01. New Guidelines for Clozapine ANC Monitoring

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Clozapine Monitoring Guidelines Update

Today, I’m discussing an important international position paper recently published in Lancet Psychiatry. This paper, led by Dan Siskind from the University of Queensland, has significant implications for clinicians prescribing clozapine and treatment systems managing patients on clozapine.

The paper’s title is “Absolute Neutrophil Count and Adverse Drug Reaction Monitoring During Clozapine Treatment: Consensus Guidelines from a Global Delphi Panel.” Let me also add a disclaimer here that I was a member of this global Delphi expert panel. These guidelines are not only important for our field but very timely.

Clozapine’s Monitoring History

But to appreciate this, I first need to give you some background. As I assume you know, clozapine while effective is more difficult to use because of a host of medical side effects including the risk of agranulocytosis that is higher for clozapine than for other antipsychotics. As a result, in the United States, this led the Federal Drug Administration or FDA to create a registry and mandatory blood work while on clozapine and this registry essentially goes back to the 1990s now in order for clozapine to be given safely.

The registry ensured early recognition of agranulocytosis, allowing for prompt clozapine discontinuation and supportive treatment initiation. This approach has undoubtedly saved lives.

However, decades of clinical experience and research have revealed that agranulocytosis risk with clozapine isn’t constant. It’s highest in the first six months of treatment, after which the risk reduces significantly (though never to zero).

Clinicians, patients and family members have questioned the benefit from lifelong monitoring particularly given the downsides such as adherence issues, not getting medications with treatment interruption if a blood draw was missed, etc.

FDA’s Recent REMS Rescission

On June 13, 2025, after years of advocacy efforts, the FDA rescinded the REMS (Risk Evaluation and Mitigation Strategy) for clozapine without replacing it. This action returned the responsibility of monitoring clozapine side effects, including severe granulocytopenia, to clinicians.

While this seems beneficial, it leaves clinicians uncertain about how to proceed, especially since the clozapine package insert wasn’t modified. It still recommends:

• Weekly ANCs for six months
• Bi-weekly ANCs for six months
• Monthly ANCs thereafter (potentially lifelong)

Global Delphi Guidelines Monitoring Recommendations

The global Delphi guidelines address this uncertainty. They suggest:

• Intense weekly ANC monitoring for 18 weeks
• Monthly monitoring until the two-year point
• After two years, if no issues arise, discuss with the patient about potentially stopping ANC monitoring. For those patients who are worried and who just want closer monitoring to continue, you of course could continue monthly monitoring.

These recommendations acknowledge the reduced risk of granulocytopenia after the initial treatment phase while maintaining vigilance.

Clinical Implications

In our psychosis program, we’re updating our clozapine guideline to align with these global Delphi recommendations. Many other treatment systems are likely having similar discussions.

These authoritative guidelines from an international expert consensus group can help clinicians worried about medico-legal liabilities when deviating from the package insert. However, careful documentation is still crucial:

• Explain why you’re deviating from the package insert
• Document risk-benefit discussions with patients and families
• Provide education about agranulocytosis symptoms and what to do if they occur
• Consider annual blood work, including a complete blood count

International Considerations

For our international audience, it’s worth noting that other countries have approached clozapine neutropenia monitoring differently. This has led to significant practice variability between countries, not driven by evidence.

Other working groups, like the European clozapine working group, have some differences in their recommendations. It’s advisable to compare guidelines before settling on your approach.

Implementing Safe Pragmatic Monitoring

The bottom line is this. While prescribing clozapine in the United States has become easier by removing the administrative burden from the registry, you still need to figure out clinically what that actually means for your patient. I think implementing the global Delphi consensus guideline in your clinic would be a pragmatic and safe way of prescribing clozapine and we should be thankful for Dan Siskind’s efforts getting this expert panel together.

If you prescribe clozapine, please go ahead and look at the full guideline.

To summarize the guidelines:

• Monitor ANC weekly for 18 weeks
• Then monthly until reaching two years
• At two years, consider stopping routine ANC monitoring after a risk-benefit discussion with the patient and family

As clinicians, it’s our responsibility to stay informed about these updates and implement them thoughtfully in our practice.

Abstract

Absolute neutrophil count and adverse drug reaction monitoring during clozapine treatment: consensus guidelines from a global Delphi panel

Dan Siskind, Korinne Northwood, Toby Pillinger et al.

In this Position Paper, the third sentence of the Summary should have read “Recommendations include lowering ANC thresholds for consideration of clozapine cessation”. The fourth sentence of the Summary should have read “Comprehensive ADR monitoring, with ANC monitoring in the first 2 years, then every 3 months after discontinuing routine ANC monitoring”. The fourth and fifth sentences in the second paragraph of the Discussion should have read “ADRs should be checked alongside ANC monitoring for the first 2 years. With discontinuation of ANC monitoring after 2 years of patients taking clozapine, ADRs should be monitored once every 3 months”. The fourth and fifth sentences in the final paragraph of the Discussion should have read “ADR monitoring should be done alongside ANC monitoring for the first 2 years. After discontinuing ANC monitoring, ADR monitoring should be done routinely every 3 months”. Figure 1 should have read “ADRs should be monitored with ANC testing appointments for the first 2 years, then ADR only (not ANC testing) every 3 months after 2 years”. These corrections have been made to the online version as of July 22, 2025, and will be made to the printed version.

Reference

Siskind D, Northwood K, Pillinger T, et al. (2025). Absolute neutrophil count and adverse drug reaction monitoring during clozapine treatment: consensus guidelines from a global Delphi panel. Lancet Psychiatry 2025; published online July 2.