Metformin and Sitagliptin interacts in the following cases:
No dose adjustment is needed for patients with mild renal impairment (glomerular filtration rate [GFR] ≥60 mL/min). A GFR should be assessed before initiation of treatment with metformincontaining products and at least annually thereafter. In patients at increased risk of further progression of renal impairment and in the elderly, renal function should be assessed more frequently, e.g. every 3-6 months.
The maximum daily dose of metformin should preferably be divided into 2-3 daily doses.
If no adequate strength of the sitagliptin/metformin combination is available, individual monocomponents should be used instead of the fixed-dose combination.
| GFR mL/min | Metformin | Sitagliptin |
|---|---|---|
| 60-89 | Maximum daily dose is 3,000 mg. Dose reduction may be considered in relation to declining renal function. | Maximum daily dose is 100 mg. |
A GFR should be assessed before initiation of treatment with metformincontaining products and at least annually thereafter. In patients at increased risk of further progression of renal impairment and in the elderly, renal function should be assessed more frequently, e.g. every 3-6 months.
The maximum daily dose of metformin should preferably be divided into 2-3 daily doses. Factors that may increase the risk of lactic acidosis should be reviewed before considering initiation of metformin in patients with GFR <60 mL/min.
If no adequate strength of the sitagliptin/metformin combination is available, individual monocomponents should be used instead of the fixed-dose combination.
| GFR mL/min | Metformin | Sitagliptin |
|---|---|---|
| 45-59 | Maximum daily dose is 2,000 mg. The starting dose is at most half of the maximum dose. | Maximum daily dose is 100 mg. |
| 30-44 | Maximum daily dose is 1,000 mg. The starting dose is at most half of the maximum dose. | Maximum daily dose is 50 mg. |
There are no adequate data from the use of sitagliptin in pregnant women. Studies in animals have shown reproductive toxicity at high doses of sitagliptin. A limited amount of data suggests the use of metformin in pregnant women is not associated with an increased risk of congenital malformations. Animal studies with metformin do not indicate harmful effects with respect to pregnancy, embryonic or foetal development, parturition or postnatal development.
Sitagliptin/metformin should not be used during pregnancy. If a patient wishes to become pregnant or if a pregnancy occurs, treatment should be discontinued and the patient switched to insulin treatment as soon as possible.
No studies in lactating animals have been conducted with the combined active substances of this medicinal product. In studies performed with the individual active substances, both sitagliptin and metformin are excreted in the milk of lactating rats. Metformin is excreted in human milk in small amounts. It is not known whether sitagliptin is excreted in human milk. Sitagliptin/metformin must therefore not be used in women who are breast-feeding.
Animal data do not suggest an effect of treatment with sitagliptin on male and female fertility. Human data are lacking.
Sitagliptin/metformin combination has no or negligible influence on the ability to drive and use machines. However, when driving or using machines, it should be taken into account that dizziness and somnolence have been reported with sitagliptin. In addition, patients should be alerted to the risk of hypoglycaemia when sitagliptin/metformin is used in combination with a sulphonylurea or with insulin.
There have been no therapeutic clinical trials conducted with sitagliptin/metformin tablets however bioequivalence of sitagliptin/metformin with co-administered sitagliptin and metformin has been demonstrated. Serious adverse reactions including pancreatitis and hypersensitivity reactions have been reported. Hypoglycaemia has been reported in combination with sulphonylurea (13.8%) and insulin (10.9%).
Adverse reactions are listed below as MedDRA preferred term by system organ class and absolute frequency (Table). Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000) and not known (cannot be estimated from the available data).
The frequency of adverse reactions identified from placebo-controlled clinical studies of sitagliptin and metformin alone, and post-marketing experience:
| Adverse reaction | Frequency of adverse reaction |
|---|---|
| Blood and lymphatic system disorders | |
| thrombocytopenia | Rare |
| Immune system disorders | |
| hypersensitivity reactions including anaphylactic responses* | Frequency not known |
| Metabolism and nutrition disorders | |
| hypoglycaemia | Common |
| Vitamin B12 decrease/deficiency | Common |
| Nervous system disorders | |
| somnolence | Uncommon |
| Respiratory, thoracic and mediastinal disorders | |
| interstitial lung disease* | Frequency not known |
| Gastrointestinal disorders | |
| diarrhoea | Uncommon |
| nausea | Common |
| flatulence | Common |
| constipation | Uncommon |
| upper abdominal pain | Uncommon |
| vomiting | Common |
| acute pancreatitis*,‡ | Frequency not known |
| fatal and non-fatal haemorrhagic and necrotizing pancreatitis* | Frequency not known |
| Skin and subcutaneous tissue disorders | |
| pruritus* | Uncommon |
| angioedema* | Frequency not known |
| rash* | Frequency not known |
| urticaria* | Frequency not known |
| cutaneous vasculitis* | Frequency not known |
| exfoliative skin conditions including Stevens-Johnson syndrome* | Frequency not known |
| bullous pemphigoid* | Frequency not known |
| Musculoskeletal and connective tissue disorders | |
| arthralgia* | Frequency not known |
| myalgia* | Frequency not known |
| pain in extremity* | Frequency not known |
| back pain* | Frequency not known |
| arthropathy* | Frequency not known |
| Renal and urinary disorders | |
| impaired renal function* | Frequency not known |
| acute renal failure* | Frequency not known |
* Adverse reactions were identified through post-marketing surveillance.
‡ See TECOS Cardiovascular Safety Study below.
Some adverse reactions were observed more frequently in studies of combination use of sitagliptin and metformin with other anti-diabetic medicinal products than in studies of sitagliptin and metformin alone. These included hypoglycaemia (frequency very common with sulphonylurea or insulin), constipation (common with sulphonylurea), peripheral oedema (common with pioglitazone), and headache and dry mouth (uncommon with insulin).
In monotherapy studies of sitagliptin 100 mg once daily alone compared to placebo, adverse reactions reported 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).
Gastrointestinal symptoms were reported very commonly in clinical studies and post-marketing use of metformin. 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. Additional adverse reactions associated with metformin include metallic taste (common); lactic acidosis, liver function disorders, hepatitis, urticaria, erythema, and pruritus (very rare). 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). Frequency categories are based on information available from metformin Summary of Product Characteristics available in the EU.
In clinical trials with sitagliptin/metformin in paediatric patients with type 2 diabetes mellitus aged 10 to 17 years, the profile of adverse reactions was generally comparable to that observed in adults. In paediatric patients on or not on background insulin, sitagliptin was associated with an increased risk of hypoglycaemia.
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 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 HbA1c and CV risk factors. The overall incidence of serious adverse events in patients receiving sitagliptin was similar to that in patients receiving placebo.
In the intention-to-treat population, among patients who were using insulin and/or a sulfonylurea at baseline, the incidence of severe hypoglycaemia 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 hypoglycaemia 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.
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