Source: European Medicines Agency (EU) Revision Year: 2021 Publisher: Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see sections 4.4 and 4.8).
Tesavel should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
Use of DPP-4 inhibitors has been associated with a risk of developing acute pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. Resolution of pancreatitis has been observed after discontinuation of sitagliptin (with or without supportive treatment), but very rare cases of necrotising or haemorrhagic pancreatitis and/or death have been reported. If pancreatitis is suspected, Tesavel and other potentially suspect medicinal products should be discontinued; ifacute pancreatitis is confirmed, Tesavel should not be restarted. Caution should be exercised in patients with a history of pancreatitis.
In clinical trials of Tesavel as monotherapy and as part of combination therapy with medicinal products not known to cause hypoglycaemia (i.e. metformin and/or a PPAR agonist), rates of hypoglycaemia reported with sitagliptin were similar to rates in patients taking placebo. Hypoglycaemia has been observed when sitagliptin was used in combination with insulin or a sulphonylurea. Therefore, to reduce the risk of hypoglycaemia, a lower dose of sulphonylurea or insulin may be considered (see section 4.2).
Sitagliptin is renally excreted. To achieve plasma concentrations of sitagliptin similar to those in patients with normal renal function, lower dosages are recommended in patients with GFR <45 mL/min, as well as in ESRD patients requiring haemodialysis or peritoneal dialysis (see sections 4.2 and 5.2).
When considering the use of sitagliptin in combination with another anti-diabetic medicinal product, its conditions for use in patients with renal impairment should be checked.
Post-marketing reports of serious hypersensitivity reactions in patients treated with sitagliptin have been reported. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after initiation of treatment, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, Tesavel should be discontinued. Other potential causes for the event should be assessed, and alternative treatment for diabetes initiated.
There have been post-marketing reports of bullous pemphigoid in patients taking DPP-4 inhibitors including sitagliptin. If bullous pemphigoid is suspected, Tesavel should be discontinued.
This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.
Clinical data described below suggest that the risk for clinically meaningful interactions by co-administered medicinal products is low.
In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin is CYP3A4, with contribution from CYP2C8. In patients with normal renal function, metabolism, including via CYP3A4, plays only a small role in the clearance of sitagliptin. Metabolism may play a more significant role in the elimination of sitagliptin in the setting of severe renal impairment or end-stage renal disease (ESRD). For this reason, it is possible that potent CYP3A4 inhibitors (i.e. ketoconazole, itraconazole, ritonavir, clarithromycin) could alter the pharmacokinetics of sitagliptin in patients with severe renal impairment or ESRD. The effect of potent CYP3A4 inhibitors in the setting of renal impairment has not been assessed in a clinical study.
In vitro transport studies showed that sitagliptin is a substrate for p-glycoprotein and organic anion transporter-3 (OAT3). OAT3 mediated transport of sitagliptin was inhibited in vitro by probenecid, although the risk of clinically meaningful interactions is considered to be low. Concomitant administration ofOAT3 inhibitors has not been evaluated in vivo.
Metformin: Co-administration of multiple twice-daily doses of 1,000 mg metformin with 50 mg sitagliptin did not meaningfully alter the pharmacokinetics ofsitagliptin in patients with type 2 diabetes.
Ciclosporin: A study was conducted to assess the effect of ciclosporin, a potent inhibitor of p-glycoprotein, on the pharmacokinetics of sitagliptin. Co-administration of a single 100 mg oral dose of sitagliptin and a single 600 mg oral dose of ciclosporin increased the AUC and Cmax of sitagliptin by approximately 29% and 68%, respectively. These changes in sitagliptin pharmacokinetics were not considered to be clinically meaningful. The renal clearance ofsitagliptin was not meaningfully altered. Therefore, meaningful interactions would not be expected with other p-glycoprotein inhibitors.
Digoxin: Sitagliptin had a small effect on plasma digoxin concentrations. Following administration of 0.25 mg digoxin concomitantly with 100 mg of sitagliptin daily for 10 days, the plasma AUC of digoxin was increased on average by 11%, and the plasma Cmax on average by 18%. No dose adjustment of digoxin is recommended. However, patients at risk of digoxin toxicity should be monitored for this when sitagliptin and digoxin are administered concomitantly.
In vitro data suggest that sitagliptin does not inhibit nor induce CYP450 isoenzymes. In clinical studies, sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptives, providing in vivo evidence of a low propensity for causing interactions with substrates of CYP3A4, CYP2C8, CYP2C9, and organic cationic transporter (OCT). Sitagliptin may be a mild inhibitor of p-glycoprotein in vivo.
There are no adequate data from the use of sitagliptin in pregnant women. Studies in animals have shown reproductive toxicity at high doses (see section 5.3). The potential risk for humans is unknown. Due to lack of human data, Tesavel should not be used during pregnancy.
It is unknown whether sitagliptin is excreted in human breast milk. Animal studies have shown excretion of sitagliptin in breast milk. Tesavel should not be used during breast-feeding.
Animal data do not suggest an effect of treatment with sitagliptin on male and female fertility. Human data are lacking.
Tesavel 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.
In addition, patients should be alerted to the risk of hypoglycaemia when Tesavel is used in combination with a sulphonylurea or with insulin.
Serious adverse reactions including pancreatitis and hypersensitivity reactions have been reported. Hypoglycaemia has been reported in combination with sulphonylurea (4.7%-13.8%) and insulin (9.6%) (see section 4.4).
Adverse reactions are listed below (Table 1) by system organ class and frequency. 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).
Table 1. The frequency of adverse reactions identified from placebo-controlled clinical studies of sitagliptin monotherapy 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 |
| Nervous system disorders | |
| headache | Common |
| dizziness | Uncommon |
| Respiratory, thoracic and mediastinal disorders | |
| interstitial lung disease* | Frequency not known |
| Gastrointestinal disorders | |
| constipation | Uncommon |
| vomiting* | Frequency not known |
| 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 |
| 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 section 4.4.
‡ See TECOS Cardiovascular Safety Study below.
In addition to the drug-related adverse experiences described above, adverse experiences reported regardless of causal relationship to medication and occurring in at least 5% and more commonly in patients treated with sitagliptin included upper respiratory tract infection and nasopharyngitis. Additional adverse experiences reported regardless of causal relationship to medication that occurred more frequently in patients treated with sitagliptin (not reaching the 5% level, but occurring with an incidence of >0.5% higher with sitagliptin than that in the control group) included osteoarthritis and pain in extremity.
Some adverse reactions were observed more frequently in studies of combination use of sitagliptin with other anti-diabetic medicinal products than in studies of sitagliptin monotherapy. These included hypoglycaemia (frequency very common with the combination of sulphonylurea and metformin), influenza (common with insulin (with or without metformin)), nausea and vomiting (common with metformin), flatulence (common with metformin or pioglitazone), constipation (common with the combination of sulphonylurea and metformin), peripheral oedema (common with pioglitazone or the combination of pioglitazone and metformin), somnolence and diarrhoea (uncommon with metformin), and dry mouth (uncommon with insulin (with or without metformin)).
In clinical trials with sitagliptin in paediatric patients with type 2 diabetes mellitus aged 10 to 17 years, the profile of adverse reactions was comparable to that observed in adults. 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 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.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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