The benefits of the combined use of JUVISYNC with the following drugs should be carefully weighed against the potential risks of combinations: amiodarone, dronedarone, verapamil, diltiazem, amlodipine, ranolazine and lipid-lowering drugs other than gemfibrozil (other fibrates or ≥1 g/day of niacin), [see Drug Interactions (7.2, 7.3, 7.4); Table 6 in Clinical Pharmacology (12.3)].

Cases of myopathy, including 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. Caution should be used when treating Chinese patients with JUVISYNC 100 mg/40 mg or 50 mg/40 mg per day coadministered with lipid-modifying doses of niacin-containing products. It is unknown if the risk for myopathy with coadministration of JUVISYNC with lipid-modifying doses of niacin-containing products observed in Chinese patients applies to other Asian patients [see Drug Interactions (7.4)].

Prescribing recommendations for interacting agents are summarized in Table 1 [see also Dosage and Administration (2.4); Drug Interactions (7.1, 7.2, 7.3); Clinical Pharmacology (12.3)].

Table 1: Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis  Interacting Agents Prescribing Recommendations
Strong CYP3A4 Inhibitors, e.g.:
  Itraconazole
  Ketoconazole
  Posaconazole
  Voriconazole
  Erythromycin
  Clarithromycin
  Telithromycin
  HIV protease inhibitors
  Boceprevir
  Telaprevir
  Nefazodone
Gemfibrozil
Cyclosporine
Danazol Contraindicated with JUVISYNC
Verapamil
Diltiazem
Dronedarone Do not exceed 10 mg simvastatin (100 mg/10 mg or 50 mg/10 mg JUVISYNC) daily
Amiodarone
Amlodipine
Ranolazine Do not exceed 20 mg simvastatin (100 mg/20 mg or 50 mg/20 mg JUVISYNC) daily
Grapefruit juice Avoid grapefruit juice

5.3 Liver Dysfunction
Persistent increases (to more than 3× 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 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 the Scandinavian Simvastatin Survival Study (4S) [see Clinical Studies (14.2)], the number of patients with more than one transaminase elevation to >3× ULN, over the course of the study, was not significantly different between the simvastatin and placebo groups (14 [0.7%] vs. 12 [0.6%]). Elevated transaminases resulted in the discontinuation of 8 patients from therapy in the simvastatin group (n=2221) and 5 in the placebo group (n=2223). Of the 1986 simvastatin treated patients in 4S with normal liver function tests (LFTs) at baseline, 8 (0.4%) developed consecutive LFT elevations to >3× ULN and/or were discontinued due to transaminase elevations during the 5.4 y