In patients with type 2 diabetese mellitus, in placebo-controlled clinical trials 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 6.
Click on icon to see table/diagram/image
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 (sitagliptin 100 mg 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 prespecified 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 7).
Click on icon to see table/diagram/image
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%).
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%), 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 sitagliptin 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%).
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 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 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 acute pancreatitis was 0.1/100 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.)
With the combination of sitagliptin and metformin, no clinically significant changes in vital signs or in ECG (including in QTc interval) were observed.
Established Adverse Reactions with Sitagliptin: There were no drug-related adverse reactions reported that occurred with an incidence of ≥1% in patients receiving sitagliptin.
Established Adverse Reactions with Metformin: Gastrointestinal symptoms eg, nausea, vomiting, diarrhea, abdominal pain and loss of appetite (>10%) are very common. These occur most frequently during initiation of therapy and resolve spontaneously in most cases. To prevent these gastrointestinal symptoms, it is recommended that metformin be taken in 2 or 3 daily doses during or after meals. A slow increase of the dose may also improve gastrointestinal tolerability.
Metallic taste (3%) is common.
Mild erythema has been reported in some hypersensitive individuals. The incidence of such effects is regarded as very rare (<0.01%).
A decrease of vitamin B12 absorption with decrease of serum levels have been observed in patients treated with long-term metformin and appears generally to be without clinical significance (<0.01%).
Lactic acidosis (0.03 cases/1000 patient-years) is very rare.
Post-Marketing Experience: The following additional adverse reactions have been identified during post-marketing 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 Precautions); acute pancreatitis including fatal and nonfatal hemorrhagic and necrotizing pancreatitis (see Precautions); worsening renal function including acute renal failure (sometimes requiring dialysis); upper respiratory tract infection; nasopharyngitis; constipation; vomiting; headache.
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 (WBC) count (approximately 200 cells/microL difference in WBC versus 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-week 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).