Vigilance and Monitoring for Clozapine Toxicity During COVID-19 Infection and Recommendations for Management

Context: Cases of clozapine toxicity have been reported coinciding with COVID-19 infections

There are three issues to consider:

1. The impact of COVID-19 infection on hepatic cytochromes (CYP 1A2, 3A, and 2C19) and consequently on clozapine metabolism and clozapine levels
2. The impact on clozapine levels if smoking cigarettes decreases or stops during COVID-19 infection
3. Co-prescription of Paxlovid^® for mild to moderate COVID-19 which is contraindicated in a clozapine-treated patient (Update: no longer contraindicated per the package insert but an abundance of caution is prudent if the medication is co-prescribed with clozapine)

Issue 1: The major pathway for clozapine metabolism is via the hepatic cytochrome CYP 1A2 isoenzyme, with minor pathways including CYP 3A and 2C19. Inhibition of these metabolic pathways can elevate clozapine levels, and in some individuals, result in signs and symptoms of clozapine toxicity.

• A recent study evaluated the impact of moderate to severe COVID-19 infection among patients on their hepatic cytochrome status. The Geneva phenotyping cocktail was used to probe the activity of the six main isoforms of hepatic cytochromes during the first 72 hours, and 3 months later (Lenoir et al, 2021). Please see a brief note on the Geneva phenotyping cocktail just prior to the “References” section. The metabolic ratios of CYP 1A2 decreased by 53%, 2C19 by 75%, and 3A by 23%, and a phenotypic switch from normal to poor metabolizer or from ultrarapid to normal metabolizer was observed in 71%, 46%, and 43% of subjects for CYP1A2, CYP2C19, and CYP3A, respectively, during COVID-19 (Lenoir et al, 2021). The decrease in CYP 1A2 and 2C19 activity was inversely correlated with pro-inflammatory markers, CRP and IL-6. None of the patients in the study received clozapine. Nevertheless, several cases of clozapine toxicity have been reported among clozapine treated patients who develop COVID-19 (e.g., Tio et al, 2021; Chengappa et al, 2022, Clinebell et al, 2023) suggesting that rapid elevation of clozapine levels in some patients might occur due to the phenoconversion of their metabolic status occasioned by inflammatory pathology affecting the cytochrome enzymes (de Leon et al, 2020, Lenoir et al, 2021).

Issue 2: Smoking cigarettes (even as few as 8 cigarettes per day) induces CYP 1A2 activity due to actions of aryl hydrocarbons in cigarette smoke acting on the aromatic hydrocarbon receptors. The net result is greater production of CYP 1A2 enzyme and significant lowering of clozapine blood levels. Therefore, changes in smoking status (tapering, stopping or resumption) can have a significant impact on the increase or decrease in clozapine blood levels, (Meyer and Stahl, 2020).

• During symptomatic COVID-19 infection, which itself might induce a rapid rise in clozapine levels, patients may refrain from smoking cigarettes, or the medical or nursing staff in ambulatory settings where patients reside may curtail smoking due to respiratory concerns, isolation/quarantine requirements, etc.  Therefore, smoking reduction/cessation could further elevate clozapine levels.

Issue 3: Co-prescription of Paxlovid^® (ritonavir-nirmatrelvir combination) for mild to moderate COVID-19 in clozapine treated patients.

• Ritonavir, in the nirmatrelvir-ritonavir combination (brand name: Paxlovid^®) is a strong inhibitor of CYP 3A4, and interestingly, ritonavir is an inducer of CYP 1A2. Paxlovid^® is contraindicated for concomitant use with lurasidone and pimozide, but no longer contraindicated for concomitant use with clozapine. Ritonavir can elevate clozapine levels. A more detailed explanation and recommendation on the use of Paxlovid^® and clozapine is available on SMI Adviser here. We recommend an abundance of caution in using Paxlovid^® concomitantly with clozapine.
• Remdesivir (brand name: Veklury^®) is indicated for mild to moderate COVID-19 and also in hospitalized patients as an IV infusion. It is an inhibitor of CYP 3A4, a minor metabolic pathway for clozapine. Remdesivir is unlikely to have drug interactions with clozapine.

Guidance and Recommendations with reference to the three issues described above:

• Remain clinically vigilant for potential clozapine toxicity during COVID-19 infection and outbreaks. Remember a second or third bout of COVID-19 could present with moderate to severe clinical features compared to a milder first episode, (Clinebell et al 2023).
• What might clozapine toxicity look like?
  • Clozapine toxicity may present as some combination of severe sedation, emergence or worsening hypersalivation, mental status changes including delirium, difficulty walking and/or talking. As clozapine level rise rapidly (often > 1000 ng/ml), pre-seizure activity such as myoclonic jerks or full-fledged seizures might occur.
• If a clozapine treated patient tests positive for COVID-19 but is asymptomatic, and there are no signs or symptoms of clozapine toxicity, monitor and be vigilant for signs of clozapine toxicity. In such instances, “watchful waiting” may be adequate. A clozapine/norclozapine level could be ordered if no recent levels are available. The frequency of communications with the patient, caregivers, healthcare and nursing staff with regards to changes in symptoms, mental state or vital signs should be increased for a week or two.
• If a patient develops mild to moderate to severe symptoms of COVID-19, it is possible that a moderate to severe inflammatory response could inhibit the hepatic cytochromes that metabolize clozapine and levels could rise rapidly. Monitor and act quickly if clozapine toxicity occurs.
  • Lower the dose of clozapine by 40% to 50% and order a clozapine level. Depending on the local facilities, remember clozapine levels may not be returned for 3 or more days, therefore do not wait to lower the clozapine dosage in the face of concern for clozapine toxicity.
  • In extreme situations, clozapine may need to be discontinued temporarily, but this should be avoided except in rare circumstances. Be reminded that abrupt stoppage of clozapine may be accompanied by rebound psychoses and/or cholinergic rebound. Patients who have clozapine stopped must be covered for cholinergic rebound based on their pre-infection dose. For nonsmokers, 50 mg clozapine = 1 mg benztropine; for smokers, 100 mg clozapine = 1 mg benztropine. There is no need to exceed 6 mg/d of benztropine as this dose should prevent cholinergic rebound even if prior exposure exceeded this equivalent.
  • If the patient is not hospitalized in an acute medical care facility for severe COVID-19 but is being cared for in a psychiatric hospital or adult residential care setting where there is nursing support, daily communication with nursing staff, patients, caregivers, or other health care providers is strongly recommended. Also recommended is the daily monitoring of vital signs and pulse oximetry, if available.  A similar recommendation regarding frequent communication and vital sign/pulse oximetry monitoring would apply to patients residing in supervised homes or living with caregivers or on their own, (Chengappa et al, 2022, Clinebell et al, 2023).
  • Hemodynamic instability, the need for respiratory support (e.g., rapidly dropping pulse oxygen reading to 90 percent or less, breathing difficulty), fever, and seizures typically result in a 9-1-1 call and transfer to an acute care medical facility.
  • If patients are transferred to urgent or emergency care facilities, doctor to doctor or nurse to nurse/doctor communication is vital to ensure that the information on the contraindication of the use of Paxlovid concomitantly with clozapine is communicated clearly on paper and/or verbally and/or electronically and documented in the medical record.
  • As COVID-19 resolves in patients with clozapine toxicity, ordering clozapine levels may help guide the titration back to the pre-COVID-19 daily dose of clozapine (Siskind et al, 2020), especially if positive psychotic symptoms worsen or reemerge. Remember under non-inflammatory conditions, clozapine levels are recommended to be checked after 5-7 days at a target daily dose (i.e., at steady state and trough level 12 ± 2 hours). However, in view of the inflammatory impact on the cytochrome system, it is possible that the time to steady state levels may be harder to predict, and it may take many weeks for hepatic cytochrome activity to return to baseline. Dosage increases will be dictated by psychiatric symptoms, adverse effects, and trough clozapine levels post-acute COVID-19.
  • A return to pre-COVID-19 lifestyles may include smoking cigarettes and high caffeine consumption both of which impact clozapine levels in opposite directions, decrease and increase, respectively.

Additional Considerations:

• Consult with COVID-19 resource centers/infectious disease specialists regarding use of alternatives to Paxlovid^® if treatment is indicated for clozapine-treated patients experiencing mild to moderate COVID-19 to prevent them from progressing to more serious COVID-19 disease. Approvals or Emergency Use Authorizations (EUA) by the US FDA include: Lagevrio^® (molnupiravir), this agent has not shown impact on CYP enzymes thus far. Veklury^® (remdesivir) for intravenous use, it is an inhibitor of CYP 3A4 but unlikely to impact clozapine levels. Bebtelovimab (monoclonal antibody) injection for intravenous use, no known interaction with CYP enzymes.  Additional emergency use or approvals of treatments for mild to moderate COVID-19 by the FDA remain ongoing. Therefore, it remains prudent for the clinician/pharmacy community to review potential drug-interactions that newly approved or EUA agents may have on clozapine treated patients.
• Consideration could be given to developing continuing education materials for healthcare providers, staff at clozapine clinics, as well as patient and care-giver handouts on the issues of clozapine toxicity during COVID-19 and the contraindication of concomitantly prescribing Paxlovid^® with clozapine. Example: Monitoring for Clozapine Toxicity with a Focus on COVID-19 Infection | UPMC (upmcphysicianresources.com)
•  The Geneva Phenotyping Cocktail: This is a laboratory method to measure the activity of six different isoforms of the P450 cytochrome (CYP) phenotypes in an individual person. The cocktail uses the metabolic ratios of the concentration of the metabolite divided by the concentration of the substrate used to probe the six CYPs. Based on this metabolic ratio, individual people are classified as “poor” or “normal” or “ultrarapid” metabolizers of CYP1A2, 2C19, 3A, 2B6 and 2C9, and in the case of CYP 2D6, “intermediate” metabolizers are also characterized. The probes to measure the activity of the different cytochromes in the Geneva cocktail include caffeine 50 mg, CYP1A2; bupropion 20 mg, CYP2B6; flurbiprofen 10 mg, CYP2C9; omeprazole 10 mg, CYP2C19; dextromethorphan 10 mg, CYP2D6; midazolam 1 mg, CYP3A; fexofenadine 25 mg, P-glycoprotein (Lenoir et al, 2021 and cross-references in that article)
• Be reminded other antipsychotic medications – such as olanzapine (and others) that are metabolized mainly by CYP1A2 could be impacted by COVID-19 infection and this could result in elevated blood levels of olanzapine, and in turn, clinical features indicating greater anticholinergic burden e.g., dry mouth, constipation, tachycardia, blurred vision, urinary retention, and delirium may be noted.  Likewise, haloperidol levels could rise due to CYP3A4 inhibition and result in Parkinsonian side effects (shuffling gait, tremors, stiffness, etc.) (Clinebell et al 2023). If clinically appropriate, actionable steps might include lowering the dosage of olanzapine, haloperidol, etc., till the effects of the COVID-19 infection resolve.

These recommendations are provided courtesy of Roy Chengappa, MD, Professor of Psychiatry at University of Pittsburgh, Jane Thomas, BSN, RN-BC, Nurse Manager, Kimberly Clinebell, MD, Clinical Assistant Professor of Psychiatry, Melanie Yabs, PharmD, MS, BCPP, Clinical Pharmacist; all authors are affiliated with Western Psychiatric Hospital-UPMC. 

REFERENCES

• Lenoir, C., Terrier, J., Gloor, Y., et al. 2021. Impact of SARS-CoV-2 Infection (COVID-19) on Cytochromes P450 Activity Assessed by the Geneva Cocktail. Clinical Pharmacology & Therapeutics. 110 (5), 1358-1367. doi:10.1002/cpt.2412.
• Siskind, D., Honer, W.G., Clark, S., et al. 2020. Consensus statement on the use of clozapine during the COVID-19 pandemic. J Psychiatry Neurosci. 45(3):222-223. doi: 10.1503/jpn.200061
• Tio, N., Schulte PFJ., Martens HJM. Clozapine Intoxication in COVID-19. 2021. Am J Psychiatry. 178:123-127.
• Chengappa KNR., Thomas J., Kahn CE., et al. 2022. COVID-19 infection, fluctuations in the clozapine/norclozapine levels and metabolic ratio and clozapine toxicity: An illustrative case-report. Schizophrenia Research. 244:66-68. https://doi.org/10.1016/j.schres.2022.05.009
• de Leon, J., Ruan CJ., Schoretsanitis, G., et al. A Rational Use of Clozapine Based on Adverse Drug Reactions, Pharmacokinetics, and Clinical Pharmacopsychology. Psychother Psychosom 2020; 89:200–214. DOI: 10.1159/000507638
• Meyer JM, Stahl SM. The Clozapine Handbook. New York, NY. Cambridge University Press, 2020.
• Clinebell K, Thomas J, Yabs M, Chengappa KNR. Longitudinal observations of the severity of COVID-19 infection and its impact on clozapine/norclozapine levels and clozapine toxicity in patients experiencing multiple episodes. Schizophrenia Research. 2023 13; 262:142-145. doi: 10.1016/j.schres.2023.11.002.