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New FDA Warning on Clozapine
This adverse reaction to clozapine causes more fatalities than neutropenia. Here’s how to prevent it.
This adverse reaction to clozapine causes more fatalities than neutropenia. Here’s how to prevent it.
Neutropenia is the most notorious risk on clozapine, but it’s not the deadliest. That distinction belongs to ileus, an intestinal blockage that results from severe slowing of the bowels. In January 2020 the FDA strengthened their warning on this problem, which has a fatality rate of 15% to 28% compared with 2% to 4% for severe neutropenia.1 There are ways to manage and prevent ileus, and I’ll review those here, drawing from Jonathan Meyer’s practical guide to all things clozapine, The Clozapine Handbook.
1. Pretreatment. Ileus is part of a spectrum of gastrointestinal hypomotility that ranges from constipation to bowel obstruction. 80% of clozapine-treated patients have some evidence of hypomotility, or slowing, in their bowels, so it is safe to plan for the worst. Start patients on docusate (Colace) 250 mg qhs along with their first clozapine prescription.1
2. Reduce constipating medications
• Anticholinergics
• Antipsychotics
• Tricyclic antidepressants
• Antiparkinsonian medications (benztropine, diphenhydramine, trihexyphenidyl)
• Meds for overactive bladder (oxybutynin, tolterodine, trospium, darifenacin, solifenacin)
• Iron
• Opioids
Patients with schizophrenia often take other constipating medications, such as benztropine, diphenhydramine (Benadryl), and other antipsychotics. These should be lowered whenever possible as the interactions are substantial. Anticholinergics, for example, raised the risk of ileus six-fold when taken with clozapine.2
3. Caution with Bulk-Forming Laxatives. Laxatives like psyllium (Metamucil), polycarbophil (FiberCon), and methylcellulose (Citrucel) may help general constipation, but they can be dangerous when the cause is clozapine-induced hypomotility.1 The bulk they form can block the intestines. For the same reason, insoluble fibers should be minimized in the diet. These are the ones that don’t dissolve in water: nuts, seeds, celery, and the skin of fruits and vegetables. A slow gut does better with soft, moist foods and lots of hydration. Other dietary steps for gastrointestinal hypomotility are collected in a patient-friendly guide from Australia.
4. An Evidence-Based Protocol. Constipation may be a common medical problem, but many of its treatments have surprisingly little evidence to support their use. The Porirua Protocol is the only evidence-based algorithm for managing hypomotility on clozapine. In a small study, it reduced the prevalence of gastrointestinal hypomotility from 86% to 50%.3 The protocol was developed in New Zealand and benefits from a little translation: “bd” means “bid”; “Macrogol 1 sachet bd” means “polyethylene glycol PEG-3350 13.125 g bid”; and the doses in step-1 are docusate 100 mg qhs and senna 16 mg qhs.
6. Beyond the Protocol. Many patients on clozapine end up needing two treatments to manage their constipation on a daily basis. In addition to the options in the Porirua Protocol, there is lactulose (30 ml qd to bid) and bisacodyl (5 mg qhs to bid). It’s best to choose options with different mechanisms of action. Patients may also require a rescue therapy for exacerbations, such as:
Magnesium hydroxide (400 mg magnesium hydroxide per 5 ml): 5 ml po qd prn
Magnesium citrate (17.45 g magnesium citrate per 300 ml): 300 ml po q week prn
Mineral or water-based enemas: 1 per rectum qd prn
Beyond the Protocol (cont’d). If impaction is suspected, magnesium should be avoided and enemas are preferred.1
A frequent need for rescue therapies should prompt a reconsideration of their routine treatment. Secretogogues are good second-line options:
Lubiprostone (8-24 mcg bid, take with food and water)
Linaclotide (145-290 mcg qd, give > 30 min before first meal)
Plecanatide (3 mg qd)
7. Emergencies. Warning Signs of Ileus:
Fewer than 3 bowel movements a week
Hard or dry stools
Difficulty passing gas
Moderate to severe abdominal pain lasting > 1 hour
Nausea, vomiting
Bloating or belly swelling
Bloody diarrhea
Total bowel obstruction, or ileus, is a medical emergency that necessitates referral to urgent care or an emergency department. Left untreated, ileus can progress to bowel ischemia, perforation, peritonitis, sepsis, and death. Warn patients early in the treatment to call you if they have any of the signs above.1
8. Conclusion. Gastrointestinal hypomotility is the most common medical reason for clozapine discontinuation. Careful management can allow those patients to stay on this life-saving therapy. Despite a daunting list of medical risks, patients who take clozapine tend to live longer than those on other antipsychotics.4
References
1. Meyer JM, Stahl SM. The Clozapine Handbook. Cambridge University Press; 2019.
2. Nielsen J, Meyer JM. Risk factors for ileus in patients with schizophrenia. Schizophr Bull. 2012;38:592–598.
3. Every-Palmer S, Ellis PM, Nowitz M, et al. The porirua protocol in the treatment of clozapine-induced gastrointestinal hypomotility and constipation: a pre- and post-treatment study. CNS Drugs. 2017;31:75–85.
4. Vermeulen JM, van Rooijen G1, van de Kerkhof MPJ, et al. Clozapine and long-term mortality risk in patients with schizophrenia: A systematic review and meta-analysis of studies lasting 1.1-12.5 years. Schizophr Bull. 2019;45:315-329
Dr Aiken is the Director of the Mood Treatment Center, Editor in Chief of The Carlat Psychiatry Report, and Instructor in Clinical Psychiatry at the Wake Forest University School of Medicine. He is the author of The Depression and Bipolar Workbook and coauthor, with Jim Phelps, MD, of Bipolar, Not So Much. He can be heard in the weekly Carlat Psychiatry Podcast with his co-host Kellie Newsome, PMH-NP. Dr Aiken is Section Chief of Psychiatric Times. The author does not accept honoraria from pharmaceutical companies but receives royalties for his books.