PATIENT SAFETY
December 15, 2023

Patient Safety Alert: Serious Harm Associated With Failure to Adjust Clozapine Dosing

​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​AUTHOR BIOGRAPHY
The Patient Safety Authority (patientsafety.pa.gov) is an independent state agency that oversees the Pennsylvania 
Patient Safety Reporting System (PA-PSRS), the largestdatabase of its kind in the United States

SAFETY ALERT

We have received Pennsylvania Patient Safety Reporting System (PA-PSRS) reports of serious harm associated with a failure to adjust dosing upon reinitiation of clozapine therapy. Clozapine is an atypical antipsychotic approved for the treatment of treatment-resistant schizophrenia.1 Despite its clinical effectiveness, it is used as a last-line therapy and 
has risk evaluation and mitigation strategy (REMS)11  requirements because it can cause a number of serious and potentially fatal adverse effects such as agranulocytosis.1,4-6 Additionally, clozapine requires dose adjustments when used concomitantly with several categories of medications, such as CYP inducers and inhibitors, anticholinergic drugs, and drugs that cause QT interval prolongation.1

In patients who have discontinued clozapine for two or more days, the manufacturer recommends the therapy be reinitiated at 12.5 milligrams once daily or twice daily to reduce the risk of hypotension, bradycardia, and syncope.1 Cases of severe cardiovascular effects have been documented in patients whose doses were not titrated appropriately after an interruption in therapy.7

Action Items:
  • ​Design and implement effective “hard stops” and alerts in the electronic health record (EHR) to notify any new starts, last date taken, and interruption of therapy for more than two days. 
  • Document in the EHR any changes that are made to the medication therapy, including the rationale.
  • Record the details of medication administration in the medication administration record (MAR) and not solely in the text of the progress notes.
  • Ensure medication reconciliation includes date last taken. 
  • Verify the enrollment of the patient in REMS to avoid a disruption in therapy.
  • Educate the multidisciplinary healthcare team on the prescribing and safety information 
  • of clozapine, including strategies to detect early signs of adverse effects. Ensure that drug 
  • information and institution-specific guidelines, if available, are easily accessible to the healthcare team.
  • Ensure periodic review of high-alert medications or medications that require REMS by the pharmacy and therapeutics (P&T) committee. Review should include verification that  alerts or hard stops within the EHR function as intended and an analysis of the frequency at which they are triggered.
  • Enhance drug-checking software and clinical decision support within the EHR. Review and streamline the process to minimize alert fatigue and continually monitor its effectiveness. 

References

  1. National Library of Medicine. Label: Clozapine Tablet. Dailymed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d5c8a456-6f3c-4963-b321-4ed746f690e4. Updated December 28, 2022. Accessed November 22, 2023.
  2. U.S. Food and Drug Administration. Risk Evaluation and Mitigation Strategies (REMS). FDA. https://www.fda.gov/drugs/drug-safety-and-availability/risk-evaluation-and-mitigation-strategies-rems. Updated May 16, 2023. Accessed November 22, 2023.
  3. U.S. Food and Drug Administration (FDA). Approved Risk Evaluation and Mitigation Strategies (REMS): Clozapine. FDA. https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm?event=RemsDetails page&REMS=351. Updated September 29, 2023. Accessed November 22, 2023.
  4. Clozapine REMS. What is the Clozapine REMS? Clozapine REMS website. https://www.newclozapinerems.com. Accessed November 22, 2023.
  5. Imazu S, Hata T, Toyoda K, Kubo Y, Yamauchi S, Kinoshita S, et al. Safety Profile of Clozapine: Analysis Using National Registry Data in Japan. J Psychiatr Res.2021;141:116-23. doi: 10.1016/​j.jpsychires.2021.06.041.
  6. Khalid M, Jegede O, Gayam V, Yang YC, Shrestha B, Mandal A, et al. Clozapine-Induced Cardiotoxicity Presenting as Sepsis: A Case Report and Literature Review. Case Reports in Medicine. 2019;2019:3435108. doi: 10.1155/2019/3435108.
  7. Institute for Safe Medication Practices. ISMP: Restarting Clozapine Too Rapidly Can Cause Severe Cardiovascular Effects. National Association of Boards of Pharmacy. https://nabp.pharmacy/news/blog/regulatory_news/ismp-restarting-clozapine-too-rapidly-can-cause-severe-cardiovascular-effects/2022. Published September 9, 2022. Accessed November 22, 2023.​
​​Keywords: 
clozapine, Clozaril, antipsychotic, schizophrenia, medication safety, medication error​​​
​

ADDENDUM​​

​This addendum updates our “Patient Safety Alert: Serious Harm Associated With Failure to Adjust Clozapine Dosing” published on Decem​ber 15, 2023.

On February 24, 2025, the U.S. Food and Drug Administration (FDA) removed the risk evaluation and mitigation strategy (REMS) program for clozapine. This change eliminated the requirement for prescribers, pharmacies, and patients to participate in REMS and report absolute neutrophil count (ANC) results before clozapine is dispensed. Despite the discontinuation of the Clozapine REMS, the FDA still advises adherence to ANC monitoring frequencies specified in the clozapine prescribing information, and the existing boxed warnings regarding severe neutropenia remain in effect. 

Reference

U.S. Food and Drug Administration. Information on Clozapine. FDA. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-andproviders/information-clozapine. Published February 25, 2025. Accessed February 26, 2025.

How to Cite the Original Article
Patient Safety Authority. Patient Safety Alert: Serious Harm Associated With Failure to Adjust Clozapine Dosing. Patient Safety. 2023;5(3):90674. doi:10.33940/001c.90674

How to Cite This Addendum
Patient Safety Authority. Addendum to “Patient Safety Alert: Serious Harm Associated With Failure 
to Adjust Clozapine Dosing.” Patient Safety. 2025;7(2):154226. doi:10.33940/001c.154226​