Trajenta · 4.8 Undesirable effects · 1

HOS-095846 · has-adverse-reaction-information · PDF-Seite 5

Summary of the safety profile In the pooled analysis of the placebo-controlled trials, the overall incidence of adverse events in patients treated with placebo was similar to linagliptin 5 mg (63.4% versus 59.1%). Discontinuation of therapy due to adverse events was higher in patients who received placebo as compared to linagliptin 5 mg (4.3% versus 3.4%). The most frequently reported adverse reaction was “hypoglycaemia” observed under the triple combination, linagliptin plus metformin plus sulphonylurea 14.8% versus 7.6% in placebo. In the placebo-controlled studies 4.9% of patients experienced “hypoglycaemia” as an adverse reaction under linagliptin. Of these, 4.0% were mild and 0.9% were moderate and 0.1% were classified as severe in intensity. Pancreatitis was reported more often in patients randomized to linagliptin (7 events in 6 580 patients receiving linagliptin versus 2 events in 4 383 patients receiving placebo). Tabulated list of adverse reactions Due to the impact of the background therapy on adverse reactions (e.g. on hypoglycaemias), adverse reactions were analysed based on the respective treatment regimens (monotherapy, add-on to metformin, add-on to meformin plus sulphonylurea, and add-on to insulin). The placebo-controlled studies included studies where linagliptin was given as - monotherapy with short-term duration of up to 4 weeks - monotherapy with ≥ 12 week duration - add-on to metformin - add-on to metformin + sulphonylurea - add on to metformin and empagliflozin - add-on to insulin with or without metformin Adverse reactions classified by system organ class and MedDRA preferred terms reported in patients who received 5 mg linagliptin in double-blind studies as monotherapy or as add-on therapy are presented in the table below (see table 1). 5 The adverse reactions are listed by absolute 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) or not known (cannot be estimated from the available data). Table 1 Adverse reactions reported in patients who received linagliptin 5 mg daily as monotherapy or as add-on therapies in clinical trial and from post-marketing experience System organ class Frequency of adverse reaction Adverse reaction Infections and

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HOS-095842 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-095841 · has-indication-information · PDF-Seite 2

Trajenta is indicated in adults with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycaemic control as: monotherapy • when metformin is inappropriate due to intolerance, or contraindicated due to renal impairment. combination therapy • in combination with other medicinal products for the treatment of diabetes, including insulin, when these do not provide adequate glycaemic control (see sections 4.4, 4.5 and 5.1 for available data on different combinations).

HOS-095844 · has-interaction-information · PDF-Seite 3

In vitro assessment of interactions Linagliptin is a weak competitive and a weak to moderate mechanism-based inhibitor of CYP isozyme CYP3A4, but does not inhibit other CYP isozymes. It is not an inducer of CYP isozymes. Linagliptin is a P-glycoprotein substrate, and inhibits P-glycoprotein mediated transport of digoxin with low potency. Based on these results and in vivo interaction studies, linagliptin is considered unlikely to cause interactions with other P-gp substrates. In vivo assessment of interactions Effects of other medicinal products on linagliptin Clinical data described below suggest that the risk for clinically meaningful interactions by co-administered medicinal products is low. Rifampicin: multiple co-administration of 5 mg linagliptin with rifampicin, a potent inductor of P-glycoprotein and CYP3A4, resulted in a 39.6% and 43.8% decreased linagliptin steady-state AUC 3 and Cmax, respectively, and about 30% decreased DPP-4 inhibition at trough. Thus, full efficacy of linagliptin in combination with strong P-gp inducers might not be achieved, particularly if these are administered long-term. Co-administration with other potent inducers of P-glycoprotein and CYP3A4, such as carbamazepine, phenobarbital and phenytoin has not been studied. Ritonavir: co-administration of a single 5 mg oral dose of linagliptin and multiple 200 mg oral doses of ritonavir, a potent inhibitor of P-glycoprotein and CYP3A4, increased the AUC and Cmax of linagliptin approximately twofold and threefold, respectively. The unbound concentrations, which are usually less than 1% at the therapeutic dose of linagliptin, were increased 4-5-fold after co- administration with ritonavir. Simulations of steady-state plasma concentrations of linagliptin with and without ritonavir indicated that the increase in exposure will be not associated with an increased accumulation. These changes in linagliptin pharmacokinetics were not considered to be clinically relevant. Therefore, clinically relevant interactions would not be expected with other P-glycoprotein/CYP3A4 inhibitors. Metformin: co-administration of multiple three times daily doses of 850 mg metformin with 10 mg linagliptin once daily did not clinical meaningfully alter the pharmacokinetics of linagliptin in healthy volunteers. Sulphonylureas: the steady-state pharmacokinetics of 5 mg linagliptin was not changed by concomitant administration of a single 1.75 mg dose g

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HOS-095845 · has-pregnancy-information · PDF-Seite 5

Pregnancy The use of linagliptin has not been studied in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of linagliptin during pregnancy. Breast-feeding Available pharmacokinetic data in animals have shown excretion of linagliptin/metabolites in milk. A risk to the breast-fed child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from linagliptin therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility No studies on the effect on human fertility have been conducted for linagliptin. Animal studies do not indicate direct or indirect harmful effects with respect to fertility (see section 5.3).

HOS-095843 · has-warning-information · PDF-Seite 3

General Linagliptin should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Hypoglycaemia Linagliptin alone showed a comparable incidence of hypoglycaemia to placebo. In clinical trials of linagliptin as part of combination therapy with medicinal products not known to cause hypoglycaemia (metformin), rates of hypoglycaemia reported with linagliptin were similar to rates in patients taking placebo. When linagliptin was added to a sulphonylurea (on a background of metformin), the incidence of hypoglycaemia was increased over that of placebo (see section 4.8). Sulphonylureas and insulin are known to cause hypoglycaemia. Therefore, caution is advised when linagliptin is used in combination with a sulphonylurea and/or insulin. A dose reduction of the sulphonylurea or insulin may be considered (see section 4.2). Acute pancreatitis Use of DPP-4 inhibitors has been associated with a risk of developing acute pancreatitis. Acute pancreatitis has been observed in patients taking linagliptin. In a cardiovascular and renal safety study (CARMELINA) with median observation period of 2.2 years, adjudicated acute pancreatitis was reported in 0.3% of patients treated with linagliptin and in 0.1% of patients treated with placebo. Patients should be informed of the characteristic symptoms of acute pancreatitis. If pancreatitis is suspected, Trajenta should be discontinued; if acute pancreatitis is confirmed, Trajenta should not be restarted. Caution should be exercised in patients with a history of pancreatitis. Bullous pemphigoid Bullous pemphigoid has been observed in patients taking linagliptin. In the CARMELINA study, bullous pemphigoid was reported in 0.2% of patients on treatment with linagliptin and in no patient on placebo. If bullous pemphigoid is suspected, Trajenta should be discontinued.