteers receiving low doses of warfarin. Also, bleeding and/or increased pro-thrombin time has 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 ensure 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.

Antipyrine

Lovastatin had no effect on the pharmacokinetics of antipyrine or its metabolites. However, since lovastatin is metabolized by the cytochrome P450 isoform 3A4, this does not preclude an interaction with other drugs metabolized by the same isoform (see WARNINGS, Myopathy/ Rhabdomyolysis).

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 lovastatin immediate-release 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 reduc-tase inhibitors on male fertility have not been studied in adequate numbers of male 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 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 chro-matolysis 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 lovas-tatin at a dose of 180 mg/kg/day, a dose which produced plasma drug levels (Cmax) which were about 30times higher than the mean values in humans taking 80mg/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.

Last reviewed on RxList: 7/31/2007
This monograph has been modified to include the generic and brand name in many instances.