Xigduo XR is indicated as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes mellitus.
Dapagliflozin is indicated to reduce:
 The risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and established cardiovascular disease (CVD) or multiple cardiovascular (CV) risk factors.
 The risk of cardiovascular death and hospitalization for heart failure in adults with heart failure (NYHA class II-IV) with reduced ejection fraction.
 The risk of sustained estimated glomerular filtration rate decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure in adults with chronic kidney disease at risk of progression.

Xigduo XR is not recommended:
 For patients with type 1 diabetes mellitus or diabetic ketoacidosis.
 Because of the metformin component, the use of XIGDUO XR is limited to adults with type 2 diabetes mellitus for all indications.
 For the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of immunosuppressive therapy for kidney disease. XIGDUO XR is not expected to be effective in these
populations.

Recommended Dosing

Healthcare providers should individualize the starting dose of Xigduo XR based on the patient’s

current treatment. [See Pharmaceutical form and strengths (3)]

Take XIGDUO XR orally once daily in the morning with food. with gradual dose escalation to reduce the gastrointestinal (GI) side effects due to metformin.

Xigduo XR tablets must be swallowed whole and never crushed, cut, or chewed. Occasionally, the inactive ingredients of Xigduo XR will be eliminated in the faeces as a soft, hydrated mass that may resemble the original tablet.

Dosing may be adjusted based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 10 mg dapagliflozin and 2000 mg metformin HCl. Patients taking an evening dose of metformin XR should skip their last dose before starting Xigduo XR.

In patients with volume depletion, correcting this condition prior to initiation of Xigduo XR is recommended [see Special warnings and precautions for use (4.4), Use in Specific Populations].

Patients with Renal Impairment

No dosage adjustment for Xigduo XR is indicated in patients with mild renal impairment (eGFR

of 60 mL/min/1.73 m2 or greater).

Assessment of renal function is recommended prior to initiation of Xigduo XR therapy and periodically thereafter.

Xigduo XR should not be used in patients with moderate to severe renal impairment (defined as eGFR <60 mL/min/1.73 m2 or CrCl <60 mL/min, or end-stage renal disease [ESRD]) [see Contraindications (4.3), Special warnings and precautions for use (4.4), Interaction with other medicinal products and other forms of interaction (4.5), and Use in Specific Populations].

Lactic Acidosis

Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with Xigduo XR; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 g/mL are generally found.

The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low    (approximately    0.03    cases/1000    patient-years,    with    approximately    0.015    fatal cases/1000 patient-years). In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple  concomitant  medications.  Patients  with  congestive  heart  failure  requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient’s age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function

in patients taking metformin and by use of the minimum effective dose of metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function.  Metformin  treatment  should  not  be  initiated  in  patients  80  years  of  age  unless measurement of creatinine clearance demonstrates that renal function is not reduced,  as  these patients are more susceptible to developing lactic acidosis. In addition, metformin  should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability  to clear lactate, metformin should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake  when  taking metformin since  alcohol  potentiates  the  effects  of  metformin  hydrochloride  on  lactate  metabolism.  In addition, metformin should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure.

The onset of lactic acidosis often is subtle and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The patient and the patient’s physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur. Metformin should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose, and if indicated, blood pH, lactate levels, and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of metformin, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.

Levels of fasting venous plasma lactate above the upper limit of normal (ULN), but <5 mmol/L, in patients taking metformin do not necessarily indicate impending lactic acidosis and may be explainable  by  other  mechanisms,  such  as  poorly  controlled  diabetes  or  obesity,  vigorous physical activity, or technical problems in sample handling.

Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).

Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis  who is  taking metformin,  the drug should  be discontinued  immediately and general supportive measures promptly instituted. Because metformin hydrochloride is dialyzable (with  a  clearance  of  up  to  170 mL/min  under  good  hemodynamic  conditions),  prompt

haemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery [see Contraindications (4.3)].

Hypoxic States

Cardiovascular collapse (shock), acute congestive heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on Xigduo XR therapy, the drug should be promptly discontinued.

Use in Patients with Renal Impairment

Metformin is known to be substantially excreted by the kidney and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Therefore, Xigduo XR is contraindicated in patients with moderate to severe renal impairment [see  Contraindications  (4.3)].  Also,  dapagliflozin  increases  serum  creatinine  and  decreases eGFR. Elderly patients and patients with impaired renal function may be more susceptible to these changes. Adverse reactions related to renal function can occur after initiating Xigduo XR [see Interaction with other medicinal products and other forms of interaction (4.5)].

Before initiation of Xigduo XR therapy, and at least annually thereafter, renal function should be assessed and verified as normal or mildly impaired. In patients in whom development of renal impairment is anticipated (e.g., elderly), renal function should be assessed more frequently and Xigduo XR discontinued if evidence of moderate to severe renal impairment is present.

Hypotension

Dapagliflozin causes intravascular volume contraction. Symptomatic hypotension can occur after initiating dapagliflozin [see Interaction with other medicinal products and other forms of interaction (4.5)], particularly in patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics. Before initiating Xigduo XR in patients  with  one  or  more  of  these  characteristics,  volume  status  should  be  assessed  and corrected. Monitor for signs and symptoms of hypotension after initiating therapy.

Impaired Hepatic Function

Metformin use in patients with impaired hepatic function has been associated with some cases of lactic acidosis. Therefore, Xigduo XR should generally be avoided in patients with hepatic impairment.

Alcohol Intake

Alcohol potentiates the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving Xigduo XR.

Surgical Procedures

Use of Xigduo XR should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient’s oral intake has resumed and renal function has been evaluated as normal or mildly impaired.

Change in Clinical Status of Patients with Previously Controlled Type 2 Diabetes

A patient with type 2 diabetes, previously well controlled on Xigduo XR, who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, Xigduo XR must be stopped immediately and other appropriate corrective measures initiated.

Concomitant Medications Affecting Renal Function or Metformin Disposition

Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion [see 4.5 Interaction with other medicinal products and other forms of interaction], should be used with caution.

Radiologic Studies with Intravascular Iodinated Contrast Materials

Intravascular  contrast  studies  with  iodinated  materials  can  lead  to  acute  alteration  of  renal function  and  have  been  associated  with  lactic  acidosis  in  patients  receiving  metformin.

Therefore, in patients in whom any such study is planned, Xigduo XR should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal or mildly impaired.

Vitamin B12 Concentrations

In controlled clinical trials of metformin of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. This decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex is, however, very rarely associated with anaemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Measurement of haematologic parameters on an annual basis is advised in patients on Xigduo XR and any apparent abnormalities should be appropriately investigated and managed [see Interaction with other medicinal products and other forms of interaction (4.5)].

Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurements at 2- to 3-year intervals may be useful.

Genital Mycotic Infections

Dapagliflozin increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections [see Interaction with other medicinal products and other forms of interaction (4.5)]. Monitor and treat appropriately.

Increases in Low-Density Lipoprotein Cholesterol (LDL-C)

Increases in LDL-C occur with dapagliflozin [see Interaction with other medicinal products and other forms of interaction (4.5)]. Monitor LDL-C and treat per standard of care after initiating Xigduo XR.

Bladder Cancer

Across 22 clinical studies, newly diagnosed cases of bladder cancer were reported in 10/6045 patients (0.17%) treated with dapagliflozin and 1/3512 patient (0.03%) treated with placebo/comparator. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were 4 cases with dapagliflozin and no

cases with placebo/comparator. Bladder cancer risk factors and haematuria (a potential indicator of pre-existing tumours) were balanced between treatment arms at baseline. There were too few cases to determine whether the emergence of these events is related to dapagliflozin.

There are insufficient data to determine whether dapagliflozin has an effect on pre-existing bladder tumours. Consequently, Xigduo XR should not be used in patients with active bladder cancer. In patients with prior history of bladder cancer, the benefits of glycaemic control versus unknown risks for cancer recurrence with Xigduo XR should be considered.

Macrovascular Outcomes

There have been no  clinical studies establishing conclusive evidence of macrovascular risk reduction with Xigduo XR or any other antidiabetic drug.

Ketoacidosis

Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization have been identified in post marketing surveillance in patients with type 1 and type 2 diabetes mellitus taking sodium glucose co-transporter-2 (SGLT2) inhibitors, including dapagliflozin. XIGDUO XR is not indicated for the treatment of patients with type 1 diabetes mellitus. Patients treated with XIGDUO XR who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of blood glucose levels as ketoacidsosis associated with XIGDUO XR may be present even if blood glucose levels are less than 250 mg/dL. If ketoacidosis is suspected, XIGDUO XR should be discontinued, the patient should be evaluated and prompt treatment should be instituted. Treatment of ketoacidosis may require insulin, fluid and carbohydrate replacement. In many of the postmarketing reports, and particularly in patients with type 1 diabetes, the presence of ketoacidosis was not immediately recognized and institution of treatment was delayed because presenting blood glucose levels were below those typically expected for diabetic ketoacidosis (often less than 250 mg/dL). Signs and symptoms at presentation were consistent with dehydration and severe metabolic acidosis and included nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. In some but not all cases, factors predisposing to ketoacidosis such as insulin dose reduction, acute febrile illness, reduced caloric intake due to illness or surgery, pancreatic disorders suggesting insulin  deficiency  (e.g.,  type  1  diabetes,  history  of  pancreatitis  or  pancreatic  surgery),  and alcohol abuse were identified. Before initiating XIGDUO XR, consider factors in the patient history that may predispose to ketoacidosis including pancreatic insulin deficiency from any cause, caloric restriction and alcohol abuse. In patients treated with XIGDUO XR consider

monitoring for ketoacidosis and temporarily discontinuing XIGDUO XR in clinical situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or surgery)

Urosepsis and Pyelonephritis

There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving SGLT2 inhibitors, including dapagliflozin. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated.

Use in Specific Populations

Paediatric Use

Safety and effectiveness of Xigduo XR in paediatric patients under 18 years of age have not been established.

Geriatric Use

Xigduo XR

No Xigduo XR dosage change is recommended based on age.

Dapagliflozin

A total of 1424 (24%) of the 5936 dapagliflozin-treated patients were 65 years and over and 207 (3.5%) patients were 75 years and older in a pool of 21 double-blind, controlled, clinical safety and  efficacy studies  of  dapagliflozin.  After  controlling  for  level  of  renal  function  (eGFR), efficacy was similar for patients under age 65 years and those 65 years and older. In patients 65 years of age, a higher proportion of patients treated with dapagliflozin had adverse  reactions related to volume depletion and renal impairment or failure compared to patients  treated with placebo [see Special warnings and precautions for use (4.4) and Interaction with other medicinal products and other forms of interaction (4.5)].

Metformin hydrochloride

Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine  whether  they  respond  differently  than  younger  patients,  although  other  reported

clinical experience has not identified differences in responses between the elderly and young patients. Metformin is known to be substantially excreted by the kidney and because the risk of lactic acidosis with metformin is greater in patients with moderately to severely impaired renal function, Xigduo XR should only be used in patients with normal or mildly impaired renal function. The initial and maintenance dosing of metformin should be conservative in patients with advanced age due to the potential for decreased renal function in this population. Any dose adjustment should be based on a careful assessment of renal function.

Patients with Mild Renal Impairment (eGFR 60 to <90 mL/min/1.73 m²

Dapagliflozin

The pool of 21 double-blind, active- and placebo-controlled clinical safety and efficacy studies (dapagliflozin as monotherapy or in combination with other antidiabetic therapies) included 53% (4906/9339) of patients with mild renal impairment. The safety profile in patients with mild renal impairment is similar to that in the overall population.

Positive Urine Glucose Test

Dapagliflozin

Monitoring glycaemic control with urine glucose tests is not recommended in patients taking SGLT2  inhibitors  as  SGLT2  inhibitors  increase  urinary  glucose  excretion  and  will  lead  to positive urine glucose tests. Use alternative methods to monitor glycaemic control.

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

Dapagliflozin

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

Cationic Drugs

Metformin hydrochloride

Cationic drugs (e.g., amiloride, cimetidine, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. A 40% increase in exposure (AUC) of metformin when coadministered with cimetidine was observed in normal healthy volunteers. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of Xigduo XR and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.

Use with Other Drugs

Metformin hydrochloride

Some medications can predispose to hyperglycaemia and may lead to loss of glycaemic control. These medications include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving Xigduo XR, the patient should be observed closely for loss of glycaemic control. When such drugs are withdrawn from a patient receiving Xigduo XR, the patient should be observed closely for hypoglycaemia.

In healthy volunteers, the pharmacokinetics of metformin and propranolol, and of metformin and ibuprofen were not affected when coadministered in single-dose interaction studies.

Use with Medications Known to Cause Hypoglycaemia

Dapagliflozin

Insulin and insulin secretagogues are known to cause hypoglycaemia. Dapagliflozin can increase the  risk  of  hypoglycaemia  when  combined  with  insulin  or  an  insulin  secretagogue  [see Interaction with other medicinal products and other forms of interaction (4.5)]. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycaemia when these agents are used in combination with XIGDUO XR.

Metformin hydrochloride

Hypoglycaemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycaemic effects. Hypoglycaemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs.

Pregnancy Category C

There are no adequate and well-controlled studies of Xigduo XR or its individual components in pregnant women. Based on results of reproductive and developmental toxicity studies in animals, dapagliflozin, a component of Xigduo XR, may affect renal development and maturation. In a juvenile rat study, increased incidence and/or severity of renal pelvic and tubular dilatations were evident at the lowest tested dose which was approximately 15 times clinical exposure from a 10 mg dose.

These outcomes occurred with drug exposures during periods of animal development that correlate with the late second and third trimesters of human pregnancy. During pregnancy, consider appropriate alternative therapies, especially during the second and third trimesters. Xigduo XR should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Dapagliflozin

In a juvenile toxicity study, when dapagliflozin was dosed directly to young rats from postnatal day (PND) 21 until PND 90 at doses of 1, 15, or 75 mg/kg/day, increased kidney weights and renal pelvic and tubular dilatations were reported at all levels. Exposure at the lowest tested dose was 15 times the maximum clinical dose, based on AUC. The renal pelvic and tubular dilatations observed in juvenile animals did not fully reverse within the approximate 1-month recovery period.

In a prenatal and postnatal development study, maternal rats were dosed from gestation day 6 through lactation day 21 at doses of 1, 15, or 75 mg/kg/day, and pups were indirectly exposed in

utero and throughout lactation. Increased incidence or severity of renal pelvic dilatation was observed in adult offspring of treated dams at 75 mg/kg/day (maternal and pup dapagliflozin exposures were 1415 times and 137 times, respectively, the human values at the clinical dose). Dose-related   reductions   in   pup   body   weights   were   observed   at   doses   1 mg/kg/day (approximately 19 times the clinical dose). No adverse effects on  developmental  endpoints were noted at 1 mg/kg/day, or approximately 19 times the clinical dose.

In embryo-foetal development studies in rats and rabbits, dapagliflozin was administered for intervals   coinciding   with   the   first   trimester   period   of   organogenesis   in   humans.   No developmental toxicities were observed in rabbits at any dose tested. In rats, dapagliflozin was neither embryolethal nor teratogenic at doses up to 75 mg/kg/day or 1441 times the maximum clinical dose of 10 mg. At higher doses in rats, malformations of blood vessels, ribs, vertebrae, manubria, and skeletal variations in foetuses at 150 mg/kg or 2344 times the 10 mg  clinical dose were observed.

Metformin hydrochloride

Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 and 6 times the MRHD of 2000 mg based on body surface area comparisons for rats and rabbits, respectively. Determination of foetal concentrations demonstrated a partial placental barrier to metformin.

Nursing Mothers

It is not known whether Xigduo XR is excreted in human milk. In studies performed with the individual components, both dapagliflozin (reaching levels 0.49 times that found in maternal plasma) and metformin are excreted in the milk of lactating rats.

Data in juvenile rats directly exposed to dapagliflozin showed risk to the developing kidney (renal pelvic and tubular dilatations) during maturation. Since human kidney maturation occurs in utero and in the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney. Because many drugs are excreted in human milk and because of the potential for serious  adverse reactions in nursing infants from dapagliflozin, a decision should be made whether to discontinue nursing or to discontinue Xigduo XR, taking into account the importance of the drug to the mother.

No studies on the effects on the ability to drive and use machines have been performed.

The following important adverse reactions are described below and elsewhere in the labelling:

•  Use in Patients with Renal Impairment [see Special warnings and precautions for use (4.4)]

•  Hypotension [see Special warnings and precautions for use (4.4)]

•  Use with Medications Known to Cause Hypoglycaemia [see Interaction with other medicinal products and other forms of interaction (4.5)]

•  Vitamin B12 Concentrations [see Special warnings and precautions for use (4.4)]

•  Genital Mycotic Infections [see Special warnings and precautions for use (4.4)]

•  Increases  in  Low-Density  Lipoprotein  Cholesterol  (LDL-C)  [see  Special  warnings  and precautions for use (4.4)]

•  Bladder Cancer [see Special warnings and precautions for use (4.4)]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Dapagliflozin and Metformin hydrochloride

Data from a prespecified pool of patients from 8 short-term, placebo-controlled studies of dapagliflozin  coadministered  with  metformin  immediate  or  extended-release  was  used  to evaluate safety. This pool included several add-on studies (metformin alone and in combination with a dipeptidyl peptidase-4 [DPP4] inhibitor and metformin, or insulin and metformin, 2 initial combination with metformin studies, and 2 studies of patients with cardiovascular disease [CVD] and type 2 diabetes who received their usual treatment [with metformin as background therapy]). For studies that included background therapy with and without metformin, only patients who received metformin were included in the 8-study placebo-controlled pool. Across these 8 studies

983 patients were treated once daily with dapagliflozin 10 mg and metformin and 1185 were treated with placebo and metformin. These 8 studies provide a mean duration of exposure of 23 weeks. The mean age of the population was 57 years and 2% were older than 75 years. Fifty-four

percent (54%) of the population was male; 88% White, 6% Asian, and 3% Black or African American. At baseline, the population had diabetes for an average of 8 years, mean haemoglobin A1c (HbA1c) was 8.4%, and renal function was normal or mildly impaired in 90% of patients and moderately impaired in 10% of patients.

The overall incidence of adverse events for the 8-study, short-term, placebo-controlled pool in patients treated with dapagliflozin 10 mg and metformin was 60.3% compared to 58.2% for the placebo and metformin group. Discontinuation of therapy due to adverse events in patients who received dapagliflozin 10 mg and metformin was 4% compared to 3.3% for the placebo and metformin group. The most commonly reported events leading to discontinuation and reported in at least 3 patients treated with dapagliflozin 10 mg and metformin were renal impairment (0.7%), increased blood creatinine (0.2%), decreased renal creatinine clearance (0.2%), and urinary tract infection (0.2%).

Table  1  shows  common  adverse  reactions  associated  with  the  use  of  dapagliflozin  and metformin. These adverse reactions were not present at baseline, occurred more commonly on dapagliflozin and metformin than on placebo, and occurred in at least 2% of patients treated with either dapagliflozin 5 mg or dapagliflozin 10 mg.

Table 1:                      Adverse Reactions in Placebo-Controlled Studies Reported in 2%

of Patients Treated with Dapagliflozin and Metformin

Table 1:                      Adverse Reactions in Placebo-Controlled Studies Reported in 2%

of Patients Treated with Dapagliflozin and Metformin

*    Genital mycotic infections include the following adverse reactions, listed in order of frequency reported for females: vulvovaginal mycotic infection, vaginal infection, genital infection, vulvovaginitis, fungal genital infection, vulvovaginal candidiasis, vulval abscess, genital candidiasis, and vaginitis bacterial. (N for

females: Placebo and metformin=534, dapagliflozin 5 mg and metformin=223, dapagliflozin 10 mg and metformin=430).

†    Urinary tract infections include the following adverse reactions, listed in order of frequency reported: urinary tract infection, cystitis, pyelonephritis, urethritis, and

prostatitis.

‡    Genital mycotic infections include the following adverse reactions, listed in order of frequency reported for males: balanitis, fungal genital infection, balanitis candida, genital candidiasis, genital infection, posthitis, balanoposthitis. (N for males: Placebo and metformin=651, dapagliflozin 5 mg and metformin=187, dapagliflozin 10 mg and metformin=553).

§    Increased urination includes the following adverse reactions, listed in order of frequency reported: pollakiuria, polyuria, and urine output increased.

Metformin hydrochloride

In placebo-controlled monotherapy trials of metformin extended-release, diarrhoea and nausea/vomiting were reported in >5% of metformin-treated patients and more commonly than in placebo-treated patients (9.6% versus 2.6% for diarrhoea and 6.5% versus 1.5% for nausea/vomiting). Diarrhoea led to discontinuation of study medication in 0.6% of the patients treated with metformin extended-release.

Pool of 12 Placebo-Controlled Studies for Dapagliflozin 5 and 10 mg

Dapagliflozin

The data in Table 2 are derived from 12 placebo-controlled studies ranging from 12 to 24 weeks. In 4 studies dapagliflozin was used as monotherapy, and in 8 studies dapagliflozin was used as add-on to background antidiabetic therapy or as combination therapy with metformin [see Clinical Studies].

These data reflect exposure of 2338 patients to dapagliflozin with a mean exposure duration of

21 weeks. Patients received placebo (N=1393), dapagliflozin 5 mg (N=1145), or dapagliflozin

10 mg (N=1193) once daily. The mean age of the population was 55 years and 2% were older than 75 years of age. Fifty percent (50%) of the population were male; 81% were White, 14% were Asian, and 3% were Black or African American. At baseline, the population had diabetes for an average of 6 years, had a mean HbA1c of 8.3%, and 21% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired in 92% of patients and moderately impaired in 8% of patients (mean eGFR 86 mL/min/1.73 m2).

Table 2 shows common adverse reactions associated with the use of dapagliflozin. These adverse reactions  were  not  present  at  baseline,  occurred  more  commonly on  dapagliflozin  than  on placebo, and occurred in at least 2% of patients treated with either dapagliflozin 5 mg or dapagliflozin 10 mg.

Table 2:                       Adverse Reactions in Placebo-Controlled Studies Reported in 2% of

Patients Treated with Dapagliflozin

Table 2:                       Adverse Reactions in Placebo-Controlled Studies Reported in 2% of

Patients Treated with Dapagliflozin

*    Genital mycotic infections include the following adverse reactions, listed in order of frequency reported for females: vulvovaginal mycotic infection, vaginal infection, vulvovaginal candidiasis, vulvovaginitis, genital infection, genital candidiasis, fungal genital infection, vulvitis, genitourinary tract infection, vulval

abscess, and vaginitis bacterial. (N for females: Placebo=677, dapagliflozin 5 mg=581, dapagliflozin 10 mg=598).

†    Urinary tract infections include the following adverse reactions, listed in order of frequency reported: urinary tract infection, cystitis, Escherichia urinary tract

infection, genitourinary tract infection, pyelonephritis, trigonitis, urethritis, kidney infection, and prostatitis.

‡    Increased urination includes the following adverse reactions, listed in order of frequency reported: pollakiuria, polyuria, and urine output increased.

§    Genital mycotic infections include the following adverse reactions, listed in order of frequency reported for males: balanitis, fungal genital infection, balanitis candida, genital candidiasis, genital infection male, penile infection, balanoposthitis, balanoposthitis infective, genital infection, posthitis. (N for males: Placebo=716, dapagliflozin 5 mg=564, dapagliflozin 10 mg=595).

Pool of 13 Placebo-Controlled Studies for Dapagliflozin 10 mg

The safety and tolerability of dapagliflozin 10 mg was also evaluated in a larger placebo- controlled study pool. This pool combined 13 placebo-controlled studies, including 3 monotherapy studies, 9 add-on to background antidiabetic therapy studies, and an initial combination with metformin study. Across these 13 studies, 2360 patients were treated once daily with dapagliflozin 10 mg for a mean duration of exposure of 22 weeks. The mean age of the population was 59 years and 4% were older than 75 years. Fifty-eight percent (58%) of the population were male; 84% were White, 9% were Asian, and 3% were Black or African American. At baseline, the population had diabetes for an average of 9 years, had a mean HbA1c of 8.2%, and 30% had established microvascular disease. Baseline renal function was normal or mildly impaired in 88% of patients and moderately impaired in 11% of patients (mean eGFR

82 mL/min/1.73 m2).

Volume Depletion

Dapagliflozin can cause intravascular volume depletion which may sometimes manifest as symptomatic hypotension or
acute transient changes in creatinine. There have been post-marketing reports of acute kidney injury, some requiring
hospitalization and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including dapagliflozin. Patients
with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics may be at
increased risk for volume depletion or hypotension. Before initiating XIGDUO XR in patients with one or more of these
characteristics, assess volume status and renal function. Monitor for signs and symptoms of hypotension and renal function after initiating therapy.

Table 3:                       Adverse Reactions of Volume Depletion* in Clinical Studies with

Dapagliflozin

*    Volume depletion includes reports of dehydration, hypovolemia, orthostatic hypotension, or hypotension.

Impairment of Renal Function

Use of dapagliflozin was associated with increases in serum creatinine and decreases in eGFR (see Table 4). In patients with normal or mildly impaired renal function at baseline, serum creatinine and eGFR returned to baseline values at Week 24. Renal-related adverse reactions, including renal failure and blood creatinine increase, were more frequent in patients treated with dapagliflozin (see Table 5). Elderly patients and patients with impaired renal function were more susceptible to these adverse reactions (see Table 5). Sustained decreases in eGFR were seen in patients with moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m2).

Table 4:                       Changes in Serum Creatinine and eGFR Associated with Dapagliflozin in the Pool of 12 Placebo-Controlled Studies and Moderate Renal Impairment Study

Table 5:                       Proportion of Patients with at Least One Renal Impairment-Related

Adverse Reaction

Table 5:                       Proportion of Patients with at Least One Renal Impairment-Related

Adverse Reaction

* Subset of patients from the pool of 12 placebo-controlled studies with long-term extensions.

†    Subset of patients from the pool of 13 placebo-controlled studies with long-term extensions.

The safety of dapagliflozin was evaluated in a study of patients with moderate renal impairment (eGFR

30 to less than 60 mL/min/1.73 m2). In this study 13 patients experienced bone fractures for treatment durations up to 104 weeks. No fractures occurred in the placebo group, 5 occurred in the dapagliflozin 5 mg group, and 8 occurred in the dapagliflozin 10 mg group. Eight of these 13 fractures were in patients who had a baseline eGFR of 30 to 45 mL/min/1.73 m2. Eleven of the 13 fractures were reported within the first 52 weeks. There was no apparent pattern with respect to the anatomic site of fracture.

Hypoglycaemia

The frequency of hypoglycaemia by study [see Clinical Studies] is shown in Table 6. hypoglycaemia was more frequent when dapagliflozin was added to sulfonylurea or insulin [see Special warnings and precautions for use (4.4)].

Table 6:                       Incidence of Major* and Minor† Hypoglycaemia in Placebo-Controlled

Studies

Table 6:                       Incidence of Major* and Minor† Hypoglycaemia in Placebo-Controlled

Studies

*   Major episodes of hypoglycaemia were defined as symptomatic episodes requiring external (third party) assistance due to severe impairment in consciousness or behaviour with a capillary or plasma glucose value <54 mg/dL and prompt recovery after glucose or glucagon administration.

†   Minor episodes of hypoglycaemia were defined as either a symptomatic episode with a capillary or plasma glucose measurement <63 mg/dL regardless of need for external assistance, or an asymptomatic capillary or plasma glucose measurement <63 mg/dL that does not qualify as a major episode.

‡   OAD = oral antidiabetic therapy.

Genital Mycotic Infections

Genital mycotic infections were more frequent with dapagliflozin treatment. Genital mycotic infections were reported in 0.9% of patients on placebo, 5.7% on dapagliflozin 5 mg, and 4.8% on dapagliflozin 10 mg, in the 12-study placebo-controlled pool. Discontinuation from study due to genital infection occurred in 0% of placebo-treated patients and 0.2% of patients treated with dapagliflozin 10 mg. Infections were more frequently reported in females than in males (see Table 2). The most frequently reported genital mycotic infections were vulvovaginal mycotic infections in females and balanitis in males. Patients with a history of genital mycotic infections were more likely to have a genital mycotic infection during the study than those with no prior history (10.0%, 23.1%, and 25.0% versus 0.8%, 5.9%, and 5.0% on placebo, dapagliflozin 5 mg, and dapagliflozin 10 mg, respectively).

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., angioedema, urticaria, hypersensitivity) were reported with dapagliflozin treatment. Across the clinical program, serious anaphylactic reactions and severe cutaneous  adverse  reactions  and  angioedema  were  reported  in  0.2%  of  comparator-treated patients and 0.3% of dapagliflozin-treated patients. If hypersensitivity reactions occur, discontinue use of dapagliflozin; treat per standard of care and monitor until signs and symptoms resolve.

Laboratory Tests Increase in Haematocrit Dapagliflozin

In the pool of 13 placebo-controlled studies, increases from baseline in mean haematocrit values

were observed in dapagliflozin-treated patients starting at Week 1 and continuing up to Week 16, when the maximum mean difference from baseline was observed. At Week 24, the mean changes from baseline in haematocrit were −0.33% in the placebo group and 2.30% in the dapagliflozin

10 mg group. By Week 24, haematocrit values >55% were reported in 0.4% of placebo-treated patients and 1.3% of dapagliflozin 10 mg–treated patients.

Increase in Serum Inorganic Phosphorus

Dapagliflozin

In the pool of 13 placebo-controlled studies, increases from baseline in mean serum phosphorus levels were reported at Week 24 in dapagliflozin 10 mg–treated patients compared with placebo- treated patients (mean increases of 0.13 mg/dL versus −0.04 mg/dL, respectively). Higher proportions of patients with marked laboratory abnormalities of hyperphosphatemia (5.6 mg/dL if age 17-65 or 5.1 mg/dL if age 66) were reported in the dapagliflozin 10 mg group versus the placebo group at Week 24 (1.7% versus 0.9%, respectively).

Increase in Low-Density Lipoprotein Cholesterol Dapagliflozin

Dapagliflozin

In the pool of 13 placebo-controlled studies, changes from baseline in mean lipid values were reported in dapagliflozin-treated patients compared to placebo-treated patients. Mean percent change from baseline at Week 24 were 0.0% versus 2.5% for total cholesterol and −1.0% versus

2.9% for LDL cholesterol in the placebo and dapagliflozin 10 mg groups, respectively.

Vitamin B12 Concentrations

Metformin hydrochloride

Metformin may lower serum vitamin B12 concentrations. Measurement of haematologic parameters on an annual basis is advised in patients on Xigduo XR and any apparent abnormalities should be appropriately investigated and managed. [See Special warnings and precautions for use (4.4)]

Dapagliflozin

There were no reports of overdose during the clinical development program for dapagliflozin. 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.

Metformin hydrochloride

Overdose of metformin hydrochloride has occurred, including ingestion of amounts >50 grams. Hypoglycaemia was reported in approximately 10% of cases, but no causal association with metformin   hydrochloride   has   been   established.   Lactic   acidosis   has   been   reported   in approximately 32% of metformin overdose cases [see Special warnings and precautions for use (4.4)]. Metformin is dialysable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, haemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

Mechanism of Action

Xigduo XR

Xigduo XR combines two antihyperglycaemic agents with complementary mechanisms of action to improve glycaemic control in patients with type 2 diabetes: dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and metformin hydrochloride, a biguanide.

Dapagliflozin

Sodium-glucose cotransporter 2 (SGLT2), expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Dapagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, dapagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.

Metformin hydrochloride

Metformin improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose

uptake and utilization. Metformin does not produce hypoglycaemia in either patients with type 2 diabetes or in healthy subjects, except in unusual circumstances [see Special warnings and precautions for use (4.4)], and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

Description

Xigduo XR (dapagliflozin and metformin HCl extended-release) tablets contain two oral antihyperglycaemic medications used in the management of type 2 diabetes: dapagliflozin and metformin hydrochloride.

Dapagliflozin

Dapagliflozin is described chemically as D-glucitol, 1,5-anhydro-1-C-[4-chloro-3-[(4- ethoxyphenyl)methyl]phenyl]-, (1S)-, compounded with (2S)-1,2-propanediol, hydrate (1:1:1). The empirical  formula  is  C21H25ClO6•C3H8O2•H2O  and  the formula  weight  is  502.98.  The

structural formula is:

Metformin hydrochloride

Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is a white to off-white crystalline compound with a molecular formula of C4H11N5•HCl and a molecular weight of 165.63. Metformin hydrochloride is freely soluble in water, slightly soluble in alcohol, and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. The structural formula is:

Xigduo XR

Xigduo XR is available for oral administration as tablets containing the equivalent of 5 mg dapagliflozin as dapagliflozin propanediol and 500 mg metformin hydrochloride (Xigduo XR 5 mg/500 mg), the equivalent of 5 mg dapagliflozin as dapagliflozin propanediol and 1000 mg metformin hydrochloride (Xigduo XR 5 mg/1000 mg), the equivalent of 10 mg dapagliflozin as dapagliflozin propanediol and 500 mg metformin hydrochloride (Xigduo XR 10 mg/500 mg), or the equivalent of 10 mg dapagliflozin as dapagliflozin propanediol and 1000 mg metformin hydrochloride (Xigduo XR 10 mg/1000 mg).

Each film-coated tablet of Xigduo XR contains the following inactive ingredients: microcrystalline cellulose, lactose anhydrous, crospovidone, silicon dioxide, magnesium stearate, carboxymethylcellulose sodium, and hypromellose 2208. The 5 mg/500 mg and 5 mg/1000 mg strength tablets of Xigduo XR also contain hypromellose 2910.

The film coatings contain the following inactive ingredients: polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc. Additionally, the film coating for the Xigduo XR 5 mg/500 mg tablets contains FD&C Yellow No. 6/Sunset Yellow FCF aluminium lake and the film coating for the Xigduo XR 5 mg/1000 mg, 10 mg/500 mg, and 10 mg/1000 mg tablets contains iron oxides.

General

Dapagliflozin

Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in patients  with  type  2  diabetes  mellitus  following  the  administration  of  dapagliflozin  (see Figure 1). Dapagliflozin doses of 5 or 10 mg per day in patients with type 2 diabetes mellitus for

12 weeks resulted in excretion of approximately 70 grams of glucose in the urine per day. A near maximum glucose excretion was observed at the dapagliflozin daily dose of 20 mg. This urinary glucose excretion with dapagliflozin also results in increases in urinary volume [see Undesirable Effects (4.8)].

Cardiac Electrophysiology

Dapagliflozin was not associated with clinically meaningful prolongation of QTc interval at daily doses up to 150 mg (15 times the recommended dose) in a study of healthy subjects. In addition, no clinically meaningful effect on QTc interval was observed following single doses of up to

500 mg (50 times the recommended dose) dapagliflozin in healthy subjects.

Xigduo XR

Xigduo XR combination tablets are considered to be bioequivalent to coadministration of corresponding doses of dapagliflozin (FORXIGA) and metformin hydrochloride extended- release (GLUCOPHAGE® XR) administered together as individual tablets.

The administration of Xigduo XR in healthy subjects after a standard meal compared to the fasted state resulted in the same extent of exposure for both dapagliflozin and metformin extended-release. Compared to the fasted state, the standard meal resulted in 35% reduction and a delay of 1 to 2 hours in the peak plasma concentrations of dapagliflozin. This effect of food is not considered to be clinically meaningful. Food has no relevant effect on the pharmacokinetics of metformin when administered as Xigduo XR combination tablets.

Absorption

Dapagliflozin

Following oral administration of dapagliflozin, the maximum plasma concentration (Cmax) is usually attained within 2 hours under fasting state. The Cmax and AUC values increase dose proportionally with increase in dapagliflozin dose in the therapeutic dose range. The absolute oral bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%. Administration  of dapagliflozin  with  a high-fat  meal  decreases  its  Cmax  by up  to  50% and prolongs Tmax  by approximately 1 hour, but does not alter AUC as compared with the fasted state. These changes are not considered to be clinically meaningful and dapagliflozin can be administered with or without food.

Metformin hydrochloride

Following a single oral dose of metformin extended-release, Cmax  is achieved with a median value of 7 hours and a range of 4 to 8 hours. The extent of metformin absorption (as measured by AUC) from the metformin extended-release tablet increased by approximately 50% when given with food. There was no effect of food on Cmax and Tmax of metformin.

Distribution

Dapagliflozin

Dapagliflozin is approximately 91% protein bound. Protein binding is not altered in patients with renal or hepatic impairment.

Metformin hydrochloride

Distribution studies with extended-release metformin have not been conducted; however, the apparent volume of distribution (V/F) of metformin following single oral doses of immediate- release metformin 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes.

Metabolism

Dapagliflozin

The metabolism of dapagliflozin is primarily mediated by UGT1A9; CYP-mediated metabolism is a minor clearance pathway in humans. Dapagliflozin is extensively metabolized, primarily to yield   dapagliflozin   3-O-glucuronide,   which   is   an   inactive   metabolite.   Dapagliflozin

3-O-glucuronide accounted for 61% of a 50 mg [14C]-dapagliflozin dose and is the predominant drug-related component in human plasma.

Metformin hydrochloride

Intravenous single-dose studies in healthy subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) or biliary excretion.

Metabolism studies with extended-release metformin tablets have not been conducted.

Elimination

Dapagliflozin

Dapagliflozin and related metabolites are primarily eliminated via the renal pathway. Following a single 50 mg dose of [14C]-dapagliflozin, 75% and 21% total radioactivity is excreted in urine and faeces, respectively. In urine, less than 2% of the dose is excreted as parent drug. In faeces, approximately 15% of the dose is excreted as parent drug. The mean plasma terminal half-life (t½) for dapagliflozin is approximately 12.9 hours following a single oral dose of dapagliflozin

10 mg.

Metformin hydrochloride

Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life  is  approximately  17.6  hours,  suggesting  that  the  erythrocyte  mass  may  be  a compartment of distribution.

Specific Populations Renal Impairment Xigduo XR

Use of metformin in patients with renal impairment increases the risk for lactic acidosis. Because

Xigduo XR contains metformin, Xigduo XR is contraindicated in patients with moderate to severe renal impairment [see Contraindications (4.3) and Special warnings and precautions for use (4.4)]. No dose adjustment of Xigduo XR is required in patients with mild renal impairment [see Use in Specific Populations].

Dapagliflozin

At steady-state (20 mg once-daily dapagliflozin for 7 days), patients with type 2 diabetes with mild, moderate, or severe renal impairment (as determined by eGFR) had geometric mean systemic exposures of dapagliflozin that were 45%, 2.04-fold, and 3.03-fold higher, respectively, as compared to patients with type 2 diabetes with normal renal function. Higher systemic exposure of dapagliflozin in patients with type 2 diabetes mellitus with renal impairment did not

result in a correspondingly higher 24-hour glucose excretion. The steady-state 24-hour urinary glucose excretion in patients with type 2 diabetes and mild, moderate, and severe renal impairment was 42%, 80%, and 90% lower, respectively, than in patients with type 2 diabetes with normal renal function. The impact of haemodialysis on dapagliflozin exposure is not known [see Posology and Administration (4.2), Special warnings and precautions for use (4.4), and Use in Specific Populations].

Metformin hydrochloride

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

Hepatic Impairment

Xigduo XR

Use of metformin in patients with hepatic impairment has been associated with some cases of lactic  acidosis.  Because  Xigduo  XR  contains  metformin,  Xigduo  XR  should  generally  be avoided in patients with hepatic impairment [see Special warnings and precautions for use (4.4)].

Dapagliflozin

In patients with mild and moderate hepatic impairment (Child-Pugh Classes A and B), mean Cmax  and AUC of dapagliflozin were up to 12% and 36% higher, respectively, as compared to healthy matched control subjects following single-dose administration of 10 mg dapagliflozin. These  differences  were  not  considered  to  be  clinically meaningful.  In  patients  with  severe hepatic impairment (Child-Pugh Class C), mean Cmax and AUC of dapagliflozin were up to 40% and 67% higher, respectively, as compared to healthy matched controls.

Metformin hydrochloride

No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment.

Geriatric

Dapagliflozin

Based on a population pharmacokinetic analysis, age does not have a clinically meaningful effect on systemic exposures of dapagliflozin; thus, no dose adjustment is recommended.

Metformin hydrochloride

Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggests that total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmax  is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function.

Xigduo XR should not be initiated in patients of any age unless measurement of creatinine clearance demonstrates that renal function is only normal or mildly impaired [see Special warnings and precautions for use (4.4) and Use in Specific Populations].

Paediatric

Pharmacokinetics of Xigduo XR in the paediatric population has not been studied.

Gender

Dapagliflozin

Based on a population pharmacokinetic analysis, gender does not have a clinically meaningful effect on systemic exposures of dapagliflozin; thus, no dose adjustment is recommended.

Metformin hydrochloride

Metformin pharmacokinetic parameters did not differ significantly between healthy subjects and patients with type 2 diabetes when analyzed according to gender (males=19, females=16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycaemic effect of metformin was comparable in males and females.

Race

Dapagliflozin

Based on a population pharmacokinetic analysis, race (White, Black, or Asian) does not have a clinically meaningful effect on systemic exposures of dapagliflozin; thus, no dose adjustment is recommended.

Metformin hydrochloride

No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycaemic effect was comparable in Whites (n=249), Blacks (n=51), and Hispanics (n=24).

Body Weight

Dapagliflozin

Based on a population pharmacokinetic analysis, body weight does not have a clinically meaningful effect on systemic exposures of dapagliflozin; thus, no dose adjustment is recommended.

Drug Interactions

• The concomitant use of XIGDUO XR with specific drugs may increase the risk of metformin-associated lactic acidosis:
those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation (e.g. cationic drugs). Therefore, consider more frequent monitoring of patients.

• Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium

In Vitro Assessment of Drug Interactions

Dapagliflozin

In in-vitro studies, dapagliflozin and dapagliflozin 3-O-glucuronide neither inhibited CYP 1A2,

2C9, 2C19, 2D6, 3A4, nor induced CYP 1A2, 2B6, or 3A4. Dapagliflozin is a weak substrate of the P-glycoprotein (P-gp) active transporter, and dapagliflozin 3-O-glucuronide is a substrate for the OAT3 active transporter. Dapagliflozin or dapagliflozin 3-O-glucuronide did not meaningfully inhibit P-gp, OCT2, OAT1, or OAT3 active transporters. Overall, dapagliflozin is unlikely to affect the pharmacokinetics of concurrently administered medications that are P-gp, OCT2, OAT1, or OAT3 substrates.

Effects of Other Drugs on Metformin

Table 7 shows the effect of other coadministered drugs on metformin.

Table 7:                       Effect of Coadministered Drug on Plasma Metformin Systemic Exposure

* All metformin and coadministered drugs were given as single doses.

†    Percent change (with/without coadministered drug and no change = 0%); ↑ and ↓ indicate the exposure

increase and decrease, respectively.

‡    AUC = AUC(INF).

§    Ratio of arithmetic means.

Effects of Metformin on Other Drugs

Table 8 shows the effect of metformin on other coadministered drugs.

Table 8:                       Effect of Metformin on Coadministered Drug Systemic Exposure

* All metformin and coadministered drugs were given as single doses.

†    Percent change (with/without coadministered drug and no change = 0%); ↑ and ↓ indicate the exposure

increase and decrease, respectively.

‡    AUC = AUC(INF) unless otherwise noted.

§    Ratio of arithmetic means, p-value of difference <0.05.

¶    AUC(0-24 hr) reported.

#    Ratio of arithmetic means.

Effects of Other Drugs on Dapagliflozin

Table 9 shows the effect of coadministered drugs on dapagliflozin. No dose adjustments are recommended for dapagliflozin.

Table 9:                       Effects of Coadministered Drugs on Dapagliflozin Systemic Exposure

* Single dose unless otherwise noted.

†    Percent change (with/without coadministered drug and no change = 0%); ↑ and ↓ indicate the exposure

increase and decrease, respectively.

‡    AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses.

Effects of Dapagliflozin on Other Drugs

Table 10 shows the effect of dapagliflozin on other coadministered drugs. Dapagliflozin did not meaningfully affect the pharmacokinetics of the coadministered drugs.

Table 10:                     Effects of Dapagliflozin on the Systemic Exposures of Coadministered Drugs

*    Single dose unless otherwise noted.

†    Percent change (with/without coadministered drug and no change = 0%); ↑ and ↓ indicate the exposure

increase and decrease, respectively.

‡    AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses.

CLINICAL STUDIES

There have been no clinical efficacy studies conducted with Xigduo XR combination tablets to characterize its effect on HbA1c reduction. Xigduo XR is considered to be bioequivalent to coadministered dapagliflozin and metformin hydrochloride extended-release (XR) tablets [see

Clinical  Pharmacology].  Relative  bioavailability  studies  between  Xigduo  XR  and coadministered dapagliflozin and metformin hydrochloride immediate-release (IR) tablets have not been conducted. The metformin hydrochloride XR tablets and metformin hydrochloride IR tablets have a similar extent of absorption (as measured by AUC), while peak plasma levels of XR tablets are approximately 20% lower than those of IR tablets at the same dose.

The coadministration of dapagliflozin and metformin XR tablets has been studied in treatment- naive patients inadequately controlled on diet and exercise alone. The coadministration of dapagliflozin and metformin IR or XR tablets has been studied in patients with type 2 diabetes inadequately controlled on metformin and compared with a sulfonylurea (glipizide) in combination with metformin. Treatment with dapagliflozin plus metformin at all doses produced clinically  relevant  and  statistically  significant  improvements  in  HbA1c  and  fasting  plasma glucose (FPG) compared to placebo in combination with metformin (initial or add-on therapy). HbA1c reductions were seen across subgroups including gender, age, race, duration of disease, and baseline BMI.

Initial Combination Therapy with Metformin Extended-Release

A total of 1241 treatment-naive patients with inadequately controlled type 2 diabetes (HbA1c

7.5% and 12%) participated in 2 active-controlled studies of 24-week duration to evaluate the safety and efficacy of initial therapy with dapagliflozin 5 mg or 10 mg in combination  with metformin XR formulation.

In 1 study, 638 patients were randomised to 1 of 3 treatment arms following a 1-week lead-in period: dapagliflozin 10 mg plus metformin XR (up to 2000 mg/day), dapagliflozin 10 mg plus placebo, or metformin XR (up to 2000 mg/day) plus placebo. Metformin XR dose was up- titrated weekly in 500 mg increments, as tolerated, with a median dose achieved of 2000 mg.

The combination treatment of dapagliflozin 10 mg plus metformin XR provided statistically significant  improvements  in  HbA1c  and  FPG  compared  with  either  of  the  monotherapy treatments and statistically significant reduction in body weight compared with metformin XR alone  (see  Table  11  and  Figure  2).  Dapagliflozin  10  mg  as  monotherapy  also  provided statistically significant  improvements  in  FPG  and  statistically significant  reduction  in  body weight compared with metformin alone and was noninferior to metformin XR monotherapy in lowering HbA1c.

Table 11:                     Results at Week 24 (LOCF*) in an Active-Controlled Study of

Dapagliflozin Initial Combination Therapy with Metformin XR

*    LOCF: last observation (prior to rescue for rescued patients) carried forward.

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

‡    Least squares mean adjusted for baseline value.

§    p-value <0.0001.

¶    Noninferior versus metformin XR.

#    p-value <0.05.

In a second study, 603 patients were randomised to 1 of 3 treatment arms following a 1-week lead-in period: dapagliflozin 5 mg plus metformin XR (up to 2000 mg/day), dapagliflozin 5 mg plus placebo, or metformin XR (up to 2000 mg/day) plus placebo. Metformin XR dose was up- titrated weekly in 500 mg increments, as tolerated, with a median dose achieved of 2000 mg.

The combination treatment of dapagliflozin 5 mg plus metformin XR provided statistically significant  improvements  in  HbA1c  and  FPG  compared  with  either  of  the  monotherapy treatments and statistically significant reduction in body weight compared with metformin XR alone (see Table 12).

Table 12:                     Results at Week 24 (LOCF*) in an Active-Controlled Study of

Dapagliflozin Initial Combination Therapy with Metformin XR

*    LOCF: last observation (prior to rescue for rescued patients) carried forward.

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

‡    Least squares mean adjusted for baseline value.

§    p-value <0.0001.

¶    p-value <0.05.

Add-On to Metformin Immediate-Release

A total of 546 patients with type 2 diabetes with inadequate glycaemic control (HbA1c 7% and

10%)  participated  in  a  24-week,  placebo-controlled  study  to  evaluate  dapagliflozin  in

combination with metformin. Patients on metformin at a dose of at least 1500 mg/day were randomised after completing a 2-week, single-blind, placebo lead-in period. Following the lead- in period, eligible patients were randomised to dapagliflozin 5 mg, dapagliflozin 10 mg, or placebo in addition to their current dose of metformin.

As add-on treatment to metformin, dapagliflozin 10 mg provided statistically significant improvements  in  HbA1c  and  FPG,  and  statistically  significant  reduction  in  body  weight compared with placebo at Week 24 (see Table 13 and Figure 3). Statistically significant (p<0.05 for both doses) mean changes from baseline in systolic blood pressure relative to placebo plus metformin  were  −4.5 mmHg  and  −5.3  mmHg  with  dapagliflozin  5  mg  and  10  mg  plus metformin, respectively.

Table 13:                     Results of a 24-Week (LOCF*) Placebo-Controlled Study of Dapagliflozin in Add-On Combination with Metformin

Table 13:                     Results of a 24-Week (LOCF*) Placebo-Controlled Study of Dapagliflozin in Add-On Combination with Metformin

*    LOCF: last observation (prior to rescue for rescued patients) carried forward.

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

‡    Least squares mean adjusted for baseline value.

§    p-value <0.00001 versus placebo + metformin.

¶    p-value <0.05 versus placebo + metformin.

Active Glipizide-Controlled Study Add-On to Metformin Immediate-Release

A total of 816 patients with type 2 diabetes with inadequate glycaemic control (HbA1c >6.5% and 10%) were randomised in a 52-week, glipizide-controlled, noninferiority study to evaluate dapagliflozin  as  add-on  therapy to  metformin.  Patients  on  metformin  at  a  dose  of  at  least

1500 mg/day  were  randomised  following  a  2-week  placebo  lead-in  period  to  glipizide  or

dapagliflozin  (5  or  2.5  mg,  respectively)  and  were  up-titrated  over  18  weeks  to  optimal glycaemic effect (FPG <110 mg/dL, <6.1 mmol/L) or to the highest dose level (up to glipizide

20 mg and dapagliflozin 10 mg) as tolerated by patients. Thereafter, doses were kept constant,

except for down-titration to prevent hypoglycaemia.

At the end of the titration period, 87% of patients treated with dapagliflozin had been titrated to the maximum study dose (10 mg) versus 73% treated with glipizide (20 mg). Dapagliflozin

treatment led to a similar mean reduction in HbA1c from baseline at Week 52, compared with glipizide, thus demonstrating noninferiority (see Table 14). Dapagliflozin treatment led to a statistically significant mean reduction in body weight from baseline at Week 52 compared with a mean increase in body weight in the glipizide group. Statistically significant (p<0.0001) mean change  from  baseline  in  systolic  blood  pressure  relative  to  glipizide  plus  metformin  was

−5.0 mmHg with dapagliflozin plus metformin.

Table 14:                     Results at Week 52 (LOCF*) in an Active-Controlled Study Comparing

Dapagliflozin to Glipizide as Add-On to Metformin

* LOCF: last observation carried forward.

†    Randomised and treated patients with baseline and at least 1 postbaseline efficacy measurement.

‡    Least squares mean adjusted for baseline value.

§    Noninferior to glipizide + metformin.

¶    p-value <0.0001.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Xigduo XR

No  animal  studies  have  been  conducted  with  Xigduo  XR  to  evaluate  carcinogenesis, mutagenesis, or impairment of fertility. The following data are based on the findings in the studies with dapagliflozin and metformin individually.

Dapagliflozin

Dapagliflozin did not induce tumours in either mice or rats at any of the doses evaluated in 2- year carcinogenicity studies. Oral doses in mice consisted of 5, 15, and 40 mg/kg/day in males and 2, 10, and 20 mg/kg/day in females, and oral doses in rats were 0.5, 2, and 10 mg/kg/day for both males and females. The highest doses evaluated in mice were approximately 72 times (males) and 105 times (females) the clinical dose of 10 mg/day based on AUC exposure. In rats, the highest dose was approximately 131 times (males) and 186 times (females) the clinical dose of 10 mg/day based on AUC exposure.

Dapagliflozin was negative in the Ames mutagenicity assay and was positive in a series of in vitro clastogenicity assays in the presence of S9 activation and at concentrations 100 g/mL. Dapagliflozin was negative for clastogenicity in a series of in vivo studies evaluating micronuclei or DNA repair in rats at exposure multiples >2100 times the clinical dose.

There was no carcinogenicity or mutagenicity signal in animal studies, suggesting that dapagliflozin does not represent a genotoxic risk to humans.

Dapagliflozin had no effects on mating, fertility, or early embryonic development in treated male or female rats at exposure multiples 1708 and 998 times the maximum recommended human doses in males and females, respectively.

Metformin hydrochloride

Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 and 1500 mg/kg/day, respectively. These doses are both approximately 4 times the MRHD of 2000 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumourigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day.

There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames  test  (S.  typhimurium),  gene  mutation  test  (mouse  lymphoma  cells),  or  chromosomal

aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative.

Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately 3 times the MRHD based on body surface area comparisons.

CARBOXYMETHYLCELLULOSE SODIUM

HYPROMELLOSE 2208

MICROCRYSTALLINE CELLULOSE PH302

SILICON DIOXIDE

MAGNESIUM STEARATE

LACTOSE ANHYDROUS

CROSPOVIDONE

Opadry II Yellow 85F12372

Not Applicable

Store below 30^OC

XIGDUOTM  XR (dapagliflozin and metformin HCl extended-release) tablets have markings on one side, are plain on the reverse side, and are available in the strengths and packages listed in Table 15.

Not all pack sizes may be marketed in your country.

No special requirements.