Vipidia · 4.6 Fertility, pregnancy and lactation · 1

HOS-095928 · has-adverse-reaction-information · PDF-Seite 6

Summary of the safety profile The information provided is based on a total of 9,405 patients with type 2 diabetes mellitus, including 3,750 patients treated with 25 mg alogliptin and 2,476 patients treated with 12.5 mg alogliptin, who participated in one phase 2 or 12 phase 3 double-blind, placebo- or active-controlled clinical studies. In addition, a cardiovascular outcomes study with 5,380 patients with type 2 diabetes mellitus and a recent acute coronary syndrome event was conducted with 2,701 randomised to alogliptin and 2,679 randomised to placebo. These studies evaluated the effects of alogliptin on glycaemic control and its safety as monotherapy, as initial combination therapy with metformin or a thiazolidinedione, and as add-on therapy to metformin, or a sulphonylurea, or a thiazolidinedione (with or without metformin or a sulphonylurea), or insulin (with or without metformin). 6 In a pooled analysis of the data from 13 studies, the overall incidences of adverse events, serious adverse events and adverse events resulting in discontinuation of therapy were comparable in patients treated with 25 mg alogliptin, 12.5 mg alogliptin, active control or placebo. The most common adverse reaction in patients treated with 25 mg alogliptin was headache. The safety of alogliptin between the elderly (≥ 65 years old) and non-elderly (< 65 years old) was similar. Tabulated list of adverse reactions The adverse reactions are listed 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); not known (cannot be estimated from available data). In the pooled pivotal phase 3 controlled clinical studies of alogliptin as monotherapy and as add-on combination therapy involving 5,659 patients, the observed adverse reactions are listed below (Table 1). Table 1: Adverse reactions System organ class Frequency of adverse reactions Adverse reaction Infections and infestations upper respiratory tract infections common nasopharyngitis common Immune system disorders hypersensitivity not known Metabolism and nutrition disorders hypoglycaemia

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HOS-095924 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or history of a serious hypersensitivity reaction, including anaphylactic reaction, anaphylactic shock, and angioedema, to any dipeptidyl-peptidase-4 (DPP-4) inhibitor (see sections 4.4 and 4.8).

HOS-095923 · has-indication-information · PDF-Seite 2

Vipidia is indicated in adults aged 18 years and older with type 2 diabetes mellitus to improve glycaemic control in combination with other glucose lowering medicinal products including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control (see sections 4.4, 4.5 and 5.1 for available data on different combinations).

HOS-095926 · has-interaction-information · PDF-Seite 5

Effects of other medicinal products on alogliptin Alogliptin is primarily excreted unchanged in the urine and metabolism by the cytochrome (CYP) P450 enzyme system is negligible (see section 5.2). Interactions with CYP inhibitors are thus not expected and have not been shown. Results from clinical interaction studies also demonstrate that there are no clinically relevant effects of gemfibrozil (a CYP2C8/9 inhibitor), fluconazole (a CYP2C9 inhibitor), ketoconazole (a CYP3A4 inhibitor), cyclosporine (a p-glycoprotein inhibitor), voglibose (an alpha-glucosidase inhibitor), digoxin, metformin, cimetidine, pioglitazone or atorvastatin on the pharmacokinetics of alogliptin. Effects of alogliptin on other medicinal products In vitro studies suggest that alogliptin does not inhibit nor induce CYP 450 isoforms at concentrations achieved with the recommended dose of 25 mg alogliptin (see section 5.2). Interaction with substrates of CYP 450 isoforms are thus not expected and have not been shown. In studies in vitro, alogliptin was found to be neither a substrate nor an inhibitor of key transporters associated with disposition of the active substance in the kidney: organic anion transporter-1, organic anion transporter-3 or organic cationic transporter-2 (OCT2). Furthermore, clinical data do not suggest interaction with p-glycoprotein inhibitors or substrates. 5 In clinical studies, alogliptin had no clinically relevant effect on the pharmacokinetics of caffeine, (R)-warfarin, pioglitazone, glyburide, tolbutamide, (S)-warfarin, dextromethorphan, atorvastatin, midazolam, an oral contraceptive (norethindrone and ethinyl oestradiol), digoxin, fexofenadine, metformin, or cimetidine, thus providing in vivo evidence of a low propensity to cause interaction with substrates of CYP1A2, CYP3A4, CYP2D6, CYP2C9, p-glycoprotein, and OCT2. In healthy subjects, alogliptin had no effect on prothrombin time or International Normalised Ratio (INR) when administered concomitantly with warfarin. Combination with other anti-diabetic medicinal products Results from studies with metformin, pioglitazone (thiazolidinedione), voglibose (alpha-glucosidase inhibitor) and glyburide (sulphonylurea) have shown no clinically relevant pharmacokinetic interactions.

HOS-095927 · has-pregnancy-information · PDF-Seite 6

Pregnancy There are no data from the use of alogliptin 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 alogliptin during pregnancy. Breast-feeding It is unknown whether alogliptin is excreted in human milk. Animal studies have shown excretion of alogliptin in milk (see section 5.3). A risk to the suckling child cannot be excluded. A decision on whether to discontinue breast-feeding or to discontinue alogliptin therapy should be made taking into account the benefit of breast-feeding for the child and the benefit of alogliptin therapy for the woman. Fertility The effect of alogliptin on fertility in humans has not been studied. No adverse effects on fertility were observed in animal studies (see section 5.3).

HOS-095925 · has-warning-information · PDF-Seite 4

General Vipidia should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. Vipidia is not a substitute for insulin in insulin-requiring patients. Use with other antihyperglycaemic medicinal products and hypoglycaemia Due to the increased risk of hypoglycaemia in combination with a sulphonylurea, insulin or combination therapy with thiazolidinedione plus metformin, a lower dose of these medicinal products may be considered to reduce the risk of hypoglycaemia when these medicinal products are used in combination with alogliptin (see section 4.2). Combinations not studied Alogliptin has not been studied in combination with sodium glucose co-transporter 2 (SGLT-2) inhibitors or glucagon like peptide 1 (GLP-1) analogues nor formally as triple therapy with metformin and a sulphonylurea. Renal impairment As there is a need for dose adjustment in patients with moderate or severe renal impairment, or end-stage renal disease requiring dialysis, appropriate assessment of renal function is recommended prior to initiation of alogliptin therapy and periodically thereafter (see section 4.2). Experience in patients requiring renal dialysis is limited. Alogliptin has not been studied in patients undergoing peritoneal dialysis (see sections 4.2 and 5.2). Hepatic impairment Alogliptin has not been studied in patients with severe hepatic impairment (Child-Pugh score > 9) and is, therefore, not recommended for use in such patients (see sections 4.2 and 5.2). Cardiac failure Experience of alogliptin use in clinical studies in patients with congestive heart failure of New York Heart Association (NYHA) functional class III and IV is limited and caution is warranted in these patients. Hypersensitivity reactions Hypersensitivity reactions, including anaphylactic reactions, angioedema and exfoliative skin conditions including Stevens-Johnson syndrome and erythema multiforme have been observed for DPP-4 inhibitors and have been spontaneously reported for alogliptin in the post-marketing setting. In clinical studies of alogliptin, anaphylactic reactions were reported with a low incidence. 4 Acute pancreatitis Use of DPP-4 inhibitors has been associated with a risk of developing acute pancreatitis. In a pooled analysis of the data from 13 studies, the overall rates of pancreatitis reports in patients treated with 25 mg alogliptin, 12.5 mg alogliptin, active control or

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