QTERN 5mg / 10mg film-coated tablets medication leaflet

Qtern 5 mg/10 mg film-coated tablets

Each tablet contains saxagliptin hydrochloride equivalent to 5 mg saxagliptin and dapagliflozinpropanediol monohydrate equivalent to 10 mg dapagliflozin.

Each tablet contains 40 mg of lactose.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Light brown to brown, biconvex, 0.8 cm round, film-coated tablet, with “5/10” printed on one side,and “1122” printed on the other side, in blue ink.

Qtern, fixed dose combination of saxagliptin and dapagliflozin, is indicated in adults aged 18 years andolder with type 2 diabetes mellitus:

- to improve glycaemic control when metformin and/or sulphonylurea (SU) and one of themonocomponents of Qtern do not provide adequate glycaemic control,

- when already being treated with the free combination of dapagliflozin and saxagliptin.

(See sections 4.2, pct. 4.4, 4.5 and 5.1 for available data on combinations studied.)

The recommended dose is one 5 mg saxagliptin/10 mg dapagliflozin tablet once daily (see sections 4.5and 4.8).

If a dose is missed and it is ≥ 12 hours until the next dose, the dose should be taken. If a dose is missedand it is < 12 hours until the next dose, the missed dose should be skipped and the next dose taken atthe usual time.

No dose adjustment is recommended based on renal function.

Qtern should not be used in patients with a glomerular filtration rate (GFR) persistently < 45 mL/min,or in patients with end-stage renal disease (ESRD) (see sections 4.4, pct. 4.8, 5.1 and 5.2).

This medicinal product can be used in patients with mild or moderate hepatic impairment. Patientswith moderate hepatic impairment should be evaluated prior to initiation and during treatment.

It is not recommended for use in patients with severe hepatic impairment (see section 4.4).

No dose adjustment is recommended based on age.

The safety and efficacy of this medicinal product in children and adolescents aged 0 to < 18 years havenot yet been established. No data are available.

Qtern is taken orally once daily. It may be taken at any time of day with or without food. Tablet is tobe swallowed whole.

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1, or history of aserious hypersensitivity reaction, including anaphylactic reaction, anaphylactic shock, andangioedema, to any dipeptidyl peptidase-4 (DPP-4) inhibitor or to any sodium-glucose co-transporter 2(SGLT2) inhibitor (see sections 4.4, pct. 4.8 and 6.1).

Use of DPP-4 inhibitors has been associated with a risk of developing acute pancreatitis. Patientsshould be informed of the characteristic symptoms of acute pancreatitis; persistent, severe abdominalpain. If pancreatitis is suspected, this medicinal product should be discontinued; if acute pancreatitis isconfirmed, it should not be restarted. Caution should be exercised in patients with a history ofpancreatitis.

In post-marketing experience of saxagliptin, there have been spontaneously reported adverse reactionsof acute pancreatitis (see section 4.8).

The glucose lowering efficacy of dapagliflozin is dependent on renal function, and is reduced inpatients with GFR < 45 mL/min and is likely absent in patients with severe renal impairment (seesections 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 ofincrease in creatinine, phosphorus, parathyroid hormone (PTH) and hypotension, compared withplacebo.

This medicinal product should not be used in patients with a GFR persistently < 45 mL/min. Thesaxagliptin/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 inkeeping with routine care, renal assessment should be done periodically thereafter (see sections 4.2and 5.2). If renal function persistently falls below GFR < 45 mL/min, treatment with this medicinalproduct should be discontinued.

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 leadto the modest decrease in blood pressure observed in clinical studies (see section 5.1). It may be morepronounced in patients with very high blood glucose concentrations.

Caution should be exercised in patients for whom a dapagliflozin-induced drop in blood pressure couldpose a risk, such as patients on anti-hypertensive therapy with a history of hypotension or elderlypatients.

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,laboratory tests including haematocrit and electrolytes) is recommended. Temporary interruption oftreatment with this medicinal product is recommended for patients who develop volume depletion untilthe depletion is corrected (see section 4.8).

Use in patients with hepatic impairment

There is limited experience in clinical trials in patients with hepatic impairment. Dapagliflozin andsaxagliptin exposure is increased in patients with severe hepatic impairment (see sections 4.2 and 5.2).

The saxagliptin/dapagliflozin fixed dose combination can be used in patients with mild or moderatehepatic impairment. Patients with moderate hepatic impairment should be evaluated prior to initiationand during treatment. This medicinal product is not recommended for use in patients with severehepatic impairment (see section 4.2).

Rare cases of diabetic ketoacidosis (DKA), including life-threatening and fatal cases, have beenreported in patients treated with SGLT2 inhibitors, including dapagliflozin. In a number of cases, thepresentation of the condition was atypical with only moderately increased blood glucose values, below14 mmol/litres (250 mg/dL). It is not known if DKA is more likely to occur with higher doses ofdapagliflozin.

The risk of diabetic ketoacidosis must be considered in the event of non-specific symptoms such asnausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusualfatigue or sleepiness. Patients should be assessed for ketoacidosis immediately if these symptomsoccur, regardless of blood glucose level.

In patients where DKA is suspected or diagnosed, treatment with this medicinal product should bediscontinued immediately.

Treatment should be interrupted in patients who are hospitalised for major surgical procedures or acuteserious medical illnesses. Monitoring of ketones is recommended in these patients. Measurement ofblood ketone levels is preferred to urine. Treatment with dapagliflozin may be restarted when theketone values are normal and the patient’s condition has stabilised.

Before initiating treatment with this medicinal product, factors in the patient history that maypredispose to ketoacidosis should be considered.

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) orpatients with a history of pancreatitis), patients with conditions that lead to restricted food intake orsevere dehydration, patients for whom insulin doses are reduced and patients with increased insulinrequirements due to acute medical illness, surgery or alcohol abuse. SGLT2 inhibitors should be usedwith caution in these patients.

Restarting SGLT2 inhibitor treatment in patients with previous DKA while on SGLT2 inhibitortreatment is not recommended, unless another clear precipitating factor is identified and resolved.

The safety and efficacy of the saxagliptin/dapagliflozin fixed dose combination in patients with type 1diabetes have not been established and it should not be used for treatment of patients with type 1diabetes. In type 1 diabetes mellitus studies with dapagliflozin, DKA was reported with commonfrequency.

Post-marketing cases of necrotising fasciitis of the perineum (also known as Fournier’s gangrene) havebeen reported in female and male patients taking SGLT2 inhibitors (see section 4.8). This is a rare butserious and potentially life-threatening event that requires urgent surgical intervention and antibiotictreatment.

Patients should be advised to seek medical attention if they experience a combination of symptoms ofpain, tenderness, erythema, or swelling in the genital or perineal area, with fever or malaise. Be awarethat either uro-genital infection or perineal abscess may precede necrotising fasciitis. If Fournier’sgangrene is suspected, Qtern should be discontinued and prompt treatment (including antibiotics andsurgical debridement) should be instituted.

This medicinal product must not be used in patients who have had any serious hypersensitivity reactionto a DPP-4 inhibitor or a SGLT2 inhibitor (see section 4.3).

During post-marketing experience with saxagliptin, including spontaneous reports and clinical trials,the following adverse reactions have been reported with the use of saxagliptin: serious hypersensitivityreactions, including anaphylactic reaction, anaphylactic shock, and angioedema. This medicinalproduct should be discontinued if a serious hypersensitivity reaction is suspected. The event should beassessed and alternative treatment for diabetes should be instituted (see section 4.8).

Urinary tract infections

Urinary glucose excretion may be associated with an increased risk of urinary tract infection;therefore, temporary interruption of this medicinal product should be considered when treatingpyelonephritis or urosepsis.

Elderly patients may be at a greater risk for volume depletion and are more likely to be treated withdiuretics.

Elderly patients are more likely to have impaired renal function, and/or to be treated withanti-hypertensive medicinal products that may cause changes in renal function such asangiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II type 1 receptor blockers (ARB).

The same recommendations for monitoring of renal function apply to elderly patients as to all patients(see sections 4.2, pct. 4.4, pct. 4.8, and 5.1).

Therapeutic experience with this medicinal product in patients 65 years and older is limited, and verylimited in patients 75 years and older.

Ulcerative and necrotic skin lesions have been reported in extremities of monkeys in non-clinicaltoxicology studies with saxagliptin (see section 5.3). Skin lesions were not observed at an increasedincidence in saxagliptin clinical trials. Post-marketing reports of rash have been described in the DPP-4inhibitor class. Rash is also noted as an adverse reaction for this medicinal product (see section 4.8).

Therefore, in keeping with routine care of the diabetic patient, monitoring for skin disorders, such asblistering, ulceration or rash is recommended.

Bullous pemphigoid

Post-marketing cases of bullous pemphigoid requiring hospitalisation have been reported with DPP4inhibitor use, including saxagliptin. In reported cases, patients typically responded to topical orsystemic immunosuppressive treatment and discontinuation of the DPP4 inhibitor. If a patientdevelops blisters or erosions while receiving saxagliptin and bullous pemphigoid is suspected, thismedicinal product should be discontinued and referral to a dermatologist should be considered fordiagnosis and appropriate treatment (see section 4.8).

Cardiac failure

Experience with dapagliflozin in New York Heart Association (NYHA) class IV is limited. Experiencein NYHA class III-IV is limited with saxagliptin.

In the SAVOR trial, a small increase in the rate for hospitalisation for heart failure was observed in thesaxagliptin-treated patients compared to placebo, although a causal relationship has not beenestablished (see section 5.1). Additional analysis did not indicate a differential effect among NYHAclasses.

Caution is warranted if the saxagliptin/dapagliflozin fixed dose combination is used in patients whohave known risk factors for hospitalisation for heart failure, such as a history of heart failure ormoderate to severe renal impairment. Patients should be advised of the characteristic symptoms ofheart failure, and to immediately report such symptoms.

Arthralgia

Joint pain, which may be severe, has been reported in post-marketing reports for DPP-4 inhibitors (seesection 4.8). Patients experienced relief of symptoms after discontinuation of the medicinal productand some experienced recurrence of symptoms with reintroduction of the same or another DPP-4inhibitor. Onset of symptoms following initiation of therapy may be rapid or may occur after longerperiods of treatment. If a patient presents with severe joint pain, continuation of therapy should beindividually assessed.

Immunocompromised patients, such as patients who have undergone organ transplantation or patientsdiagnosed with human immunodeficiency syndrome have not been studied in the saxagliptin clinicalprogramme. The efficacy and safety profile of the saxagliptin/dapagliflozin fixed dose combination inthese patients has not been established.

An increase in cases of lower limb amputation (primarily of the toe) has been observed in ongoinglong-term, clinical studies with another SGLT2 inhibitor. It is unknown whether this constitutes a classeffect. Like for all diabetic patients it is important to counsel patients on routine preventative foot care.

Use with medicinal products known to cause hypoglycaemia

Both saxagliptin and dapagliflozin can individually increase the risk of hypoglycaemia whencombined with an insulin secretagogue. If this medicinal product is used in combination with insulinsecretagogue (sulphonylurea), a reduction in the dose of sulphonylurea may be required to minimisethe risk of hypoglycaemia (see section 4.8).

Due to the mechanism of action of dapagliflozin, patients taking this medicinal product will testpositive for glucose in their urine.

Use with potent CYP3A4 inducers

Using CYP3A4 inducers like carbamazepine, dexamethasone, phenobarbital, phenytoin, and rifampicinmay reduce the glycaemic lowering effect of this medicinal product. Glycaemic control should beassessed when it is used concomitantly with a potent CYP3A4/5 inducer (see section 4.5).

The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, totallactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially‘sodium-free’.

Dapagliflozin may add to the diuretic effect of thiazide and loop diuretics and may increase the risk ofdehydration 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 reductionin the dose of sulphonylurea may be required to minimise the risk of hypoglycaemia (see section 4.4).

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 productsdid 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 ofdapagliflozin.

Effect of other medicinal products on saxagliptin or dapagliflozin

Saxagliptin: Concomitant administration of saxagliptin with the moderate inhibitor of CYP3A4/5diltiazem, increased the Cmax and AUC of saxagliptin by 63% and 2.1-fold, respectively, and thecorresponding values for the active metabolite were decreased by 44% and 34%, respectively. Thesepharmacokinetic 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 correspondingvalues for the active metabolite were decreased by 95% and 88%, respectively. These pharmacokineticeffects are not clinically meaningful and do not require dose adjustment.

Concomitant administration of saxagliptin with the potent CYP3A4/5 inducer rifampicin reduced Cmaxand AUC of saxagliptin by 53% and 76%, respectively. The exposure of the active metabolite and theplasma DPP-4 activity inhibition over a dose interval were not influenced by rifampicin (seesection 4.4).

The coadministration of saxagliptin and CYP3A4/5 inducers, other than rifampicin (such ascarbamazepine, dexamethasone, phenobarbital and phenytoin) has not been studied and may result indecreased plasma concentration of saxagliptin and increased concentration of its major metabolite.

Glycaemic control should be carefully assessed when saxagliptin is used concomitantly with a potent

CYP3A4/5 inducer.

In studies conducted in healthy subjects, neither the pharmacokinetics of saxagliptin nor its majormetabolite were meaningfully altered by metformin, glibenclamide, pioglitazone, digoxin, simvastatin,omeprazole, antacids or famotidine.

Dapagliflozin: Following coadministration of dapagliflozin with rifampicin (an inducer of variousactive transporters and drug-metabolising enzymes) a 22% decrease in dapagliflozin systemicexposure (AUC) was observed, but with no clinically meaningful effect on 24-hour urinary glucoseexcretion. No dose adjustment is recommended. A clinically relevant effect with other inducers (e.g.

carbamazepine, phenytoin, phenobarbital) is not expected.

Following coadministration of dapagliflozin with mefenamic acid (an inhibitor of UGT1A9), a 55%increase in dapagliflozin systemic exposure was seen, but with no clinically meaningful effect on24-hour urinary glucose excretion.

Effect of saxagliptin or dapagliflozin on other medicinal products

Saxagliptin: Saxagliptin did not meaningfully alter the pharmacokinetics of metformin, glibenclamide(a CYP2C9 substrate), pioglitazone [a CYP2C8 (major) and CYP3A4 (minor) substrate], digoxin (a

P-gp substrate), simvastatin (a CYP3A4 substrate), the active components of a combined oralcontraceptive (ethinylestradiol and norgestimate), diltiazem or ketoconazole.

Dapagliflozin: Dapagliflozin may increase renal lithium excretion and the blood lithium levels may bedecreased. Serum concentration of lithium should be monitored more frequently after dapagliflozininitiation. Please refer the patient to the lithium prescribing doctor in order to monitor serumconcentration of lithium.

In interaction studies conducted in healthy subjects, using mainly a single-dose design, dapagliflozindid not alter the pharmacokinetics of metformin, pioglitazone [a CYP2C8 (major) and CYP3A4(minor) substrate], sitagliptin, glimepiride (a CYP2C9 substrate), hydrochlorothiazide, bumetanide,valsartan, digoxin (a P-gp substrate) or warfarin (S-warfarin, a CYP2C9 substrate), or theanticoagulatory effects of warfarin as measured by INR. Combination of a single dose of dapagliflozin20 mg and simvastatin (a CYP3A4 substrate) resulted in a 19% increase in AUC of simvastatin and31% increase in AUC of simvastatin acid. The increase in simvastatin and simvastatin acid exposuresare not considered clinically relevant.

Monitoring glycaemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG areunreliable in assessing glycaemic control in patients taking SGLT2 inhibitors. Use of alternativemethods to monitor glycaemic control is advised.

There are no data from the use of saxagliptin and dapagliflozin in pregnant women. Studies in animalswith saxagliptin have shown reproductive toxicity at high doses (see section 5.3). Studies withdapagliflozin in rats have shown toxicity to the developing kidney in the time period corresponding tothe second and third trimesters of human pregnancy (see section 5.3). Therefore, Qtern should not beused during pregnancy. If pregnancy is detected, treatment with Qtern should be discontinued.

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. Availablepharmacodynamic/toxicological data in animals have shown excretion of dapagliflozin/metabolites inmilk, as well as pharmacologically-mediated effects in breast-feeding offspring (see section 5.3). Arisk to the newborns/infants cannot be excluded. Qtern should not be used while breast-feeding.

The effect of saxagliptin and dapagliflozin on fertility in humans has not been studied. In male andfemale rats, dapagliflozin showed no effects on fertility at any dose tested. Effects on fertility wereobserved using saxagliptin in male and female rats at high doses producing overt signs of toxicity (seesection 5.3).

Qtern has no or negligible influence on the ability to drive and use machines. When driving or usingmachines, it should be taken into account that dizziness has been reported in studies with combineduse of saxagliptin and dapagliflozin. In addition, patients should be alerted to the risk ofhypoglycaemia if used in combination with other anti-diabetic medicinal products known to causehypoglycaemia (e.g. sulphonylureas).

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 diabetesmellitus (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 to52 weeks (see section 5.1). The pooled safety analysis comprised 3 treatment groups: saxagliptin plusdapagliflozin plus metformin (492 subjects), saxagliptin plus metformin (336 subjects), anddapagliflozin plus metformin (341 subjects). The safety profile of the combined use of saxagliptin plusdapagliflozin plus metformin was comparable to the adverse reactions identified for the respectivemonocomponents.

The most frequently reported adverse reactions associated with Qtern are upper respiratory tractinfections (very common), hypoglycaemia when used with SU (very common), and urinary tractinfections (common). Diabetic ketoacidosis may occur rarely (see section 4.4).

The adverse reactions are presented in table 1. The safety profile is based on the summarised data fromthe saxagliptin/dapagliflozin combination clinical trials pooled safety data, and also clinical trials,post-authorisation safety studies and post-marketing experience with the monocomponents. Theadverse reactions are listed by system organ class (SOC) and frequency. Frequency categories weredefined 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 estimatedfrom the available data).

Table 1. Compilation of reported adverse reactions

System Very

CommonA UncommonB Rare Very rare Not knownorgan class common

Infections Upper Urinary tract Fungal Necrotisingand respiratory infection2, infection fasciitis of theinfestations tract vulvovaginitis perineuminfection1 , balanitis and (Fournier’srelated genital gangrene)C,F,7infection3,gastroenteritis

D

Immune Hypersensitiv Anaphylacticsystem ity reactionsC reactionsdisorders includinganaphylacticshockC

Metabolism Hypoglycaem Dyslipidaemi Volume Diabeticand nutrition iaD (when a4 depletionF, ketoacidosisF,disorders used with SU) thirst G,7

Nervous Headache,system dizzinessdisorders

Gastrointesti Abdominal Constipation,nal disorders painC, dry mouth,diarrhoea, pancreatitisCdyspepsiaD,gastritisD,nauseaC,vomitingD

Skin and Rash5 DermatitisC, AngioedemaC Bulloussubcutaneou pruritusC, pemphigoidC,7s tissue urticariaCdisorders

Musculoskel Arthralgia,etal and back pain,connective myalgiaDtissuedisorders

Renal and Dysuria, Nocturia Tubulo-urinary polyuriaD,6 interstitialdisorders nephritis

Reproductiv Erectilee system and dysfunction,breast pruritusdisorders genital,vulvovaginalp ruritus

General FatigueD,disorders oedemaand peripheralDadministrati

System Very

CommonA UncommonB Rare Very rare Not knownorgan class commonon siteconditions

Investigation Creatinine Bloods renal creatinineclearance increaseddecreased during initialduring initial treatmentF,treatmentF, blood ureahaematocrit increased,increasedE weightdecreased

A Adverse reactions reported in ≥ 2% of subjects treated with the combined use of saxagliptin + dapagliflozin inthe pooled safety analysis, or if reported in < 2% in the pooled safety analysis, they were based on theindividual monocomponents data.

B Frequencies of all uncommon adverse reactions were based on the individual monocomponents data.

C Adverse reaction originates from saxagliptin or dapagliflozin post-marketing surveillance data.

D Adverse reactions were reported in ≥ 2% of subjects with either monocomponent and ≥ 1% more thanplacebo, but not in the pooled analysis.

E Haematocrit values > 55% were reported in 1.3% of the subjects treated with dapagliflozin 10 mg versus0.4% of placebo subjects.

F Frequency is based on events in the dapagliflozin clinical programme.

G Reported in the dapagliflozin cardiovascular outcomes study in patients with type 2 diabetes (DECLARE).

Frequency is based on annual rate.1 Upper respiratory tract infection includes the following preferred terms: nasopharyngitis, influenza, upperrespiratory tract infection, pharyngitis, rhinitis, sinusitis, pharyngitis bacterial, tonsillitis, acute tonsillitis,laryngitis, viral pharyngitis, and viral upper respiratory tract infection.2 Urinary tract infection includes the following preferred terms: urinary tract infection, Escherichia urinarytract infection, pyelonephritis, and prostatitis.3 Vulvovaginitis, balanitis and related genital infection include the following preferred terms: vulvovaginalmycotic infection, balanoposthitis, genital infection fungal, vaginal infection, and vulvovaginitis.4 Dyslipidaemia includes the following preferred terms: dyslipidaemia, hyperlipidaemia,hypercholesterolaemia, and hypertriglyceridaemia.5 Rash was reported during the post-marketing use of saxagliptin and dapagliflozin. Preferred terms reported indapagliflozin clinical trials included in order of frequency: rash, rash generalised, rash pruritic, rash macular,rash maculo-papular, rash pustular, rash vesicular, and rash erythematous.6 Polyuria includes the following preferred terms: polyuria, and pollakiuria.7 See section 4.4

SU=sulphonylurea

Vulvovaginitis, balanitis and related genital infections

Saxagliptin/dapagliflozin combination: The reported adverse events of vulvovaginitis, balanitis andrelated genital infections from pooled safety analysis were reflective of the safety profile ofdapagliflozin. Adverse events of genital infection were reported in 3.0% in the saxagliptin plusdapagliflozin plus metformin group, 0.9% of saxagliptin plus metformin group and 5.9% of subjects inthe dapagliflozin plus metformin group. The majority of the genital infection adverse events werereported in females (84% of subjects with a genital infection), were mild or moderate in intensity, ofsingle occurrence, and most patients continued on therapy.

Cases of phimosis/acquired phimosis have been reported with dapagliflozin concurrent with genitalinfections and in some cases, circumcision was required.

In the pooled safety analysis, the overall incidence of hypoglycaemia (all reported events includingthose with central laboratory FPG ≤ 3.9 mmol/L) was 2.0% in subjects treated with saxagliptin 5 mgplus dapagliflozin 10 mg plus metformin (combination therapy), 0.6% in the saxagliptin plusmetformin group, and 2.3% in the dapagliflozin plus metformin group.

In a 24-week study comparing the combination of saxagliptin and dapagliflozin plus metformin withor without SU, with insulin plus metformin with or without SU, the overall incidence rates forhypoglycaemia in patients without a background treatment of SU, were 12.7% for the combinationcompared to 33.1% for insulin. The overall incidence rates of hypoglycaemia in two 52-week studiescomparing the combination therapy to glimepiride (SU) were: for the 1st study, 4.2% for thecombination therapy versus 27.9% for glimepiride plus metformin versus 2.9% for dapagliflozin plusmetformin; for the 2nd study, 18.5% for the combination therapy versus 43.1% for glimepiride plusmetformin.

Saxagliptin/dapagliflozin combination: Events suggestive of volume depletion (hypotension,dehydration, and hypovolaemia) were reported in two subjects (0.4%) in the saxagliptin plusdapagliflozin plus metformin group (serious adverse event [SAE] of syncope and an AE of urineoutput decreased), and 3 subjects (0.9%) in the dapagliflozin plus metformin group (2 AEs of syncopeand 1 of hypotension).

Events related to decreased renal function

Saxagliptin/dapagliflozin combination: In the pooled safety analysis, the incidence of adverse eventsrelated to decreased renal function was 2.0% subjects in the saxagliptin plus dapagliflozin plusmetformin group, 1.8% subjects in the saxagliptin plus metformin group, and 0.6% subjects in thedapagliflozin plus metformin group. Subjects with adverse events of renal impairment had lower meaneGFR values at baseline of 61.8 mL/min/1.73m2 compared to 93.6 mL/min/1.73m2 in the overallpopulation. The majority of events were considered non-serious, mild or moderate in intensity, andresolved. The change in mean eGFR from baseline at week 24 was -1.17 mL/min/1.73m2 in thesaxagliptin plus dapagliflozin plus metformin group, -0.46 mL/min/1.73 m2 in saxagliptin plusmetformin, and 0.81 mL/min/1.73m2 in dapagliflozin plus metformin.

Dapagliflozin: Adverse reactions related to increased creatinine have been reported for dapagliflozinas a monocomponent. The increases in creatinine were generally transient during continuous treatmentor reversible after discontinuation of treatment.

Cases of Fournier’s gangrene have been reported post-marketing in patients taking SGLT2 inhibitors,including dapagliflozin (see section 4.4).

In the dapagliflozin cardiovascular outcomes study (DECLARE) with 17 160 type 2 diabetes mellituspatients and a median exposure time of 48 months, a total of 6 cases of Fournier’s gangrene werereported, one in the dapagliflozin-treated group and 5 in the placebo group.

In the dapagliflozin cardiovascular outcomes study (DECLARE), with a median exposure time of48 months, events of DKA were reported in 27 patients in the dapagliflozin 10 mg group and12 patients in the placebo group. The events occurred evenly distributed over the study period. Of the27 patients with DKA events in the dapagliflozin group, 22 had concomitant insulin treatment at thetime of the event. Precipitating factors for DKA were as expected in a type 2 diabetes mellituspopulation (see section 4.4).

Urinary tract infections

Saxagliptin/dapagliflozin combination: In the pooled safety analysis, urinary tract infections (UTIs)were balanced across the 3 treatment groups: 5.7% in the saxagliptin plus dapagliflozin plus metformingroup, 7.4% in the saxagliptin plus metformin group and 5.6% in the dapagliflozin plus metformingroup. One patient in the saxagliptin plus dapagliflozin plus metformin group experienced an SAE ofpyelonephritis and discontinued treatment. The majority of the urinary tract infection adverse eventswere reported in females (81% of subjects with UTI), were mild or moderate in intensity, of singleoccurrence, and most patients continued on therapy.

Laboratory findings

Decrease in lymphocyte counts

Saxagliptin: In a pool of 5 placebo-controlled studies, a small decrease in absolute lymphocyte countwas observed, approximately 100 cells/µl relative to placebo. Mean absolute lymphocyte countsremained stable with daily dosing up to 102 weeks in duration. This decrease in mean absolutelymphocyte count was not associated with clinically relevant adverse reactions.

Saxagliptin/dapagliflozin combination: Data from the saxagliptin plus dapagliflozin plus metformintreatment arms of 3 phase 3 trials, demonstrated trends of mean percent increases from baseline(rounded to the nearest tenth) in total cholesterol (Total C) (ranging from 0.4% to 3.8%), LDL-C(ranging from 2.1% to 6.9%) and HDL-C (ranging 2.3% to 5.4%) along with mean percent decreasesfrom baseline in triglycerides (ranging from -3.0% to -10.8%).

Saxagliptin/dapagliflozin combination: Of the 1 169 subjects treated in the pooled safety data from the3 clinical trials, 1 007 subjects (86.1%) were aged < 65 years, 162 subjects (13.9%) were aged≥ 65 years, and 9 subjects (0.8%) were aged ≥ 75 years. Generally, the most common adverse eventsreported in ≥ 65 years old were similar to < 65 years old. Therapeutic experience in patients 65 yearsand older is limited, and very limited in patients 75 years and older.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no information available on overdose with the saxagliptin/dapagliflozin fixed dosecombination. In the event of an overdose, appropriate supportive treatment should be initiated asdictated by the patient’s clinical status.

Saxagliptin

Saxagliptin had no clinically meaningful effect on QTc interval or heart rate at oral doses up to 400 mgdaily for 2 weeks (80 times the recommended dose). Saxagliptin and its major metabolite are removedby haemodialysis (23% of dose over four hours).

Dapagliflozin

Dapagliflozin did not show any toxicity in healthy subjects at single oral doses up to 500 mg (50 timesthe maximum recommended human dose). These subjects had detectable glucose in the urine for adose-related period of time (at least 5 days for the 500 mg dose), with no reports of dehydration,hypotension or electrolyte imbalance, and with no clinically meaningful effect on QTc interval. Theincidence of hypoglycaemia was similar to placebo. In clinical studies where once-daily doses of up to100 mg (10 times the maximum recommended human dose) were administered for 2 weeks in healthysubjects and type 2 diabetes subjects, the incidence of hypoglycaemia was slightly higher than placeboand was not dose-related. Rates of adverse events including dehydration or hypotension were similarto placebo, and there were no clinically meaningful dose-related changes in laboratory parameters,including serum electrolytes and biomarkers of renal function. The removal of dapagliflozin byhaemodialysis has not been studied.

Pharmacotherapeutic group: Drugs used in diabetes, combinations of oral blood glucose loweringdrugs, ATC code: A10BD21

This medicinal product combines saxagliptin and dapagliflozin with complementary mechanisms ofaction to improve glycaemic control. Saxagliptin, through the selective inhibition of dipeptidylpeptidase-4 (DPP-4), enhances glucose-mediated insulin secretion (incretin effect). Dapagliflozin, aselective inhibitor of sodium-glucose co-transporter 2 (SGLT2), inhibits renal glucose reabsorptionindependently of insulin. Actions of both medicinal products are regulated by the plasma glucoselevel.

Saxagliptin

Saxagliptin is a highly potent (Ki: 1.3 nM), selective, reversible and competitive inhibitor of DPP-4, anenzyme responsible for the breakdown of incretin hormones. This results in a glucose-dependentincrease in insulin secretion, thus reducing fasting and post-prandial blood glucose concentrations.

Dapagliflozin

Dapagliflozin is a highly potent (Ki: 0.55 nM), selective and reversible inhibitor of SGLT2.

Inhibition of SGLT2 by dapagliflozin reduces reabsorption of glucose from the glomerular filtrate inthe proximal renal tubule with a concomitant reduction in sodium reabsorption leading to urinaryexcretion of glucose and osmotic diuresis. Dapagliflozin therefore increases the delivery of sodium tothe distal tubule which increases tubuloglomerular feedback and reduces intraglomerular pressure.

This combined with osmotic diuresis leads to a reduction in volume overload, reduced blood pressure,and lower preload and afterload, which may have beneficial effects on cardiac remodelling anddiastolic function, and preserve renal function. The cardiac and renal benefits of dapagliflozin are notsolely dependent on the blood glucose-lowering effect. Other effects include an increase inhaematocrit and reduction in body weight.

Dapagliflozin improves both fasting and post-prandial plasma glucose levels by reducing renal glucosereabsorption leading to urinary glucose excretion. This glucose excretion (glucuretic effect) isobserved after the first dose, is continuous over the 24-hour dosing interval and is sustained for theduration of treatment. The amount of glucose removed by the kidney through this mechanism isdependent upon the blood glucose concentration and GFR. Thus, in subjects with normal bloodglucose, dapagliflozin has a low propensity to cause hypoglycaemia. Dapagliflozin does not impairnormal endogenous glucose production in response to hypoglycaemia. Dapagliflozin actsindependently of insulin secretion and insulin action. Improvement in homeostasis model assessmentfor beta cell function (HOMA beta-cell) has been observed in clinical studies with dapagliflozin.

The SGLT2 is selectively expressed in the kidney. Dapagliflozin does not inhibit other glucosetransporters important for glucose transport into peripheral tissues and is > 1 400 times more selectivefor SGLT2 versus SGLT1, the major transporter in the gut responsible for glucose absorption.

In patients with type 2 diabetes, administration of saxagliptin inhibited DPP-4 enzyme activitythroughout a 24-hour period. The inhibition of plasma DPP-4 activity by saxagliptin for at least24 hours after oral administration of saxagliptin is due to high potency, high affinity, and extendedbinding to the active site. After an oral glucose load, this produced in a 2- to 3-fold increase incirculating levels glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropicpolypeptide (GIP), decreased glucagon concentrations, and increased beta-cell responsiveness,resulting in higher insulin and C-peptide concentrations. The rise in insulin from pancreaticbeta-cells and the decrease in glucagon from pancreatic alpha-cells were associated with lowerfasting glucose concentrations and reduced glucose excursion following an oral glucose load or ameal.

Dapagliflozin’s glucuretic effect is observed after the first dose, is continuous over the 24-hour dosinginterval, and is sustained for the duration of treatment. Increases in the amount of glucose excreted inthe urine were observed in healthy subjects and in subjects with type 2 diabetes mellitus following theadministration of dapagliflozin. Approximately 70 g of glucose was excreted in the urine per day(corresponding to 280 kcal/day) at a dapagliflozin dose of 10 mg/day in subjects with type 2 diabetesmellitus for 12 weeks. Evidence of sustained glucose excretion was seen in subjects with type 2diabetes mellitus given dapagliflozin 10 mg/day for up to 2 years. Urinary uric acid excretion was alsoincreased transiently (for 3-7 days) and accompanied by a sustained reduction in serum uric acidconcentration. At 24 weeks, reductions in serum uric acid concentrations ranged from -48.3 to -18.3micromoles/L (-0.87 to -0.33 mg/dL).

The safety and efficacy of the 5 mg saxagliptin/10 mg dapagliflozin fixed-dose combination wasevaluated in three phase 3, randomised, double-blind, active/placebo-controlled clinical trials in1 169 adult subjects with type 2 diabetes mellitus. One trial with saxagliptin and dapagliflozin addedconcomitantly to metformin was conducted for 24 weeks. Two add-on therapy trials, which addedeither dapagliflozin to saxagliptin plus metformin or saxagliptin to dapagliflozin plus metformin, werealso conducted for 24 weeks followed by a 28 week extension treatment period. The safety profile ofthe combined use of saxagliptin plus dapagliflozin in these trials for up to 52 weeks was comparable tothe safety profiles for the monocomponents.

Concomitant therapy with saxagliptin and dapagliflozin in patients inadequately controlled onmetformin

A total of 534 adult patients with type 2 diabetes mellitus and inadequate glycaemic control onmetformin alone (HbA1c ≥ 8% and ≤ 12%) participated in this 24-week randomised, double-blind,active comparator-controlled superiority trial to compare the combination of saxagliptin anddapagliflozin added concurrently to metformin, versus saxagliptin (DPP-4 inhibitor) or dapagliflozin(SGLT2 inhibitor) added to metformin. Patients were randomised to one of three double-blindtreatment groups to receive saxagliptin 5 mg and dapagliflozin 10 mg added to metformin, saxagliptin5 mg and placebo added to metformin, or dapagliflozin 10 mg and placebo added to metformin.

The saxagliptin and dapagliflozin group achieved significantly greater reductions in HbA1c versuseither the saxagliptin group or dapagliflozin group at 24 weeks (see table 2).

Table 2. HbA1c at week 24 in active-controlled study comparing the combination of saxagliptinand dapagliflozin added concurrently to metformin with either saxagliptin or dapagliflozinadded to metformin

Saxagliptin 5 mg+ dapagliflozin Dapagliflozin

Efficacy parameter 10 mg Saxagliptin 5 mg 10 mg+ metformin + metformin + metformin

N=1792 N=1762 N=1792

HbA1c (%) at week 241

Baseline (mean) 8.93 9.03 8.87

Change from baseline (adjustedmean3) −1.47 −0.88 −1.20(95% confidence interval [CI]) (−1.62, −1.31) (−1.03, −0.72) (−1.35, −1.04)

Difference from saxagliptin +metformin (adjusted mean3) −0.594(95% CI) (−0.81, −0.37) - -

Difference from dapagliflozin +metformin (adjusted mean3) −0.275(95% CI) (−0.48, −0.05) - -1 LRM=Longitudinal repeated measures (using values prior to rescue).

2 Randomised and treated patients.

3 Least squares mean adjusted for baseline value.

4 p-value < 0.0001.

5 p-value=0.0166.

The majority of patients in this study had a baseline HbA1c of > 8% (see table 3). The combination ofsaxagliptin and dapagliflozin added to metformin consistently demonstrated greater reductions in

HbA1c, irrespective of baseline HbA1c compared with saxagliptin or dapagliflozin alone added tometformin. In a separate pre-specified subgroup analysis, mean reductions from baseline in HbA1cwere generally greater for patients with higher baseline HbA1c values.

Table 3. HbA1c subgroup analysis by baseline HbA1c at week 24 in randomised subjects

Adjusted mean change from baseline by baseline

HbA1c

Treatments < 8.0% ≥ 8% to < 9.0% ≥ 9.0%

Saxagliptin + dapagliflozin +metformin

Adjusted mean change from-0.80 -1.17 -2.03baseline(n=37) (n=56) (n=65)(95% CI) (-1.12, -0.47) (-1.44, -0.90) (-2.27, -1.80)

Saxagliptin + metformin

Adjusted mean change from -0.69 -0.51 -1.32baseline(n=29) (n=51) (n=63)(95% CI) (-1.06, -0.33) (-0.78, -0.25) (-1.56, -1.09)

Dapagliflozin + metformin

Adjusted mean change from -0.45 -0.84 -1.87baseline(n=37) (n=52) (n=62)(95% CI) (-0.77, -0.13) (-1.11, -0.57) (-2.11, -1.63)n=number of subjects with non-missing baseline and a week 24 value.

Proportion of patients achieving HbA1c < 7%

Forty-one point four percent (41.4%) (95% CI [34.5, 48.2]) of patients in the saxagliptin anddapagliflozin combination group achieved HbA1c levels of less than 7% compared to 18.3%(95% CI [13.0, 23.5]) patients in the saxagliptin group and 22.2% (95% CI [16.1, 28.3]) patients in thedapagliflozin group.

Add-on therapy with dapagliflozin in patients inadequately controlled on saxagliptin plus metformin

A 24-week randomised, double-blind, placebo-controlled study compared the sequential addition of10 mg dapagliflozin to 5 mg saxagliptin and metformin to the addition of placebo to 5 mg saxagliptin(DPP-4 inhibitor) and metformin in patients with type 2 diabetes mellitus and inadequate glycaemiccontrol (HbA1c ≥ 7% and ≤ 10.5%). Three hundred twenty (320) subjects were randomised equallyinto either the dapagliflozin added to saxagliptin plus metformin treatment group or placebo plussaxagliptin plus metformin treatment group. Patients who completed the initial 24-week study periodwere eligible to enter a controlled 28-week long-term study extension (52 weeks).

The group with dapagliflozin sequentially added to saxagliptin and metformin achieved statisticallysignificant (p-value < 0.0001) greater reductions in HbA1c versus the group with placebo sequentiallyadded to saxagliptin plus metformin group at 24 weeks (see table 4). The effect in HbA1c observed atweek 24 was sustained at week 52.

Add-on therapy with saxagliptin in patients inadequately controlled on dapagliflozin plus metformin

A 24-week randomised, double-blind, placebo-controlled study conducted on patients with type 2diabetes mellitus and inadequate glycaemic control (HbA1c ≥ 7% and ≤ 10.5%) on metformin anddapagliflozin alone, compared the sequential addition of 5 mg saxagliptin to 10 mg dapagliflozin andmetformin, to the addition of placebo to 10 mg dapagliflozin and metformin, 153 patients wererandomised into the saxagliptin added to dapagliflozin plus metformin treatment group, and162 patients were randomised into the placebo added to dapagliflozin plus metformin treatment group.

Patients who completed the initial 24-week study period were eligible to enter a controlled 28 weeklong-term study extension (52 weeks). The safety profile of saxagliptin added to dapagliflozin plusmetformin in the long-term treatment period was consistent with that previously observed in theclinical trial experience for the concomitant therapy study and that observed in the 24-week treatmentperiod in this study.

The group with saxagliptin sequentially added to dapagliflozin and metformin achieved statisticallysignificant (p-value < 0.0001) greater reductions in HbA1c versus the group with placebo sequentiallyadded to dapagliflozin plus metformin group at 24 weeks (see table 4). The effect in HbA1c observedat week 24 was sustained at week 52.

Table 4. HbA1c change from baseline at week 24 excluding data after rescue for randomisedsubjects - studies MB102129 and CV181168

Sequential add-on clinical trials

Study MB102129 Study CV181168

Dapagliflozin Saxagliptin

Efficacy10 mg add to 5 mg added to Placebo +parameter saxagliptin Placebo + dapagliflozin dapagliflozin5 mg + saxagliptin 5 mg + 10 mg + 10 mg +metformin metformin metformin metformin(N=160) † (N=160) † (N=153) † (N=162) †

HbA1c (%) at week 24*

Baseline(mean) 8.24 8.16 7.95 7.85

Change frombaseline(adjusted‡ −0.82 −0.10 −0.51 −0.16mean )(95% CI) (−0.96, 0.69) (−0.24, 0.04) (−0.63, −0.39) (−0.28, −0.04)

Difference in

HbA1c effect

Adjustedmean −0.72 −0.35(95% CI) (−0.91, −0.53) (−0.52, −0.18)p-value < 0.0001 < 0.0001 LRM=Longitudinal repeated measures (using values prior to rescue).

† N is the number of randomised and treated patients.

‡ Least squares mean adjusted for baseline value.

Proportion of patients achieving HbA1c < 7%

The proportion of patients achieving HbA1c < 7.0% at week 24 in the add-on therapy withdapagliflozin to saxagliptin plus metformin trial was higher in the dapagliflozin plus saxagliptin plusmetformin group 38.0% (95% CI [30.9, 45.1]) compared to the placebo plus saxagliptin plusmetformin group 12.4% (95% CI [7.0, 17.9]). The effect in HbA1c observed at week 24 was sustainedat week 52. The proportion of patients achieving HbA1c < 7% at week 24 for add-on therapy withsaxagliptin to dapagliflozin plus metformin trial was higher in the saxagliptin plus dapagliflozin plusmetformin group 35.3% (95% CI [28.2, 42.2]) compared to the placebo plus dapagliflozin plusmetformin group 23.1% (95% CI [16.9, 29.3]). The effect in HbA1c observed at week 24 wassustained at week 52.

In the concomitant study, the adjusted mean change from baseline in body weight at week 24(excluding data after rescue) was −2.05 kg (95% CI [−2.52, −1.58]) in the saxagliptin 5 mg plusdapagliflozin 10 mg plus metformin group and −2.39 kg (95% CI [−2.87, −1.91]) in the dapagliflozin10 mg plus metformin group, while the saxagliptin 5 mg plus metformin group had no change(0.00 kg) (95% CI [−0.48, 0.49]).

Treatment with the saxagliptin/dapagliflozin fixed dose combination resulted in change from baselinefor systolic blood pressure ranging from -1.3 to -2.2 mmHg and for diastolic blood pressure rangingfrom -0.5 to -1.2 mmHg caused by its mild diuretic effect. The modest lowering effects on BP wereconsistent over time and a similar number of subjects had systolic BP < 130 mmHg or diastolic BP< 80 mmHg at week 24 across the treatment groups.

In the pool of three studies, cardiovascular (CV) events that were adjudicated and confirmed as CVevents were reported in a total of 1.0% of subjects in the saxagliptin plus dapagliflozin plus metformingroup, 0.6% in the saxagliptin plus metformin group, and 0.9% in the dapagliflozin plus metformingroup.

Cardiovascular outcomes studies in patients with type 2 diabetes mellitus

No cardiovascular outcomes studies have been conducted to evaluate the saxagliptin/dapagliflozincombination.

Saxagliptin assessment of vascular outcomes recorded in patients with diabetes mellitus - thrombolysisin myocardial infarction (SAVOR) study

SAVOR was a CV outcome trial in 16 492 patients with HbA1c ≥ 6.5% and < 12% (12 959 withestablished CV disease; 3 533 with multiple risk factors only) who were randomised to saxagliptin(n=8 280) or placebo (n=8 212) added to regional standards of care for HbA1c and CV risk factors.

The study population included those ≥ 65 years (n=8 561) and ≥ 75 years (n=2 330), with normal ormild renal impairment (n=13 916) as well as moderate (n=2 240) or severe (n=336) renal impairment.

The primary safety (non-inferiority) and efficacy (superiority) endpoint was a composite endpointconsisting of the time-to-first occurrence of any of the following major adverse CV events (MACE):

CV death, nonfatal myocardial infarction, or nonfatal ischemic stroke.

After a mean follow up of 2 years, the trial met its primary safety endpoint demonstrating saxagliptindoes not increase the cardiovascular risk in patients with type 2 diabetes compared to placebo whenadded to current background therapy.

No benefit was observed for MACE or all-cause mortality.

One component of the secondary composite endpoint, hospitalisation for heart failure, occurred at agreater rate in the saxagliptin group (3.5%) compared with the placebo group (2.8%), with nominalstatistical significance favouring placebo [HR=1.27; (95% CI 1.07, 1.51); P=0.007]. Clinicallyrelevant factors predictive of increased relative risk with saxagliptin treatment could not be definitivelyidentified. Subjects at higher risk for hospitalisation for heart failure, irrespective of treatmentassignment, could be identified by known risk factors for heart failure such as baseline history of heartfailure or impaired renal function. However, subjects on saxagliptin with a history of heart failure orimpaired renal function at baseline were not at an increased risk relative to placebo for the primary orsecondary composite endpoints or all-cause mortality.

Another secondary endpoint, all-cause mortality, occurred at a rate of 5.1% in the saxagliptin groupand 4.6% in the placebo group. CV deaths were balanced across the treatment groups. There was anumerical imbalance in non-CV death, with more events on saxagliptin (1.8%) than placebo (1.4%)[HR=1.27; (95% CI 1.00, 1.62); P=0.051].

Dapagliflozin Effect on Cardiovascular Events (DECLARE)

Dapagliflozin Effect on Cardiovascular Events (DECLARE) was an international, multicentre,randomised, double-blind, placebo-controlled clinical study conducted to determine the effect ofdapagliflozin compared with placebo on cardiovascular outcomes when added to current backgroundtherapy. All patients had type 2 diabetes mellitus and either at least two additional cardiovascular riskfactors (age ≥ 55 years in men or ≥ 60 years in women and one or more of dyslipidaemia, hypertensionor current tobacco use) or established cardiovascular disease.

Of 17 160 randomised patients, 6 974 (40.6%) had established cardiovascular disease and10 186 (59.4%) did not have established cardiovascular disease. 8 582 patients were randomised todapagliflozin 10 mg and 8 578 to placebo and were followed for a median of 4.2 years.

The mean age of the study population was 63.9 years, 37.4% were female. In total, 22.4% had haddiabetes for ≤ 5 years, mean duration of diabetes was 11.9 years. Mean HbA1c was 8.3% and mean

BMI was 32.1 kg/m2.

At baseline, 10.0% of patients had a history of heart failure. Mean eGFR was 85.2 mL/min/1.73 m2,7.4% of patients had eGFR < 60 mL/min/1.73 m2, and 30.3% of patients had micro- ormacroalbuminuria (urine albumin to creatinine ratio [UACR] ≥ 30 to ≤ 300 mg/g or > 300 mg/g,respectively).

Most patients (98%) used one or more diabetic medicinal products at baseline, including metformin(82%), insulin (41%) and sulfonylurea (43%).

The primary endpoints were time to first event of the composite of cardiovascular death, myocardialinfarction or ischaemic stroke (MACE) and time to first event of the composite of hospitalisation forheart failure or cardiovascular death. The secondary endpoints were a renal composite endpoint andall-cause mortality.

Major adverse cardiovascular events

Dapagliflozin 10 mg demonstrated non-inferiority versus placebo for the composite of cardiovasculardeath, myocardial infarction or ischaemic stroke (one-sided p < 0.001).

Heart failure or cardiovascular death

Dapagliflozin 10 mg demonstrated superiority versus placebo in preventing the composite ofhospitalisation for heart failure or cardiovascular death (Figure 1). The difference in treatment effectwas driven by hospitalisation for heart failure, with no difference in cardiovascular death (Figure 2).

The treatment benefit of dapagliflozin over placebo was observed both in patients with and withoutestablished cardiovascular disease, with and without heart failure at baseline, and was consistent acrosskey subgroups, including age, gender, renal function (eGFR) and region.

Figure 1: Time to first occurrence of hospitalisation for heart failure or cardiovascular death

Patients at risk is the number of patients at risk at the beginning of the period.

HR=Hazard ratio CI=Confidence interval.

Results on primary and secondary endpoints are displayed in Figure 2. Superiority of dapagliflozinover placebo was not demonstrated for MACE (p=0.172). The renal composite endpoint and all-causemortality were therefore not tested as part of the confirmatory testing procedure.

Figure 2: Treatment effects for the primary composite endpoints and their components, and thesecondary endpoints and components

Renal composite endpoint defined as: sustained confirmed ≥ 40% decrease in eGFR to eGFR<60 mL/min/1.73 m2 and/or end-stage renal disease (dialysis ≥ 90 days or kidney transplantation, sustainedconfirmed eGFR < 15 mL/min/1.73 m2) and/or renal or cardiovascular death.

p-values are two-sided. p-values for the secondary endpoints and for single components are nominal. Time tofirst event was analysed in a Cox proportional hazards model. The number of first events for the singlecomponents are the actual number of first events for each component and does not add up to the number ofevents in the composite endpoint.

CI=confidence interval.

Dapagliflozin reduced the incidence of events of the composite of confirmed sustained eGFR decrease,end-stage renal disease, renal or cardiovascular death. The difference between groups was driven byreductions in events of the renal components; sustained eGFR decrease, end-stage renal disease andrenal death (Figure 2).

The hazard ratio for time to nephropathy (sustained eGFR decrease, end-stage renal disease and renaldeath) was 0.53 (95% CI 0.43, 0.66) for dapagliflozin versus placebo.

In addition, dapagliflozin reduced the new onset of sustained albuminuria (hazard ratio 0.79[95% CI 0.72, 0.87]) and led to greater regression of macroalbuminuria (hazard ratio 1.82[95% CI 1.51, 2.20]) compared with placebo.

Moderate renal impairment CKD 3A (eGFR ≥ 45 to < 60 mL/min/1.73 m2)

Dapagliflozin

The efficacy of dapagliflozin was assessed in a dedicated study in diabetic patients with an eGFR ≥ 45to < 60 mL/min/1.73 m2 who had inadequate glycaemic control on usual care. Treatment withdapagliflozin resulted in reductions in HbA1c and body weight compared with placebo (Table 5).

Table 5. Results at week 24 of a placebo-controlled study of dapagliflozin in diabetic patientswith an eGFR ≥ 45 to < 60 mL/min/1.73 m2

Dapagliflozina Placeboa10 mg

Nb 159 161

HbA1c (%)

Baseline (mean) 8.35 8.03

Change from baselineb −0.37 −0.03

Difference from placebob −0.34*(95% CI) (−0.53, −0.15)

Body weight (kg)

Baseline (mean) 92.51 88.30

Percent change from baselinec −3.42 −2.02

Difference in percent change from −1.43*placeboc(−2.15, −0.69)(95% CI)a Metformin or metformin hydrochloride were part of the usual care in 69.4% and 64.0% of the patients forthe dapagliflozin and placebo groups, respectively.b Least squares mean adjusted for baseline value.c Derived from least squares mean adjusted for baseline value.

* p ≤ 0.001.

At week 24, treatment with dapagliflozin demonstrated reductions in fasting plasma glucose (FPG)−1.19 mmol/L (−21.46 mg/dL) compared to −0.27 mmol/L (−4.87 mg/dL) for placebo (p ≤ 0.001), andreductions in seated systolic blood pressure (SBP) −4.8 mmHg compared to −1.7 mmHg for placebo(p < 0.05).

The European Medicines Agency has waived the obligation to submit the results of studies with Qternin all subsets of the paediatric population in the treatment of type 2 diabetes (see section 4.2 forinformation on paediatric use).

Saxagliptin/dapagliflozin combination: Overall, the pharmacokinetics of saxagliptin and dapagliflozinwere not affected in clinically relevant manner when administered as a fixed dose combinationcompared with independent doses of saxagliptin and dapagliflozin.

The following reflects the pharmacokinetic properties of the saxagliptin/dapagliflozin fixed dosecombination unless stated that the presented data are from administration of saxagliptin ordapagliflozin.

Bioequivalence has been confirmed between the Qtern 5 mg/10 mg tablet and the individualsaxagliptin 5 mg and dapagliflozin 10 mg tablets after single dose administration in the fasted state inhealthy subjects. The pharmacokinetics of dapagliflozin, and saxagliptin and its major metabolite weresimilar in healthy subjects and in patients with type 2 diabetes.

Administration of the saxagliptin/dapagliflozin fixed dose combination with a high-fat meal decreasesdapagliflozin Cmax by up to 35% and prolongs Tmax by approximately 1.5 hours, but does not alter

AUC as compared with the fasted state. These changes are not considered to be clinically meaningful.

There was no food effect observed for saxagliptin. This medicinal product can be administered with orwithout food.

Saxagliptin/dapagliflozin combination: No interaction studies have been performed with thesaxagliptin/dapagliflozin fixed dose combination and other medicinal products. Such studies have beenconducted with the individual active substances.

Saxagliptin: In in vitro studies, saxagliptin and its major metabolite neither inhibited CYP1A2, 2A6,2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4, nor induced CYP1A2, 2B6, 2C9, or 3A4.

Dapagliflozin: In in vitro studies, dapagliflozin neither inhibited cytochrome P450 (CYP) 1A2,

CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, nor induced CYP1A2,

CYP2B6 or CYP3A4. Therefore, dapagliflozin is not expected to alter the metabolic clearance ofcoadministered medicinal products that are metabolised by these enzymes.

Saxagliptin: Saxagliptin was rapidly absorbed after oral administration in the fasted state, withmaximum plasma concentrations (Cmax) of saxagliptin and its major metabolite attained within 2 and4 hours (Tmax), respectively. The Cmax and AUC values of saxagliptin and its major metaboliteincreased proportionally with the increment in the saxagliptin dose, and this dose-proportionality wasobserved in doses up to 400 mg. Following a 5 mg single oral dose of saxagliptin to healthy subjects,the mean plasma AUC values for saxagliptin and its major metabolite were 78 ng h/mL and214 ng h/mL, respectively. The corresponding plasma Cmax values were 24 ng/mL and 47 ng/mL,respectively. The intra-subject coefficients of variation for saxagliptin Cmax and AUC were less than12%.

Dapagliflozin: Dapagliflozin was rapidly and well absorbed after oral administration. Maximumdapagliflozin plasma concentrations (Cmax) were usually attained within 2 hours after administration inthe fasted state. Geometric mean steady-state dapagliflozin Cmax and AUCτ values following once daily10 mg doses of dapagliflozin were 158 ng/mL and 628 ng h/mL, respectively. The absolute oralbioavailability of dapagliflozin following the administration of a 10 mg dose is 78%.

Saxagliptin: The in vitro protein binding of saxagliptin and its major metabolite in human serum isnegligible. Thus, changes in blood protein levels in various disease states (e.g. renal or hepaticimpairment) are not expected to alter the disposition of saxagliptin. The volume of distribution ofsaxagliptin was 205 L.

Dapagliflozin: Dapagliflozin is approximately 91% protein bound. Protein binding was not altered invarious disease states (e.g. renal or hepatic impairment). The mean steady-state volume of distributionof dapagliflozin was 118 L.

Saxagliptin: The biotransformation of saxagliptin is primarily mediated by cytochrome P450 3A4/5(CYP3A4/5). The major active metabolite of saxagliptin, 5-OH-saxagliptin, is also a selective,reversible, competitive DPP-4 inhibitor, half as potent as saxagliptin.

Dapagliflozin: Dapagliflozin is extensively metabolised, primarily to yielddapagliflozin 3-O-glucuronide, which is an inactive metabolite. Dapagliflozin 3-O-glucuronide orother metabolites do not contribute to the glucose-lowering effects. The formation ofdapagliflozin 3-O-glucuronide is mediated by UGT1A9, an enzyme present in the liver and kidney,and CYP-mediated metabolism was a minor clearance pathway in humans.

Saxagliptin: The mean plasma terminal half-life (t1/2) values for saxagliptin and its major metaboliteare 2.5 hours and 3.1 hours respectively, and the mean t1/2 value for plasma DPP-4 inhibition was26.9 hours. Saxagliptin is eliminated by both renal and hepatic pathways. Following a single 50 mgdose of 14C-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin,its active metabolite, and total radioactivity, respectively. The average renal clearance of saxagliptin(~230 mL/min) was greater than the average estimated glomerular filtration rate (~120 mL/min),suggesting some active renal excretion.

Dapagliflozin: The mean plasma terminal half-life (t1/2) for dapagliflozin was 12.9 hours following asingle oral dose of dapagliflozin 10 mg to healthy subjects. The mean total systemic clearance ofdapagliflozin administered intravenously was 207 mL/min. Dapagliflozin and related metabolites areprimarily eliminated via urinary excretion with less than 2% as unchanged dapagliflozin.

Saxagliptin: The Cmax and AUC of saxagliptin and its major metabolite increased proportionally tothe saxagliptin dose. No appreciable accumulation of either saxagliptin or its major metabolite wasobserved with repeated once-daily dosing at any dose level. No dose- and time-dependence wasobserved in the clearance of saxagliptin and its major metabolite over 14 days of once-daily dosingwith saxagliptin at doses ranging from 2.5 mg to 400 mg.

Dapagliflozin: Dapagliflozin exposure increased proportional to the increment in dapagliflozin doseover the range of 0.1 to 500 mg and its pharmacokinetics did not change with time upon repeated dailydosing for up to 24 weeks.

Saxagliptin: After a single dose of saxagliptin in subjects with mild, moderate or severe renalimpairment (or ESRD) classified on the basis of creatinine clearance the mean AUC values ofsaxagliptin were 1.2-, and up to 2.1- and 4.5- fold higher, respectively, than AUC values in subjectswith normal renal function. The AUC values of 5-OH-saxagliptin were also increased. The degree ofrenal impairment did not affect the Cmax of saxagliptin or its major metabolite.

Dapagliflozin: At steady-state (20 mg once-daily dapagliflozin for 7 days), subjects with type 2diabetes mellitus and mild, moderate or severe renal impairment (as determined by iohexol plasmaclearance) had mean systemic exposures of dapagliflozin of 32%, 60% and 87% higher, respectively,than those of subjects with type 2 diabetes mellitus and normal renal function. The steady-state24-hour urinary glucose excretion was highly dependent on renal function and 85, 52, 18 and 11 g ofglucose/day was excreted by subjects with type 2 diabetes mellitus and normal renal function or mild,moderate or severe renal impairment, respectively. The impact of haemodialysis on dapagliflozinexposure is not known.

Saxagliptin: In subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), or severe(Child-Pugh class C) hepatic impairment the exposures to saxagliptin were 1.1-, 1.4- and 1.8-foldhigher, respectively, and the exposures to BMS-510849 (saxagliptin metabolite) were 22%, 7%and 33% lower, respectively, than those observed in healthy subjects.

Dapagliflozin: In subjects with mild or moderate hepatic impairment (Child-Pugh classes A and B),mean Cmax and AUC of dapagliflozin were up to 12% and 36% higher, respectively, compared tohealthy matched control subjects. These differences were not considered to be clinically meaningful.

In subjects with severe hepatic impairment (Child-Pugh class C) mean Cmax and AUC of dapagliflozinwere 40% and 67% higher than matched healthy controls, respectively.

Saxagliptin: Elderly patients (65-80 years) had about 60% higher saxagliptin AUC than young patients(18-40 years). This is not considered clinically meaningful, therefore, no dose adjustment forsaxagliptin is recommended on the basis of age alone.

Dapagliflozin: There is no clinically meaningful increase in exposure based on age alone in subjectsup to 70 years old. However, an increased exposure due to age-related decrease in renal function canbe expected. There are insufficient data to draw conclusions regarding exposure in patients> 70 years old.

Saxagliptin: Females had approximately 25% higher systemic exposure values for saxagliptin. Therewere no clinically relevant differences observed in saxagliptin pharmacokinetics between males andfemales.

Dapagliflozin: The mean dapagliflozin AUCss in females was estimated to be about 22% higher than inmales.

Saxagliptin: Race was not identified as a statistically significant covariate on the apparent clearance ofsaxagliptin and its metabolite.

Dapagliflozin: There were no clinically relevant differences in systemic exposures between White,

Black or Asian races.

Saxagliptin: Body weight had a small and non-clinically meaningful impact on saxagliptin exposure.

Females had approximately 25% higher systemic-exposure values for saxagliptin, this difference isconsidered not clinically relevant.

Dapagliflozin: Dapagliflozin exposure was found to decrease with increased weight. Consequently,low-weight patients may have somewhat increased exposure and patients with high-weight somewhatdecreased exposure. However, the differences in exposure were not considered clinically meaningful.

Non-clinical studies of either saxagliptin or dapagliflozin revealed no special hazard for humans basedon conventional studies of safety pharmacology, genotoxicity or carcinogenicity.

Saxagliptin produced reversible skin lesions (scabs, ulcerations and necrosis) in extremities (tail, digits,scrotum and/or nose) in cynomolgus monkeys. The no effect level (NOEL) for the lesions is 1 and2 times the human exposure of saxagliptin and the major metabolite respectively, at the recommendedhuman dose (RHD) of 5 mg/day. The clinical relevance of the skin lesions is not known and skinlesions have not been observed in humans.

Immune related findings of minimal, nonprogressive, lymphoid hyperplasia in spleen, lymph nodes andbone marrow with no adverse sequelae have been reported in all species tested at exposures startingfrom 7 times the RHD.

Saxagliptin produced gastrointestinal toxicity in dogs, including bloody/mucoid faeces andenteropathy at higher doses with a NOEL 4 and 2 times the human exposure for saxagliptin and themajor metabolite, respectively at RHD. The effect on offspring body weights were noted untilpostnatal day 92 and 120 in females and males, respectively.

Saxagliptin has effects on fertility in male and female rats at high doses producing overt signs oftoxicity. Saxagliptin was not teratogenic at any doses evaluated in rats or rabbits. At high doses in rats,saxagliptin caused reduced ossification (a developmental delay) of the foetal pelvis and decreasedfoetal body weight (in the presence of maternal toxicity), with a NOEL 303 and 30 times the humanexposure for saxagliptin and the major metabolite, respectively, at RHD. In rabbits, the effects ofsaxagliptin were limited to minor skeletal variations observed only at maternally toxic doses (NOEL158 and 224 times the human exposure for saxagliptin and the major metabolite, respectively at

RHD). In a pre- and postnatal developmental study in rats, saxagliptin caused decreased pup weight atmaternally toxic doses, with NOEL 488 and 45 times the human exposure for saxagliptin and themajor metabolite, respectively at RHD. The effect on offspring body weights were noted until postnatalday 92 and 120 in females and males, respectively.

Direct administration of dapagliflozin to weanling juvenile rats and indirect exposure during latepregnancy (corresponding to the second and third trimesters of pregnancy with respect to human renalmaturation) and lactation are each associated with increased incidence and/or severity of renal pelvicand tubular dilatations in progeny.

In a juvenile study, when dapagliflozin was dosed directly to young rats from postnatal day 21 untilpostnatal day 90, renal pelvic and tubular dilatations (with dose-related increases in kidney weight andmacroscopic kidney enlargement) were reported at all dose levels; pup exposures at the lowest dosetested were ≥ 15 times the maximum recommended human dose. The renal pelvic and tubulardilatations observed in juvenile animals did not fully reverse within the approximate 1-month recoveryperiod.

Dapagliflozin dosed to maternal rats from gestation day 6 through postnatal day 21, and pups wereindirectly exposed in utero and throughout lactation. Increased incidence or severity of renal pelvicdilatation was observed in adult offspring of treated dams, although only at the highest dose tested (atmaternal and pup dapagliflozin exposures of 1 415 times and 137 times, respectively, the humanvalues at the maximum recommended human dose [MRHD]). Additional developmental toxicity waslimited to dose-related reductions in pup body weights, and observed only at doses ≥ 15 mg/kg/day(pup exposures ≥ 29 times the human values at the MRHD). Maternal toxicity was evident only at thehighest dose tested, and limited to transient reductions in body weight and food consumption at dose.

The NOAEL for developmental toxicity is associated with a maternal systemic exposure 19 times thehuman values at the MRHD.

In studies of embryo-foetal development in rabbits, dapagliflozin caused neither maternal nordevelopmental toxicities at any dose tested; the highest dose tested corresponded to a systemicexposure 1 191 times the MRHD. In rats, dapagliflozin was neither embryolethal nor teratogenic atexposures up to 1 441 times the human values at the MRHD.

Microcrystalline cellulose (E460i)

Croscarmellose sodium (E468)

Magnesium stearate (E470b)

Dental type silica (E551)

Poly(vinyl alcohol) (E1203)

Macrogol 3350 (E1521)

Titanium dioxide (E171)

Talc (E553b)

Iron oxide yellow (E172)

Iron oxide red (E172)

Shellac

Indigo carmine aluminium lake (E132)

Not applicable.

3 years

This medicinal product does not require any special storage conditions.

PA/Alu/PVC-Alu blister.

Pack sizes of 14, 28, and 98 film-coated tablets in calendar blisters.

Pack size of 30 film-coated tablets in blisters.

Not all pack sizes may be marketed.

No special requirements.

AstraZeneca AB

SE-151 85 Södertälje

Sweden

EU/1/16/1108/001 14 film-coated tablets

EU/1/16/1108/002 28 film-coated tablets

EU/1/16/1108/003 98 film-coated tablets

EU/1/16/1108/004 30 film-coated tablets

Date of first authorisation: 15 July 2016

Date of latest renewal: 19 May 2021

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu