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.
Clinical Trials Experience: In controlled clinical studies as both monotherapy and combination therapy, the overall incidence of adverse reactions with Januvia was similar to that reported with placebo. Discontinuation of therapy due to clinical adverse reactions was also similar to placebo.
Two placebo-controlled monotherapy studies, one of 18- and one of 24-week duration, included patients treated with Januvia 100 mg daily, Januvia 200 mg daily and placebo. Two 24-week, placebo-controlled combination studies, one with metformin and one with pioglitazone, were also conducted. In addition to a stable dose of metformin or pioglitazone, patients whose diabetes was not adequately controlled were given either Januvia 100 mg daily or placebo. The adverse reactions, reported regardless of investigator assessment of causality in ≥5% of patients treated with Januvia 100 mg daily as monotherapy or in combination with pioglitazone and more commonly than in patients treated with placebo, are shown in Table 4. (See Table 4.)
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In patients receiving Januvia in combination with metformin, there were no adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients and more commonly than in patients given placebo.
The overall incidence of hypoglycemia in patients treated with Januvia 100 mg was similar to placebo (1.2% vs 0.9%). The incidence of selected GI adverse reactions in patients treated with Januvia was as follows: Abdominal pain (Januvia 100 mg, 2.3%; placebo, 2.1%), nausea (1.4%, 0.6%) and diarrhea (3%, 2.3%).
No clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed in patients treated with Januvia.
Laboratory Tests: The incidence of laboratory adverse reactions in patients treated with Januvia 100 mg was 8.2% compared to 9.8% in 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. In a 12-week study of 91 patients with chronic renal insufficiency, 37 patients with moderate renal insufficiency were randomized to Januvia 50 mg daily, while 14 patients with the same magnitude of renal impairment were randomized to placebo. Mean (SE) increases in serum creatinine were observed in patients treated with Januvia [0.12 mg/dL (0.04)] and in patients treated with placebo [0.07 mg/dL (0.07)]. The clinical significance of this added increase in serum creatinine relative to placebo is not known.
Post-Marketing Experience: The following additional adverse reactions have been identified during post-approval use of Januvia. 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, including anaphylaxis, angioedema, rash and urticaria.