This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

NAME OF THE MEDICINAL PRODUCT

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains dapagliflozin propanediol monohydrate equivalent to 5 mg dapagliflozin. Excipient with known effect: Each tablet contains 25 mg of lactose anhydrous. For the full list of excipients, see section 6.1.

PHARMACEUTICAL FORM

Film-coated tablet (tablet). Yellow, biconvex, 0.7 cm diameter round, film-coated tablets with "5" engraved on one side and "1427" engraved on the other side.

CLINICAL PARTICULARS

Posology and method of administration

The recommended dose is 10 mg dapagliflozin once daily for monotherapy and add-on combination therapy with other glucose-lowering medicinal products including insulin. When dapagliflozin is used in combination with insulin or an insulin secretagogue, such as a sulphonylurea, a lower dose of insulin or insulin secretagogue may be considered to reduce the risk of hypoglycaemia (see sections 4.5 and 4.8).

The efficacy of dapagliflozin is dependent on renal function, and efficacy is reduced in patients who have moderate renal impairment and likely absent in patients with severe renal impairment. Forxiga is not recommended for use in patients with moderate to severe renal impairment (patients with creatinine clearance [CrCl] < 60 ml/min or estimated glomerular filtration rate [eGFR] < 60 ml/min/1.73 m2, see sections 4.4, 4.8, 5.1 and 5.2). No dosage adjustment is indicated in patients with mild renal impairment.

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

In general, no dosage adjustment is recommended based on age. Renal function and risk of volume depletion should be taken into account (see sections 4.4 and 5.2). Due to the limited therapeutic experience in patients 75 years and older, initiation of dapagliflozin therapy is not recommended.

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

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

Contraindications

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

Special warnings and precautions for use

Forxiga should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

The efficacy of dapagliflozin is dependent on renal function, and efficacy is reduced in patients who have moderate renal impairment and likely absent in patients with severe renal impairment (see section 4.2). In subjects with moderate renal impairment (patients with CrCl < 60 ml/min or eGFR < 60 ml/min/1.73 m2), a higher proportion of subjects treated with dapagliflozin had adverse reactions of increase in creatinine, phosphorus, parathyroid hormone (PTH) and hypotension, compared with placebo. Forxiga is not recommended for use in patients with moderate to severe renal impairment (patients with CrCl < 60 ml/min or eGFR < 60 ml/min/1.73 m2). Forxiga has not been studied in severe renal impairment (CrCl < 30 ml/min or eGFR < 30 ml/min/1.73 m2) or end-stage renal disease (ESRD). Monitoring of renal function is recommended as follows:

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

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

Due to its mechanism of action, dapagliflozin increases diuresis associated with a modest decrease in blood pressure (see section 5.1), which may be more pronounced in patients with very high blood glucose concentrations. Dapagliflozin is not recommended for use in patients receiving loop diuretics (see section 4.5) or who are volume depleted, e.g. due to acute illness (such as gastrointestinal illness). Caution should be exercised in patients for whom a dapagliflozin-induced drop in blood pressure could pose a risk, such as patients with known cardiovascular disease, patients on anti-hypertensive therapy with a history of hypotension or elderly patients. For patients receiving dapagliflozin, in case of intercurrent conditions that may lead to volume depletion, careful monitoring of volume status (e.g. physical examination, blood pressure measurements, laboratory tests including haematocrit) and electrolytes is recommended. Temporary interruption of treatment with dapagliflozin is recommended for patients who develop volume depletion until the depletion is corrected (see section 4.8).

Urinary tract infections were more frequently reported for dapagliflozin 10 mg compared to placebo in a pooled analysis up to 24 weeks (see section 4.8). Pyelonephritis was uncommon and occurred at a similar frequency to control. Urinary glucose excretion may be associated with an increased risk of urinary tract infection; therefore, temporary interruption of dapagliflozin should be considered when treating pyelonephritis or urosepsis.

Elderly 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). In subjects >= 65 years of age, a higher proportion of subjects treated with dapagliflozin had adverse reactions related to renal impairment or failure compared with placebo. The most commonly reported adverse reaction related to renal function was serum creatinine increases, the majority of which were transient and reversible (see section 4.8). Elderly patients may be at a greater risk for volume depletion and are more likely to be treated with diuretics. In subjects >= 65 years of age, a higher proportion of subjects treated with dapagliflozin had adverse reactions related to volume depletion (see section 4.8). Therapeutic experience in patients 75 years and older is limited. Initiation of dapagliflozin therapy in this population is not recommended (see sections 4.2 and 5.2).

Experience in NYHA class I-II is limited, and there is no experience in clinical studies with dapagliflozin in NYHA class III-IV.

While a causal relationship between dapagliflozin and bladder cancer is unlikely (see sections 4.8 and 5.3), as a precautionary measure, dapagliflozin is not recommended for use in patients concomitantly treated with pioglitazone. Available epidemiological data for pioglitazone suggest a small increased risk of bladder cancer in diabetic patients treated with pioglitazone.

Haematocrit increase was observed with dapagliflozin treatment (see section 4.8); therefore, caution in patients with already elevated haematocrit is warranted.

Dapagliflozin has not been studied in combination with glucagon-like peptide 1 (GLP-1) analogues.

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

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

Interaction with other medicinal products and other forms of interaction

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

Insulin and insulin secretagogues, 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).

The metabolism of dapagliflozin is primarily via glucuronide conjugation mediated by UDP glucuronosyltransferase 1A9 (UGT1A9). In in vitro studies, dapagliflozin neither inhibited cytochrome P450 (CYP) 1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, nor induced CYP1A2, CYP2B6 or CYP3A4. Therefore, dapagliflozin is not expected to alter the metabolic clearance of coadministered medicinal products that are metabolised by these enzymes.

Interaction studies conducted in healthy subjects, using mainly a single dose design, suggest that the pharmacokinetics of dapagliflozin are not altered by metformin, pioglitazone, sitagliptin, glimepiride, voglibose, hydrochlorothiazide, bumetanide, valsartan, or simvastatin. Following coadministration of dapagliflozin with rifampicin (an inducer of various active transporters and drug-metabolising enzymes) a 22% decrease in dapagliflozin systemic exposure (AUC) was observed, but with no clinically meaningful effect on 24-hour urinary glucose excretion. No dose adjustment is recommended. A clinically relevant effect with other inducers (e.g. carbamazepine, phenytoin, phenobarbital) is not expected. Following coadministration of dapagliflozin with mefenamic acid (an inhibitor of UGT1A9), a 55% increase in dapagliflozin systemic exposure was seen, but with no clinically meaningful effect on 24-hour urinary glucose excretion. No dose adjustment is recommended.

In interaction studies conducted in healthy subjects, using mainly a single-dose design, dapagliflozin did not alter the pharmacokinetics of metformin, pioglitazone, sitagliptin, glimepiride, hydrochlorothiazide, bumetanide, valsartan, digoxin (a P-gp substrate) or warfarin (S-warfarin, a CYP2C9 substrate), or the anticoagulatory effects of warfarin as measured by INR. Combination of a single dose of dapagliflozin 20 mg and simvastatin (a CYP3A4 substrate) resulted in a 19% increase in AUC of simvastatin and 31% increase in AUC of simvastatin acid. The increase in simvastatin and simvastatin acid exposures are not considered clinically relevant.

The effects of smoking, diet, herbal products and alcohol use on the pharmacokinetics of dapagliflozin have not been studied.

Fertility, pregnancy and lactation

There are no data from the use of dapagliflozin in pregnant women. Studies in rats have shown toxicity to the developing kidney in the time period corresponding to the second and third trimesters of human pregnancy (see section 5.3). Therefore, the use of dapagliflozin is not recommended during the second and third trimesters of pregnancy. When pregnancy is detected, treatment with dapagliflozin should be discontinued. Breast-feeding It is unknown whether dapagliflozin and/or its metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of dapagliflozin/metabolites in milk, as well as pharmacologically-mediated effects in nursing offspring (see section 5.3). A risk to the newborns/infants cannot be excluded. Dapagliflozin should not be used while breast-feeding.

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

Effects on ability to drive and use machines

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

Undesirable effects

Summary of the safety profile

In a pre-specified pooled analysis of 12 placebo-controlled studies, 1,193 subjects were treated with dapagliflozin 10 mg and 1,393 were treated with placebo. The overall incidence of adverse events (short-term treatment) in subjects treated with dapagliflozin 10 mg was similar to placebo. Few adverse events led to discontinuation of treatment and were balanced across study groups. The most commonly reported events leading to discontinuation in patients treated with dapagliflozin 10 mg were increased blood creatinine (0.4%), urinary tract infections (0.3%), nausea (0.2%), dizziness (0.2%), and rash (0.2%). One subject receiving dapagliflozin experienced a liver adverse event with diagnoses of drug induced hepatitis and/or autoimmune hepatitis. The most frequently reported adverse reaction was hypoglycaemia, which depended on the type of background therapy used in each study. The frequency of minor episodes of hypoglycaemia was similar between treatment groups, including placebo, with the exceptions of studies with add-on sulphonylurea (SU) and add-on insulin therapies. Combination therapies with sulphonylurea and add-on insulin had higher rates of hypoglycaemia (see Hypoglycaemia below).

Tabulated list of adverse reactions

The following adverse reactions have been identified in the placebo-controlled clinical trials. None were found to be dose-related. Adverse reactions listed below are classified according to frequency and system organ class (SOC). Frequency categories are defined according to the following convention: very common (>= 1/10), common (>= 1/100 to < 1/10), uncommon (>= 1/1,000 to < 1/100), rare (>= 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data). Table 1. Adverse reactions in placebo-controlled studiesa

System organ class	Very common	Common *	Uncommon * *
Infections and infestations		Vulvovaginitis, balanitis and related genital infections b ,c Urinary tract infection b	Vulvovaginal pruritus
Metabolism and nutrition disorders	Hypoglycaemia (when used with SU or insulin) b		Volume depletion b ,e Thirst
Gastrointestinal disorders			Constipation
Skin and subcutaneous tissue disorders			Hyperhidrosis
Musculoskeletal and connective tissue disorders		Back pain
Renal and urinary disorders		Dysuria Polyuria d	Nocturia
Investigations		Dyslipidaemia f Haematocrit increased g	Blood creatinine increased Blood urea increased

The table shows up to 24-week (short-term) data regardless of glycaemic rescue.

See corresponding subsection below for additional information.

Vulvovaginitis, balanitis and related genital infections includes, e.g. the predefined preferred terms: vulvovaginal mycotic infection, vaginal infection, balanitis, genital infection fungal, vulvovaginal candidiasis, vulvovaginitis, balanitis candida, genital candidiasis, genital infection, genital infection male, penile infection, vulvitis, vaginitis bacterial, vulval abscess.

Polyuria includes the preferred terms: pollakiuria, polyuria, urine output increased.

Volume depletion includes, e.g. the predefined preferred terms: dehydration, hypovolaemia, hypotension.

Mean percent change from baseline for dapagliflozin 10 mg versus placebo, respectively, was: total cholesterol 1.4% versus -0.4%; HDL cholesterol 5.5% versus 3.8%; LDL cholesterol 2.7% versus -1.9%; triglycerides -5.4%

versus -0.7%.

Mean changes from baseline in haematocrit were 2.15% for dapagliflozin 10 mg versus -0.40% for placebo.

Reported in >= 2% of subjects treated with dapagliflozin 10 mg and >= 1% more frequently than placebo.

* *

Reported in >= 0.2% of subjects and >= 0.1% more and at least 3 more subjects treated with dapagliflozin 10 mg regardless of glycaemic rescue compared to placebo.

Description of selected adverse reactions

Hypoglycaemia

The frequency of hypoglycaemia depended on the type of background therapy used in each study. For studies of dapagliflozin in monotherapy, as add-on to metformin or as add-on to sitagliptin (with or without metformin), the frequency of minor episodes of hypoglycaemia was similar (< 5%) between treatment groups, including placebo up to 102 weeks of treatment. Across all studies, major events of hypoglycaemia were uncommon and comparable between the groups treated with dapagliflozin or placebo. Studies with add-on sulphonylurea and add-on insulin therapies had higher rates of hypoglycaemia (see section 4.5). In an add-on to glimepiride study, minor episodes of hypoglycaemia were reported more frequently in the group treated with dapagliflozin 10 mg plus glimepiride (6.0%) than in the placebo plus glimepiride group (2.1%). In an add-on to insulin study, episodes of major hypoglycaemia were reported in 0.5% and 1.0% of subjects treated with dapagliflozin 10 mg plus insulin at Weeks 24 and 104, respectively, and in 0.5% of subjects treated with placebo plus insulin groups at Weeks 24 and 104. At Weeks 24 and 104, minor episodes of hypoglycaemia were reported, respectively, in 40.3% and 53.1% of subjects who received dapagliflozin 10 mg plus insulin and in 34.0% and 41.6% of the subjects who received placebo plus insulin.

Volume depletion

Reactions related to volume depletion (including, reports of dehydration, hypovolaemia or hypotension) were reported in 0.8% and 0.4% 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).

Vulvovaginitis, balanitis and related genital infections

Vulvovaginitis, balanitis and related genital infections were reported in 4.8% and 0.9% 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 (6.9% and 1.5% for dapagliflozin and placebo, respectively), and subjects with a prior history were more likely to have a recurrent infection.

Urinary tract infections

Urinary tract infections were more frequently reported for dapagliflozin 10 mg compared to placebo (4.3% versus 3.7%, 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.

Parathyroid hormone (PTH)

Small increases in serum PTH levels were observed with increases being larger in subjects with higher baseline PTH concentrations. Bone mineral density measurements in patients with normal or mildly impaired renal function did not indicate bone loss over a treatment period of one year.

Malignancies

During clinical trials, the overall proportion of subjects with malignant or unspecified tumours was similar between those treated with dapagliflozin (1.47%) and placebo/comparator (1.35%), and there was no carcinogenicity or mutagenicity signal in animal data (see section 5.3). When considering the cases of tumours occurring in the different organ systems, the relative risk associated with dapagliflozin was above 1 for some tumours (bladder, prostate, breast) and below 1 for others (e.g. blood and lymphatic, ovary, renal tract), not resulting in an overall increased tumour risk associated with dapagliflozin. The increased/decreased risk was not statistically significant in any of the organ systems. Considering the lack of tumour findings in non-clinical studies as well as the short latency between first drug exposure and tumour diagnosis, a causal relationship is considered unlikely. Since the numerical imbalance of breast, bladder and prostate tumours must be considered with caution, it will be further investigated in post-authorisation studies.

Special populations

Elderly patients (>= 65 years)

In subjects >= 65 years of age, adverse reactions related to renal impairment or failure were reported in 2.5% of subjects treated with dapagliflozin and 1.1% of subjects treated with placebo (see section 4.4). The most commonly reported adverse reaction related to renal function was increased serum creatinine. The majority of these reactions were transient and reversible. In subjects >= 65 years of age, adverse reactions of volume depletion, most commonly reported as hypotension, were reported in 1.5% and 0.4% of dapagliflozin-treated subjects and placebo-treated subjects, respectively (see section 4.4).

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

Overdose

Dapagliflozin did not show any toxicity in healthy subjects at single oral doses up to 500 mg (50 times the maximum recommended human dose). These subjects had detectable glucose in the urine for a dose-related period of time (at least 5 days for the 500 mg dose), with no reports of dehydration, hypotension or electrolyte imbalance, and with no clinically meaningful effect on QTc interval. The incidence of hypoglycaemia was similar to placebo. In clinical studies where once-daily doses of up to 100 mg (10 times the maximum recommended human dose) were administered for 2 weeks in healthy subjects and type 2 diabetes subjects, the incidence of hypoglycaemia was slightly higher than placebo and was not dose-related. Rates of adverse events including dehydration or hypotension were similar to placebo, and there were no clinically meaningful dose-related changes in laboratory parameters, including serum electrolytes and biomarkers of renal function. In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient's clinical status. The removal of dapagliflozin by haemodialysis has not been studied.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacotherapeutic group: Drugs used in diabetes, Other blood glucose lowering drugs, excluding insulins, ATC code: A10BX09

Dapagliflozin is a highly potent (Ki: 0.55 nM), selective and reversible inhibitor of sodium-glucose co-transporter 2 (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 Forxiga. Urinary glucose excretion (glucuresis) induced by dapagliflozin is associated with caloric loss and reduction in weight. Inhibition of glucose and sodium co-transport by dapagliflozin is also associated with mild diuresis and transient natriuresis. Dapagliflozin does not inhibit other glucose transporters important for glucose transport into peripheral tissues and is > 1,400 times more selective for SGLT2 versus SGLT1, the major transporter in the gut responsible for glucose absorption.

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).

Twelve double-blind, randomised, controlled clinical trials were conducted with 6,144 subjects with type 2 diabetes to evaluate the efficacy and safety of Forxiga; 4,164 subjects in these studies were treated with dapagliflozin. Eleven studies had a treatment period of 24 weeks duration, 6 with long-term extensions ranging from 24 to 78 weeks (up to a total study duration of 102 weeks), and one study was 52 weeks in duration with a long-term extension of 52 weeks (total study duration of 104 weeks). Mean duration of diabetes ranged from 1.4 to 16.9 years. Fifty-one percent had mild renal impairment and 11% had moderate renal impairment. Fifty-one percent (51%) of the subjects were men, 83% were White, 10% were Asian, 3% were Black and 4% were of other racial groups. Eighty percent (80%) of the subjects had a body mass index (BMI) >= 27.

A double-blind, placebo-controlled study of 24-week duration (with an additional extension period) was conducted to evaluate the safety and efficacy of monotherapy with Forxiga in subjects with inadequately controlled type 2 diabetes mellitus. Once-daily treatment with dapagliflozin resulted in statistically significant (p < 0.0001) reductions in HbA1c compared to placebo (Table 2). In the extension period, HbA1c reductions were sustained through Week 102 (-0.63%, and -0.18% adjusted mean change from baseline for dapagliflozin 10 mg and placebo, respectively). Table 2. Results at Week 24 (LOCFa) of a placebo-controlled study of dapagliflozin as monotherapy

Monotherapy

Dapagliflozin 10 mg

Placebo

HbA1c (%)

Baseline (mean)

Subjects (%) achieving: HbA1c < 7%

Body weight (kg)

Baseline (mean) Change from baselinec Difference from placeboc (95% CI) 94.13 -3.16 -0.97 (-2.20, 0.25) 88.77 -2.19

All randomised subjects who took at least one dose of double-blind study medication during the short-term double-blind period

Not evaluated for statistical significance as a result of the sequential testing procedure for secondary end points

In a 52-week, active-controlled non-inferiority study (with a 52-week extension period), Forxiga was evaluated as add-on therapy to metformin compared with a sulphonylurea (glipizide) as add-on therapy to metformin in subjects with inadequate glycaemic control (HbA1c > 6.5% and <= 10%). The results showed a similar mean reduction in HbA1c from baseline to Week 52, compared to glipizide, thus demonstrating non-inferiority (Table 3). At Week 104, adjusted mean change from baseline in HbA1c was -0.32% for dapagliflozin and -0.14% for glipizide. At 52 and 104 weeks, a significantly lower proportion of subjects in the group treated with dapagliflozin (3.5% and 4.3%, respectively) experienced at least one event of hypoglycaemia compared to the group treated with glipizide (40.8% and 47.0%, respectively). The proportion of subjects remaining in the study at Week 104 was 56.2% for the group treated with dapagliflozin and 50.0% for the group treated with glipizide. Table 3. Results at Week 52 (LOCFa) in an active-controlled study comparing dapagliflozin to glipizide as add-on to metformin

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS