New Clozapine Guidelines Likely to Limit Treatment Interruptions

New and less stringent guidelines on blood monitoring for patients receiving clozapine are likely to substantially reduce the number of patients meeting criteria for hematologic events requiring treatment interruption, according to a report published July 18 in the Journal of Clinical Psychiatry.

Treatment with clozapine poses an increased risk of agranulocytosis (rapid drop in white blood cells) and requires monitoring through regular blood draws examining white cell counts.

In 2015, the Food and Drug Administration (FDA) eliminated the total white blood cell count from the monitoring algorithm and lowered the threshold for interrupting clozapine treatment from an absolute neutrophil count (ANC) of 1,500/uL to 1,000/uL.

To estimate the impact of the clozapine guideline changes on prescriptions, Ryan S. Sultan, M.D., of the Columbia University Medical Center and the New York State Psychiatric Institute and colleagues analyzed prescribing records for antipsychotic medications in the Veterans Integrated Service Network 7 database from 1999 to 2012 (before the FDA revised the guidelines). The researchers then simulated the effect on prescribing by applying the 2015 guidelines to this population.

From a cohort of 14,620 patients with schizophrenia, just 246 (1.7 percent) received clozapine. Under the pre-2015 guidelines, five patients qualified for treatment interruption during the first year of clozapine treatment, while only one patient would have qualified when the current guidelines were applied.

“[C]lozapine-induced hematologic episodes that warrant discontinuation or interruption of treatment, though uncommon, were considerably more prevalent under the previous guidelines than they would be using the current FDA monitoring recommendations,” the authors wrote. “These findings are consistent with the intent of the new FDA guidelines and have practical implications for the continuity of clozapine treatment in community practice.”

In an interview with Psychiatric News, Sultan said he hopes the study results encourage clinicians to prescribe clozapine for treatment-resistant schizophrenia.

“Clozapine is such an important medication. We know that 30 percent of patients with schizophrenia are treatment resistant, yet clozapine accounts for only about five percent of antipsychotic prescriptions,” he said. “Our study demonstrates that events requiring treatment interruption are rare generally, which should provide reassurance to clinicians. The new changes should allow for a simpler treatment algorithm, and should allow for longer continuity of care for more patients.

“By reducing this clinical burden, we hope the changes will encourage clinicians to prescribe clozapine for patients who could benefit from it,” he said.

Sultan emphasized that as a simulation of the effects on prescribing of the new guidelines, the study cannot speak to the effect on safety. He said prospective studies of patients being treated under the new, less stringent guidelines are necessary.

Nevertheless, he noted that there was no incidence of agranulocytosis among any of the patients receiving clozapine during the 1999-2012 period. Moreover, Sultan and colleagues said there are some 125 other medications—many of them not for psychiatric conditions—that are also associated with agranulocytosis, but which don’t have the strict level of monitoring required for patients receiving clozapine.

A systematic review published in the Annals of Internal Medicine in May 2007 concluded that many drugs can cause nonchemotherapy drug-induced agranulocytosis. Drugs for which more than 10 reports of agranulocytosis were available included carbimazole, clozapine, dapsone, dipyrone, methimazole, penicillin G, procainamide, propylthiouracil, rituximab, sulfasalazine, and ticlopidine, the authors noted.

“The FDA’s change to the clozapine monitoring system places clozapine closer in line with other pharmacologic agents that have been associated with agranulocytosis,” Sultan said.

Deanna Kelly, Pharm. D., director and chief of the Treatment Research Program at the Maryland Psychiatric Research Center, reviewed the report for Psychiatric News. She has advocated for wider clinician use of clozapine and has argued for a variety of methods for breaking down barriers including revisiting guidelines for initiation and monitoring of the medication.

“Interrupting therapy unnecessarily can have serious consequences, including the risk of suicide. Given the challenges and complexities of initiation and maintenance of clozapine, all efforts to successfully maintain treatment should be pursued,” she told Psychiatric News. “This retrospective cohort study showed us exactly what we hoped would be happening after the guideline changes, that discontinuation of clozapine due to a variability in ANC levels based on pre-2015 guidelines would be reduced under new guidelines.

Kelly added, “Clozapine was used in less than two percent of patients [with schizophrenia in the study cohort] and this low rate continues nationwide. While the study doesn't estimate how many more may have been treated with relaxation of guidelines, overcoming a variety of barriers that lead to the underuse of clozapine should be a national priority. Being able to smoothly maintain patients who are known to have variability in the ANC is critical to improving treatment and recovery.”

The study was funded by a National Institutes of Health research training grant and the Veterans Affairs Merit Review Program. ■