Janumet Adverse Reactions

In placebo-controlled clinical trials, in patients with type 2 diabetes mellitus, the combination of sitagliptin and metformin was generally well tolerated. The overall incidence of side effects reported in patients receiving the combination of sitagliptin and metformin was similar to that reported in patients receiving the combination of placebo and metformin.
Combination Therapy with Sitagliptin and Metformin: Initial Therapy: In a 24-week placebo-controlled factorial study of initial therapy with sitagliptin 50 mg twice daily in combination with metformin at 500 or 1000 mg twice daily, the drug-related adverse reactions reported in ≥1% of patients receiving combination therapy (and greater than in patients receiving placebo) are shown in Table 1. (See Table 1.)

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Add-on Combination Therapy to Metformin: In a 24-week placebo-controlled study of sitagliptin added to ongoing metformin therapy, 464 patients on metformin were treated with sitagliptin 100 mg once daily and 237 patients were given placebo with metformin. The only drug-related adverse reaction reported that occurred with an incidence of ≥1% and higher than placebo in patients receiving sitagliptin and metformin was nausea (100 mg sitagliptin and metformin, 1.1%; placebo and metformin, 0.4%).
Hypoglycemia and Gastrointestinal Adverse Experiences: In the placebo-controlled studies of combination therapy with sitagliptin and metformin, the incidence of hypoglycemia (regardless of investigator assessment of causality) reported in patients treated with the combination of sitagliptin and metformin was similar to that reported for patients treated with metformin and placebo. The incidences of pre-specified gastrointestinal adverse experiences in patients treated with the combination of sitagliptin and metformin were similar to those reported for patients treated with metformin alone. (See Table 2.)

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In all studies, adverse experiences of hypoglycemia were based on all reports of symptomatic hypoglycemia; a concurrent glucose measurement was not required.
Sitagliptin in Combination with Metformin and a Sulfonylurea: In a 24-week placebo-controlled study of sitagliptin 100 mg daily added to ongoing combination treatment with glimepiride ≥4 mg daily and metformin ≥1500 mg daily, the drug-related adverse reactions reported in ≥1% of patients treated with sitagliptin (N=116) and more commonly than in patients treated with placebo (N=113) were hypoglycemia (sitagliptin, 13.8%; placebo, 0.9%) and constipation (1.7%, 0.0%).
Sitagliptin in Combination with Metformin and a PPARγ Agonist: In a placebo-controlled study of sitagliptin 100 mg daily added to ongoing combination treatment with metformin and rosiglitazone, the drug-related adverse reactions reported through the primary time point at Week 18 in ≥1% of patients treated with sitagliptin (N=170) and more commonly than in patients treated with placebo (N=92) were: headache (sitagliptin, 2.4%; placebo, 0.0%), diarrhea (1.8%, 1.1%), nausea (1.2%, 1.1%), hypoglycemia (1.2%, 0.0%), and vomiting (1.2%, 0.0%). Through Week 54, the drug-related adverse reactions reported in ≥1% of patients treated with sitagliptin and more commonly than in patients treated with placebo were: headache (2.4%, 0.0%), hypoglycemia (2.4%, 0.0%), upper respiratory tract infection (1.8%, 0.0%), nausea (1.2%, 1.1%), cough (1.2%, 0.0%), fungal skin infection (1.2%, 0.0%), peripheral edema (1.2%, 0.0%), and vomiting (1.2%, 0.0%).
Sitagliptin in Combination with Metformin and Insulin: In a 24-week placebo-controlled study of sitagliptin 100 mg added to ongoing combination treatment with metformin ≥1500 mg daily and stable-dose insulin, the only drug-related adverse reaction reported in ≥1% of patients treated with sitagliptin (N=229) and more commonly than in patients treated with placebo (N=233) was hypoglycemia (sitagliptin, 10.9%; placebo, 5.2%). In another 24-week study of patients receiving sitagliptin as add-on therapy while undergoing insulin intensification (with or without metformin), the only drug-related adverse reaction reported in ≥1% in patients treated with sitagliptin and metformin and more commonly than in patients treated with placebo and metformin was vomiting (sitagliptin and metformin, 1.1%; placebo and metformin, 0.4%).
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 also TECOS Cardiovascular Safety Study, as follows. (See Pancreatitis under PRECAUTIONS.)
With the combination of sitagliptin and metformin, no clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed.
Adverse Reactions Reported with Sitagliptin: There were no drug-related adverse reactions reported that occurred with an incidence of ≥1% in patients receiving sitagliptin.
Adverse Reactions Reported with Metformin: Adverse reactions reported (regardless of causality) in greater than 5% of patients treated with metformin and more commonly than in patients treated with placebo are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, 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 study population included a total of 2,004 patients ≥75 years of age (970 treated with sitagliptin and 1,034 treated with placebo). 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 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.
Postmarketing Experience: Additional adverse reactions have been identified during postmarketing use of JANUMET or sitagliptin, one of the components of JANUMET. These reactions have been reported when JANUMET or sitagliptin have been used alone 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 CONTRAINDICATIONS and Sitagliptin phosphate: Hypersensitivity Reactions under PRECAUTIONS); acute pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing pancreatitis (see Pancreatitis under PRECAUTIONS); worsening renal function, including acute renal failure (sometimes requiring dialysis); bullous pemphigoid (see Sitagliptin phosphate: Bullous Pemphigoid under PRECAUTIONS); upper respiratory tract infection; nasopharyngitis; constipation; vomiting; headache; arthralgia; myalgia; pain in extremity; back pain; pruritus.
Laboratory Test Findings: Sitagliptin phosphate: The incidence of laboratory adverse experiences was similar in patients treated with sitagliptin and metformin compared to patients treated with placebo and metformin. 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 a small 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.
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 Metformin hydrochloride under PRECAUTIONS).