Xigduo Xr

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  • CHF and arrhythmias
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PAGE CONTENTS
  • Jump to Section
  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Xigduo Xr Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Dapagliflozin, metformin HCl ext-rel; 2.5mg/1000mg, 5mg/500mg, 5mg/1000mg, 10mg/500mg, 10mg/1000mg; tabs.

    Pharmacological Class

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

    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

    How Supplied

    Xigduo® 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:

    • 2.5mg/1000mg – light brown to brown, biconvex, oval-shaped; “1074” and “2.5/1000” debossed on one side and plain on the reverse side; Bottle of 60

    • 5mg/500mg – orange, biconvex, capsule-shaped; "1070" and "5/500" debossed on one side and plain on the reverse side; Bottles of 30, 500

    • 5mg/1000mg – pink to dark pink, biconvex, oval-shaped; "1071" and "5/1000" debossed on one side and plain on the reverse side; Bottles of 30, 60, 90, 400

    • 10mg/500mg – pink, biconvex, capsule-shaped; "1072" and "10/500" debossed on one side and plain on the reverse side; Bottles of 30, 500

    • 10mg/1000mg – yellow to dark yellow, biconvex, oval-shaped; "1073" and "10/1000" debossed on one side and plain on the reverse side; Bottles of 30, 90, 400

    Storage

    Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. 

    Manufacturer

    AstraZeneca Pharmaceuticals

    Generic Availability

    NO

    Mechanism of Action

    Dapagliflozin inhibits SGLT2, thereby reducing the reabsorption of filtered glucose and lowers the renal threshold for glucose, and increasing urinary glucose excretion. It also reduces sodium reabsorption and increases the delivery of sodium to the distal tubule. Metformin lowers both basal and postprandial plasma glucose, decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.

    Xigduo Xr Indications

    Indications

    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.

    Xigduo Xr Dosage and Administration

    Prior to Treatment Evaluations

    Assess renal function before initiating and periodically thereafter.

    Assess volume status and, if necessary, correct volume depletion prior to initiation.

    Adult

    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

    <18yrs: not established.

    Xigduo Xr Contraindications

    Contraindications

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

    Xigduo Xr Boxed Warnings

    Boxed Warning

    Lactic acidosis.

    Boxed Warning

    Lactic Acidosis

    • Metformin-associated lactic acidosis was associated with elevated blood lactate levels (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL.  

    • Discontinue Xigduo XR immediately if metformin-associated lactic acidosis is suspected, and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

    • Risk factors for metformin-associated lactic acidosis include renal or hepatic impairment, concomitant use of certain drugs (eg, carbonic anhydrase inhibitors such as topiramate), ≥65yrs of age, undergoing radiological contrast study, surgery and other procedures, hypoxic states (eg, acute congestive heart failure), and excessive alcohol intake. 

    Xigduo Xr Warnings/Precautions

    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 if confirmed. Monitor for resolution of ketoacidosis before restarting. Withhold (at least 3 days), if possible, prior to major surgery or procedures associated with prolonged fasting. 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.

    Warnings/Precautions

    Lactic Acidosis 

    • Metformin-associated lactic acidosis was associated with elevated blood lactate levels (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL.  

    • Discontinue Xigduo XR immediately if metformin-associated lactic acidosis is suspected, and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

    • Risk factors for metformin-associated lactic acidosis include renal or hepatic impairment, concomitant use of certain drugs (eg, carbonic anhydrase inhibitors such as topiramate), ≥65yrs of age, undergoing radiological contrast study, surgery and other procedures, hypoxic states (eg, acute congestive heart failure), and excessive alcohol intake.

    • Renal or Hepatic Impairment: 

      • Obtain eGFR prior to initiation. Obtain eGFR at least annually in all patients. Assess renal function more frequently in patients at increased risk for developing renal impairment (eg, elderly).

      • Avoid use of Xigduo XR in patients with clinical or laboratory evidence of hepatic disease.

    • Radiological Studies With Contrast:

      • Discontinue 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 48hrs after imaging, then restart Xigduo XR if renal function is stable.

    • Surgery and Other Procedures:

      • Temporarily discontinue Xigduo XR while patients have restricted food and fluid intake.

    • Hypoxic States:

      • 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. 

      • Discontinue Xigduo XR if these events occur. 

    • Excessive Alcohol Intake:

      • Warn patients to avoid excessive intake of alcohol while taking Xigduo XR.

    Ketoacidosis

    • Not recommended for improving glycemic control in patients with type 1 diabetes mellitus.

    • Assess for ketoacidosis regardless of blood glucose levels in patients who present with signs and symptoms consistent with severe metabolic acidosis.

    • Discontinue if suspected, evaluate and treat if confirmed.

    • Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include under-insulinization due to insulin dose reduction or missed insulin doses, acute febrile illness, reduced caloric intake, ketogenic diet, surgery, volume depletion, and alcohol abuse.

    • Withhold for at least 3 days, if possible, prior to major surgery or procedures associated with prolonged fasting.

    Volume Depletion 

    • Dapagliflozin may cause intravascular volume depletion which may manifest as symptomatic hypotension or acute transient changes in creatinine.

    • Increased risk for volume depletion or hypotension in patients with renal impairment (eGFR <60mL/min/1.73m2), elderly, or patients on loop diuretics.

    • Assess volume status and renal function prior to initiation; monitor during therapy.

    Urosepsis and Pyelonephritis

    • Increased risk for UTIs when SGLT2 inhibitors are used.

    • Evaluate for signs and symptoms of UTIs and treat promptly, if indicated.

    Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues 

    • Increased risk for hypoglycemia when Xigduo XR is used concomitantly with insulin and/or an insulin secretagogue. To minimize the risk, a lower dose of insulin or insulin secretagogue may be required.

    Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)

    • Assess for necrotizing fasciitis if pain or tenderness, erythema, or swelling in the genital or perineal area, fever or malaise occur.

    • If suspected, discontinue Xigduo XR and initiate treatment immediately with broad-spectrum antibiotics, and surgical debridement, if necessary.

    Vitamin B12 Concentrations 

    • Measure hematologic parameters on an annual basis and vitamin B12 at 2- to 3-year intervals in patients on Xigduo XR and manage any abnormalities.

    Genital Mycotic Infections

    • Increased risk of genital mycotic infections especially in patients with a history genital mycotic infections. Monitor and treat appropriately.

    Geriatric Considerations

    No dosage adjustment is needed based on age. Monitor renal function more frequently in elderly patients.

    Renal Impairment Considerations

    Initiation of Xigduo XR is not recommended if eGFR <45mL/min/1.73m2.

    Xigduo XR is contraindicated in patients with severe renal impairment (eGFR <30mL/min/1.73m2), ESRD, or on dialysis.

    Hepatic Impairment Considerations

    Not recommended to use in patients with hepatic impairment.

    Other Considerations for Specific Populations

    Females and Males of Reproductive Potential

    • Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin may result in ovulation in some anovulatory women. 

    Xigduo Xr Pharmacokinetics

    Absorption

    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%. 

    Metformin HCl

    • The 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. 

    Distribution

    Dapagliflozin

    • Plasma protein bound: ~91%. 

    Metformin HCl

    • Negligibly bound to plasma proteins.

    • The apparent volume of distribution (V/F) of metformin following single oral doses of immediate-release metformin 850 mg averaged 654 ± 358 L.

    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. 

    Elimination

    Dapagliflozin

    • Renal (75%), fecal (21%). 

    • Half-life: ~12.9 hours.

    Metformin HCl

    • Renal (90%).

    • Half-life: ~6.2 hours.

     

    Xigduo Xr Interactions

    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.

    Xigduo Xr Adverse Reactions

    Adverse Reactions

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

    Xigduo Xr Clinical Trials

    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]).

    Xigduo Xr Note

    Not Applicable

    Xigduo Xr Patient Counseling

    Patient Counseling

    Lactic Acidosis

    • Inform patients of the risks for lactic acidosis due to the metformin component. Discontinue immediately and notify a healthcare provider if unexplained hyperventilation, myalgia, malaise, unusual somnolence, dizziness, slow or irregular heartbeat, sensation of feeling cold (especially in the extremities), or other nonspecific symptoms occur.

    • Counsel patients against excessive alcohol intake.

    • Advise patients on the importance of regularly testing renal function and hematological parameters during treatment.

    • Advise patients to inform their healthcare provider prior to surgical or radiological procedure.

    Ketoacidosis

    • Check for ketones (when possible) if symptoms consistent with ketoacidosis occur, regardless of blood glucose levels.

    • Discontinue and seek medical attention immediately if symptoms of ketoacidosis occur (eg, nausea, vomiting, abdominal pain, tiredness, and labored breathing).

    Volume Depletion

    • Symptomatic hypotension may occur. Ensure adequate fluid intake. 

    Serious Urinary Tract Infections

    • Seek medical advice promptly if symptoms of urinary tract infections occur.

    Hypoglycemia

    • Increased risk of hypoglycemia when Xigduo XR is added to an insulin secretagogue (eg, sulfonylurea) or insulin.

    Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) 

    • Seek medical attention promptly if pain or tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, along with a fever above 100.4°F or malaise develop.

    Genital Mycotic Infections in Females (e.g., Vulvovaginitis)

    • Inform of treatment options and when to seek medical advice on the signs and symptoms of vaginal yeast infections.

    Genital Mycotic Infections in Males (e.g., Balanitis or Balanoposthitis) 

    • Inform male patients that yeast infections of the penis (eg, balanitis or balanoposthitis) may occur, especially in patients with prior history.

    Hypersensitivity Reactions

    • Report any signs or symptoms suggesting allergic reaction or angioedema.

    Pregnancy

    • Immediately inform healthcare provider if pregnant or planning to become pregnant.

    Lactation

    • Not recommended to use Xigduo XR while breastfeeding.

    Administration

    • Xigduo XR must be swallowed whole and not crushed or chewed. Inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet.

    Laboratory Tests

    • Patients taking Xigduo XR will test positive for glucose in their urine.

    Xigduo Xr Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Dapagliflozin, metformin HCl ext-rel; 2.5mg/1000mg, 5mg/500mg, 5mg/1000mg, 10mg/500mg, 10mg/1000mg; tabs.

    Pharmacological Class

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

    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

    How Supplied

    Xigduo® 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:

    • 2.5mg/1000mg – light brown to brown, biconvex, oval-shaped; “1074” and “2.5/1000” debossed on one side and plain on the reverse side; Bottle of 60

    • 5mg/500mg – orange, biconvex, capsule-shaped; "1070" and "5/500" debossed on one side and plain on the reverse side; Bottles of 30, 500

    • 5mg/1000mg – pink to dark pink, biconvex, oval-shaped; "1071" and "5/1000" debossed on one side and plain on the reverse side; Bottles of 30, 60, 90, 400

    • 10mg/500mg – pink, biconvex, capsule-shaped; "1072" and "10/500" debossed on one side and plain on the reverse side; Bottles of 30, 500

    • 10mg/1000mg – yellow to dark yellow, biconvex, oval-shaped; "1073" and "10/1000" debossed on one side and plain on the reverse side; Bottles of 30, 90, 400

    Storage

    Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. 

    Manufacturer

    AstraZeneca Pharmaceuticals

    Generic Availability

    NO

    Mechanism of Action

    Dapagliflozin inhibits SGLT2, thereby reducing the reabsorption of filtered glucose and lowers the renal threshold for glucose, and increasing urinary glucose excretion. It also reduces sodium reabsorption and increases the delivery of sodium to the distal tubule. Metformin lowers both basal and postprandial plasma glucose, decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.

    Xigduo Xr Indications

    Indications

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

    Limitations of Use

    Not for improving glycemic control in patients with type 1 diabetes. Due to the metformin component, the use of Xigduo XR is limited to adults with type 2 diabetes mellitus for all indications.

    Xigduo Xr Dosage and Administration

    Prior to Treatment Evaluations

    Assess renal function before initiating and periodically thereafter.

    Assess volume status and, if necessary, correct volume depletion prior to initiation.

    Adult

    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

    <18yrs: not established.

    Xigduo Xr Contraindications

    Contraindications

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

    Xigduo Xr Boxed Warnings

    Boxed Warning

    Lactic acidosis.

    Boxed Warning

    Lactic Acidosis

    • Metformin-associated lactic acidosis was associated with elevated blood lactate levels (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL.  

    • Discontinue Xigduo XR immediately if metformin-associated lactic acidosis is suspected, and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

    • Risk factors for metformin-associated lactic acidosis include renal or hepatic impairment, concomitant use of certain drugs (eg, carbonic anhydrase inhibitors such as topiramate), ≥65yrs of age, undergoing radiological contrast study, surgery and other procedures, hypoxic states (eg, acute congestive heart failure), and excessive alcohol intake. 

    Xigduo Xr Warnings/Precautions

    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 if confirmed. Monitor for resolution of ketoacidosis before restarting. Withhold (at least 3 days), if possible, prior to major surgery or procedures associated with prolonged fasting. 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.

    Warnings/Precautions

    Lactic Acidosis 

    • Metformin-associated lactic acidosis was associated with elevated blood lactate levels (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL.  

    • Discontinue Xigduo XR immediately if metformin-associated lactic acidosis is suspected, and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

    • Risk factors for metformin-associated lactic acidosis include renal or hepatic impairment, concomitant use of certain drugs (eg, carbonic anhydrase inhibitors such as topiramate), ≥65yrs of age, undergoing radiological contrast study, surgery and other procedures, hypoxic states (eg, acute congestive heart failure), and excessive alcohol intake.

    • Renal or Hepatic Impairment: 

      • Obtain eGFR prior to initiation. Obtain eGFR at least annually in all patients. Assess renal function more frequently in patients at increased risk for developing renal impairment (eg, elderly).

      • Avoid use of Xigduo XR in patients with clinical or laboratory evidence of hepatic disease.

    • Radiological Studies With Contrast:

      • Discontinue 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 48hrs after imaging, then restart Xigduo XR if renal function is stable.

    • Surgery and Other Procedures:

      • Temporarily discontinue Xigduo XR while patients have restricted food and fluid intake.

    • Hypoxic States:

      • 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. 

      • Discontinue Xigduo XR if these events occur. 

    • Excessive Alcohol Intake:

      • Warn patients to avoid excessive intake of alcohol while taking Xigduo XR.

    Ketoacidosis

    • Not recommended for improving glycemic control in patients with type 1 diabetes mellitus.

    • Assess for ketoacidosis regardless of blood glucose levels in patients who present with signs and symptoms consistent with severe metabolic acidosis.

    • Discontinue if suspected, evaluate and treat if confirmed.

    • Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include under-insulinization due to insulin dose reduction or missed insulin doses, acute febrile illness, reduced caloric intake, ketogenic diet, surgery, volume depletion, and alcohol abuse.

    • Withhold for at least 3 days, if possible, prior to major surgery or procedures associated with prolonged fasting.

    Volume Depletion 

    • Dapagliflozin may cause intravascular volume depletion which may manifest as symptomatic hypotension or acute transient changes in creatinine.

    • Increased risk for volume depletion or hypotension in patients with renal impairment (eGFR <60mL/min/1.73m2), elderly, or patients on loop diuretics.

    • Assess volume status and renal function prior to initiation; monitor during therapy.

    Urosepsis and Pyelonephritis

    • Increased risk for UTIs when SGLT2 inhibitors are used.

    • Evaluate for signs and symptoms of UTIs and treat promptly, if indicated.

    Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues 

    • Increased risk for hypoglycemia when Xigduo XR is used concomitantly with insulin and/or an insulin secretagogue. To minimize the risk, a lower dose of insulin or insulin secretagogue may be required.

    Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)

    • Assess for necrotizing fasciitis if pain or tenderness, erythema, or swelling in the genital or perineal area, fever or malaise occur.

    • If suspected, discontinue Xigduo XR and initiate treatment immediately with broad-spectrum antibiotics, and surgical debridement, if necessary.

    Vitamin B12 Concentrations 

    • Measure hematologic parameters on an annual basis and vitamin B12 at 2- to 3-year intervals in patients on Xigduo XR and manage any abnormalities.

    Genital Mycotic Infections

    • Increased risk of genital mycotic infections especially in patients with a history genital mycotic infections. Monitor and treat appropriately.

    Geriatric Considerations

    No dosage adjustment is needed based on age. Monitor renal function more frequently in elderly patients.

    Renal Impairment Considerations

    Initiation of Xigduo XR is not recommended if eGFR <45mL/min/1.73m2.

    Xigduo XR is contraindicated in patients with severe renal impairment (eGFR <30mL/min/1.73m2), ESRD, or on dialysis.

    Hepatic Impairment Considerations

    Not recommended to use in patients with hepatic impairment.

    Other Considerations for Specific Populations

    Females and Males of Reproductive Potential

    • Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin may result in ovulation in some anovulatory women. 

    Xigduo Xr Pharmacokinetics

    Absorption

    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%. 

    Metformin HCl

    • The 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. 

    Distribution

    Dapagliflozin

    • Plasma protein bound: ~91%. 

    Metformin HCl

    • Negligibly bound to plasma proteins.

    • The apparent volume of distribution (V/F) of metformin following single oral doses of immediate-release metformin 850 mg averaged 654 ± 358 L.

    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. 

    Elimination

    Dapagliflozin

    • Renal (75%), fecal (21%). 

    • Half-life: ~12.9 hours.

    Metformin HCl

    • Renal (90%).

    • Half-life: ~6.2 hours.

     

    Xigduo Xr Interactions

    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.

    Xigduo Xr Adverse Reactions

    Adverse Reactions

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

    Xigduo Xr Clinical Trials

    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).

    Xigduo Xr Note

    Not Applicable

    Xigduo Xr Patient Counseling

    Patient Counseling

    Lactic Acidosis

    • Inform patients of the risks for lactic acidosis due to the metformin component. Discontinue immediately and notify a healthcare provider if unexplained hyperventilation, myalgia, malaise, unusual somnolence, dizziness, slow or irregular heartbeat, sensation of feeling cold (especially in the extremities), or other nonspecific symptoms occur.

    • Counsel patients against excessive alcohol intake.

    • Advise patients on the importance of regularly testing renal function and hematological parameters during treatment.

    • Advise patients to inform their healthcare provider prior to surgical or radiological procedure.

    Ketoacidosis

    • Check for ketones (when possible) if symptoms consistent with ketoacidosis occur, regardless of blood glucose levels.

    • Discontinue and seek medical attention immediately if symptoms of ketoacidosis occur (eg, nausea, vomiting, abdominal pain, tiredness, and labored breathing).

    Volume Depletion

    • Symptomatic hypotension may occur. Ensure adequate fluid intake. 

    Serious Urinary Tract Infections

    • Seek medical advice promptly if symptoms of urinary tract infections occur.

    Hypoglycemia

    • Increased risk of hypoglycemia when Xigduo XR is added to an insulin secretagogue (eg, sulfonylurea) or insulin.

    Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) 

    • Seek medical attention promptly if pain or tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, along with a fever above 100.4°F or malaise develop.

    Genital Mycotic Infections in Females (e.g., Vulvovaginitis)

    • Inform of treatment options and when to seek medical advice on the signs and symptoms of vaginal yeast infections.

    Genital Mycotic Infections in Males (e.g., Balanitis or Balanoposthitis) 

    • Inform male patients that yeast infections of the penis (eg, balanitis or balanoposthitis) may occur, especially in patients with prior history.

    Hypersensitivity Reactions

    • Report any signs or symptoms suggesting allergic reaction or angioedema.

    Pregnancy

    • Immediately inform healthcare provider if pregnant or planning to become pregnant.

    Lactation

    • Not recommended to use Xigduo XR while breastfeeding.

    Administration

    • Xigduo XR must be swallowed whole and not crushed or chewed. Inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet.

    Laboratory Tests

    • Patients taking Xigduo XR will test positive for glucose in their urine.

    Xigduo Xr Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Dapagliflozin, metformin HCl ext-rel; 2.5mg/1000mg, 5mg/500mg, 5mg/1000mg, 10mg/500mg, 10mg/1000mg; tabs.

    Pharmacological Class

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

    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

    How Supplied

    Xigduo® 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:

    • 2.5mg/1000mg – light brown to brown, biconvex, oval-shaped; “1074” and “2.5/1000” debossed on one side and plain on the reverse side; Bottle of 60

    • 5mg/500mg – orange, biconvex, capsule-shaped; "1070" and "5/500" debossed on one side and plain on the reverse side; Bottles of 30, 500

    • 5mg/1000mg – pink to dark pink, biconvex, oval-shaped; "1071" and "5/1000" debossed on one side and plain on the reverse side; Bottles of 30, 60, 90, 400

    • 10mg/500mg – pink, biconvex, capsule-shaped; "1072" and "10/500" debossed on one side and plain on the reverse side; Bottles of 30, 500

    • 10mg/1000mg – yellow to dark yellow, biconvex, oval-shaped; "1073" and "10/1000" debossed on one side and plain on the reverse side; Bottles of 30, 90, 400

    Storage

    Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. 

    Manufacturer

    AstraZeneca Pharmaceuticals

    Generic Availability

    NO

    Mechanism of Action

    Dapagliflozin inhibits SGLT2, thereby reducing the reabsorption of filtered glucose and lowers the renal threshold for glucose, and increasing urinary glucose excretion. It also reduces sodium reabsorption and increases the delivery of sodium to the distal tubule. Metformin lowers both basal and postprandial plasma glucose, decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.

    Xigduo Xr Indications

    Indications

    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.

    Xigduo Xr Dosage and Administration

    Prior to Treatment Evaluations

    Assess renal function before initiating and periodically thereafter.

    Assess volume status and, if necessary, correct volume depletion prior to initiation.

    Adult

    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

    <18yrs: not established.

    Xigduo Xr Contraindications

    Contraindications

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

    Xigduo Xr Boxed Warnings

    Boxed Warning

    Lactic acidosis.

    Boxed Warning

    Lactic Acidosis

    • Metformin-associated lactic acidosis was associated with elevated blood lactate levels (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL.  

    • Discontinue Xigduo XR immediately if metformin-associated lactic acidosis is suspected, and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

    • Risk factors for metformin-associated lactic acidosis include renal or hepatic impairment, concomitant use of certain drugs (eg, carbonic anhydrase inhibitors such as topiramate), ≥65yrs of age, undergoing radiological contrast study, surgery and other procedures, hypoxic states (eg, acute congestive heart failure), and excessive alcohol intake. 

    Xigduo Xr Warnings/Precautions

    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 if confirmed. Monitor for resolution of ketoacidosis before restarting. Withhold (at least 3 days), if possible, prior to major surgery or procedures associated with prolonged fasting. 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.

    Warnings/Precautions

    Lactic Acidosis 

    • Metformin-associated lactic acidosis was associated with elevated blood lactate levels (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL.  

    • Discontinue Xigduo XR immediately if metformin-associated lactic acidosis is suspected, and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

    • Risk factors for metformin-associated lactic acidosis include renal or hepatic impairment, concomitant use of certain drugs (eg, carbonic anhydrase inhibitors such as topiramate), ≥65yrs of age, undergoing radiological contrast study, surgery and other procedures, hypoxic states (eg, acute congestive heart failure), and excessive alcohol intake.

    • Renal or Hepatic Impairment: 

      • Obtain eGFR prior to initiation. Obtain eGFR at least annually in all patients. Assess renal function more frequently in patients at increased risk for developing renal impairment (eg, elderly).

      • Avoid use of Xigduo XR in patients with clinical or laboratory evidence of hepatic disease.

    • Radiological Studies With Contrast:

      • Discontinue 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 48hrs after imaging, then restart Xigduo XR if renal function is stable.

    • Surgery and Other Procedures:

      • Temporarily discontinue Xigduo XR while patients have restricted food and fluid intake.

    • Hypoxic States:

      • 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. 

      • Discontinue Xigduo XR if these events occur. 

    • Excessive Alcohol Intake:

      • Warn patients to avoid excessive intake of alcohol while taking Xigduo XR.

    Ketoacidosis

    • Not recommended for improving glycemic control in patients with type 1 diabetes mellitus.

    • Assess for ketoacidosis regardless of blood glucose levels in patients who present with signs and symptoms consistent with severe metabolic acidosis.

    • Discontinue if suspected, evaluate and treat if confirmed.

    • Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include under-insulinization due to insulin dose reduction or missed insulin doses, acute febrile illness, reduced caloric intake, ketogenic diet, surgery, volume depletion, and alcohol abuse.

    • Withhold for at least 3 days, if possible, prior to major surgery or procedures associated with prolonged fasting.

    Volume Depletion 

    • Dapagliflozin may cause intravascular volume depletion which may manifest as symptomatic hypotension or acute transient changes in creatinine.

    • Increased risk for volume depletion or hypotension in patients with renal impairment (eGFR <60mL/min/1.73m2), elderly, or patients on loop diuretics.

    • Assess volume status and renal function prior to initiation; monitor during therapy.

    Urosepsis and Pyelonephritis

    • Increased risk for UTIs when SGLT2 inhibitors are used.

    • Evaluate for signs and symptoms of UTIs and treat promptly, if indicated.

    Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues 

    • Increased risk for hypoglycemia when Xigduo XR is used concomitantly with insulin and/or an insulin secretagogue. To minimize the risk, a lower dose of insulin or insulin secretagogue may be required.

    Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)

    • Assess for necrotizing fasciitis if pain or tenderness, erythema, or swelling in the genital or perineal area, fever or malaise occur.

    • If suspected, discontinue Xigduo XR and initiate treatment immediately with broad-spectrum antibiotics, and surgical debridement, if necessary.

    Vitamin B12 Concentrations 

    • Measure hematologic parameters on an annual basis and vitamin B12 at 2- to 3-year intervals in patients on Xigduo XR and manage any abnormalities.

    Genital Mycotic Infections

    • Increased risk of genital mycotic infections especially in patients with a history genital mycotic infections. Monitor and treat appropriately.

    Geriatric Considerations

    No dosage adjustment is needed based on age. Monitor renal function more frequently in elderly patients.

    Renal Impairment Considerations

    Initiation of Xigduo XR is not recommended if eGFR <45mL/min/1.73m2.

    Xigduo XR is contraindicated in patients with severe renal impairment (eGFR <30mL/min/1.73m2), ESRD, or on dialysis.

    Hepatic Impairment Considerations

    Not recommended to use in patients with hepatic impairment.

    Other Considerations for Specific Populations

    Females and Males of Reproductive Potential

    • Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin may result in ovulation in some anovulatory women. 

    Xigduo Xr Pharmacokinetics

    Absorption

    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%. 

    Metformin HCl

    • The 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. 

    Distribution

    Dapagliflozin

    • Plasma protein bound: ~91%. 

    Metformin HCl

    • Negligibly bound to plasma proteins.

    • The apparent volume of distribution (V/F) of metformin following single oral doses of immediate-release metformin 850 mg averaged 654 ± 358 L.

    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. 

    Elimination

    Dapagliflozin

    • Renal (75%), fecal (21%). 

    • Half-life: ~12.9 hours.

    Metformin HCl

    • Renal (90%).

    • Half-life: ~6.2 hours.

     

    Xigduo Xr Interactions

    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.

    Xigduo Xr Adverse Reactions

    Adverse Reactions

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

    Xigduo Xr Clinical Trials

    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]). 

    Xigduo Xr Note

    Not Applicable

    Xigduo Xr Patient Counseling

    Patient Counseling

    Lactic Acidosis

    • Inform patients of the risks for lactic acidosis due to the metformin component. Discontinue immediately and notify a healthcare provider if unexplained hyperventilation, myalgia, malaise, unusual somnolence, dizziness, slow or irregular heartbeat, sensation of feeling cold (especially in the extremities), or other nonspecific symptoms occur.

    • Counsel patients against excessive alcohol intake.

    • Advise patients on the importance of regularly testing renal function and hematological parameters during treatment.

    • Advise patients to inform their healthcare provider prior to surgical or radiological procedure.

    Ketoacidosis

    • Check for ketones (when possible) if symptoms consistent with ketoacidosis occur, regardless of blood glucose levels.

    • Discontinue and seek medical attention immediately if symptoms of ketoacidosis occur (eg, nausea, vomiting, abdominal pain, tiredness, and labored breathing).

    Volume Depletion

    • Symptomatic hypotension may occur. Ensure adequate fluid intake. 

    Serious Urinary Tract Infections

    • Seek medical advice promptly if symptoms of urinary tract infections occur.

    Hypoglycemia

    • Increased risk of hypoglycemia when Xigduo XR is added to an insulin secretagogue (eg, sulfonylurea) or insulin.

    Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) 

    • Seek medical attention promptly if pain or tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, along with a fever above 100.4°F or malaise develop.

    Genital Mycotic Infections in Females (e.g., Vulvovaginitis)

    • Inform of treatment options and when to seek medical advice on the signs and symptoms of vaginal yeast infections.

    Genital Mycotic Infections in Males (e.g., Balanitis or Balanoposthitis) 

    • Inform male patients that yeast infections of the penis (eg, balanitis or balanoposthitis) may occur, especially in patients with prior history.

    Hypersensitivity Reactions

    • Report any signs or symptoms suggesting allergic reaction or angioedema.

    Pregnancy

    • Immediately inform healthcare provider if pregnant or planning to become pregnant.

    Lactation

    • Not recommended to use Xigduo XR while breastfeeding.

    Administration

    • Xigduo XR must be swallowed whole and not crushed or chewed. Inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet.

    Laboratory Tests

    • Patients taking Xigduo XR will test positive for glucose in their urine.

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