Edistride

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS



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1. NAME OF THE MEDICINAL PRODUCT

Edistride 5 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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

Excipient with known effect:
Each 5 mg tablet contains 25 mg of lactose anhydrous.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM 

Film-coated tablet (tablet).

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

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Type 2 diabetes mellitus
Edistride is indicated in adults 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.

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

Type 1 diabetes mellitus
Edistride is indicated in adults for the treatment of insufficiently controlled type 1 diabetes mellitus as 
an adjunct to insulin in patients with BMI ≥ 27 kg/m2, when insulin alone does not provide adequate 
glycaemic control despite optimal insulin therapy.

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).

Type 1 diabetes mellitus
Treatment with Edistride is to be initiated and supervised by specialists in type 1 diabetes.

The recommended dose is 5 mg once daily.

Dapagliflozin must only be administered as an adjunct to insulin. 



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Before initiating treatment with dapagliflozin:
 Risk factors for diabetic ketoacidosis (DKA) should be assessed (see section 4.4).
 It should be ensured that ketone levels are normal. If ketones are elevated (blood beta-

hydroxybutyrate reading greater than 0.6 mmol/L or urine ketones one plus (+)), treatment with 
dapagliflozin should not be started until the ketone levels are normal (see section 4.4).

 It should be ensured that the patient demonstrates the ability to monitor ketone levels.
 It is recommended that patients obtain several baseline ketone levels over one to two weeks 

prior to initiation of dapagliflozin therapy, and patients should become familiar with how their 
behaviours and circumstances affect their ketone levels.

 Patients should be informed, in a dedicated education session, on the risk of DKA, how to 
recognize DKA risk factors, signs or symptoms, how and when to monitor ketone levels and 
what actions to take at elevated ketone readings (see section 4.4).

 Correction of volume depletion prior to initiation of dapagliflozin is recommended in patients 
with this condition (see section 4.4).

In order to avoid hypoglycaemia with the first dose of dapagliflozin, a 20% reduction in the first 
mealtime bolus insulin may be considered. Subsequent bolus doses should be adjusted individually 
based on blood glucose results. No reduction in basal insulin is recommended when initiating 
dapagliflozin. Subsequently, basal insulin should be adjusted based on blood glucose results. When 
needed, insulin dose reduction should be done cautiously to avoid ketosis and DKA.

Ketone monitoring during treatment:
During the initial one to two weeks of treatment with dapagliflozin, ketones should be monitored on a 
regular basis, then the frequency of ketone level testing should be individualized, according to the 
patient's lifestyle and/or risk factors (see section 4.4).

Patients should be informed about what actions to take if ketone levels are elevated. The 
recommended actions are listed in Table 1. Measurement of blood ketone levels is preferred to urine.

Table 1

Clinical 
stage

Blood Ketone (beta-
hydroxybutyrate)

Urine Ketone Actions 

Ketonaemia 0.6-1.5 mmol/L Trace or Small 
+ 

The patient may need to take 
extra insulin and drink water. 
The patient should measure 
blood glucose and consider 
taking extra carbohydrates if the 
glucose levels are normal or 
low.

Ketone levels should be 
measured again after two hours.

The patient should immediately 
seek medical advice and stop 
taking dapagliflozin if levels 
persist and symptoms present.

Impending 
DKA

> 1.5-3.0 mmol/L Moderate 
++ 

The patient should immediately 
seek medical advice and stop 
taking dapagliflozin.

The patient may need to take 
extra insulin and drink water. 
The patient should measure 
blood glucose and consider 
taking extra carbohydrates if the 



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glucose levels are normal or 
low.

Ketone levels should be 
measured again after two hours.

Probable 
DKA

> 3.0 mmol/L Large to very large 
+++ / ++++ 

The patient should go to 
emergency department without 
delay and stop taking 
dapagliflozin.

The patient may need to take 
extra insulin and drink water. 
The patient should measure 
blood glucose and consider 
taking extra carbohydrates if the 
glucose levels are normal or 
low.

Special populations
Renal impairment
Edistride should not be initiated in patients with a glomerular filtration rate [GFR] < 60 mL/min and 
should be discontinued at GFR persistently below 45 mL/min (see sections 4.4, 4.8, 5.1 and 5.2).

No dose adjustment is required based on renal function.

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 when indicated (see sections 4.1 of the 10 mg SmPC, 4.4 and 5.2).

Elderly (≥ 65 years)
In general, no dose adjustment is recommended based on age. Renal function and risk of volume 
depletion should be taken into account (see sections 4.4 and 5.2).

Paediatric population
The safety and efficacy of dapagliflozin in children aged 0 to < 18 years have not yet been established. 
No data are available.

Method of administration
Edistride can be taken orally once daily at any time of day with or without food. Tablets are to be 
swallowed whole.

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

Renal impairment
The glycaemic efficacy of dapagliflozin is dependent on renal function, and efficacy is reduced in 
patients who have moderate renal impairment and is likely absent in patients with severe renal 
impairment (see section 4.2). In subjects with moderate renal impairment (GFR < 60 mL/min), a 
higher proportion of subjects treated with dapagliflozin had adverse reactions of increase in creatinine, 
phosphorus, parathyroid hormone (PTH) and hypotension, compared with placebo.



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Edistride should not be initiated in patients with a GFR < 60 mL/min and should be discontinued at 
GFR persistently below 45 mL/min. Edistride has not been studied in severe renal impairment 
(GFR < 30 mL/min) or end-stage renal disease (ESRD).

Monitoring of renal function is recommended as follows:
• Prior to initiation of dapagliflozin and at least yearly, thereafter (see sections 4.2, 4.8, 5.1 and 

5.2).
• Prior to initiation of concomitant medicinal products that may reduce renal function and 

periodically thereafter.
• For renal function with GFR < 60 mL/min, at least 2 to 4 times per year.

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), 
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
Sodium-glucose co-transporter 2 (SGLT2) inhibitors should be used with caution in patients with 
increased risk of DKA. Patients who may be at higher risk of DKA include patients with a low 
beta-cell function reserve (e.g. type 1 diabetes patients, 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.

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.

Before initiating dapagliflozin, factors in the patient history that may predispose to ketoacidosis should 
be considered.

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.

Type 2 diabetes mellitus
Rare cases of DKA, including life-threatening and fatal cases, have been reported in patients treated 
with 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).



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

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.

Type 1 diabetes mellitus
In type 1 diabetes mellitus studies with dapagliflozin, patients had a higher number of DKA events 
compared with the placebo group (see section 4.8). 

Before initiating dapagliflozin
Before starting treatment, patients should be evaluated with respect to DKA risk. 
Dapagliflozin should not be initiated when patients are at a higher risk of DKA, such as:
 Patients with low insulin needs.
 Patient not on optimal insulin dose or who have recent issues with noncompliance or recurrent 

errors with insulin dosing and who are unlikely to maintain adequate insulin dosing.
 Patients with increased insulin requirements due to acute medical illness or surgery. 
 Patients who insist on maintaining caloric restriction, carbohydrate restriction or ketogenic diet 

or who chronically under-dose insulin (e.g. in order to remain in a lipolytic state). 
 Patients with recent or recurrent history of DKA. 
 Patients with elevated ketones levels (BHB reading is greater than 0.6 mmol/L or urine ketones 

one plus (+)). If ketones are elevated (blood beta-hydroxybutyrate reading 0.6 mmol/L or 
greater), treatment with dapagliflozin should not be started until the ketone levels are normal 
(see section 4.2).

 Patients unable or unwilling to monitor ketones.
 Patients with excessive alcohol consumption or who use illicit drugs.

Patients using an insulin infusion pump have a higher risk of DKA and should be experienced with 
pump use, common trouble-shooting strategies when interruptions of insulin delivery via pump occur 
(issues with insertion site, clogged tubing, empty reservoir, etc.) and use of supplemental insulin 
injections with pen or syringe as needed in case of pump failure.  Patients should consider monitoring 
ketones levels three to four hours after changing pump materials. Patients using a pump should also 
check their ketone levels with any suspected insulin interruption, regardless of blood glucose levels. 
Insulin injections should be given within 2 hours of an unexplained high blood glucose/ketone value 
and dapagliflozin treatment should be interrupted.

 The patients should be educated on the risk of DKA, emphasizing that DKA could occur even 
when blood glucose levels are below 14 mmol/L (250 mg/dL). 

 The patient should be informed how to recognize the risk factors which can predispose to 
ketosis (including starvation ketosis) and DKA and how to recognize DKA signs or symptoms.

 Dapagliflozin should only be given to patients who are able to monitor ketone levels and are 
educated in when it is most appropriate to do so. 

 Dapagliflozin should only be given to patients with access to ketone testing materials and 
immediate access to a clinician if blood or urine ketones are elevated.

 The patients should be educated on what actions to take when ketosis/DKA is suspected and 
when to discontinue dapagliflozin therapy (see section 4.2). 

 DKA should be treated as per standard of care. Supplemental carbohydrate may be required in 
addition to hydration and additional rapid insulin (see Table 1 in section 4.2).

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

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.



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During treatment with dapagliflozin:
 Insulin therapy should be continuously optimised.  
 When needed to prevent hypoglycaemia, insulin dose reduction should be done cautiously to 

avoid ketosis and DKA (see section 4.2).
 In the event of a marked reduction of insulin need, discontinuation of dapagliflozin should be 

considered.

Ketone monitoring:
The patient should be advised to test their ketone level (urine or blood) if signs or symptoms of 
ketoacidosis occur. Measurement of blood ketone levels is preferred to urine. Ketones should be 
monitored on a regular basis during the initial one to two weeks, then the frequency of ketone level 
testing should be individualised, according to the patient's lifestyle and/or risk factors (see section 4.2).
Ketone levels should be also checked in situations that may predispose to or increase risk of DKA. 

Patients must be informed about what actions to take if ketone levels are elevated. The recommended 
actions are listed in Table 1 (see section 4.2).

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

Urinary tract infections
Urinary glucose excretion may be associated with an increased risk of urinary tract infection; 
therefore, temporary interruption of dapagliflozin should be considered when treating 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
There is no experience in clinical studies with dapagliflozin in NYHA class IV.

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

Urine laboratory assessments
Due to its mechanism of action, patients taking Edistride will test positive for glucose in their urine.



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

4.5 Interaction with other medicinal products and other forms of interaction

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

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).

In patients with type 1 diabetes mellitus and a known risk of frequent or severe hypoglycaemia, it may 
be necessary to reduce the insulin dose at the time of initiating treatment with dapagliflozin to 
decrease the risk of hypoglycaemia. When needed, insulin dose reduction should be done cautiously to 
avoid ketosis and DKA (see section 4.2).

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
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

Edistride 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 (see section 5.1), 8,574 patients received 
dapagliflozin 10 mg and 8,569 received placebo for a median 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.

Type 1 diabetes mellitus
In two placebo-controlled studies in subjects with type 1 diabetes mellitus, 548 subjects were treated 
with dapagliflozin 5 mg plus adjustable insulin and 532 were treated with placebo plus adjustable 
insulin.



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The most frequently reported adverse reactions associated with dapagliflozin in patients with type 1 
diabetes mellitus were genital infections, which were more frequent in females. Diabetic ketoacidosis 
was reported with common frequency. See “Description of selected adverse reactions” and section 4.4.

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 2. Adverse reactions in placebo-controlled clinical studiesa and postmarketing experience
System organ 
class

Very common Common* Uncommon** Rare Very rare

Infections and 
infestations

Vulvovaginitis
, balanitis and 
related genital 
infections*,b,c

Urinary tract 
infection*,b,d

Fungal 
infection**

Necrotising 
fasciitis of 
the 
perineum 
(Fournier's 
gangrene)b,i

Metabolism and 
nutrition 
disorders

Hypoglycaemia 
(when used 
with SU or 
insulin)b

Diabetic 
ketoacidosis
(when used in 
type 1 diabetes 
mellitus)b,i,k

Volume 
depletionb,e

Thirst**

Diabetic 
ketoacidosis
(when used 
in type 2 
diabetes 
mellitus)b,i,l

Nervous system 
disorders

Dizziness

Gastrointestinal 
disorders

Constipation**

Dry mouth**

Skin and 
subcutaneous 
tissue disorders

Rashj Angioedema

Musculoskeletal 
and connective 
tissue disorders

Back pain*

Renal and 
urinary 
disorders

Dysuria
Polyuria*,f

Nocturia**

Reproductive 
system and 
breast 
disorders

Vulvovaginal 
pruritus**

Pruritus 
genital**

Investigations Haematocrit 
increasedg

Creatinine 
renal clearance 
decreased 
during initial 
treatmentb

Dyslipidaemiah

Blood 
creatinine 
increased 
during initial 
treatment**,b

Blood urea 
increased**

Weight 
decreased**

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



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vulvovaginitis, balanitis candida, genital candidiasis, genital infection, genital infection male, penile infection, 
vulvitis, vaginitis bacterial, vulval abscess.

dUrinary tract infection includes the following preferred terms, listed in order of frequency reported: urinary tract 
infection, cystitis, Escherichia urinary tract infection, genitourinary tract infection, pyelonephritis, trigonitis, 
urethritis, kidney infection and prostatitis.

eVolume depletion includes, e.g. the predefined preferred terms: dehydration, hypovolaemia, hypotension.
fPolyuria includes the preferred terms: pollakiuria, polyuria, urine output increased.
gMean changes from baseline in haematocrit were 2.30% for dapagliflozin 10 mg versus –0.33% for placebo. 
Haematocrit values >55% were reported in 1.3% of the subjects treated with dapagliflozin 10 mg versus 0.4% 
of placebo subjects.

hMean percent change from baseline for dapagliflozin 10 mg versus placebo, respectively, was: total 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%.

iSee section 4.4
jAdverse 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.

kFrequency of adverse reaction was identified from the full study population in 2 placebo-controlled studies in 
subjects with type 1 diabetes mellitus.

lReported in the cardiovascular outcomes study in patients with type 2 diabetes. 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.

Description of selected adverse reactions
Clinical studies in type 2 diabetes mellitus
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 dapagliflozin cardiovascular outcomes study, the number of patients with serious adverse events 
of genital infections were few and balanced: 2 patients in each of the dapagliflozin and placebo 
groups.

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 dapagliflozin cardiovascular outcomes 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 each study.

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).



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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).

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 dapagliflozin cardiovascular outcomes 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.

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 dapagliflozin cardiovascular outcomes 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 ACE-I/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.

Diabetic ketoacidosis
In the dapagliflozin cardiovascular outcomes 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).

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 dapagliflozin cardiovascular outcomes 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.

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). This 



13

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 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 ≤ 0.5 mg/dL from baseline. The increases in creatinine were generally transient 
during continuous treatment or reversible after discontinuation of treatment.

In the dapagliflozin cardiovascular outcomes 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.

Clinical studies in type 1 diabetes mellitus
The safety profile of dapagliflozin in subjects with type 1 diabetes mellitus was similar to the known 
safety profile of dapagliflozin in subjects with type 2 diabetes mellitus, with the exception of a higher 
number of DKA events in dapagliflozin-treated subjects in the type 1 diabetes mellitus studies.

Diabetic ketoacidosis
In the two placebo-controlled clinical studies of dapagliflozin in type 1 diabetes mellitus, patients were 
advised to monitor blood ketones in case of suspected symptoms of DKA and seek medical 
advice/attention if their self-measured blood ketone reading was ≥ 0.6 mmol/L. In the pooled 52-week 
data, events of DKA were reported in 22 (4.0%) patients in the dapagliflozin 5 mg group and 6 (1.1%) 
patients in the placebo group, with corresponding incidence rates per 100 patient years of 4.62 for 
dapagliflozin 5 mg and 1.27 for placebo. DKA events occurred evenly distributed over the clinical 
study period. Inadequate insulin doses (missed insulin dose or insulin pump failure) were the most 
common precipitating factors. 6 of 23 events of DKA in the dapagliflozin 5 mg group occurred in 
patients with blood glucose in the euglycaemic range (< 14 mmol/L or 250 mg/dL).

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

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.

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.



14

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.

The SGLT2 is selectively expressed in the kidney with no expression detected in more than 70 other 
tissues including liver, skeletal muscle, adipose tissue, breast, bladder and brain. SGLT2 is the 
predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into 
the circulation. Despite the presence of hyperglycaemia in type 2 diabetes, reabsorption of filtered 
glucose continues. 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. 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 Edistride.

Urinary glucose excretion (glucuresis) induced by dapagliflozin is associated with caloric loss and 
reduction in weight. Inhibition of glucose and sodium co-transport by dapagliflozin is also associated 
with mild diuresis and transient natriuresis.

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 
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
Both improvement of glycaemic control and reduction of cardiovascular morbidity and mortality are 
an integral part of the treatment of type 2 diabetes.

Fourteen double-blind, randomised, controlled clinical studies were conducted with 7,056 subjects 
with type 2 diabetes to evaluate the glycaemic efficacy and safety of Edistride; 4,737 subjects in these 



15

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 Edistride 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 3).

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 3. Results at Week 24 (LOCFa) of a placebo-controlled study of dapagliflozin as 
monotherapy

Monotherapy 
Dapagliflozin

10 mg
Placebo

Nb 70 75
HbA1c (%)
Baseline (mean)

Change from baselinec

Difference from placeboc

    (95% CI)

8.01
-0.89
-0.66*

(-0.96, -0.36)

7.79
-0.23

Subjects (%) achieving:
HbA1c < 7%

Adjusted for baseline 50.8§ 31.6
Body weight (kg)

Baseline (mean)
Change from baselinec

Difference from placeboc

    (95% CI)

94.13
-3.16
-0.97

(-2.20, 0.25)

88.77
-2.19

aLOCF: Last observation (prior to rescue for rescued subjects) carried forward
bAll randomised subjects who took at least one dose of double-blind study medication during the short-term 

double-blind period
cLeast 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), 
Edistride 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 4). At Week 104, adjusted mean change from 



16

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 4. 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)
Change from baselinec

Difference from glipizide + metforminc

    (95% CI)

7.69
-0.52
0.00d

(-0.11, 0.11)

7.74
-0.52

Body weight (kg)
Baseline (mean)
Change from baselinec

Difference from glipizide + metforminc

    (95% CI)

88.44
-3.22
-4.65*

(-5.14, -4.17)

87.60
1.44

aLOCF: Last observation carried forward
bRandomised and treated subjects with baseline and at least 1 post-baseline efficacy measurement
cLeast squares mean adjusted for baseline value
dNon-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 5, 6 and 7).

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.



17

Table 5. 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
10 mg

Placebo Dapagliflozin
10 mg

Placebo

Nb 135 137 223 224

HbA1c (%)
Baseline (mean)
Change from
  baselinec

Difference from
  placeboc

    (95% CI)

7.92

-0.84

-0.54*

(-0.74, -0.34)

8.11

-0.30

7.90

-0.45

-0.48*

(-0.62, -0.34)

7.97

0.04

Subjects (%) achieving:
HbA1c < 7%

Adjusted for baseline

40.6** 25.9

Body weight (kg)
Baseline (mean)
Change from
  baselinec

Difference from
  placeboc

    (95% CI)

86.28

-2.86

-1.97*

(-2.63, -1.31)

87.74

-0.89

91.02

-2.14

-1.89*

(-2.37, -1.40)

89.23

-0.26

1Metformin ≥ 1500 mg/day; 
2sitagliptin 100 mg/day
aLOCF: Last observation (prior to rescue for rescued subjects) carried forward
bAll randomised subjects who took at least one dose of double-blind study medicinal product during the 

short-term double-blind period
cLeast 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



18

Table 6. 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
(glimepiride1)

Sulphonylurea
+ Metformin2

Dapagliflozin
10 mg

Placebo Dapagliflozin
10 mg

Placebo

Na 151 145 108 108

HbA1c (%)b

Baseline (mean)
Change from baselinec

Difference from placeboc

    (95% CI)

8.07
-0.82
-0.68*

(-0.86, -0.51)

8.15
-0.13

8.08
-0.86

−0.69*

(−0.89, −0.49)

8.24
-0.17

Subjects (%) achieving:
HbA1c < 7% (LOCF)d

Adjusted for baseline 31.7* 13.0 31.8* 11.1

Body weight (kg) 
(LOCF)d

Baseline (mean)
Change from baselinec

Difference from placeboc

    (95% CI)

80.56
-2.26
-1.54*

(-2.17, -0.92)

80.94
-0.72

88.57
-2.65

−2.07*

(−2.79, −1.35)

90.07
-0.58

1glimepiride 4 mg/day; 
2Metformin (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.
aRandomised and treated patients with baseline and at least 1 post-baseline efficacy measurement.
bColumns 1 and 2, HbA1c analysed using LOCF (see footnote d); Columns 3 and 4, HbA1c analysed using 

LRM (see footnote e)
cLeast squares mean adjusted for baseline value
dLOCF: Last observation (prior to rescue for rescued subjects) carried forward
eLRM: Longitudinal repeated measures analysis
*p-value < 0.0001 versus placebo + oral glucose-lowering medicinal product(s)



19

Table 7. 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
+ insulin

± oral glucose-lowering 
medicinal products2

Placebo
+ insulin

± oral glucose-lowering 
medicinal products2

Nb 194 193
HbA1c (%)

Baseline (mean)
Change from baselinec

Difference from placeboc

    (95% CI)

8.58
-0.90
-0.60*

(-0.74, -0.45)

8.46
-0.30

Body weight (kg)
Baseline (mean)
Change from baselinec

Difference from placeboc

    (95% CI)

94.63
-1.67
-1.68*

(-2.19, -1.18)

94.21
0.02

Mean daily insulin dose (IU)1

Baseline (mean)
Change from baselinec

Difference from placeboc

    (95% CI)
Subjects with mean daily 
insulin dose reduction of at 
least 10% (%)

77.96
-1.16
-6.23*

(-8.84, -3.63)

19.7**

73.96
5.08

11.0
aLOCF: Last observation (prior to or on the date of the first insulin up-titration, if needed) carried forward
bAll randomised subjects who took at least one dose of double-blind study medicinal product during the short-

term double-blind period
cLeast 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
1Up-titration of insulin regimens (including short-acting, intermediate, and basal insulin) was only allowed if 

subjects met pre-defined FPG criteria.
2Fifty 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 8), and led to 
greater reductions in fasting plasma glucose (FPG) (compared to the individual components) and body 
weight (compared to metformin).



20

Table 8. Results at Week 24 (LOCFa) in an active-controlled study of dapagliflozin and 
metformin combination therapy in drug-naive patients

Parameter

Dapagliflozin 10 mg 
+

Metformin

Dapagliflozin 10 
mg

Metformin

Nb 211b 219b 208b

HbA1c (%)
Baseline (mean)
Change from baselinec

Difference from dapagliflozinc

    (95% CI)
Difference from metforminc

    (95% CI)

9.10
-1.98

−0.53*

(−0.74, −0.32)
−0.54*

(−0.75, −0.33)

9.03
-1.45

−0.01
(−0.22, 0.20)

9.03
-1.44

aLOCF: last observation (prior to rescue for rescued patients) carried forward.
bAll randomised patients who took at least one dose of double-blind study medication during the short-term 
double-blind period.
cLeast squares mean adjusted for baseline value.
*p-value <0.0001.

Combination therapy with prolonged-release exenatide
In a 28-week, double-blind, active comparator-controlled study, the combination of dapagliflozin 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 9).

Table 9. 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 
QD

+

Prolonged-release 
exenatide 2 mg QW

Dapagliflozin 10 mg 
QD

+

Placebo QW

Prolonged-release 
exenatide 2 mg 

QW

+

Placebo QD

N 228 230 227

HbA1c (%)
Baseline (mean) 9.29 9.25 9.26
Change from baselinea -1.98 -1.39 -1.60

Mean difference in change 
from baseline between 
combination and single 
medicinal product (95% CI)

-0.59*

(-0.84, -0.34)

-0.38**

(-0.63, -0.13)

Subjects (%) achieving 
HbA1c 7%

44.7 19.1 26.9

Body weight (kg)
Baseline (mean) 92.13 90.87 89.12
Change from baseline a -3.55 -2.22 -1.56

Mean difference in change 
from baseline between 
combination and single 
medicinal product (95% CI)

-1.33*

(-2.12, -0.55)

-2.00*

(-2.79, -1.20)

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



21

aAdjusted 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 
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 5 and 6). 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 4) 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 9).

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 Edistride plus metformin showed a numerical decrease in 
visceral adipose tissue compared with placebo plus metformin treatment in a magnetic resonance 
imaging substudy.



22

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 
(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 10).

Table 10. 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

Dapagliflozina

10 mg
Placeboa

Nb 159 161
HbA1c (%)
Baseline (mean) 8.35 8.03
Change from baselineb -0.37 -0.03
Difference from placebob

    (95% CI)
-0.34*

(-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 
placeboc

    (95% CI)

-1.43*

(-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).



23

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 (urine albumin to creatinine ratio [UACR] ≥ 30 to ≤ 300 mg/g or > 300 mg/g, 
respectively).

Most patients (98%) used one or more diabetic medications 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.



24

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.

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 renal disease (dialysis ≥ 90 days or kidney transplantation, sustained confirmed eGFR < 15 mL/min/1.73 m2) 
and/or renal or cardiovascular death.



25

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

The hazard ratio for time to nephropathy (sustained eGFR decrease, end-stage renal 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 (hazard ratio 0.79 
[95% CI 0.72, 0.87]) and led to greater regression of macroalbuminuria (hazard ratio 1.82
[95% CI 1.51, 2.20]) compared with placebo.

Type 1 diabetes mellitus
Dapagliflozin as an adjunct to adjustable insulin was studied in two 24-week randomised, double-
blind, placebo-controlled clinical studies with a 28-week extension to evaluate the efficacy and safety 
in adult patients with type 1 diabetes mellitus and inadequate glycaemic control (defined as 
HbA1c ≥ 7.5%) on insulin alone. Following an 8-week lead-in period to optimise each patient’s 
diabetes management (glycaemic control including hyperglycaemia and hypoglycaemia, diet and 
exercise patterns), a total of 1,646 patients with HbA1c ≥ 7.5% and ≤ 10.5% were randomised to 5 mg 
dapagliflozin once daily, 10 mg dapagliflozin once daily or placebo once daily. Throughout the study, 
insulin dose was adjusted as deemed appropriate. 

Glycaemic control
At Week 24, treatment with dapagliflozin once daily provided statistically significant improvements in 
HbA1c compared with placebo (Table 11). This finding was consistent across subgroups. At Week 52, 
adjusted mean changes from baseline in HbA1c relative to placebo were -0.33% and -0.20% for 
patients treated with dapagliflozin 5 mg, in the two studies, respectively. Treatment with dapagliflozin 
was not associated with an increase in percentage of patients with hypoglycaemic events compared 
with placebo. The number of patients with severe hypoglycaemia was balanced across treatment 
groups (6.9% and 7.5% at Week 24 in the dapagliflozin 5 mg and placebo groups, respectively).

The percentage of patients achieving ≥ 0.5% reductions in HbA1c without severe hypoglycaemia was 
significantly higher in patients treated with dapagliflozin compared with placebo (Table 11).

Table 11. Results at Week 24 of two placebo-controlled clinical studies of dapagliflozin as an 
adjunct to insulin in adults with type 1 diabetes mellitus

Study MB102229 Study MB102230

Efficacy Parameter Dapagliflozin
5 mg 

+ Insulin

Placebo 
+ Insulin

Dapagliflozin
5 mg

+ Insulin

Placebo 
+ Insulin

N=259 N=260 N=271 N=272

HbA1c (%)

Baseline (mean) 8.52 8.50 8.45 8.40

Change from baseline -0.45 -0.03 -0.34 0.03

Difference from placebo -0.42* -0.37*

    95% CI (-0.56, -0.28) (-0.49, -0.26)



26

Study MB102229 Study MB102230

Efficacy Parameter Dapagliflozin
5 mg 

+ Insulin

Placebo 
+ Insulin

Dapagliflozin
5 mg

+ Insulin

Placebo 
+ Insulin

Subjects (%) achieving ≥ 0.5% 
reductions in HbA1c without 
severe hypoglycaemia

49.6* 25.3 39.5* 20.1

Body weight (kg)

Baseline (mean) 81.67 84.42 79.22 79.03

Change from baseline -2.84 0.15 -2.50 0.06

Difference from placebo -2.96* -2.56*

    95% CI (-3.63, -2.28) (-3.12, -2.00)

* p < 0.0001 versus placebo

Blood glucose variability
The adjusted mean changes for dapagliflozin 5 mg relative to placebo in the mean amplitude of 
glucose excursion from baseline to Week 24 were -0.96 mmol/L (-17.30 mg/dL) and -0.55 mmol/L 
(-9.85 mg/dL) in the two studies, respectively (p < 0.0001).

Statistically significant increases in the percentage of glucose readings falling within the range of 
> 70 mg/dL to ≤ 180 mg/dL from baseline to Week 24 for dapagliflozin 5 mg relative to placebo were 
+9.11% and +9.02% in the two studies, respectively (p < 0.0001). This increase was not accompanied 
by any increase in the percentage of 24-hour glucose readings < 70 mg/dL. 

Insulin dose
Statistically significant (p < 0.0001) differences in percent reduction of total insulin dose from 
baseline for dapagliflozin 5 mg relative to placebo at Week 24 were -8.80% and -10.78% in the two 
studies, respectively.

Body weight
Statistically significant reductions in body weight were demonstrated for dapagliflozin compared with 
placebo (Table 11). Patients treated with dapagliflozin exhibited continuous weight loss over the 
24-week period. At Week 52, the adjusted mean changes in body weight from baseline for 
dapagliflozin 5 mg relative to placebo were -2.56 kg and -3.50 kg, in the two studies, respectively.

Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with 
dapagliflozin in one or more subsets of the paediatric population in the treatment of type 2 diabetes 
mellitus and type 1 diabetes mellitus (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, Edistride can be administered with or without food.



27

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 
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.

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 in the paediatric population have not been studied.

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.



28

Body weight
Dapagliflozin exposure was found to decrease with increased weight. Consequently, low-weight 
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 (E460i)
Lactose
Crospovidone (E1202)
Silicon dioxide (E551)



29

Magnesium stearate (E470b)

Film-coating
Polyvinyl alcohol (E1203)
Titanium dioxide (E171)
Macrogol 3350
Talc (E553b)
Iron oxide yellow (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Alu/Alu blister
Pack sizes of 14, 28 and 98 film-coated tablets in non-perforated calendar blisters
Pack sizes of 30x1 and 90x1 film-coated tablets in perforated unit dose blisters

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

7. MARKETING AUTHORISATION HOLDER

AstraZeneca AB
SE-151 85 Södertälje
Sweden

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/15/1052/001 14 film-coated tablets
EU/1/15/1052/002 28 film-coated tablets
EU/1/15/1052/003 98 film-coated tablets
EU/1/15/1052/004 30 x 1 (unit dose) film-coated tablets
EU/1/12/1052/005 90 x 1 (unit dose) film-coated tablets

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 09 November 2015



30

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu



31

1. NAME OF THE MEDICINAL PRODUCT

Edistride 10 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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

Excipient with known effect:
Each 10 mg tablet contains 50 mg of lactose anhydrous.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM 

Film-coated tablet (tablet).

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

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Edistride is indicated in adults 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.

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

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).

Special populations
Renal impairment
Edistride should not be initiated in patients with a glomerular filtration rate [GFR] < 60 mL/min and 
should be discontinued at GFR persistently below 45 mL/min (see sections 4.4, 4.8, 5.1 and 5.2).

No dose adjustment is required based on renal function.

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).



32

Elderly (≥ 65 years)
In general, no dose adjustment is recommended based on age. Renal function and risk of volume 
depletion should be taken into account (see sections 4.4 and 5.2).

Paediatric population
The safety and efficacy of dapagliflozin in children aged 0 to < 18 years have not yet been established. 
No data are available.

Method of administration
Edistride can be taken orally once daily at any time of day with or without food. Tablets are to be 
swallowed whole.

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

Renal impairment
The glycaemic efficacy of dapagliflozin is dependent on renal function, and efficacy is reduced in 
patients who have moderate renal impairment and is likely absent in patients with severe renal 
impairment (see section 4.2). In subjects with moderate renal impairment (GFR < 60 mL/min), a 
higher proportion of subjects treated with dapagliflozin had adverse reactions of increase in creatinine, 
phosphorus, parathyroid hormone (PTH) and hypotension, compared with placebo.

Edistride should not be initiated in patients with a GFR < 60 mL/min and should be discontinued at 
GFR persistently below 45 mL/min. Edistride has not been studied in severe renal impairment 
(GFR < 30 mL/min) or end-stage renal disease (ESRD).

Monitoring of renal function is recommended as follows:
• Prior to initiation of dapagliflozin and at least yearly, thereafter (see sections 4.2, 4.8, 5.1 and 

5.2).
• Prior to initiation of concomitant medicinal products that may reduce renal function and 

periodically thereafter.
• For renal function with GFR < 60 mL/min, at least 2 to 4 times per year.

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), 
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).



33

Diabetic ketoacidosis
Sodium-glucose co-transporter 2 (SGLT2) inhibitors should be used with caution in patients with 
increased risk of diabetic ketoacidosis (DKA). Patients who may be at higher risk of DKA include 
patients with a low beta-cell function reserve (e.g. type 1 diabetes patients, 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.

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.

Before initiating dapagliflozin, factors in the patient history that may predispose to ketoacidosis should 
be considered.

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.

Type 2 diabetes mellitus
Rare cases of DKA, including life-threatening and fatal cases, have been reported in patients treated 
with 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).

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

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.

Type 1 diabetes mellitus
In type 1 diabetes mellitus studies with dapagliflozin, DKA was reported with common frequency. 
Dapagliflozin 10 mg 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, Forxiga should be discontinued and prompt treatment (including antibiotics and 
surgical debridement) should be instituted.

Urinary tract infections
Urinary glucose excretion may be associated with an increased risk of urinary tract infection; 
therefore, temporary interruption of dapagliflozin should be considered when treating pyelonephritis 
or urosepsis.



34

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
There is no experience in clinical studies with dapagliflozin in NYHA class IV.

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

Urine laboratory assessments
Due to its mechanism of action, patients taking Edistride will test positive for glucose in their urine.

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

4.5 Interaction with other medicinal products and other forms of interaction

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

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.



35

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
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.

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

Edistride 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.



36

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 (see section 5.1), 8,574 patients received 
dapagliflozin 10 mg and 8,569 received placebo for a median 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.

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 
class

Very common Common* Uncommon** Rare Very rare

Infections and 
infestations

Vulvovaginitis, 
balanitis and 
related genital 
infections*,b,c

Urinary tract 
infection*,b,d

Fungal 
infection**

Necrotising 
fasciitis of 
the 
perineum 
(Fournier's 
gangrene)b,i

Metabolism and 
nutrition 
disorders

Hypoglycaemia 
(when used 
with SU or 
insulin)b

Volume 
depletionb,e

Thirst**

Diabetic 
ketoacidosisb,i,k

Nervous system 
disorders

Dizziness

Gastrointestinal 
disorders

Constipation**

Dry mouth**

Skin and 
subcutaneous 
tissue disorders

Rashj Angioedema

Musculoskeletal 
and connective 
tissue disorders

Back pain*

Renal and 
urinary 
disorders

Dysuria
Polyuria*,f

Nocturia**

Reproductive 
system and 
breast 
disorders

Vulvovaginal 
pruritus**

Pruritus 
genital**

Investigations Haematocrit 
increasedg

Creatinine 
renal clearance 
decreased 
during initial 
treatmentb

Dyslipidaemiah

Blood 
creatinine 
increased 
during initial 
treatment**,b

Blood urea 
increased**

Weight 
decreased**



37

aThe table shows up to 24-week (short-term) data regardless of glycaemic rescue.
bSee corresponding subsection below for additional information.
cVulvovaginitis, balanitis and related genital infections includes, e.g. the predefined preferred terms: 
vulvovaginal mycotic infection, vaginal infection, balanitis, genital infection fungal, vulvovaginal candidiasis, 
vulvovaginitis, balanitis candida, genital candidiasis, genital infection, genital infection male, penile infection, 
vulvitis, vaginitis bacterial, vulval abscess.

dUrinary tract infection includes the following preferred terms, listed in order of frequency reported: urinary tract 
infection, cystitis, Escherichia urinary tract infection, genitourinary tract infection, pyelonephritis, trigonitis, 
urethritis, kidney infection and prostatitis.

eVolume depletion includes, e.g. the predefined preferred terms: dehydration, hypovolaemia, hypotension.
fPolyuria includes the preferred terms: pollakiuria, polyuria, urine output increased.
gMean changes from baseline in haematocrit were 2.30% for dapagliflozin 10 mg versus –0.33% for placebo. 
Haematocrit values >55% were reported in 1.3% of the subjects treated with dapagliflozin 10 mg versus 0.4% 
of placebo subjects.

hMean percent change from baseline for dapagliflozin 10 mg versus placebo, respectively, was: total 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%.

iSee section 4.4
jAdverse 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.

kReported in the cardiovascular outcomes study in patients with type 2 diabetes. 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.

Description of selected adverse reactions
Clinical studies in type 2 diabetes mellitus
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 dapagliflozin cardiovascular outcomes study, the number of patients with serious adverse events 
of genital infections were few and balanced: 2 patients in each of the dapagliflozin and placebo 
groups.

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 dapagliflozin cardiovascular outcomes 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 each study.

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 



38

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).

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 dapagliflozin cardiovascular outcomes 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.

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 dapagliflozin cardiovascular outcomes 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 ACE-I/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.

Diabetic ketoacidosis
In the dapagliflozin cardiovascular outcomes 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).

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 dapagliflozin cardiovascular outcomes 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.



39

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). 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 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 ≤ 0.5 mg/dL from baseline. The increases in creatinine were generally transient 
during continuous treatment or reversible after discontinuation of treatment.

In the dapagliflozin cardiovascular outcomes 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.

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

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.

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.

The SGLT2 is selectively expressed in the kidney with no expression detected in more than 70 other 
tissues including liver, skeletal muscle, adipose tissue, breast, bladder and brain. SGLT2 is the 
predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into 
the circulation. Despite the presence of hyperglycaemia in type 2 diabetes, reabsorption of filtered 
glucose continues. Dapagliflozin improves both fasting and post-prandial plasma glucose levels by 



40

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. 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 Edistride.

Urinary glucose excretion (glucuresis) induced by dapagliflozin is associated with caloric loss and 
reduction in weight. Inhibition of glucose and sodium co-transport by dapagliflozin is also associated 
with mild diuresis and transient natriuresis.

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 
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
Both improvement of glycaemic control and reduction of cardiovascular morbidity and mortality are 
an integral part of the treatment of type 2 diabetes.

Fourteen double-blind, randomised, controlled clinical studies were conducted with 7,056 subjects 
with type 2 diabetes to evaluate the glycaemic efficacy and safety of Edistride; 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.



41

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 Edistride 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

10 mg
Placebo

Nb 70 75
HbA1c (%)
Baseline (mean)

Change from baselinec

Difference from placeboc

    (95% CI)

8.01
-0.89
-0.66*

(-0.96, -0.36)

7.79
-0.23

Subjects (%) achieving:
HbA1c < 7%

Adjusted for baseline 50.8§ 31.6
Body weight (kg)

Baseline (mean)
Change from baselinec

Difference from placeboc

    (95% CI)

94.13
-3.16
-0.97

(-2.20, 0.25)

88.77
-2.19

aLOCF: Last observation (prior to rescue for rescued subjects) carried forward
bAll randomised subjects who took at least one dose of double-blind study medication during the short-term 

double-blind period
cLeast 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), 
Edistride 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.



42

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)
Change from baselinec

Difference from glipizide + metforminc

    (95% CI)

7.69
-0.52
0.00d

(-0.11, 0.11)

7.74
-0.52

Body weight (kg)
Baseline (mean)
Change from baselinec

Difference from glipizide + metforminc

    (95% CI)

88.44
-3.22
-4.65*

(-5.14, -4.17)

87.60
1.44

aLOCF: Last observation carried forward
bRandomised and treated subjects with baseline and at least 1 post-baseline efficacy measurement
cLeast squares mean adjusted for baseline value
dNon-inferior to glipizide + metformin
*p-value < 0.0001

Dapagliflozin as an add-on with either metformin, glimepiride, metformin and a sulphonylurea, 
sitagliptin (with or without metformin) or insulin resulted in statistically significant reductions in 
HbA1c at 24 weeks compared with subjects receiving placebo (p < 0.0001; Tables 4, 5 and 6).

The reductions in HbA1c observed at Week 24 were sustained in add-on combination studies 
(glimepiride and insulin) with 48-week data (glimepiride) and up to 104-week data (insulin). 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.



43

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
10 mg

Placebo Dapagliflozin
10 mg

Placebo

Nb 135 137 223 224

HbA1c (%)
Baseline (mean)
Change from
  baselinec

Difference from
  placeboc

    (95% CI)

7.92

-0.84

-0.54*

(-0.74, -0.34)

8.11

-0.30

7.90

-0.45

-0.48*

(-0.62, -0.34)

7.97

0.04

Subjects (%) achieving:
HbA1c < 7%

Adjusted for baseline

40.6** 25.9

Body weight (kg)
Baseline (mean)
Change from
  baselinec

Difference from
  placeboc

    (95% CI)

86.28

-2.86

-1.97*

(-2.63, -1.31)

87.74

-0.89

91.02

-2.14

-1.89*

(-2.37, -1.40)

89.23

-0.26

1Metformin ≥ 1500 mg/day; 
2sitagliptin 100 mg/day
aLOCF: Last observation (prior to rescue for rescued subjects) carried forward
bAll randomised subjects who took at least one dose of double-blind study medicinal product during the 

short-term double-blind period
cLeast 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



44

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
(glimepiride1)

Sulphonylurea
+ Metformin2

Dapagliflozin
10 mg

Placebo Dapagliflozin
10 mg

Placebo

Na 151 145 108 108

HbA1c (%)b

Baseline (mean)
Change from baselinec

Difference from placeboc

    (95% CI)

8.07
-0.82
-0.68*

(-0.86, -0.51)

8.15
-0.13

8.08
-0.86

−0.69*

(−0.89, −0.49)

8.24
-0.17

Subjects (%) achieving:
HbA1c < 7% (LOCF)d

Adjusted for baseline 31.7* 13.0 31.8* 11.1

Body weight (kg) 
(LOCF)d

Baseline (mean)
Change from baselinec

Difference from placeboc

    (95% CI)

80.56
-2.26
-1.54*

(-2.17, -0.92)

80.94
-0.72

88.57
-2.65

−2.07*

(−2.79, −1.35)

90.07
-0.58

1glimepiride 4 mg/day; 
2Metformin (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.
aRandomised and treated patients with baseline and at least 1 post-baseline efficacy measurement.
bColumns 1 and 2, HbA1c analysed using LOCF (see footnote d); Columns 3 and 4, HbA1c analysed using 

LRM (see footnote e)
cLeast squares mean adjusted for baseline value
dLOCF: Last observation (prior to rescue for rescued subjects) carried forward
eLRM: Longitudinal repeated measures analysis
*p-value < 0.0001 versus placebo + oral glucose-lowering medicinal product(s)



45

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
+ insulin

± oral glucose-lowering 
medicinal products2

Placebo
+ insulin

± oral glucose-lowering 
medicinal products2

Nb 194 193
HbA1c (%)

Baseline (mean)
Change from baselinec

Difference from placeboc

    (95% CI)

8.58
-0.90
-0.60*

(-0.74, -0.45)

8.46
-0.30

Body weight (kg)
Baseline (mean)
Change from baselinec

Difference from placeboc

    (95% CI)

94.63
-1.67
-1.68*

(-2.19, -1.18)

94.21
0.02

Mean daily insulin dose (IU)1

Baseline (mean)
Change from baselinec

Difference from placeboc

    (95% CI)
Subjects with mean daily 
insulin dose reduction of at 
least 10% (%)

77.96
-1.16
-6.23*

(-8.84, -3.63)

19.7**

73.96
5.08

11.0
aLOCF: Last observation (prior to or on the date of the first insulin up-titration, if needed) carried forward
bAll randomised subjects who took at least one dose of double-blind study medicinal product during the short-

term double-blind period
cLeast 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
1Up-titration of insulin regimens (including short-acting, intermediate, and basal insulin) was only allowed if 

subjects met pre-defined FPG criteria.
2Fifty 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).



46

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 
+

Metformin

Dapagliflozin 10 
mg

Metformin

Nb 211b 219b 208b

HbA1c (%)
Baseline (mean)
Change from baselinec

Difference from dapagliflozinc

    (95% CI)
Difference from metforminc

    (95% CI)

9.10
-1.98

−0.53*

(−0.74, −0.32)
−0.54*

(−0.75, −0.33)

9.03
-1.45

−0.01
(−0.22, 0.20)

9.03
-1.44

aLOCF: last observation (prior to rescue for rescued patients) carried forward.
bAll randomised patients who took at least one dose of double-blind study medication during the short-term 
double-blind period.
cLeast squares mean adjusted for baseline value.
*p-value <0.0001.

Combination therapy with prolonged-release exenatide
In a 28-week, double-blind, active comparator-controlled study, the combination of dapagliflozin 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 
QD

+

Prolonged-release 
exenatide 2 mg QW

Dapagliflozin 10 mg 
QD

+

Placebo QW

Prolonged-release 
exenatide 2 mg 

QW

+

Placebo QD

N 228 230 227

HbA1c (%)
Baseline (mean) 9.29 9.25 9.26
Change from baselinea -1.98 -1.39 -1.60

Mean difference in change 
from baseline between 
combination and single 
medicinal product (95% CI)

-0.59*

(-0.84, -0.34)

-0.38**

(-0.63, -0.13)

Subjects (%) achieving 
HbA1c 7%

44.7 19.1 26.9

Body weight (kg)
Baseline (mean) 92.13 90.87 89.12
Change from baseline a -3.55 -2.22 -1.56

Mean difference in change 
from baseline between 
combination and single 
medicinal product (95% CI)

-1.33*

(-2.12, -0.55)

-2.00*

(-2.79, -1.20)

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



47

aAdjusted 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 
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 Edistride plus metformin showed a numerical decrease in 
visceral adipose tissue compared with placebo plus metformin treatment in a magnetic resonance 
imaging substudy.



48

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 
(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

Dapagliflozina

10 mg
Placeboa

Nb 159 161
HbA1c (%)
Baseline (mean) 8.35 8.03
Change from baselineb -0.37 -0.03
Difference from placebob

    (95% CI)
-0.34*

(-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 
placeboc

    (95% CI)

-1.43*

(-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).



49

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 (urine albumin to creatinine ratio [UACR] ≥ 30 to ≤ 300 mg/g or > 300 mg/g, 
respectively).

Most patients (98%) used one or more diabetic medications 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.



50

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.

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 renal disease (dialysis ≥ 90 days or kidney transplantation, sustained confirmed eGFR < 15 mL/min/1.73 m2) 
and/or renal or cardiovascular death.



51

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

The hazard ratio for time to nephropathy (sustained eGFR decrease, end-stage renal 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 (hazard ratio 0.79 
[95% CI 0.72, 0.87]) and led to greater regression of macroalbuminuria (hazard ratio 1.82 
[95% CI 1.51, 2.20]) compared with placebo.

Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with 
dapagliflozin in one or more subsets of the paediatric population in the treatment of type 2 diabetes 
(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, Edistride 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 
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.



52

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.

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 in the paediatric population have not been studied.

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 
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.



53

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 (E460i)
Lactose
Crospovidone (E1202)
Silicon dioxide (E551)
Magnesium stearate (E470b)

Film-coating
Polyvinyl alcohol (E1203)
Titanium dioxide (E171)
Macrogol 3350
Talc (E553b)
Iron oxide yellow (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years



54

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Alu/Alu blister
Pack sizes of 14, 28 and 98 film-coated tablets in non-perforated calendar blisters
Pack sizes of 30x1 and 90x1 film-coated tablets in perforated unit dose blisters

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

7. MARKETING AUTHORISATION HOLDER

AstraZeneca AB
SE-151 85 Södertälje
Sweden

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/15/1052/006 14 film-coated tablets
EU/1/15/1052/007 28 film-coated tablets
EU/1/15/1052/008 98 film-coated tablets
EU/1/15/1052/009 30 x 1 (unit dose) film-coated tablets
EU/1/15/1052/010 90 x 1 (unit dose) film-coated tablets

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 09 November 2015

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu



55

ANNEX II

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING  
AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT



56

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer(s) responsible for batch release

AstraZeneca GmbH
Tinsdaler Weg 183
22880 Wedel
Germany

AstraZeneca UK Limited
Silk Road Business Park
Macclesfield
SK10 2NA
United Kingdom

Bristol-Myers Squibb S.r.l.
Contrada Fontana del Ceraso
IT-03012 Anagni (FR)
Italy

The printed package leaflet of the medicinal product must state the name and address of the 

manufacturer responsible for the release of the concerned batch.

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Edistride 5 mg Tablets
Type 1 diabetes: Medicinal product subject to restricted medical prescription (see Annex I: Summary 
of Product Characteristics, section 4.2).
Type 2 diabetes: Medicinal product subject to medical prescription.

Edistride 10 mg Tablets
Type 2 diabetes: Medicinal product subject to medical prescription.

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

 Periodic Safety Update Reports 

The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT

 Risk Management Plan (RMP)

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP.

An updated RMP should be submitted:
 At the request of the European Medicines Agency; 



57

 Whenever the risk management system is modified, especially as the result of new information 
being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached.

Additional risk minimisation measures
Prior to launch of the new adult indication for dapagliflozin, for the treatment of insufficiently 
controlled type 1 diabetes mellitus as an adjunct to insulin in patients with BMI ≥ 27 kg/m2, when 
insulin alone does not provide adequate glycaemic control despite optimal insulin therapy, in each 
Member State, the Marketing Authorisation Holder (MAH) must agree about the content and format 
of the educational materials, including communication media, distribution modalities, and any other 
aspects of the programme, with the National Competent Authority.

The educational materials are aimed at providing guidance on how to manage risk of diabetic 
ketoacidosis (DKA) in patients with type 1 diabetes.

The MAH shall ensure that in each Member State where dapagliflozin is marketed for type 1 diabetes, 
all healthcare professionals and patients/carers who are expected to prescribe, dispense or use the 
product have access to:
 Guide for Health Care Professionals including a prescriber’s checklist
 Patient’s/Carer’s Guide
 Patient Alert Card

The guide for healthcare professionals including the prescriber’s checklist should contain the 
following key elements:
 Dapagliflozin is not a substitute for insulin (and does not alter insulin-sensitivity).
 The risk of DKA is increased with dapagliflozin treatment.
 If treated with dapagliflozin, glucose levels will not adequately reflect insulin needs, and DKA 

may occur in patients treated with dapagliflozin even if blood glucose levels are below 14 
mmol/l (250 mg/dl). Therefore, glucose monitoring must be supplemented by ketone 
monitoring. 

 Patients with euglycaemic DKA may need glucose in addition to standard of care treatment for 
DKA and dapagliflozin should be discontinued if DKA occurs.

 Guidance to the physician for assessing whether the patient is eligible for dapagliflozin 
prescription, e.g. patient selection criteria including adherence to insulin treatment and insulin 
thresholds, patient’s beta-hydroxybutyrate (BHB) < 0.6 mmol/L or urine ketones < 1+, BMI ≥ 
27 kg/m2, absence of DKA risk factors.

 Guidance to the physician for assessing whether the patient is prepared and engaged to perform 
self-ketone testing before and during therapy.

 Summary of the recommendations for patients, particularly regarding blood ketone 
measurement and managing sick days. 

 For pump users: restrict dapagliflozin prescription to patients experienced in pump use, 
common trouble-shooting strategies when interruptions of insulin delivery via pump occur in 
case of pump failure.

 Counsel the patient and evaluate their adherence to ketone monitoring while establishing their 
baseline ketone level 1 to 2 weeks before treatment initiation and ensure the patient:
o Has received education/training in ketone testing, and interpreting/acting upon test results
o Is willing/able to perform ketone testing as prescribed
o Is adequately informed about managing sick days

 Ensure the patient is on optimal insulin therapy prior to initiation of dapagliflozin treatment.
 Dapagliflozin treatment should be temporarily stopped before surgical procedures or in case of 

hospitalisation for acute serious illness.
 If addition of dapagliflozin leads to marked reduction of insulin need, discontinuation of 

dapagliflozin should be considered to avoid high risk of DKA.

The patient’s/carer’s guide should contain the following key elements:
 Dapagliflozin is not a substitute for insulin



58

 DKA may occur in patients treated with dapagliflozin even if blood glucose levels are below 14 
mmol/l (250 mg/dl), i.e. an explanation of the concept of euglycaemic DKA

 Signs/symptoms of DKA - if not adequately managed DKA can be severe and fatal. 
 How to measure ketones, how to interpret the results and what to do in case of 

hyperketonaemia/DKA (contact HCP immediately if BHB > 0.6 mmol/L with symptoms or if 
BHB > 1.5 mmol/L with or without symptoms)

 Insulin dose reduction during treatment should only be done when needed to prevent 
hypoglycaemia and should be done cautiously to avoid ketosis and DKA

 Do not start caloric restriction or carbohydrate restriction while treated

The patient alert card should contain the following key elements:
 The Patient Alert Card should be presented to any HCP consulted.
 DKA may occur in patients treated with dapagliflozin even if blood glucose levels are below 14 

mmol/l (250 mg/dl).
 Signs/symptoms of DKA.
 Patients with euglycaemic DKA should receive glucose, insulin and fluids for DKA, 

dapagliflozin should be discontinued.
 Dapagliflozin should be temporarily stopped before surgical procedures or hospitalisation for 

acute serious illness.
 Contact details of the dapagliflozin prescriber’ and ‘Name of patient’.

Obligation to conduct post-authorisation measures: 
The MAH shall complete, within the stated timeframe, the below measures:

Description Due date
Non-interventional PASS: In order to estimate the incidence of DKA in T1DM 
dapagliflozin users following implementation of RMMs in Europe, the MAH 
should conduct and submit the results from an observational cohort study using 
existing data sources in European countries where dapagliflozin will be launched 
for T1DM.

31/12/2026



59

ANNEX III

LABELLING AND PACKAGE LEAFLET



60

A. LABELLING



61

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON 5 mg

1. NAME OF THE MEDICINAL PRODUCT

Edistride 5 mg film-coated tablets
dapagliflozin

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

3. LIST OF EXCIPIENTS

Contains lactose. See package leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS 

14 film-coated tablets
28 film-coated tablets
30x1 film-coated tablets
90x1 film-coated tablets
98 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use

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



62

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

AstraZeneca AB
SE-151 85 Södertälje
Sweden

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/15/1052/001 14 film-coated tablets
EU/1/15/1052/002 28 film-coated tablets
EU/1/15/1052/003 98 film-coated tablets
EU/1/15/1052/004 30 x 1 (unit dose) film-coated tablets
EU/1/15/1052/005 90 x 1 (unit dose) film-coated tablets

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

edistride 5 mg

17. UNIQUE IDENTIFIER  2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER  HUMAN READABLE DATA

PC:
SN:
NN:



63

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON 10 mg

1. NAME OF THE MEDICINAL PRODUCT

Edistride 10 mg film-coated tablets
dapagliflozin

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

3. LIST OF EXCIPIENTS

Contains lactose. See package leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

14 film-coated tablets
28 film-coated tablets
30x1 film-coated tablets
90x1 film-coated tablets
98 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use

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



64

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

AstraZeneca AB
SE-151 85 Södertälje
Sweden

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/15/1052/006 14 film-coated tablets
EU/1/15/1052/007 28 film-coated tablets
EU/1/15/1052/008 98 film-coated tablets
EU/1/15/1052/009 30 x 1 (unit dose) film-coated tablets
EU/1/15/1052/010 90 x 1 (unit dose) film-coated tablets

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

edistride 10 mg

17. UNIQUE IDENTIFIER  2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER  HUMAN READABLE DATA

PC:
SN:
NN:



65

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTERS PERFORATED UNIT DOSE 5 mg

1. NAME OF THE MEDICINAL PRODUCT

Edistride 5 mg tablets
dapagliflozin

2. NAME OF THE MARKETING AUTHORISATION HOLDER

AstraZeneca AB

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER



66

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTERS PERFORATED UNIT DOSE 10 mg

1. NAME OF THE MEDICINAL PRODUCT

Edistride 10 mg tablets
dapagliflozin

2. NAME OF THE MARKETING AUTHORISATION HOLDER

AstraZeneca AB

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER



67

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

CALENDAR BLISTERS NON-PERFORATED 5 mg

1. NAME OF THE MEDICINAL PRODUCT

Edistride 5 mg tablets
dapagliflozin

2. NAME OF THE MARKETING AUTHORISATION HOLDER

AstraZeneca AB

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

Monday Tuesday Wednesday Thursday Friday Saturday Sunday



68

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

CALENDAR BLISTERS NON-PERFORATED 10 mg

1. NAME OF THE MEDICINAL PRODUCT

Edistride 10 mg tablets
dapagliflozin

2. NAME OF THE MARKETING AUTHORISATION HOLDER

AstraZeneca AB

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

Monday Tuesday Wednesday Thursday Friday Saturday Sunday



69

B. PACKAGE LEAFLET



70

Package leaflet: Information for the patient

Edistride 5 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, pharmacist or nurse.
- 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 Edistride is and what it is used for
2. What you need to know before you take Edistride
3. How to take Edistride
4. Possible side effects
5. How to store Edistride
6. Contents of the pack and other information

1. What Edistride is and what it is used for

What Edistride is
Edistride contains the active substance dapagliflozin. It belongs to a group of medicines called “oral 
anti-diabetics”.
 These are medicines taken by mouth for diabetes.
 They work by lowering the amount of sugar (glucose) in your blood.

Edistride is used in adult patients (aged 18 years and older).

What Edistride is used for
Edistride is used for the types of diabetes called:
 type 1 diabetes – where your body hardly produces any insulin. Edistride should only be used in 

type 1 diabetes patients who are overweight or obese.
 type 2 diabetes – where your body does not make enough insulin or is not able to use the insulin 

it produces properly.

In both types of diabetes, this leads to a high level of sugar in your blood. Edistride works by 
removing excess sugar from your body via your urine. If you have type 2 diabetes, it can also help 
prevent heart disease.

Edistride and other diabetes medicines
Type 1 diabetes:
 Edistride is used if your type 1 diabetes cannot be controlled with insulin alone.
 Edistride is used together with insulin.

Type 2 diabetes:
 Edistride is used if your type 2 diabetes cannot be controlled with diet and exercise.
 Your doctor may ask you to take Edistride:

- on its own – if you cannot tolerate metformin.
- together with other medicines to treat diabetes.



71

It is important to continue to follow the advice on diet and exercise given to you by your doctor, 
pharmacist or nurse.

2. What you need to know before you take Edistride

Do not take Edistride:
 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:
 If you 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 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 Edistride, diabetic ketoacidosis can occur even if your blood sugar is 
normal.

 The risk of getting diabetic ketoacidosis is different in the two types diabetes:
- in type 2 diabetes it is rare.
- in type 1 diabetes the risk is higher - this is because your body hardly produces any 

insulin, and diabetic ketoacidosis may occur at sudden decreases in insulin dose (such as 
missed insulin injections, or issues with your insulin pen or pump).

If you have type 1 diabetes:
 Talk with your doctor about the risk of diabetic ketoacidosis before you start to take Edistride.
 Your doctor will tell you when you may need to measure ketones in your blood or urine and 

what you need to do when your ketone levels are raised:
- At blood ketone readings from 0.6 to 1.5 mmol/L (or urine ketones reading +) you may 

need to take extra insulin, drink water, and if your blood glucose is normal or low, you 
may need to eat carbohydrates. Measure your ketone levels again in 2 hours. Seek 
medical advice immediately and stop taking Edistride if levels persist and symptoms 
present.

- At blood ketone readings over 1.5 to 3.0 mmol/L (or urine ketones reading ++) you may 
be developing diabetic ketoacidosis, seek medical advice immediately and stop taking 
Edistride. You may need to take extra insulin, drink water, and if your blood glucose is 
normal or low, you may need to eat carbohydrates. Measure your ketone levels again in 
2 hours.

- At blood ketone readings over 3.0 mmol/L (or urine ketones reading +++) you probably 
have diabetic ketoacidosis, go to the emergency department without delay and stop taking 
Edistride. You may need to take extra insulin, drink water, and if your blood glucose is 
normal or low, you may need to eat carbohydrates.

If you suspect you have diabetic ketoacidosis, contact a doctor or the nearest hospital straight away 
and do not take this medicine.

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



72

Talk to your doctor, pharmacist or nurse before taking Edistride:
 if you have a kidney problem – your doctor may ask you to take a different medicine.
 if you have a liver problem.
 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 
Edistride’.

 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 at the top of section 4. Tell your 
doctor before you start taking Edistride 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 
Edistride until you recover to prevent dehydration.

 if you often get infections of the urinary tract.

Like for all diabetic patients it is important to check your feet regularly and adhere to any other advice 
regarding foot care given by your health care professional.

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

Kidney function
Your kidneys should be checked before you start taking and whilst you are on this medicine.

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

Children and adolescents
Edistride is not recommended for children and adolescents under 18 years of age, because it has not 
been studied in these patients.

Other medicines and Edistride
Tell your doctor, pharmacist or nurse 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). Your doctor may 

ask you to stop taking Edistride. Possible signs of losing too much fluid from your body are 
listed at the top of section 4.

 if you have type 2 diabetes and 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 Edistride for type 1 diabetes, it is important that you keep using insulin.

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. 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 
Edistride if you are breast-feeding. It is not known if this medicine passes into human breast milk.

Driving and using machines
Edistride has no or negligible influence on the ability to drive and use machines.



73

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 Edistride.

Edistride contains lactose
Edistride contains lactose (milk sugar). If you have been told by your doctor that you have an 
intolerance to some sugars, contact your doctor before taking this medicine.

3. How to take Edistride

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
If you are taking Edistride for type 2 diabetes:
 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.

If you are taking Edistride for type 1 diabetes:
 The recommended dose is one 5 mg tablet each day. 

Taking this medicine
 Swallow the tablet whole with half a glass of water.
 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 Edistride together with other medicine(s) to lower the amount of sugar in 
your blood. 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. It is important to stay on any diet and 
exercise program recommended by your doctor while taking Edistride.

If you take more Edistride than you should
If you take more Edistride 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 Edistride
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 Edistride 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 Edistride to make up for a forgotten dose.

If you stop taking Edistride
Do not stop taking Edistride without talking to your doctor first. Your blood sugar may increase 
without this medicine.

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



74

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 common in patients with type 1 diabetes (may affect up to 1 in 
10 people) and 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 Edistride.

 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 Edistride and see a doctor as soon as possible if you notice any of the following 
serious side effects:

 loss of too much fluid from your body (dehydration), seen uncommonly (may affect up to 1 in 
100 people).

These are signs of dehydration:
- very dry or sticky mouth, feeling very thirsty
- feeling very sleepy or tired
- passing little or no water (urine)
- fast heartbeat.

 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
- 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:

Very common (may affect more than 1 in 10 people)
 low blood sugar levels (hypoglycaemia) - when taking this medicine with a sulphonylurea or 

insulin



75

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 Edistride:
Common
 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
 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)

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. 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 Edistride

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

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 to protect the environment.

6. Contents of the pack and other information

What Edistride contains
 The active substance is dapagliflozin.

Each Edistride 5 mg film-coated tablet (tablet) contains dapagliflozin propanediol monohydrate 
equivalent to 5 mg dapagliflozin.



76

 The other ingredients are:
 tablet core: microcrystalline cellulose (E460i), lactose (see section 2 ‘Edistride contains 

lactose’), crospovidone (E1202), silicon dioxide (E551), magnesium stearate (E470b).
 film-coating: polyvinyl alcohol (E1203), titanium dioxide (E171), macrogol 3350, talc (E553b), 

yellow iron oxide (E172).

What Edistride looks like and contents of the pack
Edistride 5 mg film-coated tablets are yellow and round with diameter of 0.7 cm. They have “5” on 
one side and “1427” on the other side.

Edistride 5 mg tablets are available in aluminium blisters in pack sizes of 14, 28 or 98 film-coated 
tablets in non-perforated calendar blisters and 30x1 or 90x1 film-coated tablets in perforated unit dose 
blisters.

Not all pack sizes may be marketed in your country.

Marketing Authorisation Holder
AstraZeneca AB
SE-151 85 Södertälje
Sweden

Manufacturer
AstraZeneca GmbH
Tinsdaler Weg 183
22880 Wedel
Germany

AstraZeneca UK Limited
Silk Road Business Park
Macclesfield
SK10 2NA
United Kingdom

Bristol-Myers Squibb Company
Contrada Fontana del Ceraso
IT-03012 Anagni (FR)
Italy

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
AstraZeneca S.A./N.V. 
Tel: +32 2 370 48 11

Lietuva
UAB AstraZeneca Lietuva
Tel: +370 5 2660550

България
АстраЗенека България ЕООД
Тел.: +359 (2) 44 55 000

Luxembourg/Luxemburg
AstraZeneca S.A./N.V. 
Tél/Tel: +32 2 370 48 11

Česká republika
AstraZeneca Czech Republic s.r.o.
Tel: +420 222 807 111

Magyarország
AstraZeneca Kft.
Tel.: +36 1 883 6500

Danmark
AstraZeneca A/S
Tlf: +45 43 66 64 62

Malta
Associated Drug Co. Ltd 
Tel: +356 2277 8000



77

Deutschland
AstraZeneca GmbH
Tel: +49 41 03 7080

Nederland
AstraZeneca BV
Tel: +31 79 363 2222

Eesti
AstraZeneca
Tel: +372 6549 600

Norge
AstraZeneca AS
Tlf: +47 21 00 64 00

Ελλάδα
AstraZeneca A.E. 
Τηλ: +30 2 106871500

Österreich
AstraZeneca Österreich GmbH
Tel: +43 1 711 31 0

España
Esteve Pharmaceuticals, S.A.
Tel: +34 93 446 60 00

Laboratorio Tau, S. A.
Tel: +34 91 301 91 00

Polska
AstraZeneca Pharma Poland Sp. z o.o. 
Tel.: +48 22 245 73 00

France
AstraZeneca
Tél: +33 1 41 29 40 00

Portugal
BIAL-Portela & Cª., S.A.

Tel.: +351 22 986 61 00

Hrvatska 
AstraZeneca d.o.o.
Tel: +385 1 4628 000

România
AstraZeneca Pharma SRL 
Tel: +40 21 317 60 41

Ireland
AstraZeneca Pharmaceuticals (Ireland) DAC
Tel: +353 1609 7100

Slovenija
AstraZeneca UK Limited 
Tel: +386 1 51 35 600

Ísland
Vistor hf.
Sími: +354 535 7000

Slovenská republika
AstraZeneca AB, o.z. 
Tel: +421 2 5737 7777 

Italia
AstraZeneca S.p.A.
Tel: +39 02 9801 1

Suomi/Finland
AstraZeneca Oy 
Puh/Tel: +358 10 23 010

Κύπρος
Αλέκτωρ Φαρµακευτική Λτδ
Τηλ: +357 22490305

Sverige
AstraZeneca AB
Tel: +46 8 553 26 000

Latvija
SIA AstraZeneca Latvija
Tel: +371 67377100

United Kingdom
AstraZeneca UK Ltd
Tel: +44 1582 836 836

This leaflet was last revised in 

Other sources of information
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu



78

Package leaflet: Information for the patient

Edistride 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, pharmacist or nurse.
- 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 Edistride is and what it is used for
2. What you need to know before you take Edistride
3. How to take Edistride
4. Possible side effects
5. How to store Edistride
6. Contents of the pack and other information

1. What Edistride is and what it is used for

What Edistride is
Edistride contains the active substance dapagliflozin. It belongs to a group of medicines called “oral 
anti-diabetics”.
 These are medicines taken by mouth for diabetes.
 They work by lowering the amount of sugar (glucose) in your blood.

Edistride is used in adult patients (aged 18 years and older).

What Edistride is used for
Edistride is used for the type of diabetes called type 2 diabetes – where your body does not make 
enough insulin or is not able to use the insulin it produces properly. This leads to a high level of sugar 
in your blood. Edistride works by removing excess sugar from your body via your urine. It can also 
help prevent heart disease.

Edistride and other diabetes medicines
Edistride is used if your type 2 diabetes cannot be controlled with diet and exercise.

Your doctor may ask you to take Edistride:
- on its own – if you cannot tolerate metformin.
- 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.

2. What you need to know before you take Edistride

Do not take Edistride:
 if you are allergic to dapagliflozin or any of the other ingredients of this medicine (listed in 

section 6).



79

Warnings and precautions
Contact a doctor or the nearest hospital straight away:
 If you 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 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 Edistride, 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. 

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

Talk to your doctor, pharmacist or nurse before taking Edistride:
 if you have “type 1 diabetes” – the type that usually starts when you are young, and your body 

does not produce any insulin.
 if you have a kidney problem – your doctor may ask you to take a different medicine.
 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 
Edistride’.

 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 at the top of section 4. Tell your 
doctor before you start taking Edistride 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 
Edistride until you recover to prevent dehydration.

 if you often get infections of the urinary tract.

Like for all diabetic patients it is important to check your feet regularly and adhere to any other advice 
regarding foot care given by your health care professional.

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

Kidney function
Your kidneys should be checked before you start taking and whilst you are on this medicine.

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

Children and adolescents
Edistride is not recommended for children and adolescents under 18 years of age, because it has not 
been studied in these patients.



80

Other medicines and Edistride
Tell your doctor, pharmacist or nurse 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). Your doctor may 

ask you to stop taking Edistride. Possible signs of losing too much fluid from your body are 
listed at the top of section 4.

 if you have type 2 diabetes and 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).

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. 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 
Edistride if you are breast-feeding. It is not known if this medicine passes into human breast milk.

Driving and using machines
Edistride 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 Edistride.

Edistride contains lactose
Edistride contains lactose (milk sugar). If you have been told by your doctor that you have an 
intolerance to some sugars, contact your doctor before taking this medicine.

3. How to take Edistride

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
If you are taking Edistride for type 2 diabetes:
 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 whole with half a glass of water.
 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 Edistride together with other medicine(s) to lower the amount of sugar in 
your blood. Remember to take these other medicine(s) as your doctor has told you. This will help get 
the best results for your health.



81

Diet and exercise can help your body use its blood sugar better. It is important to stay on any diet and 
exercise program recommended by your doctor while taking Edistride.

If you take more Edistride than you should
If you take more Edistride 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 Edistride
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 Edistride 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 Edistride to make up for a forgotten dose.

If you stop taking Edistride
Do not stop taking Edistride without talking to your doctor first. Your blood sugar may increase 
without this medicine.

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

 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.



82

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

 loss of too much fluid from your body (dehydration), seen uncommonly (may affect up to 1 in 
100 people).

These are signs of dehydration:
- very dry or sticky mouth, feeling very thirsty
- feeling very sleepy or tired
- passing little or no water (urine)
- fast heartbeat.

 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
- 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:

Very common (may affect more than 1 in 10 people)
 low blood sugar levels (hypoglycaemia) - when 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 Edistride:
Common
 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
 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)

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. 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.



83

5. How to store Edistride

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

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 to protect the environment.

6. Contents of the pack and other information

What Edistride contains
 The active substance is dapagliflozin.

Each Edistride 10 mg film-coated tablet (tablet) contains 
dapagliflozin propanediol monohydrate equivalent to 10 mg dapagliflozin.

 The other ingredients are:
 tablet core: microcrystalline cellulose (E460i), lactose (see section 2 ‘Edistride contains 

lactose’), crospovidone (E1202), silicon dioxide (E551), magnesium stearate (E470b).
 film-coating: polyvinyl alcohol (E1203), titanium dioxide (E171), macrogol 3350, talc (E553b), 

yellow iron oxide (E172).

What Edistride looks like and contents of the pack
Edistride 10 mg film-coated tablets are yellow and diamond-shaped approximately 1.1 x 0.8 cm 
diagonally. They have “10” on one side and “1428” on the other side.

Edistride 10 mg tablets are available in aluminium blisters in pack sizes of 14, 28 or 98 film-coated 
tablets in non-perforated calendar blisters and 30x1 or 90x1 film-coated tablets in perforated unit dose 
blisters.

Not all pack sizes may be marketed in your country.

Marketing Authorisation Holder
AstraZeneca AB
SE-151 85 Södertälje
Sweden

Manufacturer
AstraZeneca GmbH
Tinsdaler Weg 183
22880 Wedel
Germany

AstraZeneca UK Limited
Silk Road Business Park
Macclesfield
SK10 2NA
United Kingdom

Bristol-Myers Squibb Company
Contrada Fontana del Ceraso
IT-03012 Anagni (FR)



84

Italy

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
AstraZeneca S.A./N.V. 
Tel: +32 2 370 48 11

Lietuva
UAB AstraZeneca Lietuva
Tel: +370 5 2660550

България
АстраЗенека България ЕООД
Тел.: +359 (2) 44 55 000

Luxembourg/Luxemburg
AstraZeneca S.A./N.V. 
Tél/Tel: +32 2 370 48 11

Česká republika
AstraZeneca Czech Republic s.r.o.
Tel: +420 222 807 111

Magyarország
AstraZeneca Kft.
Tel.: +36 1 883 6500

Danmark
AstraZeneca A/S
Tlf: +45 43 66 64 62

Malta
Associated Drug Co. Ltd 
Tel: +356 2277 8000

Deutschland
AstraZeneca GmbH
Tel: +49 41 03 7080

Nederland
AstraZeneca BV
Tel: +31 79 363 2222

Eesti
AstraZeneca
Tel: +372 6549 600

Norge
AstraZeneca AS
Tlf: +47 21 00 64 00

Ελλάδα
AstraZeneca A.E. 
Τηλ: +30 2 106871500

Österreich
AstraZeneca Österreich GmbH
Tel: +43 1 711 31 0

España
Esteve Pharmaceuticals, S.A.
Tel: +34 93 446 60 00

Laboratorio Tau, S. A.
Tel: +34 91 301 91 00

Polska
AstraZeneca Pharma Poland Sp. z o.o. 
Tel.: +48 22 245 73 00

France
AstraZeneca
Tél: +33 1 41 29 40 00

Portugal
BIAL-Portela & Cª., S.A.

Tel.: +351 22 986 61 00

Hrvatska 
AstraZeneca d.o.o.
Tel: +385 1 4628 000

România
AstraZeneca Pharma SRL 
Tel: +40 21 317 60 41

Ireland
AstraZeneca Pharmaceuticals (Ireland) DAC
Tel: +353 1609 7100

Slovenija
AstraZeneca UK Limited 
Tel: +386 1 51 35 600



85

Ísland
Vistor hf.
Sími: +354 535 7000

Slovenská republika
AstraZeneca AB, o.z. 
Tel: +421 2 5737 7777 

Italia
AstraZeneca S.p.A.
Tel: +39 02 9801 1

Suomi/Finland
AstraZeneca Oy 
Puh/Tel: +358 10 23 010

Κύπρος
Αλέκτωρ Φαρµακευτική Λτδ
Τηλ: +357 22490305

Sverige
AstraZeneca AB
Tel: +46 8 553 26 000

Latvija
SIA AstraZeneca Latvija
Tel: +371 67377100

United Kingdom
AstraZeneca UK Ltd
Tel: +44 1582 836 836

This leaflet was last revised in 

Other sources of information
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET