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Altoprev (Lovastatin) - Warnings and Precautions

 
 



WARNINGS

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 10X 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 increased by concomitant use of lovastatin with the following:

Potent inhibitors of CYP3A4 : Cyclosporine, itraconazole, ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, nefazodone, or large quantities of grapefruit juice (>1 quart daily), particularly with higher doses of lovastatin (see below; CLINICAL PHARMACOLOGY, Pharmacokinetics ; PRECAUTIONS, Drug Interactions, CYP3A4 Interactions).

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 below; CLINICAL PHARMACOLOGY, Pharmacokinetics; PRECAUTIONS, Drug Interactions, Interactions With Lipid-Lowering Drugs That Can Cause Myopathy When Given Alone).

Other drugs: The risk of myopathy/rhabdomyolysis is increased when either amiodarone or verapamil is used concomitantly with higher doses of a closely related member of the HMG-CoA reductase inhibitor class (see PRECAUTIONS, Drug Interactions, Other Drug Interactions).

  • 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.

CONSEQUENTLY:

  • Use of lovastatin concomitantly with itraconazole, ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, nefazodone, or large quantities of grapefruit juice (>1 quart daily) should be avoided. If treatment with itraconazole, ketoconazole, erythromycin, or clarithromycin is unavoidable, therapy with lovastatin should be suspended during the course of treatment. Concomitant use with other medicines labeled as having a potent inhibitory effect on CYP3A4 at therapeutic doses should be avoided unless the benefits of combined therapy outweigh the increased risk.
  • The dose of lovastatin should not exceed 20 mg daily in patients receiving concomitant medication with cyclosporine, gemfibrozil, other fibrates or lipid-lowering doses (>1 g/day) of niacin. The combined use of lovastatin with fibrates or niacin should be avoided unless the benefit of further alteration in lipid levels is likely to outweigh the increased risk of this drug combination. Addition of these drugs to lovastatin typically provides little additional reduction in LDL-C, but further reductions of TG and further increases in HDL-C may be obtained.
  • The dose of Altoprev® should not exceed 20 mg daily in patients receiving concomitant medication with amiodarone or verapamil. The combined use of Altoprev® at doses higher than 20 mg daily with amiodarone or verapamil should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy.
  • 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 ULN 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.
  • From post-marketing reports with Altoprev®, myopathy and rhabdomyolysis have been reported, especially in elderly patients initiating therapy with Altoprev® at a dose of 60 mg per day. Thus, lower starting doses of Altoprev® are recommended for elderly patients, particularly those with complicated medical conditions (see DOSAGE AND ADMINISTRATION, Elderly Patients).

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.

ALTOPREV®

In controlled clinical trials (467 patients treated with ALTOPREV® and 329 patients treated with lovastatin immediate-release) no meaningful differences in transaminase elevations between the two treatments were observed.

Lovastatin Immediate-Release

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 lovastatin immediate-release, 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 lovastatin immediate-release and placebo groups [18 (0.6%) vs. 11 (0.3%)]. The starting dose of lovastatin immediate-release was 20 mg/day; 50% of the lovastatin immediate-release treated participants were titrated to 40 mg/day at Week 18. Of the 18 participants on lovastatin immediate-release 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 lovastatin immediate-release group (n=3,304) and 4 (0.1%) in the placebo group (n=3,301).

It is recommended that liver function tests be performed before the initiation of treatment, at 6 and 12 weeks after initiation of therapy or elevation of dose, and periodically thereafter (e.g., semiannually). 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) return to normal. Should an increase in AST or ALT of three times the upper limit of normal or greater persist, withdrawal of therapy with ALTOPREV® 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 ALTOPREV®.

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

PRECAUTIONS

General

ALTOPREV® may elevate creatine phosphokinase and transaminase levels (see WARNINGS and ADVERSE REACTIONS). This should be considered in the differential diagnosis of chest pain in a patient on therapy with ALTOPREV®.

Homozygous Familial Hypercholesterolemia

Lovastatin immediate-release was found to be less effective in patients with the rare homozygous familial hypercholesterolemia, possibly because these patients have no functional LDL receptors. Lovastatin immediate-release appears to be more likely to raise serum transaminases (see ADVERSE REACTIONS) in these homozygous patients.

Information for Patients

The ALTOPREV® extended-release tablets should be swallowed whole and not chewed, crushed or cut.

Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness (see WARNINGS, Myopathy/Rhabdomyolysis).

Drug Interactions

Drug interaction studies have not been performed with ALTOPREV®. The types, frequencies and magnitude of drug interactions that may be encountered when ALTOPREV® 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® 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® 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 prothrombin 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 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 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 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 21-month carcinogenic study in mice with lovastatin immediate-release, 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 lovastatin immediate-release 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 lovastatin immediate-release].

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 given lovastatin immediate-release. 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 lovastatin immediate-release (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 of lovastatin immediate-release. Liver carcinomas were significantly increased in highdose 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 with lovastatin immediate-release in a microbial mutagen test using mutant strains of Salmonella typhimurium with or without rat or mouse liver metabolic activation. In addition, no evidence of damage to genetic material was noted in an in vitro alkaline elution assay using rat or mouse hepatocytes, a V-79 mammalian cell forward mutation study, an in vitro chromosome aberration study in CHO cells, or an in vivo 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 with lovastatin immediate-release. 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.

Pregnancy

Pregnancy Category X

See CONTRAINDICATIONS.

Safety in pregnant women has not been established. Lovastatin immediate-release has been shown to produce skeletal malformations at plasma levels 40 times the human exposure (for mouse fetus) and 80 times the human exposure (for rat fetus) based on mg/m2 surface area (doses were 800 mg/kg/day). No drug-induced changes were seen in either species at multiples of 8 times (rat) or 4 times (mouse) based on surface area. No evidence of malformations was noted in rabbits at exposures up to 3 times the human exposure (dose of 15 mg/kg/day, highest tolerated dose of lovastatin immediate-release).

Rare reports of congenital anomalies have been received following intrauterine exposure to HMG-CoA reductase inhibitors. In a review2 of approximately 100 prospectively followed pregnancies in women exposed to lovastatin immediate-release or another structurally related HMG-CoA reductase inhibitor, the incidences of congenital anomalies, spontaneous abortions and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate only to exclude a 3 to 4-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. As safety in pregnant women has not been established and there is no apparent benefit to therapy with ALTOPREV® during pregnancy (see CONTRAINDICATIONS), treatment should be immediately discontinued as soon as pregnancy is recognized. ALTOPREV® should be administered to women of child-bearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazard.

Nursing Mothers

It is not known whether lovastatin is excreted in human milk. Because a small amount of another drug in this class is excreted in human breast milk and because of the potential for serious adverse reactions in nursing infants, women taking ALTOPREV® should not nurse their infants (see CONTRAINDICATIONS ).

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Because pediatric patients are not likely to benefit from cholesterol lowering for at least a decade and because experience with this drug is limited (no studies in subjects below the age of 20 years), treatment of pediatric patients with ALTOPREV® is not recommended at this time.

Geriatric Use

ALTOPREV®

Of the 467 patients who received ALTOPREV® in controlled clinical studies, 18% were 65 years and older. Of the 297 patients who received ALTOPREV® in uncontrolled clinical studies, 22% were 65 years and older. No overall differences in effectiveness or safety were observed between these patients and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Thus, lower starting doses of ALTOPREV® are recommended for elderly patients, particularly those with complicated medical conditions. (see DOSAGE AND ADMINISTRATION, Elderly Patients).

Lovastatin Immediate-Release

In pharmacokinetic studies with lovastatin immediate-release, the mean plasma level of HMG-CoA reductase inhibitory activity was shown to be approximately 45% higher in elderly patients between 70-78 years of age compared with patients between 18-30 years of age; however, clinical study experience in the elderly indicates that dosage adjustment based on this age-related pharmacokinetic difference is not needed. In the two large clinical studies conducted with lovastatin immediate-release (EXCEL and AFCAPS/TexCAPS), 21% (3094/14850) of patients were ≥65 years of age. Lipid-lowering efficacy with lovastatin was at least as great in elderly patients compared with younger patients, and there were no overall differences in safety over the 20 to 80 mg dosage range (see CLINICAL PHARMACOLOGY).

Page last updated: 2008-08-26

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