FDA approves two monitoring changes for clozapine patients.

ROCKVILLE, MD. -- The Food and Drug Administration has approved two major changes to the schedule for monitoring people on clozapine for agranulocytosis: the addition of absolute neutrophil count tests to regular monitoring and a reduction in the frequency of testing after 1 year of satisfactory white blood cell counts and absolute neutrophil counts.

The revised monitoring guidelines are as follows: Before starting treatment, patients must have a baseline white blood cell (WBC) count and an absolute neutrophil count (ANC). This should be followed by a WBC and ANC test every week for the first 6 months.

After 6 months, if WBC counts and ANCs have been acceptable (defined as a WBC greater than or equal to 3,500/[mm.sup.3] and an ANC greater than or equal to 2,000/[mm.sup.3]) and have been maintained during the first 6 months of continuous therapy, WBC counts and ANCs can be monitored every 2 weeks for the next 6 months.

After 12 months of treatment, if WBC counts and ANCs have remained at acceptable levels during the second 6 months of continuous therapy, WBC counts and ANCs can be monitored every 4 weeks.

The previous schedule neither included ANC testing nor allowed for further reductions in the frequency of testing after 1 year, with patients continuing to be tested every 2 weeks indefinitely.

Gregory Dubitsky, M.D., of the FDA's division of neuropharmacologic drug products, Rockville, Md., said in an interview that the reduction in the frequency of monitoring after 1 year was based on considerations of data from the Clozaril National Registry and experience in the United Kingdom and Australia.

"Overall, it was concluded that a change to monthly monitoring after a year in patients with normal counts would not significantly increase the risk of agranulocytosis and would be favorable to the patient in terms of convenience and discomfort from repeated venipuncture," he told this newspaper.

The decision to add ANC testing was based on the United Kingdom's experience, which suggested that moderate leukopenia might be detected earlier if ANC was used as an independent measure of hematologic function, as opposed to the total WBC count alone, he added.

An FDA analysis of the registry data found that people with moderate leukopenia appeared to be at a "considerably higher" risk of agranulocytosis, Dr. Dubitsky noted. On the basis of this finding, the label says that the benefits of continuing clozapine in such patients should be carefully balanced against this risk when deciding whether to continue treatment with the drug, he said. This information was not on the label previously. On the label, agranulocytosis is defined as an ANC below 500/[mm.sup.3].

Other changes to the label include the frequency of monitoring recommended for patients who interrupt a course of clozapine treatment, and ANC criteria for various stages of leukopenia, Dr. Dubitsky said.

Further explanations of the revised monitoring schedule and other changes are included on the new label, which was posted on the FDA's MedWatch Web site last month. Novartis, which manufactures Clozaril, the trade formulation, is planning to send out a "Dear Health Care Provider" letter explaining the changes in the monitoring schedule as well as several other unrelated changes on the label. The letter is currently being reviewed by the FDA, a spokesman for Novartis said. There are now several generic formulations of clozapine, which will also be required to make the same changes to their product labels.

The approval of clozapine in 1989 for the management of treatment-resistant schizophrenia was tied to the "no blood, no drug" requirement that the drug be made available through a special distribution system that required weekly WBC counts before the next week's supply of clozapine was provided to the patient. All the WBC data have been entered into the Clozaril National Registry and have been used to make decisions on monitoring frequency.

At recent FDA advisory panel meetings on safety issues associated with various drugs, such as Vioxx and the other COX-2 inhibitors and the acne drug isotretinoin, the clozapine "no blood, no drug" policy was raised as an example of a risk management program that makes it possible to keep a drug on the market for patients who can benefit from it, while successfully managing the drug's potential serious risks.

The monitoring schedule has been changed once before: In 1998, the schedule was changed to allow a reduction in testing WBC counts to every 2 weeks after 6 months, in patients whose WBC counts were maintained at acceptable levels during the first 6 months of weekly testing.

BY ELIZABETH MECHCATIE

Senior Writer

The revised Clozaril label is available on the FDA's Web site at: www.fda.gov/medwatch/SAFETY/2005/may05.htm#Clozaril.