As of February 24, 2025, the FDA no longer expects prescribers, patients and pharmacists to participate in the risk evaluation and mitigation strategies (REMS) program for clozapine. This means pharmacies can dispense clozapine without knowledge of the patients ANC. FDA recommends that clozapine prescribers continue to monitor their patient’s absolute neutrophil count (ANC) according to the product label. However, this change in the monitoring requirements permits prescribers to make decisions based on the welfare of individual patients.
In making decisions about monitoring, prescribers should be aware that clozapine is still associated with a risk of severe neutropenia (agranulocytosis) and myocarditis. Most serious neutropenia’s leading to clozapine cessation occurs within 18 weeks. (The period of heightened risk is similar for myocarditis.) Incidence is negligible after 2 years. Many experts believe that weekly monitoring after 18 weeks could be safely reduced to every 4 weeks and ceased after 2 years unless clinically indicated. Clozapine retrial after interruption with 2 cumulative years of unremarkable testing might not require further hematological monitoring. .Long-term risk excess is small compared with the advantages of clozapine in outcomes, including life expectancy. Relaxing long-term monitoring could favor the advantages of clozapine use, without incurring risk of neutropenia. If clozapine is discontinued, patients should be advised to notify their prescriber when they experience signs of infection or fever.
Clinicians should also be aware that the most common causes of death on clozapine are from bowel obstruction and pneumonia. As a result, all clozapine patients should notify their prescriber if they are experiencing signs of pneumonia or constipation.
The FDA’s decision does relieve many patients and prescribers of a burden that has discouraged the use of a very effective medication. It is hoped that this decision will lead to the much wider use of clozapine. Based on an analysis of 2023 data, the FDA reported that clozapine is prescribed to only 148,000 of the estimated 814,000 to 1.2 million people with treatment-resistant schizophrenia in the United States. This confirmed numerous studies indicating dramatic underutilization of clozapine, which for over 30 years has been the only medication with an FDA indication for the treatment of patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment and more recently for reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder
In addition, since clozapine’s initial approval additional studies have demonstrated its advantages in reducing the risks of relapse, hospitalization, violence, aggression, overall mortality, family burden and direct and indirect economic costs.
The American Society of Clinical Psychopharmacology (ASCP) recommends that, whenever feasible, clozapine prescribers follow the clozapine label recommendations for ANC monitoring for at least the first year of clozapine treatment. Clinicians may consider decreasing the frequency of monitoring following the first year and they may consider discontinuing annual monitoring after two years. Decisions about monitoring frequency should be made in a shared decision-making framework with patients and caregivers, and well documented in the medical record. All clozapine patients -- including those who are not receiving ANC monitoring – should be alerted to the importance of communicating to their prescriber when they experience signs of infection, fever, pneumonia, and constipation.