Januvia was generally well tolerated in controlled clinical studies as both monotherapy and combination therapy, with discontinuation of therapy due to clinical adverse experiences similar to placebo.
In 4 placebo-controlled clinical studies, as both monotherapy (1 study of 18- and 1 of 24-week duration) and add-on combination therapy with metformin or pioglitazone (both of 24-week duration), there were 1082 patients treated with Januvia 100 mg once daily and 778 patients given placebo. (Two of these studies also included 456 patients treated with Januvia 200 mg daily, 2 times the recommended daily dose.) There were no drug-related adverse reactions reported that occurred with an incidence of ≥1% in patients receiving Januvia 100 mg. Overall, the safety profile of the 200-mg daily dose was similar to that of the 100-mg daily dose.
In a prespecified pooled analysis of the previously mentioned studies, the overall incidence of adverse experiences of hypoglycemia in patients treated with Januvia 100 mg was similar to placebo (1.2% vs 0.9%). The incidence of selected gastrointestinal adverse experiences in patients treated with Januvia or placebo were: Abdominal pain (Januvia, 2.3%; placebo, 2.1%), nausea (1.4%, 0.6%), vomiting (0.8%, 0.9%) and diarrhea (3%, 2.3%).
In all studies, adverse reactions of hypoglycemia were based in all reports of symptomatic hypoglycemia; a concurrent glucose measurement was not required.
Add-on Combination with a Sulfonylurea: In a 24-week placebo-controlled study of Januvia 100 mg in combination with glimepiride or with glimepiride and metformin (Januvia, N=222; placebo, N=219), the drug-related adverse reaction reported in ≥1% of patients treated with Januvia and more commonly than in patients treated with placebo was hypoglycemia (Januvia, 9.5%; placebo, 0.9%).
Add-on Combination with Metformin and a PPARγ Agonist: In a placebo-controlled study of Januvia 100 mg in combination with metformin and rosiglitazone (Januvia, N=170; placebo, N=92), the drug-related adverse reactions reported through the primary time point at week 18 in ≥1% of patients treated with Januvia and more commonly than in patients treated with placebo were: Headache (Januvia, 2.4%; placebo, 0%), diarrhea (1.8%, 1.1%), nausea (1.2%, 1.1%), hypoglycemia (1.2%, 0%) and vomiting (1.2%, 0%). Through week 54, the drug-related adverse reactions reported in ≥1% of patients treated with Januvia and more commonly than in patients treated with placebo were: Headache (2.4%, 0%), hypoglycemia (2.4%, 0%), upper respiratory tract infection (1.8%, 0%), nausea (1.2%, 1.1%), cough (1.2%, 0%), fungal skin infection (1.2%, 0%), peripheral edema (1.2%, 0%), and vomiting (1.2%, 0%).
Initial Combination Therapy with Metformin: In a 24-week placebo-controlled factorial study of initial therapy with sitagliptin 100 mg in combination with metformin at 1000 or 2000 mg/day (administered as sitagliptin 50 mg/metformin 500 or 1000 mg twice daily), the drug-related adverse reactions reported in ≥1% of patients treated with sitagliptin plus metformin (N=372) and more commonly than in patients treated with metformin alone (N=364) were: Diarrhea (sitagliptin plus metformin, 3.5%; metformin, 3.3%), dyspepsia (1.3%; 1.1%), flatulence (1.3%; 0.5%), vomiting (1.1%; 0.3%) and headache (1.3%; 1.1%). The incidence of hypoglycemia was 1.1% in patients given sitagliptin in combination with metformin and 0.5% in patients given metformin alone.
Add-on Combination with Insulin: In a 24-week placebo-controlled study of Januvia 100 mg in combination with insulin (with or without metformin), the drug-related adverse reactions reported in ≥1% of patients treated with Januvia (N=322) and more commonly than in patients treated with placebo (N=319) were: Hypoglycemia (Januvia, 9.6%; placebo, 5.3%), influenza (1.2%, 0.3%) and headache (1.2%, 0%).
No clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed in patients treated with Januvia.
Post-Marketing Experience: Additional adverse reactions have been identified during post-marketing use of Januvia as monotherapy and/or in combination with other antihyperglycemic agents. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Hypersensitivity reactions include anaphylaxis, angioedema, rash, urticaria; cutaneous vasculitis and exfoliative skin conditions including Stevens-Johnson syndrome (see Contraindications and Precautions: Hypersensitivity Reactions); pancreatitis, worsening renal function including acute renal failure (sometimes requiring dialysis); upper respiratory tract infection; nasopharyngitis; constipation; vomiting; headache.
Laboratory Test Findings: The incidence of laboratory adverse experiences was similar in patients treated with Januvia 100 mg compared to patients treated with placebo. Across clinical studies, a small increase in white blood cell count (approximately 200 cells/microL difference in WBC vs placebo; mean baseline WBC approximately 6600 cells/microL) was observed due to an increase in neutrophils. This observation was seen in most but not all studies. This change in laboratory parameters is not considered to be clinically relevant.