Xelevia

HOS-094648 · has-adverse-reaction-information · PDF-Seite 6

Summary of the safety profile 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). Tabulated list of adverse reactions 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 Frequency not known responses*,† Metabolism and nutrition disorders hypoglycaemia† Common Nervous system disorders headache Common dizziness Uncommon 6 Adverse reaction Frequency of adverse reaction 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 Frequency not known pancreatitis*,† Skin and subcutaneous tissue disorders pruritus* Uncommon angioedema*,† Frequency not known rash*,†

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HOS-094644 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see sections 4.4 and 4.8).

HOS-094643 · has-indication-information · PDF-Seite 2

For adult patients with type 2 diabetes mellitus, Xelevia is indicated to improve glycaemic control: as monotherapy: • in patients inadequately controlled by diet and exercise alone and for whom metformin is inappropriate due to contraindications or intolerance. as dual oral therapy in combination with: • metformin when diet and exercise plus metformin alone do not provide adequate glycaemic control. • a sulphonylurea when diet and exercise plus maximal tolerated dose of a sulphonylurea alone do not provide adequate glycaemic control and when metformin is inappropriate due to contraindications or intolerance. 2 • a peroxisome proliferator-activated receptor gamma (PPAR) agonist (i.e. a thiazolidinedione) when use of a PPAR agonist is appropriate and when diet and exercise plus the PPAR agonist alone do not provide adequate glycaemic control. as triple oral therapy in combination with: • a sulphonylurea and metformin when diet and exercise plus dual therapy with these medicinal products do not provide adequate glycaemic control. • a PPAR agonist and metformin when use of a PPAR agonist is appropriate and when diet and exercise plus dual therapy with these medicinal products do not provide adequate glycaemic control. Xelevia is also indicated as add-on to insulin (with or without metformin) when diet and exercise plus stable dose of insulin do not provide adequate glycaemic control.

HOS-094646 · has-interaction-information · PDF-Seite 5

Effects of other medicinal products on sitagliptin 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 of OAT3 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 of sitagliptin 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 of sitagliptin was not meaningfully altered. Therefore, meaningful interactions would not be expected with other p-glycoprotein inhibitors. Effects of sitagliptin on other medicinal products 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.

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HOS-094647 · has-pregnancy-information · PDF-Seite 6

Pregnancy 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, Xelevia should not be used during pregnancy. Breast-feeding It is unknown whether sitagliptin is excreted in human breast milk. Animal studies have shown excretion of sitagliptin in breast milk. Xelevia should not be used during breast-feeding. Fertility Animal data do not suggest an effect of treatment with sitagliptin on male and female fertility. Human data are lacking.

HOS-094645 · has-warning-information · PDF-Seite 4

General Xelevia should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Acute pancreatitis 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, Xelevia and other potentially suspect medicinal products should be discontinued; if acute pancreatitis is confirmed, Xelevia should not be restarted. Caution should be exercised in patients with a history of pancreatitis. Hypoglycaemia when used in combination with other anti-hyperglycaemic medicinal products In clinical trials of Xelevia 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). Renal impairment 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. Hypersensitivity reactions 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 4 suspected, Xelevia should be discontinued. Other potential causes for the event should be a

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