IMPORTANT SAFETY INFORMATION FOR XIGDUO XR
WARNING: LACTIC ACIDOSIS
Risk factors include renal impairment, concomitant use of certain drugs, age >65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, 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.
If lactic acidosis is suspected, discontinue XIGDUO XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.
Contraindications
- Moderate to severe renal impairment (eGFR <60 mL/min/1.73 m2), end-stage renal disease, or patients on dialysis
- Prior serious hypersensitivity reaction to dapagliflozin or hypersensitivity to metformin hydrochloride
- Metabolic acidosis, including diabetic ketoacidosis
Warnings and Precautions
Hypotension: Dapagliflozin causes intravascular volume contraction, and symptomatic hypotension can occur. Assess and correct volume status before initiating XIGDUO XR in patients with impaired renal function, elderly patients, or patients on loop diuretics. Monitor for hypotension.
Ketoacidosis has been reported in patients with type 1 and type 2 diabetes receiving dapagliflozin. Some cases were fatal. Assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis, regardless of blood glucose level. If suspected, discontinue XIGDUO XR, evaluate and treat promptly. Before initiating XIGDUO XR, consider risk factors for ketoacidosis. Patients on XIGDUO XR may require monitoring and temporary discontinuation in situations known to predispose to ketoacidosis.
Acute Kidney Injury and Impairment in Renal Function: Dapagliflozin causes intravascular volume contraction and renal impairment, with reports of acute kidney injury requiring hospitalization and dialysis. Consider temporarily discontinuing in settings of reduced oral intake or fluid losses. If acute kidney injury occurs, discontinue and promptly treat.
Dapagliflozin increases serum creatinine and decreases eGFR. Elderly patients and patients with impaired renal function may be more susceptible to these changes. Before initiating XIGDUO XR, evaluate renal function and monitor periodically. XIGDUO XR is contraindicated in patients with an eGFR <60 mL/min/1.73 m2.
Urosepsis and Pyelonephritis: SGLT2 inhibitors increase the risk for urinary tract infections (UTIs) and serious UTIs have been reported with dapagliflozin. Evaluate for signs and symptoms of UTIs and treat promptly.
Use with Medications Known to Cause Hypoglycemia: Consider a lower dose of insulin and insulin secretagogues to reduce risk of hypoglycemia when coadministered with XIGDUO XR.
Hypoglycemia could occur when caloric intake is deficient, strenuous exercise is not compensated by caloric supplementation, or when XIGDUO XR is used with other glucose-lowering agents or ethanol.
Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Rare but serious, life-threatening cases have been reported in patients receiving SGLT2 inhibitors including dapagliflozin. Cases have been reported in females and males. Serious outcomes have included hospitalization, surgeries, and death. Assess patients presenting with pain or tenderness, erythema, swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment and discontinue XIGDUO XR.
Vitamin B12 Deficiency: Metformin may lower vitamin B12 levels. Measure hematological parameters annually.
Genital Mycotic Infections: Dapagliflozin increases the risk of genital mycotic infections, particularly in patients with prior genital mycotic infections. Monitor and treat appropriately.
Increases in Low-Density Lipoprotein Cholesterol (LDL-C) occur with dapagliflozin. Monitor LDL-C and treat per standard of care.
Bladder Cancer: An imbalance in bladder cancers was observed in clinical trials. There were too few cases to determine whether the emergence of these events is related to dapagliflozin, and insufficient data to determine whether dapagliflozin has an effect on pre-existing bladder tumors. XIGDUO XR should not be used in patients with active bladder cancer. Use with caution in patients with a history of bladder cancer.
Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with XIGDUO XR.
Adverse Reactions
Most common adverse reactions (≥5%) with dapagliflozin (5 mg or 10 mg) plus metformin vs placebo plus metformin were female genital mycotic infection (9.4%, 9.3%, 1.5%), nasopharyngitis (6.3%, 5.2%, 5.9%), urinary tract infection (6.1%, 5.5%, 3.6%), diarrhea (5.9%, 4.2%, 5.6%), and headache (5.4%, 3.3%, 2.8%), respectively.
Adverse reactions reported in >5% of patients treated with metformin XR and more commonly than in patients treated with placebo are diarrhea (9.6% vs 2.6%) and nausea/vomiting (6.5% vs 1.5%).
Use in Specific Populations
Pregnant Women: There are no adequate and well-controlled studies of XIGDUO XR or its individual components in pregnant women. Consider appropriate alternative therapies, especially during the second and third trimesters.
Nursing Mothers: Discontinue XIGDUO XR or discontinue nursing.
INDICATION AND LIMITATIONS OF USE
XIGDUO XR is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both dapagliflozin and metformin is appropriate.
XIGDUO XR is not recommended for patients with type 1 diabetes mellitus or diabetic ketoacidosis.
Please read US Full Prescribing Information 
, including Boxed WARNING about lactic acidosis and Medication Guide for XIGDUO XR.
