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FDA Updates Label for Irinotecan with PGx Data

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The US Food and Drug Administration last month added new pharmacogenetic information to the label of the metastatic colorectal cancer therapy irinotecan regarding the heightened risk for grade 4 neutropenia in patients homozygous and heterozygous for the UGT1A1*28 allele.

The FDA first updated the label for irinotecan, marketed as Camptosar by Pfizer, in 2005 with pharmacogenomic information. That earlier label did not mention the availability of a laboratory developed test to gauge patients' UGT1A1 status, but the new label notes that tests are available that can "detect the UGT1A1 6/6, 6/7 and 7/7 genotypes."

Additionally, the "Warnings" section of the earlier label informed patients and doctors that colorectal cancer patients homozygous for the UGT1A1*28 allele are at increased risk for neutropenia after treatment with the drug, and a reduced initial dosage should be considered for this subset of patients. However, four years ago, the clinical data for the risk of neutropenia in patients heterozygous for the UGT1A1*28 allele was not conclusive. "Such patients have been shown to tolerate normal starting doses," the label noted.

The new label includes data from three studies that further confirm the heightened risk for grade 4 neutropenia in patients both homozygous and heterozygous for the UGT1A1*28 allele.

In the first cited study of 66 patients receiving irinotecan as a single agent, the incidence of grade 4 neutropenia in patients homozygous for the UGT1A1*28 allele was 50 percent, and in patients heterozygous for this allele (the UGT1A1 6/7 genotype) the incidence was 12.5 percent. In the second prospective study of 250 patients receiving irinotecan in combination with 5-FU/LV, 4.5 percent of homozygous patients and 5.3 percent of heterozygous patients had grade 4 neutropenia. In the third study listed in the label, which included 109 patients, 18.2 percent of homozygous patients and 11.1 percent of heterozygous patients experienced the adverse event.

As a result of this data, the agency now recommends that the starting dose for irinotecan, when administered in combination with other agents or as a single agent, should be reduced "by at least one level … for patients known to be homozygous for the UGT1A1*28 allele." The agency, however, does not recommend a precise dose for this subset of patients, nor does it offer specific recommendations for dosing patients who are heterozygous for the allele.

─ TR

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