Qtern · 4.8 Undesirable effects · 1

HOS-217165 · has-adverse-reaction-information · PDF-Seite 9

Summary of the safety profile of saxagliptin plus dapagliflozin The combination of saxagliptin 5 mg and dapagliflozin 10 mg in 1 169 adults with type 2 diabetes mellitus (T2DM) and inadequate glycaemic control on metformin has been evaluated in three phase 3, randomised, double-blind, active/placebo-control, parallel group, multi-centre clinical trials for up to 52 weeks (see section 5.1). The pooled safety analysis comprised 3 treatment groups: saxagliptin plus dapagliflozin plus metformin (492 subjects), saxagliptin plus metformin (336 subjects), and dapagliflozin plus metformin (341 subjects). The safety profile of the combined use of saxagliptin plus dapagliflozin plus metformin was comparable to the adverse reactions identified for the respective monocomponents. 9 The most frequently reported adverse reactions associated with Qtern are upper respiratory tract infections (very common), hypoglycaemia when used with SU (very common), and urinary tract infections (common). Diabetic ketoacidosis may occur rarely (see section 4.4). Tabulated list of adverse reactions The adverse reactions are presented in table 1. The safety profile is based on the summarised data from the saxagliptin/dapagliflozin combination clinical trials pooled safety data, and also clinical trials, post-authorisation safety studies and post-marketing experience with the monocomponents. The adverse reactions are listed by system organ class (SOC) and frequency. Frequency categories were defined according to 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), and not known (cannot be estimated from the available data). Table 1. Compilation of reported adverse reactions System Very CommonA UncommonB Rare Very rare Not known organ class common Infections Upper Urinary tract Fungal Necrotising and respiratory infection2, infection fasciitis of the infestations tract vulvovaginitis perineum infection1 , balanitis and (Fournier’s related genital gangrene)C,F,7 infection3,

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HOS-217161 · has-contraindication-information · PDF-Seite 3

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 or to any sodium-glucose co-transporter 2 (SGLT2) inhibitor (see sections 4.4, 4.8 and 6.1).

HOS-217160 · has-indication-information · PDF-Seite 2

Qtern, fixed dose combination of saxagliptin and dapagliflozin, 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 Qtern do not provide adequate glycaemic control, - when already being treated with the free combination of dapagliflozin and saxagliptin. (See sections 4.2, 4.4, 4.5 and 5.1 for available data on combinations studied.)

HOS-217163 · has-interaction-information · PDF-Seite 7

Pharmacodynamic interactions Diuretics Dapagliflozin may add to the diuretic effect of thiazide and loop diuretics and may increase the risk of dehydration and hypotension (see section 4.4). Use with medicinal products known to cause hypoglycaemia If this medicinal product is used in combination with insulin secretagogue (sulphonylurea), a reduction in the dose of sulphonylurea may be required to minimise the risk of hypoglycaemia (see section 4.4). Pharmacokinetic interactions Saxagliptin: The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). Dapagliflozin: The metabolism of dapagliflozin is primarily via glucuronide conjugation mediated by UDP glucuronosyltransferase 1A9 (UGT1A9). Interactions with other oral anti-diabetic or cardiovascular medicinal products Saxagliptin: Saxagliptin did not meaningfully alter the pharmacokinetics of dapagliflozin, metformin, glibenclamide, pioglitazone, digoxin, diltiazem or simvastatin. These medicinal products 7 did not alter the pharmacokinetics of saxagliptin or its major active metabolite. Dapagliflozin: Dapagliflozin did not meaningfully alter the pharmacokinetics of saxagliptin, metformin, pioglitazone, sitagliptin, glimepiride, voglibose, hydrochlorothiazide, bumetanide, valsartan, or simvastatin. These medicinal products did not alter the pharmacokinetics of dapagliflozin. Effect of other medicinal products on saxagliptin or dapagliflozin Saxagliptin: Concomitant administration of saxagliptin with the moderate inhibitor of CYP3A4/5 diltiazem, increased the Cmax and AUC of saxagliptin by 63% and 2.1-fold, respectively, and the corresponding values for the active metabolite were decreased by 44% and 34%, respectively. These pharmacokinetic effects are not clinically meaningful and do not require dose adjustment. Concomitant administration of saxagliptin with the potent inhibitor of CYP3A4/5 ketoconazole, increased the Cmax and AUC of saxagliptin by 62% and 2.5-fold, respectively, and the corresponding values for the active metabolite were decreased by 95% and 88%, respectively. These pharmacokinetic effects are not clinically meaningful and do not require dose adjustment. Concomitant administration of saxagliptin with the potent CYP3A4/5 inducer rifampicin reduced Cmax and AUC of saxagliptin by 53% and 76%, respectively. The exposure of the active metabolite and the plasma DPP-4 activity inhibition over a dose inte

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HOS-217164 · has-pregnancy-information · PDF-Seite 9

Pregnancy There are no data from the use of saxagliptin and dapagliflozin in pregnant women. Studies in animals with saxagliptin have shown reproductive toxicity at high doses (see section 5.3). Studies with dapagliflozin in rats have shown toxicity to the developing kidney in the time period corresponding to the second and third trimesters of human pregnancy (see section 5.3). Therefore, Qtern should not be used during pregnancy. If pregnancy is detected, treatment with Qtern should be discontinued. Breast-feeding It is unknown whether saxagliptin and dapagliflozin and/or its metabolites are excreted in human milk. Animal studies have shown excretion of saxagliptin and/or metabolite in milk. Available pharmacodynamic/toxicological data in animals have shown excretion of dapagliflozin/metabolites in milk, as well as pharmacologically-mediated effects in breast-feeding offspring (see section 5.3). A risk to the newborns/infants cannot be excluded. Qtern should not be used while breast-feeding. Fertility The effect of saxagliptin and dapagliflozin on fertility in humans has not been studied. In male and female rats, dapagliflozin showed no effects on fertility at any dose tested. Effects on fertility were observed using saxagliptin in male and female rats at high doses producing overt signs of toxicity (see section 5.3).

HOS-217162 · has-warning-information · PDF-Seite 3

Acute pancreatitis Use of DPP-4 inhibitors has been associated with a risk of developing acute pancreatitis. Patients should be informed of the characteristic symptoms of acute pancreatitis; persistent, severe abdominal pain. If pancreatitis is suspected, this medicinal product should be discontinued; if acute pancreatitis is confirmed, it should not be restarted. Caution should be exercised in patients with a history of pancreatitis. In post-marketing experience of saxagliptin, there have been spontaneously reported adverse reactions of acute pancreatitis (see section 4.8). Renal impairment The glucose lowering efficacy of dapagliflozin is dependent on renal function, and is reduced in patients with GFR < 45 mL/min and is likely absent in patients with severe renal impairment (see sections 4.2, 5.1 and 5.2). In one study in patients with type 2 diabetes mellitus with moderate renal impairment (GFR < 60 mL/min), a higher proportion of patients treated with dapagliflozin had adverse reactions of increase in creatinine, phosphorus, parathyroid hormone (PTH) and hypotension, compared with placebo. This medicinal product should not be used in patients with a GFR persistently < 45 mL/min. The saxagliptin/dapagliflozin fixed dose combination has not been studied in severe renal impairment (GFR < 30 mL/min) or end-stage renal disease (ESRD). Assessment of renal function is recommended prior to initiation of this medicinal product, and in keeping with routine care, renal assessment should be done periodically thereafter (see sections 4.2 and 5.2). If renal function persistently falls below GFR < 45 mL/min, treatment with this medicinal product should be discontinued. 3 Use in patients at risk for volume depletion and/or hypotension Due to dapagliflozin’s mechanism of action, this medicinal product increases diuresis which may lead to the modest decrease in blood pressure observed in clinical studies (see section 5.1). It may be more pronounced in patients with very high blood glucose concentrations. Caution should be exercised in patients for whom a dapagliflozin-induced drop in blood pressure could pose a risk, such as patients on anti-hypertensive therapy with a history of hypotension or elderly patients. In case of intercurrent conditions that may lead to volume depletion (e.g. gastrointestinal illness), careful monitoring of volume status (e.g. physical examination, blood pressure measurements, l

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