FDA and Health Canada recently approved Paxlovid as an oral treatment option for mild-to-moderate COVID-19 who are at high risk of progression to severe COVID-19. It is a combination drug containing nirmatrelvir/ritonavir. Nirmatrelvir works by binding to SARS-CoV-2 3CL protease to ultimately stop viral replication. Ritonavir does not have any antiviral activity against COVID-19 but increases concentrations of nirmatrelvir by decreasing its metabolism by CYP3A4 enzyme. Ritonavir is a potent inhibitor of CYP3A4 and various drug transporters such as P-glycoprotein. CYP3A4 and P-glycoprotein are involved in the metabolism and elimination of many commonly prescribed drugs. Thus it is very important to review a patient’s current medication regimen to check for clinically significant interactions.

Potential medication interaction management options may include depending on the medication:

• Holding the interacting medication and resuming two days after completing the Paxlovid course
• Using an alternative medication that does not interact or adjusting the dose of the interacting medication while on Paxlovid
• Use an alternative COVID-19 agent.

I will discuss Paxlovid interactions with some commonly prescribed medications and potential management options. It is not an exhaustive list, and a pharmacist consultation with the patient may be helpful before prescribing Paxlovid for a comprehensive review of interactions.

CYP3A-4 inducing medications 

Paxlovid is contraindicated in patients taking any CYP3A4 inducing agent as these medications significantly decrease the concentration of Paxlovid and thus decrease its effectiveness. Holding the interacting medicines is not an option as the enzyme induction effect does not immediately dissipate when a medication is stopped. Alternative COVID treatment should be considered in patients that have taken an enzyme inducer within the past 14 days. Common drugs include anticonvulsants (carbamazepine, eslicarbazepine, oxcarbazepine, phenobarbital, phenytoin, primidone), antimycobacterials (rifampin), and St. John’s Wort.

Medications dependent on CYP3A4 metabolism 

The onset of CYP3A4 inhibition by ritonavir is rapid and significant. It can lead to high serum concentrations of some medications which can lead to serious adverse events. For drugs with a prolonged half-life, stopping the medication will not help reduce the interaction risk as the medication is slowly eliminated from the body, and an alternative COVID-19 treatment should be used. Common drugs include antiarrhythmics (amiodarone, dronedarone, flecainide, propafenone, quinidine), antipsychotics (lurasidone, clozapine), and fentanyl.

Some medications may either be held, dose-adjusted, or changed to alternative therapy temporarily while on Paxlovid.

Anticoagulants (apixaban, edoxaban, rivaroxaban): Use alternative COVID-19 agent if possible. Otherwise, if used for venous thromboembolism; the anticoagulant should be held and restarted two days after completing the Paxlovid course and the patient should be bridged with a low molecular weight heparin. For atrial fibrillation, apixaban and edoxaban may be dose adjusted or an alternative COVID-19 treatment should be considered. There is no dose adjustment recommended for rivaroxaban; an alternative should be considered. If clinically appropriate, patients on warfarin should be monitored for signs of increased bleeding/bruising and INR.

Alfuzosin: Alfuzosin levels may be increased significantly; hold and restart two days after Paxlovid is completed.

Opioids (hydrocodone, oxycodone, tramadol): Opioid dose should be reduced temporarily and resume the usual dose two days after Paxlovid is completed.

Calcium channel blockers (amlodipine, diltiazem, felodipine, nifedipine, verapamil): Consider reducing the dose temporarily and resume the usual dose two days after Paxlovid is completed.

Atorvastatin/rosuvastatin: Hold and restart the usual dose two days after Paxlovid is completed. Dose reduction may be considered.

The list of interactions with Paxlovid is long. These are some of the commonly used medications that interact with Paxlovid and management strategies. Pharmacists can be a valuable resource for assessing and helping manage these interactions.

Param Patel is a pharmacist.

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