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U.S. Department of Health and Human Services

Safety

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Altoprev (Lovastatin Extended-release) Tablets

Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER)

 

April 2014

Summary View

6. ADVERSE REACTIONS

6.1 Clinical Trial Adverse Reactions
  • In controlled clinical trials with Altoprev, (467 patients with mean exposure to study drug of approximately 11.6 weeks), 3.2% of patients were discontinued due to adverse reactions. This was similar to the discontinuation rate in the placebo (2/34, 5.9%) and lovastatin immediate-release (3.3%) treatment groups.

added below Table 2: Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)

  • In AFCAPS/TexCAPS [see Clinical Pharmacology (12)] 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.
  • In AFCAPS/TexCAPS, the number of participants with consecutive elevations of either alanine........ 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).

7 DRUG INTERACTIONS

  • Removed Sections 7.10 (Propranolol), 7.11 (Digoxin), and 7.12 (Oral Hypoglycemic Agents). The information from these sections was incorporated into Section 12.3 (CLINICAL PHARMACOLOGY, Pharmacokinetics), see Table 5 

 

April 2012

Summary View

CONTRAINDICATIONS

  • Concomitant administration with strong CYP3A4 inhibitors (e.g., Itraconazole, Ketoconazole,Posaconazole, HIV protease inhibitors, Boceprevir, Telaprevir, Erythromycin, Clarithromycin, Telithromycin and Nefazodone).
 

WARNINGS

  • As with other HMG-CoA reductase inhibitors, 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…
  • Strong inhibitors of CYP3A4: The risk of myopathy appears to be increased by high levels of HMG-CoA reductase inhibitory activity in plasma…
  • Although not studied clinically, Voriconazole has been shown to inhibit Lovastatin metabolism in vitro (human liver microsomes)…
  • Gemfibrozil: The combined use of Lovastatin with Gemfibrozil should be avoided.
  • Other lipid-lowering drugs: Caution should be used when prescribing other fibrates or lipid-lowering doses (≥1 g/day) of niacin with lovastatin, as these agents can cause myopathy when given alone…
  • Cyclosporine: The use of lovastatin with cyclosporine should be avoided.
  • Danazol, diltiazem or verapamil with higher doses of lovastatin: The dose of lovastatin should not exceed 20 mg daily in patients receiving concomitant medication with Danazol, Diltiazem, or Verapamil. The benefits of the use of Lovastatin in patients receiving Danazol, Diltiazem, or Verapamil should be carefully weighed against the risks of these combinations.
  • Amiodarone: The dose of lovastatin should not exceed 40 mg daily in patients receiving concomitant medication with amiodarone. The combined use of lovastatin at doses higher than 40 mg daily with amiodarone should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy. 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.
  • Colchicine: Cases of myopathy, including rhabdomyolysis, have been reported with Lovastatin coadministered with Colchicine, and caution should be exercised when prescribing Lovastatin with colchicine.
  • Ranolazine: The risk of myopathy, including rhabdomyolysis, may be increased by concomitant administration of Ranolazine. Dose adjustment of Lovastatin may be considered during coadministration with Ranolazine
 

PRECAUTIONS

  • It is recommended that liver enzymes be checked before starting therapy, and if signs or symptoms of liver injury occur. All patients treated with ALTOPREV should be advised to report promptly any symptoms that may indicate liver injury, including fatigue. anorexia, right upper abdominal discomfort, dark urine or jaundice..
 
CYP3A4 Interactions
  • Strong inhibitors of CYP3A4 (e.g., itraconazole, ketoconazole, posaconazole, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, and erythromycin), and large quantities of grapefruit juice (>1 quart daily)
  • In vitro studies have demonstrated that voriconazole inhibits the metabolism of lovastatin. Adjustment of the lovastatin dose may be needed to reduce the risk of myopathy, including rhabdomyolysis, if voriconazole must be used concomitantly with lovastatin.
 
Other Drug Interactions:
  • Cyclosporine: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of cyclosporine.
  • Danazol, Diltiazem, or Verapamil: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of danazol, diltiazem, or verapamil particularly with higher doses of lovastatin.
  • Amiodarone: The risk of myopathy/rhabdomyolysis is increased when amiodarone is used concomitantly with a closely related member of the HMG-CoA reductase inhibitor class
  • Colchicine: Cases of myopathy, including rhabdomyolysis. have been reported with lovastatin coadministered with colchicine.
  • Ranolazine: The risk of myopathy, including rhabdomyolysis may be increased by concomitant administration of ranolazine.
 
Endocrine Function
  • Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including lovastatin.
 

ADVERSE REACTIONS

Concomitant Therapy
  • The combined use of lovastatin with cyclosporine or gemfibrozil should be avoided. Caution should be used when prescribing other fibrates or lipidlowering doses (≥1 g/day) of niacin with lovastatin.
Neurological:
  • There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (l day to years) and symptom resolution (median of 3 weeks).
Gastrointestinal:
  • fatal and non-fatal hepatic failure.