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U.S. Department of Health and Human Services

Safety

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Vytorin (ezetimibe/simvastatin) tablet

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

 

February 2014

Summary View

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

Summary View

 

CONTRAINDICATIONS

Concomitant administration of strong CYP3A4 inhibitors
  • boceprevir
  • telaprevir
 

WARNINGS AND PRECAUTIONS

Drug Interactions
  • Certain drugs that inhibit this metabolic pathway can raise the plasma levels of simvastatin and may increase the risk of myopathy. These include … boceprevir, telaprevir…
 

DRUG INTERACTIONS

Niacin

  • The benefits of the combined use of Vytorin with niacin should be carefully weighed against the potential risks of myopathy/rhabdomyolysis.
 
Fibrates
  • Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of fibrates, Vytorin should be administered with caution when used concomitantly with fibrates (other than gemfibrozil, which is contraindicated)

 

January 2012

Summary View

5 WARNINGS AND PRECAUTIONS

5.1 Myopathy/Rhabdomyolysis
  • ...In the Study of Heart and Renal Protection (SHARP), 9270 patients with chronic kidney disease were allocated.....
5.2 Liver Enzymes
  • In SHARP, 9270 patients with chronic kidney disease were allocated.....

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience
Study of Heart and Renal Protection
  • In SHARP, 9270 patients were allocated to VYTORIN 10/20 mg daily (n=4650) or placebo (n=4620) for a median follow-up period of 4.9 years. The proportion....

8 USE IN SPECIAL POPULATIONS

8.6 Renal Impairment
  • In the SHARP trial of 9270 patients with.....

 

 

December 2011

 

 

 

Patient Package Insert

What are the possible side effects of Vytorin?
  • memory loss
  • confusion

 

October 2011

 

 

 

WARNINGS AND PRECAUTIONS

Myopathy/Rhabdomyolysis
  • Vytorin therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Vytorin therapy should also ...
Liver Enzymes
  • There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including simvastatin. If serious liver injury ...

ADVERSE REACTIONS

Post-Marketing Experience
  • There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated...

PATIENT COUNSELING INFORMATION

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

PATIENT PACKAGE INSERT

“What are the possible side effects of Vytorin?”...
  • Your doctor should do blood tests to check your liver before you start taking Vytorin and if you have any.....

 

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
  • Predisposing factors for myopathy include advanced age (≥65 years), female gender, uncontrolled hypothyroidism, and renal impairment.
  • The incidence of myopathy with 80 mg (0.61%) was disproportionately higher than that observed at the lower doses.
  • In a clinical trial in which 12,064 patients with a history of myocardial infarction were treated with simvastatin (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 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 10/80-mg dose of Vytorin should be used only in patients who have been taking Vytorin 10/80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity. If, however, a patient who is currently tolerating the 10/80-mg dose of Vytorin 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 or statin-based regimen 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.
Drug Interactions
  • In vitro studies have demonstrated a potential for voriconazole to inhibit the metabolism of simvastatin. Adjustment of the Vytorin dose may be needed to reduce the risk of myopathy/rhabdomyolysis if voriconazole must be used concomitantly with Vytorin.
  • The combined use of Vytorin with gemfibrozil, cyclosporine, or danazol is contraindicated.
  • Caution should be used when prescribing other fibrates with Vytorin, 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 Vytorin with colchicine.
  • Caution should be used when treating Chinese patients with Vytorin in doses exceeding 10/20 mg/day coadministered with lipid-modifying doses of niacin-containing products.
Liver Enzymes
  • 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.

DRUG INTERACTIONS

Strong CYP3A4 Inhibitors, cyclosporine or danazol
  • 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 Vytorin be considered during concomitant use of voriconazole and Vytorin 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. Lipid-Lowering Drugs That Can Cause Myopathy When Given Alone
  • Gemfibrozil: Contraindicated with Vytorin.
  • Other fibrates: Caution should be used when prescribing with Vytorin Amiodarone, Ranolazine, Calcium Channel Blockers
  • The risk of myopathy/, including rhabdomyolysis, is increased by concomitant administration of amiodarone, ranolazine, or calcium channel blockers such as verapamil, diltiazem or amlodipine.

Colchicine

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

USE IN SPECIFIC POPULATIONS

Geriatric Use
  • Because advanced age (≥65 years) is a predisposing factor for myopathy, including rhabdomyolysis, Vytorin 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.

 

December 2010

 

 

 

ADVERSE REACTIONS

Post-Marketing Experience
  • erectile dysfunction
  • interstitial lung disease

PATIENT PACKAGE INSERT

What are the possible side effects of Vytorin?
  • Erectile dysfunction
  • breathing problems including persistent cough and/or shortness of breath or fever

 

April 2010

April 2010 Summary View


 

WARNINGS and PRECAUTIONS

Drug Interactions

The benefits of the combined use of VYTORIN with the following drugs should be carefully weighed against the potential risks of combinations: diltiazem.

TABLE 1 Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis
  • Diltiazem: Do not exceed 10/40 mg Vytorin daily
  • The combined use of Vytorin in patients at doses higher than 10/40 mg daily with diltiazem should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy.

 

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 or ezetimibe/simvastatin 10/40 mg coadministered with lipid-modifying doses of a niacin-containing product. Because the risk for myopathy is dose-related, Chinese patients should not receive Vytorin 10/80 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 Vytorin coadministered with lipid-modifying doses of niacin containing products. Because the risk for myopathy is dose-related, Chinese patients should not receive Vytorin 10/80 mg coadministered with lipid-modifying doses of niacin-containing products.