1.3.

1 Dapagliflozin
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SUMMARY OF PRODUCT CHARACTERISTICS,

LABELLING AND PACKAGE LEAFLET

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SUMMARY OF PRODUCT CHARACTERISTICS

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1. NAME OF THE MEDICINAL PRODUCT

<Invented name> 5 mg film-coated tablets

<Invented name> 10 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

<Invented name> 5 mg film-coated tablets

Each film-coated tablet contains 5 mg dapagliflozin (from dapagliflozin propanediol monohydrate
form).

<Invented name> 10 mg film-coated tablets

Each film-coated tablet contains 10 mg dapagliflozin (from dapagliflozin propanediol monohydrate
form).

Excipient with known effect:

<Invented name> 5 mg film-coated tablets
Each film-coated tablet contains 48.7 mg lactose.

<Invented name> 10 mg film-coated tablets

Each film-coated tablet contains 97.4 mg lactose.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet (tablet)

<Invented name> 5 mg film-coated tablets:

Light brownish yellow, round, biconvex, film-coated tablets, marked with “5” on one side. Tablet
dimension: diameter approx. 7 mm.

<Invented name> 10 mg film-coated tablets:

Light brownish yellow, oval, biconvex, film-coated tablets, scored on one side. One side of score line
is marked with “1” and the other with “0”. The tablet can be divided into equal doses. Tablet
dimension: approx. 13 x 6.5 mm.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Type 2 diabetes mellitus

<Invented name> is indicated in adults and children aged 10 years and above for the treatment
of insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise
- as monotherapy when metformin is considered inappropriate due to intolerance.
- in addition to other medicinal products for the treatment of type 2 diabetes.

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

Heart failure

<Invented name> is indicated in adults for the treatment of symptomatic chronic heart
failure.

Chronic kidney disease

<Invented name> is indicated in adults for the treatment of chronic kidney disease.

4.2 Posology and method of administration

Posology

Type 2 diabetes mellitus

The recommended dose is 10 mg dapagliflozin once daily.

When dapagliflozin is used in combination with insulin or an insulin secretagogue, such as a

sulphonylurea, a lower dose of insulin or insulin secretagogue may be considered to reduce the
risk of hypoglycaemia (see sections 4.5 and 4.8).

Heart failure
The recommended dose is 10 mg dapagliflozin once daily.

Chronic kidney disease

The recommended dose is 10 mg dapagliflozin once daily.

Special populations
Renal impairment
No dose adjustment is required based on renal function.

Due to limited experience, it is not recommended to initiate treatment with dapagliflozin in

patients with GFR < 25 mL/min.

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

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

Elderly (≥ 65 years)
No dose adjustment is recommended based on age.

Paediatric population
No dose adjustment is required for the treatment of type 2 diabetes mellitus in children aged

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10 years and 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
of chronic kidney disease in children < 18 years have not yet been established. No data are
available.

Method of administration

Dapagliflozin can be taken orally once daily at any time of day with or without food.
Tablets are to be swallowed with half a glass of water. The 10 mg tablet can be divided into
equal doses or for ease of swallowing.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

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

Renal impairment

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

The glucose lowering efficacy of dapagliflozin is dependent on renal function, and is reduced in
patients with GFR < 45 mL/min and is likely absent in patients with severe renal impairment (see
sections 4.2, 5.1 and 5.2).

In one study in patients with type 2 diabetes mellitus with moderate renal impairment (GFR <
60 mL/min), a higher proportion of patients treated with dapagliflozin had adverse reactions of
increase in creatinine, phosphorus, parathyroid hormone (PTH) and hypotension, compared with
placebo.

Hepatic impairment

There is limited experience in clinical studies in patients with hepatic impairment. Dapagliflozin
exposure 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 modest
decrease in blood pressure observed in clinical studies (see section 5.1). It may be more pronounced in
patients with very high blood glucose concentrations.

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

In case of intercurrent conditions that may lead to volume depletion (e.g. gastrointestinal illness),

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careful monitoring of volume status (e.g. physical examination, blood pressure measurements,
laboratory tests including haematocrit and electrolytes) is recommended. Temporary interruption of
treatment with dapagliflozin is recommended for patients who develop volume depletion until the
depletion is corrected (see section 4.8).

Diabetic ketoacidosis

Rare cases of diabetic ketoacidosis (DKA), including life-threatening and fatal cases, have been
reported in patients treated with sodium-glucose co-transporter 2 (SGLT2) inhibitors, including
dapagliflozin. In a number of cases, the presentation of the condition was atypical with only
moderately increased blood glucose values, below 14 mmol/L (250 mg/dL).
The risk of diabetic ketoacidosis must be considered in the event of non-specific symptoms such as
nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual
fatigue or sleepiness. Patients should be assessed for ketoacidosis immediately if these symptoms
occur, regardless of blood glucose level.

In patients where DKA is suspected or diagnosed, dapagliflozin treatment should be stopped

immediately.

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

Before initiating dapagliflozin, factors in the patient history that may predispose 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) or
patients with a history of pancreatitis), patients with conditions that lead to restricted food intake or
severe dehydration, patients for whom insulin doses are reduced and patients with increased insulin
requirements due to acute medical illness, surgery or alcohol abuse. SGLT2 inhibitors should be used
with caution in these patients.

Restarting SGLT2 inhibitor treatment in patients experiencing a DKA while on SGLT2 inhibitor
treatment 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.

Necrotising fasciitis of the perineum (Fournier’s gangrene)

Postmarketing cases of necrotising fasciitis of the perineum (also known as Fournier’s gangrene) have
been reported in female and male patients taking SGLT2 inhibitors (see section 4.8). This is a rare but
serious and potentially life-threatening event that requires urgent surgical intervention and antibiotic
treatment.

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

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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 pyelonephritis
or urosepsis.

Elderly (≥ 65 years)

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

Elderly patients are more likely to have impaired renal function, and/or to be treated with anti-
hypertensive medicinal products that may cause changes in renal function such as angiotensin-
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 (see sections
4.2, 4.4, 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.

Chronic kidney disease

There is no experience with dapagliflozin for the treatment of chronic kidney disease in patients
without diabetes who do not have albuminuria. Patients with albuminuria may benefit more from
treatment with dapagliflozin.

Lower limb amputations

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 this
constitutes a class effect. It is important to counsel patients with diabetes on routine preventative foot
care.

Urine laboratory assessments

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

Excipients

<Invented name> contains lactose. Patients with rare hereditary problems of galactose intolerance,
total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-
free’.

4.5 Interaction with other medicinal products and other forms of interaction

Pharmacodynamic interactions

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

Insulin and insulin secretagogues

Insulin and insulin secretagogues, such as sulphonylureas, cause hypoglycaemia. Therefore, a lower
dose of insulin or an insulin secretagogue may be required to reduce the risk of hypoglycaemia when
used in combination with dapagliflozin in patients with type 2 diabetes mellitus (see sections 4.2 and
4.8).

Pharmacokinetic interactions

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 medicinal
products 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 the
pharmacokinetics 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 transporters
and drug-metabolising enzymes) a 22% decrease in dapagliflozin systemic exposure (AUC) was
observed, but with no clinically meaningful effect on 24-hour urinary glucose excretion. 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 on 24-
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 and
dose changes. Please refer the patient to the lithium prescribing doctor in order to monitor serum
concentration of lithium.

In interaction studies conducted in healthy subjects, using mainly a single-dose design, dapagliflozin
did 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 a
single 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 and
simvastatin acid exposures are not considered clinically relevant.

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Interference with 1,5-anhydroglucitol (1,5-AG) assay

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

Paediatric population
Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Pregnancy

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

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

Breast-feeding

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

Fertility

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.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

Type 2 diabetes mellitus

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

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

In the dapagliflozin cardiovascular outcomes study in type 2 diabetes mellitus (DECLARE study, see
section 5.1), 8,574 patients received dapagliflozin 10 mg and 8,569 received placebo for a median

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exposure 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.

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

Chronic kidney disease

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 median exposure
time of 27 months. The patient population included patients with type 2 diabetes mellitus and without
diabetes, with eGFR ≥ 25 to ≤ 75 mL/min/1.73 m2, and albuminuria (urine albumin creatinine ratio
[UACR] ≥ 200 and ≤ 5000 mg/g). Treatment was continued if eGFR fell to levels below 25
mL/min/1.73 m2.

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

Tabulated list of adverse reactions

The following adverse reactions have been identified in the placebo-controlled clinical studies and
postmarketing surveillance. None were found to be dose-related. Adverse reactions listed below are
classified according to frequency and system organ class (SOC). Frequency categories are defined
according 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 not
known (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 rare

class
Infections and Vulvovaginitis, Fungal Necrotising
infestations balanitis and infection** fasciitis of the
related genital perineum
infections*,b,c (Fournier's
Urinary tract gangrene)b,i
infection*,b,d
Metabolism and Hypoglycaemia Volume Diabetic
nutrition (when used depletionb,e ketoacidosis
disorders with SU or Thirst** (when used
insulin)b in type 2
diabetes

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mellitus)b,i,k

Nervous system Dizziness

disorders
Gastrointestinal Constipation**
disorders Dry mouth**
Skin and Rashj Angioedema
subcutaneous
tissue disorders
Musculoskeletal Back pain*
and connective
tissue disorders
Renal and Dysuria Nocturia** Tubulointerstitial
urinary Polyuria*,f nephritis
disorders
Reproductive Vulvovaginal
system and pruritus**
breast disorders Pruritus
genital**
Investigations Haematocrit Blood
increasedg creatinine
Creatinine renal increased
clearance during initial
decreased treatment**,b
during initial Blood urea
treatmentb increased**
h
Dyslipidaemia Weight
decreased**
a The table shows up to 24-week (short-term) data regardless of glycaemic rescue.
b See corresponding subsection below for additional information.
c Vulvovaginitis, 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.
d Urinary tract infection includes the following preferred terms, listed in order of frequency reported: urinary tract infection,

cystitis, Escherichia urinary tract infection, genitourinary tract infection, pyelonephritis, trigonitis, urethritis, kidney
infection and prostatitis.
e Volume depletion includes, e.g. the predefined preferred terms: dehydration, hypovolaemia, hypotension.
f Polyuria includes the preferred terms: pollakiuria, polyuria, urine output increased.
g Mean 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.
h Mean percent change from baseline for dapagliflozin 10 mg versus placebo, respectively, was: total cholesterol 2.5% versus

0.0%; HDL cholesterol 6.0% versus 2.7%; LDL cholesterol 2.9% versus -1.0%; triglycerides -2.7% versus -0.7%.
i See section 4.4
j Adverse reaction was identified through postmarketing surveillance. Rash includes the following preferred terms, listed in

order of frequency in clinical studies: rash, rash generalised, rash pruritic, rash macular, rash maculo-papular, rash pustular,
rash vesicular, and rash erythematous. In active- and placebo-controlled clinical studies (dapagliflozin, N=5936, All
control, N=3403), the frequency of rash was similar for dapagliflozin (1.4%) and all control (1.4%), respectively.
k Reported in the cardiovascular outcomes study in patients with type 2 diabetes (DECLARE). Frequency is based on annual

rate.
* Reported in ≥ 2% of subjects and ≥ 1% more and at least 3 more subjects treated with dapagliflozin 10 mg compared 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 to placebo.
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Description of selected adverse reactions

Vulvovaginitis, balanitis and related genital infections

In the 13-study safety pool, vulvovaginitis, balanitis and related genital infections were reported in
5.5% and 0.6% of subjects who received dapagliflozin 10 mg and placebo, respectively. Most
infections were mild to moderate, and subjects responded to an initial course of standard treatment and
rarely resulted in discontinuation from dapagliflozin treatment. These infections were more frequent in
females (8.4% and 1.2% for dapagliflozin and placebo, respectively), and subjects with a prior history
were more likely to have a recurrent infection.

In the DECLARE study, the numbers of patients with serious adverse events of genital infections were
few 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 the
dapagliflozin group and one in the placebo group. There were 7 (0.3%) patients with adverse events
leading to discontinuations due to genital infections in the dapagliflozin group and none in the placebo
group.
In the DELIVER study, one (< 0.1%) patient in each treatment group reported a serious adverse event
of genital infections. There were 3 (0.1%) patients with adverse events leading to discontinuations 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 genital
infections in the dapagliflozin group and none in the placebo group. There were 3 (0.1%) patients with
adverse events leading to discontinuation due to genital infections in the dapagliflozin group and none
in the placebo group. Serious adverse events of genital infections or adverse events leading to
discontinuation 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 in
some cases, circumcision was required.

Necrotising fasciitis of the perineum (Fournier’s gangrene)

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 of
48 months, a total of 6 cases of Fournier’s gangrene were reported, one in the dapagliflozin-treated
group and 5 in the placebo group.

Hypoglycaemia
The frequency of hypoglycaemia depended on the type of background therapy used in the clinical
studies in diabetes mellitus.

For studies of dapagliflozin in monotherapy, as add-on to metformin or as add-on to sitagliptin (with

or 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, major
events of hypoglycaemia were uncommon and comparable between the groups treated with
dapagliflozin or placebo. Studies with add-on sulphonylurea and add-on insulin therapies had higher
rates of hypoglycaemia (see section 4.5).
In an add-on to glimepiride study, at weeks 24 and 48, minor episodes of hypoglycaemia were
reported more frequently in the group treated with dapagliflozin 10 mg plus glimepiride (6.0% and
7.9%, respectively) than in the placebo plus glimepiride group (2.1% and 2.1%, respectively).

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In an add-on to insulin study, episodes of major hypoglycaemia were reported in 0.5% and 1.0% of
subjects 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, minor
episodes of hypoglycaemia were reported, respectively, in 40.3% and 53.1% of subjects who received
dapagliflozin 10 mg plus insulin and in 34.0% and 41.6% of the subjects who received placebo plus
insulin.

In an add-on to metformin and a sulphonylurea study, up to 24 weeks, no episodes of major

hypoglycaemia were reported. Minor episodes of hypoglycaemia were reported in 12.8% of subjects
who received dapagliflozin 10 mg plus metformin and a sulphonylurea and in 3.7% of subjects who
received placebo plus metformin and a sulphonylurea.

In the DECLARE study, no increased risk of major hypoglycaemia was observed with dapagliflozin
therapy compared with placebo. Major events of hypoglycaemia were reported in 58 (0.7%) patients
treated 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 the
dapagliflozin and placebo treatment groups.
In the DELIVER study, major events of hypoglycaemia were reported in 6 (0.2%) patients in the
dapagliflozin group and 7 (0.2%) in the placebo group. Major events 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 the
dapagliflozin group and 28 (1.3%) patients in the placebo group and observed only in patients with
type 2 diabetes mellitus.

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

In the DECLARE study, the numbers of patients with events suggestive of volume depletion were
balanced between treatment groups: 213 (2.5%) and 207 (2.4%) in the dapagliflozin and placebo
groups, respectively. Serious adverse events were reported in 81 (0.9%) and 70 (0.8%) in the
dapagliflozin and placebo group, respectively. Events were generally balanced between treatment
groups across subgroups of age, diuretic use, blood pressure and angiotensin converting enzyme
inhibitors (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 volume
depletion 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 were 170
(7.2%) in the dapagliflozin group and 153 (6.5%) in the placebo group. There were fewer patients with
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 of presence of
diabetes at baseline and baseline eGFR.
In the DELIVER study, the numbers of patients with serious events of symptoms suggestive of volume
depletion were 35 (1.1%) in the dapagliflozin group and 31 (1.0%) in the placebo group.

In the DAPA-CKD study, the numbers of patients with events suggestive of volume depletion were
120 (5.6%) in the dapagliflozin group and 84 (3.9%) in the placebo group. There were 16 (0.7%)

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patients with serious events of symptoms suggestive of volume depletion in the dapagliflozin 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 in
27 patients in the dapagliflozin 10 mg group and 12 patients in the placebo group. The events occurred
evenly distributed over the study period. Of the 27 patients with DKA events in the dapagliflozin
group, 22 had concomitant insulin treatment at the time of the event. Precipitating factors for DKA
were 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 the
dapagliflozin group and none in the placebo group.
In the DELIVER study, events of DKA were reported in 2 patients with type 2 diabetes mellitus in the
dapagliflozin group and none in the placebo group.

In the DAPA-CKD study, events of DKA were not reported in any patient in the dapagliflozin group
and 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 for dapagliflozin 10
mg compared to placebo (4.7% versus 3.5%, respectively; see section 4.4). Most infections were mild
to moderate, and subjects responded to an initial course of standard treatment and rarely resulted in
discontinuation from dapagliflozin treatment. These infections were more frequent in females, 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 for
dapagliflozin 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 infections
were 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 the
dapagliflozin and placebo groups.
In the DELIVER study the numbers of patients with serious adverse events of urinary tract infections
were 41 (1.3%) in the dapagliflozin group and 37 (1.2%) in the placebo group. There were 13 (0.4%)
patients with adverse events leading to discontinuations due to urinary 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 tract
infections were 29 (1.3%) in the dapagliflozin group and 18 (0.8%) in the placebo group. There were 8
(0.4%) patients with adverse events leading to discontinuations due to urinary tract infections in the
dapagliflozin group and 3 (0.1%) in the placebo group. The numbers of patients without diabetes
reporting serious adverse events of urinary tract infections or adverse events leading to discontinuation
due to urinary tract infections were similar between treatment groups (6 [0.9%] versus 4 [0.6%] for
serious adverse events, and 1 [0.1%] versus 0 for adverse events leading to discontinuation, in the
dapagliflozin and placebo groups, respectively).

Increased creatinine
Adverse reactions related to increased creatinine were grouped (e.g. decreased renal creatinine
clearance, renal impairment, increased blood creatinine and decreased glomerular filtration rate). In
the 13-study safety pool, this grouping of reactions was reported in 3.2% and 1.8% of patients who
received dapagliflozin 10 mg and placebo, respectively. In patients with normal renal function or mild
renal impairment (baseline eGFR ≥ 60 mL/min/1.73 m2) this grouping of reactions were reported in

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1.3% and 0.8% of patients who received dapagliflozin 10 mg and placebo, respectively. These
reactions 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 serum
creatinine changes of ≤ 44 micromoles/L (≤ 0.5 mg/dL) from baseline. The increases in creatinine
were 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 than
60 mL/min/1.73 m2), eGFR decreased over time in both treatment groups. At 1 year, mean eGFR was
slightly lower, and at 4 years, mean eGFR was slightly higher in the dapagliflozin group compared
with the placebo group.

In the DAPA-HF and DELIVER studies, eGFR decreased over time in both the dapagliflozin group
and the placebo group. In DAPA-HF, the initial decrease in mean eGFR was -4.3 mL/min/1.73 m2 in
the dapagliflozin group and -1.1 mL/min/1.73 m2 in the placebo group. At 20 months, change from
baseline in eGFR was similar between the treatment groups: -5.3 mL/min/1.73 m2 for dapagliflozin
and -4.5 mL/min/1.73 m2 for placebo. In DELIVER, the decrease in mean eGFR at one month was -
3.7 mL/min/1.73 m2 in the dapagliflozin group and -0.4 mL/min/1.73 m2 in the placebo group. At 24
months, change from baseline in eGFR was similar between treatment groups: -4.2 mL/min/1.73 m2 in
the dapagliflozin group and -3.2 mL/min/1.73 m2 in the placebo group.

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

Paediatric population

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare
professionals are asked to report any suspected adverse reactions via the national reporting system
listed in Appendix V.

4.9 Overdose

Symptoms
Dapagliflozin did not show any toxicity in healthy subjects at single oral doses up to 500 mg (50 times
the maximum recommended human dose). These subjects had detectable glucose in the urine for a
dose-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. The
incidence of hypoglycaemia was similar to placebo. In clinical studies where once-daily doses of up to
100 mg (10 times the maximum recommended human dose) were administered for 2 weeks in healthy
subjects and type 2 diabetes subjects, the incidence of hypoglycaemia was slightly higher than placebo
and was not dose-related. Rates of adverse events including dehydration or hypotension were similar
to placebo, and there were no clinically meaningful dose-related changes in laboratory parameters,
including serum electrolytes and biomarkers of renal function.

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

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

inhibitors, ATC code: A10BK01

Mechanism of action

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 in
the proximal renal tubule with a concomitant reduction in sodium reabsorption leading to urinary
excretion of glucose and osmotic diuresis. Dapagliflozin therefore increases the delivery of sodium to
the 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 and
diastolic function, and preserve renal function. The cardiac and renal benefits of dapagliflozin are not
solely dependent on the blood glucose-lowering effect and not limited to patients with diabetes as
demonstrated in the DAPA-HF, DELIVER and DAPA-CKD studies. Other effects include an increase
in haematocrit and reduction in body weight.

Dapagliflozin improves both fasting and post-prandial plasma glucose levels by reducing renal
glucose reabsorption leading to urinary glucose excretion. This glucose excretion (glucuretic effect) is
observed after the first dose, is continuous over the 24-hour dosing interval and is sustained for the
duration of treatment. The amount of glucose removed by the kidney through this mechanism is
dependent upon the blood glucose concentration and GFR. Thus, in subjects with normal blood
glucose, dapagliflozin has a low propensity to cause hypoglycaemia. Dapagliflozin does not impair
normal endogenous glucose production in response to hypoglycaemia. Dapagliflozin acts
independently of insulin secretion and insulin action. Improvement in homeostasis model assessment
for 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 glucose
transporters important for glucose transport into peripheral tissues and is > 1,400 times more selective
for SGLT2 versus SGLT1, the major transporter in the gut responsible for glucose absorption.

Pharmacodynamic effects

Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in
subjects with type 2 diabetes mellitus following the administration 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 diabetes mellitus for 12 weeks. Evidence of sustained
glucose excretion was seen in subjects with type 2 diabetes mellitus given dapagliflozin 10 mg/day for
up to 2 years.

This urinary glucose excretion with dapagliflozin also results in osmotic diuresis and increases in
urinary volume in subjects with type 2 diabetes mellitus. Urinary volume increases in subjects with

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type 2 diabetes mellitus treated with dapagliflozin 10 mg were sustained at 12 weeks and amounted to
approximately 375 mL/day. The increase in urinary volume was associated with a small and transient
increase in urinary sodium excretion that was not associated with changes in serum sodium
concentrations.

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

Clinical efficacy and safety

Type 2 diabetes mellitus

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

Fourteen double-blind, randomised, controlled clinical studies were conducted with 7,056 adult
subjects with type 2 diabetes to evaluate the glycaemic efficacy and safety of dapagliflozin; 4,737
subjects in these studies were treated with dapagliflozin. Twelve studies had a treatment period of
24 weeks duration, 8 with long-term extensions ranging from 24 to 80 weeks (up to a total study
duration of 104 weeks), one study had a 28-week treatment period, and one study was 52 weeks in
duration with long-term extensions of 52 and 104 weeks (total study duration of 208 weeks). Mean
duration of diabetes ranged from 1.4 to 16.9 years. Fifty percent (50%) had mild renal impairment and
11% had moderate 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 the subjects had a body mass index (BMI) ≥27. Furthermore, two 12-week, placebo-controlled
studies were conducted in patients with inadequately controlled type 2 diabetes and hypertension.
A cardiovascular outcomes study (DECLARE) was conducted with dapagliflozin 10 mg compared
with placebo in 17,160 patients with type 2 diabetes mellitus with or without established
cardiovascular disease to evaluate the effect on cardiovascular and renal events.

Glycaemic control
Monotherapy
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 dapagliflozin in subjects with
inadequately controlled type 2 diabetes mellitus. Once-daily treatment with dapagliflozin resulted in
statistically 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 as

monotherapy

Monotherapy
Dapagliflozin Placebo
10 mg
Nb 70 75
HbA1c (%)
Baseline (mean) 8.01 7.79
Change from baselinec -0.89 -0.23
Difference from placeboc -0.66*

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(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)
a LOCF: Last observation (prior to rescue for rescued subjects) carried forward
b All randomised subjects who took at least one dose of double-blind study medicinal product during the short-term double-
blind period
c Least 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 end points

Add-on combination therapy

In a 52-week, active-controlled non-inferiority study (with 52- and 104-week extension periods),
dapagliflozin was evaluated as add-on therapy to metformin compared with a sulphonylurea
(glipizide) as add-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,
compared to glipizide, thus demonstrating non-inferiority (Table 3). At week 104, adjusted mean
change from baseline in HbA1c was -0.32% for dapagliflozin and -0.14% for glipizide. At week 208,
adjusted mean 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%, 4.3% and 5.0%, respectively) experienced at least one event of hypoglycaemia
compared to the group treated with glipizide (40.8%, 47.0% and 50.0%, respectively). The proportion
of subjects remaining in the study at week 104 and week 208 was 56.2% and 39.7% for the group
treated with dapagliflozin 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 to

glipizide as add-on to metformin

Parameter Dapagliflozin + metformin Glipizide+ 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)
a LOCF: Last observation carried forward
b Randomised and treated subjects with baseline and at least 1 post-baseline efficacy measurement
c Least squares mean adjusted for baseline value
d Non-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).
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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). At week
48 when added to sitagliptin (with or without metformin), the adjusted mean change from baseline for
dapagliflozin 10 mg and placebo was -0.30% and 0.38%, respectively. For the add-on to metformin
study, HbA1c reductions were sustained through week 102 (-0.78% and 0.02% adjusted mean change
from baseline for 10 mg and placebo, respectively). At week 104 for insulin (with or without
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. At weeks 48
and 104, the insulin dose remained stable compared to baseline in subjects treated with dapagliflozin
10 mg at an average dose of 76 IU/day. In the placebo group there was a mean increase of 10.5 IU/day
and 18.3 IU/day from baseline (mean average dose of 84 and 92 IU/day) at weeks 48 and 104,
respectively. The proportion of subjects remaining in the study at week 104 was 72.4% for the 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-on

combination with metformin or sitagliptin (with or without metformin)

Add-on combination
Metformin1 DPP-4 inhibitor
(sitagliptin2) ± metformin1
Dapagliflozin Placebo Dapagliflozin Placebo
10 mg 10 mg
Nb 135 137 223 224
HbA1c (%)
Baseline (mean) 7.92 8.11 7.90 7.97

Change from baselinec -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 from baselinec -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)
1 Metformin ≥ 1500 mg/day;
2 Sitagliptin 100 mg/day
a LOCF: Last observation (prior to rescue for rescued subjects) carried forward
b All randomised subjects who took at least one dose of double-blind study medicinal product during the short-term double-

blind period
c Least 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 combination

with sulphonylurea (glimepiride) or metformin and a sulphonylurea

Add-on combination
Sulphonylurea Sulphonylurea

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(glimepiride1) + metformin2
Dapagliflozin Placebo Dapagliflozin Placebo
10 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)
1 Glimepiride 4 mg/day;
2 Metformin (immediate- or extended-release formulations) ≥1500 mg/day plus maximum tolerated dose, which must be at
least half maximum dose, of a sulphonylurea for at least 8 weeks prior to enrolment.
a Randomised and treated patients with baseline and at least 1 post-baseline efficacy measurement.
b Columns 1 and 2, HbA1c analysed using LOCF (see footnote d); Columns 3 and 4, HbA1c analysed using LRM (see

footnote e)
c Least squares mean adjusted for baseline value
d LOCF: Last observation (prior to rescue for rescued subjects) carried forward
e LRM: 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 in

combination with insulin (alone or with oral glucose-lowering medicinal products)

Parameter Dapagliflozin 10 mg Placebo

+ insulin + insulin
± oral glucose-lowering ± oral glucose-lowering
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 daily insulin
dose reduction of at least 10% (%) 19.7** 11.0
a LOCF: Last observation (prior to or on the date of the first insulin up-titration, if needed) carried forward
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b All randomised subjects who took at least one dose of double-blind study medicinal product during the short- term double-
blind period
c Least 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 product
1 Up-titration of insulin regimens (including short-acting, intermediate, and basal insulin) was only allowed if subjects met

pre-defined FPG criteria.

2 Fifty percent of subjects were on insulin monotherapy at baseline; 50% were on 1 or 2 oral glucose-lowering medicinal

product(s) in addition to insulin: Of this latter group, 80% were on metformin alone, 12% were on metformin plus
sulphonylurea therapy, and the rest were on other oral glucose-lowering medicinal products.

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 and
safety of dapagliflozin (5 mg or 10 mg) in combination with metformin in drug-naive patients versus
therapy with the monocomponents.

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

Table 7. Results at week 24 (LOCFa) in an active-controlled study of dapagliflozin and

metformin combination therapy in drug-naive patients

Parameter Dapagliflozin 10 mg Dapagliflozin 10 mg Metformin

+ 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)
a LOCF: last observation (prior to rescue for rescued patients) carried forward.
b All randomised patients who took at least one dose of double-blind study medicinal product during the short-term double-
blind period.
c Least 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 and
prolonged-release exenatide (a GLP-1 receptor agonist) was compared to dapagliflozin alone and
prolonged-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. The
combination treatment with dapagliflozin 10 mg and prolonged-release exenatide group showed
superior reductions in HbA1c from baseline compared to dapagliflozin alone and prolonged-release
exenatide alone (Table 8).

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

Parameter Dapagliflozin 10 mg Dapagliflozin 10 mg Exenatide 2 mg

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QD QD prolonged-release
+ + QW
Exenatide 2 mg Placebo QW +
prolonged-release Placebo QD
QW
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 change
from baseline between
-0.59* -0.38**
combination and single
medicinal product
(95% CI) (-0.84, -0.34) (-0.63, -0.13)
Subjects (%) achieving:
44.7 19.1 26.9
HbA1c < 7%
Body weight (kg)
Baseline (mean) 92.13 90.87 89.12
Change from baselinea -3.55 -2.22 -1.56
Mean difference in change
from baseline between
-1.33* -2.00*
combination and single
medicinal product
(95% CI) (-2.12, -0.55) (-2.79, -1.20)
QD=once daily, QW=once weekly, N=number of patients, CI=confidence interval.
a Adjusted least squares means (LS Means) and treatment group difference(s) in the change from baseline values 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 fixed factors, 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 medicinal product.

Fasting plasma glucose

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 resulted
in statistically significant reductions in FPG (-1.90 to -1.20 mmol/L [-34.2 to -21.7 mg/dL]) compared
to placebo (-0.33 to 0.21 mmol/L [-6.0 to 3.8 mg/dL]). This effect was observed at week 1 of treatment
and maintained in studies extended through week 104.

Combination therapy of dapagliflozin 10 mg and prolonged-release exenatide resulted in significantly

greater 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 with
dapagliflozin 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 significant
reductions 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 in

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reductions 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 significantly

greater reductions in 2-hour post-prandial glucose at week 28 compared to either medicinal product
alone.

Body weight
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 weight
reduction at 24 weeks (p < 0.0001, Tables 4 and 5). These effects were sustained in longer-term
studies. At 48 weeks, the difference for dapagliflozin as add-on to sitagliptin (with or without
metformin) compared with placebo was -2.22 kg. At 102 weeks, the difference for dapagliflozin as
add-on to metformin compared with placebo, or as add-on to insulin compared with placebo was -2.14
and -2.88 kg, respectively.

As an add-on therapy to metformin in an active-controlled non-inferiority study, dapagliflozin resulted

in 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 significantly

greater 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 evaluate
body composition demonstrated reductions with dapagliflozin 10 mg plus metformin compared with
placebo plus metformin, respectively, in body weight and body fat mass as measured by DXA rather
than lean tissue or fluid loss. Treatment with dapagliflozin plus metformin showed a numerical
decrease in visceral adipose tissue compared with placebo plus metformin treatment in a magnetic
resonance imaging substudy.

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

Combination therapy of dapagliflozin 10 mg and prolonged-release exenatide resulted in a

significantly greater reduction in systolic blood pressure at week 28 (-4.3 mmHg) compared to
dapagliflozin 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 controlled type
2 diabetes and hypertension (despite pre-existing stable treatment with an ACE-I or ARB in one study
and an ACE-I or ARB plus one additional antihypertensive treatment in another study) were treated
with dapagliflozin 10 mg or placebo. At week 12 for both studies, dapagliflozin 10 mg plus usual
antidiabetic treatment provided improvement in HbA1c and decreased the placebo-corrected systolic
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 with
dapagliflozin demonstrated reductions in seated systolic blood pressure at week 24: -4.8 mmHg
compared to -1.7 mmHg for placebo (p < 0.05).

Glycaemic control in patients with moderate renal impairment CKD 3A

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(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 ≥ 45
to < 60 mL/min/1.73 m2 who had inadequate glycaemic control on usual care. Treatment with
dapagliflozin 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 patients

with an eGFR ≥ 45 to < 60 mL/min/1.73 m2

Dapagliflozin 10 mga Placeboa

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
(95% CI) (-2.15, -0.69)
a Metformin or metformin hydrochloride were part of the usual care in 69.4% and 64.0% of the patients for the 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

Patients with baseline HbA1c ≥ 9%

In a pre-specified analysis of subjects with baseline HbA1c ≥ 9.0%, treatment with dapagliflozin
10 mg resulted in statistically significant reductions in HbA1c at week 24 as a monotherapy (adjusted
mean change from baseline: -2.04% and 0.19% for dapagliflozin 10 mg and placebo, 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 of
dapagliflozin compared with placebo on cardiovascular outcomes when added to current background
therapy. All patients had type 2 diabetes mellitus and either at least two additional cardiovascular risk
factors (age ≥ 55 years in men or ≥ 60 years in women and one or more of dyslipidaemia, hypertension
or current tobacco use) or established cardiovascular disease.

Of 17,160 randomised patients, 6,974 (40.6%) had established cardiovascular disease and 10,186
(59.4%) did not have established cardiovascular disease. 8,582 patients were randomised to
dapagliflozin 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 had
diabetes 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- or
macroalbuminuria (UACR ≥ 30 to ≤ 300 mg/g or > 300 mg/g, respectively).
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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, myocardial
infarction or ischaemic stroke (MACE) and time to first event of the composite of hospitalisation for
heart failure or cardiovascular death. The secondary endpoints were a renal composite endpoint and
all-cause mortality.

Major adverse cardiovascular events

Dapagliflozin 10 mg demonstrated non-inferiority versus placebo for the composite of cardiovascular
death, 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 of
hospitalisation for heart failure or cardiovascular death (Figure 1). The difference in treatment effect
was 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 without
established cardiovascular disease, with and without heart failure at baseline, and was consistent
across 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 dapagliflozin
over placebo was not demonstrated for MACE (p=0.172). The renal composite endpoint and all-cause
mortality were therefore not tested as part of the confirmatory testing procedure.

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Figure 2: Treatment effects for the primary composite endpoints and their components, and the
secondary 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 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 was
analysed in a Cox proportional hazards model. The number of first events for the single components are the actual number of
first events for each component and does not add up to the number of events in the composite endpoint.
CI=confidence interval.

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

The hazard ratio (HR) for time to nephropathy (sustained eGFR decrease, end-stage kidney disease
and 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.

Heart failure

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 ventricular
ejection 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 and worsening
heart failure.
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Of 4,744 patients, 2,373 were randomised to dapagliflozin 10 mg and 2,371 to placebo and followed
for 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-ischaemic and
8% were of unknown aetiology. In each treatment group, 42% of the patients had a history of type 2
diabetes mellitus, and an additional 3% of the patients in each group were classified as having type 2
diabetes mellitus based on a HbA1c ≥ 6.5% at both enrolment and randomisation. Patients were on
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 receptor
antagonist (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 eGFR
was 66 mL/min/1.73 m2, 41% of patients had eGFR < 60 mL/min/1.73 m2 and 15% had eGFR <
45 mL/min/1.73 m2.

Cardiovascular death and worsening heart failure

Dapagliflozin was superior to placebo in preventing the primary composite endpoint of cardiovascular
death, 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 for
heart 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
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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 treatment
effect (Figure 4). There were few urgent heart failure visits.

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

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 not
add 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 and
recurrent) and cardiovascular death; there were 567 events in the dapagliflozin group versus 742
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 diabetes
mellitus and without diabetes. Dapagliflozin reduced the primary composite endpoint of incidence of
cardiovascular death and worsening heart failure with a HR of 0.75 (95% CI 0.63, 0.90) in patients
with 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 across
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other 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 failure
symptom frequency and severity, including fatigue, peripheral oedema, dyspnoea and orthopnoea. The
score ranges from 0 to 100, with higher scores representing better health status.
Treatment with dapagliflozin resulted in a statistically significant and clinically meaningful benefit
over 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 and
symptom burden contributed to the results. Benefit was seen both in improving heart failure symptoms
and 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 dapagliflozin
treatment group compared with placebo. The proportion of patients with a clinically meaningful
deterioration, defined as 5 points or more, was lower for the dapagliflozin treatment group compared
to 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 and
deterioration on the KCCQ-TSS at 8 months

Change from baseline Dapagliflozin Placebo

at 8 months: 10 mg na=2062
na=2086
Improvement n (%) n (%) Odds ratioc p-valuef
improvedb improvedb (95% CI)
≥ 5 points 933 (44.7) 794 (38.5) 1.14 0.0002
(1.06, 1.22)
≥ 10 pints 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-valuef
deterioratedd 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 died prior
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 prior to the

given timepoint are counted as deteriorated.

e For deterioration, an odds ratio < 1 favours dapagliflozin 10 mg.
f p-values are nominal.

Nephropathy
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 placebo
group.
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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-controlled
study in patients aged ≥ 40 years with heart failure (NYHA class II-IV) with LVEF > 40% and
evidence of structural heart disease, to determine the effect of dapagliflozin compared with placebo on
the 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 followed
for a median of 28 months. The study included 654 (10%) subacute heart failure patients (defined as
randomised during hospitalisation for heart failure or within 30 days of discharge). The mean age of
the 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 therapy
included 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% had
eGFR < 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 of
cardiovascular 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 for
heart failure or urgent heart failure visit

Placebo

Pa
tie
nt Dapagliflozin
s
wi
th
ev
en
t

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.

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

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 not
add 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 error
control as a secondary endpoint.

Dapagliflozin was superior to placebo in reducing the total number of heart failure events (defined as
first and recurrent hospitalisation for heart failure or urgent heart failure visits) and cardiovascular
death; 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 across
subgroups of patients with LVEF ≤ 49%, 50–59%, and ≥ 60%. Effects were also consistent across
other 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 failure
symptoms, 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 the results.

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 the dapagliflozin
treatment group; 24.1% of patients on dapagliflozin versus 29.1% on placebo experienced a moderate
deterioration (Odds Ratio 0.78 [95% CI 0.64, 0.95]) and 13.5% of patients on dapagliflozin versus

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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 the
composite endpoint of cardiovascular death, hospitalisation for heart failure or urgent heart failure
visit was 0.78 (95% CI 0.72, 0.85), p < 0.0001. The treatment effect was consistent across the LVEF
range, without attenuation of effect by LVEF.

In a pre-specified subject level pooled analysis of the DAPA-HF and DELIVER studies, dapagliflozin
compared 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.

Chronic kidney disease

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) with eGFR ≥
25 to ≤ 75 mL/min/1.73 m2 and albuminuria (UACR ≥ 200 and ≤ 5000 mg/g) to determine the effect of
dapagliflozin compared with placebo, when added to background standard of care therapy, on the
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 a
renal transplant), cardiovascular or renal death.

Of 4,304 patients, 2,152 were randomised to dapagliflozin 10 mg and 2,152 to placebo and followed
for a median of 28.5 months. Treatment was continued if eGFR fell to levels below
25 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 was
43.1 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 2
diabetes mellitus. Patients were on standard of care (SOC) therapy; 97.0% of patients were treated
with 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 by
the independent Data Monitoring Committee. Dapagliflozin was superior to placebo in preventing the
primary 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 the
primary composite endpoint, the treatment effect was evident beginning at 4 months and was
maintained through the end of study (Figure 7).

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

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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 treatment
effect. Dapagliflozin also reduced the incidence of the composite endpoint of ≥ 50% sustained decline
in eGFR, end-stage kidney disease or renal death and the composite endpoint of cardiovascular death
and hospitalisation for heart failure. Treatment with dapagliflozin improved overall survival in chronic
kidney disease patients with a significant reduction in all-cause mortality (Figure 8).

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

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The number of first events for the single components are the actual number of first events for each component and does not
add 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 2
diabetes mellitus and without diabetes. Dapagliflozin reduced the primary composite endpoint of
≥ 50% sustained decline in eGFR, reaching end-stage kidney disease, cardiovascular or renal death
with a HR of 0.64 (95% CI 0.52, 0.79) in patients with type 2 diabetes mellitus and 0.50 (95% CI 0.35,
0.72) in patients without diabetes.

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

Paediatric population

Type 2 diabetes mellitus

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, insulin or
a combination of metformin and insulin. At randomisation, 74% of the patients were < 18 years of age.
The adjusted mean change in HbA1c for dapagliflozin relative to placebo from baseline to week 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 observed in the adult
population treated with dapagliflozin. Safety and tolerability were further confirmed in a 28-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 with the
reference medicinal product containing dapagliflozin in all subsets of the paediatric population in the
prevention of cardiovascular events in patients with chronic heart failure and in the treatment of
chronic kidney disease (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Absorption

Dapagliflozin was rapidly and well absorbed after oral administration. Maximum dapagliflozin plasma
concentrations (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 of
dapagliflozin were 158 ng/mL and 628 ng h/mL, respectively. The absolute oral bioavailability of
dapagliflozin following the administration of a 10 mg dose is 78%. Administration with a high-fat
meal decreased dapagliflozin Cmax by up to 50% and prolonged Tmax by approximately 1 hour, but did
not alter AUC as compared with the fasted state. These changes are not considered to be clinically
meaningful. Hence, dapagliflozin can be administered with or without food.

Distribution

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

Biotransformation

Dapagliflozin is extensively metabolised, primarily to yield dapagliflozin 3-O-glucuronide, which is

an inactive metabolite. Dapagliflozin 3-O-glucuronide or other metabolites do not contribute to the
glucose-lowering effects. The formation of dapagliflozin 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.

Elimination

The mean plasma terminal half-life (t1/2) for dapagliflozin was 12.9 hours following a single oral dose

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of dapagliflozin 10 mg to healthy subjects. The mean total systemic clearance of dapagliflozin

administered intravenously was 207 mL/min. Dapagliflozin and related metabolites are primarily
eliminated via urinary excretion with less than 2% as unchanged dapagliflozin. After administration of
a 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.

Linearity

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

Special populations

Renal impairment
At steady-state (20 mg once-daily dapagliflozin for 7 days), subjects with type 2 diabetes mellitus and
mild, moderate or severe renal impairment (as determined by iohexol plasma clearance) 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-state 24-hour urinary glucose
excretion was highly dependent on renal function and 85, 52, 18 and 11 g of glucose/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 dapagliflozin exposure is not known. The
effect of reduced renal function on systemic exposure was evaluated in a population pharmacokinetic
model. Consistent with previous results, model predicted AUC was higher in patients with chronic
kidney disease compared with patients with normal renal function, and was not meaningfully different
in chronic kidney disease patients with type 2 diabetes mellitus and without diabetes.

Hepatic impairment
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 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 dapagliflozin were 40% and
67% higher than matched healthy controls, respectively.

Elderly (≥ 65 years)
There is no clinically meaningful increase in exposure based on age alone in subjects up to 70 years
old. However, an increased exposure due to age-related decrease in renal function can be expected.
There are insufficient data to draw conclusions regarding exposure in patients > 70 years old.

Paediatric population
Pharmacokinetics and pharmacodynamics (glucosuria) in children with type 2 diabetes mellitus aged
10-17 years were similar to those observed in adults with type 2 diabetes mellitus.

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

Race
There were no clinically relevant differences in systemic exposures between White, Black or Asian
races.

Body weight
Dapagliflozin exposure was found to decrease with increased weight. Consequently, low-weight

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patients may have somewhat increased exposure and patients with high weight somewhat decreased
exposure. However, the differences in exposure were not considered clinically meaningful.

5.3 Preclinical safety data

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

Reproductive and developmental toxicity

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

In a juvenile toxicity study, when dapagliflozin was dosed directly to young rats from postnatal day 21
until postnatal day 90, renal pelvic and tubular dilatations were reported at all dose levels; pup
exposures at the lowest dose tested were ≥ 15 times the maximum recommended human dose. These
findings were associated with dose-related increases in kidney weight and macroscopic kidney
enlargement observed at all doses. The renal pelvic and tubular dilatations observed in juvenile
animals 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 6
through postnatal day 21, and pups were indirectly exposed in utero and throughout lactation. (A
satellite study was conducted to assess dapagliflozin exposures in milk and pups.) Increased incidence
or severity of renal pelvic dilatation was observed in adult offspring of treated dams, although only at
the highest dose tested (associated maternal and pup dapagliflozin exposures were 1,415 times and
137 times, respectively, the human values at the maximum recommended human dose). Additional
developmental toxicity was limited to dose-related reductions in pup body weights, and observed only
at doses ≥ 15 mg/kg/day (associated with pup exposures that are ≥ 29 times the human values at the
maximum 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 observed
adverse effect level (NOAEL) for developmental toxicity, the lowest dose tested, is associated with a
maternal systemic exposure multiple that is approximately 19 times the human value at the maximum
recommended human dose.

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

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core
Microcrystalline cellulose

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Lactose monohydrate
Hydroxypropylcellulose
Crospovidone (type A)
Microcrystalline cellulose (type 102)
Sodium stearyl fumarate

Film coating
Poly(vinyl alcohol)
Macrogol 3350
Titanium dioxide (E171)
Talc
Yellow iron oxide (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Blister (OPA/Alu/PVC//Alu): 14, 28, 30, 98 or 100 film-coated tablets, in a box.

Blister (OPA/Alu/PVC//Alu), calendar pack: 14, 28 or 98 film-coated tablets, in a box.
Perforated unit dose blister (OPA/Alu/PVC//Alu): 14 x 1, 28 x 1, 30 x 1, 98 x 1 or 100 x 1 film-coated
tablet, in a box.
Perforated unit dose blister (OPA/Alu/PVC//Alu), calendar pack: 14 x 1, 28 x 1 or 98 x 1 film-coated
tablet, in a box.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements for disposal.

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

7. MARKETING AUTHORISATION HOLDER

[To be completed nationally]

8. MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally]

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9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

[To be completed nationally]

10. DATE OF REVISION OF THE TEXT

[To be completed nationally]

Detailed information on this medicinal product is available on the website of {name of Member State
Agency (link)}

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LABELLING

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING

BOX

1. NAME OF THE MEDICINAL PRODUCT

<Invented name> 5 mg film-coated tablets

<Invented name> 10 mg film-coated tablets

dapagliflozin

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 5 mg dapagliflozin (from dapagliflozin propanediol monohydrate

form).
Each film-coated tablet contains 10 mg dapagliflozin (from dapagliflozin propanediol monohydrate
form).

3. LIST OF EXCIPIENTS

Contains lactose.
See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

Film-coated tablet

14 film-coated tablets
28 film-coated tablets
30 film-coated tablets
98 film-coated tablets
100 film-coated tablets
14 x 1 film-coated tablet
28 x 1 film-coated tablet
30 x 1 film-coated tablet
98 x 1 film-coated tablet
100 x 1 film-coated tablet

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Oral use

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6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

[To be completed nationally]

12. MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally]

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

[To be completed nationally]

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

<Invented name> 5 mg
<Invented name> 10 mg
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17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTER

1. NAME OF THE MEDICINAL PRODUCT

<Invented name> 5 mg film-coated tablets

<Invented name> 10 mg film-coated tablets

For multilingual blisters

<Invented name> 5 mg tablets
<Invented name> 10 mg tablets

dapagliflozin

2. NAME OF THE MARKETING AUTHORISATION HOLDER

[To be completed nationally]

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

Calendar pack
Mon.
Tue.
Wed.
Thu.
Fri.
Sat.
Sun.

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PACKAGE LEAFLET

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Package leaflet: Information for the patient

<Invented name> 5 mg film-coated tablets

<Invented name> 10 mg film-coated tablets
dapagliflozin

Read all of this leaflet carefully before you start taking this medicine because it contains
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,
even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side
effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What <Invented name> is and what it is used for
2. What you need to know before you take <Invented name>
3. How to take <Invented name>
4. Possible side effects
5. How to store <Invented name>
6. Contents of the pack and other information

1. What <Invented name> is and what it is used for

What <Invented name> is

<Invented name> contains the active substance dapagliflozin. It belongs to a group of medicines called
“sodium glucose co-transporter-2 (SGLT2) inhibitors”. They work by blocking the SGLT2 protein in
your kidney. By blocking this protein, blood sugar (glucose), salt (sodium) and water are removed
from your body via the urine.

What <Invented name> is used for

<Invented name> is used to treat:

˗ Type 2 diabetes
- in adults and children aged 10 years and older.
- if your type 2 diabetes cannot be controlled with diet and exercise.
- <Invented name> can be used on its own or together with other medicines to treat
diabetes.
- It is important to continue to follow the advice on diet and exercise given to you by your
doctor, pharmacist or nurse.

˗ Heart failure
- in adults (aged 18 years and older) when the heart does not pump blood as well as it
should.

˗ Chronic kidney disease

- in adults with reduced kidney function.

What is type 2 diabetes and how does <Invented name> help?

˗ In type 2 diabetes your body does not make enough insulin or is not able to use the insulin it

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makes properly. This leads to a high level of sugar in your blood. This can lead to serious
problems like heart or kidney disease, blindness, and poor circulation in your arms and legs.
˗ <Invented name> works by removing excess sugar from your body. It can also help prevent
heart disease.

What is heart failure and how does <Invented name> help?

˗ This type of heart failure occurs when the heart does not pump blood to the lungs and the rest of
the body as well as it should. This can lead to serious medical problems and need for hospital
care.
˗ The most common symptoms of heart failure are feeling breathless, feeling tired or very tired all
the time, and ankle swelling.
˗ <Invented name> helps protect your heart from getting worse and improves your symptoms. It
can lower the need to go to hospital and can help some patients to live longer.

What is chronic kidney disease and how does <Invented name> help?
˗ When you have chronic kidney disease, your kidneys may gradually lose their function. This
means they would not be able to clean and filter your blood the way they should. Loss of kidney
function can lead to serious medical problems and need for hospital care.
˗ <Invented name> helps protect your kidneys from losing their function. That can help some
patients to live longer.

2. What you need to know before you take <Invented name>

Do not take <Invented name>

- if you are allergic to dapagliflozin or any of the other ingredients of this medicine (listed in
section 6).

Warnings and precautions

Contact a doctor or the nearest hospital straight away:

Diabetic ketoacidosis:
˗ If you have diabetes and experience feeling sick or being sick, stomach pain, excessive thirst,
fast and deep breathing, confusion, unusual sleepiness or tiredness, a sweet smell to your breath,
a sweet or metallic taste in your mouth, or a different odour to your urine or sweat or rapid
weight loss.
˗ The above symptoms could be a sign of “diabetic ketoacidosis” – a rare but serious, sometimes
life-threatening problem you can get with diabetes because of increased levels of “ketone
bodies” in your urine or blood, seen in tests.
˗ The risk of developing diabetic ketoacidosis may be increased with prolonged fasting, excessive
alcohol consumption, dehydration, sudden reductions in insulin dose, or a higher need of insulin
due to major surgery or serious illness.
˗ When you are treated with <Invented name>, diabetic ketoacidosis can occur even if your blood
sugar is normal.
If you suspect you have diabetic ketoacidosis, contact a doctor or the nearest hospital straight away
and do not take this medicine.

Necrotising fasciitis of the perineum:

˗ Talk to your doctor immediately if you develop a combination of symptoms of pain, tenderness,
redness, or swelling of the genitals or the area between the genitals and the anus with fever or
feeling generally unwell. These symptoms could be a sign of a rare but serious or even life-
threatening infection, called necrotising fasciitis of the perineum or Fournier’s gangrene which

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destroys the tissue under the skin. Fournier’s gangrene has to be treated immediately.

Talk to your doctor, pharmacist or nurse before taking <Invented name>:

˗ if you have “type 1 diabetes” – the type that usually starts when you are young, and your body
does not produce any insulin. <Invented name> should not be used to treat this condition.
˗ if you have diabetes and have a kidney problem – your doctor may ask you to take additional or
a different medicine to control your blood sugar.
˗ if you have a liver problem – your doctor may start you on a lower dose.
˗ if you are on medicines to lower your blood pressure (anti-hypertensives) and have a history of
low blood pressure (hypotension). More information is given below under ‘Other medicines and
<Invented name>’.
˗ if you have very high levels of sugar in your blood which may make you dehydrated (lose too
much body fluid). Possible signs of dehydration are listed in section 4. Tell your doctor before
you start taking <Invented name> if you have any of these signs.
˗ if you have or develop nausea (feeling sick), vomiting or fever or if you are not able to eat or
drink. These conditions can cause dehydration. Your doctor may ask you to stop taking
<Invented name> until you recover to prevent dehydration.
˗ if you often get infections of the urinary tract.

If any of the above applies to you (or you are not sure), talk to your doctor, pharmacist or nurse before
taking <Invented name>.

Diabetes and foot care

If you have diabetes, it is important to check your feet regularly and adhere to any other advice
regarding foot care given by your health care professional.

Urine glucose
Because of how <Invented name> works, your urine will test positive for sugar while you are on this
medicine.

Children and adolescents

<Invented name> can be used in children aged 10 years and older for the treatment of type 2 diabetes.
No data are available in children below 10 years of age.

<Invented name> is not recommended for children and adolescents under 18 years of age for the
treatment of heart failure or for the treatment of chronic kidney disease, because it has not been
studied in these patients.

Other medicines and <Invented name>

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other
medicines.
Especially tell your doctor:
˗ if you are taking a medicine used to remove water from the body (diuretic).
˗ if you are taking other medicines that lower the amount of sugar in your blood such as insulin or
a “sulphonylurea” medicine. Your doctor may want to lower the dose of these other medicines,
to prevent you from getting low blood sugar levels (hypoglycaemia).
˗ if you are taking lithium because <Invented name> can lower the amount of lithium in your
blood.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask
your doctor or pharmacist for advice before taking this medicine.

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You should stop taking this medicine if you become pregnant, since it is not recommended during the
second and third trimesters of pregnancy. Talk to your doctor about the best way to control your blood
sugar while you are pregnant.

Talk to your doctor if you would like to or are breast-feeding before taking this medicine. Do not use
<Invented name> if you are breast-feeding. It is not known if this medicine passes into human breast
milk.

Driving and using machines

<Invented name> has no or negligible influence on the ability to drive and use machines.

Taking this medicine with other medicines called sulphonylureas or with insulin can cause too low
blood sugar levels (hypoglycaemia), which may cause symptoms such as shaking, sweating and
change in vision, and may affect your ability to drive and use machines.

Do not drive or use any tools or machines, if you feel dizzy taking <Invented name>.

<Invented name> contains lactose and sodium

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor
before taking this medicinal product.
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-
free’.

3. How to take <Invented name>

Always take this medicine exactly as your doctor has told you. Check with your doctor, pharmacist or
nurse if you are not sure.

How much to take

˗ The recommended dose is one 10 mg tablet each day.
˗ Your doctor may start you on a 5 mg dose if you have a liver problem.
˗ Your doctor will prescribe the strength that is right for you.

Taking this medicine

˗ Swallow the tablet with half a glass of water. The 10 mg tablet can be divided into equal doses
or to ease of swallowing.
˗ You can take your tablet with or without food.
˗ You can take the tablet at any time of the day. However, try to take it at the same time each day.
This will help you to remember to take it.

Your doctor may prescribe <Invented name> together with other medicine(s). Remember to take these
other medicine(s) as your doctor has told you. This will help get the best results for your health.

Diet and exercise can help your body use its blood sugar better. If you have diabetes, it is important to
stay on any diet and exercise program recommended by your doctor while taking <Invented name>.

If you take more <Invented name> than you should

If you take more <Invented name> tablets than you should, talk to a doctor or go to a hospital
immediately. Take the medicine pack with you.

If you forget to take <Invented name>

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What to do if you forget to take a tablet depends on how long it is until your next dose.
˗ If it is 12 hours or more until your next dose, take a dose of <Invented name> as soon as you
remember. Then take your next dose at the usual time.
˗ If it is less than 12 hours until your next dose, skip the missed dose. Then take your next dose at
the usual time.
˗ Do not take a double dose of <Invented name> to make up for a forgotten dose.

If you stop taking <Invented name>

Do not stop taking <Invented name> without talking to your doctor first. If you have diabetes, your
blood sugar may increase without this medicine.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Contact a doctor or the nearest hospital straight away if you have any of the following side
effects:

˗ angioedema, seen very rarely (may affect up to 1 in 10,000 people).

These are signs of angioedema:
- swelling of the face, tongue or throat
- difficulties swallowing
- hives and breathing problems

˗ diabetic ketoacidosis - this is rare in patients with type 2 diabetes (may affect up to 1 in 1,000
people).
These are the signs of diabetic ketoacidosis (see also section 2 Warnings and precautions):
- increased levels of “ketone bodies” in your urine or blood
- feeling sick or being sick
- stomach pain
- excessive thirst
- fast and deep breathing
- confusion
- unusual sleepiness or tiredness
- a sweet smell to your breath, a sweet or metallic taste in your mouth or a different odour
to your urine or sweat
- rapid weight loss
This may occur regardless of blood sugar level. Your doctor may decide to temporarily or permanently
stop your treatment with <Invented name>.

˗ necrotising fasciitis of the perineum or Fournier’s gangrene, a serious soft tissue infection of
the genitals or the area between the genitals and the anus, seen very rarely.

Stop taking <Invented name> and see a doctor as soon as possible if you notice any of the
following serious side effects:

˗ urinary tract infection, seen commonly (may affect up to 1 in 10 people).

These are signs of a severe infection of the urinary tract:
- fever and/or chills

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- burning sensation when passing water (urinating)

- pain in your back or side
Although uncommon, if you see blood in your urine, tell your doctor immediately.

Contact your doctor as soon as possible if you have any of the following side effects:

˗ low blood sugar levels (hypoglycaemia), seen very commonly (may affect more than 1 in 10
people) in patients with diabetes taking this medicine with a sulphonylurea or insulin. These are
the signs of low blood sugar:
- shaking, sweating, feeling very anxious, fast heart beat
- feeling hungry, headache, change in vision
- a change in your mood or feeling confused
Your doctor will tell you how to treat low blood sugar levels and what to do if you get any of the signs
above.

Other side effects when taking<Invented name>:

Common (may affect up to 1 in 10 people)
˗ genital infection (thrush) of your penis or vagina (signs may include irritation, itching, unusual
discharge or odour)
˗ back pain
˗ passing more water (urine) than usual or needing to pass water more often
˗ changes in the amount of cholesterol or fats in your blood (shown in tests)
˗ increases in the amount of red blood cells in your blood (shown in tests)
˗ decreases in creatinine renal clearance (shown in tests) in the beginning of treatment
˗ dizziness
˗ rash

Uncommon (may affect up to 1 in 100 people)

˗ loss of too much fluid from your body (dehydration, signs may include very dry or sticky
mouth, passing little or no urine or fast heartbeat)
˗ thirst
˗ constipation
˗ awakening from sleep at night to pass urine
˗ dry mouth
˗ weight decreased
˗ increases in creatinine (shown in laboratory blood tests) in the beginning of treatment
˗ increases in urea (shown in laboratory blood tests)

Very rare (may affect up to 1 in 10,000 people)

˗ inflammation of the kidneys (tubulointerstitial nephritis)

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects
not listed in this leaflet. You can also report side effects directly via the national reporting system
listed in Appendix V. By reporting side effects you can help provide more information on the safety of
this medicine.

5. How to store <Invented name>

Keep this medicine out of the sight and reach of children.

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 1.3.1 Dapagliflozin
SPC, Labeling and Package Leaflet Common

Do not use this medicine after the expiry date which is stated on the blister or carton after EXP. The
expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to
throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What <Invented name> contains

- The active substance is dapagliflozin.
<Invented name> 5 mg film-coated tablets
Each film-coated tablet contains 5 mg dapagliflozin (from dapagliflozin propanediol
monohydrate form).
<Invented name> 10 mg film-coated tablets
Each film-coated tablet contains 10 mg dapagliflozin (from dapagliflozin propanediol
monohydrate form).
- The other ingredients are:
- tablet core: microcrystalline cellulose, lactose monohydrate, hydroxypropylcellulose,
crospovidone (type A), microcrystalline cellulose (type 102) and sodium stearyl fumarate
- film coating: poly(vinyl alcohol), macrogol 3350, titanium dioxide (E171), talc and
yellow iron oxide (E172). See section 2 "<Invented name> contains lactose and sodium".

What <Invented name> looks like and contents of the pack

5 mg: Light brownish yellow, round, biconvex, film-coated tablets, marked with “5” on one side.
Tablet dimension: diameter approx. 7 mm.
10 mg: Light brownish yellow, oval, biconvex, film-coated tablets, scored on one side. One side of
score line is marked with “1” and the other with “0”. The tablet can be divided into equal doses. Tablet
dimension: approx. 13 x 6.5 mm.

<Invented name> is available in packs containing:

- 14, 28, 30, 98 or 100 film-coated tablets, in non-perforated blister.
- 14, 28 or 98 film-coated tablets, in non-perforated blister, calendar pack.
- 14 x 1, 28 x 1, 30 x 1, 98 x 1 or 100 x 1 film-coated tablets, in perforated unit dose blister.
- 14 x 1, 28 x 1 or 98 x 1 film-coated tablets, in perforated unit dose blister, calendar pack.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

[To be completed nationally]

This medicine is authorised in the Member States of the European Economic Area under the
following names:
[To be completed nationally]

This leaflet was last revised in

[To be completed nationally]

Detailed information on this medicine is available on the website of {name of Member State Agency
(link)}

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1.3.1 Dapagliflozin
SPC, Labeling and Package Leaflet Common

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