Janumet XR Side Effects

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.
Sitagliptin and Metformin Coadministration in Patients with Type 2 Diabetes Inadequately Controlled on Diet and Exercise: Table 7 summarizes the most common (≥5% of patients) adverse reactions reported (regardless of investigator assessment of causality) in a 24-week placebo-controlled factorial study in which sitagliptin and metformin were coadministered to patients with type 2 diabetes inadequately controlled on diet and exercise. (See Table 7.)

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Sitagliptin Add-on Therapy in Patients with Type 2 Diabetes Inadequately Controlled on Metformin Alone: In a 24-week placebo-controlled trial of sitagliptin 100 mg administered once daily added to a twice daily metformin regimen, there were no adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients and more commonly than in patients given placebo. Discontinuation of therapy due to clinical adverse reactions was similar to the placebo treatment group (sitagliptin and metformin, 1.9%; placebo and metformin, 2.5%).
Gastrointestinal Adverse Reactions: The incidences of pre-selected gastrointestinal adverse experiences in patients treated with sitagliptin and metformin were similar to those reported for patients treated with metformin alone. (See Table 8.)

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Sitagliptin in Combination with Metformin and Glimepiride: In a 24-week placebo-controlled study of sitagliptin 100 mg as add-on therapy in patients with type 2 diabetes inadequately controlled on metformin and glimepiride (sitagliptin, N=116; placebo, N=113), the adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients treated with sitagliptin and more commonly than in patients treated with placebo were: hypoglycemia (Table 9) and headache (6.9%, 2.7%).
Sitagliptin in Combination with Metformin and Insulin: In a 24-week placebo-controlled study of sitagliptin 100 mg as add-on therapy in patients with type 2 diabetes inadequately controlled on metformin and stable-dose insulin (sitagliptin, N=229; placebo, N=233), the only adverse reaction reported regardless of investigator assessment of causality in ≥5% of patients treated with sitagliptin and more commonly than in patients treated with placebo was hypoglycemia (Table 9). In another 24-week study of patients receiving sitagliptin as add-on therapy while undergoing insulin intensification (with or without metformin), among patients treated with sitagliptin and metformin, there were no adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients and more commonly than in patients treated with placebo and metformin.
Hypoglycemia: In all (N=5) studies, adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia; a concurrent glucose measurement was not required although most (77%) reports of hypoglycemia were accompanied by a blood glucose measurement ≤70 mg/dL. When the combination of sitagliptin and metformin was coadministered with a sulfonylurea or with insulin, the percentage of patients reporting at least one adverse reaction of hypoglycemia was higher than that observed with placebo and metformin coadministered with a sulfonylurea or with insulin (see Table 9).

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The overall incidence of reported adverse reactions of hypoglycemia in patients with type 2 diabetes inadequately controlled on diet and exercise was 0.6% in patients given placebo, 0.6% in patients given sitagliptin alone, 0.8% in patients given metformin alone, and 1.6% in patients given sitagliptin in combination with metformin. In patients with type 2 diabetes inadequately controlled on metformin alone, the overall incidence of adverse reactions of hypoglycemia was 1.3% in patients given add-on sitagliptin and 2.1% in patients given add-on placebo.
Vital Signs and Electrocardiograms: With the combination of sitagliptin and metformin, no clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed.
Pancreatitis: 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 events 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 Precautions). See also TECOS Cardiovascular Safety Study, as follows.
Sitagliptin: The most common adverse experience in sitagliptin monotherapy reported regardless of investigator assessment of causality in ≥5% of patients and more commonly than in patients given placebo was nasopharyngitis.
Metformin hydrochloride: The most common (>5%) established adverse reactions due to initiation of metformin therapy are diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache.
TECOS Cardiovascular Safety Study: The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) included 7,332 patients treated with sitagliptin, 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 sitagliptin 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 sitagliptin-treated patients and 17.7% of the placebo-treated patients) and renal failure (1.4% of sitagliptin-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 sitagliptin 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 sitagliptin-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 sitagliptin-treated patients and 0.7% in placebo-treated patients. The incidence of adjudication-confirmed pancreatitis events was 0.3% in sitagliptin-treated patients and 0.2% in placebo-treated patients. The incidence of adjudication-confirmed malignancy events was 3.7% in sitagliptin-treated patients and 4.0% in placebo-treated patients.
Pediatric Population: In a pooled analysis of two placebo-controlled clinical studies with JANUMET and JANUMET XR in pediatric patients aged 10 to 17 years with type 2 diabetes, the drug-related adverse reactions reported through the 54-week treatment period in ≥1% of patients in the JANUMET/JANUMET XR group (N=107) and more commonly than in patients in the Metformin/Metformin XR group (N=113) were diarrhea (JANUMET/JANUMET XR, 2.8%; Metformin/Metformin XR, 0.9%), nausea (2.8%, 0.9%), and hypoglycemia (6.5%, 3.5%).
The profile of side effects was comparable to that observed in adults. There were no clinically relevant differences between the JANUMET/JANUMET XR and Metformin/Metformin XR groups through Week 54 in laboratory safety endpoints, vital signs, indices of adiposity, or growth and development endpoints.
Laboratory Tests: Sitagliptin: The incidence of laboratory adverse reactions was similar in patients treated with sitagliptin and metformin (7.6%) compared to patients treated with placebo and metformin (8.7%). In most but not all 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 a small increase in neutrophils. This change in laboratory parameters is not considered to be clinically relevant.
Metformin hydrochloride: In controlled clinical trials of metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum Vitamin B₁₂ levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B₁₂ absorption from the B₁₂-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or Vitamin B₁₂ supplementation. (See Precautions.)
Postmarketing Experience: Additional adverse reactions have been identified during postapproval use of sitagliptin with or without metformin, and/or in combination with other antidiabetic medications. 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 Precautions); upper respiratory tract infection; hepatic enzyme elevations; acute pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing pancreatitis (see 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 Precautions); constipation; vomiting; headache; myalgia; pain in extremity; back pain; pruritus.