5.6 Hypersensitivity Reactions
[See also Adverse Reactions (6.2).]

There have been postmarketing reports of serious hypersensitivity reactions in patients treated with sitagliptin. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after initiation of treatment with sitagliptin, with some reports occurring after the first dose.

If a hypersensitivity reaction is suspected, discontinue JUVISYNC, assess for other potential causes for the event, and institute alternative treatment.

Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution in a patient with a history of angioedema with another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with JUVISYNC.

5.7 Endocrine Function
Increases in A1C and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including simvastatin.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

JUVISYNC

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In a pooled subgroup analysis of 19 controlled clinical studies of sitagliptin involving 1582 patients whose background therapy included simvastatin, incidences of adverse reactions for patients treated with sitagliptin and simvastatin (n=827) were similar to those for patients treated with control therapy (placebo or active comparator) and simvastatin (n=755). Among these patients, 3.3% of the sitagliptin-treated group and 4.2% of controls discontinued due to adverse reactions.

Sitagliptin

In controlled clinical studies as both monotherapy and combination therapy with metformin, pioglitazone, or rosiglitazone and metformin, the overall incidence of adverse reactions, hypoglycemia, and discontinuation of therapy due to clinical adverse reactions with sitagliptin were similar to placebo. In combination with glimepiride, with or without metformin, the overall incidence of clinical adverse reactions with sitagliptin was higher than with placebo, in part related to a higher incidence of hypoglycemia (see Table 4); the incidence of discontinuation due to clinical adverse reactions was similar to placebo.

Two placebo-controlled monotherapy studies, one of 18- and one of 24-week duration, included patients treated with sitagliptin 100 mg daily, sitagliptin 200 mg daily, and placebo. Five placebo-controlled add-on combination therapy studies were also conducted: one with metformin; one with pioglitazone; one with metformin and rosiglitazone; one with glimepiride (with or without metformin); and one with insulin (with or without metformin). In these trials, patients with inadequate glycemic control on a stable dose of the background therapy were randomized to add-on therapy with sitagliptin 100 mg daily or placebo. The adverse reactions, excluding hypoglycemia, reported regardless of investigator assessment of causality in ≥5% of patients treated with sitagliptin 100 mg daily and m