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FDA: 25 Questions About the Clozapine REMS

The Angry Moms have questions for the FDA that we would like answered.


Interrupting clozapine treatment is far more dangerous than missing a routine blood test, yet patients are frequently subjected to blocked refills and strict limitations on dispensed quantities. While this is not the stated intent of the clozapine REMS, this is its sole function.


1.       Formal guidelines for diabetics suggest patients always have 2 weeks’ worth of insulin on hand. What is being done to ensure clozapine patients always have emergency doses available?


Clozapine patients are given strictly rationed pills in as little as 7-day quantities. This requires frequent trips to the pharmacy and frequent clinical interactions. This places a heavy burden on patients, caregivers, pharmacists, ACT teams and case managers.


2.       What is being done to end this dangerous practice of “pill rationing” that significantly adds to clozapine interruption risks and is a major reason why prescribers hesitate to use clozapine for patients that need it?


3.       What is being done to ensure patients receive at least a 30-day prescription, comparable to other lifesaving medications?


The “additional enforcement discretion” announcements and provisions for pharmacists to dispense clozapine without a REMS authorization have been confusing and ineffective. Many pharmacies have responded by implementing even tighter restrictions, treating clozapine like a controlled substance.


4.       What is being done to correct the messaging and error-proof pharmacy interactions with the REMS so that all active clozapine prescriptions are dispensed without delay?


The risk of clozapine-induced neutropenia is less than one half of 1%, and cases are rarely fatal. Yet the cumulative lifetime risk of death by suicide for individuals with schizophrenia is 5%. Clozapine is the only medication FDA-approved to reduce suicidal behaviors; for every death associated with clozapine-induced neutropenia, clozapine prevents as many as 100 suicide deaths.


5.       What is being done to facilitate early use of clozapine in suicidal patients?


6.       What is being done to increase clozapine utilization, which will save thousands of lives?


Clozapine-induced neutropenia is much more prevalent in older patient populations. The risk in young patients, those in their teens and twenties, at the age of onset of treatment-resistant schizophrenia have minuscule risks of developing this condition. Yet this is the time when clozapine treatment offers the greatest lifesaving benefit and opportunity to dramatically change the course of illness.


7.       What is being done to limit testing and remove burdensome REMS requirements for young patients in this critical treatment window that do not benefit from frequent ANC testing?


After 18 weeks of clozapine treatment, the risks of severe neutropenia drop significantly; the risk becomes lower than other antipsychotics. Yet both the clozapine product label and REMS requirements continue to mandate far more frequent ANC testing than any other drug, long after the risks have subsided.


8.       What is being done to update the guidelines in the clozapine product label to reduce the frequency of testing and to eliminate the burden of a restrictive REMS after the first 18 weeks?

 

While the REMS allows prescribers to waive tests, very few are willing to use that feature. Many hospitals and clinics even have policies that prevent prescribers from waiving tests, and many pharmacies or pharmacists have policies that refuse to dispense the drug if any tests are missing.


9.       What is being done to provide clozapine prescribers appropriate guidance on the risk and benefits of clozapine and when it is appropriate to waive routine tests?


10.   What is being done to correct clinical policies, remove liability, and alleviate fear of liability, from prescribers, clinics and pharmacies that continue to prescribe and dispense clozapine in the absence of routine tests?


Patients admitted to acute psychiatric inpatient settings often experience delays in receiving clozapine compared to other medications. Many psychiatric hospitals don’t carry clozapine in their formularies and require “extra” tests before administering the drug. These policies are dangerous and discriminatory.


11.   What is being done to ensure all inpatient facilities carry clozapine in their on-site formularies for prompt use in admitting patients?


12.   What is being done to hold hospitals accountable to recognize the current patient REMS status rather than interrupting clozapine treatment for duplicative and “extra” patient testing?


Treatment-resistant schizophrenia involves serious risks of self-injury, suicide, violence, and extreme suffering. Clozapine is often the only solution, yet many individuals who need clozapine are unable to participate in the clozapine REMS for a variety of reasons.


13.   What is being done to allow compassionate use of clozapine outside of the regulatory REMS in cases where the risk of harm outweighs the benefits of routine testing?


14.   What is being done to facilitate the initiation of clozapine if baseline blood tests cannot be obtained?


15.   What is being done to facilitate the initiation of clozapine in cases where adherence to the testing schedule is anticipated to be difficult, and therefore doctors are unwilling to conduct an appropriate trial?


16.   What is being done to facilitate the use of clozapine in incarcerated populations, including maintaining treatment when inmates are transferred between facilities and after sentencing?


Dangerously ill, disabled, and incapacitated individuals at all stages of clozapine treatment have no choice to receive this lifesaving treatment without participating in the burdensome REMS program.


17.   What is being done to enable patients, guardians, or designated representatives to decline mandatory testing with informed consent so that they can determine for themselves the risks and benefits of ANC testing relative to a disruption in clozapine treatment?


18.   Similarly, what is being done to allow initiation of clozapine in such circumstances, without enrolling in the program?


Prior to 2005, clozapine patient testing could include either a WBC or an ANC. In difficult blood draw circumstances, the WBC could be done with a simple finger prick, which wasn’t possible for ANC. In 2005, the FDA eliminated the WBC option and restricted testing to only allow ANC, effectively eliminating any options for a finger prick alternative. In 2018, a finger prick device was FDA-approved to measure ANC for clozapine patients.


19.   What is being done to reinstate the previous guidelines that allowed WBC as an alternative to an ANC measurement, in cases when venous blood draws are too difficult?


20.   What is being done to facilitate the use of finger prick ANC devices in psychiatric hospitals, outpatient clinics and residential treatment centers?


Currently ANC devices cost $1500 for patients to use at home, with $30 test strips. This is negligible compared to the costs of NOT using clozapine, yet insurance companies (including Medicare and Medicaid) won’t cover this technology.


21.   What is being done to require that insurers cover the costs of this vital technology?


The clozapine REMS would save far more lives if it did the exact opposite of its current function: if it ensured continuity of medication, prompt refills and access to emergency doses. But the current clozapine REMS doesn’t track filled prescriptions, dispensed doses, provider refill authorization status, manufacturer distribution, pharmacy stock, or drug availability.


22.   What is being done to correct these major hazards associated with the current clozapine REMS strategy given that it is intended to be a patient safety program?


For three decades clozapine has required excessive patient testing and a strict REMS that is not commensurate with clozapine’s neutropenia risks when compared to other medications, including other psychiatric medications. The mere existence of extreme testing requirements and a rigid REMS has over-inflated the risks of this highly effective medication and caused an entire field of medicine to avoid the drug, wrongly labeling clozapine as “a last resort.” This misconception about clozapine has caused woeful underutilization, suffering and deaths.


23.   What is being done to correct misconceptions about clozapine among psychiatric providers?


On January 7th, 2024, the British newspaper The Times published a feature story by Sean O’Neill titled “Britain’s most dangerous prescription drug — linked to 400 deaths a year.” This important report revealed disturbing deaths associated with clozapine use. Doctors failed to adequately monitor for toxicity, pneumonia, heart conditions, bowel obstructions, and complications associated with interrupted treatment. Not a single neutropenia death was mentioned. Several statements in the report imply that hypervigilance toward monitoring and preventing neutropenia has caused providers to neglect far more frequent and serious clozapine risks.


24.   What is being done to train doctors to appropriately manage clozapine patients?


25.   What is being done to improve the safety and accuracy of the clozapine product label with respect to appropriate dosing, titration schedules, monitoring serum levels, managing tobacco interactions, and interruption and re-initiation risks?


We hope the FDA will provide a response to our questions.


Sincerely,


The Angry Moms




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