Select therapeutic use:

CHF and arrhythmias:

Indications for: XIGDUO XR

Dapagliflozin: 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. To reduce the risk of cardiovascular death and hospitalization for heart failure in adults with heart failure (NYHA class II-IV) with reduced ejection fraction.

Limitations of Use:

Due to the metformin component, the use of Xigduo XR is limited to adults with type 2 diabetes mellitus for all indications.

Clinical Trials:

Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

  • The international, multicenter, randomized, double-blind, placebo-controlled, Dapagliflozin Effect on Cardiovascular Events (DECLARE, NCT01730534) study evaluated the effect of dapagliflozin 10 mg relative to placebo on cardiovascular (CV) outcomes when added to current background therapy.

  • Patients had type 2 diabetes and either established CV disease or 2 or more additional CV risk factors. At the discretion of investigators, adjustments could be made to concomitant antidiabetic and atherosclerotic therapies. 17160 patients were randomly assigned 1:1 to receive dapagliflozin 10 mg or placebo, and were followed for a median of 4.2 years.

  • The dapagliflozin 10 mg treatment arm achieved superiority to placebo in reducing the incidence of the primary composite endpoint of hospitalization for heart failure or CV death (hazard ratio, 0.83 [95% CI, 0.73-0.95]; P =.005).

Heart Failure with Reduced Ejection Fraction

  • In the DAPA-HF (Dapagliflozin and Prevention of Adverse-outcomes in Heart Failure) study, patients with heart failure and reduced ejection fraction (LVEF ≤40%), with and without type 2 diabetes, were randomly assigned to receive dapagliflozin 10 mg or placebo in addition to standard of care. The primary composite outcome was the time to first occurrence of cardiovascular death or hospitalization for heart failure or an urgent heart failure visit.

  • In the overall population, dapagliflozin met primary composite endpoint reducing the incidence of CV death, hospitalization, or urgent heart failure visit  (HR, 0.74 [95% CI, 0.65-0.85]; P <.0001).

  • Dapagliflozin also reduced the incidence of the primary composite endpoint in patients with type 2 diabetes mellitus (HR, 0.75 [95% CI, 0.63-0.90]; P <.0001) and in patients with type 2 diabetes mellitus and metformin as background therapy (HR, 0.67 [95% CI, 0.51-0.88]).

Adult Dosage:

Swallow whole. Take in the AM with food. Individualize. Give dapagliflozin 10mg once daily. May adjust dose as tolerated; max 10mg/2000mg daily. Renal impairment (eGFR 30–<45mL/min/1.73m2): initiation is not recommended. Assess benefit/risk of continuing therapy if eGFR falls persistently <45mL/min/1.73m2.

Children Dosage:

<18yrs: not established.

XIGDUO XR Contraindications:

Severe renal impairment (eGFR <30mL/min/1.73m2), ESRD, or on dialysis. Metabolic acidosis, diabetic ketoacidosis.

Boxed Warning:

Lactic acidosis.

XIGDUO XR Warnings/Precautions:

Increased risk of metformin-associated lactic acidosis in renal or hepatic impairment, concomitant use of certain drugs (eg, cationic drugs), ≥65yrs of age, undergoing radiological contrast study, surgery and other procedures, hypoxic states, and excessive alcohol intake; discontinue if lactic acidosis occurs. Discontinue at time of, or prior to intravascular iodinated contrast imaging in patients with a history of hepatic impairment, alcoholism, heart failure, or will be given intra-arterial contrast; reevaluate eGFR 48hrs after procedure and restart therapy if renally stable. Assess volume status and renal function prior to initiation. Correct volume depletion before initiating, if needed. Monitor for hypotension and renal function (esp. elderly, patients with renal impairment, or on loop diuretics) during therapy. Assess for ketoacidosis in presence of signs/symptoms of metabolic acidosis, regardless of blood glucose levels; discontinue if suspected, evaluate and treat; consider risk factors before initiation (eg, pancreatic insulin deficiency, caloric restriction, alcohol abuse). Consider temporarily discontinuing prior to scheduled surgery (for ≥3 days) or other clinical situations (eg, prolonged fasting due to illness or post-surgery). Necrotizing fasciitis of the perineum (Fournier's gangrene); discontinue and treat immediately if suspected; use alternative antidiabetic. Monitor for genital mycotic infections, UTIs (including urosepsis, pyelonephritis), hematology (esp. serum Vit. B12); treat if needed. Hepatic impairment: not recommended. Pregnancy (2nd & 3rd trimesters), nursing mothers: not recommended.

XIGDUO XR Classification:

Sodium-glucose co-transporter 2 (SGLT2) inhibitor + biguanide.

XIGDUO XR Interactions:

Increased risk of lactic acidosis with topiramate, other carbonic anhydrase inhibitors (eg, zonisamide, acetazolamide, dichlorphenamide); monitor. Concomitant cationic drugs that interfere with renal tubular transport systems (eg, ranolazine, vandetanib, dolutegravir, cimetidine) may increase metformin levels. Diuretics, steroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, CCBs, and isoniazid may cause hyperglycemia; monitor. Avoid excessive alcohol. β-blockers may mask hypoglycemia. May need a lower dose of concomitant insulin or insulin secretagogue (eg, sulfonylurea) to reduce risk of hypoglycemia. Dapagliflozin may antagonize serum lithium concentrations; monitor levels more frequently. Dapagliflozin will lead to false (+) urine glucose tests or unreliable measurements of 1, 5-AG assay; use alternative methods to monitor glycemic control.

Adverse Reactions:

Female genital mycotic infections, nasopharyngitis, UTIs, diarrhea, headache, nausea, vomiting; ketoacidosis, acute kidney injury; rare: lactic acidosis.

Metabolism:

Dapagliflozin

  • UGT1A9 (primary), CYP-mediated metabolism (minor).

  • Dapagliflozin is extensively metabolized, primarily to yield dapagliflozin 3-O-glucuronide, which is an inactive metabolite.

Metformin HCl

  • 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. 

Drug Elimination:

Dapagliflozin

  • Renal (75%), fecal (21%). 

  • Half-life: ~12.9 hours.

Metformin HCl

  • Renal (90%).

  • Half-life: ~6.2 hours.

 

Generic Drug Availability:

NO

How Supplied:

XR tabs 2.5mg/1000mg—60; 5mg/ 500mg, 10mg/500mg—30, 500; 5mg/1000mg—30, 60, 90, 400; 10mg/1000mg—30, 90, 400

Diabetes:

Indications for: XIGDUO XR

Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Limitations of Use:

Not recommended in patients with type 1 diabetes; may increase risk of diabetic ketoacidosis. Due to the metformin component, the use of Xigduo XR is limited to adults with type 2 diabetes mellitus for all indications.

Clinical Trials:

Glycemic Control - Initial Combination Therapy with Metformin Extended-Release

  • A total of 1236 treatment-naive patients with inadequately controlled type 2 diabetes mellitus (HbA1c ≥7.5% and ≤12%) were evaluated in 2 active-controlled studies of 24-week duration for initial therapy with dapagliflozin 5 mg (NCT00643851) or 10 mg (NCT00859898) in combination with metformin extended-release (XR) formulation. 

  • Study 1:

    • 638 patients were randomly assigned 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.

    • Treatment with dapagliflozin plus metformin XR achieved 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.

    • Treatment with dapagliflozin 10 mg monotherapy also achieved statistically significantly improvements in FPG and statistically significant reduction in body weight compared with metformin alone and was noninferior to metformin XR monotherapy in lowering HbA1c.

  • Study 2:

    • 603 patients were randomly assigned 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.

    • Treatment with dapagliflozin plus metformin XR achieved 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.

Glycemic Control - Add-On to Metformin Immediate-Release

  • A total of 546 patients with type 2 diabetes mellitus with inadequate glycemic control (HbA1c ≥7% and ≤10%) participated in a 24-week, placebo-controlled study to evaluate dapagliflozin in combination with metformin (NCT00528879). 

  • Patients were on a metformin dose of at least 1500 mg/day and randomly assigned after a 2-week, single-blind, placebo lead-in period. After the lead-in period, eligible patients were randomly assigned to receive dapagliflozin 5 mg, 10 mg, or placebo, in addition to their current dose of metformin.

  • Dapagliflozin 10 mg achieved statistically significant improvements in HbA1c and FPG, and statistically significant reduction in body weight at week 24 compared with placebo. 

  • Dapagliflozin 5 mg and 10 mg plus metformin also achieved statistically significant mean changes from baseline in systolic blood pressure of -4.5 mmHg and -5.3 mmHg, respectively, compared with placebo plus metformin (P <.05 for both doses).

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

  • A total of 816 patients with type 2 diabetes mellitus with inadequate glycemic control (HbA1c >6.5% and ≤10%) were randomized in a 52-week, glipizide-controlled, noninferiority study to evaluate dapagliflozin as add-on therapy to metformin (NCT00660907). 

  • Patients were on a metformin dose of at least 1500 mg/day and randomly assigned after a 2-week placebo lead-in period to glipizide or dapagliflozin (5 mg or 2.5 mg, respectively) and were up-titrated over 18 weeks or to the highest dose level as tolerated.

  • Treatment with dapagliflozin demonstrated noninferiority achieving a similar mean reduction in HbA1c from baseline to week 52 compared with glipizide. Dapagliflozin achieved a statistically significant mean reduction in body weight from baseline to week 52 compared with a mean increase in body weight for glipizide. Dapagliflozin plus metformin had a statistically significant (P <.0001) mean change from baseline in systolic blood pressure of −5.0 mmHg relative to glipizide plus metformin. 

Glycemic Control - Use in Patients with Type 2 Diabetes Mellitus and Moderate Renal Impairment  

  • In a 24-week, double-blind, placebo-controlled clinical study (NCT02413398), dapagliflozin was evaluated in patients with type 2 diabetes mellitus and moderate renal impairment (eGFR 45–<60mL/min/1.73m2). Patients were randomly assigned to receive either dapagliflozin 10 mg or placebo once daily.

  • Dapagliflozin achieved statistically significant reductions in HbA1c compared with placebo (adjusted mean difference from placebo, -0.3 [95% CI, -0.5, -0.1]; P =.008).

Adult Dosage:

Swallow whole. Take in the AM with food. Individualize. Glycemic control (not already on dapagliflozin): initiate with dapagliflozin 5mg once daily. May adjust dose as tolerated; max 10mg/2000mg daily. Renal impairment (eGFR 30–<45mL/min/1.73m2): initiation is not recommended. Assess benefit/risk of continuing therapy if eGFR falls persistently <45mL/min/1.73m2.

Children Dosage:

<18yrs: not established.

XIGDUO XR Contraindications:

Severe renal impairment (eGFR <30mL/min/1.73m2), ESRD, or on dialysis. Metabolic acidosis, diabetic ketoacidosis.

Boxed Warning:

Lactic acidosis.

XIGDUO XR Warnings/Precautions:

Increased risk of metformin-associated lactic acidosis in renal or hepatic impairment, concomitant use of certain drugs (eg, cationic drugs), ≥65yrs of age, undergoing radiological contrast study, surgery and other procedures, hypoxic states, and excessive alcohol intake; discontinue if lactic acidosis occurs. Discontinue at time of, or prior to intravascular iodinated contrast imaging in patients with a history of hepatic impairment, alcoholism, heart failure, or will be given intra-arterial contrast; reevaluate eGFR 48hrs after procedure and restart therapy if renally stable. Assess volume status and renal function prior to initiation. Correct volume depletion before initiating, if needed. Monitor for hypotension and renal function (esp. elderly, patients with renal impairment, or on loop diuretics) during therapy. Assess for ketoacidosis in presence of signs/symptoms of metabolic acidosis, regardless of blood glucose levels; discontinue if suspected, evaluate and treat; consider risk factors before initiation (eg, pancreatic insulin deficiency, caloric restriction, alcohol abuse). Consider temporarily discontinuing prior to scheduled surgery (for ≥3 days) or other clinical situations (eg, prolonged fasting due to illness or post-surgery). Necrotizing fasciitis of the perineum (Fournier's gangrene); discontinue and treat immediately if suspected; use alternative antidiabetic. Monitor for genital mycotic infections, UTIs (including urosepsis, pyelonephritis), hematology (esp. serum Vit. B12); treat if needed. Hepatic impairment: not recommended. Pregnancy (2nd & 3rd trimesters), nursing mothers: not recommended.

XIGDUO XR Classification:

Sodium-glucose co-transporter 2 (SGLT2) inhibitor + biguanide.

XIGDUO XR Interactions:

Increased risk of lactic acidosis with topiramate, other carbonic anhydrase inhibitors (eg, zonisamide, acetazolamide, dichlorphenamide); monitor. Concomitant cationic drugs that interfere with renal tubular transport systems (eg, ranolazine, vandetanib, dolutegravir, cimetidine) may increase metformin levels. Diuretics, steroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, CCBs, and isoniazid may cause hyperglycemia; monitor. Avoid excessive alcohol. β-blockers may mask hypoglycemia. May need a lower dose of concomitant insulin or insulin secretagogue (eg, sulfonylurea) to reduce risk of hypoglycemia. Dapagliflozin may antagonize serum lithium concentrations; monitor levels more frequently. Dapagliflozin will lead to false (+) urine glucose tests or unreliable measurements of 1, 5-AG assay; use alternative methods to monitor glycemic control.

Adverse Reactions:

Female genital mycotic infections, nasopharyngitis, UTIs, diarrhea, headache, nausea, vomiting; ketoacidosis, acute kidney injury; rare: lactic acidosis.

Metabolism:

Dapagliflozin

  • UGT1A9 (primary), CYP-mediated metabolism (minor).

  • Dapagliflozin is extensively metabolized, primarily to yield dapagliflozin 3-O-glucuronide, which is an inactive metabolite.

Metformin HCl

  • 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. 

Drug Elimination:

Dapagliflozin

  • Renal (75%), fecal (21%). 

  • Half-life: ~12.9 hours.

Metformin HCl

  • Renal (90%).

  • Half-life: ~6.2 hours.

 

Generic Drug Availability:

NO

How Supplied:

XR tabs 2.5mg/1000mg—60; 5mg/ 500mg, 10mg/500mg—30, 500; 5mg/1000mg—30, 60, 90, 400; 10mg/1000mg—30, 90, 400

Miscellaneous urogenital disorders:

Indications for: XIGDUO XR

Dapagliflozin: to reduce the risk of sustained eGFR decline, end-stage kidney disease, CV death, and hospitalization for heart failure in adults with chronic kidney disease at risk of progression.

Limitations of Use:

Due to the metformin component, the use of Xigduo XR is limited to adults with type 2 diabetes mellitus for all indications. Not recommended 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; not expected to be effective in these populations.

Clinical Trials:

Chronic Kidney Disease (CKD)

  • Tthe DAPA-CKD (Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients with Chronic Kidney Disease) study included patients with CKD (eGFR between 25 and 75 mL/min/1.73 m2) and albuminuria (urine albumin creatinine ratio [UACR] between 200 and 5000 mg/g) who were receiving standard of care background therapy (including a maximally tolerated dose of an ACE inhibitor or ARB).

  • 4304 patients were randomly assigned 1:1 to receive dapagliflozin 10 mg or placebo and were followed for a median of 28.5 months. The primary composite endpoint was at least a 50% sustained decline in eGFR, progression to ESKD (defined as sustained eGFR <15 mL/min/1.73m2, initiation of chronic dialysis treatment or renal transplant), CV or renal death.

  • In the overall population, dapagliflozin 10 mg met primary composite endpoint achieving a sustained decline in eGFR, progression to ESKD, CV or renal death (HR, 0.61 [95% CI, 0.51-0.72]; P <.0001).

  • The treatment benefit of dapagliflozin was consistent in reducing the incidence of primary composite endpoint in patients with type 2 diabetes mellitus (HR, 0.64 [95% CI, 0.52-0.79]) and in patients with type 2 diabetes mellitus and metformin as background therapy (HR, 0.74 [95% CI, 0.53-1.03]). 

  • The treatment benefit of dapagliflozin 10 mg was consistent in reducing the incidence of the composite endpoint of CV death or hospitalization for heart failure and all-cause mortality in patients with type 2 diabetes mellitus (HR 0.70 [95% CI 0.53, 0.92] and HR 0.74 [95% CI 0.56, 0.98], respectively) and in patients with type 2 diabetes mellitus and metformin as background therapy (HR 0.59 [95% CI 0.38, 0.91] and HR 0.71 [95% CI 0.46, 1.10]). 

Adult Dosage:

Swallow whole. Take in the AM with food. Individualize. Give dapagliflozin 10mg once daily. May adjust dose as tolerated; max 10mg/2000mg daily. Renal impairment (eGFR 30–<45mL/min/1.73m2): initiation is not recommended. Assess benefit/risk of continuing therapy if eGFR falls persistently <45mL/min/1.73m2.

Children Dosage:

<18yrs: not established.

XIGDUO XR Contraindications:

Severe renal impairment (eGFR <30mL/min/1.73m2), ESRD, or on dialysis. Metabolic acidosis, diabetic ketoacidosis.

Boxed Warning:

Lactic acidosis.

XIGDUO XR Warnings/Precautions:

Increased risk of metformin-associated lactic acidosis in renal or hepatic impairment, concomitant use of certain drugs (eg, cationic drugs), ≥65yrs of age, undergoing radiological contrast study, surgery and other procedures, hypoxic states, and excessive alcohol intake; discontinue if lactic acidosis occurs. Discontinue at time of, or prior to intravascular iodinated contrast imaging in patients with a history of hepatic impairment, alcoholism, heart failure, or will be given intra-arterial contrast; reevaluate eGFR 48hrs after procedure and restart therapy if renally stable. Assess volume status and renal function prior to initiation. Correct volume depletion before initiating, if needed. Monitor for hypotension and renal function (esp. elderly, patients with renal impairment, or on loop diuretics) during therapy. Assess for ketoacidosis in presence of signs/symptoms of metabolic acidosis, regardless of blood glucose levels; discontinue if suspected, evaluate and treat; consider risk factors before initiation (eg, pancreatic insulin deficiency, caloric restriction, alcohol abuse). Consider temporarily discontinuing prior to scheduled surgery (for ≥3 days) or other clinical situations (eg, prolonged fasting due to illness or post-surgery). Necrotizing fasciitis of the perineum (Fournier's gangrene); discontinue and treat immediately if suspected; use alternative antidiabetic. Monitor for genital mycotic infections, UTIs (including urosepsis, pyelonephritis), hematology (esp. serum Vit. B12); treat if needed. Hepatic impairment: not recommended. Pregnancy (2nd & 3rd trimesters), nursing mothers: not recommended.

XIGDUO XR Classification:

Sodium-glucose co-transporter 2 (SGLT2) inhibitor + biguanide.

XIGDUO XR Interactions:

Increased risk of lactic acidosis with topiramate, other carbonic anhydrase inhibitors (eg, zonisamide, acetazolamide, dichlorphenamide); monitor. Concomitant cationic drugs that interfere with renal tubular transport systems (eg, ranolazine, vandetanib, dolutegravir, cimetidine) may increase metformin levels. Diuretics, steroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, CCBs, and isoniazid may cause hyperglycemia; monitor. Avoid excessive alcohol. β-blockers may mask hypoglycemia. May need a lower dose of concomitant insulin or insulin secretagogue (eg, sulfonylurea) to reduce risk of hypoglycemia. Dapagliflozin may antagonize serum lithium concentrations; monitor levels more frequently. Dapagliflozin will lead to false (+) urine glucose tests or unreliable measurements of 1, 5-AG assay; use alternative methods to monitor glycemic control.

Adverse Reactions:

Female genital mycotic infections, nasopharyngitis, UTIs, diarrhea, headache, nausea, vomiting; ketoacidosis, acute kidney injury; rare: lactic acidosis.

Metabolism:

Dapagliflozin

  • UGT1A9 (primary), CYP-mediated metabolism (minor).

  • Dapagliflozin is extensively metabolized, primarily to yield dapagliflozin 3-O-glucuronide, which is an inactive metabolite.

Metformin HCl

  • 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. 

Drug Elimination:

Dapagliflozin

  • Renal (75%), fecal (21%). 

  • Half-life: ~12.9 hours.

Metformin HCl

  • Renal (90%).

  • Half-life: ~6.2 hours.

 

Generic Drug Availability:

NO

How Supplied:

XR tabs 2.5mg/1000mg—60; 5mg/ 500mg, 10mg/500mg—30, 500; 5mg/1000mg—30, 60, 90, 400; 10mg/1000mg—30, 90, 400