Error Alert
Institute for Safe Medication Practices, Horsham, PA
In July 2021, a new REMS platform was initiated by FDA to merge divergent registries into one, and recertification of health care practitioners was supposed to be completed by November 15, 2021. However, this transition was not a smooth one. Instead, practitioners ran into problems, including high call volumes and long wait times.
Restarting risks
One case shows the dangers such problems can pose. A 40-year-old woman who had been taking a total daily dose of clozapine 500 mg as an outpatient hadn’t received her medication for nearly two weeks due to her psychiatrist’s difficulties in registering via the updated REMS. She was admitted to a hospital psychiatric unit and restarted on clozapine.
Her physician did not want to restart her at the full dose since she had not been taking it for nearly two weeks. He thought a reduced dose of 400 mg was appropriate since the patient had been stable on 500 mg daily for an extended time.
Unfortunately, a little over one hour after receiving her first dose, the patient was found pulseless face down in her room. Cardiopulmonary resuscitation was initiated with return of spontaneous circulation, but she suffered cerebral hypoxia and ongoing shock.
Clozapine reinitiation as a cause of the cardiac arrest is a diagnosis of exclusion, and no other etiology of the cardiac arrest was found in this case.
Warnings and precautions
Many health care practitioners are aware of the issue of clozapine-associated neutropenia and infection risk because the REMS program is designed to manage these risks.
However, it is clear that many practitioners are not aware of the potential for severe adverse cardiovascular effects, including cardiac arrest, especially when the drug is abruptly discontinued and then restarted after two days or more.
Clozapine has a boxed warning stating the following: “Orthostatic hypotension, bradycardia, syncope, and cardiac arrest have occurred with clozapine treatment.
“The risk is highest during the initial titration period, particularly with rapid dose escalation.
“These reactions can occur with the first dose, with doses as low as 12.5 mg per day. Initiate treatment at 12.5 mg once or twice daily; titrate slowly; and use divided dosages.”
Product labeling (not within the boxed warning) further states: “When restarting clozapine tablets in patients who have discontinued clozapine tablets (i.e., two days or more since the last dose), reinitiate with 12.5 mg once daily or twice daily.
This is necessary to minimize the risk of hypotension, bradycardia, and syncope. If that dose is well-tolerated, the dose may be increased to the previous therapeutic dose more quickly than recommended for initial treatment.”
Similar wording is also included in the warnings and precautions section of the package insert. Unfortunately, these warning statements are not being effectively communicated and/or taught to many health care practitioners.
Takeaways
Ensure all practitioners handling clozapine are aware of the potential for adverse cardiovascular effects.
Alert practitioners to the need to restart clozapine treatment at 12.5 mg once or twice daily when there has been a break in therapy for two days or longer.
Investigate options to develop clinical decision support to help ensure practitioners check the date and time of the patient’s last dose and to restart therapy according to manufacturer guidelines.
When dispensing clozapine and counseling patients, inquire about the date and amount of the last dose taken.
The hospital where this event occurred is considering an electronic requirement for the prescriber to input the patient’s previous dose and when the last dose was administered when entering a new order. ■