Leitlinien & Arzneimittelsicherheit

HOS-095920 · has-adverse-reaction-information · PDF-Seite 10

Summary of the safety profile Acute pancreatitis is a serious adverse reaction and is attributed to the alogliptin component of Incresync (see section 4.4). Hypersensitivity reactions, including Stevens-Johnson syndrome, anaphylactic reactions, and angioedema are serious and are attributed to the alogliptin component of Incresync (see section 4.4). Other reactions such as upper respiratory tract infections, sinusitis, headache, hypoglycaemia, nausea, weight increase and oedema may occur commonly (≥ 1/100 to < 1/10). Clinical studies conducted to support the efficacy and safety of Incresync involved the co-administration of alogliptin and pioglitazone as separate tablets. However, the results of bioequivalence studies have demonstrated that Incresync film-coated tablets are bioequivalent to the corresponding doses of alogliptin and pioglitazone co-administered as separate tablets. The information provided is based on a total of 3,504 patients with type 2 diabetes mellitus, including 1,908 patients treated with alogliptin and pioglitazone, who participated in 4 phase 3 double-blind, placebo- or active-controlled clinical studies. These studies evaluated the effects of co-administered alogliptin and pioglitazone on glycaemic control and their safety as initial combination therapy, as dual therapy in patients initially treated with pioglitazone alone (with or without metformin or a sulphonylurea), and as add-on therapy to metformin. 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). 10 Table 1: Adverse reactions System organ class Frequency of adverse reactions Adverse reaction Alogliptin Pioglitazone Incresync Infections and infestations upper respiratory tract infections common common common nasopharyngitis common sinusitis uncommon common Neoplasms benign, malignant and unspecified (including cysts and polyps) bladder cancer uncommon Immune system disorders

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HOS-095916 · has-contraindication-information · PDF-Seite 4

- Hypersensitivity to the active substances 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) - Cardiac failure or history of cardiac failure (NYHA stages I to IV; see section 4.4) - Hepatic impairment (see section 4.4) - Diabetic ketoacidosis - Current bladder cancer or a history of bladder cancer (see section 4.4) - Uninvestigated macroscopic haematuria (see section 4.4)

HOS-095915 · has-indication-information · PDF-Seite 3

Incresync is indicated as a second or third line treatment in adult patients aged 18 years and older with type 2 diabetes mellitus:  as an adjunct to diet and exercise to improve glycaemic control in adult patients (particularly overweight patients) inadequately controlled on pioglitazone alone, and for whom metformin is inappropriate due to contraindications or intolerance.  in combination with metformin (i.e. triple combination therapy) as an adjunct to diet and exercise to improve glycaemic control in adult patients (particularly overweight patients) inadequately controlled on their maximal tolerated dose of metformin and pioglitazone. In addition, Incresync can be used to replace separate tablets of alogliptin and pioglitazone in those adult patients aged 18 years and older with type 2 diabetes mellitus already being treated with this combination. After initiation of therapy with Incresync, patients should be reviewed after 3 to 6 months to assess adequacy of response to treatment (e.g. reduction in HbA1c). In patients who fail to show an adequate response, Incresync should be discontinued. In light of potential risks with prolonged pioglitazone therapy, prescribers should confirm at subsequent routine reviews that the benefit of Incresync is maintained (see section 4.4).

HOS-095918 · has-interaction-information · PDF-Seite 8

Co-administration of 25 mg alogliptin once daily and 45 mg pioglitazone once daily for 12 days in healthy subjects had no clinically relevant effects on the pharmacokinetics of alogliptin, pioglitazone or their active metabolites. Specific pharmacokinetic drug interaction studies have not been performed with Incresync. The following section outlines the interactions observed with the individual components of Incresync (alogliptin/pioglitazone) as reported in their respective Summary of Product Characteristics. Interactions with pioglitazone Co-administration of pioglitazone with gemfibrozil (an inhibitor of cytochrome P450 2C8) is reported to result in a 3-fold increase in AUC for pioglitazone. Since there is a potential for an increase in dose-related adverse reactions, a decrease in the dose of pioglitazone may be needed when gemfibrozil is concomitantly administered. Close monitoring of glycaemic control should be considered (see section 4.4). Co-administration of pioglitazone with rifampicin (an inducer of cytochrome P450 2C8) is reported to result in a 54% decrease in AUC for pioglitazone. The pioglitazone dose may need to be increased when rifampicin is concomitantly administered. Close monitoring of glycaemic control should be considered (see section 4.4). Interaction studies have shown that pioglitazone has no relevant effect on either the pharmacokinetics or pharmacodynamics of digoxin, warfarin, phenprocoumon or metformin. Co-administration of pioglitazone with sulphonylureas does not appear to affect the pharmacokinetics of the sulphonylurea. Studies in man suggest no induction of the main inducible cytochrome P450, 1A, 2C8/9 and 3A4. In vitro studies have shown no inhibition of any subtype of cytochrome P450. Interactions with substances metabolised by these enzymes, e.g. oral contraceptives, cyclosporin, calcium channel blockers and HMGCoA reductase inhibitors, are not to be expected. 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. 8 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

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HOS-095919 · has-pregnancy-information · PDF-Seite 9

Pregnancy There are no data from the use of Incresync in pregnant women. Studies in animals with alogliptin plus pioglitazone as combination treatment have shown reproductive toxicity (slight augmentation of pioglitazone-related foetal growth retardation and foetal visceral variations, see section 5.3). Incresync should not be used during pregnancy. Risk related to alogliptin 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). Risk related to pioglitazone There are no adequate human data to determine the safety of pioglitazone during pregnancy. Foetal growth restriction was apparent in animal studies with pioglitazone. This was attributable to the action of pioglitazone in diminishing the maternal hyperinsulinaemia and increased insulin resistance that occurs during pregnancy, thereby reducing the availability of metabolic substrates for foetal growth. The relevance of such a mechanism in humans is unclear. Breast-feeding No studies in lactating animals have been conducted with the combined active substances of Incresync. In studies performed with the individual active substances, both alogliptin and pioglitazone were excreted in the milk of lactating rats. It is unknown whether alogliptin and pioglitazone are excreted in human milk. A risk to the suckling child cannot be excluded. 9 A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Incresync therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility The effect of Incresync on fertility in humans has not been studied. No adverse effects on fertility were observed in animal studies conducted with alogliptin (see section 5.3). In animal fertility studies conducted with pioglitazone there was no effect on copulation, impregnation or fertility index.

HOS-095917 · has-warning-information · PDF-Seite 4

General Incresync should not be used in patients with type 1 diabetes mellitus. Incresync is not a substitute for insulin in insulin-requiring patients. 4 Fluid retention and cardiac failure Pioglitazone can cause fluid retention, which may exacerbate or precipitate heart failure. When treating patients who have at least one risk factor for development of congestive heart failure (e.g. prior myocardial infarction or symptomatic coronary artery disease or the elderly), physicians should start pioglitazone therapy with the lowest available dose and increase the dose gradually. Patients should be observed for signs and symptoms of heart failure, weight gain or oedema; particularly those with reduced cardiac reserve. There have been post-marketing cases of cardiac failure reported when pioglitazone was used in combination with insulin or in patients with a history of cardiac failure. Patients should be observed for signs and symptoms of heart failure, weight gain and oedema when pioglitazone is used in combination with insulin. Since insulin and pioglitazone are both associated with fluid retention, concomitant administration may increase the risk of oedema. Post marketing cases of peripheral oedema and cardiac failure have also been reported in patients with concomitant use of pioglitazone and nonsteroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors. Incresync should be discontinued if any deterioration in cardiac status occurs. A cardiovascular outcome study of pioglitazone has been performed in patients under 75 years with type 2 diabetes mellitus and pre-existing major macrovascular disease. Pioglitazone or placebo was added to existing anti-diabetic and cardiovascular therapy for up to 3.5 years. This study showed an increase in reports of heart failure, however this did not lead to an increase in mortality in this study. Elderly patients In light of age-related risks (especially bladder cancer, fractures and heart failure associated with the pioglitazone component), the balance of benefits and risks should be considered carefully both before and during Incresync treatment in the elderly. Bladder cancer Cases of bladder cancer were reported more frequently in a meta-analysis of controlled clinical studies with pioglitazone (19 cases from 12,506 patients, 0.15%) than in control groups (7 cases from 10,212 patients, 0.07%) HR = 2.64 (95% CI 1.11-6.31, P = 0.029). After

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