FORXIGA 5mg tablets medication leaflet

Forxiga 5 mg film-coated tablets

Forxiga 10 mg film-coated tablets

Forxiga 5 mg film-coated tablets

Each tablet contains dapagliflozin propanediol monohydrate equivalent to 5 mg dapagliflozin.

Each 5 mg tablet contains 25 mg of lactose.

Forxiga 10 mg film-coated tablets

Each tablet contains dapagliflozin propanediol monohydrate equivalent to 10 mg dapagliflozin.

Each 10 mg tablet contains 50 mg of lactose.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Forxiga 5 mg film-coated tablets

Yellow, biconvex, 0.7 cm diameter round, film-coated tablets with “5” engraved on one side and“1427” engraved on the other side.

Forxiga 10 mg film-coated tablets

Yellow, biconvex, approximately 1.1 x 0.8 cm diagonally diamond-shaped, film-coated tablets with“10” engraved on one side and “1428” engraved on the other side.

Forxiga is indicated in adults and children aged 10 years and above for the treatment of insufficientlycontrolled type 2 diabetes mellitus as an adjunct to diet and exercise

- as monotherapy when metformin is considered inappropriate due to intolerance.

- in addition to other medicinal products for the treatment of type 2 diabetes.

For study results with respect to combination of therapies, effects on glycaemic control, cardiovascularand renal events, and the populations studied, see sections 4.4, 4.5 and 5.1.

Forxiga is indicated in adults for the treatment of symptomatic chronic heart failure.

Forxiga is indicated in adults for the treatment of chronic kidney disease.

The recommended dose is 10 mg dapagliflozin once daily.

When dapagliflozin is used in combination with insulin or an insulin secretagogue, such as asulphonylurea, a lower dose of insulin or insulin secretagogue may be considered to reduce the risk ofhypoglycaemia (see sections 4.5 and 4.8).

The recommended dose is 10 mg dapagliflozin once daily.

The recommended dose is 10 mg dapagliflozin once daily.

No dose adjustment is required based on renal function.

Due to limited experience, it is not recommended to initiate treatment with dapagliflozin in patientswith GFR < 25 mL/min.

In patients with type 2 diabetes mellitus, the glucose lowering efficacy of dapagliflozin is reducedwhen the glomerular filtration rate (GFR) is < 45 mL/min and is likely absent in patients with severerenal impairment. Therefore, if GFR falls below 45 mL/min, additional glucose lowering treatmentshould be considered in patients with type 2 diabetes mellitus if further glycaemic control is needed(see sections 4.4, pct. 4.8, 5.1 and 5.2).

No dose adjustment is necessary for patients with mild or moderate hepatic impairment. In patientswith severe hepatic impairment, a starting dose of 5 mg is recommended. If well tolerated, the dosemay be increased to 10 mg (see sections 4.4 and 5.2).

No dose adjustment is recommended based on age.

No dose adjustment is required for the treatment of type 2 diabetes mellitus in children aged 10 yearsand above (see sections 5.1 and 5.2). No data are available for children below 10 years of age.

The safety and efficacy of dapagliflozin for the treatment of heart failure or for the treatment ofchronic kidney disease in children < 18 years have not yet been established. No data are available.

Forxiga can be taken orally once daily at any time of day with or without food. Tablets are to beswallowed whole.

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

Dapagliflozin should not be used in patients with type 1 diabetes mellitus (see “Diabetic ketoacidosis”in section 4.4).

Due to limited experience, it is not recommended to initiate treatment with dapagliflozin in patientswith GFR < 25 mL/min.

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 reactionsof increase in creatinine, phosphorus, parathyroid hormone (PTH) and hypotension, compared withplacebo.

There is limited experience in clinical studies in patients with hepatic impairment. Dapagliflozinexposure is increased in patients with severe hepatic impairment (see sections 4.2 and 5.2).

Use in patients at risk for volume depletion and/or hypotension

Due to its mechanism of action, dapagliflozin increases diuresis which may lead to the modestdecrease in blood pressure observed in clinical studies (see section 5.1). It may be more pronounced inpatients with very high blood glucose concentrations.

Caution should be exercised in patients for whom a dapagliflozin-induced drop in blood pressurecould pose a risk, such as patients on anti-hypertensive therapy with a history of hypotension orelderly 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,laboratory tests including haematocrit and electrolytes) is recommended. Temporary interruption oftreatment with dapagliflozin is recommended for patients who develop volume depletion until thedepletion is corrected (see section 4.8).

Rare cases of diabetic ketoacidosis (DKA), including life-threatening and fatal cases, have beenreported in patients treated with sodium-glucose co-transporter 2 (SGLT2) inhibitors, includingdapagliflozin. In a number of cases, the presentation of the condition was atypical with onlymoderately increased blood glucose values, below 14 mmol/L (250 mg/dL).

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, dapagliflozin treatment should be stoppedimmediately.

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 dapagliflozin, factors in the patient history that may predispose to ketoacidosis shouldbe 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 experiencing a DKA while on SGLT2 inhibitortreatment is not recommended, unless another clear precipitating factor is identified and resolved.

In type 1 diabetes mellitus studies with dapagliflozin, DKA was reported with common frequency.

Dapagliflozin should not be used for treatment of patients with type 1 diabetes.

Postmarketing 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, Forxiga should be discontinued and prompt treatment (including antibiotics andsurgical debridement) should be instituted.

Urinary tract infections

Urinary glucose excretion may be associated with an increased risk of urinary tract infection;therefore, temporary interruption of dapagliflozin should be considered when treating pyelonephritisor 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 renal function apply to elderly patients as to all patients (seesections 4.2, pct. 4.4, pct. 4.8 and 5.1).

Cardiac failure

Experience with dapagliflozin in NYHA class IV is limited.

Infiltrative cardiomyopathy

Patients with infiltrative cardiomyopathy have not been studied.

There is no experience with dapagliflozin for the treatment of chronic kidney disease in patientswithout diabetes who do not have albuminuria. Patients with albuminuria may benefit more fromtreatment with dapagliflozin.

Increased haematocrit

Increased haematocrit has been observed with dapagliflozin treatment (see section 4.8). Patients withpronounced elevations in haematocrit should be monitored and investigated for underlyinghaematological disease.

An increase in cases of lower limb amputation (primarily of the toe) has been observed in long-term,clinical studies in type 2 diabetes mellitus with SGLT2 inhibitors. It is unknown whether thisconstitutes a class effect. It is important to counsel patients with diabetes on routine preventative footcare.

Due to its mechanism of action, patients taking Forxiga will test positive for glucose in their urine.

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

Dapagliflozin may add to the diuretic effect of thiazide and loop diuretics and may increase the risk ofdehydration and hypotension (see section 4.4).

Insulin and insulin secretagogues, such as sulphonylureas, cause hypoglycaemia. Therefore, a lowerdose of insulin or an insulin secretagogue may be required to reduce the risk of hypoglycaemia whenused in combination with dapagliflozin in patients with type 2 diabetes mellitus (see sections 4.2 and4.8).

The metabolism of dapagliflozin is primarily via glucuronide conjugation mediated by

UDP glucuronosyltransferase 1A9 (UGT1A9).

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 of coadministered medicinalproducts that are metabolised by these enzymes.

Effect of other medicinal products on dapagliflozin

Interaction studies conducted in healthy subjects, using mainly a single-dose design, suggest that thepharmacokinetics of dapagliflozin are not altered by metformin, pioglitazone, sitagliptin, glimepiride,voglibose, hydrochlorothiazide, bumetanide, valsartan, or simvastatin.

Following coadministration of dapagliflozin with rifampicin (an inducer of various active transportersand drug-metabolising enzymes) a 22% decrease in dapagliflozin systemic exposure (AUC) wasobserved, but with no clinically meaningful effect on 24-hour urinary glucose excretion. No doseadjustment 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. No dose adjustment is recommended.

Effect of dapagliflozin on other medicinal products

Dapagliflozin may increase renal lithium excretion and the blood lithium levels may be decreased.

Serum concentration of lithium should be monitored more frequently after dapagliflozin initiation anddose changes. 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, sitagliptin, glimepiride,hydrochlorothiazide, bumetanide, valsartan, digoxin (a P-gp substrate) or warfarin (S-warfarin, a

CYP2C9 substrate), or the anticoagulatory effects of warfarin as measured by INR. Combination of asingle dose of dapagliflozin 20 mg and simvastatin (a CYP3A4 substrate) resulted in a 19% increase in

AUC of simvastatin and 31% increase in AUC of simvastatin acid. The increase in simvastatin andsimvastatin acid exposures are 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.

Interaction studies have only been performed in adults.

There are no data from the use of dapagliflozin in pregnant women. Studies in rats have showntoxicity to the developing kidney in the time period corresponding to the second and third trimesters ofhuman pregnancy (see section 5.3). Therefore, the use of dapagliflozin is not recommended during thesecond and third trimesters of pregnancy.

When pregnancy is detected, treatment with dapagliflozin should be discontinued.

It is unknown whether dapagliflozin and/or its metabolites are excreted in human milk. Availablepharmacodynamic/toxicological data in animals have shown excretion of dapagliflozin/metabolites inmilk, as well as pharmacologically-mediated effects in nursing offspring (see section 5.3). A risk tothe newborns/infants cannot be excluded. Dapagliflozin should not be used while breast-feeding.

The effect of dapagliflozin on fertility in humans has not been studied. In male and female rats,dapagliflozin showed no effects on fertility at any dose tested.

Forxiga has no or negligible influence on the ability to drive and use machines. Patients should bealerted to the risk of hypoglycaemia when dapagliflozin is used in combination with a sulphonylureaor insulin.

In the clinical studies in type 2 diabetes, more than 15,000 patients have been treated withdapagliflozin.

The primary assessment of safety and tolerability was conducted in a pre-specified pooled analysis of13 short-term (up to 24 weeks) placebo-controlled studies with 2,360 subjects treated withdapagliflozin 10 mg and 2,295 treated with placebo.

In the dapagliflozin cardiovascular outcomes study in type 2 diabetes mellitus (DECLARE study, seesection 5.1), 8,574 patients received dapagliflozin 10 mg and 8,569 received placebo for a medianexposure time of 48 months. In total, there were 30,623 patient-years of exposure to dapagliflozin.

The most frequently reported adverse reactions across the clinical studies were genital infections.

In the dapagliflozin cardiovascular outcome study in patients with heart failure with reduced ejectionfraction (DAPA-HF study), 2,368 patients were treated with dapagliflozin 10 mg and 2,368 patientswith placebo for a median exposure time of 18 months. The patient population included patients withtype 2 diabetes mellitus and without diabetes, and patients with eGFR ≥ 30 mL/min/1.73 m2. In thedapagliflozin cardiovascular outcome study in patients with heart failure with left ventricular ejectionfraction > 40% (DELIVER), 3,126 patients were treated with dapagliflozin 10 mg and 3,127 patientswith placebo for a median exposure time of 27 months. The patient population included patients withtype 2 diabetes mellitus and without diabetes, and patients with eGFR ≥ 25 mL/min/1.73 m2.

The overall safety profile of dapagliflozin in patients with heart failure was consistent with the knownsafety profile of dapagliflozin.

In the dapagliflozin renal outcome study in patients with chronic kidney disease (DAPA-CKD),2,149 patients were treated with dapagliflozin 10 mg and 2,149 patients with placebo for a medianexposure time of 27 months. The patient population included patients with type 2 diabetes mellitus andwithout diabetes, with eGFR ≥ 25 to ≤ 75 mL/min/1.73 m2, and albuminuria (urine albumin creatinineratio [UACR] ≥ 200 and ≤ 5000 mg/g). Treatment was continued if eGFR fell to levels below25 mL/min/1.73 m2.

The overall safety profile of dapagliflozin in patients with chronic kidney disease was consistent withthe known safety profile of dapagliflozin.

The following adverse reactions have been identified in the placebo-controlled clinical studies andpostmarketing surveillance. None were found to be dose-related. Adverse reactions listed below areclassified according to frequency and system organ class (SOC). Frequency categories are definedaccording to the following convention: 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 notknown (cannot be estimated from the available data).

Table 1. Adverse reactions in placebo-controlled clinical studiesa and postmarketing experience

System organ Very common Common* Uncommon** Rare Very rareclass

Infections and Vulvovaginitis, Fungal Necrotisinginfestations balanitis and infection** fasciitis of therelated genital perineuminfections*,b,c (Fournier's

Urinary tract gangrene)b,iinfection*,b,d

Metabolism and Hypoglycaemia Volume Diabeticnutrition (when used depletionb,e ketoacidosisdisorders with SU or Thirst** (when used ininsulin)b type 2 diabetesmellitus)b,i,k

Nervous system Dizzinessdisorders

Gastrointestinal Constipation**disorders Dry mouth**

Skin and Rashj Angioedemasubcutaneoustissue disorders

Musculoskeletal Back pain*and connectivetissue disorders

Renal and Dysuria Nocturia** Tubulointerstitialurinary Polyuria*,f nephritisdisorders

Reproductive Vulvovaginalsystem and pruritus**breast Pruritusdisorders genital**

Investigations Haematocrit Bloodincreasedg creatinine

Creatinine renal increasedclearance during initialdecreased treatment**,bduring initial Blood ureatreatmentb increased**

Dyslipidaemiah Weightdecreased**aThe table shows up to 24-week (short-term) data regardless of glycaemic rescue.bSee corresponding subsection below for additional information.cVulvovaginitis, balanitis and related genital infections includes, e.g. the predefined preferred terms:

vulvovaginal mycotic infection, vaginal infection, balanitis, genital infection fungal, vulvovaginal candidiasis,vulvovaginitis, balanitis candida, genital candidiasis, genital infection, genital infection male, penile infection,vulvitis, vaginitis bacterial, vulval abscess.dUrinary tract infection includes the following preferred terms, listed in order of frequency reported: urinary tractinfection, cystitis, Escherichia urinary tract infection, genitourinary tract infection, pyelonephritis, trigonitis,urethritis, kidney infection and prostatitis.eVolume depletion includes, e.g. the predefined preferred terms: dehydration, hypovolaemia, hypotension.fPolyuria includes the preferred terms: pollakiuria, polyuria, urine output increased.gMean changes from baseline in haematocrit were 2.30% for dapagliflozin 10 mg versus -0.33% for placebo.

Haematocrit values >55% were reported in 1.3% of the subjects treated with dapagliflozin 10 mg versus 0.4%of placebo subjects.hMean percent change from baseline for dapagliflozin 10 mg versus placebo, respectively, was: total cholesterol2.5% versus 0.0%; HDL cholesterol 6.0% versus 2.7%; LDL cholesterol 2.9% versus -1.0%; triglycerides -2.7%versus -0.7%.iSee section 4.4.jAdverse reaction was identified through postmarketing surveillance. Rash includes the following preferredterms, listed in order of frequency in clinical studies: rash, rash generalised, rash pruritic, rash macular, rashmaculo-papular, rash pustular, rash vesicular, and rash erythematous. In active- and placebo-controlled clinicalstudies (dapagliflozin, N=5936, All control, N=3403), the frequency of rash was similar for dapagliflozin(1.4%) and all control (1.4%), respectively.kReported in the cardiovascular outcomes study in patients with type 2 diabetes (DECLARE). Frequency isbased on annual rate.

*Reported in ≥ 2% of subjects and ≥ 1% more and at least 3 more subjects treated with dapagliflozin 10 mgcompared to placebo.

**Reported by the investigator as possibly related, probably related or related to study treatment and reported in≥ 0.2% of subjects and ≥ 0.1% more and at least 3 more subjects treated with dapagliflozin 10 mg compared toplacebo.

Vulvovaginitis, balanitis and related genital infections

In the 13-study safety pool, vulvovaginitis, balanitis and related genital infections were reported in5.5% and 0.6% of subjects who received dapagliflozin 10 mg and placebo, respectively. Mostinfections were mild to moderate, and subjects responded to an initial course of standard treatment andrarely resulted in discontinuation from dapagliflozin treatment. These infections were more frequent infemales (8.4% and 1.2% for dapagliflozin and placebo, respectively), and subjects with a prior historywere more likely to have a recurrent infection.

In the DECLARE study, the numbers of patients with serious adverse events of genital infections werefew and balanced: 2 patients in each of the dapagliflozin and placebo groups.

In the DAPA-HF study, no patient reported serious adverse events of genital infections in thedapagliflozin group and one in the placebo group. There were 7 (0.3%) patients with adverse eventsleading to discontinuations due to genital infections in the dapagliflozin group and none in the placebogroup. In the DELIVER study, one (< 0.1%) patient in each treatment group reported a serious adverseevent of genital infections. There were 3 (0.1%) patients with adverse events leading todiscontinuations due to genital infection in the dapagliflozin group and none in the placebo group.

In the DAPA-CKD study, there were 3 (0.1%) patients with serious adverse events of genitalinfections in the dapagliflozin group and none in the placebo group. There were 3 (0.1%) patients withadverse events leading to discontinuation due to genital infections in the dapagliflozin group and nonein the placebo group. Serious adverse events of genital infections or adverse events leading todiscontinuation due to genital infections were not reported for any patients without diabetes.

Cases of phimosis/acquired phimosis have been reported concurrent with genital infections and insome cases, circumcision was required.

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

In the DECLARE study with 17,160 type 2 diabetes mellitus patients and a median exposure time of48 months, a total of 6 cases of Fournier’s gangrene were reported, one in the dapagliflozin-treatedgroup and 5 in the placebo group.

The frequency of hypoglycaemia depended on the type of background therapy used in the clinicalstudies in diabetes mellitus.

For studies of dapagliflozin in monotherapy, as add-on to metformin or as add-on to sitagliptin (withor without metformin), the frequency of minor episodes of hypoglycaemia was similar (< 5%)between treatment groups, including placebo up to 102 weeks of treatment. Across all studies, majorevents of hypoglycaemia were uncommon and comparable between the groups treated withdapagliflozin or placebo. Studies with add-on sulphonylurea and add-on insulin therapies had higherrates of hypoglycaemia (see section 4.5).

In an add-on to glimepiride study, at weeks 24 and 48, minor episodes of hypoglycaemia werereported more frequently in the group treated with dapagliflozin 10 mg plus glimepiride (6.0% and7.9%, respectively) than in the placebo plus glimepiride group (2.1% and 2.1%, respectively).

In an add-on to insulin study, episodes of major hypoglycaemia were reported in 0.5% and 1.0% ofsubjects treated with dapagliflozin 10 mg plus insulin at weeks 24 and 104, respectively, and in 0.5%of subjects treated with placebo plus insulin groups at weeks 24 and 104. At weeks 24 and 104, minorepisodes of hypoglycaemia were reported, respectively, in 40.3% and 53.1% of subjects who receiveddapagliflozin 10 mg plus insulin and in 34.0% and 41.6% of the subjects who received placebo plusinsulin.

In an add-on to metformin and a sulphonylurea study, up to 24 weeks, no episodes of majorhypoglycaemia were reported. Minor episodes of hypoglycaemia were reported in 12.8% of subjectswho received dapagliflozin 10 mg plus metformin and a sulphonylurea and in 3.7% of subjects whoreceived placebo plus metformin and a sulphonylurea.

In the DECLARE study, no increased risk of major hypoglycaemia was observed with dapagliflozintherapy compared with placebo. Major events of hypoglycaemia were reported in 58 (0.7%) patientstreated with dapagliflozin and 83 (1.0%) patients treated with placebo.

In the DAPA-HF study, major events of hypoglycaemia were reported in 4 (0.2%) patients in both thedapagliflozin and placebo treatment groups. In the DELIVER study, major events of hypoglycaemiawere reported in 6 (0.2%) patients in the dapagliflozin group and 7 (0.2%) in the placebo group. Majorevents of hypoglycaemia were only observed in patients with type 2 diabetes mellitus.

In the DAPA-CKD study, major events of hypoglycaemia were reported in 14 (0.7%) patients in thedapagliflozin group and 28 (1.3%) patients in the placebo group and observed only in patients withtype 2 diabetes mellitus.

In the 13-study safety pool, reactions suggestive of volume depletion (including, reports ofdehydration, hypovolaemia or hypotension) were reported in 1.1% and 0.7% of subjects who receiveddapagliflozin 10 mg and placebo, respectively; serious reactions occurred in < 0.2% of subjectsbalanced between dapagliflozin 10 mg and placebo (see section 4.4).

In the DECLARE study, the numbers of patients with events suggestive of volume depletion werebalanced between treatment groups: 213 (2.5%) and 207 (2.4%) in the dapagliflozin and placebogroups, respectively. Serious adverse events were reported in 81 (0.9%) and 70 (0.8%) in thedapagliflozin and placebo group, respectively. Events were generally balanced between treatmentgroups across subgroups of age, diuretic use, blood pressure and angiotensin converting enzymeinhibitors (ACE-I)/angiotensin II type 1 receptor blockers (ARB) use. In patients with eGFR< 60 mL/min/1.73 m2 at baseline, there were 19 events of serious adverse events suggestive of volumedepletion in the dapagliflozin group and 13 events in the placebo group.

In the DAPA-HF study, the numbers of patients with events suggestive of volume depletion were170 (7.2%) in the dapagliflozin group and 153 (6.5%) in the placebo group. There were fewer patientswith serious events of symptoms suggestive of volume depletion in the dapagliflozin group(23 [1.0%]) compared with the placebo group (38 [1.6%]). Results were similar irrespective ofpresence of diabetes at baseline and baseline eGFR. In the DELIVER study, the numbers of patientswith serious events of symptoms suggestive of volume depletion were 35 (1.1%) in the dapagliflozingroup and 31 (1.0%) in the placebo group.

In the DAPA-CKD study, the numbers of patients with events suggestive of volume depletion were120 (5.6%) in the dapagliflozin group and 84 (3.9%) in the placebo group. There were16 (0.7%) patients with serious events of symptoms suggestive of volume depletion in thedapagliflozin group and 15 (0.7%) patients in the placebo group.

Diabetic ketoacidosis in type 2 diabetes mellitus

In the DECLARE study, with a median exposure time of 48 months, events of DKA were reported in27 patients in the dapagliflozin 10 mg group and 12 patients in the placebo group. The events occurredevenly distributed over the study period. Of the 27 patients with DKA events in the dapagliflozingroup, 22 had concomitant insulin treatment at the time of the event. Precipitating factors for DKAwere as expected in a type 2 diabetes mellitus population (see section 4.4).

In the DAPA-HF study, events of DKA were reported in 3 patients with type 2 diabetes mellitus in thedapagliflozin group and none in the placebo group. In the DELIVER study, events of DKA werereported in 2 patients with type 2 diabetes mellitus in the dapagliflozin group and none in the placebogroup.

In the DAPA-CKD study, events of DKA were not reported in any patient in the dapagliflozin groupand in 2 patients with type 2 diabetes mellitus in the placebo group.

Urinary tract infections

In the 13-study safety pool, urinary tract infections were more frequently reported fordapagliflozin 10 mg compared to placebo (4.7% versus 3.5%, respectively; see section 4.4). Mostinfections were mild to moderate, and subjects responded to an initial course of standard treatment andrarely resulted in discontinuation from dapagliflozin treatment. These infections were more frequent infemales, and subjects with a prior history were more likely to have a recurrent infection.

In the DECLARE study, serious events of urinary tract infections were reported less frequently fordapagliflozin 10 mg compared with placebo, 79 (0.9%) events versus 109 (1.3%) events, respectively.

In the DAPA-HF study, the numbers of patients with serious adverse events of urinary tract infectionswere 14 (0.6%) in the dapagliflozin group and 17 (0.7%) in the placebo group. There were 5 (0.2%)patients with adverse events leading to discontinuations due to urinary tract infections in each of thedapagliflozin and placebo groups. In the DELIVER study the numbers of patients with serious adverseevents of urinary tract infections were 41 (1.3%) in the dapagliflozin group and 37 (1.2%) in theplacebo group. There were 13 (0.4%) patients with adverse events leading to discontinuations due tourinary tract infections in the dapagliflozin group and 9 (0.3%) in the placebo group.

In the DAPA-CKD study, the numbers of patients with serious adverse events of urinary tractinfections were 29 (1.3%) in the dapagliflozin group and 18 (0.8%) in the placebo group. There were8 (0.4%) patients with adverse events leading to discontinuations due to urinary tract infections in thedapagliflozin group and 3 (0.1%) in the placebo group. The numbers of patients without diabetesreporting serious adverse events of urinary tract infections or adverse events leading to discontinuationdue to urinary tract infections were similar between treatment groups (6 [0.9%] versus 4 [0.6%] forserious adverse events, and 1 [0.1%] versus 0 for adverse events leading to discontinuation, in thedapagliflozin and placebo groups, respectively).

Increased creatinine

Adverse reactions related to increased creatinine were grouped (e.g. decreased renal creatinineclearance, renal impairment, increased blood creatinine and decreased glomerular filtration rate). Inthe 13-study safety pool, this grouping of reactions was reported in 3.2% and 1.8% of patients whoreceived dapagliflozin 10 mg and placebo, respectively. In patients with normal renal function or mildrenal impairment (baseline eGFR ≥ 60 mL/min/1.73 m2) this grouping of reactions were reported in1.3% and 0.8% of patients who received dapagliflozin 10 mg and placebo, respectively. Thesereactions were more common in patients with baseline eGFR ≥ 30 and < 60 mL/min/1.73 m2 (18.5%dapagliflozin 10 mg versus 9.3% placebo).

Further evaluation of patients who had renal-related adverse events showed that most had serumcreatinine changes of ≤ 44 micromoles/L (≤ 0.5 mg/dL) from baseline. The increases in creatininewere generally transient during continuous treatment or reversible after discontinuation of treatment.

In the DECLARE study, including elderly patients and patients with renal impairment (eGFR less than60 mL/min/1.73 m2), eGFR decreased over time in both treatment groups. At 1 year, mean eGFR wasslightly lower, and at 4 years, mean eGFR was slightly higher in the dapagliflozin group comparedwith the placebo group.

In the DAPA-HF and DELIVER studies, eGFR decreased over time in both the dapagliflozin groupand the placebo group. In DAPA-HF, the initial decrease in mean eGFR was -4.3 mL/min/1.73 m2 inthe dapagliflozin group and -1.1 mL/min/1.73 m2 in the placebo group. At 20 months, change frombaseline in eGFR was similar between the treatment groups: -5.3 mL/min/1.73 m2 for dapagliflozinand -4.5 mL/min/1.73 m2 for placebo. In DELIVER, the decrease in mean eGFR at one monthwas -3.7 mL/min/1.73 m2 in the dapagliflozin group and -0.4 mL/min/1.73 m2 in the placebo group. At24 months, change from baseline in eGFR was similar between treatmentgroups: -4.2 mL/min/1.73 m2 in the dapagliflozin group and -3.2 mL/min/1.73 m2 in the placebogroup.

In the DAPA-CKD study, eGFR decreased over time in both the dapagliflozin group and the placebogroup. The initial (day 14) decrease in mean eGFR was -4.0 mL/min/1.73 m2 in the dapagliflozingroup and -0.8 mL/min/1.73 m2 in the placebo group. At 28 months, change from baseline in eGFRwas -7.4 mL/min/1.73 m2 in the dapagliflozin group and -8.6 mL/min/1.73 m2 in the placebo group.

The dapagliflozin safety profile observed in a clinical study in children aged 10 years and above withtype 2 diabetes mellitus (see section 5.1) was similar to that observed in the studies in adults.

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.

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.

In the event of an overdose, appropriate supportive treatment should be initiated as dictated by thepatient’s clinical status. The removal of dapagliflozin by haemodialysis has not been studied.

Pharmacotherapeutic group: Drugs used in diabetes, sodium-glucose co-transporter 2 (SGLT2)inhibitors, ATC code: A10BK01

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 and not limited to patients with diabetes asdemonstrated in the DAPA-HF, DELIVER and DAPA-CKD studies. Other effects include an increasein haematocrit 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.

Increases in the amount of glucose excreted in the urine were observed in healthy subjects and insubjects with type 2 diabetes mellitus following the administration of dapagliflozin. Approximately70 g of glucose was excreted in the urine per day (corresponding to 280 kcal/day) at a dapagliflozindose of 10 mg/day in subjects with type 2 diabetes mellitus for 12 weeks. Evidence of sustainedglucose excretion was seen in subjects with type 2 diabetes mellitus given dapagliflozin 10 mg/day forup to 2 years.

This urinary glucose excretion with dapagliflozin also results in osmotic diuresis and increases inurinary volume in subjects with type 2 diabetes mellitus. Urinary volume increases in subjects withtype 2 diabetes mellitus treated with dapagliflozin 10 mg were sustained at 12 weeks and amounted toapproximately 375 mL/day. The increase in urinary volume was associated with a small and transientincrease in urinary sodium excretion that was not associated with changes in serum sodiumconcentrations.

Urinary uric acid excretion was also increased transiently (for 3-7 days) and accompanied by asustained reduction in serum uric acid concentration. At 24 weeks, reductions in serum uric acidconcentrations ranged from -48.3 to -18.3 micromoles/L (-0.87 to -0.33 mg/dL).

Improvement of glycaemic control and reduction of cardiovascular and renal morbidity and mortalityare integral parts of the treatment of type 2 diabetes.

Fourteen double-blind, randomised, controlled clinical studies were conducted with 7,056 adultsubjects with type 2 diabetes to evaluate the glycaemic efficacy and safety of Forxiga; 4,737 subjectsin these studies were treated with dapagliflozin. Twelve studies had a treatment period of 24 weeksduration, 8 with long-term extensions ranging from 24 to 80 weeks (up to a total study duration of104 weeks), one study had a 28-week treatment period, and one study was 52 weeks in duration withlong-term extensions of 52 and 104 weeks (total study duration of 208 weeks). Mean duration ofdiabetes ranged from 1.4 to 16.9 years. Fifty percent (50%) had mild renal impairment and 11% hadmoderate renal impairment. Fifty-one percent (51%) of the subjects were men, 84% were White, 8%were Asian, 4% were Black and 4% were of other racial groups. Eighty-one percent (81%) of thesubjects had a body mass index (BMI)  27. Furthermore, two 12-week, placebo-controlled studieswere conducted in patients with inadequately controlled type 2 diabetes and hypertension.

A cardiovascular outcomes study (DECLARE) was conducted with dapagliflozin 10 mg comparedwith placebo in 17,160 patients with type 2 diabetes mellitus with or without establishedcardiovascular disease to evaluate the effect on cardiovascular and renal events.

A double-blind, placebo-controlled study of 24-week duration (with an additional extension period)was conducted to evaluate the safety and efficacy of monotherapy with Forxiga in subjects withinadequately controlled type 2 diabetes mellitus. Once-daily treatment with dapagliflozin resulted instatistically significant (p < 0.0001) reductions in HbA1c compared to placebo (Table 2).

In the extension period, HbA1c reductions were sustained through week 102 (-0.61%,and -0.17% adjusted mean change from baseline for dapagliflozin 10 mg and placebo, respectively).

Table 2. Results at week 24 (LOCFa) of a placebo-controlled study of dapagliflozin asmonotherapy

Dapagliflozin Placebo10 mg

Nb 70 75

HbA1c (%)

Baseline (mean) 8.01 7.79

Change from baselinec -0.89 -0.23

Difference from placeboc -0.66*(95% CI) (-0.96, -0.36)

Subjects (%) achieving:

HbA1c < 7%

Adjusted for baseline 50.8§ 31.6

Body weight (kg)

Baseline (mean) 94.13 88.77

Change from baselinec -3.16 -2.19

Difference from placeboc -0.97(95% CI) (-2.20, 0.25)aLOCF: Last observation (prior to rescue for rescued subjects) carried forwardbAll randomised subjects who took at least one dose of double-blind study medicinal product during theshort-term double-blind periodcLeast squares mean adjusted for baseline value

*p-value < 0.0001 versus placebo§Not evaluated for statistical significance as a result of the sequential testing procedure for secondary endpoints

Add-on combination therapy

In a 52-week, active-controlled non-inferiority study (with 52- and 104-week extension periods),

Forxiga was evaluated as add-on therapy to metformin compared with a sulphonylurea (glipizide) asadd-on therapy to metformin in subjects with inadequate glycaemic control (HbA1c > 6.5% and≤ 10%). The results showed a similar mean reduction in HbA1c from baseline to week 52, comparedto glipizide, thus demonstrating non-inferiority (Table 3). At week 104, adjusted mean change frombaseline in HbA1c was -0.32% for dapagliflozin and -0.14% for glipizide. At week 208, adjustedmean change from baseline in HbA1c was -0.10% for dapagliflozin and 0.20% for glipizide. At 52,104 and 208 weeks, a significantly lower proportion of subjects in the group treated with dapagliflozin(3.5%, pct. 4.3% and 5.0%, respectively) experienced at least one event of hypoglycaemia compared to thegroup treated with glipizide (40.8%, 47.0% and 50.0%, respectively). The proportion of subjectsremaining in the study at week 104 and week 208 was 56.2% and 39.7% for the group treated withdapagliflozin and 50.0% and 34.6% for the group treated with glipizide.

Table 3. Results at week 52 (LOCFa) in an active-controlled study comparing dapagliflozin toglipizide as add-on to metformin

Dapagliflozin Glipizide

Parameter + metformin + metformin

Nb 400 401

HbA1c (%)

Baseline (mean) 7.69 7.74

Change from baselinec -0.52 -0.52

Difference from glipizide + metforminc 0.00d(95% CI) (-0.11, 0.11)

Body weight (kg)

Baseline (mean) 88.44 87.60

Change from baselinec -3.22 1.44

Difference from glipizide + metforminc -4.65*(95% CI) (-5.14, -4.17)aLOCF: Last observation carried forwardbRandomised and treated subjects with baseline and at least 1 post-baseline efficacymeasurementcLeast squares mean adjusted for baseline valuedNon-inferior to glipizide + metformin

*p-value < 0.0001

Dapagliflozin as an add-on with either metformin, glimepiride, metformin and a sulphonylurea,sitagliptin (with or without metformin) or insulin resulted in statistically significant reductions in

HbA1c at 24 weeks compared with subjects receiving placebo (p < 0.0001; Tables 4, 5 and 6).

The reductions in HbA1c observed at week 24 were sustained in add-on combination studies(glimepiride and insulin) with 48-week data (glimepiride) and up to 104-week data (insulin). Atweek 48 when added to sitagliptin (with or without metformin), the adjusted mean change frombaseline for dapagliflozin 10 mg and placebo was -0.30% and 0.38%, respectively. For the add-on tometformin study, HbA1c reductions were sustained through week 102 (-0.78% and 0.02% adjustedmean change from baseline for 10 mg and placebo, respectively). At week 104 for insulin (with orwithout additional oral glucose-lowering medicinal products), the HbA1c reductions were -0.71%and -0.06% adjusted mean change from baseline for dapagliflozin 10 mg and placebo, respectively. Atweeks 48 and 104, the insulin dose remained stable compared to baseline in subjects treated withdapagliflozin 10 mg at an average dose of 76 IU/day. In the placebo group there was a mean increaseof 10.5 IU/day and 18.3 IU/day from baseline (mean average dose of 84 and 92 IU/day) at weeks 48and 104, respectively. The proportion of subjects remaining in the study at week 104 was 72.4% forthe group treated with dapagliflozin 10 mg and 54.8% for the placebo group.

Table 4. Results of 24-week (LOCFa) placebo-controlled studies of dapagliflozin in add-oncombination with metformin or sitagliptin (with or without metformin)

Add-on combination

Metformin1 DPP-4 inhibitor(sitagliptin2) ± metformin1

Dapagliflozin Placebo Dapagliflozin Placebo10 mg 10 mg

Nb 135 137 223 224

HbA1c (%)

Baseline (mean) 7.92 8.11 7.90 7.97

Change frombaselinec -0.84 -0.30 -0.45 0.04

Difference from

*placeboc -0.54* -0.48(95% CI) (-0.74, -0.34) (-0.62, -0.34)

Subjects (%) achieving:

HbA1c < 7%

Adjusted for baseline 40.6** 25.9

Body weight (kg)

Baseline (mean) 86.28 87.74 91.02 89.23

Change frombaselinec -2.86 -0.89 -2.14 -0.26

Difference from

*placeboc -1.97* -1.89(95% CI) (-2.63, -1.31) (-2.37, -1.40)1Metformin ≥ 1500 mg/day;2sitagliptin 100 mg/dayaLOCF: Last observation (prior to rescue for rescued subjects) carried forwardbAll randomised subjects who took at least one dose of double-blind study medicinal product during the short-termdouble-blind periodcLeast squares mean adjusted for baseline value

*p-value < 0.0001 versus placebo + oral glucose-lowering medicinal product

**p-value < 0.05 versus placebo + oral glucose-lowering medicinal product

Table 5. Results of 24-week placebo-controlled studies of dapagliflozin in add-on combinationwith sulphonylurea (glimepiride) or metformin and a sulphonylurea

Add-on combination

Sulphonylurea Sulphonylurea(glimepiride1) + metformin2

Dapagliflozin Placebo Dapagliflozin Placebo10 mg 10 mg

Na 151 145 108 108

HbA1c (%)b

Baseline (mean) 8.07 8.15 8.08 8.24

Change from baselinec -0.82 -0.13 -0.86 -0.17

*

Difference from placeboc -0.68* −0.69(95% CI) (-0.86, -0.51) (−0.89, −0.49)

Subjects (%) achieving:

HbA1c < 7% (LOCF)d

Adjusted for baseline 31.7* 13.0 31.8* 11.1

Body weight (kg)(LOCF)d

Baseline (mean) 80.56 80.94 88.57 90.07

Change from baselinec -2.26 -0.72 -2.65 -0.58

*

Difference from placeboc -1.54* −2.07(95% CI) (-2.17, -0.92) (−2.79, −1.35)1glimepiride 4 mg/day;2Metformin (immediate- or extended-release formulations) ≥1500 mg/day plus maximum tolerated dose, whichmust be at least half maximum dose, of a sulphonylurea for at least 8 weeks prior to enrolment.aRandomised and treated patients with baseline and at least 1 post-baseline efficacy measurement.bColumns 1 and 2, HbA1c analysed using LOCF (see footnote d); Columns 3 and 4, HbA1c analysed using LRM(see footnote e)cLeast squares mean adjusted for baseline valuedLOCF: Last observation (prior to rescue for rescued subjects) carried forwardeLRM: Longitudinal repeated measures analysis

*p-value < 0.0001 versus placebo + oral glucose-lowering medicinal product(s)

Table 6. Results at week 24 (LOCFa) in a placebo-controlled study of dapagliflozin incombination with insulin (alone or with oral glucose-lowering medicinal products)

Dapagliflozin 10 mg Placebo+ insulin + insulin± oral glucose-lowering ± oral glucose-lowering

Parameter medicinal products2 medicinal products2

Nb 194 193

HbA1c (%)

Baseline (mean) 8.58 8.46

Change from baselinec -0.90 -0.30

Difference from placeboc -0.60*(95% CI) (-0.74, -0.45)

Body weight (kg)

Baseline (mean) 94.63 94.21

Change from baselinec -1.67 0.02

Difference from placeboc -1.68*(95% CI) (-2.19, -1.18)

Mean daily insulin dose (IU)1

Baseline (mean) 77.96 73.96

Change from baselinec -1.16 5.08

Difference from placeboc -6.23*(95% CI) (-8.84, -3.63)

Subjects with mean dailyinsulin dose reduction of atleast 10% (%) 19.7** 11.0aLOCF: Last observation (prior to or on the date of the first insulin up-titration, if needed) carried forwardbAll randomised subjects who took at least one dose of double-blind study medicinal product during the short-term double-blind periodcLeast squares mean adjusted for baseline value and presence of oral glucose-lowering medicinal product

*p-value < 0.0001 versus placebo + insulin ± oral glucose-lowering medicinal product

**p-value < 0.05 versus placebo + insulin ± oral glucose-lowering medicinal product1Up-titration of insulin regimens (including short-acting, intermediate, and basal insulin) was only allowed ifsubjects met pre-defined FPG criteria.2Fifty percent of subjects were on insulin monotherapy at baseline; 50% were on 1 or 2 oral glucose-loweringmedicinal product(s) in addition to insulin: Of this latter group, 80% were on metformin alone, 12% wereon metformin plus sulphonylurea therapy, and the rest were on other oral glucose-lowering medicinalproducts.

In combination with metformin in drug-naive patients

A total of 1,236 drug-naive patients with inadequately controlled type 2 diabetes (HbA1c ≥ 7.5% and≤ 12%) participated in two active-controlled studies of 24 weeks duration to evaluate the efficacy andsafety of dapagliflozin (5 mg or 10 mg) in combination with metformin in drug-naive patients versustherapy with the monocomponents.

Treatment with dapagliflozin 10 mg in combination with metformin (up to 2000 mg per day) providedsignificant improvements in HbA1c compared to the individual components (Table 7), and led togreater reductions in fasting plasma glucose (FPG) (compared to the individual components) and bodyweight (compared to metformin).

Table 7. Results at week 24 (LOCFa) in an active-controlled study of dapagliflozin andmetformin combination therapy in drug-naive patients

Dapagliflozin 10 mg Dapagliflozin 10 mg Metformin+

Parameter metformin

Nb 211b 219b 208b

HbA1c (%)

Baseline (mean) 9.10 9.03 9.03

Change from baselinec -1.98 -1.45 -1.44

Difference from dapagliflozinc −0.53*(95% CI) (−0.74, −0.32)

Difference from metforminc −0.54* −0.01(95% CI) (−0.75, −0.33) (−0.22, 0.20)aLOCF: last observation (prior to rescue for rescued patients) carried forward.bAll randomised patients who took at least one dose of double-blind study medicinal product during theshort-term double-blind period.cLeast squares mean adjusted for baseline value.

*p-value <0.0001.

Combination therapy with prolonged-release exenatide

In a 28-week, double-blind, active comparator-controlled study, the combination of dapagliflozin andprolonged-release exenatide (a GLP-1 receptor agonist) was compared to dapagliflozin alone andprolonged-release exenatide alone in subjects with inadequate glycaemic control on metformin alone(HbA1c ≥ 8% and ≤ 12%). All treatment groups had a reduction in HbA1c compared to baseline. Thecombination treatment with dapagliflozin 10 mg and prolonged-release exenatide group showedsuperior reductions in HbA1c from baseline compared to dapagliflozin alone and prolonged-releaseexenatide alone (Table 8).

Table 8. Results of one 28-week study of dapagliflozin and prolonged-release exenatide versusdapagliflozin alone and prolonged-release exenatide alone, in combination with metformin(intent to treat patients)

Dapagliflozin 10 mg Dapagliflozin 10 mg Prolonged-release

QD QD exenatide 2 mg+ + QWprolonged-release placebo QW +

Parameter exenatide 2 mg QW placebo QD

N 228 230 227

HbA1c (%)

Baseline (mean) 9.29 9.25 9.26

Change from baselinea -1.98 -1.39 -1.60

Mean difference in changefrom baseline between -0.59* -0.38**combination and single (-0.84, -0.34) (-0.63, -0.13)medicinal product (95% CI)

Subjects (%) achieving44.7 19.1 26.9

HbA1c  7%

Body weight (kg)

Baseline (mean) 92.13 90.87 89.12

Change from baseline a -3.55 -2.22 -1.56

Mean difference in changefrom baseline between -1.33* -2.00*combination and single (-2.12, -0.55) (-2.79, -1.20)medicinal product (95% CI)

QD=once daily, QW=once weekly, N=number of patients, CI=confidence interval.

aAdjusted least squares means (LS Means) and treatment group difference(s) in the change from baselinevalues at week 28 are modelled using a mixed model with repeated measures (MMRM) including treatment,region, baseline HbA1c stratum (< 9.0% or ≥ 9.0%), week, and treatment by week interaction as fixedfactors, and baseline value as a covariate.

*p < 0.001, **p < 0.01.

P-values are all adjusted p-values for multiplicity.

Analyses exclude measurements post rescue therapy and post premature discontinuation of study medicinalproduct.

Treatment with dapagliflozin 10 mg as a monotherapy or as an add-on to either metformin,glimepiride, metformin and a sulphonylurea, sitagliptin (with or without metformin) or insulin resultedin statistically significant reductions in FPG (-1.90 to -1.20 mmol/L [-34.2 to -21.7 mg/dL]) comparedto placebo (-0.33 to 0.21 mmol/L [-6.0 to 3.8 mg/dL]). This effect was observed at week 1 oftreatment and maintained in studies extended through week 104.

Combination therapy of dapagliflozin 10 mg and prolonged-release exenatide resulted in significantlygreater reductions in FPG at week 28: -3.66 mmol/L (-65.8 mg/dL), compared to -2.73 mmol/L(-49.2 mg/dL) for dapagliflozin alone (p < 0.001) and -2.54 mmol/L (-45.8 mg/dL) for exenatide alone(p < 0.001).

In a dedicated study in diabetic patients with an eGFR ≥ 45 to < 60 mL/min/1.73 m2, treatment withdapagliflozin demonstrated reductions in FPG at week 24: -1.19 mmol/L (-21.46 mg/dL) compared to

- 0.27 mmol/L (-4.87 mg/dL) for placebo (p=0.001).

Post-prandial glucose

Treatment with dapagliflozin 10 mg as an add-on to glimepiride resulted in statistically significantreductions in 2-hour post-prandial glucose at 24 weeks that were maintained up to week 48.

Treatment with dapagliflozin 10 mg as an add-on to sitagliptin (with or without metformin) resulted inreductions in 2-hour post-prandial glucose at 24 weeks that were maintained up to week 48.

Combination therapy of dapagliflozin 10 mg and prolonged-release exenatide resulted in significantlygreater reductions in 2-hour post-prandial glucose at week 28 compared to either medicinal productalone.

Dapagliflozin 10 mg as an add-on to metformin, glimepiride, metformin and a sulphonylurea,sitagliptin (with or without metformin) or insulin resulted in statistically significant body weightreduction at 24 weeks (p < 0.0001, Tables 4 and 5). These effects were sustained in longer-termstudies. At 48 weeks, the difference for dapagliflozin as add-on to sitagliptin (with or withoutmetformin) compared with placebo was -2.22 kg. At 102 weeks, the difference for dapagliflozin asadd-on to metformin compared with placebo, or as add-on to insulin compared with placebo was -2.14and -2.88 kg, respectively.

As an add-on therapy to metformin in an active-controlled non-inferiority study, dapagliflozin resultedin a statistically significant body weight reduction compared with glipizide of -4.65 kg at 52 weeks(p < 0.0001, Table 3) that was sustained at 104 and 208 weeks (-5.06 kg and -4.38 kg, respectively).

The combination of dapagliflozin 10 mg and prolonged-release exenatide demonstrated significantlygreater weight reductions compared to either medicinal product alone (Table 8).

A 24-week study in 182 diabetic subjects using dual energy X-ray absorptiometry (DXA) to evaluatebody composition demonstrated reductions with dapagliflozin 10 mg plus metformin compared withplacebo plus metformin, respectively, in body weight and body fat mass as measured by DXA ratherthan lean tissue or fluid loss. Treatment with Forxiga plus metformin showed a numerical decrease invisceral adipose tissue compared with placebo plus metformin treatment in a magnetic resonanceimaging substudy.

In a pre-specified pooled analysis of 13 placebo-controlled studies, treatment with dapagliflozin 10 mgresulted in a systolic blood pressure change from baseline of -3.7 mmHg and diastolic blood pressureof -1.8 mmHg versus -0.5 mmHg systolic and -0.5 mmHg diastolic blood pressure for placebo groupat week 24. Similar reductions were observed up to 104 weeks.

Combination therapy of dapagliflozin 10 mg and prolonged-release exenatide resulted in asignificantly greater reduction in systolic blood pressure at week 28 (-4.3 mmHg) compared todapagliflozin alone (-1.8 mmHg, p < 0.05) and prolonged-release exenatide alone (-1.2 mmHg,p < 0.01).

In two 12-week, placebo-controlled studies a total of 1,062 patients with inadequately controlledtype 2 diabetes and hypertension (despite pre-existing stable treatment with an ACE-I or ARB in onestudy and an ACE-I or ARB plus one additional antihypertensive treatment in another study) weretreated with dapagliflozin 10 mg or placebo. At week 12 for both studies, dapagliflozin 10 mg plususual antidiabetic treatment provided improvement in HbA1c and decreased the placebo-correctedsystolic blood pressure on average by 3.1 and 4.3 mmHg, respectively.

In a dedicated study in diabetic patients with an eGFR ≥ 45 to < 60 mL/min/1.73 m2, treatment withdapagliflozin demonstrated reductions in seated systolic blood pressure at week 24: -4.8 mmHgcompared to -1.7 mmHg for placebo (p < 0.05).

Glycaemic control in patients with moderate renal impairment CKD 3A(eGFR ≥ 45 to < 60 mL/min/1.73 m2)

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 9).

Table 9. 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 valuec Derived from least squares mean adjusted for baseline value

* p<0.001

Patients with baseline HbA1c ≥ 9%

In a pre-specified analysis of subjects with baseline HbA1c ≥ 9.0%, treatment withdapagliflozin 10 mg resulted in statistically significant reductions in HbA1c at week 24 as amonotherapy (adjusted mean change from baseline: -2.04% and 0.19% for dapagliflozin 10 mg andplacebo, respectively) and as an add-on to metformin (adjusted mean change from baseline: -1.32%and -0.53% for dapagliflozin and placebo, respectively).

Cardiovascular and renal outcomes

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 (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 consistentacross key 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/orend-stage kidney disease (dialysis ≥ 90 days or kidney transplantation, sustained confirmed 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 to first event wasanalysed in a Cox proportional hazards model. The number of first events for the single components are the actual number offirst events for each component and does not add up to the number of events in the composite endpoint.

CI=confidence interval.

Dapagliflozin reduced the incidence of events of the composite of confirmed sustained eGFRdecrease, end-stage kidney disease, renal or cardiovascular death. The difference between groups wasdriven by reductions in events of the renal components; sustained eGFR decrease, end-stage kidneydisease and renal death (Figure 2).

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

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

DAPA-HF study: Heart failure with reduced ejection fraction (LVEF ≤ 40%)

Dapagliflozin And Prevention of Adverse outcomes in Heart Failure (DAPA-HF) was an international,multicentre, randomised, double-blind, placebo-controlled study in patients with heart failure (New

York Heart Association [NYHA] functional class II-IV) with reduced ejection fraction (left ventricularejection fraction [LVEF] ≤ 40%) to determine the effect of dapagliflozin compared with placebo,when added to background standard of care therapy, on the incidence of cardiovascular death andworsening heart failure.

Of 4,744 patients, 2,373 were randomised to dapagliflozin 10 mg and 2,371 to placebo and followedfor a median of 18 months. The mean age of the study population was 66 years, 77% were male.

At baseline, 67.5% of the patients were classified as NYHA class II, 31.6% class III and 0.9%class IV, median LVEF was 32%, 56% of the heart failures were ischaemic, 36% were non-ischaemicand 8% were of unknown aetiology. In each treatment group, 42% of the patients had a history oftype 2 diabetes mellitus, and an additional 3% of the patients in each group were classified as havingtype 2 diabetes mellitus based on a HbA1c ≥ 6.5% at both enrolment and randomisation. Patients wereon standard of care therapy; 94% of patients were treated with ACE-I, ARB or angiotensin receptor-neprilysin inhibitor (ARNI, 11%), 96% with beta-blocker, 71% with mineralocorticoid receptorantagonist (MRA), 93% with diuretic and 26% had an implantable device (with defibrillator function).

Patients with eGFR ≥ 30 mL/min/1.73 m2 at enrolment were included in the study. The mean eGFRwas 66 mL/min/1.73 m2, 41% of patients had eGFR < 60mL/min/1.73 m2 and 15% hadeGFR < 45 mL/min/1.73 m2.

Cardiovascular death and worsening heart failure

Dapagliflozin was superior to placebo in preventing the primary composite endpoint of cardiovasculardeath, hospitalisation for heart failure or urgent heart failure visit (HR 0.74 [95% CI 0.65, 0.85],p < 0.0001). The effect was observed early and was sustained throughout the duration of the study(Figure 3).

Figure 3: Time to first occurrence of the composite of cardiovascular death, hospitalisation forheart failure or urgent heart failure visit

An urgent heart failure visit was defined as an urgent, unplanned, assessment by a physician, e.g. in an Emergency

Department, and requiring treatment for worsening heart failure (other than just an increase in oral diuretics).

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

All three components of the primary composite endpoint individually contributed to the treatmenteffect (Figure 4). There were few urgent heart failure visits.

Figure 4: Treatment effects for the primary composite endpoint, its components and all-causemortality

An urgent heart failure visit was defined as an urgent, unplanned, assessment by a physician, e.g. in an Emergency

Department, and requiring treatment for worsening heart failure (other than just an increase in oral diuretics).

The number of first events for the single components are the actual number of first events for each component and does notadd up to the number of events in the composite endpoint.

Event rates are presented as the number of subjects with event per 100 patient years of follow-up.

p-values for single components and all-cause mortality are nominal.

Dapagliflozin also reduced the total number of events of hospitalisations for heart failure (first andrecurrent) and cardiovascular death; there were 567 events in the dapagliflozin group versus742 events in the placebo group (Rate Ratio 0.75 [95% CI 0.65, 0.88]; p=0.0002).

The treatment benefit of dapagliflozin was observed in heart failure patients both with type 2 diabetesmellitus and without diabetes. Dapagliflozin reduced the primary composite endpoint of incidence ofcardiovascular death and worsening heart failure with a HR of 0.75 (95% CI 0.63, 0.90) in patientswith diabetes and 0.73 (95% CI 0.60, 0.88) in patients without diabetes.

The treatment benefit of dapagliflozin over placebo on the primary endpoint was also consistent acrossother key subgroups, including concomitant heart failure therapy, renal function (eGFR), age, gender,and region.

Patient reported outcome - heart failure symptoms

The treatment effect of dapagliflozin on heart failure symptoms was assessed by the Total Symptom

Score of the Kansas City Cardiomyopathy Questionnaire (KCCQ-TSS), which quantifies heart failuresymptom frequency and severity, including fatigue, peripheral oedema, dyspnoea and orthopnoea. Thescore ranges from 0 to 100, with higher scores representing better health status.

Treatment with dapagliflozin resulted in a statistically significant and clinically meaningful benefitover placebo in heart failure symptoms, as measured by change from baseline at month 8 in the

KCCQ-TSS, (Win Ratio 1.18 [95% CI 1.11, 1.26]; p < 0.0001). Both symptom frequency andsymptom burden contributed to the results. Benefit was seen both in improving heart failure symptomsand in preventing deterioration of heart failure symptoms.

In responder analyses, the proportion of patients with a clinically meaningful improvement on the

KCCQ-TSS from baseline at 8 months, defined as 5 points or more, was higher for the dapagliflozintreatment group compared with placebo. The proportion of patients with a clinically meaningfuldeterioration, defined as 5 points or more, was lower for the dapagliflozin treatment group comparedto placebo. The benefits observed with dapagliflozin remained when applying more conservative cut-offs for larger clinically meaningful change (Table 10).

Table 10. Number and percent of patients with clinically meaningful improvement anddeterioration on the KCCQ-TSS at 8 months

Dapagliflozin Placebo

Change from baseline at 8 months: 10 mg na=2062na=2086

Improvement n (%) n (%) Odds ratioc p-valuefimprovedb improvedb (95% CI)≥ 5 points 933 (44.7) 794 (38.5) 1.14 0.0002(1.06, 1.22)≥ 10 points 689 (33.0) 579 (28.1) 1.13 0.0018(1.05, 1.22)≥ 15 points 474 (22.7) 406 (19.7) 1.10 0.0300(1.01, 1.19)

Deterioration n (%) n (%) Odds ratioe p-valuefdeterioratedd deterioratedd (95% CI)≥ 5 points 537 (25.7) 693 (33.6) 0.84 <0.0001(0.78, 0.89)≥ 10 points 395 (18.9) 506 (24.5) 0.85 <0.0001(0.79, 0.92)a Number of patients with an observed KCCQ-TSS or who died prior to 8 months.b Number of patients who had an observed improvement of at least 5, 10 or 15 points from baseline. Patients who diedprior to the given timepoint are counted as not improved.c For improvement, an odds ratio > 1 favours dapagliflozin 10 mg.d Number of patients who had an observed deterioration of at least 5 or 10 points from baseline. Patients who died priorto the given timepoint are counted as deteriorated.e For deterioration, an odds ratio < 1 favours dapagliflozin 10 mg.f p-values are nominal.

There were few events of the renal composite endpoint (confirmed sustained ≥ 50% eGFR decrease,

ESKD, or renal death); the incidence was 1.2% in the dapagliflozin group and 1.6% in the placebogroup.

DELIVER study: Heart failure with left ventricular ejection fraction > 40%

Dapagliflozin Evaluation to Improve the LIVEs of Patients with PReserved Ejection Fraction Heart

Failure (DELIVER) was an international, multicentre, randomised, double-blind, placebo-controlledstudy in patients aged ≥ 40 years with heart failure (NYHA class II-IV) with LVEF > 40% andevidence of structural heart disease, to determine the effect of dapagliflozin compared with placebo onthe incidence of cardiovascular death and worsening heart failure.

Of 6,263 patients, 3,131 were randomised to dapagliflozin 10 mg and 3,132 to placebo and followedfor a median of 28 months. The study included 654 (10%) subacute heart failure patients (defined asrandomised during hospitalisation for heart failure or within 30 days of discharge). The mean age ofthe study population was 72 years and 56% were male.

At baseline, 75% patients were classified as NYHA class II, 24% class III and 0.3% class IV. Median

LVEF was 54%, 34% of the patients had LVEF ≤ 49%, 36% had LVEF 50-59% and 30% had

LVEF ≥ 60%. In each treatment group, 45% had a history of type 2 diabetes mellitus. Baseline therapyincluded ACEi/ARB/ARNI (77%), beta-blockers (83%) diuretics (98%) and MRA (43%).

The mean eGFR was 61 mL/min/1.73 m2, 49% of patients had eGFR < 60mL/min/1.73 m2, 23% hadeGFR < 45 mL/min/1.73 m2, and 3% had eGFR < 30 mL/min/1.73 m2.

Dapagliflozin was superior to placebo in reducing the incidence of the primary composite endpoint ofcardiovascular death, hospitalisation for heart failure or urgent heart failure visit (HR 0.82[95% CI 0.73, 0.92]; p=0.0008) (Figure 5).

Figure 5: Time to first occurrence of the composite of cardiovascular death, hospitalisation forheart failure or urgent heart failure visit

Placebo

Dapagliflozin

Dapagliflozin vs. Placebo

HR (95% CI): 0.82 (0.73, 0.92) P-value: 0.0008

Months from randomisation

Patients at risk

Dapagliflozin:

Placebo:

An urgent heart failure visit was defined as an urgent, unplanned, assessment by a physician, e.g. in an Emergency

Department, and requiring treatment for worsening heart failure (other than just an increase in oral diuretics).

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

Figure 6 presents the contribution of the three components of the primary composite endpoint to thetreatment effect.

Patients with event (%)

Figure 6: Treatment effects for the primary composite endpoint and its components

An urgent heart failure visit was defined as an urgent, unplanned, assessment by a physician, e.g. in an Emergency

Department, and requiring treatment for worsening heart failure (other than just an increase in oral diuretics).

The number of first events for the single components are the actual number of first events for each component and does notadd up to the number of events in the composite endpoint.

Event rates are presented as the number of subjects with event per 100 patient years of follow-up.

Cardiovascular death, here presented as a component of the primary endpoint, was also tested under formal Type 1 errorcontrol as a secondary endpoint.

Dapagliflozin was superior to placebo in reducing the total number of heart failure events (defined asfirst and recurrent hospitalisation for heart failure or urgent heart failure visits) and cardiovasculardeath; there were 815 events in the dapagliflozin group versus 1057 events in the placebo group (Rate

Ratio 0.77 [95% CI 0.67, 0.89]; p=0.0003).

The treatment benefit of dapagliflozin over placebo on the primary endpoint was observed acrosssubgroups of patients with LVEF ≤ 49%, 50-59%, and ≥ 60%. Effects were also consistent acrossother key subgroups categorised by e.g. age, gender, NYHA class, NT-proBNP level, subacute status,and type 2 diabetes mellitus status.

Patient reported outcome - heart failure symptoms

Treatment with dapagliflozin resulted in a statistically significant benefit over placebo in heart failuresymptoms, as measured by change from baseline at month 8 in the KCCQ-TSS, (Win Ratio 1.11[95% CI 1.03, 1.21]; p=0.0086). Both symptom frequency and symptom burden contributed to theresults.

In responder analyses, the proportion of patients who experienced a moderate (≥ 5 points) or large(≥ 14 points) deterioration on the KCCQ-TSS from baseline at 8 months was lower in thedapagliflozin treatment group; 24.1% of patients on dapagliflozin versus 29.1% on placeboexperienced a moderate deterioration (Odds Ratio 0.78 [95% CI 0.64, 0.95]) and 13.5% of patients ondapagliflozin versus 18.4% on placebo experienced a large deterioration (Odds Ratio 0.70[95% CI 0.55, 0.88]). The proportion of patients with a small to moderate improvement (≥ 13 points)or a large improvement (≥ 17 points) did not differ between treatment groups.

Heart failure across DAPA-HF and DELIVER studies

In a pooled analysis of DAPA-HF and DELIVER, the HR for dapagliflozin versus placebo on thecomposite endpoint of cardiovascular death, hospitalisation for heart failure or urgent heart failurevisit was 0.78 (95% CI 0.72, 0.85), p < 0.0001. The treatment effect was consistent across the LVEFrange, without attenuation of effect by LVEF.

In a pre-specified subject level pooled analysis of the DAPA-HF and DELIVER studies, dapagliflozincompared with placebo reduced the risk of cardiovascular death (HR 0.85 [95% CI 0.75, 0.96],p=0.0115). Both studies contributed to the effect.

The Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in

Patients with Chronic Kidney Disease (DAPA-CKD) was an international, multicentre, randomised,double-blind, placebo-controlled study in patients with chronic kidney disease (CKD) witheGFR ≥ 25 to ≤ 75 mL/min/1.73 m2 and albuminuria (UACR ≥ 200 and ≤ 5000 mg/g) to determine theeffect of dapagliflozin compared with placebo, when added to background standard of care therapy, onthe incidence of the composite endpoint of ≥ 50% sustained decline in eGFR, end-stage kidney disease(ESKD) (defined as sustained eGFR < 15 mL/min/1.73 m2, chronic dialysis treatment or receiving arenal transplant), cardiovascular or renal death.

Of 4,304 patients, 2,152 were randomised to dapagliflozin 10 mg and 2,152 to placebo and followedfor a median of 28.5 months. Treatment was continued if eGFR fell to levels below25 mL/min/1.73 m2 during the study and could be continued in cases when dialysis was needed.

The mean age of the study population was 61.8 years, 66.9% were male. At baseline, mean eGFR was43.1 mL/min/1.73 m2 and median UACR was 949.3 mg/g, 44.1% of patients had eGFR 30 to< 45 mL/min/1.73 m2 and 14.5% had eGFR < 30 mL/min/1.73 m2. 67.5% of the patients had type 2diabetes mellitus. Patients were on standard of care (SOC) therapy; 97.0% of patients were treatedwith an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB).

The study was stopped early for efficacy prior to the planned analysis based on a recommendation bythe independent Data Monitoring Committee. Dapagliflozin was superior to placebo in preventing theprimary composite endpoint of ≥ 50% sustained decline in eGFR, reaching end-stage kidney disease,cardiovascular or renal death. Based on the Kaplan-Meier plot for the time to first occurrence of theprimary composite endpoint, the treatment effect was evident beginning at 4 months and wasmaintained through the end of study (Figure 7).

Figure 7: Time to first occurrence of the primary composite endpoint, ≥ 50% sustained declinein eGFR, end-stage kidney disease, cardiovascular or renal death

Placebo

Dapagliflozin

HR (95%CI): P-value:

Months from randomisation

Patients at risk

Dapagliflozin:

Placebo:

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

All four components of the primary composite endpoint individually contributed to the treatmenteffect. Dapagliflozin also reduced the incidence of the composite endpoint of ≥ 50% sustained declinein eGFR, end-stage kidney disease or renal death and the composite endpoint of cardiovascular deathand hospitalisation for heart failure. Treatment with dapagliflozin improved overall survival in chronickidney disease patients with a significant reduction in all-cause mortality (Figure 8).

Patients with event (%)

Figure 8: Treatment effects for the primary and secondary composite endpoints, their individualcomponents, and all-cause mortality

The number of first events for the single components are the actual number of first events for each component and does notadd up to the number of events in the composite endpoint.

Event rates are presented as the number of subjects with event per 100 patient years of follow-up.

Hazard ratio estimates are not presented for subgroups with less than 15 events in total, both arms combined.

The treatment benefit of dapagliflozin was consistent in chronic kidney disease patients with type 2diabetes mellitus and without diabetes. Dapagliflozin reduced the primary composite endpoint of≥ 50% sustained decline in eGFR, reaching end-stage kidney disease, cardiovascular or renal deathwith a HR of 0.64 (95% CI 0.52, 0.79) in patients with type 2 diabetes mellitus and0.50 (95% CI 0.35, 0.72) in patients without diabetes.

The treatment benefit of dapagliflozin over placebo on the primary endpoint was also consistent acrossother key subgroups, including eGFR, age, gender, and region.

In a clinical study in children and adolescents aged 10-24 years with type 2 diabetes mellitus,39 patients were randomised to dapagliflozin 10 mg and 33 to placebo, as add-on to metformin, insulinor a combination of metformin and insulin. At randomisation, 74% of the patients were < 18 years ofage. The adjusted mean change in HbA1c for dapagliflozin relative to placebo from baseline toweek 24 was -0.75% (95% CI -1.65, 0.15). In the age group < 18 years the adjusted mean change in

HbA1c for dapagliflozin relative to placebo was -0.59% (95% CI -1.66, 0.48). In the age group≥ 18 years, the mean change from baseline in HbA1c was -1.52% in the dapagliflozin treated group(n=9) and 0.17% in the placebo treated group (n=6). Efficacy and safety were similar to that observedin the adult population treated with dapagliflozin. Safety and tolerability were further confirmed in a28-week safety extension of the study.

Heart failure and chronic kidney disease

The European Medicines Agency has waived the obligation to submit the results of studies withdapagliflozin in all subsets of the paediatric population in the prevention of cardiovascular events inpatients with chronic heart failure and in the treatment of chronic kidney disease (see section 4.2 forinformation on paediatric use).

Dapagliflozin was rapidly and well absorbed after oral administration. Maximum dapagliflozin plasmaconcentrations (Cmax) were usually attained within 2 hours after administration in the fasted state.

Geometric mean steady-state dapagliflozin Cmax and AUCτ values following once daily 10 mg doses ofdapagliflozin were 158 ng/mL and 628 ng h/mL, respectively. The absolute oral bioavailability ofdapagliflozin following the administration of a 10 mg dose is 78%. Administration with a high-fatmeal decreased dapagliflozin Cmax by up to 50% and prolonged Tmax by approximately 1 hour, but didnot alter AUC as compared with the fasted state. These changes are not considered to be clinicallymeaningful. Hence, Forxiga can be administered with or without food.

Dapagliflozin is approximately 91% protein bound. Protein binding was not altered in various diseasestates (e.g. renal or hepatic impairment). The mean steady-state volume of distribution of dapagliflozinwas 118 liters.

Dapagliflozin is extensively metabolised, primarily to yield dapagliflozin 3-O-glucuronide, which isan inactive metabolite. Dapagliflozin 3-O-glucuronide or other metabolites do not contribute to theglucose-lowering effects. The formation of dapagliflozin 3-O-glucuronide is mediated by UGT1A9, anenzyme present in the liver and kidney, and CYP-mediated metabolism was a minor clearancepathway in humans.

The mean plasma terminal half-life (t1/2) for dapagliflozin was 12.9 hours following a single oral doseof dapagliflozin 10 mg to healthy subjects. The mean total systemic clearance of dapagliflozinadministered intravenously was 207 mL/min. Dapagliflozin and related metabolites are primarilyeliminated via urinary excretion with less than 2% as unchanged dapagliflozin. After administration ofa 50 mg [14C]-dapagliflozin dose, 96% was recovered, 75% in urine and 21% in faeces. In faeces,approximately 15% of the dose was excreted as parent drug.

Dapagliflozin exposure increased proportional to the increment in dapagliflozin dose over the range of0.1 to 500 mg and its pharmacokinetics did not change with time upon repeated daily dosing for up to24 weeks.

At steady-state (20 mg once-daily dapagliflozin for 7 days), subjects with type 2 diabetes mellitus andmild, moderate or severe renal impairment (as determined by iohexol plasma clearance) had meansystemic exposures of dapagliflozin of 32%, 60% and 87% higher, respectively, than those of subjectswith type 2 diabetes mellitus and normal renal function. The steady-state 24-hour urinary glucoseexcretion was highly dependent on renal function and 85, 52, 18 and 11 g of glucose/day was excretedby subjects with type 2 diabetes mellitus and normal renal function or mild, moderate or severe renalimpairment, respectively. The impact of haemodialysis on dapagliflozin exposure is not known. Theeffect of reduced renal function on systemic exposure was evaluated in a population pharmacokineticmodel. Consistent with previous results, model predicted AUC was higher in patients with chronickidney disease compared with patients with normal renal function, and was not meaningfully differentin chronic kidney disease patients with type 2 diabetes mellitus and without diabetes.

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 to healthy matchedcontrol subjects. These differences were not considered to be clinically meaningful. In subjects withsevere hepatic impairment (Child-Pugh class C) mean Cmax and AUC of dapagliflozin were 40% and67% higher than matched healthy controls, respectively.

There is no clinically meaningful increase in exposure based on age alone in subjects up to70 years old. However, an increased exposure due to age-related decrease in renal function can beexpected. There are insufficient data to draw conclusions regarding exposure in patients> 70 years old.

Pharmacokinetics and pharmacodynamics (glucosuria) in children with type 2 diabetes mellitus aged10-17 years were similar to those observed in adults with type 2 diabetes mellitus.

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

There were no clinically relevant differences in systemic exposures between White, Black or Asianraces.

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

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and fertility. Dapagliflozindid not induce tumours in either mice or rats at any of the doses evaluated in two-year carcinogenicitystudies.

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

In a juvenile toxicity study, when dapagliflozin was dosed directly to young rats from postnatal day 21until postnatal day 90, renal pelvic and tubular dilatations were reported at all dose levels; pupexposures at the lowest dose tested were ≥ 15 times the maximum recommended human dose. Thesefindings were associated with dose-related increases in kidney weight and macroscopic kidneyenlargement observed at all doses. The renal pelvic and tubular dilatations observed in juvenileanimals did not fully reverse within the approximate 1-month recovery period.

In a separate study of pre- and postnatal development, maternal rats were dosed from gestation day 6through postnatal day 21, and pups were indirectly exposed in utero and throughout lactation. (Asatellite study was conducted to assess dapagliflozin exposures in milk and pups.) Increased incidenceor severity of renal pelvic dilatation was observed in adult offspring of treated dams, although only atthe highest dose tested (associated maternal and pup dapagliflozin exposures were 1,415 times and137 times, respectively, the human values at the maximum recommended human dose). Additionaldevelopmental toxicity was limited to dose-related reductions in pup body weights, and observed onlyat doses ≥ 15 mg/kg/day (associated with pup exposures that are ≥ 29 times the human values at themaximum recommended human dose). Maternal toxicity was evident only at the highest dose tested,and limited to transient reductions in body weight and food consumption at dose. The no observedadverse effect level (NOAEL) for developmental toxicity, the lowest dose tested, is associated with amaternal systemic exposure multiple that is approximately 19 times the human value at the maximumrecommended human dose.

In additional studies of embryo-foetal development in rats and rabbits, dapagliflozin was administeredfor intervals coinciding with the major periods of organogenesis in each species. Neither maternal nordevelopmental toxicities were observed in rabbits at any dose tested; the highest dose tested isassociated with a systemic exposure multiple of approximately 1,191 times the maximumrecommended human dose. In rats, dapagliflozin was neither embryolethal nor teratogenic atexposures up to 1,441 times the maximum recommended human dose.

Microcrystalline cellulose (E460i)

Crospovidone (E1202)

Silicon dioxide (E551)

Magnesium stearate (E470b)

Polyvinyl alcohol (E1203)

Titanium dioxide (E171)

Macrogol 3350 (E1521)

Talc (E553b)

Iron oxide yellow (E172)

Not applicable.

3 years

This medicinal product does not require any special storage conditions.

Alu/Alu blister

Forxiga 5 mg film-coated tablets

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

Pack sizes of 30x1 and 90x1 film-coated tablets in perforated unit dose blisters.

Forxiga 10 mg film-coated tablets

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

Pack sizes of 10x1, 30x1 and 90x1 film-coated tablets in perforated unit dose blisters.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

AstraZeneca AB

SE-151 85 Södertälje

Sweden

Forxiga 5 mg film-coated tablets

EU/1/12/795/001 14 film-coated tablets

EU/1/12/795/002 28 film-coated tablets

EU/1/12/795/003 98 film-coated tablets

EU/1/12/795/004 30 x 1 (unit dose) film-coated tablets

EU/1/12/795/005 90 x 1 (unit dose) film-coated tablets

Forxiga 10 mg film-coated tablets

EU/1/12/795/006 14 film-coated tablets

EU/1/12/795/007 28 film-coated tablets

EU/1/12/795/008 98 film-coated tablets

EU/1/12/795/009 30 x 1 (unit dose) film-coated tablets

EU/1/12/795/010 90 x 1 (unit dose) film-coated tablets

EU/1/12/795/011 10 x 1 (unit dose) film-coated tablets

Date of first authorisation: 12 November 2012

Date of latest renewal: 28 August 2017

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

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