Well, it’s Friday, the day after the big update to the Clozapine REMS Program website. I don’t notice any major differences. I can navigate it pretty well. I still have a list of patients whose management I’m not responsible for and my contact at the program tells me that’s unlikely to change. That means I get “Alert” messages that I’m not accountable for.
But I’m fretful when I see that they are not being addressed–or startled when I see them disappear. This tends to raise a troubling question at times for me. What, if anything, ought I do when I see that a patient’s Alert is not being dealt with–at least while I’m looking at it? Is that a patient safety issue that I’m bound to report to the Clozapine REMS Program? Should I try to contact the Prescriber?
In one case I did just that! The Alert disappeared even before I was able to connect with the person. If the Alert was for me, it should not have vanished because I didn’t do anything.
It’s a little spooky. Am I an unwitting Peeping Prescriber?
Another row of activities has been stacked above the patient chart, giving me the illusion of control over the list of patients whose management I’m not accountable for, yet whose data is making me think maybe I should be collaborating with a Prescriber or two. All I can do really is sort them differently.
But I cannot remove their names. They beckon me, in a way. In time I’ll learn to not make them my problem. But what if Prescribers are not certified by December 14, 2015? What will happen? I’m told that clozapine dispensing would be unlikely to be abruptly halted. What would probably occur is that the guilty Prescriber would get a nasty note from the FDA. What would happen after that is unclear.
We’re all referred to as “Prescribers.” That is a very politically chosen egalitarian term for the many different clinicians who have been managing patients on clozapine. They include primary care physicians, neurologists in some cases, nurse practitioners (some of whom may never certify because of the challenges in that complex process), physician assistants as well as psychiatrists.
Despite the many non-psychiatrists out there who manage clozapine, my hospital will allow neither psychiatry residents nor non-psychiatric physicians to write the initial prescriptions for it. Only a psychiatrist who is on faculty can do that. It’s a puzzling hospital policy which is at variance with what actually happens in the world at large.
I discussed the many side effects with my contact at the Clozapine REMS Program (who has been very helpful, by the way). He wondered aloud why neutropenia is the one the program picked to monitor.
It’s the easiest.
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Clozapine in the General Hospital: Update
Jim Amos, MD
Right Click Hyperlinks
About 30% patients with schizophrenia are minimally responsive to antipsychotics
Excessively high mortality rates in patients
Clozapine first antipsychotic to demonstrate efficacy in treatment-resistant patients
Clozapine first introduced in Europe 1971 but voluntarily withdrawn in 1975 due to agranulocytosis
In 1989, studies showed more effective than any other antipsychotic in treating schizophrenia
Approved by FDA for treatment-resistant schizophrenia, requiring blood testing to monitor for agranulocytosis
Efficacy shown for treatment refractory patients, moderates violence, decreases suicidal behaviors, may improve cognition
Clozapine article in Dec 2009 Current Psychiatry (Box 1 outdated and the 5 clozapine registries are replaced by REMS Program, otherwise this is a nice review)
Five Black Box Warnings by the FDA
Agranulocytosis (now severe neutropenia)
Other adverse cardiovascular and respiratory effects
Increased mortality in the demented elderly with psychosis
Clozapine Risk Evaluation and Mitigation Strategy (REMS) Program as of October 12, 2015 (right click link below)
Physicians, pharmacies, and patients must be registered with this new centralized clozapine registry
Many non-psychiatric clinicians including primary care clinicians are “Prescribers”
Key changes in Monitoring
Absolute Neutrophil Count (ANC) only result acceptable for monitoring neutropenia
Patients with Benign Ethnic Neutropenia BEN) have separate ANC parameters
Prescribers have more flexibility on continuing and resuming treatment in neutropenic patients
ANC thresholds lower
If the patient goes without clozapine for more than 48 hours, must retitrate from zero
Patients are often on doses ranging from 300 to 700 milligrams a day
Titration is a tedious and slow process that can take up to two weeks on an inpatient psychiatric unit
Writing the orders in an electronic health record can be especially tricky
Special situations CL psychiatrists must be aware of before automatically reauthorizing clozapine on medically hospitalized patients
Patients hospitalized for problems like bowel obstruction
Patients hospitalized for new onset seizures
Patients hospitalized for any of the other FDA Black Box Warnings
Patients with delirium
Patients with new onset diabetic ketoacidosis
Patients without access to cigarettes
Clozapine Induced Gastrointestinal Hypomotility
Bowel obstruction can arise from constipation, a common side effect of clozapine; associated with morbidity and higher mortality
Patients should be on a bowel regimen to prevent constipation
If this is a reason for medical hospitalization, should stop clozapine while the patient is getting med-surg treatment
This risks relapse to psychosis
Clozapine associated with increased risk for seizures
Linked to total daily dose 600 mg or blood level greater than 600 micrograms/L
Often recommended to add anticonvulsant in this context
avoid carbamazepine as it interacts synergistically with clozapine increasing risk for agranulocytosis
Valproate often recommended in this setting
Must weigh benefits and risks of continuing clozapine
Patients with new onset diabetic ketoacidosis can have that as a consequence of clozapine treatment
Clozapine is a highly anticholinergic drug, so can potentially exacerbate delirium
Monitor neutropenia per FDA-approved Clozapine REMS Program, the single centralized registry as of October 12, 2015
Nicotine can lower clozapine blood levels; so when patients who smoke don’t have access to tobacco in hospital, clozapine blood levels can rise to toxic levels
Many patients on combinations of antipsychotics for various reasons, often including clozapine
This is a controversial practice and many experts don’t recommend it because of:
Modest evidence for theoretical basis
Limited statistical evidence for modest efficacy
Association of antipsychotic polypharmacy with increased mortality, metabolic syndrome, decreased cognitive functioning, low adherence
1. Fakra, E. and J.M. Azorin, Clozapine for the treatment of schizophrenia. Expert Opin Pharmacother, 2012. 13(13): p. 1923-35.
2. Lochmann van Bennekom, M.W., H.J. Gijsman, and F.G. Zitman, Antipsychotic polypharmacy in psychotic disorders: a critical review of neurobiology, efficacy, tolerability and cost effectiveness. J Psychopharmacol, 2013. 27(4): p. 327-36.
3. Stark, A. and J. Scott, A review of the use of clozapine levels to guide treatment and determine cause of death. Aust N Z J Psychiatry, 2012. 46(9): p. 816-25.
4. Moran, M. (2015) Why Won’t Clinicians Use Clozapine Despite Proven Superiority? Psychiatric News
Blood monitoring requirements and concerns over agranulocytosis may be what’s to blame for the underuse of a medication that has been found effective for treating patients with treatment-resistant schizophrenia: