XIGDUO 5mg / 850mg film-coated tablets medication leaflet

Xigduo 5 mg/850 mg film-coated tablets

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

Xigduo 5 mg/850 mg film-coated tablets

Each tablet contains dapagliflozin propanediol monohydrate equivalent to 5 mg dapagliflozin and850 mg of metformin hydrochloride.

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

Each tablet contains dapagliflozin propanediol monohydrate equivalent to 5 mg dapagliflozin and1,000 mg of metformin hydrochloride.

For the full list of excipients, see section 6.1.

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.

Xigduo is indicated in adults for the treatment of type 2 diabetes mellitus as an adjunct to diet andexercise:

* in patients insufficiently controlled on their maximally tolerated dose of metformin alone

* in combination with other medicinal products for the treatment of diabetes in patientsinsufficiently controlled with metformin and these medicinal products

* in patients already being treated with the combination of dapagliflozin and metformin asseparate tablets.

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

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 dapagliflozinand metformin (see section 2).

For patients insufficiently controlled on metformin monotherapy or metformin in combination withother medicinal products for the treatment of diabetes

Patients insufficiently controlled on metformin alone or in combination with other medicinal productsfor the treatment of diabetes should receive a total daily dose of Xigduo equivalent todapagliflozin 10 mg, plus the total daily dose of metformin, or the nearest therapeutically appropriatedose, already being taken. When Xigduo is used in combination with insulin or an insulinsecretagogue such as sulphonylurea, a lower dose of insulin or sulphonylurea may be considered toreduce 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 thenearest therapeutically appropriate dose of metformin.

A GFR should be assessed before initiation of treatment with metformin containing medicinalproducts and at least annually thereafter. In patients at increased risk of further progression of renalimpairment and in the elderly, renal function should be assessed more frequently, e.g. every3-6 months.

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

If no adequate strength of Xigduo is available, individual monocomponents should be used instead ofthe fixed dose combination.

Table 1. Dosage in patients with renal impairment

GFR mL/min Metformin Dapagliflozin

Maximum daily dose is 3000 mg. Maximum daily dose is 10 mg.60-89

Dose reduction may be considered inrelation to declining renal function.

Maximum daily dose is 2000 mg. Maximum daily dose is 10 mg.45-59

The starting dose is at most half of themaximum dose.

Maximum daily dose is 1000 mg. Maximum daily dose is 10 mg.30-44 The starting dose is at most half of the The glucose lowering efficacy ofmaximum dose. dapagliflozin is reduced.

Maximum daily dose is 10 mg.

Due to limited experience, it is notrecommended to initiate treatment< 30 Metformin is contraindicated. with dapagliflozin in patients with

GFR < 25 mL/min.

The glucose lowering efficacy ofdapagliflozin is likely absent.

This medicinal product must not be used in patients with hepatic impairment (see sections pct. 4.3, pct. 4.4 and5.2).

Because metformin is eliminated in part by the kidney, and because elderly patients are more likely tohave 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).

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

Xigduo should be given twice daily with meals to reduce the gastrointestinal adverse reactionsassociated with metformin.

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, pct. 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, pct. 4.4 and 5.2);

- acute alcohol intoxication, alcoholism (see section 4.5).

Lactic acidosis

Lactic acidosis, a very rare but serious metabolic complication, most often occurs at acute worseningof renal function or cardiorespiratory illness or sepsis. Metformin accumulation occurs at acuteworsening 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 betemporarily discontinued and contact with a healthcare professional is recommended.

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

Patients and/or caregivers should be informed on the risk of lactic acidosis. Lactic acidosis ischaracterised by acidotic dyspnoea, abdominal pain, muscle cramps, asthenia and hypothermiafollowed by coma. In case of suspected symptoms, the patient should stop taking Xigduo and seekimmediate 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.

Patients with known or suspected mitochondrial diseases

In patients with known mitochondrial diseases such as Mitochondrial Encephalomyopathy with Lactic

Acidosis, and Stroke-like episodes (MELAS) syndrome and Maternally Inherited Diabetes and

Deafness (MIDD), metformin is not recommended due to the risk of lactic acidosis exacerbation andneurologic complications which may lead to worsening of the disease.

In case of signs and symptoms suggestive of MELAS syndrome or MIDD after the intake ofmetformin, treatment with metformin should be withdrawn immediately and prompt diagnosticevaluation should be performed.

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

Metformin is excreted by the kidney, and moderate to severe renal insufficiency increases the risk oflactic acidosis (see section 4.4). Renal function should be assessed before initiation of treatment andregularly thereafter (see section 4.2). Metformin is contraindicated in patients with GFR < 30 mL/minand should be temporarily discontinued in the presence of conditions that alter renal function (seesection 4.3).

Decreased renal function in elderly patients is frequent and asymptomatic. Special caution should beexercised in situations where renal function may become impaired, for example when initiatinganti-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 modestdecrease in blood pressure observed in clinical studies (see section 5.1). It may be more pronounced inpatients with high blood glucose concentrations.

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

In case of intercurrent conditions that may lead to volume depletion (e.g. gastrointestinal illness),careful monitoring of volume status (e.g. physical examination, blood pressure measurements,laboratory tests including haematocrit and electrolytes) is recommended. Temporary interruption oftreatment with this medicinal product is recommended for patients who develop volume depletionuntil the depletion is corrected (see section 4.8).

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

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

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

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

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

Prolonged ketoacidosis and prolonged glucosuria have been observed with dapagliflozin. Ketoacidosismay last longer after discontinuation of dapagliflozin than expected from the plasma half-life (seesection 5.2). Dapagliflozin-independent factors, such as insulin deficiency, might be involved inprolonged periods of ketoacidosis.

Patients who may be at higher risk of DKA include patients with a low beta-cell function reserve (e.g.

type 2 diabetes patients with low C-peptide or latent autoimmune diabetes in adults (LADA) orpatients with a history of pancreatitis), patients with conditions that lead to restricted food intake orsevere dehydration, patients for whom insulin doses are reduced and patients with increased insulinrequirements due to acute medical illness, surgery or alcohol abuse. SGLT2 inhibitors should be usedwith caution in these patients.

Restarting SGLT2 inhibitor treatment in patients with previous DKA while on SGLT2 inhibitortreatment 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 mellitusstudies, DKA was reported with common frequency.

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 arare but serious and potentially life-threatening event that requires urgent surgical intervention andantibiotic treatment.

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

Urinary tract infections

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

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

Elderly patients are more likely to have impaired renal function, and/or to be treated withanti-hypertensive medicinal products that may cause changes in renal function such asangiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II type 1 receptor blockers (ARB).

The same recommendations for renal function apply to elderly patients as to all patients (seesections 4.2, pct. 4.4, pct. 4.8 and 5.1).

Cardiac failure

Experience with dapagliflozin in New York Heart Association (NYHA) class IV is limited.

Increased haematocrit

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

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

Due to its mechanism of action, patients taking this medicinal product will test positive for glucose intheir 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 bediscontinued prior to, or at the time of, the imaging procedure and not restarted until at least 48 hoursafter, provided that renal function has been re-evaluated and found to be stable (see sections 4.2and 4.5).

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 nutritionand 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 previouslywell-controlled on it who develops laboratory abnormalities or clinical illness (especially vague andpoorly 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 stoppedimmediately and other appropriate corrective measures initiated.

Vitamin B12 decrease/deficiency

Metformin may reduce vitamin B12 serum levels. The risk of low vitamin B12 levels increases withincreasing metformin dose, treatment duration, and/or in patients with risk factors known to causevitamin B12 deficiency. In case of suspicion of vitamin B12 deficiency (such as anaemia orneuropathy), vitamin B12 serum levels should be monitored. Periodic vitamin B12 monitoring could benecessary in patients with risk factors for vitamin B12 deficiency. Metformin therapy should becontinued for as long as it is tolerated and not contraindicated and appropriate corrective treatment forvitamin B12 deficiency provided in line with current clinical guidelines.

This medicinal product contains less than 1 mmol (23 mg) sodium per tablet, i.e. is essentially“sodium free”.

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

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

Dapagliflozin

This medicinal product may add to the diuretic effect of thiazide and loop diuretics and may increasethe risk of dehydration and hypotension (see section 4.4).

Insulin and insulin secretagogues, such as sulphonylureas, cause hypoglycaemia. Therefore, a lowerdose of insulin or an insulin secretagogue may be required to reduce the risk of hypoglycaemia whenused in combination with dapagliflozin (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, this medicinal product is not expected to alter the metabolic clearance of coadministeredmedicinal 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 thepharmacokinetics of dapagliflozin are not altered by pioglitazone, sitagliptin, glimepiride, voglibose,hydrochlorothiazide, bumetanide, valsartan, or simvastatin.

Following coadministration of dapagliflozin with rifampicin (an inducer of various active transportersand drug-metabolising enzymes) a 22% decrease in dapagliflozin systemic exposure (AUC) wasobserved, but with no clinically meaningful effect on 24-hour urinary glucose excretion. No doseadjustment is recommended. A clinically relevant effect with other inducers (e.g. carbamazepine,phenytoin, phenobarbital) is not expected.

Following coadministration of dapagliflozin with mefenamic acid (an inhibitor of UGT1A9), a 55%increase in dapagliflozin systemic exposure was seen, but with no clinically meaningful effect on24-hour urinary glucose excretion. No dose adjustment is recommended.

Effect of dapagliflozin on other medicinal products

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

Serum concentration of lithium should be monitored more frequently after dapagliflozin initiation.

Please refer the patient to the lithium prescribing doctor in order to monitor serum concentration oflithium.

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

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

Interaction studies have only been performed in adults.

Cationic substances that are eliminated by renal tubular secretion (e.g. cimetidine) may interact withmetformin by competing for common renal tubular transport systems. A study conducted in sevennormal healthy volunteers showed that cimetidine, administered as 400 mg twice daily, increasedmetformin systemic exposure (AUC) by 50% and Cmax by 81%. Therefore, close monitoring ofglycaemic control, dose adjustment within the recommended posology and changes in diabetictreatment should be considered when cationic medicinal products that are eliminated by renal tubularsecretion are coadministered.

Alcohol

Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in the case offasting, malnutrition or hepatic impairment due to the metformin active substance of this medicinalproduct (see section 4.4). Consumption of alcohol and medicinal products containing alcohol shouldbe 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 bediscontinued prior to, or at the time of the imaging procedure and not restarted until at least 48 hoursafter, provided that renal function has been re-evaluated and found to be stable (see sections 4.2and 4.4).

Combination requiring precautions for use

Glucocorticoids (given by systemic and local routes), beta-2 agonists, and diuretics have intrinsichyperglycaemic activity. The patient should be informed and more frequent blood glucose monitoringperformed, especially at the beginning of treatment with such medicinal products. If necessary, thedose of the glucose-lowering medicinal product should be adjusted during therapy with the othermedicinal product and on its discontinuation.

Some medicinal products can adversely affect renal function which may increase the risk of lacticacidosis, 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 suchproducts in combination with metformin, close monitoring of renal function is necessary.

Insulin and insulin secretagogues, such as sulphonylureas, cause hypoglycaemia. Therefore, a lowerdose of insulin or an insulin secretagogue may be required to reduce the risk of hypoglycaemia whenused in combination with metformin (see sections 4.2 and 4.8).

There are no data from the use of Xigduo or dapagliflozin in pregnant women. Studies in rats treatedwith dapagliflozin have shown toxicity to the developing kidney in the time period corresponding tothe second and third trimesters of human pregnancy (see section 5.3). Therefore, the use of thismedicinal product is not recommended during the second and third trimesters of pregnancy. A limitedamount of data from the use of metformin in pregnant women does not indicate an increased risk ofcongenital malformations. Animal studies with metformin do not indicate harmful effects with respectto 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 isnot treated with this medicinal product, but insulin be used to maintain blood glucose levels as close tonormal as possible, to reduce the risk of malformations of the foetus associated with abnormal bloodglucose levels.

It is unknown whether this medicinal product or dapagliflozin (and/or its metabolites) are excreted inhuman milk. Available pharmacodynamic/toxicological data in animals have shown excretion ofdapagliflozin/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 thenewborns/infants cannot be excluded.

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

The effect of this medicinal product or dapagliflozin on fertility in humans has not been studied. Inmale 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).

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

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

In an analysis of 5 placebo-controlled dapagliflozin add-on to metformin studies, the safety resultswere 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 wereidentified for the dapagliflozin plus metformin group compared with those reported for the individualcomponents. In the separate dapagliflozin add-on to metformin pooled analysis, 623 subjects weretreated with dapagliflozin 10 mg as add-on to metformin and 523 were treated with placebo plusmetformin.

Dapagliflozin

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

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

In the dapagliflozin cardiovascular outcomes study (DECLARE, see section 5.1), 8,574 patientsreceived dapagliflozin 10 mg and 8,569 received placebo for a median exposure time of 48 months. Intotal, there were 30,623 patient-years of exposure to dapagliflozin.

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

The following adverse reactions have been identified in the placebo-controlled dapagliflozin plusmetformin clinical studies, dapagliflozin clinical studies and metformin clinical studies andpost-marketing experience. None were found to be dose-related. Adverse reactions listed below areclassified according to frequency and system organ class. Frequency categories are defined accordingto 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 (cannotbe estimated from the available data).

Table 2. Adverse reactions in dapagliflozin and metformin immediate-release clinical trial andpost-marketing dataa

System organ Very common Common Uncommon Rare Very rareclass

Infections and Vulvovaginitis, Fungal Necrotisinginfestations balanitis and infection** fasciitis ofrelated genital the perineuminfections*,b,c (Fournier’s

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

Metabolism and Hypoglycaemia Vitamin B12 Volume Diabetic Lacticnutrition (when used decrease/ depletionb,e ketoacidosisb,j,k acidosisdisorders with SU or deficiencyj,§ Thirst**insulin)b

Nervous system Tastedisorders disturbance§

Dizziness

Gastrointestinal Gastro- Constipation**disorders intestinal Dry mouth**symptomsh,§

Hepatobiliary Liverdisorders functiondisorders§

Hepatitis§

Skin and Rashl Urticaria§subcutaneous Erythema§tissue disorders Pruritus§

Musculo- Back pain*skeletal andconnectivetissue disorders

Renal and Dysuria Nocturia** Tubulo-urinary Polyuria*,f interstitialdisorders nephritis

Reproductive Vulvovaginalsystem and pruritus**breast disorders Pruritusgenital**

Investigations Haematocrit Bloodincreasedg creatinine

Creatinine increasedrenal clearance during initialdecreased treatment**,bduring initial Blood ureatreatmentb increased**

Dyslipidaemiai Weightdecreased**aThe table shows adverse reactions identified from up to 24-week (short-term) data regardless of glycaemicrescue, except those marked with § (see below).bSee corresponding subsection below for additional information.cVulvovaginitis, balanitis and related genital infections includes, e.g. the predefined preferred terms:

vulvovaginal mycotic infection, vaginal infection, balanitis, genital infection fungal, vulvovaginal candidiasis,vulvovaginitis, balanitis candida, genital candidiasis, genital infection, genital infection male, penile infection,vulvitis, vaginitis bacterial, vulval abscess.dUrinary tract infection includes the following preferred terms, listed in order of frequency reported: urinary tractinfection, cystitis, Escherichia urinary tract infection, genitourinary tract infection, pyelonephritis, trigonitis,urethritis, kidney infection and prostatitis.

eVolume depletion includes, e.g. the predefined preferred terms: dehydration, hypovolaemia, hypotension.fPolyuria includes the preferred terms: pollakiuria, polyuria, urine output increased.gMean changes from baseline in haematocrit were 2.30% for dapagliflozin 10 mg versus -0.33% for placebo.

Haematocrit values > 55% were reported in 1.3% of the subjects treated with dapagliflozin 10 mg versus 0.4%of placebo subjects.hGastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite occur mostfrequently during initiation of therapy and resolve spontaneously in most cases.iMean percent change from baseline for dapagliflozin 10 mg versus placebo, respectively, was: total cholesterol2.5% versus 0.0%; HDL cholesterol 6.0% versus 2.7%; LDL cholesterol 2.9% versus -1.0%; triglycerides -2.7%versus -0.7%.jSee section 4.4.kReported in the cardiovascular outcomes study in patients with type 2 diabetes (DECLARE). Frequency isbased on annual rate.lAdverse reaction was identified through post-marketing surveillance with the use of dapagliflozin. Rashincludes the following preferred terms, listed in order of frequency in clinical trials: rash, rash generalised, rashpruritic, rash macular, rash maculo-papular, rash pustular, rash vesicular, and rash erythematous. In active- andplacebo-controlled clinical trials (dapagliflozin, N=5936, All control, N=3403), the frequency of rash wassimilar 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 mgcompared to placebo.

**Reported by the investigator as possibly related, probably related or related to study treatment and reported in≥ 0.2% of subjects and ≥ 0.1% more and at least 3 more subjects treated with dapagliflozin 10 mg compared toplacebo.§Adverse reaction and frequency categories for metformin are based on information from the metformin

Summary of Product Characteristics available in the European Union.

Dapagliflozin plus metformin

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

In an add-on to metformin and a sulphonylurea study, up to 24 weeks, minor episodes ofhypoglycaemia were reported in 12.8% of subjects who received dapagliflozin 10 mg plus metforminand a sulphonylurea and in 3.7% of subjects who received placebo plus metformin and asulphonylurea. 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 in5.5% and 0.6% of subjects who received dapagliflozin 10 mg and placebo, respectively. Mostinfections were mild to moderate, and subjects responded to an initial course of standard treatment andrarely resulted in discontinuation from dapagliflozin treatment. These infections were more frequent infemales (8.4% and 1.2% for dapagliflozin and placebo, respectively), and subjects with a prior historywere more likely to have a recurrent infection.

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

Cases of phimosis/acquired phimosis have been reported with dapagliflozin concurrent with genitalinfections and in some cases, circumcision was required.

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

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

The frequency of hypoglycaemia depended on the type of background therapy used in each study.

For studies of dapagliflozin as add-on to metformin or as add-on to sitagliptin (with or withoutmetformin), the frequency of minor episodes of hypoglycaemia was similar (< 5%) between treatmentgroups, including placebo up to 102 weeks of treatment. Across all studies, major events ofhypoglycaemia were uncommon and comparable between the groups treated with dapagliflozin orplacebo. In a study with add-on insulin therapy, higher rates of hypoglycaemia were observed (seesection 4.5).

In an add-on to insulin study up to 104 weeks, episodes of major hypoglycaemia were reported in0.5% and 1.0% of subjects in dapagliflozin 10 mg plus insulin at weeks 24 and 104, respectively, andin 0.5% of subjects treated with placebo plus insulin groups at weeks 24 and 104. At weeks 24 and104, minor episodes of hypoglycaemia were reported, respectively, in 40.3% and 53.1% of subjectswho received dapagliflozin 10 mg plus insulin and in 34.0% and 41.6% of the subjects who receivedplacebo plus insulin.

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

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

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

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

Urinary tract infections

In the 13-study safety pool, urinary tract infections were more frequently reported for dapagliflozincompared with placebo (4.7% versus 3.5%, respectively; see section 4.4). Most infections were mildto moderate, and subjects responded to an initial course of standard treatment and rarely resulted indiscontinuation from dapagliflozin treatment. These infections were more frequent in females, andsubjects with a prior history were more likely to have a recurrent infection.

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

Increased creatinine

Adverse reactions related to increased creatinine were grouped (e.g. decreased renal creatinineclearance, renal impairment, increased blood creatinine and decreased glomerular filtration rate). Thisgrouping of reactions was reported in 3.2% and 1.8% of patients who received dapagliflozin 10 mgand placebo, respectively. In patients with normal renal function or mild renal impairment (baselineeGFR ≥ 60 mL/min/1.73 m2) this grouping of reactions was reported in 1.3% and 0.8% of patientswho received dapagliflozin 10 mg and placebo, respectively. These reactions were more common inpatients with baseline eGFR ≥ 30 and < 60 mL/min/1.73 m2 (18.5% dapagliflozin 10 mg versus 9.3%placebo).

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

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

Dapagliflozin

Dapagliflozin did not show any toxicity in healthy subjects at single oral doses up to 500 mg (50 timesthe maximum recommended human dose). These subjects had detectable glucose in the urine for adose-related period of time (at least 5 days for the 500 mg dose), with no reports of dehydration,hypotension or electrolyte imbalance, and with no clinically meaningful effect on QTc interval. Theincidence of hypoglycaemia was similar to placebo. In clinical studies where once daily doses of up to100 mg (10 times the maximum recommended human dose) were administered for 2 weeks in healthysubjects and type 2 diabetes subjects, the incidence of hypoglycaemia was slightly higher than placeboand was not dose-related. Rates of adverse events including dehydration or hypotension were similarto placebo, and there were no clinically meaningful dose-related changes in laboratory parameters,including serum electrolytes and biomarkers of renal function.

In the event of an overdose, appropriate supportive treatment should be initiated as dictated by thepatient’s clinical status.

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

Pharmacotherapeutic group: Drugs used in diabetes, combinations of oral blood glucose loweringdrugs, ATC code: A10BD15

Xigduo combines two anti-hyperglycaemic medicinal products with different and complementarymechanisms 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.

Inhibition of SGLT2 by dapagliflozin reduces reabsorption of glucose from the glomerular filtrate inthe proximal renal tubule with a concomitant reduction in sodium reabsorption leading to urinaryexcretion of glucose and osmotic diuresis. Dapagliflozin therefore increases the delivery of sodium tothe distal tubule which increases tubuloglomerular feedback and reduces intraglomerular pressure.

This combined with osmotic diuresis leads to a reduction in volume overload, reduced blood pressure,and lower preload and afterload, which may have beneficial effects on cardiac remodelling anddiastolic function, and preserve renal function. The cardiac and renal benefits of dapagliflozin are notsolely dependent on the blood glucose-lowering effect. Other effects include an increase inhaematocrit and reduction in body weight.

Dapagliflozin improves both fasting and post-prandial plasma glucose levels by reducing renal glucosereabsorption leading to urinary glucose excretion. This glucose excretion (glucuretic effect) isobserved after the first dose, is continuous over the 24-hour dosing interval and is sustained for theduration of treatment. The amount of glucose removed by the kidney through this mechanism isdependent upon the blood glucose concentration and GFR. Thus, in subjects with normal bloodglucose, dapagliflozin has a low propensity to cause hypoglycaemia. Dapagliflozin does not impairnormal endogenous glucose production in response to hypoglycaemia. Dapagliflozin actsindependently of insulin secretion and insulin action. Improvement in homeostasis model assessmentfor beta cell function (HOMA beta-cell) has been observed in clinical studies with dapagliflozin.

The SGLT2 is selectively expressed in the kidney. Dapagliflozin does not inhibit other glucosetransporters important for glucose transport into peripheral tissues and is > 1,400 times more selectivefor SGLT2 versus SGLT1, the major transporter in the gut responsible for glucose absorption.

Metformin is a biguanide with anti-hyperglycaemic effects, lowering both basal and postprandialplasma 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 utilisationin muscle;

- by delaying intestinal glucose absorption.

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

GLUT-4).

Dapagliflozin

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

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

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

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

In humans, independently of its action on glycaemia, metformin has favourable effects on lipidmetabolism. This has been shown at therapeutic doses in controlled, medium-term or long-termclinical 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 weightloss.

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

The coadministration of dapagliflozin and metformin has been studied in subjects, with type 2diabetes, inadequately controlled on diet and exercise alone, and in subjects inadequately controlled onmetformin 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 statisticallysignificant 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. HbA1creductions were seen across subgroups including gender, age, race, duration of disease, and baselinebody mass index (BMI). Additionally, at week 24, clinically relevant and statistically significantimprovements in mean changes from baseline in body weight were seen with dapagliflozin andmetformin combination treatments compared with control. Body weight reductions were sustained inlong-term extensions up to 208 weeks. Additionally, dapagliflozin twice-daily treatment added tometformin 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 andhypertension.

In the DECLARE study, dapagliflozin as adjunct to standard care therapy reduced cardiovascular andrenal events in patients with type 2 diabetes.

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 toweek 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% fordapagliflozin and 0.20% for glipizide, respectively. At 52, 104 and 208 weeks, a significantly lowerproportion of subjects in the group treated with dapagliflozin (3.5%, pct. 4.3% and 5.0%, respectively)experienced at least one event of hypoglycaemia compared with the group treated with glipizide(40.8%, 47% and 50.0%, respectively). The proportion of subjects remaining in the study at week 104and week 208 was 56.2% and 39.7% for the group treated with dapagliflozin and 50.0% and 34.6% forthe group treated with glipizide.

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

Dapagliflozin Glipizide

Parameter + metformin + metformin

Nb 400 401

HbA1c (%)

Baseline (mean) 7.69 7.74

Change from baselinec -0.52 -0.52

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

Body weight (kg)

Baseline (mean) 88.44 87.60

Change from baselinec -3.22 1.44

Difference from glipizide + metforminc -4.65*(95% CI) (-5.14, -4.17)aLOCF: Last observation carried 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 weekscompared with subjects receiving placebo (p < 0.0001; Tables 4, 5 and 6). Dapagliflozin 5 mg twicedaily provided statistically significant reductions in HbA1c at 16 weeks compared with subjectsreceiving placebo (p < 0.0001; Table 4).

The reductions in HbA1c observed at week 24 were sustained in the add-on combination studies. Forthe add-on to metformin study, HbA1c reductions were sustained through week 102 (-0.78% and0.02% adjusted mean change from baseline for dapagliflozin 10 mg and placebo, respectively). Atweek 48 for metformin plus sitagliptin, the adjusted mean change from baseline fordapagliflozin 10 mg and placebo was -0.44% and 0.15%, respectively. At week 104 for insulin (withor without additional oral glucose-lowering medicinal products, including metformin), the HbA1creductions were -0.71% and -0.06% adjusted mean change from baseline for dapagliflozin 10 mg andplacebo, respectively. At weeks 48 and 104, the insulin dose remained stable compared to baseline insubjects treated with dapagliflozin 10 mg at an average dose of 76 IU/day. In the placebo group therewas an increase of 10.5 IU/day and 18.3 IU/day from baseline (mean average dose of 84 and92 IU/day) at weeks 48 and 104, respectively. The proportion of subjects remaining in the study atweek 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 seenin the total study population were seen in subjects treated with dapagliflozin with insulin plusmetformin. At week 24, HbA1c change from baseline in subjects treated with dapagliflozin plusinsulin with metformin was -0.93%.

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

Add-on combination

Metformin1 Metformin1, b Metformin1 + sitagliptin2

Dapagliflozin Placebo Dapagliflozin Placebo Dapagliflozin Placebo10 mg QD QD 5 mg BID BID 10 mg QD QD

Nc 135 137 99 101 113 113

HbA1c (%)

Baseline 7.92 8.11 7.79 7.94 7.80 7.87(mean)

Change from -0.84 -0.30 -0.65 -0.30 -0.43 -0.02baselined

Difference -0.54* -0.35* -0.40*fromplacebod(95% CI) (-0.74, -0.34) (-0.52, -0.18) (-0.58, -0.23)

Subjects (%)achieving:

HbA1c < 7%

Adjusted forbaseline 40.6** 25.9 38.2** 21.4(N=90) (N=87)

Body weight(kg) 86.28 87.74 93.62 88.82 93.95 94.17

Baseline(mean) -2.86 -0.89 -2.74 -0.86 -2.35 -0.47

Change frombaselined -1.97* -1.88*** -1.87*

Differencefromplacebod(95% CI) (-2.63, -1.31) (-2.52, -1.24) (-2.61, -1.13)

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

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

Add-on combination

Sulphonylurea+ metformin1

Dapagliflozin Placebo10 mg

Na 108 108

HbA1c (%)b

Baseline (mean) 8.08 8.24

Change from Baselinec -0.86 -0.17

Difference from Placeboc -0.69*(95% CI) (-0.89, -0.49)

Subjects (%) achieving:

HbA1c < 7%

Adjusted for baseline 31.8* 11.1

Body weight (kg)

Baseline (mean) 88.57 90.07

Change from Baselinec -2.65 -0.58

Difference from Placeboc -2.07*(95% CI) (-2.79, -1.35)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).

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

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

Parameter medicinal products2 medicinal products2

Nb 194 193

HbA1c (%)

Baseline (mean) 8.58 8.46

Change from baselinec -0.90 -0.30

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

Body weight (kg)

Baseline (mean) 94.63 94.21

Change from baselinec -1.67 0.02

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

Mean daily insulin dose (IU)1

Baseline (mean) 77.96 73.96

Change from baselinec -1.16 5.08

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

Subjects with mean daily insulindose reduction of at least 19.7** 11.010% (%)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 ifsubjects met pre-defined FPG criteria.2Fifty percent of subjects were on insulin monotherapy at baseline; 50% were on 1 or 2 oral glucose-loweringmedicinal product(s) in addition to insulin: Of this latter group, 80% were on metformin alone, 12% wereon metformin plus sulphonylurea therapy, and the rest were on other oral glucose-lowering medicinalproducts.

In combination with metformin in drug-naive patients

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

Treatment with dapagliflozin 10 mg in combination with metformin (up to 2,000 mg per day) providedsignificant improvements in HbA1c compared to the individual components (Table 7), and led togreater reductions in FPG (compared to the individual components) and body weight (compared tometformin).

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

Dapagliflozin 10 Dapagliflozin 10 Metforminmg + mg

Parameter metformin

Nb 211b 219b 208b

HbA1c (%)

Baseline (mean) 9.10 9.03 9.03

Change from baselinec -1.98 -1.45 -1.44

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

Difference from metforminc -0.54* -0.01(95% CI) (-0.75, -0.33) (-0.22, 0.20)aLOCF: last observation (prior to rescue for rescued patients) carried forward.bAll randomised patients who took at least one dose of double-blind study medicinal product during 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 andprolonged-release exenatide (a GLP-1 receptor agonist) was compared to dapagliflozin alone andprolonged-release exenatide alone in subjects with inadequate glycaemic control on metformin alone(HbA1c ≥ 8% and ≤ 12%). All treatment groups had a reduction in HbA1c compared to baseline. Thecombination treatment with dapagliflozin 10 mg and prolonged-release exenatide group showedsuperior reductions in HbA1c from baseline compared to dapagliflozin alone and prolonged-releaseexenatide alone (Table 8).

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

Dapagliflozin 10 mg Dapagliflozin 10 mg Prolonged-release

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

Parameter exenatide 2 mg QW placebo QD

N 228 230 227

HbA1c (%)

Baseline (mean) 9.29 9.25 9.26

Change from baselinea -1.98 -1.39 -1.60

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

Subjects (%) achieving44.7 19.1 26.9

HbA1c  7%

Body weight (kg)

Baseline (mean) 92.13 90.87 89.12

Change from baselinea -3.55 -2.22 -1.56

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

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

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

*p < 0.001, **p < 0.01.

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

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

Treatment with dapagliflozin as an add-on to either metformin alone (dapagliflozin 10 mg QD ordapagliflozin 5 mg BID) or metformin plus sitagliptin, sulphonylurea or insulin resulted in statisticallysignificant 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 wasobserved 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 significantlygreater reductions in FPG at week 28: -3.66 mmol/L (-65.8 mg/dL), compared to -2.73 mmol/L(-49.2 mg/dL) for dapagliflozin alone (p < 0.001) and -2.54 mmol/L (-45.8 mg/dL) for exenatide alone(p < 0.001).

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

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

Post-prandial glucose

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

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

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 instatistically significant body weight reduction up to 24 weeks (p < 0.0001, Tables 4, 5 and 6). Theseeffects were sustained in longer-term trials. At 48 weeks, the difference for dapagliflozin as add-on tometformin plus sitagliptin compared with placebo was -2.07 kg. At 102 weeks, the difference fordapagliflozin as add-on to metformin compared with placebo or as add-on to insulin compared withplacebo was -2.14 and -2.88 kg, respectively.

As an add-on therapy to metformin in an active-controlled non-inferiority study, dapagliflozin resultedin a statistically significant body weight 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 significantlygreater 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 evaluatebody composition demonstrated reductions with dapagliflozin 10 mg plus metformin compared withplacebo plus metformin, respectively, in body weight and body fat mass as measured by DXA ratherthan lean tissue or fluid loss. Treatment with dapagliflozin 10 mg plus metformin showed a numericaldecrease in visceral adipose tissue compared with placebo plus metformin treatment in a magneticresonance imaging substudy.

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

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

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

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

Patients with baseline HbA1c ≥ 9%

In a pre-specified analysis of subjects with baseline HbA1c ≥ 9.0%, treatment withdapagliflozin 10 mg resulted in statistically significant reductions in HbA1c at week 24 as an add-onto 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 ≥ 45to < 60 mL/min/1.73 m2 who had inadequate glycaemic control on usual care. Treatment withdapagliflozin resulted in reductions in HbA1c and body weight compared with placebo (Table 9).

Table 9. Results at week 24 of a placebo-controlled study of dapagliflozin in diabetic patientswith an eGFR ≥ 45 to < 60 mL/min/1.73 m2

Dapagliflozina Placeboa10 mg

Nb 159 161

HbA1c (%)

Baseline (mean) 8.35 8.03

Change from baselineb -0.37 -0.03

Difference from placebob -0.34*(95% CI) (-0.53, -0.15)

Body weight (kg)

Baseline (mean) 92.51 88.30

Percent change from baselinec -3.42 -2.02

Difference in percent change from -1.43*placeboc(95% CI) (-2.15, -0.69)a Metformin or metformin hydrochloride were part of the usual care in 69.4% and 64.0% of the patients forthe 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 ofdapagliflozin compared with placebo on cardiovascular outcomes when added to current backgroundtherapy. All patients had type 2 diabetes mellitus and either at least two additional cardiovascular riskfactors (age ≥ 55 years in men or ≥ 60 years in women and one or more of dyslipidaemia, hypertensionor current tobacco use) or established cardiovascular disease.

Of 17,160 randomised patients, 6,974 (40.6%) had established cardiovascular disease and10,186 (59.4%) did not have established cardiovascular disease. 8,582 patients were randomised todapagliflozin 10 mg and 8,578 to placebo, and were followed for a median of 4.2 years.

The mean age of the study population was 63.9 years, 37.4% were female. In total, 22.4% had haddiabetes for ≤ 5 years, mean duration of diabetes was 11.9 years. Mean HbA1c was 8.3% and mean

BMI was 32.1 kg/m2.

At baseline, 10.0% of patients had a history of heart failure. Mean eGFR was 85.2 mL/min/1.73 m2,7.4% of patients had eGFR < 60 mL/min/1.73 m2, and 30.3% of patients had micro- ormacroalbuminuria (urine albumin to creatinine ratio [UACR] ≥ 30 to ≤ 300 mg/g or > 300 mg/g,respectively).

Most patients (98%) used one or more diabetic medicinal products at baseline, including metformin(82%), insulin (41%) and sulfonylurea (43%).

The primary endpoints were time to first event of the composite of cardiovascular death, myocardialinfarction or ischaemic stroke (MACE) and time to first event of the composite of hospitalisation forheart failure or cardiovascular death. The secondary endpoints were a renal composite endpoint andall-cause mortality.

Major adverse cardiovascular events

Dapagliflozin 10 mg demonstrated non-inferiority versus placebo for the composite of cardiovasculardeath, myocardial infarction or ischaemic stroke (one-sided p < 0.001).

Heart failure or cardiovascular death

Dapagliflozin 10 mg demonstrated superiority versus placebo in preventing the composite ofhospitalisation for heart failure or cardiovascular death (Figure 1). The difference in treatment effectwas driven by hospitalisation for heart failure, with no difference in cardiovascular death (Figure 2).

The treatment benefit of dapagliflozin over placebo was observed both in patients with and withoutestablished cardiovascular disease, with and without heart failure at baseline, and was consistentacross key subgroups, including age, gender, renal function (eGFR) and region.

Figure 1: Time to first occurrence of hospitalisation for heart failure or cardiovascular death

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

HR=Hazard ratio CI=Confidence interval.

Results on primary and secondary endpoints are displayed in Figure 2. Superiority of dapagliflozinover placebo was not demonstrated for MACE (p=0.172). The renal composite endpoint and all-causemortality were therefore not tested as part of the confirmatory testing procedure.

Figure 2: Treatment effects for the primary composite endpoints and their components, and thesecondary endpoints and components

Renal composite endpoint defined as: sustained confirmed ≥ 40% decrease in eGFR to eGFR < 60 mL/min/1.73 m2 and/orend-stage renal disease (dialysis ≥ 90 days or kidney transplantation, sustained confirmed eGFR < 15 mL/min/1.73 m2)and/or renal or cardiovascular death.

p-values are two-sided. p-values for the secondary endpoints and for single components are nominal. Time to first event wasanalysed in a Cox proportional hazards model. The number of first events for the single components are the actual number offirst events for each component and does not add up to the number of events in the composite endpoint.

CI=confidence interval.

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

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

The prospective randomised (UKPDS) study has established the long-term benefit of intensive bloodglucose control in type 2 diabetes. Analysis of the results for overweight patients treated withmetformin after failure of diet alone showed:

- a significant reduction of the absolute risk of any diabetes-related complication in the metformingroup (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: metformin7.5 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: metformin13.5 events/1,000 patient-years versus diet alone 20.6 events/1,000 patient-years, (p=0.011), andversus the combined sulphonylurea and insulin monotherapy groups18.9 events/1,000 patient-years (p=0.021);

- a significant reduction in the absolute risk of myocardial infarction: metformin11 events/1,000 patient-years, diet alone 18 events/1,000 patient-years, (p=0.01).

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 4.2for information on paediatric use).

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

The pharmacokinetics of 5 mg dapagliflozin twice daily and 10 mg dapagliflozin once daily werecompared in healthy subjects. Administration of 5 mg dapagliflozin twice daily gave similar overallexposures (AUCss) over a 24-hour period as 10 mg dapagliflozin administered once daily. Asexpected, dapagliflozin 5 mg administered twice daily compared with 10 mg dapagliflozin once dailyresulted in lower peak dapagliflozin plasma concentrations (Cmax) and higher trough plasmadapagliflozin concentrations (Cmin).

Interaction with food

The administration of this medicinal product in healthy volunteers after a high fat meal compared toafter the fasted state resulted in the same extent of exposure for both dapagliflozin and metformin. Themeal resulted in a delay of 1 to 2 hours in the peak concentrations and a decrease in the maximumplasma concentration of 29% of dapagliflozin and 17% of metformin. These changes are notconsidered to be clinically meaningful.

Pharmacokinetics in the paediatric population have not been studied.

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

Dapagliflozin

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

Geometric mean steady-state dapagliflozin Cmax and AUCτ values following once daily 10 mg doses ofdapagliflozin were 158 ng/mL and 628 ng h/mL, respectively. The absolute oral bioavailability ofdapagliflozin following the administration of a 10 mg dose is 78%.

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

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

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

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

At steady-state (20 mg once-daily dapagliflozin for 7 days), subjects with type 2 diabetes mellitus andmild, moderate or severe renal impairment (as determined by iohexol plasma clearance) had meansystemic exposures of dapagliflozin of 32%, 60% and 87% higher, respectively, than those of subjectswith type 2 diabetes mellitus and normal renal function. The steady-state 24-hour urinary glucoseexcretion was highly dependent on renal function and 85, 52, 18 and 11 g of glucose/day was excretedby subjects with type 2 diabetes mellitus and normal renal function or mild, moderate or severe renalimpairment, respectively. The impact of haemodialysis on dapagliflozin exposure is not known.

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

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

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

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

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

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

After an oral dose of metformin, tmax is reached in 2.5 h. Absolute bioavailability of a 500 mg or850 mg metformin tablet is approximately 50-60% in healthy subjects. After an oral dose, thenon-absorbed fraction recovered in faeces was 20-30%.

After oral administration, metformin absorption is saturable and incomplete. It is assumed that thepharmacokinetics of metformin absorption is non-linear. At the usual metformin doses and dosingschedules, steady-state plasma concentrations are reached within 24-48 hours and are generally lessthan 1 μg/mL. In controlled clinical trials, maximum metformin plasma levels (Cmax) did not exceed5 μg/mL, even at maximum doses.

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

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

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

In patients with decreased renal function (based on measured creatinine clearance), the plasma andblood half-life of metformin is prolonged and the renal clearance is decreased in proportion to thedecrease in creatinine clearance, leading to increased levels of metformin in plasma.

Coadministration of dapagliflozin and metformin

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dosetoxicity.

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 safetypharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and fertility. Dapagliflozindid not induce tumours in either mice or rats at any of the doses evaluated in two-year carcinogenicitystudies.

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

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

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

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

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproductionand development.

Hydroxypropyl cellulose (E463)

Microcrystalline cellulose (E460(i))

Magnesium stearate (E470b)

Sodium starch glycolate type A

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)

Not applicable.

3 years

This medicinal product does not require any special storage conditions.

PVC/PCTFE/Alu blister.

Pack sizes14, 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.

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

AstraZeneca AB

SE-151 85 Södertälje

Sweden

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)

Date of first authorisation: 16 January 2014

Date of latest renewal: 28 September 2018

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

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