Zocor Warnings

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Zocor Warnings

Myopathy/Rhabdomyolysis

Zocor (simvastatin), 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 Zocor (simvastatin) 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 Zocor (simvastatin).

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 Zocor (simvastatin).

Other drugs: Amiodarone or verapamil with higher doses of Zocor (simvastatin). In an ongoing clinical trial, myopathy has been reported in 6% of patients receiving Zocor (simvastatin) 80 mg and amiodarone. In an analysis of clinical trials involving 25,248 patients treated with simvastatin 20 to 80 mg, the incidence of myopathy was higher in patients receiving verapamil and simvastatin (4/635; 0.63%) than in patients taking simvastatin without a calcium channel blocker (13/21,224; 0.061%).

• The risk of myopathy/rhabdomyolysis is dose related. The incidence in clinical trials, in which patients were carefully monitored and some interacting drugs were excluded, has been approximately 0.02% at 20 mg, 0.07% at 40 mg and 0.3% at 80 mg.

Consequently:

1. Use of Zocor (simvastatin) 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 simvastatin 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.
2. The dose of Zocor (simvastatin) should not exceed 10 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 Zocor (simvastatin) 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 Zocor (simvastatin) typically provides little additional reduction in LDL-C, but further reductions of TG and further increases in HDL-C may be obtained.
3. The dose of Zocor (simvastatin) should not exceed 20 mg daily in patients receiving concomitant medication with amiodarone or verapamil. The combined use of Zocor (simvastatin) 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.
4. All patients starting therapy with Zocor (simvastatin), or whose dose of simvastatin is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. Zocor (simvastatin) 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 Zocor (simvastatin) or whose dose is being increased, but there is no assurance that such monitoring will prevent myopathy.
5. Many of the patients who have developed rhabdomyolysis on therapy with Zocor (simvastatin) have had complicated medical histories, including renal insufficiency usually as a consequence of long-standing diabetes mellitus. Such patients merit closer monitoring. Therapy with Zocor (simvastatin) should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.

Liver Dysfunction

Persistent increases (to more than 3X the ULN) in serum transaminases have occurred in approximately 1% of patients who received simvastatin in clinical studies. When Zocor (simvastatin) treatment was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pretreatment levels. The increases were not associated with jaundice or other clinical signs or symptoms. There was no evidence of hypersensitivity.

In 4S, the number of patients with more than one transaminase elevation to > 3X ULN, over the course of the study, was not significantly different between the Zocor (simvastatin) and placebo groups (14 [0.7%] vs. 12 [0.6%]). Elevated transaminases resulted in the discontinuation of 8 patients from therapy in the Zocor (simvastatin) group (n=2,221) and 5 in the placebo group (n=2,223). Of the 1,986 simvastatin treated patients in 4S with normal liver function tests (LFTs) at baseline, only 8 (0.4%) developed consecutive LFT elevations to > 3X ULN and/or were discontinued due to transaminase elevations during the 5.4 years (median follow-up) of the study. Among these 8 patients, 5 initially developed these abnormalities within the first year. All of the patients in this study received a starting dose of 20 mg of Zocor (simvastatin); 37% were titrated to 40 mg.

In 2 controlled clinical studies in 1,105 patients, the 12-month incidence of persistent hepatic transaminase elevation without regard to drug relationship was 0.9% and 2.1% at the 40- and 80-mg dose, respectively. No patients developed persistent liver function abnormalities following the initial 6 months of treatment at a given Zocor dose.

It is recommended that liver function tests be performed before the initiation of treatment, and thereafter when clinically indicated. Patients titrated to the 80-mg Zocor dose should receive an additional test prior to titration, 3 months after titration to the 80-mg dose, and periodically thereafter (e.g., semiannually) for the first year of treatment. 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 3X ULN or greater persist, withdrawal of therapy with Zocor 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 diseases or unexplained transaminase elevations are contraindications to the use of Zocor (simvastatin).

As with other lipid-lowering agents, moderate (less than 3X ULN) elevations of serum transaminases have been reported following therapy with Zocor (simvastatin). These changes appeared soon after initiation of therapy with simvastatin, were often transient, were not accompanied by any symptoms and did not require interruption of treatment.

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