Synjardy

HOS-097028 · has-adverse-reaction-information · PDF-Seite 12

Summary of the safety profile The most commonly reported adverse reactions in clinical trials were hypoglycaemia in combination with insulin and/or sulphonylurea and gastrointestinal symptoms (nausea, vomiting, diarrhoea, abdominal pain and loss of appetite). No additional adverse reactions were identified in clinical trials with empagliflozin as add-on to metformin compared to the side effects of the single components. Tabulated list of adverse reactions 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). 12 Table 2: Tabulated list of adverse reactions (MedDRA) from placebo-controlled studies and from post-marketing experience System organ Very common Common Uncommon Rare Very rare class Infections and Vaginal moniliasis, Necrotising infestations vulvovaginitis, fasciitis of balanitis and other the genital infection1, 2 perineum Urinary tract (Fournier´s infection (including gangrene) a pyelonephritis and urosepsis)1, 2 Metabolism and Hypoglycaemia Thirst2 Diabetic Lactic acidosis3 nutrition (when used Vitamin B12 ketoacidosisa disorders with decrease/deficiency3,a sulphonylurea or insulin)1 Nervous system Taste disturbance3 disorders Vascular Volume disorders depletion1, 2, d Gastrointestinal Gastrointestinal Constipation disorders symptoms3, 4

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HOS-097024 · has-contraindication-information · PDF-Seite 5

• Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. • Any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis) (see section 4.4). • Diabetic pre-coma. • Severe renal failure (eGFR < 30 mL/min/1.73 m2) (see sections 4.2 and 4.4). • Acute conditions with the potential to alter renal function such as: dehydration, severe infection, shock (see sections 4.4 and 4.8). • Disease which may cause tissue hypoxia (especially acute disease, or worsening of chronic disease) such as: decompensated heart failure, respiratory failure, recent myocardial infarction, shock (see section 4.4). • Hepatic impairment, acute alcohol intoxication, alcoholism (see sections 4.2 and 4.5).

HOS-097023 · has-indication-information · PDF-Seite 3

Synjardy is indicated in adults and children aged 10 years and above for the treatment of type 2 diabetes mellitus as an adjunct to diet and exercise: • in patients insufficiently controlled on their maximally tolerated dose of metformin alone • in combination with other medicinal products for the treatment of diabetes, in patients insufficiently controlled with metformin and these medicinal products • in patients already being treated with the combination of empagliflozin and metformin as separate tablets. For study results with respect to combinations, effects on glycaemic control and cardiovascular events, and the population studied, see sections 4.4, 4.5 and 5.1.

HOS-097026 · has-interaction-information · PDF-Seite 9

Co-administration of multiple doses of empagliflozin and metformin does not meaningfully alter the pharmacokinetics of either empagliflozin or metformin in healthy subjects. No interaction studies have been performed for Synjardy. The following statements reflect the information available on the individual active substances. Empagliflozin 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). 9 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 Synjardy 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 we

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HOS-097027 · has-pregnancy-information · PDF-Seite 11

Pregnancy There are no data from the use of this medicinal product or 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. A limited amount of data suggests that the use of metformin in pregnant women is not associated with an increased risk of congenital malformations. Animal studies with the combination of empagliflozin and metformin or with metformin alone have shown reproductive toxicity at higher doses of metformin only (see section 5.3). 11 When the patient plans to become pregnant, and during pregnancy, it is recommended that diabetes is not treated with this medicinal product, but insulin be used to maintain blood glucose levels as close to normal as possible, to reduce the risk of malformations of the foetus associated with abnormal blood glucose levels. Breast-feeding Metformin is excreted into human milk. No effects have been shown in breastfed newborns/infants of treated women. No data in humans are available on excretion of empagliflozin into milk. Available animal data have shown excretion of empagliflozin and metformin in milk. A risk to the newborns/infants cannot be excluded. This medicinal product should not be used during breast feeding. Fertility No studies on the effect on human fertility have been conducted for this medicinal product or empagliflozin. Animal studies with empagliflozin and metformin do not indicate direct or indirect harmful effects with respect to fertility (see section 5.3).

HOS-097025 · has-warning-information · PDF-Seite 5

General Empagliflozin should not be used in patients with type 1 diabetes mellitus (see “Diabetic ketoacidosis” in section 4.4). Lactic acidosis Lactic acidosis, a very rare but serious metabolic complication, most often occurs at acute worsening of renal function or cardiorespiratory illness or sepsis. Metformin accumulation occurs at acute worsening of renal function and increases the risk of lactic acidosis. In case of dehydration (severe diarrhoea or vomiting, fever or reduced fluid intake), metformin should be temporarily discontinued and contact with a health care professional is recommended. Medicinal products that can acutely impair renal function (such as antihypertensives, diuretics and NSAIDs) should be initiated with caution in metformin-treated patients. Other risk factors for lactic acidosis are excessive alcohol intake, hepatic insufficiency, inadequately controlled diabetes, ketosis, prolonged fasting and any conditions associated with hypoxia, as well as concomitant use of medicinal products that may cause lactic acidosis (see sections 4.3 and 4.5). Patients and/or care-givers should be informed of the risk of lactic acidosis. Lactic acidosis is characterised by acidotic dyspnea, abdominal pain, muscle cramps, asthenia and hypothermia followed by coma. In case of suspected symptoms, the patient should stop taking metformin and seek immediate medical attention. Diagnostic laboratory findings are decreased blood pH (< 7.35), increased plasma lactate levels (> 5 mmol/L) and an increased anion gap and lactate/pyruvate ratio. 5 Patients with known or suspected mitochondrial diseases In patients with known mitochondrial diseases such as Mitochondrial Encephalopathy with Lactic Acidosis, and Stroke-like episodes (MELAS) syndrome and Maternal inherited diabetes and deafness (MIDD), metformin is not recommended due to the risk of lactic acidosis exacerbation and neurologic complications which may lead to worsening of the disease. In case of signs and symptoms suggestive of MELAS syndrome or MIDD after the intake of metformin, treatment with metformin should be withdrawn immediately and prompt diagnostic evaluation should be performed. 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 w

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