Reduced Clozapine Monitoring During COVID Did Not Result in More Neutropenia or Discontinuation

Patients using clozapine for at least a year were not more likely to experience severe neutropenia or to discontinue the medication during the COVID-19 pandemic, when laboratory monitoring became less frequent, according to a report in Psychiatric Services.

Early in the pandemic, the Food and Drug Administration (FDA) removed penalties against health care professionals who were unable to meet the stringent laboratory monitoring requirements for clozapine. Then, in May 2020, an expert workgroup released a consensus statement suggesting that the frequency of monitoring could be reduced from every month to every three months for patients on continuous clozapine treatment for at least one year and no history of neutropenia.

(The FDA recently eliminated their requirements for clozapine prescribing but still recommend that clinicians monitor neutrophil levels according to prescribing information.)

Allison L. Little, Pharm.D., of the Corporal Michael J. Crescenz Department of Veterans Affairs (VA) Medical Center in Philadelphia, and colleagues analyzed data on 2,106 patients in the Veterans Health Administration who had been using clozapine for at least 12 months prior to March 2020; the study period was from March 1, 2020, to July 31, 2021. Clozapine discontinuation was determined to have occurred if the most recent clozapine prescription was coded as “discontinued” and no active prescriptions were listed in the medical record.

Little and colleagues also classified patients according to neutropenia status, with severe neutropenia defined as an absolute neutrophil count (ANC) of less than 500/μL. They further classified patients according to the length of their longest interval between laboratory monitoring: less than 30 days, 31 to 55 days, 56 to 90 days, 91 to 179 days, and greater than180 days.

On average, the longest ANC monitoring gap was 87.8 days, consistent with the consensus statement. No patients discontinued clozapine because of severe neutropenia. In fact, only one patient developed severe neutropenia, and after cessation and careful monitoring, that patient began a new trial of clozapine.

Moreover, the researchers found that longer intervals between ANC monitoring did not increase the rate of clozapine discontinuation. Overall, clozapine discontinuation for any reason occurred in 96 patients.

“More studies are needed to confirm the noninferiority of extended-interval laboratory monitoring for patients receiving clozapine,” the researchers wrote, but added that mental health providers should “consider these results to help bolster prescribing of this highly effective yet underutilized treatment option.”

For related information, see the Psychiatric News article “FDA Has Ended the Clozapine REMS. What Happens Now?”

(Image: Getty Images/iStock/Bacsica)

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Today Is Deadline to Recertify in Modified Clozapine REMS, Re-enroll Patients

Today—Monday, November 15—is the last day for physicians and pharmacies to recertify in the updated Clozapine Risk Evaluation and Mitigation Strategy (REMS), a safety program required by the Food and Drug Administration (FDA) to manage patients’ risk of neutropenia associated with clozapine treatment. Physicians must also re-enroll all their clozapine patients in the REMS program by today’s deadline. After today, noncertified prescribers and pharmacies will no longer be able to receive or dispense clozapine.

Clozapine is an effective medication for treating patients with refractory schizophrenia, but in rare instances the medication can lead to a rapid and severe loss of neutrophils (a type of white blood cell). This loss of neutrophils can potentially lead to fatal infections; thus, patients taking clozapine must undergo regular blood testing. The FDA’s REMS program ensures that physicians/pharmacies that dispense clozapine understand and can manage these risks.

In July the FDA approved modifications to the Clozapine REMS, which necessitated the recertification and reenrollment process. Among the important changes:

• Physicians must use a new patient status form to document neutrophil monitoring for all patients prescribed clozapine and submit the form to REMS monthly. The new form also requires physicians to submit neutrophil results for patients who have recently discontinued clozapine.
• Pharmacies will no longer be permitted to use telecommunication to verify a patient can use clozapine safely. Instead, they must obtain authorization to dispense either through the Clozapine Call Center (888-586-0758) or online at www.clozapineREMS.com.

To recertify and re-enroll patients in the Clozapine REMS, visit https://www.newclozapinerems.com. More information on the changes for prescribers is posted at cpmg-prchanged-whats changed prescriber v00_04 clean.pdf.

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Risk of Agranulocytosis for Patients on Clozapine May Be Overstated, Study Shows

Neutropenia appears to be common both in patients with schizophrenia who are taking clozapine as well as those who have never used clozapine. Moreover, progression from mild neutropenia (1500-1900/mm3) to agranulocytosis appears to be rare, according to a report in BMC Psychiatry.

The results suggest that the risk of agranulocytosis associated with clozapine may be overstated. They also appear to lend support to the 2015 decision by the Food and Drug Administration to lower the neutrophil count cutoff at which patients are required to discontinue Clozaril from 1500/mm3 to 1000/mm3.

Clozapine has been shown to be the drug of choice for treatment-resistant schizophrenia. Yet since its introduction, the drug has been linked to a risk for agranulocytosis, requiring regular blood monitoring, a disincentive to both clinicians and patients. Guidelines originally called for discontinuation of the medication when neutrophil counts dropped below 1500/mm. That was lowered to 1000/mm3 in 2015; in Europe and the U.K., the lower limit is still 1500/mm3.

Engilbert Sigurdsson, M.D., and colleagues at the University of Iceland and Landspitali University, Reykjavik, sought to analyze the risk of neutropenia and the progression to agranulocytosis in a sample of patients with schizophrenia in Iceland. In that country, providing blood samples at certain intervals is not required for dispensing clozapine. The patient sample included those who were taking clozapine and those who had never used the drug.

Searching the electronic health records of Landspitali, the National University Hospital of Iceland, they identified 201 patients with schizophrenia treated with clozapine and 410 patients with schizophrenia who had never taken clozapine. They identified patients who developed neutropenia/agranulocytosis through neutrophil counts in the databases. They also examined the frequency of neutrophil measurements.

Despite being monitored much less frequently, the rate of neutropenia overall was not significantly greater for patients on clozapine than for patients who had never used the medication. Only mild neutropenia (between 1500-1900/mm3) was more common in clozapine users, and none of those patients (n=24, or 12.8%) progressed to agranulocytosis. For moderate (1000-1400/mm3) and severe neutropenia (500-1000/mm3), the rate was actually higher among patients who had never been prescribed clozapine.

Sigurdsson and colleagues stated that the results support the safety of lowering the neutrophil-count cutoff for discontinuation of clozapine from 1500 to the U.S. standard of 1000/mm3. “This change would result in a much lower rate of clozapine discontinuation, and our findings suggest that the progression to agranulocytosis would remain a rare event,” they wrote.

For related information see the article, "Addressing Barriers to Clozapine Underutilization: A National Effort."

(Image: SeventyFour/istock.com)

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