FDA expands exenatide use; warns of renal-failure risk

Yael Waknine

November 03, 2009

Silver Spring, MD - The US Food and Drug Administration (FDA) has issued a warning about the incretin mimetic exenatide (Byetta, Amylin Pharmaceuticals) the same day the agency approved an expanded indication, allowing its first-line use along with diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus [1].

The warning includes 78 postmarketing reports of kidney dysfunction, including acute renal failure and insufficiency, received between April 2005 and October 2008, in 6.6 million users. "Some cases occurred in patients with preexisting kidney disease or in patients with one or more risk factors for developing kidney problems," according to an alert sent yesterday from MedWatch, the FDA's safety information and adverse-event reporting program.

The FDA emphasizes that exenatide should not be used in patients with severe renal impairment (creatinine clearance <30 mL/min) or end-stage renal disease, and it advises caution during initiation of therapy and dose increases in patients with moderate renal dysfunction (creatinine clearance 30-50 mL/min).

Patients receiving exenatide should be carefully monitored for signs and symptoms of altered renal function, including increased serum creatinine, changes in urination, unexplained swelling in the extremities, blood-pressure increases, lethargy, changes in appetite or digestion, or the emergence of a dull ache in the mid- to lower back.

The agency notes that alterations in kidney function may also occur as a consequence of diabetes itself, other chronic conditions (eg, pancreatitis and hypertension), or concomitant use of certain medications (nonsteroidal anti-inflammatory drugs, diuretics, and antihypertensives). Discontinuation of exenatide should be considered if kidney dysfunction cannot be explained by these or other causes such as nausea, vomiting, and dehydration.

The approval of exenatide monotherapy was based on clinical data showing that three months of treatment at doses of 5 µg or 10 µg significantly reduced mean hemoglobin A1C levels by 0.7% and 0.9%, respectively, and yielded mean weight losses of 6.0 lbs and 6.4 lbs, respectively.

The most commonly reported adverse event was nausea, which occurred in 3% of patients receiving the 5-µg dose and 13% of those taking 10 µg of exenatide daily. Hypoglycemia was reported at rates of 5% and 4%, respectively; no severe hypoglycemic events were noted.

Exenatide was previously approved as adjunctive therapy to improve glycemic control in patients with type 2 diabetes mellitus who have not achieved adequate glycemic control on metformin; a sulfonylurea; a thiazolidinedione; a combination of metformin and a sulfonylurea; or a combination of metformin and a thiazolidinedione.

More information is available on the FDA's MedWatch website.

Adverse events related to the use of exenatide should be communicated to the FDA's MedWatch reporting program by telephone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online, or by mail to 5600 Fishers Lane, Rockville, MD 20852-9787.

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