Xigduo XR by AstraZeneca

The FDA has approved Xigduo XR (dapagliflozin and metformin HCl extended-release tablets) as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (DM) when treatment with both dapagliflozin and metformin is appropriate. The approval carries the limitation that Xigduo XR is not for the treatment of type 1 DM or diabetic ketoacidosis.¹ DM is estimated to affect 29.1 million Americans and more than 382 million people worldwide. Type 2 DM accounts for approximately 90% to 95% of all cases diagnosed in the United States. Dapaglifozin is marketed as a singleentity tablet in the United States under the trade name Farxiga.²

Pharmacology

Dapagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor. SGLT2 is expressed in the proximal renal tubules and is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. By inhibiting SGLT2, dapagliflozin reduces the reabsorption of filtered glucose and lowers the renal threshold for glucose, resulting in an increase in urinary glucose excretion. Metformin, a biguanide, decreases hepatic glucose production, decreases intestinal glucose absorption, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.¹

Dosage and Administration

The starting dose of Xigduo XR should be individualized based on the patient’s current medication regimen. It should be given once daily in the morning with food, and swallowed whole. Dose escalation should occur gradually to minimize gastrointestinal side effects. The maximum daily dose is 10 mg of dapagliflozin/2000 mg of metformin HCl extended-release. No dosage adjustment is required for patients with mild renal impairment; however, it should not be used in patients with moderate to severe renal impairment (CrCl <60 mL/min) or end-stage renal disease.¹

Clinical Trials

Clinical studies were not conducted with Xigduo XR combination tablets, as bioequivalence was demonstrated in healthy adults with individual tablets of dapagliflozin and metformin XR. The safety and efficacy of dapagliflozin and metformin IR or XR was previously established in 4 phase 3 clinical trials. The trials, on which the FDA based its approval of Xigduo XR, consisted of patients who were treatment-naïve or were inadequately controlled on metformin, and compared dapagliflozin and metformin with glipizide and metformin.²

Contraindications, Warnings, and Precautions

Xigduo XR carries a boxed warning regarding the potential for lactic acidosis to occur due to metformin accumulation. This risk increases in patients with conditions such as sepsis, dehydration, hepatic impairment, renal impairment, and acute congestive heart failure, as well as with excessive alcohol intake. If acidosis is suspected, Xigduo XR should be discontinued and the patient hospitalized immediately.

Xigduo XR is contraindicated for use in patients with moderate to severe renal impairment, a history of serious hypersensitivity to dapagliflozin or metformin HCl, or metabolic acidosis, including diabetic ketoacidosis.

Patients using Xigduo XR should be cautioned against excessive alcohol intake. Xigduo XR should be avoided in patients with hepatic impairment. Renal function should be assessed prior to initiation of treatment with Xigduo XR and yearly thereafter. Patients undergoing radiologic studies with intravenous administration of iodinated contrast material or any surgical procedures that require food and fluid restriction should have Xigduo XR temporarily discontinued. Volume status should be assessed and hypovolemia corrected before treatment with Xigduo XR is begun, especially in elderly patients. Patients using insulin or an insulin secretagogue may require a lower dose of the insulin or the insulin secretagogue to minimize the risk of hypoglycemia. Metformin may lower vitamin B₁₂ levels, which should be monitored yearly. Dapagliflozin increases the risk of genital mycotic infections, and patients should be monitored and treated appropriately. The low-density lipoprotein cholesterol (LDL-C) level may increase during treatment with dapagliflozin. Therefore, the LDL-C level should be monitored, and elevations should be treated per the standard of care. Patients with active bladder cancer should not use dapagliflozin, and it should be used cautiously in patients with a history of bladder cancer. No clinical studies have established conclusive evidence that treatment with Xigduo XR, or any other antidiabetic medication, will reduce the macrovascular risks of DM. Xigduo XR is a pregnancy category C medication. It should not be used during breast-feeding. Concomitant administration of Xigduo XR with cationic drugs that are eliminated by renal tubular secretion may reduce metformin elimination.

The most common adverse reactions (≥5%) were female genital mycotic infection, nasopharyngitis, urinary tract infection, diarrhea, and headache.¹

Dr. Holmberg earned her PharmD from the University of Connecticut and completed an ambulatory care residency at the Phoenix VA Healthcare System. Her practice has also included pediatrics and inpatient mental health. She resides in Phoenix, Arizona.

References

1. Xigduo XR [package insert]. AstraZeneca website. www.azpicentral.com/xigduo/pi_xigduoxr.pdf. Accessed January 2015.

2. US FDA approves once-daily Xigduo XR tablets for adults with type 2 diabetes. AstraZeneca website. www.astrazeneca-us.com/media/press-releases/Article/20141030-us-fda-approves-oncedaily-xigduo-xr-tablets. Accessed January 2015.