A closer look at new FDA actions: Merck & Co's Janumet

Merck & Co's Janumet

Merck & Co's antihyperglycemic drug sitagliptin/metformin HCl (Janumet) was approved by the FDA in April 2007 for the treatment of type 2 diabetes in combination with diet and exercise.^{1 Janumet is a tablet combining the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin and the biguanide metformin. The single-agent sitagliptin (Januvia) was approved by the FDA in October 2006 as monotherapy for type 2 diabetes in combination with diet and exercise.}2

Pharmacology

Throughout the day and when blood glucose levels are increased, the intestine releases incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide that regulate the physiologic insulin homeostasis.3 These hormones increase the synthesis and release of insulin from the pancreatic beta cells when blood glucose levels are normal or increased. In addition, hepatic glucose production is reduced when GLP-1 decreases glucagon secretion from pancreatic alpha cells.This normal homeostasis is disturbed when the enzyme DPP-4 inactivates the incretin hormones.^{3 Sitagliptin inhibition of the DPP-4 enzyme leads to increased levels of incretin hormones that help the synthesis and release of insulin and the suppression of glucagon.}3Metformin exerts its action by decreasing hepatic glucose production and intestinal absorption of glucose and by improving insulin sensitivity.^{3 Janumet combination tablets, administered to healthy patients, demonstrated bioequivalence to corresponding doses of sitagliptin and metformin administered as individual tablets.}3

Clinical Trials

The efficacy and safety of combination-therapy sitagliptin and metformin were demonstrated in a clinical trial designed to add sitagliptin therapy in patients not adequately controlled on metformin monotherapy.4 A 24-week randomized, double-blind, placebo-controlled, parallel-group study enrolled 701 patients (with a mean baseline A1C of 8%) to receive either sitagliptin 100 mg or matching placebo in addition to ongoing =1500-mg/day metformin therapy.⁴ The primary efficacy end point was a change in A1C at 24 weeks. More patients (47%) in the sitagliptin-and-metformin arm achieved an A1C <7%, compared with 18.3% of the patients in the placebo-and-metformin arm.⁴ The combination therapy also was superior in achieving the secondary end points, which included reducing fasting plasma glucose and 2-hour postprandial glucose from baseline.

Contraindications

Elimination of sitagliptin and metformin occurs primarily via renal excretion. Therefore, an assessment of renal function should be made before Janumet therapy is initiated.³ Metformin accumulation occurs during renal insufficiency, and it is associated with lactic acidosis. Regular monitoring of renal function should be continued during Janumet therapy, and the minimum effective dose of metformin should be used.³ Janumet should be avoided in patients with hepatic impairment, which also is associated with lactic acidosis.

Janumet should be temporarily discontinued during major surgical procedures, when there is a decrease in caloric intake, because of the risk of hypoglycemia.

Janumet should be discontinued and the patient should be hospitalized and managed symptomatically if lactic acidosis is suspected.

Drugs eliminated by renal tubular secretion have the theoretical potential for interaction with Janumet. Therefore, careful patient monitoring is recommended. Clinical data are not available regarding Janumet use in pregnant women or whether Janumet is excreted in breast milk. Janumet is in pregnancy category B.

The most common adverse event reported with sitagliptin is nasopharyngitis. The most common adverse events with initial metformin therapy are nausea, vomiting, diarrhea, flatulence, indigestion, and headache.3

Outlook

The dose should be titrated up for patients starting initial Janumet therapy. The maximum recommended daily dose is 100 mg sitagliptin and 2000 mg metformin, administered twice daily with food.^{3 Janumet is available in 50-mg/500-mg and 50-mg/1000-mg sitagliptin/metformin tablets. Patients switching from individual-tablet therapy to Janumet should be started on the dose already being taken.}3Patients should be advised to avoid alcohol intake and should be counseled on signs and symptoms of lactic acidosis. Janumet is not recommended for patients with type 1 diabetes.3References

1. www.janumet.com/sitagliptin_metformin_HCl/janumet/hcp/index.jsp. Accessed June 29, 2007.

2. www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails..Accessed July 8, 2007.

3. Janumet Product Information. Whitehouse Station, NJ: Merck & Co.

4. Dear Healthcare Professional Letter from Merck Medical Information. Dated June 29, 2007.