Jardiance · 4.1 Therapeutic indications · 1

HOS-096578 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile Type 2 diabetes mellitus A total of 15 582 patients with type 2 diabetes were included in clinical studies to evaluate the safety of empagliflozin, of which 10 004 patients received empagliflozin, either alone or in combination with metformin, a sulphonylurea, pioglitazone, DPP-4 inhibitors, or insulin. In 6 placebo-controlled trials of 18 to 24 weeks duration, 3 534 patients were included of which 1 183 8 were treated with placebo and 2 351 with empagliflozin. The overall incidence of adverse events in patients treated with empagliflozin was similar to placebo. The most frequently reported adverse reaction was hypoglycaemia when used with sulphonylurea or insulin (see description of selected adverse reactions). Heart failure The EMPEROR studies included patients with heart failure and either reduced ejection fraction (N = 3 726) or preserved ejection fraction (N = 5 985) treated with empagliflozin 10 mg or placebo. Approximately half of the patients had type 2 diabetes mellitus. The most frequent adverse reaction of the pooled EMPEROR-Reduced and EMPEROR-Preserved studies was volume depletion (empagliflozin 10 mg: 11.4%. placebo: 9.7%). Chronic kidney disease The EMPA-KIDNEY study included patients with chronic kidney disease (N = 6 609) treated with 10 mg empagliflozin or placebo. About 44% of the patients had type 2 diabetes mellitus. The most frequent adverse events in the EMPA-KIDNEY study were gout (empagliflozin 7.0% vs placebo 8.0%), and acute kidney injury (empagliflozin 2.8% vs placebo 3.5%) which were more frequently reported in patients on placebo. The overall safety profile of empagliflozin was generally consistent across the studied indications. Tabulated list of adverse reactions Adverse reactions classified by system organ class and MedDRA preferred terms reported in patients who received empagliflozin in placebo-controlled studies are presented in the table below (Table 1). 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), or very rare (< 1/10 000), and not known (cannot be estimated from the available data). Table 1: Tabulated list of adverse reactions (MedDRA) from reported placebo-controlled studies and from post-marketing experience System organ Very common Common

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HOS-096574 · has-contraindication-information · PDF-Seite 4

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

HOS-096573 · has-indication-information · PDF-Seite 2

Type 2 diabetes mellitus Jardiance is indicated in adults and children aged 10 years and above for the treatment of insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise - as monotherapy when metformin is considered inappropriate due to intolerance - in addition to other medicinal products for the treatment of diabetes For study results with respect to combination of therapies, effects on glycaemic control, cardiovascular and renal events, and the populations studied, see sections 4.4, 4.5 and 5.1. Heart failure Jardiance is indicated in adults for the treatment of symptomatic chronic heart failure. 2 Chronic kidney disease Jardiance is indicated in adults for the treatment of chronic kidney disease.

HOS-096576 · has-interaction-information · PDF-Seite 7

Pharmacodynamic interactions 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). Insulin and insulin secretagogues Insulin and insulin secretagogues, such as sulphonylureas, may increase the risk of hypoglycaemia. Therefore, a lower dose of insulin or an insulin secretagogue may be required to reduce the risk of hypoglycaemia when used in combination with empagliflozin (see sections 4.2 and 4.8). Pharmacokinetic interactions Effects of other medicinal products on empagliflozin In vitro data suggest that the primary route of metabolism of empagliflozin in humans is glucuronidation by uridine 5'-diphosphoglucuronosyltransferases UGT1A3, UGT1A8, UGT1A9, and UGT2B7. Empagliflozin is a substrate of the human uptake transporters OAT3, OATP1B1, and OATP1B3, but not OAT1 and OCT2. Empagliflozin is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). 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. The effect of UGT induction (e.g. induction by rifampicin or phenytoin) on empagliflozin has not been studied. Co-treatment with known inducers of UGT enzymes is not recommended due to a potential risk of decreased efficacy. If an inducer of these UGT enzymes must be co-administered, monitoring of glycaemic control to assess response to Jardiance is appropriate. 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. Empagliflozin exposure was similar with and without co-administration with verapamil, a P-gp inhibitor, indicating that inhibition of P-gp does not have any clinically relevant effect on empagliflozin. Interaction studies suggest that the pharmacokinetics of empagliflozin were not influenced by co- administration with metformin, glimepiride, piogl

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HOS-096577 · has-pregnancy-information · PDF-Seite 8

Pregnancy There are no data from the use of empagliflozin in pregnant women. Animal studies show that empagliflozin crosses the placenta during late gestation to a very limited extent but do not indicate direct or indirect harmful effects with respect to early embryonic development. However, animal studies have shown adverse effects on postnatal development (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Jardiance during pregnancy. Breast-feeding No data in humans are available on excretion of empagliflozin into milk. Available toxicological data in animals have shown excretion of empagliflozin in milk. A risk to the newborns/infants cannot be excluded. Jardiance should not be used during breast-feeding. Fertility No studies on the effect on human fertility have been conducted for Jardiance. Animal studies do not indicate direct or indirect harmful effects with respect to fertility (see section 5.3).

HOS-096575 · has-warning-information · PDF-Seite 4

General Empagliflozin should not be used in patients with type 1 diabetes mellitus (see “Ketoacidosis” in section 4.4). Ketoacidosis Cases of ketoacidosis, including life-threatening and fatal cases, have been reported in patients with diabetes mellitus 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 ketoacidosis is more likely to occur with higher doses of empagliflozin. Although ketoacidosis is less likely to occur in patients without diabetes mellitus, cases have also been reported in these patients. The risk of ketoacidosis 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 ketoacidosis 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 ketoacidosis and prolonged glucosuria have been observed with empagliflozin. 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 ketoacidosis. Patients who may be at higher risk of ketoacidosis 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 cautio

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