Glyxambi

HOS-097175 · has-adverse-reaction-information · PDF-Seite 9

Summary of the safety profile The most frequent adverse reaction was urinary tract infection (7.5% with Glyxambi 10 mg empagliflozin/5 mg linagliptin and 8.5% with Glyxambi 25 mg empagliflozin/5 mg linagliptin) (see Description of selected adverse reactions). The most serious adverse reactions were ketoacidosis (< 0.1%), pancreatitis (0.2 %), hypersensitivity (0.6 %), and hypoglycaemia (2.4 %) (see section 4.4). Overall, the safety profile of Glyxambi was in line with the safety profiles of the individual active substances (empagliflozin and linagliptin). No additional adverse reactions were identified with Glyxambi. Tabulated list of adverse reactions The adverse reactions shown in the table below (see Table 2) are listed by system organ class and are based on the safety profiles of empagliflozin and linagliptin monotherapy. Frequency categories are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), 9 rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000) and not known (cannot be estimated from the available data). Table 2 Tabulated list of adverse reactions (MedDRA) from reported placebo-controlled trials and from post-marketing experience System organ class Frequency Adverse reaction Infections and infestations Common Urinary tract infection1,* (including pyelonephritis and urosepsis)4 Common Vaginal moniliasis, vulvovaginitis, balanitis and other genital infections1,* Common Nasopharyngitis2 Rare Necrotising fasciitis of the perineum (Fournier´s gangrene)# Immune system disorders Uncommon Hypersensitivity2 Uncommon Angioedema3,4, urticaria3,4 Metabolism and nutrition Common Hypoglycaemia (when used with disorders sulphonylurea or insulin)*

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HOS-097171 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substances, to any other Sodium-Glucose-Co-Transporter-2 (SGLT2) inhibitor, to any other Dipeptidyl-Peptidase-4 (DPP-4) inhibitor, or to any of the excipients listed in section 6.1.

HOS-097170 · has-indication-information · PDF-Seite 2

Glyxambi, fixed dose combination of empagliflozin and linagliptin, is indicated in adults aged 18 years and older with type 2 diabetes mellitus: • to improve glycaemic control when metformin and/or sulphonylurea (SU) and one of the monocomponents of Glyxambi do not provide adequate glycaemic control • when already being treated with the free combination of empagliflozin and linagliptin (See sections 4.2, 4.4, 4.5 and 5.1 for available data on combinations studied)

HOS-097173 · has-interaction-information · PDF-Seite 7

No drug interaction studies have been performed with Glyxambi and other medicinal products; however, such studies have been conducted with the individual active substances. Based on results of pharmacokinetic studies, no dose adjustment of Glyxambi is recommended when co-administered with commonly prescribed medicinal products, except those mentioned below. Pharmacodynamic interactions Insulin and sulphonylureas Insulin and sulphonylureas may increase the risk of hypoglycaemia. Therefore, a lower dose of insulin or sulphonylureas may be required to reduce the risk of hypoglycaemia when used in combination with Glyxambi (see sections 4.2, 4.4 and 4.8). Diuretics Empagliflozin may add to the diuretic effect of thiazide and loop diuretics and may increase the risk of dehydration and hypotension (see section 4.4). Pharmacokinetic interactions Effects of other medicinal products on empagliflozin Empagliflozin is mainly excreted unchanged. A minor fraction is metabolised via uridine 5'-diphosphoglucuronosyltransferases (UGT); therefore, a clinically relevant effect of UGT inhibitors on empagliflozin is not expected (see section 5.2). The effect of UGT induction on empagliflozin (e.g. 7 induction by rifampicin or phenytoin) has not been studied. Co-treatment with known inducers of UGT enzymes is not recommended due to a potential risk of decreased efficacy of empagliflozin. If an inducer of these UGT enzymes must be co-administered, monitoring of glycaemic control to assess response to Glyxambi is appropriate. Co-administration of empagliflozin with probenecid, an inhibitor of UGT enzymes and OAT3, resulted in a 26% increase in peak empagliflozin plasma concentrations (Cmax) and a 53% increase in area under the concentration-time curve (AUC). These changes were not considered to be clinically meaningful. An interaction study with gemfibrozil, an in vitro inhibitor of OAT3 and OATP1B1/1B3 transporters, showed that empagliflozin Cmax increased by 15% and AUC increased by 59% following co- administration. These changes were not considered to be clinically meaningful. Inhibition of OATP1B1/1B3 transporters by co-administration with rifampicin resulted in a 75% increase in Cmax and a 35% increase in AUC of empagliflozin. These changes were not considered to be clinically meaningful. Interaction studies suggest that the pharmacokinetics of empagliflozin were not influenced by co- administration with metfo

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HOS-097174 · has-pregnancy-information · PDF-Seite 9

Pregnancy There are no data from the use of empagliflozin and linagliptin in pregnant women. Animal studies have shown that empagliflozin and linagliptin cross the placenta during late gestation, but do not indicate direct or indirect harmful effects with respect to early embryonic development with either empagliflozin or linagliptin (see section 5.3). Animal studies with empagliflozin have shown adverse effects on postnatal development (see section 5.3). As a precautionary measure it is preferable to avoid the use of Glyxambi during pregnancy. Breast-feeding No data in humans are available on excretion of empagliflozin and linagliptin into milk. Available non-clinical data in animals have shown excretion of empagliflozin and linagliptin in milk. A risk to newborns or infants cannot be excluded. Glyxambi should not be used during breast-feeding. Fertility No trials on the effect on human fertility have been conducted with Glyxambi or with the individual active substances. Non-clinical studies with empagliflozin and linagliptin as single agents do not indicate direct or indirect harmful effects with respect to fertility (see section 5.3).

HOS-097172 · has-warning-information · PDF-Seite 4

Diabetic ketoacidosis Rare cases of diabetic ketoacidosis (DKA), including life-threatening and fatal cases, have been reported in patients treated with SGLT2 inhibitors, including empagliflozin. In a number of cases, the presentation of the condition was atypical with only moderately increased blood glucose values, below 14 mmol/L (250 mg/dL). It is not known if DKA is more likely to occur with higher doses of empagliflozin. The risk of DKA must be considered in the event of non-specific symptoms such as nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigue or sleepiness. Patients should be assessed for ketoacidosis immediately if these symptoms occur, regardless of blood glucose level. In patients where DKA is suspected or diagnosed, treatment with empagliflozin should be discontinued immediately. Treatment should be interrupted in patients who are hospitalised for major surgical procedures or acute serious medical illnesses. Monitoring of ketones is recommended in these patients. Measurement of blood ketone levels is preferred to urine. Treatment with empagliflozin may be restarted when the ketone values are normal and the patient’s condition has stabilised. Before initiating empagliflozin, factors in the patient history that may predispose to ketoacidosis should be considered. Prolonged diabetic ketoacidosis and prolonged glucosuria have been observed with empagliflozin. Diabetic ketoacidosis may last longer after discontinuation of empagliflozin than expected from the plasma half-life (see section 5.2). Empagliflozin-independent factors, such as insulin deficiency, might be involved in prolonged periods of diabetic ketoacidosis. 4 Patients who may be at higher risk of DKA include patients with a low beta-cell function reserve (e.g. type 2 diabetes patients with low C-peptide or latent autoimmune diabetes in adults (LADA) or patients with a history of pancreatitis), patients with conditions that lead to restricted food intake or severe dehydration, patients for whom insulin doses are reduced and patients with increased insulin requirements due to acute medical illness, surgery or alcohol abuse. SGLT2 inhibitors should be used with caution in these patients. Restarting SGLT2 inhibitor treatment in patients with previous DKA while on SGLT2 inhibitor treatment is not recommended, unless another clear precipitating factor is identified an

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