Dapagliflozin propanediol and Metformin

XIGDUO XR is a combination of dapagliflozin and metformin hydrochloride (HCl) extended-release, indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus. Dapagliflozin, when used as a component of XIGDUO XR, is indicated in adults with type 2 diabetes mellitus to reduce the risk of: • Sustained eGFR decline, end‑stage kidney disease, (CV) death, and hospitalization for heart failure in patients with chronic kidney disease at risk of progression. • CV 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 CV disease or multiple CV risk factors.

Dapagliflozin Sodium-glucose cotransporter 2 (SGLT2), expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Dapagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, dapagliflozin reduces reabsorption of filtered glucose, and thereby promotes urinary glucose excretion. Dapagliflozin also reduces sodium reabsorption and increases the delivery of sodium to the distal tubule. This may influence several physiological functions including, but not restricted to, lowering both pre- and afterload of the heart and downregulation of sympathetic activity, and decreased intraglomerular pressure which is believed to be mediated by increased tubuloglomerular feedback.

• Assess renal function prior to initiating and then as clinically indicated. • Assess volume status and correct volume depletion before initiating. • Individualize the starting dosage based on the patient’s current treatment. • Administer orally once daily in the morning with food. • To improve glycemic control, for patients aged 10 years and older not already taking dapagliflozin, the recommended starting dosage for dapagliflozin is 5 mg once daily. • For indications in adults related to heart failure and chronic kidney disease the recommended dosage of dapagliflozin is 10 mg once daily. • Do not exceed a daily dosage of 10 mg dapagliflozin/2,000 mg metformin HCl extended-release. • See Full Prescribing Information for dosage recommendations in patients with renal impairment. • XIGDUO XR may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures.

XIGDUO XR is contraindicated in patients with: • Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) or end-stage renal disease. • History of a serious hypersensitivity reaction to dapagliflozin, metformin HCl, or any of the excipients in XIGDUO XR. Serious hypersensitivity reactions, including anaphylaxis and angioedema have been reported with dapagliflozin. • Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin. • Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) or end-stage renal disease.

Boxed warning (lactic acidosis •): 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. • Lactic Acidosis: See boxed warning. • 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 XIGDUO XR if ketoacidosis is suspected. Monitor patients for resolution of ketoacidosis before restarting.

The following important adverse reactions are described below and elsewhere in the labeling: • Lactic Acidosis • Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis • Volume Depletion • Genitourinary Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene), and Genital Mycotic Infections • Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues • Vitamin B 12 Deficiency • Adverse reactions reported in >5% of patients treated with XIGDUO XR were female genital mycotic infection, nasopharyngitis, urinary tract infection, diarrhea, and headache. • Adverse reactions reported in >5% of patients treated with metformin extended-release are: diarrhea and nausea/vomiting.

Table 6: Clinically Relevant Interactions with XIGDUO XR 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 XIGDUO XR may increase the risk for lactic acidosis. Intervention Consider more frequent monitoring of these patients.

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).