Januvia Adverse Reactions

Clinical Trials Experience: 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 controlled clinical studies as both monotherapy and combination therapy with metformin, or pioglitazone, the overall incidence of adverse reactions, hypoglycemia, and discontinuation of therapy due to clinical adverse reactions with JANUVIA were similar to placebo. In combination with glimepiride, with or without metformin, the overall incidence of clinical adverse reactions with JANUVIA was higher than with placebo, in part related to a higher incidence of hypoglycemia (see Table 11); 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 JANUVIA 100 mg daily, JANUVIA 200 mg daily, and placebo. Four placebo-controlled add-on combination therapy studies were also conducted: one with metformin; one with pioglitazone, 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 JANUVIA 100 mg daily or placebo. The adverse reactions, excluding hypoglycemia, reported regardless of investigator assessment of causality in ≥5% of patients treated with JANUVIA 100 mg daily and more commonly than in patients treated with placebo, are shown in Table 9 for the clinical trials of at least 18 weeks duration. Incidences of hypoglycemia are shown in Table 11. (See Table 9.)

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In the 24-week study of patients receiving JANUVIA as add-on combination therapy 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.
In the 24-week study of patients receiving JANUVIA as add-on therapy to stable-dose insulin (with or without 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, except for hypoglycemia (see Table 11). In another 24-week study of patients receiving JANUVIA as add-on therapy while undergoing insulin intensification (with or without metformin), the only adverse experience reported regardless of investigator assessment of causality in ≥5% of patients treated with JANUVIA and more commonly than in patients treated with placebo was diarrhea (JANUVIA 5.2%; placebo 3.3%).
In a pooled analysis of the two monotherapy studies, the add-on to metformin study, and the add-on to pioglitazone study, the incidence of selected gastrointestinal 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 (3.0%, 2.3%).
In an additional, 24-week, placebo-controlled factorial study of initial therapy with sitagliptin in combination with metformin, the adverse reactions reported (regardless of investigator assessment of causality) in ≥5% of patients are shown in Table 10. (See Table 10.)

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No clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed in patients treated with JANUVIA.
In a pooled analysis of 19 double-blind clinical trials that included data from 10,246 patients randomized to receive sitagliptin 100 mg/day (N=5429) or corresponding (active or placebo) control (N=4817), the incidence of non-adjudicated acute pancreatitis was 0.1 per 100 patient-years in each group (4 patients with an event in 4708 patient-years for sitagliptin and 4 patients with an event in 3942 patient-years for control). (See Pancreatitis under Precautions.) See also TECOS Cardiovascular Safety Study, as follows.
TECOS Cardiovascular Safety Study: The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) included 7,332 patients treated with JANUVIA, 100 mg daily (or 50 mg daily if the baseline estimated glomerular filtration rate (eGFR) was ≥30 and <50 mL/min/1.73 m²), and 7,339 patients treated with placebo in the intention-to-treat population. Both treatments were added to usual care targeting regional standards for HbA_1c and CV risk factors. The overall incidence of serious adverse events in patients receiving JANUVIA was similar to that in patients receiving placebo. Assessment of pre-specified diabetes-related complications revealed similar incidences between groups including infections (18.4% of the JANUVIA-treated patients and 17.7% of the placebo-treated patients) and renal failure (1.4% of JANUVIA-treated patients and 1.5% of placebo-treated patients). The study population included a total of 2,004 patients ≥75 years of age (970 treated with JANUVIA and 1,034 treated with placebo). The adverse event profile in patients ≥75 years of age was generally similar to the overall population.
In the intention-to-treat population, among patients who were using insulin and/or a sulfonylurea at baseline, the incidence of severe hypoglycemia was 2.7% in JANUVIA-treated patients and 2.5% in placebo-treated patients; among patients who were not using insulin and/or a sulfonylurea at baseline, the incidence of severe hypoglycemia was 1.0% in JANUVIA-treated patients and 0.7% in placebo-treated patients. The incidence of adjudication-confirmed pancreatitis events was 0.3% in JANUVIA-treated patients and 0.2% in placebo-treated patients. The incidence of adjudication-confirmed malignancy events was 3.7% in JANUVIA-treated patients and 4.0% in placebo-treated patients.
Pediatric Population: In clinical trials with sitagliptin in pediatric patients with type 2 diabetes mellitus aged 10 to 17 years, the profile of adverse reactions was comparable to that observed in adults.
Hypoglycemia: In all (N=9) studies, adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia. A concurrent blood glucose measurement was not required although most (74%) reports of hypoglycemia were accompanied by a blood glucose measurement ≤70 mg/dL. When JANUVIA was co-administered with a sulfonylurea or with insulin, the percentage of patients with at least one adverse reaction of hypoglycemia was higher than in the corresponding placebo group (see Table 11).

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In the 24-week, placebo-controlled factorial study of initial therapy with JANUVIA in combination with metformin, the incidence of hypoglycemia was 0.6% in patients given placebo, 0.6% in patients given JANUVIA alone, 0.8% in patients given metformin alone, and 1.6% in patients given JANUVIA in combination with metformin.
Laboratory Tests: Across clinical studies, the incidence of laboratory adverse reactions was similar in patients treated with JANUVIA 100 mg compared to patients treated with placebo. A small increase in white blood cell count (WBC) was observed due to an increase in neutrophils. This increase in WBC (of approximately 200 cells/microL vs placebo, in four pooled placebo-controlled clinical studies, with a mean baseline WBC count of approximately 6600 cells/microL) 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.
Postmarketing Experience: Additional adverse reactions have been identified during postapproval 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 including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, and exfoliative skin conditions including Stevens-Johnson syndrome. (See Hypersensitivity Reactions under Precautions); hepatic enzyme elevations; acute pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing pancreatitis (see Important Limitations of Use under Indications/Uses; Pancreatitis under Precautions); worsening renal function, including acute renal failure (sometimes requiring dialysis) and tubulointerstitial nephritis; bullous pemphigoid [see Bullous Pemphigoid under Precautions); severe and disabling arthralgia (see Severe and Disabling Arthralgia under Precautions); constipation; vomiting; headache; myalgia; pain in extremity; back pain; pruritus.