A 40-year-old woman with schizoaffective disorder had been taking a total daily dose of cloZAPine 500 mg for at least 10 years. Recently she had not received the drug for nearly 2 weeks due to problems her psychiatrist had with registering for the updated Risk Evaluation and Mitigation Strategies (REMS) certification. According to the REMS, prescribers must be certified to prescribe cloZAPine for outpatient use, patients must be enrolled in the cloZAPine REMS program by a certified physician to receive treatment, and pharmacies must be certified to receive and dispense cloZAPine. In July 2021, a new REMS platform (http://www.newclozapinerems.com) was initiated by the US Food and Drug Administration (FDA) to merge different registries into one. However, there have been technical issues with the program, making it challenging for practitioners to register resulting in treatment delays.
The patient 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 2 weeks. He thought a reduced daily dose of 400 mg was appropriate since the patient had been stable on a daily dose of 500 mg. Unfortunately, a little more than 1 hour after receiving her first 400 mg dose, the patient was found pulseless. Cardiopulmonary resuscitation was initiated but the patient suffered cerebral hypoxia and shock. CloZAPine re-initiation as a cause of cardiac arrest is a diagnosis of exclusion, and no other etiology of the cardiac arrest was found.
Many prescribers, nurses, and pharmacists are aware of the issue of cloZAPine-associated neutropenia and infection risk, in part because the REMS program is designed to manage these risks. However, many 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 2 days or more. CloZAPine has a Boxed Warning that states, "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), re-initiate 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 healthcare practitioners.
All healthcare practitioners who prescribe, dispense, or administer cloZAPine should be made aware of the potential for adverse cardiovascular effects, especially considering the potential for breaks in therapy with the ongoing problems with REMS recertification. Specifically, let them know that cloZAPine treatment should be restarted at 12.5 mg once or twice daily when there has been a break in therapy for 2 days or longer. When collecting information about the patient's medications, inquire about and document 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 for cloZAPine. Also, the pharmacy may be required to gather this information for all new orders for cloZAPine. The hospital is also considering an electronic inquiry regarding whether the order is new or if cloZAPine is being restarted, along with providing dosing information. FDA and product manufacturers should work together to incorporate into the boxed warning a recommendation to slowly re-initiate cloZAPine after a break in therapy for 2 days or longer.
Look-Alike Cartons: Potential for Wrong Specialty Product to be Dispensed
An error occurred when a pharmacy dispensed three ACTEMRAACTPEN (tocilizumab) prefilled pen devices and one ACTEMRA prefilled syringe. Actemra is an interleukin-6 (IL-6) receptor antagonist used to treat rheumatoid arthritis and other inflammatory conditions. Although there are similarities between these products, the administration instructions differ for the pen and syringe, so there is a risk the patient will not know how to administer the medication if they receive the incorrect device. In this case the patient noticed the error, called the pharmacist, and received education about using the prefilled syringe. Similarities between the products likely contributed to this error.
There are two other specialty drug products packaged in cartons that look similar and could also contribute to errors. SIMPONI (golimumab) is a tumor necrosis factor blocker used to treat moderate-to-severe rheumatoid arthritis and active psoriatic arthritis alone, or in combination with methotrexate; active ankylosing spondylitis; and moderate-to-severe ulcerative colitis with an inadequate response or intolerance to prior treatment or requiring continuous steroid therapy. It is available in 50 mg/0.5 mL and 100 mg/mL prefilled syringes and prefilled autoinjectors. The cartons in which they are packaged look very similar (Figure 1). However, the syringes and autoinjectors have different directions for use, so a mix-up between the two could lead to patient self-administration errors.
The other product with similar-looking cartons is SKYRIZI (risankizumab-rzaa). Skyrizi is an interleukin-23 (IL-23) antagonist indicated for the treatment of moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy as well as active psoriatic arthritis in adults. Like Actemra, the cartons for the Skyrizi prefilled syringes and prefilled pen device look nearly identical (Figure 2) with similar blue waves at the bottom of the panel and the concentration highlighted in black. If a patient received the wrong device, they may not be educated on how to properly use the device, they could have a device misfire and waste the medication, or they may use the device incorrectly and not receive their full dose.