Clinical

Sitagliptin allergy characterized by "serious" morbidity: report

NEW YORK - In the first two years after approval of sitagliptin (Januvia; Merck & Co) for type 2 diabetes, a review of the FDA's Adverse Event Reports System (AERS) turned up 48 cases consistent with drug allergy associated with its use.

These allergic reactions to sitagliptin are characterized by "serious morbidity," including serious skin reactions, anaphylaxis and angioedema, the reviewers report in a research letter published July 12th in the Archives of Internal Medicine.

Dr. Shrey Desai, from the Society for Education, Welfare and Action-Rural (SEWA-Rural), Jhagadia, India, and colleagues at the US Food and Drug Administration point out in the letter that sitagliptin was the first dipeptidyl peptidase-4 inhibitor (DPP-4) approved by the FDA in October 2006. One year after approval, reports of hypersensitivity reactions to the drug -- most occurring in the first 3 months of initiation -- prompted updated labeling to reflect this possibility.

By November 2008, 48 cases of sitagliptin-associated drug allergy had been documented in the AERS database. The adverse events occurred within 6 weeks of starting sitagliptin and "suggested at least a possible causal relationship between the adverse event and sitagliptin use," the researchers say.

Using World Health Organization criteria for causality, 5 cases were classified as "certain," 30 as "probable," and 13 as "possible" in relation to sitagliptin use.

Serious skin reactions were the most common allergic reaction (26 of 48 cases; 54%), followed by anaphylaxis (15 cases; 31%), angioedema without upper airway obstruction/symptomatology (4 cases; 8%) and vasculitis (3 cases; 6%).

There were no deaths, but 37 patients (77%) had to be hospitalized because of hypersensitivity reactions and 4 (8%) had to be put on a ventilator, admitted to the ICU or given pressors. In five cases, the reaction recurred when sitagliptin therapy was resumed. In 36 cases (75%), the reaction resolved when sitagliptin was discontinued.

Dr. Desai and colleagues say there are several potential limitations to their analysis and data source. First, the voluntary nature of reporting these events (to the AERS) has "numerous biases and the information content or quality is highly variable."

Second, the fact that case definitions used in the analysis were modified from current clinical case definitions "raises concerns about inadvertently including or excluding potential cases and the introduction of misclassification bias into the case series." To address this, the researchers independently reviewed all cases and included only those that were mutually agreed upon.

"More studies are needed to determine the incidence and predisposing factors for allergic reactions in patients taking sitagliptin," the research team concludes.

The authors report no relevant financial disclosures related to this research. At the time this project was initiated, Dr. Desai was on a practicum rotation with the FDA as a resident physician with Johns Hopkins. Three other authors are employed at the FDA.

Arch Intern Med 2010;170:1169-1171.

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