warnings and cautions
5 WARNINGS AND PRECAUTIONS SIMCOR should not be substituted for equivalent doses of immediate-release (crystalline) niacin. For patients switching from immediate-release niacin to SIMCOR, therapy with SIMCOR should be initiated at 500/20 mg and appropriately titrated to the desired therapeutic response. Patients already taking simvastatin 20-40 mg who need additional management of their lipid levels may be started on a SIMCOR dose of 500/40 mg once daily at bedtime. Doses of SIMCOR greater than 2000/40 mg are not recommended. Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Risks increase with higher doses, advanced age (≥ 65), hypothyroidism, renal impairment, and concomitant use of cyclosporine, danazol, gemfibrozil, amiodarone, and verapamil and potent CYP3A4 inhibitors. (5.1) Liver enzyme abnormalities and monitoring: Persistent elevations in hepatic transaminase can occur. Monitor liver enzymes before and during treatment. (5.2) Severe hepatic toxicity has occurred in patients substituting sustained-release niacin for immediate-release niacin at equivalent doses. If switching from niacin preparations other than niacin extended-release (NIASPAN), initiate with lowest SIMCOR dose; niacin extended-release can be converted at equivalent doses. (5.2) Niacin extended-release can increase serum glucose levels. Glucose levels should be closely monitored in diabetic or potentially diabetic patients particularly during the first few months of use. (5.3) 5.1 Myopathy/Rhabdomyolysis Simvastatin Simvastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times 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. As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose related. In a clinical trial database in which 41,050 patients were treated with simvastatin with 24,747 (approximately 60%) treated for at least 4 years, the incidence of myopathy was approximately 0.02%, 0.08%, and 0.53% at 20, 40, and 80 mg/day, respectively. In these trials, patients were carefully monitored and some interacting medicinal products were excluded. Potent inhibitors of CYP3A4: The risk of myopathy appears to be increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Simvastatin is metabolized by the cytochrome P450 isoform 3A4. Certain drugs which share this metabolic pathway can raise the plasma levels of simvastatin and may increase the risk of myopathy. These include cyclosporine, itraconazole, ketoconazole, and other antifungal azoles, the macrolide antibiotics erythromycin and clarithromycin, and the ketolide antibiotic telithromycin, HIV protease inhibitors, the antidepressant nefazodone, or large quantities of grapefruit juice (> 1 quart daily). The risk of myopathy/rhabdomyolysis is increased by concomitant use of simvastatin and, therefore, SIMCOR with the following: Potent inhibitors of cytochrome P-450 isoform, 3A4 (CYP 3A4): Itraconazole, ketoconazole, and other antifungal azoles Macrolide antibiotics erythromycin, clarithromycin, and telithromycin HIV protease inhibitors Antidepressant nefazodone Grapefruit juice in large quantities (> 1 quart daily) The use of SIMCOR concomitantly with these potent CYP3A4 inhibitors should be avoided. [See Drug Interactions (7.1) ] Cyclosporine or Danazol: Simvastatin dose should not exceed 10 mg daily in combination with cyclosporine or danazol. Therefore, the combined used of SIMCOR with cyclosporine or danazol should be avoided. [See Drug Interactions (7.2) ] Gemfibrozil: Simvastatin dose should not exceed 10 mg daily when concomitantly used with gemfibrozil. Therefore, the combined use of SIMCOR with gemfibrozil should be avoided. [See Drug Interactions (7.4) ] Other Fibrates: Combined use of SIMCOR with drugs that cause myopathy/rhabdomyolysis when given alone, such as fibrates, should be avoided. [See Drug Interactions (7.4) ] Amiodarone or Verapamil: The dose of the simvastatin component of SIMCOR should not exceed 20 mg in patients receiving amiodarone or verapamil concomitantly. The combined use of the 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. [See Drug Interactions (7.3) ] SIMCOR Myopathy and/or rhabdomyolysis have been reported when simvastatin is used in combination with lipid-altering doses (≥ 1 gram/day) of niacin. Physicians contemplating the use of SIMCOR, a combination of simvastatin and niacin extended-release (NIASPAN), should weigh the potential benefits and risks, and should carefully monitor for any signs and symptoms of muscle pain, tenderness, or weakness, particularly during the initial month of treatment or during any period of upward dosage titration of either drug. Periodic determination of serum creatine kinase (CK) determinations may be considered in such situations, but there is no assurance that such monitoring will prevent myopathy. Patients starting therapy with SIMCOR should be advised of the risk of myopathy, and told to report promptly unexplained muscle pain, tenderness, or weakness. A CK level above 10 times ULN in a patient with unexplained muscle symptoms indicates myopathy. SIMCOR therapy should be discontinued if myopathy is diagnosed or suspected. In patients with complicated medical histories predisposing to rhabdomyolysis, such as renal insufficiency, dose escalation requires caution. Also, as there are no known adverse consequences of brief interruption of therapy, treatment with SIMCOR should be stopped for a few days before elective major surgery and when any major acute medical or surgical condition supervenes (e.g., sepsis, hypotension, dehydration, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures). 5.2 Liver Dysfunction Cases of severe hepatic toxicity, including fulminant hepatic necrosis, have occurred in patients who have substituted sustained-release (modified-release, timed-release) niacin products for immediate-release (crystalline) niacin at equivalent doses. Patients previously receiving niacin products other than niacin extended-release (NIASPAN) should be started on SIMCOR at the lowest recommended starting dose. [See Dosage and Administration (2) ] SIMCOR should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver disease or unexplained transaminase elevations are contraindications to the use of SIMCOR. [See Contraindications (4) ] Niacin extended-release (NIASPAN) and simvastatin can cause abnormal liver tests. In a simvastatin-controlled, 24 week study with SIMCOR in 641 patients, there were no persistent increases (to more than 3x the ULN) in serum transaminases. In three placebo-controlled clinical studies of niacin extended-release, patients with normal serum transaminases levels at baseline did not experience any transaminase elevations greater than 3x the ULN. 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 drug treatment was interrupted or discontinued in these patients, the transaminases 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. Liver function tests should be performed on all patients during therapy with SIMCOR. It is recommended that liver function tests be performed before treatment begins, every 12 weeks for the first 6 months, and periodically thereafter (e.g., at approximately 6-month intervals). 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 returns to normal. Should an increase in transaminase levels of more than 3x ULN persist, or if transaminase elevations are associated with symptoms of nausea, fever, and/or malaise, withdrawal of SIMCOR therapy is recommended. 5.3 Laboratory Abnormalities Increase in Blood Glucose: Niacin treatment can increase fasting blood glucose. In a simvastatin-controlled, 24-week study with SIMCOR the change from baseline in glycosylated hemoglobin levels was 0.2% for SIMCOR-treated patients and 0.2% for simvastatin-treated patients. Diabetic or potentially diabetic patients should be observed closely during treatment with SIMCOR, particularly during the first few months of therapy. Adjustment of diet and/or hypoglycemic therapy or discontinuation of SIMCOR may be necessary. Reduction in platelet count: Niacin can reduce platelet count. In a simvastatin-controlled, 24-week study with SIMCOR the mean percent change from baseline for patients treated with 2000/40 mg daily was -5.6%. Increase in ProthrombinTime (PT): Niacin can cause small increases in PT . In a simvastatin-controlled, 24-week study with SIMCOR this effect was not seen. Increase in Uric Acid: Elevated uric acid levels have occurred with niacin therapy. In a simvastatin-controlled, 24-week study with SIMCOR this effect was not seen. Nevertheless, in patients predisposed to gout, SIMCOR therapy should be used with caution. Decrease in Phosphorus: Small dose-related reductions in phosphorous levels were seen in clinical studies with niacin. In a simvastatin-controlled, 24-week study with SIMCOR this effect was not seen.