Recommendations for Managing Patients on Pimozide, Lurasidone, or Clozapine During Treatment with a 5-Day Course of Paxlovid

Context: The FDA has issued a EUA for emergency use of unapproved Paxlovid for treatment of mild moderate COVID-19 infection. Per the Paxlovid package insert, coadministration with pimozide, lurasidone or clozapine is contraindicated.

 There are two issues to consider:

1. The impact of Paxlovid on drug metabolism (CYP 3A4 inhibition).
2. The impact of COVID-19 mild-moderate infection on CYP 1A2 activity and clozapine metabolism.

Issue 1: Paxlovid  is composed of two antiviral medications – nirmatrelvir and ritonavir. In terms of drug-drug interactions only ritonavir is of interest. Ritonavir is a strong CYP 3A4 inhibitor and has been used for over two decades to inhibit the metabolism of other antiviral agents in the context of HIV care.

• Lurasidone is metabolized by CYP 3A4. When lurasidone is administered with a strong CYP 3A4 inhibitor, the maximal plasma concentration is increased by 6.8-fold and the total drug exposure is increased by 3-fold [Chiu et al 2014]. This is a large increase in total drug exposure and places the patient at risk for side effects such as drug-induced parkinsonism and akathisia. Those on lurasidone will need to have their antipsychotic held for the 5-day course of Paxlovid treatment using the recommendations at the end of this document.
• Pimozide is mainly metabolized by CYP 3A4 and to a lesser extent by CYP 1A2. Pimozide confers a higher risk than most antipsychotics of QTc prolongation [Wenzel-Seifert et al 2011]. Drugs that inhibit pimozide’s metabolism will increase the risk of QT prolongation.
• Clozapine is primarily metabolized by CYP 1A2 and to a lesser extent by CYP 3A4 and CYP 2D6. Per the clozapine package insert, the recommendation is to reduce the clozapine dose by 1/3 during treatment with a strong CYP 1A2 inhibitor, but the package insert does not provide specific guidance when using 2D6 or 3A4 inhibitors (“Use caution and monitor patients closely when using such inhibitors.”) While ritonavir strongly inhibits CYP 3A4, it is an inducer of CYP 1A2, and increases its activity 2.9-fold [Kirby et al 2011]. Overall, it may be unnecessary to reduce the clozapine dose unless the patient is exhibiting signs of clozapine toxicity (e.g., sedation, myoclonus, new/worsening sialorrhea, ataxia, etc.) The clozapine package insert guidance appears appropriate in this context: use caution and monitor patients closely. Again, this is only a 5 day course of treatment so any effects may not be seen (if they occur at all) until the end of the antiviral treatment.  (See below for complete recommendations.)

Issue 2: The impact of COVID-19 mild-moderate infection on antipsychotic plasma levels.

COVID-19 infection can impact hepatic enzymes (CYP P450 isoforms) involved in drug metabolism, primarily CYP 1A2. During acute infections, inflammatory cytokines such as IL-6 are produced and downregulate CYP 1A2 production. Clozapine is the antipsychotic most affected by COVID-19 infection since it is so heavily dependent on 1A2 metabolism. The net result is elevation of the clozapine plasma level 3-4 fold during acute severe infections such as COVID [Meyer and Stahl 2019].  Olanzapine has dual pathways through 1A2 and a phase 2 enzyme, and the impact on its clearance is not as significant when 1A2 is inhibited or downregulated [Meyer and Stahl 2021].

Significant elevation of clozapine plasma levels have also been observed in patients who are asymptomatic or have only mild signs/symptoms of COVID-19 infection. While impairment of hepatic metabolism and elevation of medication plasma concentrations generally correlates with severity of infections, this is only a correlation. There may be atypical cases of elevated plasma levels that do not correlate with COVID-19 symptom presentation. Hence, significant elevation of clozapine levels could occur in patients who have mild signs/symptoms of COVID-19 infection or are seemingly asymptomatic.

In general, our recommendation for patients who have had a positive COVID test but have minimal or mild symptoms is to monitor the patient over the next 1-2 weeks signs for clozapine toxicity.

If any signs of toxicity are present:

1. Recheck the plasma clozapine level
2. Lower the daily clozapine dose by 25% to 50% while awaiting the level result
3. Recheck the plasma clozapine level 5 days after the dose decrease
4. When the infection has abated, titrate clozapine to the former dose [Siskind et al. 2020]

Recommendations when patients on pimozide, lurasidone, or clozapine develop mild-moderate COVID-19 infection and are treated with Paxlovid:

1. Lurasidone and pimozide treated patients: Twelve to 24 hours prior to starting Paxlovid, stop lurasidone or pimozide. On Day 4 of Paxlovid treatment, restart lurasidone or pimozide at ½ the previous dose and titrate to the previous dose over the next week.
2. Clozapine treated patients: Clozapine patients should already be monitored after a positive COVID-19 test for of any signs of clozapine toxicity. Since the net effect of Paxlovid may not alter clozapine metabolism greatly we would recommend continuing the dose of clozapine as is and monitoring for signs of clozapine toxicity. Clinicians should avoid abrupt discontinuation of clozapine due to the risk of cholinergic rebound and rebound psychosis.

If any signs of toxicity are present:

1. Recheck the plasma clozapine level
2. Lower the daily clozapine dose by 25% to 50%
3. On the day after completing treatment with Paxlovid, and provided that there are no signs toxicity, titrate the clozapine to the previous dose if dose reduction was necessary.

These recommendations are provided courtesy of Joan Striebel, MD, Psychopharmacology Consultant for California Department of State Hospitals and Assistant Clinical Professor at the David Geffen School of Medicine at UCLA Department of Psychiatry. 

REFERENCES

• Chiu YY, Ereshefsky L, Preskorn SH, Poola N, Loebel A. Lurasidone drug-drug interaction studies: a comprehensive review. Drug Metabol Drug Interact. 2014;29(3):191-202.
• Dresser GK, Spence JD, Bailey DG. Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin Pharmacokinet. 2000;38(1):41-57.
• Kirby BJ, Collier AC, Kharasch ED, et al. Complex drug interactions of HIV protease inhibitors 2: in vivo induction and in vitro to in vivo correlation of induction of cytochrome P450 1A2, 2B6, and 2C9 by ritonavir or nelfinavir.
• Meyer JM, Stahl SM.  The Clozapine Handbook. New York, NY, Cambridge University Press, 2019.
• Meyer JM, Stahl SM.  The Clinical Use of Antipsychotic Plasma Levels.  New York, NY, Cambridge University Press. 2021.
• Siskind D, Honer WG, Clark S, et al. Consensus statement on the use of clozapine during the COVID-19 pandemic. J Psychiatry Neurosci. 2020;45(3):222-223.
• Wenzel-Seifert K, Wittmann M, Haen E. QTc prolongation by psychotropic drugs and the risk of Torsade de Pointes. Dtsch Arztebl Int. 2011;108(41):687-693.