Clozapine REMS Program Ends: What Psychiatrists Need to Know

For many psychiatrists, the news from the FDA last month felt almost too good to be true: the Clozapine REMS program is being eliminated. As of February 24, 2025, this longstanding requirement – which has created barriers to prescribing one of our most effective antipsychotic medications – will be a thing of the past. In a recent fireside chat within the Osmind Psychiatry Collective, we gathered a panel of psychiatric experts to discuss what this means for clinical practice and patient care.

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The Clozapine Story: A Rollercoaster of Promise and Setbacks

Clozapine's history reads like a medical thriller – complete with breakthroughs, dramatic setbacks, and eventual redemption. Dating back to the 1950s, this medication was synthesized by Swiss pharmaceutical company Wander AG (later absorbed by Sandoz) while they were experimenting with tricyclic compounds in search of new antidepressants or antipsychotics.

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By 1958, they'd created clozapine, a dibenzodiazepine derivative that stood out immediately in early animal testing. Unlike other antipsychotics of the era, it calmed behavior without causing severe sedation or muscle stiffness – hinting at something truly novel in its mechanism.

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Human trials in the 1960s, led by German researchers like Hanns Hippius, revealed clozapine's remarkable efficacy for schizophrenia, especially in treatment-resistant cases. It reached European markets by 1971 under names like Leponex, marketed as the first "atypical" antipsychotic. What made it "atypical"? Unlike traditional antipsychotics that primarily block dopamine D2 receptors, clozapine has a unique pharmacological profile with relatively low D2 receptor affinity but significant activity at multiple serotonin receptors, histamine receptors, and muscarinic receptors.

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As I often explained to residents during training, clozapine is the only antipsychotic that is demonstrably better than haloperidol. It's also one of only two medications (along with lithium) proven to reduce suicide risk in psychiatric patients.

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The Clozapine REMS Program: How Paperwork Nearly Killed a Miracle Drug

Then disaster struck. In 1975, Finland reported a cluster of 16 deaths among patients taking clozapine. These patients developed agranulocytosis – a potentially fatal drop in white blood cells that leaves patients defenseless against infection. Panic spread, and by 1976, clozapine was pulled from shelves in many countries.

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Though the drug eventually returned to market, the FDA approved it in 1989 with stringent requirements: weekly blood tests, a national registry, and comprehensive oversight. This evolved into the Clozapine REMS (Risk Evaluation and Mitigation Strategy) program, which required:
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1. Certification of prescribers and pharmacies
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2. Patient enrollment and monitoring
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3. Regular reporting of absolute neutrophil count (ANC) results
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4. Verification of safe use conditions before dispensing

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As I've often said, if you want something to not happen, the most efficient way is to staple a piece of paper to it. Every piece of paper you staple to a process reduces that process by about 20%. With five pieces of paper, the process becomes effectively zero. That's essentially what happened with clozapine. Despite being our most effective antipsychotic, particularly for treatment-resistant cases, clozapine became dramatically underutilized – a victim of paperwork.

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Real-World Impact of Clozapine REMS: A Case Study

During our recent Osmind Psychiatry Collective fireside chat, Dr. Brittany Albright shared a powerful case that illustrates the real-world impact of these restrictions:

"I have a 40-year-old woman with schizoaffective disorder who had failed multiple antipsychotics, including long-acting injectables, and developed tardive dyskinesia. We started clozapine, and her psychosis disappeared – it was remarkable. But the labs were a nightmare. With commercial insurance, she paid a $25 copay for weekly labs plus another copay for the medication itself. The financial and logistical burden became overwhelming."

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When her psychosis returned after stopping clozapine, Dr. Albright found it easier to prescribe a brand-new, expensive medication (Cobenfy - xanomeline/trospium chloride) than to navigate the REMS hurdles to restart clozapine. This real-world example reveals how REMS requirements directly compromised patient care.

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Why the FDA Removed REMS Requirements for Clozapine

After years of advocacy from psychiatric organizations, the FDA has finally acknowledged that the REMS program had become an unnecessary barrier for clozapine. Their decision to end the program was based on several critical factors:

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1. Barrier to access: The REMS program created significant obstacles for both prescribers and patients, limiting access to this vital medication.
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2. Risk-benefit reassessment: Long-term data showed that the risk of neutropenia decreases significantly over time, becoming almost negligible after the first two years of treatment.
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3. Clinical context: The advantages of clozapine – including improved life expectancy, symptom control, and reduced suicide risk – far outweigh the small long-term risk of neutropenia.
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4. Healthcare system burden: The program placed excessive administrative requirements on prescribers, pharmacies, and healthcare systems.
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While the clozapine REMS program is being eliminated, the FDA still recommends monitoring patients' absolute neutrophil counts according to the frequencies described in the prescribing information. Information about severe neutropenia will remain in the prescribing information, including in the existing Boxed Warnings.
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How Ending Clozapine REMS Changes Clinical Practice

For clinicians and patients alike, this change simplifies the clozapine prescribing process. The most immediate practical changes include:
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1. No more REMS registration: Prescribers, pharmacies, and patients will no longer need to enroll in the Clozapine REMS program.
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2. Streamlined prescribing: The elimination of mandatory reporting removes a major administrative hurdle.
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3. Improved access: Patients can receive clozapine more quickly when needed, without delays for paperwork processing.
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4. Reduced stigma: Removing the exceptional requirements may help normalize clozapine as an option in treatment algorithms.
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During our discussion, Dr. Martha Koo highlighted how this change will particularly benefit patients in specialized settings: "We work with several all-male sober living facilities, and this will be a game-changer for them. Previously, it wasn't just the patient going to get labs – it required a staff member taking time away from other duties. The efficiency gained will make a huge difference."
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The ability to prescribe 30-day supplies rather than weekly prescriptions also represents a significant quality-of-life improvement for stable patients.
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Will We See More Clozapine Use?

The big question is whether removing REMS will increase clozapine prescribing. Our expert panel had mixed perspectives on this.

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Dr. Koo suggested that while the change is substantial, other factors may still limit widespread adoption: "Clinically, many prescribers fear the weight gain, sedation, and sialorrhea (drooling) associated with clozapine. It's a bit like lithium – another remarkably effective but underutilized medication – where concerns about lab monitoring and side effects create hesitation."

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She added that clinician comfort and familiarity play a major role: "People are comfortable with the drugs they regularly prescribe. New generations of psychiatrists coming out of training might embrace clozapine more readily, but established practitioners might stick with their familiar options."

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I would argue that this hesitation reveals a concerning trend in our field. Since the introduction of fluoxetine (Prozac) in the 1980s – the first antidepressant that wasn't acutely dangerous in overdose – psychiatry has drifted toward medications that don't require close monitoring or specialized knowledge to prescribe safely. But our most effective tools – lithium and clozapine – demand more from us as clinicians. They require blood draws, understanding of pharmacodynamics, and careful monitoring.

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In fact, I sometimes challenge colleagues: "If you're not willing to do laboratory monitoring and make complex clinical judgments, are you practicing psychiatry to its fullest potential?" These medications require us to be complete physicians – which is precisely why they deserve a place in our treatment arsenal.

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Best Practices Moving Forward

Even without REMS requirements, responsible clozapine prescribing still demands vigilance. Here are recommended best practices:
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1. Follow monitoring guidelines: Continue appropriate ANC monitoring, especially during the first six months when risk is highest.
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2. Patient education: Inform patients about symptoms of neutropenia (fever, sore throat, flu-like symptoms) that should prompt immediate medical attention.
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3. Side effect management: Proactively address common side effects like weight gain (consider adjunctive medications like GLP-1 agonists when appropriate), sedation (dose timing adjustments), and sialorrhea (anticholinergic strategies).
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4. Reconsider placement in treatment algorithms: With reduced barriers, consider clozapine earlier for patients not responding adequately to first-line treatments, particularly those showing early signs of tardive dyskinesia.
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5. Interdisciplinary coordination: Maintain clear communication with pharmacists and primary care providers about monitoring responsibilities.
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Conclusion: A New Chapter for Clozapine

The elimination of the Clozapine REMS program marks a significant victory for psychiatric care. It removes unnecessary barriers to one of our most effective medications while still preserving appropriate safety measures. For patients with treatment-resistant schizophrenia or schizoaffective disorder, this change could mean the difference between continued suffering and meaningful recovery.

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At Osmind, we're cautiously optimistic that this regulatory change will help clozapine find its proper place in treatment algorithms. We hope it will encourage psychiatrists to develop comfort with this uniquely effective medication, just as many are embracing other interventional approaches like TMS, ketamine, and psychedelics.

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The clozapine story reminds us that sometimes our most powerful tools come with complexities that demand more from us as clinicians – not just in paperwork, but in medical judgment, patient education, and thoughtful monitoring. By rising to that challenge rather than avoiding it, we can offer our patients truly comprehensive psychiatric care.

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Want to join conversations like this with fellow psychiatric clinicians? The Osmind Psychiatry Collective brings together clinical experts to discuss the latest developments in psychiatric care, share clinical insights, and advance the field together. Join our community of 1000+ forward-thinking clinicians at Osmind.org/community.