So, in honor of today being International Talk Like A Pirate Day, my official name for September 19 is Dr. Frownin’ Willie Morgan after conversion of “The Practical Psychosomaticist” on the pirate name generator site. I know, I’m not frowning.
Arrr! would be an appropriate way to start this post about the new update to the clozapine post, in view of the upcoming new FDA prescribing rules for clozapine known as the Clozapine Risk Evaluation and Mitigation Strategy (REMS) Program.
This reminded me of a recent article in Psychiatric News entitled “Why Won’t Clinicians Use Clozapine Despite Proven Superiority?” by Mark Moran (Rough Sailin’ Quinn Drake just for today) who interviewed Deanna Kelly, Pharm.D. (who, according to the pirate name generator, should be called Scurv-aceous Guidiana Bellamy which of course is the feminized version of the name which actually came up–Guideon).
Anyway, according to Scurv-aceous Guidiana, “All the data suggest this is a superior medication, particularly for treatment-resistant schizophrenia…” There is plenty of evidence for its effectiveness across several studies and it’s the only FDA-approved antipsychotic for treatment-resistant schizophrenia.
Also, in the aptly named trial in view of today’s holiday, Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS), “…clozapine treatment was associated with significantly greater improvement in Positive and Negative Symptom Scale (PANSS) total scores and higher patient subjective ratings compared with risperidone, olanzapine, quetiapine, and amisulpiride.”
But only about 5% of patients got clozapine last year in America. Cost isn’t the main issue because clozapine is available as a generic. So why do we avoid it? Without hesitation, most of us would say it’s the stringent restrictions on blood monitoring–which some might say will get much easier under the new REMS Program. It’ll be different–but for now I’m deferring judgment on whether it’ll be truly that much easier.
Arrr! Until now, five companies offer generic clozapine, each with a separate registration system for clinicians and pharmacists. That’s all going to change come October 12, 2015 when they are replaced by just one system, the REMS Program. Under the new program, only the absolute neutrophil count (ANC) will be recognized as the blood monitoring parameter of interest. That’s right, the total white blood cell count (WBC) is going away.
Shiver me timbers!
As clinicians, we’re also leery of the side effects including but not limited to agranulocytosis. There are other adverse events such as myocarditis, weight gain, seizures, sialorrhea, hypotension, clozapine-induced gastrointestinal hypomotility leading to bowel obstruction sometimes resulting in death, to name a few.
Scurv-aceous Guidiana lists the definitions of the various blood parameters in the article–which you can just forget now because it will all be different as of October 12, 2015. However, she mentions “benign ethnic neutropenia” (BEN) which has complicated access for some African Americans and Africans who can have lower WBC. That may be less of a barrier now with the REMS Program.
She also mentions the effort to reduce the administrative burden by “…several researchers…” who had petitioned the FDA to develop a centralized registry system.
Wow, which incidentally translates to “Wow” on the pirate name generator. That centralized registry system is now upon us and it’s one way experts hope to promote the culture change which could persuade more clinicians to prescribe clozapine.
Well, that brings me to the updated WordPress Presentation Shortcode slide set on clozapine in the general hospital. This is by no means an exhaustive review and barely scratches the surface of the complexity involved in using clozapine for the treatment of schizophrenia. The Disclaimer certainly applies to this short slide set on the use of clozapine in the general hospital.
Them that certify will be the lucky ones–maybe.
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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
Five Black Box Warnings by the FDA
Other adverse cardiovascular and respiratory effects
Increased mortality in the demented elderly with psychosis
Physicians and patients must be registered with a new centralized clozapine registry
Clozapine REMS Program
Resident physician can write the order, but a board-certified psychiatrist must approve it
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 Leukopenia per FDA REMS Program
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