Dapagliflozin/Metformin Hydrochloride (1 brand name, 2 dosage forms, 0 routes)
Available dosage forms: TABLET, TABLET, EXTENDED RELEASE.
Brand Names
- DAPAGLIFLOZIN AND METFORMIN HYDROCHLORIDE
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 non-specific 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 Dosage and Administration (2.1and 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 hydrochloride extended-release tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.1)].
Indications and Usage
Dapagliflozin and metformin hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride component, the use of dapagliflozin and metformin hydrochloride extended-release tablets is limited to patients with type 2 diabetes mellitus for all indications. Dapagliflozin and metformin hydrochloride 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 hydrochloride 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.
Contraindications
Dapagliflozin and metformin hydrochloride extended-release tablets are 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 hydrochloride, or any of the excipients in dapagliflozin and metformin hydrochloride extended-release tablets. 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)] .
Adverse Reactions
The following important adverse reactions are described below and elsewhere in the labeling: Lactic Acidosis [see Boxed Warning and Warnings and Precautions (5.1)] Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis [see Warnings and Precautions (5.2)] Volume Depletion [see Warnings and Precautions (5.3)] Urosepsis and Pyelonephritis [see Warnings and Precautions (5.4)] Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues [see Warnings and Precautions (5.5)] Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) [see Warnings and Precautions (5.6)] Vitamin B 12Concentrations [see Warnings and Precautions (5.7)] Genital Mycotic Infections [see Warnings and Precautions (5.8)]
Drug Interactions
Table 6: Clinically Relevant Interactions with Dapagliflozin and Metformin Hydrochloride Extended-Release Tablets 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 with dapagliflozin and metformin hydrochloride extended-release tablets 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)] . Intervention Consider the benefits and risks of concomitant use. Alcohol Clinical Impact Alcohol is known to potentiate the effect of metformin on lactate metabolism. Intervention Warn patients against excessive alcohol intake while receiving dapagliflozin and metformin hydrochloride extended-release tablets. Insulin or Insulin Secretagogues Clinical Impact The risk of hypoglycemia may be increased when dapagliflozin and metformin hydrochloride extended-release tablets are used concomitantly with insulin or insulin secretagogues (e.g., sulfonylurea) [see Warnings and Precautions (5.5)] . Intervention Concomitant use may require lower doses of insulin or the insulin secretagogue to reduce the risk of hypoglycemia. Drugs Affecting Glycemic Control Clinical Impact Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These medications include thiazides and other diuretics, corticosteroids, phenothiazi
Overdosage
Dapagliflozin In the event of an overdose, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. The removal of dapagliflozin by hemodialysis has not been studied. Metformin hydrochloride Overdose of metformin hydrochloride has occurred, including ingestion of amounts > 50 grams. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Warnings and Precautions (5.1)] . 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.