REMS for Clozapine: What Changed in 2025 and How ANC Monitoring Works Now

On February 24, 2025, the U.S. Food and Drug Administration (FDA) made a major move: they removed the mandatory REMS program for clozapine. For over a decade, this program controlled how doctors prescribed, pharmacies dispensed, and patients received this powerful antipsychotic drug. Now, those strict rules are gone. But here’s the thing - the risk of severe neutropenia hasn’t disappeared. It’s still real. What changed isn’t the danger. It’s the system.

Why Clozapine Was Treated Like a High-Risk Drug

Clozapine works when nothing else does. For people with treatment-resistant schizophrenia, it’s often the only option that brings relief from hallucinations, delusions, and suicidal thoughts. Studies show it helps 30-50% of patients who didn’t respond to other antipsychotics. But it also carries a serious risk: agranulocytosis - a sudden, dangerous drop in white blood cells called neutrophils. Without enough of these cells, the body can’t fight off infections. That’s why, back in 1989, the FDA approved clozapine with heavy restrictions. By 2015, those restrictions became a formal REMS program - a federal safety system that required every step of the process to be tracked and approved.

Under the old REMS rules:

• Doctors had to be certified to prescribe clozapine
• Pharmacies had to be certified to fill the prescription
• Patients had to enroll in the program
• Every single Absolute Neutrophil Count (ANC) blood test result had to be submitted to a national registry
• Pharmacies couldn’t dispense the drug unless the ANC was confirmed as safe

It wasn’t just paperwork. It was a bottleneck. For many patients, getting clozapine meant waiting days - sometimes weeks - while clinics scrambled to submit forms, verify results, and re-certify everyone every year. Rural clinics, small pharmacies, and under-resourced hospitals struggled the most. One 2022 survey found clinics spent an average of 3.2 hours per week just on REMS-related tasks. That’s time taken away from patient care.

The ANC Monitoring Schedule That Still Matters

Even though the REMS program is gone, ANC monitoring hasn’t disappeared. In fact, it’s more important than ever - because now, it’s up to you and your doctor to get it right.

The FDA and major medical groups still recommend this schedule:

1. Before starting clozapine: Get a baseline ANC test. It must be at least 1,500/μL for most people, or 1,000/μL if you have Benign Ethnic Neutropenia (common in people of African, Middle Eastern, or Mediterranean descent).
2. Week 1 to Month 6: Weekly ANC tests. This is when the risk of severe neutropenia is highest - especially in the first 18 weeks.
3. Month 6 to Month 12: Every two weeks, if your ANC stays in the safe range.
4. After 12 months: Monthly tests, using shared decision-making with your doctor. Some patients may need more frequent monitoring based on their history.

This schedule isn’t arbitrary. It’s based on decades of data from the U.S. Department of Veterans Affairs, Brigham and Women’s Hospital, and the FDA’s own Sentinel System. The risk drops sharply after six months, but it never hits zero. That’s why even after a year, monthly checks are still the standard.

What Changed on February 24, 2025

The big shift? No more mandatory reporting. No more central registry. No more re-certification deadlines.

Before 2025, if a patient’s ANC dropped below 1,000/μL, the pharmacy couldn’t dispense the next month’s supply until the result was submitted to the Clozapine REMS website. Now? The pharmacy just needs to know the ANC is safe - from the doctor’s notes, the lab report, or the patient’s records. No government portal. No forms. No delays.

The FDA didn’t remove the warning - they just removed the bureaucracy. The boxed warning about severe neutropenia is still on every clozapine bottle. The prescribing information from Novartis hasn’t changed on the medical risk. What changed is trust. The FDA looked at real-world data and found that doctors and pharmacists were already monitoring patients correctly - even without the system forcing them to.

Studies showed that over 90% of prescribers were following the recommended ANC schedule even before the REMS removal. That’s why the FDA concluded the program was no longer needed to protect patients. As Dr. Donna Rolin of the American Psychiatric Nurses Association put it, “Ending the REMS is a success for both providers and patients.”

Why This Matters for Patients and Providers

Before the change, only about 31.7% of eligible patients with treatment-resistant schizophrenia actually got clozapine. Why? Because the REMS program was a barrier. One patient told NAMI they waited 11 weeks just to get their first refill because their lab results got lost in the system. Another said their pharmacy refused to fill the prescription because the doctor’s office hadn’t submitted the monthly form.

Now, those delays are gone. Clinics aren’t spending hours on paperwork. Pharmacies aren’t calling the REMS contact center. Patients aren’t missing doses because of administrative errors.

And the results are already showing up. Anthem’s Provider News predicts a 25-30% increase in new clozapine starts over the next two years. Evaluate Pharma upgraded their market forecast from $487 million in 2024 to $612 million by 2026 - not because the drug got cheaper, but because more people can finally get it.

For patients, this means faster access to a life-changing medication. For doctors, it means less burnout from paperwork and more time for clinical judgment. For pharmacists, it means fewer delays and fewer phone calls.

What You Should Do Now

If you’re taking clozapine:

• Keep getting your ANC tests on schedule - don’t skip them just because the REMS is gone.
• Make sure your doctor has your latest lab results before each refill.
• Ask your pharmacy if they’re aware of the change. Some may still be using old protocols.
• If you’ve been denied clozapine before because of REMS issues, talk to your provider. You may now be eligible.

If you’re a prescriber:

• You no longer need to be certified through the Clozapine REMS website.
• You still need to follow the prescribing information - ANC monitoring is still standard of care.
• Update your clinic’s protocols. Remove any references to mandatory REMS reporting.
• Use the same ANC schedule: weekly → biweekly → monthly.

If you’re a pharmacist:

• You no longer need to verify ANC results through the REMS portal.
• You still need to confirm the patient’s ANC is within safe limits before dispensing.
• Check the patient’s medical records or ask the prescriber - don’t assume the old system still applies.

What’s Next?

The American Society of Health-System Pharmacists is rolling out updated clinical guidelines in Q3 2025 to help providers adapt to the new reality. The FDA will keep watching - through the Sentinel System - to make sure neutropenia rates don’t rise. Early data shows they haven’t.

Experts at Hyman, Phelps & McNamara say the ANC monitoring recommendations will stay in place for the foreseeable future. The incidence of severe neutropenia is still around 0.8% - low, but not zero. That’s why the boxed warning stays. That’s why monitoring continues.

The REMS program was never about safety. It was about control. And now, safety is back in the hands of doctors, patients, and the science - not the bureaucracy.