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

On February 24, 2025, the FDA made a major move: it removed the mandatory REMS program for clozapine. For decades, this program controlled how doctors prescribed, pharmacies dispensed, and patients received one of the most effective drugs for treatment-resistant schizophrenia. Now, that system is gone. But here’s the catch - the risk of severe neutropenia hasn’t disappeared. The change wasn’t about safety being less important. It was about proving that doctors and pharmacists were already doing the right thing - without the red tape.

What Was the Clozapine REMS Program?

The Risk Evaluation and Mitigation Strategy (REMS) for clozapine started in 2015 as a response to a serious, life-threatening side effect: agranulocytosis, a dangerous drop in white blood cells called neutrophils. Clozapine is incredibly effective - it works when other antipsychotics fail. But between 1% and 2% of patients developed severe neutropenia, and about 0.8% developed full-blown agranulocytosis, which can be fatal if not caught early.

To prevent this, the FDA required every step of the process to be tracked:

• Doctors had to be certified through the Clozapine REMS website.
• Pharmacies had to be certified too - and couldn’t fill prescriptions without proof.
• Patient blood tests (Absolute Neutrophil Count, or ANC) had to be submitted monthly.
• Patients had to be re-enrolled every year.
• Telephonic verification was banned after November 2021. You had to use the online portal.

This wasn’t just paperwork. It was a full-time job for clinics. One 2022 survey found that clinics spent an average of 3.2 hours per week just managing REMS forms. Pharmacies added 10-15 minutes per clozapine prescription to verify compliance. For patients in rural areas or those with unstable housing, delays were common. About 30% of people who needed clozapine couldn’t get it on time because of these rules.

Why Did the FDA Remove the REMS Program?

The FDA didn’t make this decision lightly. They spent over a year reviewing real-world data from the Sentinel System, the Department of Veterans Affairs, and Brigham and Women’s Hospital. They looked at:

• How often doctors actually checked ANC levels
• How many cases of severe neutropenia occurred after 2015
• Whether the REMS system was truly preventing harm - or just creating barriers

The results? Doctors were already following the guidelines. Even without the mandatory reporting, ANC monitoring stayed consistent. The risk of severe neutropenia remained highest in the first 18 weeks, but after that, it dropped sharply. And crucially - the number of deaths from agranulocytosis had been declining for years, even with REMS in place.

The FDA concluded: The program wasn’t adding safety. It was adding friction.

What’s Required Now?

As of February 24, 2025:

• Doctors no longer need REMS certification.
• Pharmacies don’t need to check a registry before filling clozapine.
• Patient ANC results don’t have to be submitted to a federal database.
• The FDA’s mandatory patient enrollment system is shut down.

But here’s what hasn’t changed:

• The boxed warning about severe neutropenia is still on every clozapine bottle.
• The prescribing information still recommends ANC monitoring at specific intervals:

1. Before starting: Baseline ANC test.
2. Weeks 1-18: Weekly ANC tests.
3. Weeks 19-52: Every two weeks (if ANC is above 1,500/μL for most patients, or above 1,000/μL for those with Benign Ethnic Neutropenia).
4. After 12 months: Monthly tests, using shared decision-making with the patient.

These aren’t suggestions. They’re the standard of care. The FDA and major medical groups like the American Psychiatric Association and the American Society of Health-System Pharmacists still expect them.

How Is This Different from Other REMS Drugs?

Clozapine is now unique. Most high-risk drugs still have mandatory REMS:

• Thalidomide: Still requires pregnancy testing and enrollment - because of birth defects.
• Isotretinoin (Accutane): Still requires the iPLEDGE program - monthly pregnancy tests, counseling, and strict controls.

Clozapine is the first major drug where the FDA removed a mandatory safety program and still has confidence in clinical judgment. Why? Because the risk is predictable, and monitoring is straightforward. It’s not about controlling behavior - it’s about ensuring care.

What Does This Mean for Patients?

For people with treatment-resistant schizophrenia, this change is huge.

Before 2025, only about 12% of eligible patients in the U.S. were on clozapine. Research showed that REMS was a top reason why doctors avoided prescribing it - especially in small clinics or areas with limited lab access. Now, that’s changing.

Anthem’s Provider News predicts a 25-30% increase in new clozapine starts over the next two years. More patients will get the drug that works for them. No more waiting weeks for a form to be processed. No more pharmacy refusals because the portal was down.

But patients still need to be proactive. Don’t assume your doctor will automatically check your ANC. Ask for it. Keep your lab appointments. If you feel feverish, sore throat, or unusually tired - call your provider immediately. Those are early signs of low neutrophils.

What Does This Mean for Doctors and Pharmacies?

For prescribers: You’re no longer trapped in a bureaucratic loop. You can start clozapine without jumping through federal hoops. But you’re still responsible for monitoring. If you skip ANC checks and a patient develops agranulocytosis, you’re still liable. The standard of care hasn’t changed - just the enforcement.

For pharmacists: You don’t need to log into the REMS portal anymore. You can fill clozapine like any other prescription. But you still need to verify the patient has had their ANC tested. Ask. Check the chart. Call the clinic. Documentation matters - not for the FDA, but for patient safety.

The American Pharmacists Association has already updated its guidelines. The message is clear: Remove the registry. Keep the vigilance.

What’s Next?

Manufacturers like Novartis are updating clozapine labels to remove references to REMS. The FDA is still tracking outcomes through the Sentinel System. Early data from March-June 2025 shows ANC monitoring rates remain above 95% in VA and academic centers - even without the mandatory system.

In Q3 2025, the American Society of Health-System Pharmacists will release new clinical guidelines reinforcing ANC monitoring as standard practice. Educational campaigns are being rolled out to clinics, especially in underserved areas, to ensure no one thinks monitoring is optional now.

The bottom line? Clozapine is no longer held back by bureaucracy. But its power demands responsibility. The system changed. The science didn’t.

What About Benign Ethnic Neutropenia?

Some patients - particularly those of African, Middle Eastern, or West Indian descent - naturally have lower neutrophil counts without increased infection risk. This is called Benign Ethnic Neutropenia (BEN).

Under the old REMS, these patients were often denied clozapine because their ANC fell below 1,500/μL. The FDA now explicitly recognizes BEN. For these patients:

• The ANC threshold is 1,000/μL - not 1,500/μL.
• Doctors should confirm BEN with prior lab history or genetic testing if possible.
• Monitoring frequency remains the same: weekly → biweekly → monthly.

If you’re unsure whether a patient has BEN, consult a hematologist. Don’t deny clozapine just because the ANC is low.

Final Thoughts

The removal of the clozapine REMS program isn’t a relaxation of safety - it’s a recognition of clinical competence. Doctors and pharmacists didn’t need a federal mandate to do the right thing. They just needed the freedom to do it.

Clozapine remains the gold standard for treatment-resistant schizophrenia. It saves lives. For too long, the system made it harder to get than it should have been. Now, access is improving. But vigilance hasn’t changed.

Keep checking ANC. Keep asking questions. Keep listening to your patients. That’s what safety looks like now.