DAPAGLIFLOZIN AND METFORMIN HYDROCHLORIDE
DAPAGLIFLOZIN AND METFORMIN HYDROCHLORIDE
Indications and usage Dapagliflozin and metformin HCl extended-release tablets are a combination of dapagliflozin and metformin hydrochloride (HCl) extended-release, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Dapagliflozin, when used as a component of dapagliflozin and metformin HCl extended-release tablets, is indicated in adults with type 2 diabetes mellitus to reduce the risk of: Sustained eGFR decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure in patients with chronic kidney disease at risk of progression.
Structured Monograph
Clinical summary
Indications and usage Dapagliflozin and metformin HCl extended-release tablets are a combination of dapagliflozin and metformin hydrochloride (HCl) extended-release, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Dapagliflozin, when used as a component of dapagliflozin and metformin HCl extended-release tablets, is indicated in adults with type 2 diabetes mellitus to reduce the risk of: Sustained eGFR decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure in patients with chronic kidney disease at risk of progression. Cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in patients with heart failure. Hospitalization for heart failure in patients with type 2 diabetes mellitus and either established cardiovascular disease (CVD) or multiple cardiovascular (CV) risk factors. Limitations of Use Dapagliflozin and metformin HCl extended-release tablets are not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus [see Warnings and Precautions (5.2) ]. Because of the metformin HCl component, the use of dapagliflozin and metformin HCl extended-release tablets are limited to patients with type 2 diabetes mellitus for all indications. Dapagliflozin and metformin HCl extended-release tablets are 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. Dapagliflozin and metformin HCl extended-release tablets are not expected to be effective in these populations. Pediatric use information is approved for AstraZeneca AB’s Xigduo® XR (dapagliflozin and metformin hydrochloride) Extended-Release Tablets. However, due to AstraZeneca AB’s marketing exclusivity rights, this drug product is not labeled with that information. Standard dosing Assess renal function prior to initiating and then as clinically indicated. ( 2.1 ) Assess volume status and correct volume depletion before initiating. ( 2.1 ) Individualize the starting dosage based on the patient’s current treatment. ( 2.3 ) Administer orally once daily in the morning with food. ( 2.2 ) To improve glycemic control, for patients not already taking dapagliflozin, the recommended starting dosage for dapagliflozin is 5 mg once daily. ( 2.3 ) For indications in adults related to heart failure and chronic kidney disease the recommended dosage of dapagliflozin is 10 mg once daily. ( 2.3 ) Do not exceed a daily dosage of 10 mg dapagliflozin/ 2,000 mg metformin HCl extended-release. ( 2.3 ) See Full Prescribing Information for dosage recommendations in patients with renal impairment. ( 2.4 ) Dapagliflozin and metformin HCl extended-release tablets may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. ( 2.5 ) Withhold Dapagliflozin and metformin HCl extended-release tablets for at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting. ( 2.6 ) Dose forms and strengths 5 mg DAPAGLIFLOZIN; 500 mg METFORMIN HYDROCHLORIDE; 30 1 DAPAGLIFLOZIN; 1000 mg METFORMIN HYDROCHLORIDE Contraindications Dapagliflozin and metformin HCl extended-release is contraindicated in patients with: Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) or end-stage renal disease [see Warnings and Precautions (5.1) ] . History of a serious hypersensitivity reaction to dapagliflozin, metformin HCl, or any of the excipients in dapagliflozin and metformin HCl extended-release. Serious hypersensitivity reactions, including anaphylaxis and angioedema have been reported with dapagliflozin [see Adverse Reactions (6.1) ] . Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin [see Warnings and Precautions (5.1) and Warnings and Precautions (5.2) ] . Key warnings Lactic Acidosis : See boxed warning. ( 5.1 ) Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis: Consider ketone monitoring in patients at risk for ketoacidosis, as indicated. Assess for ketoacidosis regardless of presenting blood glucose levels and discontinue dapagliflozin and metformin HCl extended-release if ketoacidosis is suspected. Monitor patients for resolution of ketoacidosis before restarting.( 5.2 ) Volume Depletion: Before initiating dapagliflozin and metformin HCl extended-release, assess and correct volume status in the elderly, patients with renal impairment or low systolic blood pressure, and in patients on diuretics. Monitor for signs and symptoms during therapy. ( 5.3 ) Urosepsis and Pyelonephritis: Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated. ( 5.4 ) Hypoglycemia: Consider a lower dosage of insulin or an insulin secretagogue to reduce the risk of hypoglycemia when
Boxed Warning
Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by 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 [see Warnings and Precautions (5.1) ] . Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high-risk groups are provided in the full prescribing information [ see D osage and Administration ( 2.1 and 2.4 ), Contraindications (4) , Warnings and Precautions (5.1) , Drug Interactions (7) , and Use in Specific Populations (8.6 , 8.7) ] . If metformin-associated lactic acidosis is suspected, immediately discontinue dapagliflozin and metformin HCl extended-release and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.1 )] .
Monitoring
- • Lactic Acidosis : See boxed warning. ( 5.1 ) Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis: Consider ketone monitoring in patients at risk for ketoacidosis, as indicated.
Interaction Notes
- • Table 6: Clinically Relevant Interactions with Dapagliflozin and Metformin Hydrochloride Extended-Release Carbonic Anhydrase Inhibitors Clinical Impact 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 withdapagliflozin and metformin hydrochloride extended-release may increase the risk for lactic acidosis.
- • Intervention Consider more frequent monitoring of these patients.
- • Drugs that Reduce Metformin Clearance Clinical Impact 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 [see Clinical Pharmacology (12.3) ] .