In 2 controlled clinical studies in 1105 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 dose.

It is recommended that liver function tests be performed before the initiation of treatment, and thereafter when clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including simvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with JUVISYNC, promptly interrupt therapy. If an alternate etiology is not found do not restart JUVISYNC. Note that ALT may emanate from muscle, therefore ALT rising with CK may indicate myopathy [see Warnings and Precautions (5.2)].

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 JUVISYNC.

As with other lipid-lowering agents, moderate (less than 3× ULN) elevations of serum transaminases have been reported following therapy with 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. [See also Adverse Reactions (6.1).]

5.4 Renal Impairment
Assessment of renal function is recommended prior to initiating JUVISYNC and periodically thereafter. JUVISYNC is not recommended for use in patients with severe renal impairment or ESRD because doses of JUVISYNC appropriate for patients with severe renal impairment or ESRD are not available in this combination product. [See Dosage and Administration (2.2); Clinical Pharmacology (12.3).]

A dosage adjustment is recommended in patients with moderate renal impairment. [See Dosage and Administration (2.2); Clinical Pharmacology (12.3).] Caution should be used to ensure that the correct dose of JUVISYNC is prescribed for patients with moderate renal impairment (creatinine clearance ≥30 to <50 mL/min).

There have been postmarketing reports of worsening renal function, including acute renal failure, sometimes requiring dialysis, in patients treated with sitagliptin. A subset of these reports involved patients with renal impairment, some of whom were prescribed inappropriate doses of sitagliptin. A return to baseline levels of renal impairment has been observed with supportive treatment and discontinuation of potentially causative agents.

Sitagliptin has not been found to be nephrotoxic in preclinical studies at clinically relevant doses, or in clinical trials.

5.5 Use with Medications Known to Cause Hypoglycemia
When sitagliptin was used in combination with a sulfonylurea or with insulin, medications known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo used in combination with a sulfonylurea or with insulin. [See Adverse Reactions (6.1).] Theref