Botched REMS Conversion was the Worst Event in Clozapine History
Below is a graph of publicly available data extracted from the FDA Adverse Event Reporting System (FAERS) database. The graph depicts the past 20 years of domestic and foreign adverse event reports for generic clozapine, Clozaril®, FazaCLo®, and Versacloz® brands.
2022 had a major spike in adverse event reports for domestic US clozapine patients, a phenomenon NOT seen in foreign reports from other countries. Over 8,200 domestic clozapine adverse events were reported in 2022; the highest in clozapine history since the FDA began collecting data in 1989. This was nearly three times higher than the preceding 5 years, which averaged about 3,000 cases per year.
The key driver of the 2022 spike was a 600% increase in US cases reporting neutropenia and related conditions. These conditions were present in 77% of the 2022 case reports - and for more than 6,000 of the 2022 cases, “neutropenia” was the only adverse event listed.
So, what happened in 2022? Was there a “bad batch” of clozapine that came through and caused an epidemic of “neutropenia” among US-only patients?
No. This had nothing to do with “neutropenia” at all.
All US clozapine patients are mandated to follow a controversial Risk Evaluation and Mitigation Strategy (REMS) program. By the FDA’s own admission, the program is undergoing “a thorough reevaluation,” as announced on September 21, 2023.
The purpose of the program is to detect clozapine-induced neutropenia, a complication that occurs in less than a quarter of a percent of clozapine patients. The condition is rarely fatal and primarily affects elderly patients during the first few months of treatment. The electronic clozapine REMS surveillance platform tracks neutropenia blood test results for clozapine patients at weekly, biweekly, and monthly intervals. The program can block pharmacy refills if a patient fails a test or falls behind in the testing requirements.
This 2022 spike in adverse events was caused by a poorly executed, unvalidated clozapine REMS program change that was rolled out on November 15, 2021. The program conversion caused months of clozapine dosing errors, lab testing errors, blocked refills, treatment interruptions, and program enrollment issues. Life-saving medication for thousands of patients was negligently disrupted. Families and patients who endured this tragic event call it “The 11/15 Disaster.” There have been injuries, hospitalizations, deaths, and an unknown number of patients wrongfully discontinued from their antipsychotic. Many clozapine patients are still having problems accessing their medication through the program.
Even though no part of the “broken” clozapine REMS platform can cause neutropenia, thousands of adverse events associated with the botched REMS conversion have been reported to the FDA as “neutropenia.” We can only surmise that this is because “neutropenia” is the adverse reaction the clozapine REMS program is intended to detect. Thus, any clozapine REMS-related problem gets automatically categorized as “neutropenia” when reported to the FDA.
Which is about as inept as the entire clozapine REMS program itself.
The Angry Moms have complained that the FDA has no system for identifying or monitoring regulation-induced adverse events. But it’s even worse than we thought:
The clozapine REMS regulatory program itself is causing harm to patients and subsequently reporting the harm caused as the very problem it is meant to detect, thereby justifying its continued harmful existence.
Read that again.
The optics here are startling. By conflating all of the clozapine REMS mishaps into one topic – neutropenia – the FDA has covered up its negligent and dangerous regulatory restrictions with innumerable false neutropenia reports. This is either profound ignorance – or the FDA is purposefully misleading the patient community into believing a 30-year lie: that the excessive blood tests and strict surveillance are benefiting clozapine patients.
The real question is, how long has this been happening? How long has the FDA been attributing regulation-caused problems to clozapine itself? How many previously documented “neutropenia” cases were false reports? How many adverse event reports were really clozapine interruptions - but the drug itself took the blame?
If it weren’t for The Angry Moms, would anyone even be asking these questions?
At least we know we aren’t imagining things (we have gotten used to that accusation). And we are right to be angry.
Even clozapine manufacturers don’t distinguish between treatment interruptions and true clozapine adverse events. One of our family members discontinued his clozapine, which resulted in a significant return of psychosis symptoms. The patient was re-initiated on clozapine, his REMS monitoring was resumed, and his symptoms abated. His clinic received a request for information from Teva Pharmaceutical Industries, LTD., the clozapine manufacturer. The form, titled “Adverse Drug Event Follow-Up Report,” asked two questions: “Did the events abate after stopping the suspect drug?” and “Did the events reappear after reintroduction?” There was nowhere on the form to report a REMS problem or symptoms from interrupted or discontinued treatment. Instead, the prescriber tried to write an explanation in the comments.
The other implication of this FAERS data analysis is that the worst thing to happen to clozapine patients in the entire 33-year history of the drug is the clozapine REMS itself. More adverse event cases labeled “neutropenia” have been reported since The 11/15 Disaster than in the preceding 15 years. The sheer magnitude of these “false flags” shows how profound the impact of regulatory restrictions can be for patients.
About two weeks after The 11/15 Disaster, in response to numerous complaints, the FDA awkwardly announced they would “not intend to object” if clozapine was dispensed without a REMS authorization. This was followed by another poorly worded announcement eleven months later, on November 2nd, 2022, stating, “The FDA is temporarily exercising additional enforcement discretion with respect to certain Clozapine REMS program requirements.”
Undoubtedly, the FDA will claim they “acted quickly” to correct the system errors following The 11/15 Disaster. They will attribute the 2023 downward trend following the 2022 spike to their ongoing “additional enforcement discretion” announcements. They may even be so bold as to claim the new REMS implemented in 2021 is “saving lives,” as evidenced by a significant drop in clozapine fatalities. Deaths reports for clozapine patients reached an all-time high of 968 in 2021 at the height of the covid-19 pandemic. Fatalities then dropped to just 177 in 2022, the second lowest in 14 years.
But looks can be deceiving. What we haven’t been told is how many individuals were disenrolled during the REMS program conversion and simply stopped receiving treatment altogether. The FDA has not responded to a Freedom of Information Act (FOIA) request for this information that the American Psychiatric Association submitted on March 3, 2022.
Many of the immediate technical problems with the new platform have been resolved, and many current users have learned to navigate the nuances of the new program. But treatment interruptions persist. Most problems go unreported. Prescription refills are blocked for logistical issues, expired patient status forms, non-adherence to the testing schedule, and general confusion about the REMS program. The FDA’s “additional enforcement discretion” announcements have only bolstered pharmacists’ misperception that clozapine is a controlled substance (it’s not), and the confusing messaging has further empowered pharmacists to block refills and limit dispensed quantities.
Many pharmacists, clinicians, and even psychiatric providers continue to operate under the deadly belief that missing a routine blood test is more dangerous than interrupting clozapine treatment. Even worse, tainted perceptions about clozapine safety, namely the falsely inflated “neutropenia” risks, have driven psychiatric providers away from using clozapine: the safest and most effective treatment for schizophrenia ever developed and the only medication FDA-indicated to prevent suicide.
While the FDA’s clozapine REMS program has caused decades of significant harm to enrolled patients, by far the largest category of individuals harmed by the clozapine REMS are those who have never even heard of the drug.
More to come.
The Angry Moms