Clozapine Safety Today: ANC Monitoring After REMS Removal

For years, getting clozapine prescribed meant jumping through a maze of paperwork, certifications, and mandatory blood test reports. Patients with treatment-resistant schizophrenia - the very people who needed this life-changing medication the most - often faced delays of weeks or even months just to start treatment. Why? Because of the FDA’s clozapine REMS program, a strict safety system designed to prevent severe neutropenia. But as of February 24, 2025, that system is gone. No more mandatory registration. No more monthly forms. No more pharmacy hold-ups waiting for verification. The FDA officially removed the mandatory Risk Evaluation and Mitigation Strategy (REMS) for clozapine. And while the risk of low white blood cell counts hasn’t disappeared, the way we manage it has changed - for the better.

Why Was Clozapine REMS Ever Required?

Clozapine is powerful. It works when nothing else does. For people with schizophrenia who haven’t responded to at least two other antipsychotics, clozapine can mean the difference between staying hospitalized and living independently. But it carries a real danger: agranulocytosis, a sudden and dangerous drop in neutrophils - the white blood cells that fight infection. In the 1980s, before any monitoring system existed, about 1 in 100 patients developed this condition. Some died. The FDA approved clozapine in 1989, but only under strict conditions. Over time, those conditions became a full-blown regulatory program.

By 2015, the Clozapine REMS program was mandatory for everyone: prescribers, pharmacies, and patients. Prescribers had to be certified. Pharmacies had to be certified. Patients had to be enrolled. And every single time a refill was due, the pharmacy had to confirm that the patient’s Absolute Neutrophil Count (ANC) had been tested and met the safety threshold - at least 1,500/μL for most people, or 1,000/μL for those with benign ethnic neutropenia. If the lab result wasn’t submitted through the REMS portal, the pharmacy couldn’t dispense the drug. It wasn’t just inconvenient - it was a barrier.

The ANC Monitoring Schedule (Still Recommended)

Even though the REMS program is gone, the medical need to monitor ANC hasn’t. The FDA still says: monitor your patient’s blood counts. The schedule hasn’t changed. It’s based on decades of data showing when the risk is highest.

• Before starting: Get a baseline ANC test. No clozapine without it.
• Weeks 1-18: Weekly ANC tests. This is when the risk of severe neutropenia is greatest.
• Months 6-12: Every two weeks, if ANC stays above the safe threshold.
• After 12 months: Monthly testing, using shared decision-making with the patient.

These aren’t suggestions. They’re the standard of care. The FDA’s 2024 review found that healthcare providers were already following these guidelines - even under REMS. That’s why the agency concluded the program wasn’t adding safety, just friction.

What Changed on February 24, 2025?

The big shift? Clozapine REMS is no longer mandatory. That means:

• Prescribers no longer need to register or re-certify through the Clozapine REMS website.
• Pharmacies don’t have to check the REMS portal before filling a prescription.
• Patient enrollment is optional. No more monthly Patient Status Forms.
• Telecommunication verification is no longer required - pharmacies can now dispense based on a lab report provided by the patient or provider.

The FDA didn’t remove the warning. The Boxed Warning about severe neutropenia is still in every clozapine package insert. The risk is real. But the agency decided the regulatory system wasn’t improving safety - it was just slowing access. A 2023 study in Schizophrenia Bulletin found clinics without dedicated REMS coordinators were nearly four times less likely to start patients on clozapine. That’s not safety - that’s neglect.

Why Now? The Evidence Behind the Decision

The FDA didn’t make this call 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 thousands of patient records. What did they find?

• Severe neutropenia still happens - but only in about 0.8% of patients, mostly in the first six months.
• Healthcare providers have gotten better at monitoring. Most are already testing ANC on schedule.
• The REMS program didn’t reduce neutropenia rates - it just added administrative work.
• Only 31.7% of eligible patients were getting clozapine before REMS removal. That’s not because doctors didn’t know it worked. It’s because the system made it too hard.

The FDA concluded: Doctors know the risk. They’re already managing it. The program isn’t helping - it’s hurting.

Impact on Patients and Providers

For patients, this change is huge. Before February 2025, about 30% of people trying to start clozapine faced delays due to REMS paperwork. One patient in Ohio waited 11 weeks just to get her first refill because her lab result didn’t upload correctly. Another in rural Kentucky couldn’t find a pharmacy certified to dispense clozapine - there weren’t any in her county. These aren’t rare stories. They were the norm.

For prescribers, it’s a relief. Psychiatrists used to spend an average of 3.2 hours a week just handling REMS paperwork. That’s time they could’ve spent with patients. For pharmacies, it’s simpler too. Before, each clozapine prescription added 10-15 minutes of verification steps. Now, it’s like any other prescription - just check the lab report, confirm the ANC is safe, and dispense.

The American Psychiatric Nurses Association called the removal a “success for both providers and patients.” The Medical Letter said it would “minimize the burden on the healthcare system.” Even industry analysts agree. Evaluate Pharma raised its forecast for clozapine sales from $487 million in 2024 to $612 million by 2026 - because more people will finally get access.

What Should You Do Now?

If you’re a prescriber: Keep monitoring ANC exactly as before. Don’t skip tests. Don’t assume the risk is gone. The Boxed Warning is still there for a reason.

If you’re a pharmacist: You no longer need REMS certification. But you still need to verify that the patient has had a recent ANC test. Ask for the lab report. If the ANC is below 1,500/μL (or 1,000/μL for benign ethnic neutropenia), don’t dispense. Contact the prescriber. That’s still your responsibility.

If you’re a patient: Don’t stop getting your blood drawn. The REMS program is gone, but your safety isn’t. Show up for your labs. Keep your provider informed. If your ANC drops, don’t wait - call your doctor right away.

What’s Next?

The FDA isn’t walking away from clozapine safety - they’re trusting clinicians to handle it. The American Society of Health-System Pharmacists is rolling out updated guidelines in Q3 2025 to reinforce best practices. Clozapine manufacturers are updating labels to remove REMS references while keeping the Boxed Warning. And the FDA will keep watching - using the Sentinel System to track neutropenia cases in real time.

This isn’t the end of safety. It’s the end of bureaucracy. The goal was always to get clozapine to the people who need it - without putting lives at risk. Now, with fewer barriers and the same vigilance, that goal is finally within reach.