Xigduo

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS



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1. NAME OF THE MEDICINAL PRODUCT

Xigduo 5 mg/850 mg film-coated tablets
Xigduo 5 mg/1,000 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Xigduo 5 mg/850 mg film-coated tablets
Each tablet contains dapagliflozin propanediol monohydrate equivalent to 5 mg dapagliflozin and 
850 mg of metformin hydrochloride.

Xigduo 5 mg/1,000 mg film-coated tablets
Each tablet contains dapagliflozin propanediol monohydrate equivalent to 5 mg dapagliflozin and 
1,000 mg of metformin hydrochloride.

Excipient(s) with known effect:
Xigduo contains less than 1 mmol sodium (23 mg) per dose, i.e. is essentially ‘sodium-free’.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet (tablet).

Xigduo 5 mg/850 mg film-coated tablets
Brown, biconvex, 9.5 x 20 mm oval, film-coated tablets engraved with “5/850” on one side and 
“1067” engraved on the other side.

Xigduo 5 mg/1,000 mg film-coated tablets
Yellow, biconvex, 10.5 x 21.5 mm oval, film-coated tablets engraved with “5/1000” on one side and 
“1069” engraved on the other side.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications 

Xigduo is indicated in adults for the treatment of type 2 diabetes mellitus as an adjunct to diet and 
exercise:
 in patients insufficiently controlled on their maximally tolerated dose of metformin alone 
 in combination with other medicinal products for the treatment of diabetes in patients 

insufficiently controlled with metformin and these medicinal products
 in patients already being treated with the combination of dapagliflozin and metformin as 

separate tablets.

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.



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4.2 Posology and method of administration

Posology
Adults with normal renal function (glomerular filtration rate [GFR] ≥ 90 mL/min)

The recommended dose is one tablet twice daily. Each tablet contains a fixed dose of dapagliflozin 
and metformin (see section 2).

For patients insufficiently controlled on metformin monotherapy or metformin in combination with 
other medicinal products for the treatment of diabetes
Patients insufficiently controlled on metformin alone or in combination with other medicinal products
for the treatment of diabetes should receive a total daily dose of Xigduo equivalent to 
dapagliflozin 10 mg, plus the total daily dose of metformin, or the nearest therapeutically appropriate 
dose, already being taken. When Xigduo is used in combination with insulin or an insulin 
secretagogue such as sulphonylurea, a lower dose of insulin or sulphonylurea may be considered to 
reduce the risk of hypoglycaemia (see sections 4.5 and 4.8).

For patients switching from separate tablets of dapagliflozin and metformin
Patients switching from separate tablets of dapagliflozin (10 mg total daily dose) and metformin to 
Xigduo should receive the same daily dose of dapagliflozin and metformin already being taken or the 
nearest therapeutically appropriate dose of metformin.

Special populations
Renal impairment
A GFR should be assessed before initiation of treatment with metformin containing medicinal 
products and at least annually thereafter. In patients at increased risk of further progression of renal 
impairment and in the elderly, renal function should be assessed more frequently, e.g. every 
3-6 months.

The maximum daily dose of metformin should preferably be divided into 2-3 daily doses. Factors that 
may increase the risk of lactic acidosis (see section 4.4) should be reviewed before considering 
initiation of metformin in patients with GFR < 60 mL/min.

If no adequate strength of Xigduo is available, individual mono-components should be used instead of 
the fixed dose combination.

Table 1. Dosage in patients with renal impairment
GFR mL/min Metformin Dapagliflozin

60-89
Maximum daily dose is 3000 mg.

Dose reduction may be considered in 
relation to declining renal function.

Maximum total daily dose is 10 mg.

45-59
Maximum daily dose is 2000 mg.

The starting dose is at most half of the 
maximum dose.

Dapagliflozin should not be initiated.

Maximum total daily dose is 10 mg.

30-44
Maximum daily dose is 1000 mg.
The starting dose is at most half of the 
maximum dose.

Dapagliflozin is not recommended.

< 30 Metformin is contraindicated. Dapagliflozin is not recommended.

Hepatic impairment
This medicinal product must not be used in patients with hepatic impairment (see sections 4.3, 4.4 and 
5.2).



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Elderly (≥ 65 years)
Because metformin is eliminated in part by the kidney, and because elderly patients are more likely to 
have decreased renal function, this medicinal product should be used with caution as age increases. 
Monitoring of renal function is necessary to aid in prevention of metformin-associated lactic acidosis, 
particularly in elderly patients (see sections 4.3 and 4.4). Risk of volume depletion with dapagliflozin 
should also be taken into account (see sections 4.4 and 5.2).

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

Method of administration
Xigduo should be given twice daily with meals to reduce the gastrointestinal adverse reactions 
associated with metformin.

4.3 Contraindications

Xigduo is contraindicated in patients with:

- hypersensitivity to the active substances or to any of the excipients listed in section 6.1;
- any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis);
- diabetic pre-coma;
- severe renal failure (GFR < 30 mL/min) (see sections 4.2, 4.4 and 5.2);
- acute conditions with the potential to alter renal function such as:

- dehydration,
- severe infection,
- shock;

- acute or chronic disease which may cause tissue hypoxia such as:
- cardiac or respiratory failure,
- recent myocardial infarction,
- shock;

- hepatic impairment (see sections 4.2, 4.4 and 5.2);
- acute alcohol intoxication, alcoholism (see section 4.5).

4.4 Special warnings and precautions for use

Lactic acidosis
Lactic acidosis, a very rare but serious metabolic complication, most often occurs at acute worsening 
of renal function or cardiorespiratory illness or sepsis. Metformin accumulation occurs at acute 
worsening of renal function and increases the risk of lactic acidosis.

In case of dehydration (severe diarrhoea or vomiting, fever or reduced fluid intake), Xigduo should be 
temporarily discontinued and contact with a health care professional is recommended.

Medicinal products that can acutely impair renal function (such as antihypertensives, diuretics and 
non-steroidal anti-inflammatory drugs [NSAIDs]) should be initiated with caution in 
metformin-treated patients. Other risk factors for lactic acidosis are excessive alcohol intake, hepatic 
insufficiency, inadequately controlled diabetes, ketosis, prolonged fasting and any conditions 
associated with hypoxia, as well as concomitant use of medicinal products that may cause lactic 
acidosis (see sections 4.3 and 4.5).

Patients and/or care-givers should be informed on the risk of lactic acidosis. Lactic acidosis is 
characterised by acidotic dyspnoea, abdominal pain, muscle cramps, asthenia and hypothermia 
followed by coma. In case of suspected symptoms, the patient should stop taking Xigduo and seek 
immediate medical attention. Diagnostic laboratory findings are decreased blood pH (< 7.35), 
increased plasma lactate levels above 5 mmol/L, and an increased anion gap and lactate/pyruvate ratio.



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Renal function
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. Xigduo should not be initiated in patients with GFR < 60 mL/min and should be 
discontinued at GFR persistently below 45 mL/min (see section 4.2).

Metformin is excreted by the kidney, and moderate to severe renal insufficiency increases the risk of 
lactic acidosis (see section 4.4). 

Monitoring of renal function:
Renal function should be assessed:
• Before initiation of treatment and regularly thereafter (see sections 4.2, 4.8, 5.1 and 5.2).
• For renal function with GFR levels < 60 mL/min and in elderly patients, at least 2 to 4 times per 

year.
• Prior to initiation of concomitant medicinal products that may reduce renal function and periodically 

thereafter.
• If renal function falls persistently below GFR 45 mL/min, treatment should be discontinued.
• Metformin is contraindicated in patients with GFR of < 30 mL/min and should be temporarily 

discontinued in the presence of conditions that alter renal function (see section 4.3).

Decreased renal function in elderly patients is frequent and asymptomatic. Special caution should be 
exercised in situations where renal function may become impaired, for example when initiating 
anti-hypertensive or diuretic therapy or when starting treatment with a NSAID.

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 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 this medicinal product is recommended for patients who develop volume depletion 
until the depletion is corrected (see section 4.8).

Diabetic ketoacidosis
Rare cases of diabetic ketoacidosis (DKA), including life-threatening and fatal cases, have been 
reported in patients treated with sodium-glucose co-transporter 2 (SGLT2) inhibitors, including 
dapagliflozin. In a number of cases, the presentation of the condition was atypical with only 
moderately increased blood glucose values, below 14 mmol/L (250 mg/dL). It is not known if DKA is 
more likely to occur with higher doses of dapagliflozin.

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

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

Treatment should be interrupted in patients who are hospitalised for major surgical procedures or acute 
serious medical illnesses. Monitoring of ketones is recommended in these patients. Measurement of 



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blood ketone levels is preferred to urine. Treatment with dapagliflozin may be restarted when the 
ketone values are normal and the patient’s condition has stabilised.

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

Patients who may be at higher risk of DKA include patients with a low beta-cell function reserve (e.g. 
type 2 diabetes patients with low C-peptide or latent autoimmune diabetes in adults (LADA) or 
patients with a history of pancreatitis), patients with conditions that lead to restricted food intake or 
severe dehydration, patients for whom insulin doses are reduced and patients with increased insulin 
requirements due to acute medical illness, surgery or alcohol abuse. SGLT2 inhibitors should be used 
with caution in these patients.

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

The safety and efficacy of Xigduo in patients with type 1 diabetes have not been established and 
Xigduo should not be used for treatment of patients with type 1 diabetes. In type 1 diabetes mellitus 
studies, DKA was reported with common frequency.

Necrotising fasciitis of the perineum (Fournier’s gangrene)
Post-marketing 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, Xigduo 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 treatment 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.



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

Administration of iodinated contrast agents
Intravascular administration of iodinated contrast agents may lead to contrast induced nephropathy, 
resulting in metformin accumulation and increased risk of lactic acidosis. Xigduo should be 
discontinued prior to, or at the time of, the imaging procedure and not restarted until at least 48 hours 
after, provided that renal function has been re-evaluated and found to be stable (see sections 4.2 
and 4.5).

Surgery
Xigduo must be discontinued at the time of surgery with general, spinal or epidural anaesthesia. 
Therapy may be restarted no earlier than 48 hours following surgery or resumption of oral nutrition 
and provided that renal function has been re-evaluated and found to be stable.

Change in clinical status of patients with previously controlled type 2 diabetes
As this medicinal product contains metformin, a patient with type 2 diabetes previously 
well-controlled on it who develops laboratory abnormalities or clinical illness (especially vague and 
poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. 
Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, 
lactate, pyruvate, and metformin levels. If acidosis of either form occurs, treatment must be stopped 
immediately and other appropriate corrective measures initiated.

4.5 Interaction with other medicinal products and other forms of interaction

Coadministration of multiple doses of dapagliflozin and metformin does not meaningfully alter the 
pharmacokinetics of either dapagliflozin or metformin in healthy subjects.

No interaction studies have been performed for Xigduo. The following statements reflect the 
information available on the individual active substances.

Dapagliflozin
Pharmacodynamic interactions
Diuretics
This medicinal product 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 (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, this medicinal product 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 pioglitazone, sitagliptin, glimepiride, voglibose, 
hydrochlorothiazide, bumetanide, valsartan, or simvastatin.



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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 pioglitazone, sitagliptin, glimepiride, hydrochlorothiazide, 
bumetanide, valsartan, digoxin (a P-gp substrate) or warfarin (S-warfarin, a CYP2C9 substrate), or the 
anti-coagulatory 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.

Metformin
Concomitant use not recommended
Cationic substances that are eliminated by renal tubular secretion (e.g. cimetidine) may interact with 
metformin by competing for common renal tubular transport systems. A study conducted in seven 
normal healthy volunteers showed that cimetidine, administered as 400 mg twice daily, increased 
metformin systemic exposure (AUC) by 50% and Cmax by 81%. Therefore, close monitoring of 
glycaemic control, dose adjustment within the recommended posology and changes in diabetic 
treatment should be considered when cationic medicinal products that are eliminated by renal tubular 
secretion are coadministered.

Alcohol
Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in the case of 
fasting, malnutrition or hepatic impairment due to the metformin active substance of this medicinal 
product (see section 4.4). Consumption of alcohol and medicinal products containing alcohol should 
be avoided.

Iodinated contrast agents
Intravascular administration of iodinated contrast agents may lead to contrast induced nephropathy, 
resulting in metformin accumulation and increased risk of lactic acidosis. Xigduo must be 
discontinued prior to, or at the time of the imaging procedure and not restarted until at least 48 hours 
after, provided that renal function has been re-evaluated and found to be stable (see sections 4.2 
and 4.4).

Combination requiring precautions for use
Glucocorticoids (given by systemic and local routes), beta-2 agonists, and diuretics have intrinsic 
hyperglycaemic activity. The patient should be informed and more frequent blood glucose monitoring 
perfomed, especially at the beginning of treatment with such medicinal products. If necessary, the 
dose of the glucose-lowering medicinal product should be adjusted during therapy with the other 
medicinal product and on its discontinuation.



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Some medicinal products can adversely affect renal function which may increase the risk of lactic 
acidosis, e.g. NSAIDs, including selective cyclo-oxygenase (COX) II inhibitors, ACE inhibitors, 
angiotensin II receptor antagonists and diuretics, especially loop diuretics. When starting or using such 
products in combination with metformin, close monitoring of renal function is necessary.

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 metformin (see sections 4.2 and 4.8)

4.6 Fertility, pregnancy and lactation

Pregnancy
There are no data from the use of Xigduo or dapagliflozin in pregnant women. Studies in rats treated 
with dapagliflozin 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 this 
medicinal product is not recommended during the second and third trimesters of pregnancy. A limited 
amount of data from the use of metformin in pregnant women does not indicate an increased risk of 
congenital malformations. Animal studies with metformin do not indicate harmful effects with respect 
to pregnancy, embryonic or foetal development, parturition or postnatal development (see section 5.3).

When the patient plans to become pregnant, and during pregnancy, it is recommended that diabetes is 
not treated with this medicinal product, but insulin be used to maintain blood glucose levels as close to 
normal as possible, to reduce the risk of malformations of the foetus associated with abnormal blood 
glucose levels.

Breast-feeding
It is unknown whether this medicinal product or 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). Metformin is excreted in human milk in small amounts. A risk to the 
newborns/infants cannot be excluded.

This medicinal product should not be used while breast-feeding.

Fertility
The effect of this medicinal product or dapagliflozin on fertility in humans has not been studied. In 
male and female rats, dapagliflozin showed no effects on fertility at any dose tested. For metformin, 
studies in animals have not shown reproductive toxicity (see section 5.3).

4.7 Effects on ability to drive and use machines

Xigduo has no or negligible influence on the ability to drive and use machines. Patients should be 
alerted to the risk of hypoglycaemia when this medicinal product is used in combination with other 
glucose-lowering medicinal products known to cause hypoglycaemia.

4.8 Undesirable effects

Xigduo has been demonstrated to be bioequivalent with coadministered dapagliflozin and metformin 
(see section 5.2). There have been no therapeutic clinical trials conducted with Xigduo tablets.

Dapagliflozin plus metformin
Summary of the safety profile
In an analysis of 5 placebo-controlled dapagliflozin add-on to metformin studies, the safety results 
were similar to that of the pre-specified pooled analysis of 13 placebo-controlled dapagliflozin studies 
(see Dapagliflozin, Summary of the safety profile below). No additional adverse reactions were 
identified for the dapagliflozin plus metformin group compared with those reported for the individual 



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components. In the separate dapagliflozin add-on to metformin pooled analysis, 623 subjects were 
treated with dapagliflozin 10 mg as add-on to metformin and 523 were treated with placebo plus 
metformin. 

Dapagliflozin
Summary of the safety profile
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.

Tabulated list of adverse reactions
The following adverse reactions have been identified in the placebo-controlled dapagliflozin plus 
metformin clinical studies, dapagliflozin clinical studies and metformin clinical studies and 
post-marketing experience. None were found to be dose-related. Adverse reactions listed below are 
classified according to frequency and system organ class. 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 dapagliflozin and metformin immediate-release clinical trial and 
post-marketing dataa

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,k

Metabolism and 
nutrition 
disorders

Hypoglycaemia 
(when used 
with SU or 
insulin)b

Volume 
depletionb,e

Thirst**

Diabetic 
ketoacidosisb,k,l

Lactic 
acidosis
Vitamin B12 
deficiencyh,§

Nervous system 
disorders

Taste 
disturbance§

Dizziness

Gastrointestinal 
disorders

Gastro-
intestinal 
symptomsi,§

Constipation**

Dry mouth**

Hepatobiliary 
disorders

Liver 
function 
disorders§

Hepatitis§

Skin and 
subcutaneous 
tissue disorders

Rashm Urticaria§

Erythema§

Pruritus§



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System organ 
class

Very common Common Uncommon Rare Very rare

Musculo-
skeletal 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

Dyslipidaemiaj

Blood 
creatinine 
increased 
during initial 
treatment**,b

Blood urea 
increased**

Weight 
decreased**

aThe table shows adverse reactions identified from up to 24-week (short-term) data regardless of glycaemic 
rescue, except those marked with §, for which adverse reaction and frequency categories are based on 
information from the metformin Summary of Product Characteristics available in the European Union.

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.

hLong-term treatment with metformin has been associated with a decrease in vitamin B12 absorption which may 
very rarely result in clinically significant vitamin B12 deficiency (e.g. megaloblastic anaemia).

iGastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite occur most 
frequently during initiation of therapy and resolve spontaneously in most cases.

jMean 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%.

kSee section 4.4
l Reported in the cardiovascular outcomes study in patients with type 2 diabetes. Frequency is based on annual 
rate.

mAdverse reaction was identified through post-marketing surveillance with the use of dapagliflozin. Rash 
includes the following preferred terms, listed in order of frequency in clinical trials: rash, rash generalised, rash 
pruritic, rash macular, rash maculo-papular, rash pustular, rash vesicular, and rash erythematous. In active- and 
placebo-controlled clinical trials (dapagliflozin, N=5936, All control, N=3403), the frequency of rash was 
similar for dapagliflozin (1.4%) and all control (1.4%), respectively.

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

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



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Description of selected adverse reactions
Dapagliflozin plus metformin
Hypoglycaemia
In studies with dapagliflozin in add-on combination with metformin, minor episodes of 
hypoglycaemia were reported at similar frequencies in the group treated with dapagliflozin 10 mg plus 
metformin (6.9%) and in the placebo plus metformin group (5.5%). No major events of 
hypoglycaemia were reported. Similar observations were made for the combination of dapagliflozin 
with metformin in drug-naive patients.

In an add-on to metformin and a sulphonylurea study, up to 24 weeks, 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. No major events of hypoglycaemia were reported.

Dapagliflozin
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 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. In a study with add-on insulin therapy, higher rates of hypoglycaemia were observed (see 
section 4.5).

In an add-on to insulin study up to 104 weeks, episodes of major hypoglycaemia were reported in
0.5% and 1.0% of subjects in 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 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.



13

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 
compared with 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 
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.



14

4.9 Overdose

Removal of dapagliflozin by haemodialysis has not been studied. The most effective method to 
remove metformin and lactate is haemodialysis.

Dapagliflozin
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.

Metformin
High overdose or concomitant risks of metformin may lead to lactic acidosis. Lactic acidosis is a 
medical emergency and must be treated in hospital.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs used in diabetes, Combinations of oral blood glucose-lowering 
drugs, ATC code: A10BD15

Mechanism of action
Xigduo combines two anti-hyperglycaemic medicinal products with different and complementary 
mechanisms of action to improve glycaemic control in patients with type 2 diabetes: dapagliflozin, a 
SGLT2 inhibitor, and metformin hydrochloride, a member of the biguanide class.

Dapagliflozin
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 dapagliflozin.

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.



15

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.

Metformin
Metformin is a biguanide with anti-hyperglycaemic effects, lowering both basal and postprandial 
plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia.

Metformin may act via three mechanisms:
- by reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis;
- by modestly increasing insulin sensitivity, improving peripheral glucose uptake and utilisation 
in muscle;
- by delaying intestinal glucose absorption.

Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase. Metformin 
increases the transport capacity of specific types of membrane glucose transporters (GLUT-1 and 
GLUT-4).

Pharmacodynamic effects
Dapagliflozin
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).

The pharmacodynamics of 5 mg dapagliflozin twice daily and 10 mg dapagliflozin once daily were 
compared in healthy subjects. The steady-state inhibition of renal glucose reabsorption and the amount 
of urinary glucose excretion over a 24-hour period was the same for both dosing regimens.

Metformin
In humans, independently of its action on glycaemia, metformin has favourable effects on lipid 
metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term 
clinical studies: metformin reduces total cholesterol, LDL cholesterol and triglyceride levels.

In clinical studies, use of metformin was associated with either a stable body weight or modest weight 
loss.

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

The coadministration of dapagliflozin and metformin has been studied in subjects, with type 2 
diabetes, inadequately controlled on diet and exercise alone, and in subjects inadequately controlled on 



16

metformin alone or in combination with a DPP-4 inhibitor (sitagliptin), sulphonylurea or insulin. 
Treatment with dapagliflozin plus metformin at all doses produced clinically relevant and statistically 
significant improvements in HbA1c and fasting plasma glucose (FPG) compared with control. 
Clinically relevant glycaemic effects were sustained in long-term extensions up to 104 weeks. HbA1c 
reductions were seen across subgroups including gender, age, race, duration of disease, and baseline 
body mass index (BMI). Additionally, at Week 24, clinically relevant and statistically significant 
improvements in mean changes from baseline in body weight were seen with dapagliflozin and 
metformin combination treatments compared with control. Body weight reductions were sustained in 
long-term extensions up to 208 weeks. Additionally, dapagliflozin twice-daily treatment added to 
metformin was shown to be effective and safe in type 2 diabetic subjects. Furthermore, two 12-week, 
placebo-controlled studies were conducted in patients with inadequately controlled type 2 diabetes and 
hypertension.

In a cardiovascular outcomes study (DECLARE), dapagliflozin as adjunct to standard care therapy 
reduced cardiovascular and renal events in patients with type 2 diabetes.

Glycaemic control
Add-on combination therapy
In a 52-week, active-controlled non-inferiority study (with 52- and 104-week extension periods), 
dapagliflozin 10 mg 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 with 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, 
respectively. At Week 208, adjusted mean change from baseline in HbA1c was -0.10% for 
dapagliflozin and 0.20% for glipizide, respectively. 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 with the group treated with glipizide 
(40.8%, 47% and 50.0%, respectively). The proportion of subjects remaining in the study at Week 104 
and Week 208 was 56.2% and 39.7% for the group treated with dapagliflozin and 50.0% and 34.6%
for the group treated with glipizide.

Table 3. Results at Week 52 (LOCFa) in an active-controlled study comparing dapagliflozin with 
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 alone, metformin in combination with sitagliptin, 
sulphonylurea or insulin (with or without additional oral glucose-lowering medicinal products, 
including metformin) resulted in statistically significant mean reductions in HbA1c at 24 weeks 
compared with subjects receiving placebo (p < 0.0001; Tables 4, 5 and 6). Dapagliflozin 5 mg twice 



17

daily provided statistically significant reductions in HbA1c at 16 weeks compared with subjects 
receiving placebo (p < 0.0001; Table 4).

The reductions in HbA1c observed at Week 24 were sustained in the add-on combination studies. 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 dapagliflozin 10 mg and placebo, respectively). At 
Week 48 for metformin plus sitagliptin, the adjusted mean change from baseline for 
dapagliflozin 10 mg and placebo was -0.44% and 0.15%, respectively. At Week 104 for insulin (with 
or without additional oral glucose-lowering medicinal products, including metformin), 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 an 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.

In a separate analysis of subjects on insulin plus metformin, similar reductions in HbA1c to those seen 
in the total study population were seen in subjects treated with dapagliflozin with insulin plus 
metformin. At Weeks 24, HbA1c change from baseline in subjects treated with dapagliflozin plus 
insulin with metformin was -0.93%.



18

Table 4. Results of (LOCFa) placebo-controlled studies up to 24 weeks of dapagliflozin in add-on 
combination with metformin or metformin plus sitagliptin

Add-on combination

Metformin1 Metformin1, b Metformin1 + Sitagliptin2

Dapagliflozin
10 mg QD

Placebo
QD

Dapagliflozin
5 mg BID

Placebo
BID

Dapagliflozin
10 mg QD

Placebo
QD

Nc 135 137 99 101 113 113

HbA1c (%)
Baseline 
(mean)
Change from
baselined

Difference 
from
placebod

    (95% CI)

7.92

-0.84

-0.54*

(-0.74, -0.34)

8.11

-0.30

7.79

-0.65

-0.35*

(-0.52, -0.18)

7.94

-0.30

7.80

-0.43

-0.40*

(-0.58, -0.23)

7.87

-0.02

Subjects (%) 
achieving:
HbA1c < 7%

Adjusted for
baseline 40.6** 25.9 38.2**

(N=90)
21.4

(N=87)

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

Difference 
from
placebod

    (95% CI)

86.28

-2.86

-1.97*

(-2.63, -1.31)

87.74

-0.89

93.62

-2.74

-1.88***

(-2.52, -1.24)

88.82

-0.86

93.95

-2.35

-1.87*

(-2.61, -1.13)

94.17

-0.47

Abbreviations: QD: once daily; BID: twice daily
1Metformin ≥ 1500 mg/day; 
2Sitagliptin 100 mg/day
aLOCF: Last observation (prior to rescue for rescued subjects) carried forward
bPlacebo-controlled 16-week study
cAll randomised subjects who took at least one dose of double-blind study medicinal product during the 

short-term double-blind period
dLeast 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
***The percent change in body weight was analysed as a key secondary endpoint (p < 0.0001); absolute body 

weight change (in kg) was analysed with a nominal p-value (p < 0.0001).



19

Table 5. Results of a 24-week placebo-controlled study of dapagliflozin in add-on combination
with metformin and a sulphonylurea

Add-on combination
Sulphonylurea
+ Metformin1

Dapagliflozin
10 mg

Placebo

Na 108 108
HbA1c (%)b

Baseline (mean)
Change from Baselinec

Difference from Placeboc

    (95% CI)

8.08
-0.86

−0.69*

(−0.89, −0.49)

8.24
-0.17

Subjects (%) achieving:
HbA1c < 7% 

Adjusted for baseline 31.8* 11.1
Body weight (kg)

Baseline (mean)
Change from Baselinec

Difference from Placeboc

    (95% CI)

88.57
-2.65

−2.07*

(−2.79, −1.35)

90.07
-0.58

1Metformin (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.
bHbA1c analysed using LRM (Longitudinal repeated measures analysis)
cLeast squares mean adjusted for baseline value
*p-value < 0.0001 versus placebo + oral glucose-lowering medicinal product(s)



20

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, including 
metformin)

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 2,000 mg per day) provided 
significant improvements in HbA1c compared to the individual components (Table 7), and led to 
greater reductions in FPG (compared to the individual components) and body weight (compared to 
metformin).



21

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 medicinal product 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 trial 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 
active agent (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 
active agent (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.



22

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 as an add-on to either metformin alone (dapagliflozin 10 mg QD or 
dapagliflozin 5 mg BID) or metformin plus sitagliptin, sulphonylurea or insulin resulted in statistically 
significant reductions in FPG (-1.90 to -1.20 mmol/L [-34.2 to -21.7 mg/dL]) compared with placebo 
(-0.58 to 0.18 mmol/L [-10.4 to 3.3 mg/dL]) at Week 16 (5 mg BID) or Week 24. 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 sitagliptin plus 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 agent alone.

Body weight
Dapagliflozin as an add-on to metformin alone or metformin plus sitagliptin, sulphonylurea or insulin 
(with or without additional oral glucose-lowering medicinal products, including metformin) resulted in 
statistically significant body weight reduction up to 24 weeks (p < 0.0001, Tables 4, 5 and 6). These 
effects were sustained in longer-term trials. At 48 weeks, the difference for dapagliflozin as add-on to 
metformin plus sitagliptin compared with placebo was -2.07 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 change 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 agent alone (Table 8).

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

Blood pressure
In a pre-specified pooled analysis of 13 placebo-controlled studies, treatment with dapagliflozin 10 mg 
resulted in a systolic blood pressure change from baseline of –3.7 mmHg and diastolic blood pressure 



23

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 at 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).

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 an add-on 
to metformin (adjusted mean change from baseline: -1.32% and -0.53% for dapagliflozin and placebo, 
respectively).

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

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 



24

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.



25

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.



26

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.

Metformin
The prospective randomised (UKPDS) study has established the long-term benefit of intensive blood 
glucose control in type 2 diabetes. Analysis of the results for overweight patients treated with 
metformin after failure of diet alone showed:
- a significant reduction of the absolute risk of any diabetes-related complication in the metformin 

group (29.8 events/1,000 patient-years) versus diet alone (43.3 events/1,000 patient-years), 
p=0.0023, and versus the combined sulphonylurea and insulin monotherapy groups 
(40.1 events/1,000 patient-years), p=0.0034;

- a significant reduction of the absolute risk of any diabetes-related mortality: metformin 
7.5 events/1,000 patient-years, diet alone 12.7 events/1,000 patient-years, p=0.017;

- a significant reduction of the absolute risk of overall mortality: metformin 
13.5 events/1,000 patient-years versus diet alone 20.6 events/1,000 patient-years, (p=0.011), and 
versus the combined sulphonylurea and insulin monotherapy groups 
18.9 events/1,000 patient-years (p=0.021);

- a significant reduction in the absolute risk of myocardial infarction: metformin 
11 events/1,000 patient-years, diet alone 18 events/1,000 patient-years, (p=0.01).

Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with 
Xigduo in all 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

Xigduo combination tablets are considered to be bioequivalent to coadministration of corresponding 
doses of dapagliflozin and metformin hydrochloride administered together as individual tablets.

The pharmacokinetics of 5 mg dapagliflozin twice daily and 10 mg dapagliflozin once daily were 
compared in healthy subjects. Administration of 5 mg dapagliflozin twice daily gave similar overall 
exposures (AUCss) over a 24-hour period as 10 mg dapagliflozin administered once daily. As 
expected, dapagliflozin 5 mg administered twice daily compared with 10 mg dapagliflozin once daily 
resulted in lower peak dapagliflozin plasma concentrations (Cmax) and higher trough plasma 
dapagliflozin concentrations (Cmin).

Interaction with food
The administration of this medicinal product in healthy volunteers after a high fat meal compared to 
after the fasted state resulted in the same extent of exposure for both dapagliflozin and metformin. The 
meal resulted in a delay of 1 to 2 hours in the peak concentrations and a decrease in the maximum 
plasma concentration of 29% of dapagliflozin and 17% of metformin. These changes are not 
considered to be clinically meaningful.



27

Paediatric population
Pharmacokinetics in the paediatric population have not been studied.

The following statements reflect the pharmacokinetic properties of the individual active substances of 
this medicinal product.

Dapagliflozin
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%.

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 with 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.



28

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.

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.

Paediatric population
Pharmacokinetics in the paediatric population have not been studied.

Metformin
Absorption
After an oral dose of metformin, tmax is reached in 2.5 h. Absolute bioavailability of a 500 mg or 
850 mg metformin tablet is approximately 50-60% in healthy subjects. After an oral dose, the 
non-absorbed fraction recovered in faeces was 20-30%.

After oral administration, metformin absorption is saturable and incomplete. It is assumed that the 
pharmacokinetics of metformin absorption is non-linear. At the usual metformin doses and dosing 
schedules, steady-state plasma concentrations are reached within 24-48 hours and are generally less 
than 1 μg/mL. In controlled clinical trials, maximum metformin plasma levels (Cmax) did not exceed 
5 μg/mL, even at maximum doses.

Distribution
Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower 
than the plasma peak and appears at approximately the same time. The red blood cells most likely 
represent a secondary compartment of distribution. The mean Vd ranged between 63-276 l.

Biotransformation
Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.

Elimination
Renal clearance of metformin is > 400 mL/min, indicating that metformin is eliminated by glomerular 
filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is 
approximately 6.5 hours.

Special populations
Renal impairment
In patients with decreased renal function (based on measured creatinine clearance), the plasma and 
blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the 
decrease in creatinine clearance, leading to increased levels of metformin in plasma.

5.3 Preclinical safety data

Coadministration of dapagliflozin and metformin
Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose 
toxicity.



29

The following statements reflect the preclinical safety data of the individual active substances of 
Xigduo.

Dapagliflozin
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.

Metformin
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction 
and development.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core
Hydroxypropyl cellulose (E463)
Microcrystalline cellulose (E460(i))



30

Magnesium stearate (E470b)
Sodium starch glycolate type A

Film-coating
Xigduo 5 mg/850 mg film-coated tablets
Polyvinyl alcohol (E1203)
Macrogol 3350 (E1521)
Talc (E553b)
Titanium dioxide (E171)
Iron oxide yellow (E172)
Iron oxide red (E172)

Xigduo 5 mg/1,000 mg film-coated tablets
Polyvinyl alcohol (E1203)
Macrogol 3350 (E1521)
Talc (E553b)
Titanium dioxide (E171)
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

PVC/PCTFE/Alu blister.

Pack sizes
14, 28, 56 and 60 film-coated tablets in non-perforated blisters.
60x1 film-coated tablets in perforated unit dose blisters.
Multipack containing 196 (2 packs of 98) film-coated tablets in non-perforated 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



31

8. MARKETING AUTHORISATION NUMBER(S)

Xigduo 5 mg/850 mg film-coated tablets
EU/1/13/900/001 Xigduo 5 mg/850 mg 14 tablets
EU/1/13/900/002 Xigduo 5 mg/850 mg 28 tablets
EU/1/13/900/003 Xigduo 5 mg/850 mg 56 tablets
EU/1/13/900/004 Xigduo 5 mg/850 mg 60 tablets
EU/1/13/900/005 Xigduo 5 mg/850 mg 60 x 1 tablet (unit dose)
EU/1/13/900/006 Xigduo 5 mg/850 mg 196 (2 x 98) tablets (multipack)

Xigduo 5 mg/1,000 mg film-coated tablets
EU/1/13/900/007 Xigduo 5 mg/1000 mg 14 tablets
EU/1/13/900/008 Xigduo 5 mg/1000 mg 28 tablets
EU/1/13/900/009 Xigduo 5 mg/1000 mg 56 tablets
EU/1/13/900/010 Xigduo 5 mg/1000 mg 60 tablets
EU/1/13/900/011 Xigduo 5 mg/1000 mg 60 x 1 tablet (unit dose)
EU/1/13/900/012 Xigduo 5 mg/1000 mg 196 (2 x 98) tablets (multipack)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 16 January 2014
Date of latest renewal: 28 September 2018

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.



32

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



33

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

Bristol Myers Squibb S.r.l.
Loc. Fontana del Ceraso 
Anagni, 03012
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

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;
 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. 



34

ANNEX III

LABELLING AND PACKAGE LEAFLET



35

A. LABELLING



36

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON – WITH BLUE BOX

1. NAME OF THE MEDICINAL PRODUCT

Xigduo 5 mg/850 mg film-coated tablets
dapagliflozin/metformin hydrochloride

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each tablet contains dapagliflozin propanediol monohydrate equivalent to 5 mg dapagliflozin and 
850 mg of metformin hydrochloride.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

14 film-coated tablets
28 film-coated tablets
56 film-coated tablets
60 film-coated tablets
60xl 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

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE



37

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AstraZeneca AB
SE-151 85 Södertälje
Sweden

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/13/900/001 
EU/1/13/900/002
EU/1/13/900/003
EU/1/13/900/004
EU/1/13/900/005

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

xigduo 5 mg/850 mg

17. UNIQUE IDENTIFIER  2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER  HUMAN READABLE DATA

PC:
SN:
NN:



38

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON – PART OF MULTIPACK - WITH BLUE BOX

1. NAME OF THE MEDICINAL PRODUCT

Xigduo 5 mg/850 mg film-coated tablets
dapagliflozin/metformin hydrochloride

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each tablet contains dapagliflozin propanediol monohydrate equivalent to 5 mg dapagliflozin and 
850 mg of metformin hydrochloride.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

Multipack: 196 (2 packs of 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

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE



39

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AstraZeneca AB
SE-151 85 Södertälje
Sweden

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/13/900/006

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

xigduo 5 mg/850 mg

17. UNIQUE IDENTIFIER  2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER  HUMAN READABLE DATA

PC:
SN:
NN:



40

PARTICULARS TO APPEAR ON THE INTERMEDIATE PACKAGING

INNER CARTON – PART OF MULTIPACK – WITHOUT BLUE BOX

1. NAME OF THE MEDICINAL PRODUCT

Xigduo 5 mg/850 mg film-coated tablets
dapagliflozin/metformin hydrochloride

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each tablet contains dapagliflozin propanediol monohydrate equivalent to 5 mg dapagliflozin and 
850 mg of metformin hydrochloride.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

98 film-coated tablets. Component of a multipack, can’t be sold separately.

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

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE



41

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AstraZeneca AB
SE-151 85 Södertälje
Sweden

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/13/900/006

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

xigduo 5 mg/850 mg

17. UNIQUE IDENTIFIER  2D BARCODE

18. UNIQUE IDENTIFIER  HUMAN READABLE DATA



42

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON – WITH BLUE BOX

1. NAME OF THE MEDICINAL PRODUCT

Xigduo 5 mg/1,000 mg film-coated tablets
dapagliflozin/metformin hydrochloride

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each tablet contains dapagliflozin propanediol monohydrate equivalent to 5 mg dapagliflozin and 
1,000 mg of metformin hydrochloride.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

14 film-coated tablets
28 film-coated tablets
56 film-coated tablets
60 film-coated tablets
60x1 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



43

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/1/13/900/007
EU/1/13/900/008
EU/1/13/900/009
EU/1/13/900/010
EU/1/13/900/011

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

xigduo 5 mg/1,000 mg

17. UNIQUE IDENTIFIER  2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER  HUMAN READABLE DATA

PC:
SN:
NN:



44

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON – PART OF MULTIPACK – WITH BLUE BOX

1. NAME OF THE MEDICINAL PRODUCT

Xigduo 5 mg/1,000 mg film-coated tablets
dapagliflozin/metformin hydrochloride

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each tablet contains dapagliflozin propanediol monohydrate equivalent to 5 mg dapagliflozin and 
1,000 mg of metformin hydrochloride.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

Multipack: 196 (2 packs of 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

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE



45

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AstraZeneca AB
SE-151 85 Södertälje
Sweden

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/13/900/012

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

xigduo 5 mg/1,000 mg

17. UNIQUE IDENTIFIER  2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER  HUMAN READABLE DATA

PC:
SN:
NN:



46

PARTICULARS TO APPEAR ON THE INTERMEDIATE PACKAGING

INNER CARTON – PART OF MULTIPACK – WITHOUT BLUE BOX

1. NAME OF THE MEDICINAL PRODUCT

Xigduo 5 mg/1,000 mg film-coated tablets
dapagliflozin/metformin hydrochloride

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each tablet contains dapagliflozin propanediol monohydrate equivalent to 5 mg dapagliflozin and 
1,000 mg of metformin hydrochloride.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

98 film-coated tablets. Component of a multipack, can’t be sold separately.

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

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE



47

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AstraZeneca AB
SE-151 85 Södertälje
Sweden

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/13/900/012

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

xigduo 5 mg/1,000 mg

17. UNIQUE IDENTIFIER  2D BARCODE

18. UNIQUE IDENTIFIER  HUMAN READABLE DATA



48

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTERS (PERFORATED)

1. NAME OF THE MEDICINAL PRODUCT

Xigduo 5 mg/850 mg tablets
dapagliflozin/metformin HCl

2. NAME OF THE MARKETING AUTHORISATION HOLDER

AstraZeneca AB

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER



49

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTERS (NON-PERFORATED)

1. NAME OF THE MEDICINAL PRODUCT

Xigduo 5 mg/850 mg tablets
dapagliflozin/metformin HCl

2. NAME OF THE MARKETING AUTHORISATION HOLDER

AstraZeneca AB

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

10 tablets blister: {Sun/Moon symbol}
14 tablets blister: Mon. Tue. Wed. Thu. Fri. Sat. Sun.
{Sun/Moon symbol}



50

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTERS (PERFORATED)

1. NAME OF THE MEDICINAL PRODUCT

Xigduo 5 mg/1,000 mg tablets
dapagliflozin/metformin HCl

2. NAME OF THE MARKETING AUTHORISATION HOLDER

AstraZeneca AB

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER



51

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTERS (NON-PERFORATED)

1. NAME OF THE MEDICINAL PRODUCT

Xigduo 5 mg/1,000 mg tablets
dapagliflozin/metformin HCl

2. NAME OF THE MARKETING AUTHORISATION HOLDER

AstraZeneca AB

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

10 tablets blister: {Sun/Moon symbol}
14 tablets blister: Mon. Tue. Wed. Thu. Fri. Sat. Sun.
{Sun/Moon symbol}



52

B. PACKAGE LEAFLET



53

Package leaflet: Information for the patient

Xigduo 5 mg/850 mg film-coated tablets
Xigduo 5 mg/1,000 mg film-coated tablets

dapagliflozin/metformin hydrochloride

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

1. What Xigduo is and what it is used for

This medicine contains two different substances called dapagliflozin and metformin. Both belong to a 
group of medicines called oral anti-diabetics. These are medicines taken by mouth for diabetes.

Xigduo is used for a type of diabetes called “type 2 diabetes” in adult patients (aged 18 years and 
older) and usually occurs when you are older. If you have type 2 diabetes, your pancreas does not 
make enough insulin or your body is not able to use the insulin it produces properly. This leads to a 
high level of sugar (glucose) in your blood. 
 Dapagliflozin works by removing excess sugar from your body via your urine and lowers the 

amount of sugar in your blood. It can also help prevent heart disease.
 Metformin works mainly by inhibiting glucose production in the liver.

To treat diabetes:
 This medicine is taken in combination with diet and exercise.
 This medicine is used if your diabetes cannot be controlled with other medicines used to treat 

diabetes.
 Your doctor may ask you to take this medicine on its own or together with other medicines to 

treat diabetes. This may be another medicine taken by mouth and/or a medicine given by 
injection, such as insulin or a GLP-1 receptor agonist (helps your body to increase the 
production of insulin when your blood sugar is high).

 If you are already taking both dapagliflozin and metformin as single tablets, your doctor may 
ask you to switch to this medicine. To avoid overdose, do not continue taking dapagliflozin and 
metformin tablets, if you are taking Xigduo.

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



54

2. What you need to know before you take Xigduo

Do not take Xigduo
 if you are allergic to dapagliflozin, metformin or any of the other ingredients of this medicine 

(listed in section 6).
 if you have ever had a diabetic coma.
 if you have uncontrolled diabetes, with, for example severe hyperglycaemia (high blood 

glucose), nausea, vomiting, diarrhoea, rapid weight loss, lactic acidosis (see “Risk of lactic 
acidosis” below) or ketoacidosis. Ketoacidosis is a condition in which substances called ‘ketone 
bodies’ accumulate in the blood and which can lead to a diabetic pre-coma. Symptoms include 
stomach pain, fast and deep breathing, sleepiness or your breath developing an unusual fruity 
smell.

 if you have severely reduced kidney function.
 if you have a severe infection.
 if you have lost a lot of water from your body (dehydration), e.g. due to long-lasting or severe 

diarrhoea, or if you have vomited several times in a row.
 if you have recently had a heart attack or if you have heart failure or serious problems with your 

blood circulation or difficulties in breathing.
 if you have problems with your liver.
 if you drink large amounts of alcohol, either every day or only from time to time (please see 

section “Xigduo with alcohol”).

Do not take this medicine if any of the above apply to you.

Warnings and precautions
Risk of lactic acidosis
Xigduo may cause a very rare, but very serious side effect called lactic acidosis, particularly if your 
kidneys are not working properly. The risk of developing lactic acidosis is also increased with 
uncontrolled diabetes, serious infections, prolonged fasting or alcohol intake, dehydration (see further 
information below), liver problems and any medical conditions in which a part of the body has a 
reduced supply of oxygen (such as acute severe heart disease). 
If any of the above apply to you, talk to your doctor for further instructions.

Stop taking Xigduo for a short time if you have a condition that may be associated with 
dehydration (significant loss of body fluids) such as severe vomiting, diarrhoea, fever, exposure to 
heat or if you drink less fluid than normal. Talk to your doctor for further instructions.

Stop taking Xigduo and contact a doctor or the nearest hospital immediately if you experience 
some of the symptoms of lactic acidosis, as this condition may lead to coma. 
Symptoms of lactic acidosis include:

- vomiting
- stomach ache (abdominal pain)
- muscle cramps
- a general feeling of not being well with severe tiredness
- difficulty in breathing
- reduced body temperature and heartbeat

Lactic acidosis is a medical emergency and must be treated in a hospital.

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

does not produce any insulin. Xigduo should not be used to treat this condition.
 if you experience rapid weight loss, 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, contact a 
doctor or the nearest hospital straight away. These symptoms could be a sign of “diabetic 



55

ketoacidosis” – a rare but serious, sometimes life-threatening problem you can get with diabetes 
because of increased levels of “ketone bodies” in your urine or blood, seen in tests. The risk of 
developing diabetic ketoacidosis may be increased with prolonged fasting, excessive alcohol 
consumption, dehydration, sudden reductions in insulin dose, or a higher need of insulin due to 
major surgery or serious illness.

 if you have problems with your kidneys. Your doctor will check your kidney function.
 if you have very high levels of glucose 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 this medicine if you have any of these signs.

 if you are taking medicines to lower blood pressure (anti-hypertensives) and have a history of 
low blood pressure (hypotension). More information is given below under ‘Other medicines and 
Xigduo’.

 if you often get infections of the urinary tract. This medicine may cause urinary tract infections 
and your doctor may want to monitor you more closely. Your doctor may consider temporarily 
changing your treatment if you develop a serious infection.

If you need to have major surgery, you must stop taking Xigduo during and for some time after the 
procedure. Your doctor will decide when you must stop and when to restart your treatment with 
Xigduo. 

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 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.

Kidney function
During treatment with Xigduo, your doctor will check your kidney function at least once every year or 
more frequently if you are elderly and/or if you have worsening kidney function.

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

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

Other medicines and Xigduo
If you need to have an injection of a contrast medium that contains iodine into your bloodstream, for 
example in the context of an X-ray or scan, you must stop taking Xigduo before or at the time of the 
injection. Your doctor will decide when you must stop and when to restart your treatment with 
Xigduo.

Tell your doctor if you are taking, have recently taken or might take any other medicines. You may 
need more frequent blood glucose and kidney function tests, or your doctor may adjust the dosage of 
Xigduo. It is especially important to mention the following:
 if you are taking medicines which increase urine production (diuretics). Your doctor may ask 

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



56

 if you are taking other medicines that lower the amount of sugar in your blood such as insulin or 
a “sulphonylurea” medicine. Your doctor may want to lower the dose of these other medicines, 
to prevent you from getting blood sugar levels that are too low (hypoglycaemia).

 if you are taking cimetidine, a medicine used to treat stomach problems.
 if you are using bronchodilators (beta-2 agonists) which are used to treat asthma.
 if you are using corticosteroids (used to treat inflammation in diseases like asthma and arthritis) 

that are given by mouth, as an injection, or inhaled.
 if you are using medicines used to treat pain and inflammation (NSAID and COX-2-inhibitors, 

such as ibuprofen and celecoxib).
 if you are using certain medicines for the treatment of high blood pressure (ACE inhibitors and 

angiotensin II receptor antagonists).

Xigduo with alcohol
Avoid excessive alcohol intake while taking Xigduo since this may increase the risk of lactic acidosis 
(see “Warnings and precautions”).

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 (the last 
six months) 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. You should 
not use this medicine if you are breast-feeding. Metformin passes into human milk in small amounts. It 
is not known if dapagliflozin passes into human breast milk.

Driving and using machines
This medicine has no or negligible influence on the ability to drive and use machines. Taking it with 
other medicines that lower the amount of sugar in your blood, such as insulin or a “sulphonylurea” 
medicine, can cause too low blood sugar levels (hypoglycaemia), which may cause symptoms such as 
weakness, dizziness, increased sweating, fast heart beat, change in vision or difficulties concentrating, 
and may affect your ability to drive and use machines. Do not drive or use any tools or machines, if 
you start to feel these symptoms.

Sodium content
This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say it is essentially
‘sodium-free’.

3. How to take Xigduo

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

How much to take
 The amount of this medicine that you will take varies depending on your condition and the 

doses you currently take of metformin and/or individual tablets of dapagliflozin and metformin. 
Your doctor will tell you exactly which strength of this medicine to take.

 The recommended dose is one tablet twice a day.

Taking this medicine
 Swallow the tablet whole with half a glass of water.
 Take your tablet with food. This is to reduce the risk of side effects in the stomach.
 Take your tablet twice daily, once in the morning (breakfast) and once in the evening (dinner).



57

Your doctor may prescribe this medicine together with other medicine(s) to lower the amount of sugar 
in your blood. These may be medicine(s) by mouth or given by injection, such as insulin or a GLP-1 
receptor agonist. 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
To control your diabetes, you still need to keep to diet and exercise, even when you are taking this 
medicine. So it is important to keep following the advice about diet and exercise from your doctor, 
pharmacist or nurse. In particular, if you are following a diabetic weight control diet, continue to 
follow it while you are taking this medicine.

If you take more Xigduo than you should
If you take more Xigduo tablets than you should, you may experience lactic acidosis. Symptoms of
lactic acidosis include feeling or being very sick, vomiting, stomach ache, muscular cramps, severe 
tiredness or difficulty breathing. If this happens to you, you may need immediate hospital treatment, as 
lactic acidosis may lead to coma. Stop taking this medicine immediately and contact a doctor or the 
nearest hospital straight away (see section 2). Take the medicine pack with you.

If you forget to take Xigduo
If you miss a dose, take it as soon as you remember. If you do not remember until it is time for your 
next dose, skip the missed dose and go back to your regular schedule. Do not take a double dose of 
this medicine to make up for a forgotten dose.

If you stop taking Xigduo
Do not stop taking this medicine 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.

Stop taking Xigduo and see a doctor straight away if you notice any of the following serious or 
potentially serious side effects:

 Lactic acidosis, seen very rarely (may affect up to 1 in 10,000 people)
Xigduo may cause a very rare, but very serious side effect called lactic acidosis (see section “Warnings 
and precautions”). If this happens you must stop taking Xigduo and contact a doctor or the nearest 
hospital immediately, as lactic acidosis may lead to coma.

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

 Diabetic ketoacidosis, seen rarely (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
- rapid weight loss
- 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.



58

This may occur regardless of blood glucose level. Your doctor may decide to temporarily or 
permanently stop your treatment with Xigduo.

 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 Xigduo and see a doctor as soon as possible if you notice any of the following serious 
or potentially serious effects:

 Dehydration: loss of too much fluid from your body, 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:

 Low blood sugar levels (hypoglycaemia), seen very commonly (may affect more than 1 in 10 
people) - when taking this medicine with a sulphonylurea or other medicines that lower the 
amount of sugar in your blood, such as 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. If you have symptoms of low blood sugar, eat glucose tablets, a high sugar snack or drink fruit 
juice. Measure your blood sugar if possible and rest.

Other side effects include:
Very common
 nausea, vomiting
 diarrhoea or stomach ache
 loss of appetite

Common
 genital infection (thrush) of your penis or vagina (signs may include irritation, itching, unusual 

discharge or odour)
 back pain
 discomfort when passing water (urine), passing more water 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
 changes in taste
 dizziness
 rash



59

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)

Very rare
 decreased vitamin B12 levels in the blood
 abnormalities in liver function tests, inflammation of the liver (hepatitis)
 redness of the skin (erythema), itching or an itchy rash (hives)

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 Xigduo

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 protect the environment.

6. Contents of the pack and other information

What Xigduo contains
 The active substances are dapagliflozin and metformin hydrochloride (metformin HCl).

Each Xigduo 5 mg/850 mg film-coated tablet (tablet) contains 
dapagliflozin propanediol monohydrate equivalent to 5 mg dapagliflozin and 850 mg 
metformin hydrochloride.
Each Xigduo 5 mg/1,000 mg film-coated tablet (tablet) contains dapagliflozin
propanediol monohydrate equivalent to 5 mg dapagliflozin and 1,000 mg 
metformin hydrochloride.

 The other ingredients are:
 tablet core: hydroxypropyl cellulose (E463), microcrystalline cellulose (E460(i)), 

magnesium stearate (E470b), sodium starch glycolate (type A).
 film-coating: polyvinyl alcohol (E1203), macrogol 3350 (E1521), talc (E553b), titanium 

dioxide (E171), iron oxide yellow (E172), iron oxide red (E172) (only Xigduo 5 mg/850 
mg).

What Xigduo looks like and contents of the pack
 Xigduo 5 mg/850 mg are 9.5 x 20 mm oval, brown film-coated tablets. They have “5/850” on 

one side and “1067” on the other side.



60

 Xigduo 5 mg/1,000 mg are 10.5 x 21.5 mm oval, yellow film-coated tablets. They have 
“5/1000” on one side and “1069” on the other side.

Xigduo 5 mg/850 mg film-coated tablets and Xigduo 5 mg/1,000 mg film-coated tablets are available 
in PVC/PCTFE/Alu blister. The pack sizes are 14, 28, 56 and 60 film-coated tablets in non-perforated 
blisters, 60x1 film-coated tablets in perforated unit dose blisters and multipack containing 
196 (2 packs of 98) film-coated tablets in non-perforated 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

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

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



61

España
AstraZeneca Farmacéutica Spain, 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
AstraZeneca Produtos Farmacêuticos, Lda. 
Tel: +351 21 434 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.


	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