Xigduo XR

Xigduo XR

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AstraZeneca
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Contents
Dapagliflozin, metformin hydrochloride.
Description
XIGDUO XR 5 mg/500 mg: Each tablet contains dapagliflozin propanediol monohydrate equivalent to 5 mg dapagliflozin and 500 mg of metformin hydrochloride.
XIGDUO XR 5 mg/1000 mg: Each tablet contains dapagliflozin propanediol monohydrate equivalent to 5 mg dapagliflozin and 1000 mg of metformin hydrochloride.
XIGDUO XR 10 mg/500 mg: Each tablet contains dapagliflozin propanediol monohydrate equivalent to 10 mg dapagliflozin and 500 mg of metformin hydrochloride.
XIGDUO XR 10 mg/1000 mg: Each tablet contains dapagliflozin propanediol monohydrate equivalent to 10 mg dapagliflozin and 1000 mg of metformin hydrochloride.
Excipients/Inactive Ingredients: Microcrystalline cellulose, lactose anhydrous, crospovidone, silicon dioxide, magnesium stearate, carboxymethylcellulose sodium, and hypromellose 2208. The 5 mg/500 mg and 10mg/500 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 5mg/500 mg tablets contains FD&C Yellow No. 6/Sunset Yellow FCF Aluminum 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.
Action
Pharmacotherapeutic group: Drugs used in diabetes, Combinations of oral blood glucose-lowering drugs. ATC code: A10BD15.
Pharmacology: Mechanism of Action: XIGDUO XR combines two antihyperglycemic agents with complementary mechanisms of action to improve glycemic 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 hypoglycemia in either patients with type 2 diabetes or in healthy subjects, except in unusual circumstances [see Precautions], 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.
Pharmacodynamics: 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). 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 Adverse Reactions]. (See figure.)


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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.
Pharmacokinetics: 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 feces, respectively. In urine, less than 2% of the dose is excreted as parent drug. In feces, 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: 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 hemodialysis on dapagliflozin exposure is not known [see Dosage & Administration, Precautions].
Metformin hydrochloride: In patients with decreased renal function, the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased [see Contraindications and Precautions].
Hepatic Impairment: 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.
Pediatric: Pharmacokinetics of XIGDUO XR in the pediatric 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 antihyperglycemic 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 antihyperglycemic 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: Specific pharmacokinetic drug interaction studies with XIGDUO XR have not been performed, although such studies have been conducted with the individual dapagliflozin and metformin components.
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 1 shows the effect of other coadministered drugs on metformin. (See Table 1.)


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Effects of Metformin on Other Drugs: Table 2 shows the effect of metformin on other coadministered drugs. (See Table 2.)


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Effects of Other Drugs on Dapagliflozin: Table 3 shows the effect of coadministered drugs on dapagliflozin. No dose adjustments are recommended for dapagliflozin. (See Table 3.)


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Effects of Dapagliflozin on Other Drugs: Table 4 shows the effect of dapagliflozin on other coadministered drugs. Dapagliflozin did not meaningfully affect the pharmacokinetics of the coadministered drugs. (See Table 4.)


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Indications/Uses
XIGDUO XR (dapagliflozin and metformin HCl extended-release) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both dapagliflozin and metformin is appropriate: in patients inadequately controlled on their maximally tolerated dose of metformin alone; in combination with other glucose-lowering medicinal products, including insulin, in patients inadequately controlled with metformin and these medicinal products (see Precautions, Interactions and Pharmacology: Pharmacodynamics under Actions for available data on different combinations); in patients already being treated with the combination of dapagliflozin and metformin as separate tablets.
Limitations of Use: XIGDUO XR is not recommended for patients with type 1 diabetes mellitus or diabetic ketoacidosis.
Dosage/Direction for Use
Recommended Dosing: Healthcare providers should individualize the starting dose of XIGDUO XR based on the patient's current treatment.
XIGDUO XR should be taken 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 feces 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 Precautions].
Patients with Renal Impairment: Assess renal function before initiating XIGDUO XR therapy and periodically thereafter.
XIGDUO XR is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m2 [see Contraindications, Precautions, Adverse Reactions].
No dose adjustment for XIGDUO XR is needed in patients with mild renal impairment (eGFR of 60 mL/min/1.73 m2 or greater).
Discontinuation for Iodinated Contrast Imaging Procedures: Discontinue XIGDUO XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart XIGDUO XR if renal function is stable [see Precautions].
Hepatic Impairment: Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. XIGDUO XR is not recommended in patients with hepatic impairment [see Precautions].
Pediatric Use: Safety and effectiveness of XIGDUO XR in pediatric patients under 18 years of age have not been established.
Geriatric Use: No XIGDUO XR dosage change is recommended based on age. More frequent assessment of renal function is recommended in elderly patients.
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 Precautions and Adverse Reactions].
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. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients [see Precautions].
Overdosage
Dapagliflozin: There were no reports of overdose during the clinical development program for dapagliflozin. In the event of an overdose, contact the Poison Control Center. It is also reasonable to employ supportive measures as dictated by the patient's clinical status. The removal of dapagliflozin by hemodialysis has not been studied.
Metformin hydrochloride: Overdose of metformin hydrochloride has occurred, including ingestion of amounts >50 grams. Hypoglycemia 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 Precautions]. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.
Contraindications
XIGDUO XR is contraindicated in patients with: hypersensitivity to the active substances or to any of the excipients; any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis); diabetic pre-coma; renal failure (GFR < 60 mL/min) (see Dosage & Administration, Precautions and Pharmacology: Pharmacokinetics under Actions); 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 Dosage & Administration, Precautions and Pharmacology: Pharmacokinetics under Actions); acute alcohol intoxication, alcoholism (see Interactions).
Special Precautions
Lactic Acidosis: There have been post-marketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis.
Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate: pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.
If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of XIGDUO XR.
In XIGDUO XR-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable, with a clearance of up to 170 mL/minute under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.
Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue XIGDUO XR and report these symptoms to their healthcare provider.
For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided as follows: Renal Impairment: The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient's renal function include [see Dosage & Administration]: Before initiating XIGDUO XR, obtain an estimated glomerular filtration rate (eGFR).
XIGDUO XR is contraindicated in patients with an eGFR less than 60 mL/minute/1.73 m2 [see Contraindications].
Obtain an eGFR at least annually in all patients taking XIGDUO XR. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
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) [see Interactions]. Therefore, consider more frequent monitoring of patients.
Age 65 or Greater: The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients.
Radiological Studies with Contrast: Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop XIGDUO XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart XIGDUO XR if renal function is stable.
Surgery and Other Procedures: Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. XIGDUO XR should be temporarily discontinued while patients have restricted food and fluid intake.
Hypoxic States: Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue XIGDUO XR.
Excessive Alcohol Intake: Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving XIGDUO XR.
Hepatic Impairment: Patients with hepatic impairment have developed with cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of XIGDUO XR in patients with clinical or laboratory evidence of hepatic disease.
Hypotension: Dapagliflozin causes intravascular volume contraction. Symptomatic hypotension can occur after initiating dapagliflozin [see Adverse Reactions], 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.
Ketoacidosis: Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization have been identified in postmarketing surveillance in patients with type 1 and type 2 diabetes mellitus taking sodium-glucose co transporter 2 (SGLT2) inhibitors, including dapagliflozin. Fatal cases of ketoacidosis have been reported in patients taking dapagliflozin. XIGDUO XR is not indicated for the treatment of patients with type 1 diabetes mellitus [see Indications].
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 ketoacidosis 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).
Acute Kidney Injury and Impairment in Renal Function: Dapagliflozin causes intravascular volume contraction [see Precautions for Use], and can cause renal impairment [see Adverse Reactions]. There have been postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients receiving dapagliflozin: some reports involved patients younger than 65 years of age.
Before initiating XIGDUO XR, consider factors that may predispose patients to acute kidney injury including hypovolemia, chronic renal insufficiency, congestive heart failure, and concomitant medications (diuretics, ACE inhibitors, ARBs, NSAIDs). Consider temporarily discontinuing XIGDUO XR in any setting of reduced oral intake (such as acute illness or fasting) or fluid losses (gastrointestinal illness or excessive heat exposure); monitor patients for signs and symptoms of acute kidney injury. If acute kidney injury occurs, discontinue XIGDUO XR promptly and institute treatment.
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 Adverse Reactions]. Renal function should be evaluated prior to initiation of XIGDUO XR and monitored periodically thereafter. XIGDUO XR is contraindicated in patients with an eGFR below 60 mL/min/1.73 m2 [see Dosage & Administration, Contraindications, Precautions].
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 [see Adverse Reactions].
Use with Medications Known to Cause Hypoglycemia: Dapagliflozin: Insulin and insulin secretagogues are known to cause hypoglycemia. Dapagliflozin can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue [see Adverse Reactions]. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when these agents are used in combination with XIGDUO XR.
Metformin hydrochloride: Hypoglycemia 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 hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs.
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 anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on XIGDUO XR and any apparent abnormalities should be appropriately investigated and managed [see Adverse Reactions].
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 Adverse Reactions]. Monitor and treat appropriately.
Increases in Low-Density Lipoprotein Cholesterol (LDL-C): Increases in LDL-C occur with dapagliflozin [see Adverse Reactions]. 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 hematuria (a potential indicator of pre-existing tumors) 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 tumors. Consequently, XIGDUO XR should not be used in patients with active bladder cancer. In patients with prior history of bladder cancer, the benefits of glycemic 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.
Lactose: The tablets contain lactose anhydrous. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.
Effects on Ability to Drive and Use Machines: Dapagliflozin or metformin have no or negligible influence on the ability to drive and use machines. Patients should be alerted to the risk of hypoglycaemia when this medicinal product is used in combination with other glucose-lowering medicinal products known to cause hypoglycaemia.
Use In Pregnancy & Lactation
Pregnancy: 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 fetus.
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-fetal 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 fetuses 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 fetal 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.
Adverse Reactions
XIGDUO XR has been demonstrated to be bioequivalent with coadministered dapagliflozin and metformin (see Pharmacology: Pharmacokinetics under Actions). There have been no therapeutic clinical trials conducted with XIGDUO XR tablets.
Dapagliflozin plus metformin: Summary of the safety profile: In an analysis of 5 placebo-controlled dapagliflozin add-on to metformin studies, the safety results were similar to that of the pre-specified pooled analysis of 13 placebo-controlled dapagliflozin studies (see Dapagliflozin: Summary of the safety profile as follows). No additional adverse reactions were identified for the dapagliflozin plus metformin group compared with those reported for the individual components. In the separate dapagliflozin add-on to metformin pooled analysis, 623 subjects were treated with dapagliflozin 10 mg as add-on to metformin and 523 were treated with placebo plus metformin.
Dapagliflozin: Summary of the safety profile: In a pre-specified pooled analysis of 13 placebo-controlled studies, 2,360 subjects were treated with dapagliflozin 10 mg and 2,295 were treated with placebo.
The most frequently reported adverse reaction was hypoglycaemia, which depended on the type of background therapy used in each study. The frequency of minor episodes of hypoglycaemia was similar between treatment groups, including placebo, with the exceptions of studies with add-on sulphonylurea (SU) and add-on insulin therapies. Combination therapies with sulphonylurea and add-on insulin had higher rates of hypoglycaemia (see Hypoglycaemia as follows).
Tabulated list of adverse reactions: The following adverse reactions have been identified in the placebo-controlled dapagliflozin plus metformin clinical trials, dapagliflozin clinical trials and metformin clinical trials and post-marketing experience. None were found to be dose-related. Adverse reactions listed as follows are classified according to frequency and system organ class. Frequency categories are defined according to the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and not known (cannot be estimated from the available data). (See Table 5.)


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Description of selected adverse reactions: Dapagliflozin plus metformin: Hypoglycaemia: In studies with dapagliflozin in add-on combination with metformin, minor episodes of hypoglycaemia were reported at similar frequencies in the group treated with dapagliflozin 10 mg plus metformin (6.9%) and in the placebo plus metformin group (5.5%). No major events of hypoglycaemia were reported. Similar observations were made for the combination of dapagliflozin with metformin in drug-naïve patients.
In an add-on to metformin and a sulphonylurea study, up to 24 weeks, minor episodes of hypoglycaemia were reported in 12.8% of subjects who received dapagliflozin 10 mg plus metformin and a sulphonylurea and in 3.7% of subjects who received placebo plus metformin and a sulphonylurea. No major events of hypoglycaemia were reported.
Dapagliflozin: Hypoglycaemia: The frequency of hypoglycaemia depended on the type of background therapy used in each study.
For studies of dapagliflozin as add-on to metformin or as add-on to sitagliptin (with or without metformin), the frequency of minor episodes of hypoglycaemia was similar (< 5%) between treatment groups, including placebo up to 102 weeks of treatment. Across all studies, major events of hypoglycaemia were uncommon and comparable between the groups treated with dapagliflozin or placebo. In a study with add-on insulin therapy, higher rates of hypoglycaemia were observed (see Interactions).
In an add-on to insulin study up to 104 weeks, episodes of major hypoglycaemia were reported in 0.5% and 1.0% of subjects in dapagliflozin 10 mg plus insulin at Weeks 24 and 104, respectively, and in 0.5% of subjects treated with placebo plus insulin groups at Weeks 24 and 104. At Weeks 24 and 104, minor episodes of hypoglycaemia were reported, respectively, in 40.3% and 53.1% of subjects who received dapagliflozin 10 mg plus insulin and in 34.0% and 41.6% of the subjects who received placebo plus insulin.
Volume depletion: Reactions related to volume depletion (including, reports of dehydration, hypovolaemia or hypotension) were reported in 1.1% and 0.7% of subjects who received dapagliflozin 10 mg and placebo, respectively; serious reactions occurred in < 0.2% of subjects balanced between dapagliflozin 10 mg and placebo (see Precautions).
Vulvovaginitis, balanitis and related genital infections: Vulvovaginitis, balanitis and related genital infections were reported in 5.5% and 0.6% of subjects who received dapagliflozin 10 mg and placebo, respectively. Most infections were mild to moderate, and subjects responded to an initial course of standard treatment and rarely resulted in discontinuation from dapagliflozin treatment. These infections were more frequent in females (8.4% and 1.2% for dapagliflozin and placebo, respectively), and subjects with a prior history were more likely to have a recurrent infection.
Urinary tract infections: Urinary tract infections were more frequently reported for dapagliflozin compared with placebo (4.7% versus 3.5%, respectively; see Precautions). Most infections were mild to moderate, and subjects responded to an initial course of standard treatment and rarely resulted in discontinuation from dapagliflozin treatment. These infections were more frequent in females, and subjects with a prior history were more likely to have a recurrent infection.
Increased creatinine: Adverse reactions related to increased creatinine were grouped (e.g. decreased renal creatinine clearance, renal impairment, increased blood creatinine and decreased glomerular filtration rate). This grouping of reactions was reported in 3.2% and 1.8% of patients who received dapagliflozin 10 mg and placebo, respectively. In patients with normal renal function or mild renal impairment (baseline eGFR ≥ 60 mL/min/1.73m2) this grouping of reactions were reported in 1.3% and 0.8% of patients who received dapagliflozin 10 mg and placebo, respectively. These reactions were more common in patients with baseline eGFR ≥ 30 and < 60 mL/min/1.73m2 (18.5% dapagliflozin 10 mg vs 9.3% placebo).
Further evaluation of patients who had renal-related adverse events showed that most had serum creatinine changes of ≤ 0.5 mg/dL from baseline. The increases in creatinine were generally transient during continuous treatment or reversible after discontinuation of treatment.
Parathyroid hormone (PTH): Small increases in serum PTH levels were observed with increases being larger in subjects with higher baseline PTH concentrations. Bone mineral density measurements in patients with normal or mildly impaired renal function did not indicate bone loss over a treatment period of two years.
Malignancies: During clinical trials, the overall proportion of subjects with malignant or unspecified tumours was similar between those treated with dapagliflozin (1.50%) and placebo/comparator (1.50%), and there was no carcinogenicity or mutagenicity signal in animal data. When considering the cases of tumours occurring in the different organ systems, the relative risk associated with dapagliflozin was above 1 for some tumours (bladder, prostate, breast) and below 1 for others (e.g. blood and lymphatic, ovary, renal tract), not resulting in an overall increased tumour risk associated with dapagliflozin. The increased/decreased risk was not statistically significant in any of the organ systems. Considering the lack of tumour findings in non-clinical studies as well as the short latency between first drug exposure and tumour diagnosis, a causal relationship is considered unlikely. Since the numerical imbalance of breast, bladder and prostate tumours must be considered with caution, it will be further investigated in post-authorisation studies.
Special populations: Elderly (≥ 65 years): In subjects ≥ 65 years of age, adverse reactions related to renal impairment or failure were reported in 7.7% of subjects treated with dapagliflozin and 3.8% of subjects treated with placebo (see Precautions). The most commonly reported adverse reaction related to renal function was increased serum creatinine. The majority of these reactions were transient and reversible. In subjects ≥ 65 years of age, adverse reactions of volume depletion, most commonly reported as hypotension, were reported in 1.7% and 0.8% of dapagliflozin-treated subjects and placebo-treated subjects, respectively (see Precautions).
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.
Drug Interactions
Positive Urine Glucose Test: Dapagliflozin: Monitoring glycemic 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 glycemic control.
Interference with 1,5-anhydroglucitol (1,5-AG) Assay: Dapagliflozin: Monitoring glycemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.
Carbonic Anhydrase Inhibitors: Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with XIGDUO XR may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients.
Drugs that Reduce Metformin Clearance: Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use.
Alcohol: Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving XIGDUO XR.
Use with Other Drugs: Metformin hydrochloride: Some medications can predispose to hyperglycemia and may lead to loss of glycemic 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 glycemic control. When such drugs are withdrawn from a patient receiving XIGDUO XR, the patient should be observed closely for hypoglycemia.
In healthy volunteers, the pharmacokinetics of metformin and propranolol, and of metformin and ibuprofen were not affected when coadministered in single-dose interaction studies.
Storage
Do not store above 30°C.
Shelf-Life: 3 years from manufacturing date.
MIMS Class
ATC Classification
A10BD15 - metformin and dapagliflozin ; Belongs to the class of combinations of oral blood glucose lowering drugs. Used in the treatment of diabetes.
Presentation/Packing
XR FC tab 5 mg/500 mg (orange, biconvex, capsule-shaped, with "1070" and "5/500" debossed on one side and plain on the reverse side) x 4 x 7's. 5 mg/1000 mg (pink to dark pink, biconvex, oval-shaped, with "1071" and "5/1000" debossed on one side and plain on the reverse side) x 4 x 7's. 10 mg/500 mg (pink, biconvex, capsule-shaped, with "1072" and "10/500" debossed on one side and plain on the reverse side) x 4 x 7's. 10 mg/1000 mg (yellow to dark yellow, biconvex, oval-shaped, with "1073" and "10/1000" debossed on one side and plain on the reverse side) x 4 x 7's.
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