ntified through postmarketing surveillance.
Additional information on the individual active substances of the fixed dose combination
Sitagliptin
In monotherapy studies of sitagliptin 100 mg once daily alone compared to placebo, adverse reactions reported as drug-related were headache, hypoglycaemia, constipation, and dizziness.
Among these patients, adverse events reported regardless of causal relationship to medicinal product occurring in at least 5 % included upper respiratory tract infection and nasopharyngitis. In addition, osteoarthritis and pain in extremity were reported with frequency uncommon (> 0.5 % higher among sitagliptin users than that in the control group).
Across clinical studies, a small increase in white blood cell (WBC) count (approximately 200 cells/microl difference in WBC vs placebo; mean baseline WBC approximately 6,600 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.
No clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed with sitagliptin treatment.
Metformin
Table 2 presents adverse reactions by system organ class and by frequency category. Frequency categories are based on information available from metformin Summary of Product Characteristics available in the EU.
Table 2. The frequency of metformin adverse reactions identified from clinical trial and postmarketing data
Adverse reaction
Frequency
Metabolism and nutrition disorders
lactic acidosis
Very rare
vitamin B12 deficiencya
Very rare
Nervous system disorders
metallic taste
Common
Gastrointestinal disorders
gastrointestinal symptomsb
Very common
Hepatobiliary disorders
liver function disorders, hepatitis
Very rare
Skin and subcutaneous tissue disorders
urticaria, erythema, pruritis
Very rare
a Long-term treatment with metformin has been associated with a decrease in vitamin B12 absorption which may very rarely result in clinically significant vitamin B12 deficiency (e.g., megaloblastic anaemia).
b Gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite occur most frequently during initiation of therapy and resolve spontaneously in most cases.
4.9 Overdose
No data are available with regard to overdose of Janumet.
During controlled clinical trials in healthy subjects, single doses of up to 800 mg sitagliptin were generally well tolerated. Minimal increases in QTc, not considered to be clinically relevant, were observed in one study at a dose of 800 mg sitagliptin. There is no experience with doses above 800 mg in clinical studies. In Phase I multiple-dose studies, there were no dose-related clinical adverse reactions observed with sitagliptin with doses of up to 600 mg per day for periods of up to 10 days and 400 mg per day f