Januvia Adverse Reactions

SITAGLIPTIN (JANUVIA) was generally well tolerated in controlled clinical studies as both monotherapy and combination therapy, with discontinuation of therapy due to clinical adverse experiences similar to placebo.
In four placebo-controlled clinical studies as both monotherapy (one study of 18- and one of 24-week duration) and add-on combination therapy with metformin or pioglitazone (both of 24-week duration), there were 1082 patients treated with SITAGLIPTIN (JANUVIA) 100 mg once daily and 778 patients given placebo. (Two of these studies also included 456 patients treated with SITAGLIPTIN (JANUVIA) 200 mg daily, two times the recommended daily dose.) There were no drug-related adverse reactions reported that occurred with an incidence of ≥ 1% in patients receiving SITAGLIPTIN (JANUVIA) 100 mg. Overall, the safety profile of the 200-mg daily dose was similar to that of the 100-mg daily dose.
In a prespecified pooled analysis of the previously mentioned studies, the overall incidence of adverse experiences of hypoglycemia in patients treated with SITAGLIPTIN (JANUVIA) 100 mg was similar to placebo (1.2% vs. 0.9%). The incidences of selected gastrointestinal adverse experiences in patients treated with SITAGLIPTIN (JANUVIA) or placebo were: abdominal pain [SITAGLIPTIN (JANUVIA), 2.3%; placebo, 2.1%], nausea (1.4%, 0.6%), vomiting (0.8%, 0.9%), and diarrhea (3.0%, 2.3%).
In all studies, adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia; a concurrent glucose measurement was not required.
Add-on Combination with a Sulfonylurea: In a 24-week placebo-controlled study of SITAGLIPTIN (JANUVIA) 100 mg in combination with glimepiride or with glimepiride and metformin [SITAGLIPTIN PHOSPHATE (JANUVIA), N=222; placebo, N=219], the drug-related adverse reaction reported in ≥ 1% of patients treated with SITAGLIPTIN (JANUVIA) and more commonly than in patients treated with placebo was hypoglycemia [SITAGLIPTIN (JANUVIA), 9.5%; placebo, 0.9%].
Add-on Combination with Metformin and a PPARγ Agonist: In a placebo-controlled study of SITAGLIPTIN (JANUVIA) 100 mg in combination with metformin and rosiglitazone [SITAGLIPTIN (JANUVIA), N=170; placebo, N=92], the drug-related adverse reactions reported through the primary time point at Week 18 in ≥ 1% of patients treated with SITAGLIPTIN (JANUVIA) and more commonly than in patients treated with placebo were: headache [SITAGLIPTIN (JANUVIA), 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 (JANUVIA) 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%).
Initial Combination Therapy with Metformin: In a 24-week placebo-controlled factorial study of initial therapy with sitagliptin 100 mg in combination with metformin at 1000 mg or 2000 mg per day (administered as sitagliptin 50 mg/metformin 500 mg or 1000 mg twice daily), the drug-related adverse reactions reported in ≥ 1% of patients treated with sitagliptin plus metformin (N=372) and more commonly than in patients treated with metformin alone (N=364) were: diarrhea (sitagliptin plus metformin, 3.5%; metformin, 3.3%), dyspepsia (1.3%; 1.1%), flatulence (1.3%; 0.5%), vomiting (1.1%; 0.3%), and headache (1.3%; 1.1%). The incidence of hypoglycemia was 1.1% in patients given sitagliptin in combination with metformin and 0.5% in patients given metformin alone.
Initial Combination Therapy with a PPARγ Agonist: In a 24-week study of initial therapy with SITAGLIPTIN (JANUVIA) at 100 mg/day in combination with pioglitazone at 30 mg/day, the only drug-related adverse reaction reported in ≥ 1% of patients treated with SITAGLIPTIN (JANUVIA) with pioglitazone (N=261) and more commonly than in patients treated with pioglitazone alone (N=259) was (asymptomatic) decreased blood glucose [SITAGLIPTIN (JANUVIA) with pioglitazone, 1.1%; pioglitazone, 0.0%]. The incidence of (symptomatic) hypoglycemia was 0.4% in patients given SITAGLIPTIN (JANUVIA) in combination with pioglitazone and 0.8% in patients given pioglitazone.
Add-on Combination with Insulin: In a 24-week placebo-controlled study of SITAGLIPTIN (JANUVIA) 100 mg in combination with stable-dose insulin (with or without metformin), the drug-related adverse reactions reported in ≥ 1% of patients treated with SITAGLIPTIN (JANUVIA) (N=322) and more commonly than in patients treated with placebo (N=319) were: hypoglycemia [SITAGLIPTIN (JANUVIA), 9.6%; placebo, 5.3%], influenza (1.2%, 0.3%), and headache (1.2%, 0.0%). In another 24-week study of patients receiving SITAGLIPTIN (JANUVIA) as add-on therapy while undergoing insulin intensification (with or without metformin), there were no drug-related adverse reactions reported that occurred with an incidence of ≥1% in patients treated with SITAGLIPTIN (JANUVIA) 100 mg and more commonly than in patients treated with placebo.
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).
No clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed in patients treated with SITAGLIPTIN (JANUVIA).
TECOS Cardiovascular Safety Study: The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) included 7,332 patients treated with SITAGLIPTIN (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 study population included a total of 2,004 patients ≥ 75 years of age [970 treated with SITAGLIPTIN (JANUVIA) and 1,034 treated with placebo]. The overall incidence of serious adverse events in patients receiving SITAGLIPTIN (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 SITAGLIPTIN (JANUVIA)-treated patients and 17.7% of the placebo-treated patients] and renal failure [1.4% of SITAGLIPTIN (JANUVIA)-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 (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 SITAGLIPTIN (JANUVIA)-treated patients and 0.7% in placebo-treated patients. The incidence of adjudication-confirmed pancreatitis events was 0.3% in SITAGLIPTIN (JANUVIA)-treated patients and 0.2% in placebo-treated patients. The incidence of adjudication-confirmed malignancy events was 3.7% in SITAGLIPTIN (JANUVIA)-treated patients and 4.0% in placebo-treated patients.
Pediatric population: In a clinical study with SITAGLIPTIN (JANUVIA) 100 mg in pediatric patients aged 10 to 17 years with type 2 diabetes, there were no drug-related adverse reactions reported through the 54-week treatment period in more than 1 patient in the SITAGLIPTIN (JANUVIA) group (N=95) and more commonly than in patients in the placebo group (N=90). There were no clinically relevant differences between the SITAGLIPTIN (JANUVIA) and placebo 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 SITAGLIPTIN (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 Contraindications and 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 Bullous pemphigoid under Precautions); upper respiratory tract infection; nasopharyngitis; constipation; vomiting; headache; arthralgia; myalgia; pain in extremity; back pain, pruritus.
Laboratory Test Findings: The incidence of laboratory adverse experiences was similar in patients treated with SITAGLIPTIN (JANUVIA) 100 mg compared to 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.