Stop Clozapine Rationing

Let's make one thing clear: Abruptly stopping clozapine is a medical emergency.

Just ask the family of Kevin Keith Langemeier, Andrew, Phyllis in Northern New York (timestamp 4:08:30), and Analisa.

Studies estimate 50% to 70% of patients who abruptly discontinue clozapine can expect rapid deterioration and cholinergic rebound, even on doses as low as 50 mg per day, typically appearing within 2 days. The results can be dangerous and may have long-lasting effects. Symptoms include rebound psychosis, agitation, vomiting, oculogyric crisis, hallucinations, anxiety, and involuntary movement disorders. (1-7)

There are reports of severe catatonic reactions following abrupt interruptions in clozapine and even reports of suicide. A vital perspective is to compare the risk of death from clozapine-induced neutropenia to the risk of suicide following an episode of untreated psychosis. Fatal severe neutropenia occurs in 0.01% to 0.03% of clozapine patients. Yet 0.31% complete suicide in the year following first-episode psychosis. This is more than a 10-fold difference. The cumulative lifetime risk of suicide in schizophrenia is around 5%, perhaps higher. (8-12)

The idea that clozapine should be abruptly stopped in an otherwise healthy patient for the sake of a routine neutropenia blood test is completely insane.

But this essential, lifesaving medication is being carelessly rationed – by the week - with frequent risk of dangerous interruptions. No other situation like this exists in the entire field of medicine.

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Note: The Angry Moms have hidden the identities and locations of Patty, Isaac, and Jonah to protect their mental health and safety.

Patty is a mother and caregiver for her son Isaac, who requires clozapine treatment. He receives behavioral health services at a community mental health center. For the first 6 months of clozapine treatment, Isaac requires a weekly blood test to measure Absolute Neutrophil Count (ANC). While he is not a fan of the frequent tests, he complies because he recognizes that he benefits from the clozapine.

The problem for Isaac is not the blood tests but the clozapine rationing.

Every Monday, Isaac must go to his clinic for the weekly blood test. The test is processed overnight, and if the ANC result is passing, he must return to the clinic on Tuesday to pick up exactly 7-days of medication from the on-site pharmacy – no more.

If the clinic is closed on a Monday holiday, he will miss some doses of medication.

If the clinic has a problem scheduling a taxi to bring him to the lab (a common problem), he will miss some doses of medication.

Isaac has no emergency doses on hand. His lifesaving clozapine is rationed down to the last pill every week. Both Isaac and his mother live in fear that, in any given week, his clozapine treatment will be interrupted.

Like many patients on clozapine, Isaac must take several adjunctive medications to treat and prevent side effects. Patty carefully organizes and manages his many prescriptions in pill boxes every week. By providing this medication oversight, she is playing a vital role in her son's recovery.

Patty had surgery earlier this month and knew she would be unable to pick up Isaac's weekly ration of clozapine. She asked the clinic for a two-week supply to cover the week of her surgery. The clinic refused. Fortunately, Patty was able to enlist a friend to help.

This family cannot make any plans or have any conflicts on a Monday or a Tuesday, or doses of medication will be missed. They cannot travel for more than seven carefully planned days. Because of clozapine rationing, they live a very restricted life.

Members of The Angry Moms spoke with four other clozapine patients at Isaac's clinic. Three reported that they had missed doses because of the clinic's clozapine rationing procedures. One patient, Jonah, missed 5 doses of clozapine because of a 2.5-day delay. This led to vomiting associated with cholinergic rebound and self-harming behaviors, including trying to set himself on fire.

Jonah's situation was not reported to any agency as a regulation-induced adverse event. Such incidents are commonplace yet never reported. Jonah was never given a substitution antipsychotic or anticholinergic medications. The missed doses were discovered two weeks later during a review of his group home’s medication log.

Kevin is a manager for a behavioral health residential facility licensed to treat about 30 patients. Kevin has stated that clozapine patients are the "most difficult." Not because of their illness, their behaviors, or even the frequent blood tests (they have a mobile phlebotomist). The primary reason is the ongoing risk of running out of medications.

"It's a struggle every week," Kevin says. "The clinics don't return our calls quickly enough. The deliveries often arrive late or on the last day. There is no wiggle room; it's very stressful for the staff."

Many clozapine patients are served by Assertive Community Treatment (ACT) teams. One ACT team member told us, "I'm not a fan of clozapine. No one likes it. It's too much work."

Other programs have shared similar frustrations. In fact, most residential treatment centers and mental health group homes refuse to accept patients requiring clozapine treatment. We called a well-known program in California, A Mission for Michael, which claims to treat schizophrenia. We asked if they use clozapine for any clients. The answer was a flat "No."

These statements and attitudes towards clozapine patients are classic examples of the systemic institutional discrimination that The Angry Moms are determined to change.

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Clozapine rationing is a dangerous practice.

Ironically, most of these community providers and mental health clinics are NOT following the current guidelines specified in the FDA's clozapine Risk Evaluation and Mitigation Strategy (REMS). In 2021, the clozapine REMS underwent significant changes in response to ongoing problems with the mistake-prone "blood for drug" program previously implemented in 2015.

Here are some new features introduced with the 2021 clozapine REMS:

• Dispensing clozapine is no longer tied to individual ANC tests for a specified frequency (i.e., verify a passing ANC within the last 7 days for a weekly monitored patient). The new process requires a monthly Patient Status Form (PSF) completed every 37 days.

• The new process for a weekly-monitored patient requires 4 tests within 37 days (likewise, for a bi-weekly monitored patient, there must be two tests within 37 days, and so on).

• There is no requirement to space these tests perfectly. All the tests can be entered at one time at the end of the 37 days while signing off the monthly PSF.

• The REMS dispense authorization (RDA) provided to the pharmacist references the PSF status (current or expired), NOT the ANC value or length of time since the last ANC test.

• If the PSF is expired, the pharmacist can still dispense an active clozapine prescription by providing a "dispense rationale," which can be used up to 3 times per patient per year. This option requires evidence of a passing ANC test within the last 30 days, regardless of patient monitoring frequency.

Any prescriber, clinic, or pharmacist that requires individual ANC test results at weekly, bi-weekly, or monthly intervals as a condition to refill or dispense clozapine is not operating in compliance with the current REMS guidelines. The dispensing of a clozapine refill is now solely based on the PSF status or a dispense rationale if the PSF is expired.

The 2021 REMS revision also added more flexibility for below-range or missing blood tests:

• Several "override" options in the PSF allow the prescriber to waive missing tests. The PSF allows reasons for patient refusal, clinician discretion, or extrinsic factors.

• Clozapine treatment can be continued with below-range ANC by submitting the PSF with a treatment rationale indicating that the benefit of continuing treatment outweighs the risk.

These are important options for ensuring patients do not have their treatment interrupted because of a logistical problem or in cases of lab errors or neutropenia unrelated to clozapine. Contrary to popular belief, most cases of neutropenia in clozapine patients are unrelated. (13)

The 2021 REMS program made obvious attempts to improve the system's flexibility and avoid treatment interruptions. However, many clinical teams and pharmacists, especially in community care settings, are NOT following the current procedures.

And the new REMS completely fails to address this dangerous matter of clozapine rationing.

The clozapine product label itself makes no mention whatsoever regarding dispensed quantities. While the guidance elaborately outlines the recommended ANC testing plan and neutropenia risks, nowhere does the label indicate the need to ration clozapine in weekly or bi-weekly quantities contingent on the completion of ANC tests.

The clozapine REMS website offers dozens of links to literature and instructions for patients, pharmacists, and prescribers. The documents outline blood testing guidelines, recommended testing frequency, ANC ranges, and thorough instructions for entering patients' ANC values, completing the PSF, and obtaining an RDA.

Yet the website offers scant guidance on dispensed quantities for outpatient pharmacies. We scoured the available literature and found a single brief mention in the 19-page document "Clozapine and the Risk of Neutropenia: A Guide for Pharmacists" which states:

The amount of clozapine that can be dispensed depends on when the patient's next blood draw is scheduled to occur, according to the monitoring frequency requirements. Pharmacies should dispense enough medication to treat the patient with clozapine until the next blood draw/ANC or as directed by the prescriber.

An obvious omission in this statement is that there is NO requirement to wait for lab results or obtain a passing ANC before dispensing clozapine. This instruction only references the scheduled blood draw itself.

Strangely, the comparable document “Clozapine and the Risk of Neutropenia: A Guide for Healthcare Providers”, specifically intended as a guide for the prescriber, does not mention prescription quantities at all. However, question seven of the “Knowledge Assessment for Prescribers” asks how much clozapine can be dispensed. The correct answer is the choice that states “Dispense enough medication to treat the patient with clozapine until the next blood draw/ANC or as directed by the prescriber.”

Apart from the standard REMS literature, there is a "pop-up" alert on the website with a link to a public notice of "additional enforcement discretion" dated November 2, 2022. This awkward announcement spells out pill rationing guidelines for inpatient pharmacies following hospital discharge:

The FDA does not intend to object if… inpatient pharmacies dispense a days supply of clozapine that aligns with the patient's monitoring frequency (e.g., weekly monitoring = 7 days' supply, twice monthly monitoring = 14 days' supply, monthly monitoring = 30 days' supply) upon discharge from an inpatient facility.

Our calls to the REMS agency acknowledged that some prescribers are writing 30-day prescriptions for weekly and bi-weekly monitored patients, and pharmacies are dispensing the full 30-day quantities prescribed. The REMS associates repeatedly state that the dispensed quantities are "at the discretion" of both the prescriber and the pharmacist.

Our conclusion is that some patients are fortunate, but most are not.

Some weekly and bi-weekly monitored clozapine patients receive 30-day supplies from the very start of clozapine treatment because they have prescribers and clinical policies that recognize the importance of maintaining patient treatment and preventing interruptions. Additionally, these patients have pharmacists that are wisely supporting the prescribers' decisions.

But most patients, like Isaac, Jonah, and the many community care patients we interviewed, are forced to endure dangerously rationed pills and risks of frequent interruptions.

Members of The Angry Moms have tried to approach our community clinics and pharmacies regarding their clozapine rationing policies. We have asked for 30-day prescriptions or at least a few days of safety stock. We have requested clinical pharmacies to honor the PSF status rather than cut off refills because of a delayed blood test. We have asked to pick up this week's clozapine supply while we are on-site for the blood test without having to make a second trip after the ANC results come back.

The responses are generally, "I’m sorry, but this is a federal mandate," and "This is how we have always done it."

As members of The Angry Moms, we are accustomed to being told we don’t know what we are talking about - from people who don’t have to live with the consequences. It is a rather powerless feeling to have your child’s life dependent on a pharmacist or clinical staff who insists they are “just following the rules.”

Perhaps the most disturbing is when clinic or pharmacy leadership is confronted with the updated REMS literature and procedures. Yet, they assert (very pridefully) that they are intentionally choosing to follow more stringent policies – like waiting for a weekly test result before dispensing a week of medication – and insist that this improves safety for the patient.

Would we ever refuse to refill an anticonvulsant prescription for an epileptic patient because they missed a routine blood test?

Would we ever ration insulin for a person with diabetes? Or try to limit how much they are "allowed" to have on hand? No, we wouldn't. In fact, some states have enacted Kevin's Law, which authorizes pharmacies to give insulin to diabetic patients in emergency situations.

Like insulin, continuous access to antipsychotic medication should be a patient right.

Yet our mental health system of care, authorized by the FDA, has enabled strict clozapine rationing policies that routinely jeopardize the health and safety of our most seriously ill psychiatric patients. Such policies also risk the health and safety of caregivers.

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There are rare situations requiring a patient to immediately interrupt clozapine, such as a valid case of clozapine-induced severe neutropenia. This situation requires immediate medical attention, substitution with a backup antipsychotic, anticholinergic medications, and possibly medication to increase neutrophils. The process should be medically supervised, probably in an inpatient setting.(5)

But there is absolutely no reason to stop clozapine in an otherwise healthy patient for the purpose of a routine blood test. And there is certainly no justification for rationing clozapine in weekly or bi-weekly quantities in relation to ANC testing frequencies. This dangerous practice must stop.

Patients and families need help, and we have an urgent plea for the FDA:

Please formalize 30-day dispensed quantities for all clozapine patients and authorize emergency doses.

Please end the deadly and dangerous practice of clozapine rationing.

We know The Angry Moms are being heard. We understand clozapine monitoring is complicated. It will take time and bureaucratic efforts to alter or modify the clozapine label, adjust the ANC testing guidance, and repair the current challenges with the clozapine REMS.

But right now, the FDA has the authority to correct this one thing.

Please do it.

The Angry Moms

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Sources:

1. Seppälä N, Kovio C, Leinonen E. Effect of anticholinergics in preventing acute deterioration in patients undergoing abrupt clozapine withdrawal. CNS Drugs. 2005;19(12):1049-55.

2. Chouinard G, Samaha AN, Chouinard VA, et al. Antipsychotic-induced dopamine supersensitivity psychosis: pharmacology, criteria, and therapy. Psychother Psychosom. 2017; 86: 189–219.

3. Shiovitz TM, Welke TL, Tigel PD, Anand R, Hartman RD, Sramek JJ, Kurtz NM, Cutler NR. Cholinergic rebound and rapid onset psychosis following abrupt clozapine withdrawal. Schizophr Bull. 1996;22(4):591-5.

4. Tollefson GD, Dellva MA, Mattler CA, et al. Controlled, double-blind investigation of the clozapine discontinuation symptoms with conversion to either olanzapine or placebo. The Collaborative Crossover Study Group. J Clin Psychopharmacol 1999; 19: 435–443.

5. Blackman G, Oloyede E, Horowitz M, Harland R, Taylor D, MacCabe J, McGuire P. Reducing the Risk of Withdrawal Symptoms and Relapse Following Clozapine Discontinuation-Is It Feasible to Develop Evidence-Based Guidelines? Schizophr Bull. 2022 Jan 21;48(1):176-189.

6. Moncrieff J. Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse. Acta Psychiatr Scand. 2006; 114: 3–13.

7. Blackman G, Oloyede E. Clozapine discontinuation withdrawal symptoms in schizophrenia. Ther Adv Psychopharmacol. 2021 Sep 18.

8. Lander M, Bastiampillai T, Sareen J. Review of withdrawal catatonia: what does this reveal about clozapine? Transl Psychiatry. 2018 Jul 31;8(1):139.

9. Sinyor M, Remington G. Is psychiatry ignoring suicide? The case for clozapine. J Clin Psychopharmacol. 2012 Jun;32(3):307-8.

10. Palmer BA, Pankratz VS, Bostwick JM. The lifetime risk of suicide in schizophrenia: a reexamination. Arch Gen Psychiatry. 2005 Mar;62(3):247-53.

11. Álvarez A, Guàrdia A, González-Rodríguez A, Betriu M, Palao D, Monreal JA, Soria V, Labad J. A systematic review and meta-analysis of suicidality in psychotic disorders: Stratified analyses by psychotic subtypes, clinical setting and geographical region. Neurosci Biobehav Rev. 2022 Dec.

12. Patchan KM, Richardson C, Vyas G, Kelly DL. The risk of suicide after clozapine discontinuation: Cause for concern. Ann Clin Psychiatry. 2015 Nov;27(4):253-6.

13. Taylor D, Vallianatou K, Whiskey E, Dzahini O, MacCabe J. Distinctive pattern of neutrophil count change in clozapine-associated, life-threatening agranulocytosis. Schizophrenia (Heidelb). 2022 Mar 14;8(1):21.