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Label Changes for:

Zocor (simvastatin) Tablets

February 2014

Changes have been made to the CONTRAINDICATIONS, WARNINGS and PRECAUTIONS sections of the safety label.

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

4 CONTRAINDICATIONS

  • Added…cobicistat-containing products

5 WARNINGS AND PRECAUTIONS

5.2 Myopathy/Rhabdomyolysis
  • Drug Interactions… paragraph added
  • Table 1 updated with cobicistat-containing products

7 DRUG INTERACTIONS

  • Added… cobicistat-containing products to the existing list of strong CYP3A4 inhibitors

MEDICATION GUIDE

Do not take [drug name] if you take:
  • medicines containing cobicistat…added

 

February 2012

 

CONTRAINDICATIONS

  • Zocor is contraindicated in the following conditions: Concomitant administration of strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin and nefazodone)

 

WARNINGS AND PRECAUTIONS

Drug Interactions
  • Certain drugs which inhibit this metabolic pathway can raise the plasma levels of simvastatin and may increase the risk of myopathy. These include itraconazole, ketoconazole, and posaconazole, the macrolide antibiotics erythromycin and clarithromycin, and the ketolide antibiotic telithromycin, HIV protease inhibitors, boceprevir, telaprevir, the antidepressant nefazodone, or large quantities of grapefruit juice (>1 quart daily).

 

October 2011   

 

WARNINGS AND PRECAUTIONS

Myopathy/Rhabdomyolysis
  • Zocor therapy should be discontinued if markedly ...
  • Amiodarone added to TABLE 1
Liver Dysfunction
  • There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients...
Endocrine Function
  • Increases in HbA1c and fasting serum glucose levels have been reported ...

 

ADVERSE REACTIONS

Post-Marketing Experience
  • fatal and non-fatal hepatic failure......added
  • There have been rare postmarketing reports of cognitive impairment.....

 

PATIENT COUNSELING INFORMATION

Liver Enzymes
  • All patients treated with ZOCOR should be advised to report promptly any symptoms that may indicate liver injury,.....

 

June 2011 

 

CONTRAINDICATIONS

  • Concomitant administration of strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, HIV protease inhibitors, erythromycin, clarithromycin, telithromycin and nefazodone).
  • Concomitant administration of gemfibrozil, cyclosporine, or danazol.

 

WARNINGS AND PRECAUTIONS

Myopathy/Rhabdomyolysis
  • ...the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum creatine kinase [CK] >10 times upper limit of normal [ULN]) in patients on 80 mg/day was approximately 0.9% compared with 0.02% for patients on 20 mg/day. The incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) in patients on 80 mg/day was approximately 0.4% compared with 0% for patients on 20 mg/day.
  • The risk of myopathy, including rhabdomyolysis, is greater in patients on simvastatin 80 mg compared with other statin therapies with similar or greater LDL-C-lowering efficacy and compared with lower doses of simvastatin. Therefore, the 80-mg dose of ZOCOR should be used only in patients who have been taking simvastatin 80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity. If, however, a patient who is currently tolerating the 80-mg dose of ZOCOR needs to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin, that patient should be switched to an alternative statin with less potential for the drug-drug interaction. Patients should be advised of the increased risk of myopathy, including rhabdomyolysis, and to report promptly any unexplained muscle pain, tenderness or weakness. If symptoms occur, treatment should be discontinued immediately
  • Therefore, the 80-mg dose of Zocor should be used only in patients who have been taking simvastatin 80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity.
  • In vitro studies have demonstrated a potential for voriconazole to inhibit the metabolism of simvastatin. Adjustment of the simvastatin dose may be needed to reduce the risk of myopathy, including rhabdomyolysis, if voriconazole must be used concomitantly with simvastatin.
  • The combined use of simvastatin with gemfibrozil, cyclosporine, or danazol is contraindicated.
  • Caution should be used when prescribing other fibrates with simvastatin, as these agents can cause myopathy when given alone and the risk is increased when they are co-administered.
  • Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing simvastatin with colchicine.
  • Caution should be used when treating Chinese patients with simvastatin in doses exceeding 20 mg/day coadministered with lipidmodifying doses of niacin-containing products.
  • Note that ALT may emanate from muscle, therefore ALT rising with CK may indicate myopathy.

 

ADVERSE REACTIONS

Clinical Trials Experience
  • In a clinical trial in which 12,064 patients with a history of myocardial infarction were treated with Zocor (mean follow-up 6.7 years), the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum creatine kinase [CK] >10 times upper limit of normal [ULN]) in patients on 80 mg/day was approximately 0.9% compared with 0.02% for patients on 20 mg/day. The incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) in patients on 80 mg/day was approximately 0.4% compared with 0% for patients on 20 mg/day. The incidence of myopathy, including rhabdomyolysis, was highest during the first year and then notably decreased during the subsequent years of treatment. In this trial, patients were carefully monitored and some interacting medicinal products were excluded.
  • ...the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum creatine kinase [CK] >10 times upper limit of normal [ULN]) in patients on 80 mg/day was approximately 0.9% compared with 0.02% for patients on 20 mg/day. The incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) in patients on 80 mg/day was approximately 0.4% compared with 0% for patients on 20 mg/day. The incidence of myopathy, including rhabdomyolysis, was highest during the first year and then notably decreased during the subsequent years of treatment. In this trial, patients were carefully monitored and some interacting medicinal products were excluded.

 

DRUG INTERACTIONS

  • Concomitant use of drugs labeled as having a strong inhibitory effect on CYP3A4 is contraindicated [see Contraindications (4)]. If treatment with itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin must be suspended during the course of treatment.
  • Although not studied clinically, voriconazole has been shown to inhibit lovastatin metabolism in vitro (human liver microsomes). Therefore, voriconazole is likely to increase the plasma concentration of simvastatin. It is recommended that dose adjustment of simvastatin be considered during concomitant use of voriconazole and simvastatin to reduce the risk of myopathy, including rhabdomyolysis.
  • Cyclosporine or Danazol: The risk of myopathy, including rhabdomyolysis is increased by concomitant administration of cyclosporine or danazol. Therefore, concomitant use of these drugs is contraindicated.

Colchicine

  • Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing simvastatin with colchicine.

 

USE IN SPECIFIC POPULATIONS

Geriatric Use
  • Because advanced age (≥65 years) is a predisposing factor for myopathy, including rhabdomyolysis, Zocor should be prescribed with caution in the elderly. In a clinical trial of patients treated with simvastatin 80 mg/day, patients ≥65 years of age had an increased risk of myopathy, including rhabdomyolysis, compared to patients <65 years of age. 

 

November 2010

 

ADVERSE REACTIONS
Postmarketing Experience
  • erectile dysfunction and interstitial lung disease

 

April 2010

WARNINGS and PRECAUTIONS

TABLE 1 Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis
  • Diltiazem: Do not exceed 40 mg simvastatin daily
  • The combined use of simvastatin in patients receiving diltiazem should not exceed 40 mg daily unless the clinical benefit is likely to outweigh the increased risk of myopathy.

DRUG INTERACTIONS

Amiodarone, Verapamil, or Diltiazem
  • The risk of myopathy/rhabdomyolysis is increased by concomitant administration of amiodarone, verapamil, or diltiazem with higher doses of simvastatin

 

March 2010

 

WARNINGS AND PRECAUTIONS

Myopathy/Rhabdomyolysis
  • Cases of myopathy/rhabdomyolysis have been observed with simvastatin coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products. In an ongoing, double-blind, randomized cardiovascular outcomes trial, an independent safety monitoring committee identified that the incidence of myopathy is higher in Chinese compared with non-Chinese patients taking simvastatin 40 mg coadministered with lipid-modifying doses of a niacin-containing product. Because the risk for myopathy is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products. It is unknown if the risk for myopathy with coadministration of simvastatin with lipid-modifying doses of niacin-containing products observed in Chinese patients applies to other Asian patients.

 

DRUG INTERACTIONS

Niacin
  • Cases of myopathy/rhabdomyolysis have been observed with simvastatin coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products. In particular, caution should be used when treating Chinese patients with simvastatin coadministered with lipid-modifying doses of niacin-containing products. Because the risk for myopathy is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products.

 

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