There are two major considerations when Paxlovid is given to patients taking some antiseizure medications (ASMs), consistent with previously documented interactions of ASMs and antiretroviral drugs, including ritonavir. ³ The first major consideration is the effect of some ASMs on Paxlovid. The ASMs carbamazepine, phenobarbital, phenytoin, and primidone (although primidone is not listed in the EUA) are contraindicated, because they are strong inducers of the CYP3A4 isozymes that metabolize Paxlovid. ⁴ Due to the strong enzymatic induction caused by these medications, there is concern for possible loss of virologic response to Paxlovid and development of resistance.

Paxlovid needs to be started soon after diagnosis of COVID-19. Clinically, if patients were to stop taking these strong enzyme-inducing ASMs, the time-dependent process of de-induction of CYP3A4 isozymes would take more time than is likely feasible, so other treatments for COVID-19, including molnupiravir or IV therapies like remdesivir, ⁵ may be appropriate. The EUA for molnupiravir, ⁶ another COVID-19 oral therapy for patients ≥18 years old, states that the drug is not a substrate of CYP enzymes or major drug transporters, and in vitro studies do not suggest inhibitory actions.

Paxlovid should be used with caution with ASMs that are weak to moderate inducers of CYP3A4. ASMs in this category that may affect Paxlovid effectiveness include the following: cenobamate, eslicarbazepine, oxcarbazepine, rufinamide, and topiramate. See Table 1 for a full list of ASMs that are CYP3A4 inducers.

Enzyme	Substrates	Enzyme Inhibitors	Enzyme Inducers
CYP3A4	cannabidiol, carbamazepine, clobazam, clonazepam, diazepam, ethosuximide, everolimus, felbamate, lacosamide, midazolam, oxcarbazepine, perampanel, stiripentol, tiagabine, zonisamide		carbamazepine, eslicarbazepine, felbamate, oxcarbazepine, perampanel, phenobarbital, phenytoin, primidone, rufinamide, stiripentol, topiramate
CYP2C19	brivaracetam, cannabidiol, clobazam, diazepam, lacosamide, phenobarbital, phenytoin, primidone, stiripentol, valproate, zonisamide	cannabidiol, eslicarbazepine, felbamate, topiramate, valproate	carbamazepine, phenobarbital, phenytoin, primidone, stiripentol
CYP2C9	carbamazepine, lacosamide, phenobarbital, primidone, valproate	perampanel, stiripentol, valproate	carbamazepine, phenobarbital, primidone
CYP2B6	clobazam, perampanel, valproate		carbamazepine, perampanel
CYP1A2	stiripentol	cannabidiol, stiripentol
UGT	cannabidiol, diazepam, lamotrigine, oxcarbazepine	valproate	lamotrigine, phenobarbital, primidone

The second major consideration is the effect of Paxlovid on the plasma levels of several drugs. ASMs that are primarily metabolized by CYP3A4 are listed in the top left cell of Table 1. Patients receiving these ASMs may warrant closer monitoring while being treated with Paxlovid. Because ritonavir is a potent, mechanism-based inhibitor (irreversible) of CYP3A4, Paxlovid may increase plasma concentrations of these drugs. Co-administration of Paxlovid with drugs that are extensively metabolized by CYP3A4 and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Of note, because of its mechanism, ritonavir de-inhibition will be slower in offset, and inhibition of metabolism by CYP3A4 may persist for at least several days following Paxlovid discontinuation. Although perampanel is a major substrate for CYP3A4, short-term addition of CYP3A4 inhibitors is unlikely to have lasting impact on perampanel concentrations due to its very long half-life.

Paxlovid (specifically ritonavir) can also inhibit P-Glycoprotein (PGP), a drug transport protein, which may impact bioavailability of some ASMs.^7,8 Patients receiving these medications may warrant closer monitoring while being treated with Paxlovid. In particular, use of Paxlovid with everolimus (which is a substrate of both 3A4 and PGP) may increase the risk of toxic adverse effects and may require a reduction in the dose of everolimus.

Ritonavir is a weak inducer of CYP1A2, CYP2C19, and CYP2C9, a moderate inducer of CYP2B6, and an inducer of UGT1A4. Notably, ritonavir combinations can significantly reduce lamotrigine plasma concentrations, presumably via induction of glucuronidation; however, data for Paxlovid are not yet available, and the clinical relevance during the short duration of Paxlovid treatment is unclear. Monitoring of lamotrigine plasma concentrations may be warranted in patients receiving Paxlovid therapy. Formulations that contain ritonavir may reduce plasma concentrations of other ASMs that are substrates of these isoenzymes, as specified in Table 1.

Additional important information for AES members about Paxlovid and ASMs is highlighted in Table 1, with the caveat that specific pharmacokinetic/pharmacodynamic (PK/PD) data and clinical outcome data are not yet available on Paxlovid for people with epilepsy.

A more complete summary of other ASM pharmacokinetics and drug interactions may be found in the AES 2020 update of A Summary of Antiseizure Medications Available in the United States. ⁹