Simvastatin - Warnings and Precautions

5 WARNINGS AND PRECAUTIONS • Myopathy and Rhabdomyolysis: Risk factors include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher ezetimibe and simvastatin tablets dosage.

Chinese patients may be at higher risk for myopathy.

Discontinue ezetimibe and simvastatin tablets if markedly elevated CK levels occur or myopathy is diagnosed or suspected.

Temporarily discontinue ezetimibe and simvastatin tablets in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis.

Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing ezetimibe and simvastatin tablets dosage.

Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. • Immune-Mediated Necrotizing Myopathy (IMNM): Rare reports of IMNM, an autoimmune myopathy, have been reported.

Discontine ezetimibe and simvastatin tablets if IMNM is suspected. • Hepatic Dysfunction: Increases in serum transaminases have occurred, some persistent.

Rare reports of fatal and non-fatal hepatic failure have occurred.

Consider testing liver enzyme before initiating therapy and as clinically indicated thereafter.

If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue ezetimibe and simvastatin tablets.

5.1 Myopathy and Rhabdomyolysis Ezetimibe and simvastatin tablets may cause myopathy and rhabdomyolysis.

Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis in patients treated with statins, including ezetimibe and simvastatin tablets.

In clinical trials of 24,747 simvastatin-treated patients with a median follow-up of 4 years, the incidence of myopathy, defined as unexplained muscle weakness, pain, or tenderness accompanied by creatinine kinase (CK) increases greater than ten times the upper limit of normal (10 X ULN), were approximately 0.03%, 0.08%, and 0.61% in patients treated with simvastatin 20 mg, 40 mg, and 80 mg daily, respectively.

In another clinical trial of 12,064 simvastatin-treated patients (with a history of myocardial infarction) with a mean follow-up of 6.7 years, the incidences of myopathy in patients taking simvastatin 20 mg and 80 mg daily were approximately 0.02% and 0.9%, respectively.

The incidences of rhabdomyolysis (defined as myopathy with a CK >40 X ULN) in patients taking simvastatin 20 mg and 80 mg daily were approximately 0% and 0.4%, respectively [ see Adverse Reactions ].

In the Trial of Heart and Renal Protection (SHARP) , 9270 patients with chronic kidney disease were allocated to receive ezetimibe and simvastatin tablets 10/20 mg daily (n=4650) or placebo (n=4620).

During a median follow-up period of 4.9 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]) was 0.2% for ezetimibe and simvastatin tablets and 0.1% for placebo: the incidence of rhabdomyolysis (defined as myopathy with a CK > 40 times ULN) was 0.09% for ezetimibe and simvastatin tablets and 0.02% for placebo.

In postmarketing experience with ezetimibe, cases of myopathy and rhabdomyolysis have been reported.

Most patients who developed rhabdomyolysis were taking a statin prior to initiating ezetimibe.

However, rhabdomyolysis has been reported with ezetimibe monotherapy and with the addition of ezetimibe to agents known to be associated with increased risk of rhabdomyolysis, such as fibric acid derivatives.

Ezetimibe and simvastatin tablets and a fenofibrate, if taking concomitantly, should both be immediately discontinued if myopathy is diagnosed or suspected.

Risk Factors for Myopathy Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs (including other lipid-lowering therapies), and higher ezetimibe and simvastatin tablets dosage; Chinese patients on ezetimibe and simvastatin tablets may be at higher risk for myopathy [ see Contraindications , Drug Interactions , and Use in Specific Populations ].

The risk of myopathy is increased by elevated plasma levels of simvastatin and simvastatin acid.

The risk is also greater in patients taking ezetimibe and simvastatin tablets 80 mg daily compared with patients taking lower ezetimibe and simvastatin tablets dosages and compared with patients using other statins with similar or greater LDL-C-lowering efficacy [ see Adverse Reactions ].

Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis The concomitant use of strong CYP3A4 inhibitors with ezetimibe and simvastatin tablets are contraindicated.