The restrictive practice of clozapine discontinuation was eliminated in 2015 in the US to allow for greater flexibility for clozapine maintenance.
The patients treated with clozapine in the UK would potentially benefit from the guidance implemented by the US Food and Drug Administration (FDA) in 2015 by reducing the rates of discontinuation.
A team, led by Ebenezer Oloyede, MPharm, Pharmacy Department, South London and Maudsley NHS Foundation Trust, investigated the implications of the less stringent clozapine discontinuation policy in the US to the more restrictive policy in the UK.
Clozapine is 1 of the more effective treatment options for treatment-resistant psychosis, often used for the treatment of different mental and mood disorders, including schizophrenia. However, patients in the UK are required to discontinue the medication indefinitely if they are placed on the Central Non-Rechallenge Database (CNRD) after their hematological parameters fall below specific thresholds.
There are only special circumstances where a patient can be rechallenged on clozapine under and off-license agreement.
However, in the US, the restrictive practice of discontinuation was eliminated in 2015 to allow for greater flexibility for clozapine maintenance when regulators reduced the absolute neutrophil count leading to treatment interruption from 1.5 × 109/L to less than 1.0 × 109/L, while platelet and white cell count monitoring were removed.
In the modeling study, the investigators examined data from all patients registered on the UK CNRD and determined the proportion of patients placed in the database who have had to discontinue clozapine treatment under the FDA criteria.
The team then compared the hematological characteristics of patients who both did and did not meet the FDA criteria for discontinuing clozapine. The characteristics included the time to registration from clozapine initiation and the proportion of cases of severe neutropenia at registration.
They then investigated the success rates for rechallenging patients that had been placed on the CNRD with clozapine, defining successful rechallenging as having no recurrence of CNRD registration.
Overall there were 3731 patients placed on the CNRD between May 2, 2002 and March 1, 2021, with a mean age of 47 years. Of this patient population, 15% (n = 566) met the equivalent criteria for clozapine discontinuation under the FDA guidelines.
The investigators then looked at the data for 519 rechallenged patients and found 81% (n = 419) were successful, while the median time to CNRD registration from clozapine initiation was 1.6 years (IQR, 0.2-4.9).
The rechallenge success rates were comparable between individuals who did or did not meet the US CNRD registration criteria (78%; n = 36 vs 81%; n = 383).
“Implementing the revised FDA monitoring criteria in the UK would substantially reduce clozapine discontinuation for hematological reasons, which would greatly improve the mental health outcomes of these patients without having a major effect on their physical health,” the authors wrote.
The study, “Relaxation of the criteria for entry to the UK Clozapine Central Non-Rechallenge Database: a modelling study,” was published online in The Lancet Psychiatry.