Deadly Secrets of the Clozapine REMS

PART 1

Patty L. has been a pharmacist for more than four decades. During the mid-2000s, Patty was responsible for all clozapine distribution in one of the largest counties in the US. At that time, clozapine still had “centralized” distribution programs. Patty’s single pharmacy location served every clozapine patient enrolled under her county's regional behavioral health authority. Each day, her team of pharmacy technicians processed dozens of weekly patient blood tests to check for signs of clozapine-induced neutropenia. Each day, Patty’s pharmacy sent couriers out to deliver clozapine to clinics and patients.

If a faxed lab report did not arrive the day it was expected, Patty’s technicians proactively called the laboratory, patients, and providers to find out what happened with the blood draw or the test results. She recalls times when her pharmacy would send a courier to deliver a single day’s worth of clozapine if necessary. For Patty’s centralized pharmacy, maintaining uninterrupted treatment was as much a priority as monitoring patients’ blood work.

Oh, how things have changed.

In 2015, the FDA stipulated a national Risk Evaluation and Mitigation Strategy (REMS) program for clozapine. The program included stringent Elements To Assure Safe Use (ETASU) that prevented non-participants from receiving clozapine. It was the most restrictive REMS program the FDA had ever developed. This new REMS required monitoring of all clozapine patients’ Absolute Neutrophil Count (ANC) values via one centralized system. However, during this process, the distribution of clozapine to patients became completely decentralized.

While hypervigilance in ANC monitoring became the FDA’s prime directive, the task of ensuring treatment continuity fell by the wayside. Patty’s job was eventually displaced. The technicians and couriers were eliminated. The management of clozapine prescriptions was disseminated among a hodgepodge of community pharmacies, clinical assistants, case managers, caregivers, and even the patients themselves.

Most shocking, the REMS program was implemented with no system to detect regulation-induced adverse events. No method or feature was enabled to track dispensed prescriptions or patient dosing. No alarm bells started ringing when a patient’s clozapine was about to run out. The sole function of this new REMS program was to block pharmacy refills if a patient’s ANC values were low or missing. Adding to this neglect, clozapine pills continued to be rationed in weekly quantities with bans on emergency doses. The trademarked slogan “No blood, No drug” was proudly displayed on the clozapine REMS website.

This marked a key transition in the history of clozapine: the risk of treatment interruption became the primary barrier to clozapine treatment, even more than the cumbersome blood tests themselves. Prescribers began citing the risk of “non-adherence” as another reason not to prescribe it. Clozapine utilization continued the tragic decline that began ever since its patent expired in the mid-1990s. Long-term studies of clozapine have consistently demonstrated a significant reduction in mortality over other treatments. Combining these projections with continued rates of underutilization means tens of thousands of patients have experienced premature and preventable death because they did not receive clozapine. The insertion of bureaucracy into patient care has proven deadly. The web-based REMS surveillance platform simply could not replace the competent set of eyes on the patient that Patty and her team of technicians and couriers could provide.

The only real mitigation for this bureaucratic disaster has been psychiatric providers writing prescriptions for higher clozapine doses so that patients can amass a safety stock with the difference. This illicit trend has allowed the deadly clozapine REMS to fly under the radar for years. Patients whose providers are unwilling to “bend the rules” experience the most tragic consequences.

While some caregivers can find clever ways to hoard a secret clozapine stash, treatment interruptions are all too common in community treatment settings. Clozapine is frequently withheld during inpatient admissions while patients are forced to wait for the results of extra blood tests. Most hospitals don’t even carry clozapine in their on-site pharmacies. In group home settings, clozapine refills often arrive 2-3 days late, possibly longer, or until a staff member notices the clozapine is missing. The patient is restarted at the full dosing when the refill finally arrives. Often, psychiatrists are never notified of these delays and interruptions.

The sad truth is most psychiatric patients don’t have the support system necessary to maintain appropriate clozapine treatment in the current environment. They don’t have Patty and her team of technicians and couriers in the background managing every pill. Instead, there is a network of underground “mothers” connecting on social media, silently overnighting emergency clozapine stock to distraught patients and their families.

In late April 2024, The Angry Moms began publishing weekly highlights of REMS-related “negligence reports” from among the thousands of families that have joined our community. The response has been unexpected. Several pharmacists and pharmacy leaders have contacted us. Our discussions have exposed a deadly secret: clozapine treatment is routinely interrupted without appropriate countermeasures: without substitute antipsychotic, without anticholinergic medications, and without appropriate re-titration.

None of the pharmacists who contacted us knew of an “interruption protocol” for clozapine. None of them were aware of the clozapine re-initiation guidance that changed in 2023:

“If one day’s dosing has been missed, resume treatment at 40% to 50% of the established dose. If two days dosing have been missed, resume dose at approximately 25% of the established dose. For longer interruptions, re-initiate at a dosage of 12.5 mg once daily or twice daily. If these dosages are well-tolerated, the dosage may be increased to the previous dosage more quickly than recommended for initial treatment.”

Considering these new 2023 re-titration guidelines, any pharmacist facing a delayed refill of even one day should contact the prescriber immediately for treatment plan instructions. If they don’t get a response, emergency doses should be dispensed until the problem is resolved.

The current clozapine label also maintains a section titled “Recurrence of Psychosis and Cholinergic Rebound after Abrupt Discontinuation of Clozapine,” which states, “If abrupt discontinuation of clozapine is necessary… monitor carefully for the recurrence of psychotic symptoms and adverse reactions related to cholinergic rebound, such as profuse sweating, headache, nausea, vomiting, and diarrhea.”

While the clozapine label doesn’t offer specifics, Dr. Meyer and Dr. Stahl’s reference guide, The Clozapine Handbook, has a detailed chapter on clozapine discontinuation with dosing instructions for anticholinergics and antipsychotic substitutions. The guidelines indicate that the management of cholinergic rebound must begin within 24 hours after clozapine discontinuation.

The lived experience documented in the “REMS negligence” reports sent to The Angry Moms each week presents common themes of psychosis, catatonia, vomiting, tremors, and other problems following abrupt clozapine discontinuation and inappropriate re-initiation. There have been major consequences, including violence, injury, hospitalizations, and the return of anosognosia, causing severe setbacks for patients and families.

Among hundreds of reports, only two treatment interruptions reported to The Angry Moms have been associated with medical necessity. Nearly all other cases of interruption or discontinuation have been lab errors, lab delays, or REMS-related problems. Not a single case received re-titration instructions when the pharmacy blocked their refill for more than one day. Not a single case received substitute antipsychotic or anticholinergic medications within 24 hours after clozapine discontinuation. The only families who don’t experience regular treatment interruptions are those who have accumulated a healthy stockpile of backup pills.

Still today, most pharmacists align their dispensing habits with the now defunct No Blood, No Drug policy. None of the FDA’s internet announcements, website pop-up notices, and automated phone alerts regarding the clozapine REMS “enforcement discretion” have made much difference.

Patty and her heroic team of couriers are long gone.

There are, of course, exceptions. The “Clozapine Team” at Golden Gate mail order pharmacy understands the nuances of clozapine monitoring and dispensing. Refills are FedEx’d to your doorstep. Patients are alerted when refills are due. This is the same pharmacy that distributes the FDA-approved Athelas® point-of-care finger stick ANC device. This life-saving technology, now used by over 15,000 clozapine patients, solves every ANC monitoring problem, ensuring both patient safety and immediate resolution for REMS-related delays.

Imagine if providers and pharmacists were appropriately trained, held accountable to the clozapine product label, and expected to coordinate an interruption protocol within 24 hours of the last missed dose. Those emergency doses would magically authorize themselves, and the FDA’s “enforcement discretion” notices would be posted in every certified pharmacy window.

We might even get our couriers back.

Of course, the best option is to eliminate all dispense authorizations, stop enabling the REMS to block refills of this lifesaving medication and ensure every clozapine patient has a finger-stick ANC device.

This madness must end.

The Angry Moms