There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [see Warnings and Precautions (5.2)].

There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).

Hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, and exfoliative skin conditions including Stevens-Johnson syndrome have been reported with sitagliptin [see Warnings and Precautions (5.6)].

An apparent hypersensitivity syndrome has been reported rarely with simvastatin which has included some of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome.

7 DRUG INTERACTIONS
[See Clinical Pharmacology (12.3).]

7.1 Strong CYP3A4 Inhibitors, Cyclosporine, or Danazol
Strong CYP3A4 inhibitors: Simvastatin, like several other inhibitors of HMG-CoA reductase, is a substrate of CYP3A4. Simvastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity; therefore it is not expected to affect the plasma concentrations of other drugs metabolized by CYP3A4.

Elevated plasma levels of HMG-CoA reductase inhibitory activity increase the risk of myopathy and rhabdomyolysis, particularly with higher doses of simvastatin. [See Warnings and Precautions (5.2); Clinical Pharmacology (12.3).] Concomitant use of drugs labeled as having a strong inhibitory effect on CYP3A4 is contraindicated [see Contraindications (4)]. If treatment with itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with JUVISYNC must be suspended during the course of treatment. If JUVISYNC is suspended during treatment with any of these agents, consideration should be given to the use of sitagliptin to maintain glycemic control until JUVISYNC can be reinstated.

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 [see Contraindications (4); Warnings and Precautions (5.2); Clinical Pharmacology (12.3)].

7.2 Lipid-Lowering Drugs That Can Cause Myopathy When Given Alone
Gemfibrozil: Contraindicated with JUVISYNC [see Contraindications (4); Warnings and Precautions (5.2)].

Other fibrates: Caution should be used when prescribing with JUVISYNC [see Warnings and Precautions (5.2)].

7.