The New COVID-19 Pill, Paxlovid, Interacts with Many Medications: Cardiac Patients Take Note

After looking closely at the drug-drug interactions listed for the new oral COVID-19 drug, Paxlovid, I realized that a large percentage of my patients are taking medications on the list.

Patients with hypertension, coronary artery disease, atrial fibrillation, and hyperlipidemia should pay close attention to what follows if they are considering starting the drug as they likely will need to stop or modify their cardiac medications and monitor their blood pressure and heart rates closely while taking it.

Paxlovid contains ritonavir-boosted nirmatrelvir.

Ritonavir has long been used to increase the levels of anti-HIV medications by strongly inhibiting the cytochrome P450 (CYP) 3A system which metabolizes many cardiac (and non-cardiac) drugs including nirmatrelvir, the active anti-SARS-CoV2 antiviral.

The EUA for Paxlovid makes it clear how important it is for patients and physicians to be aware of these powerful drug interactions:

 Clinicians who are not experienced in prescribing ritonavir-boosted drugs should refer to resources such as the EUA fact sheet for ritonavir-boosted nirmatrelvir (Paxlovid) and the Liverpool COVID-19 Drug Interactions website for additional guidance. Consultation with an expert (e.g., clinical pharmacist, HIV specialist, and/or the patient’s specialist provider[s], if applicable) should also be considered.

Cardiac Rhythm Drug Interactions with Paxlovid

Patients who are cardiac taking rhythm controlling medications (antiarrhythmics) are highly likely to experience significant drug-drug interactions if they take Paxlovid and should consult with their cardiologist about the best approach.

These charts, taken from the FDA’s Health Information For Providers document on Paxlovid show the class of drug in the left column followed by the name, the predicted change in the cardiac medication, and recommendations.

The drugs listed are highly dependent on CYP3A for clearance and elevated concentrations are associated with serious and/or life-threatening reactions

Ritonavir coadministration is contraindicated with dronedarone, encainide, flecainide, propafenone, and quinidine.

The first four are used for the maintenance of sinus rhythm in patients with atrial fibrillation. If a patient is on one of these the choices would be: 1) stop them if the increased risk of the development of atrial fibrillation is acceptable or 2) use an alternative to Paxlovid.

I don’t use quinidine and haven’t seen a patient on it for 15 years.

Amiodarone has unique pharmacokinetics and even if stopped for several days would still be in the cardiac tissue and have effects for weeks to months. Whether any patient on amiodarone could safely take Paxlovid is debatable. Input from cardiology, pharmacy, and infectious disease would be warranted before giving Paxlovid to a patient on amiodarone.

Many of my afib patients take flecainide for the maintenance of sinus rhythm. Some of them will definitely go into fibrillation if they miss one or two dosages so we will have to carefully weigh options and individualize the approach for each patient should they reach criteria for taking Paxlovid. Flecainide can be started and stopped safely as an outpatient and often restarting it converts patients safely back to normal rhythm.

The NIH COVID-19 Treatment Panel’s statement on Paxlovid (but not the Fact Sheet For Providers) lists other antiarrhythmics including disopyramide (sometimes used for atrial fibrillation in patients with hypertrophic cardiomyopathy), dofedilide (Tikosyn, occasionally used for atrial fibrillation) and mexilitene (occasionally used for refractory ventricular tachycardia.) as drugs for which physicians should “prescribe an alternative COVID-19 therapy.”

Statin Drug Interactions

Levels of the widely prescribed lipid-lowering agents, statins, are influenced by ritonavir.

Fortunately, there is no short-term risk to stopping these drugs so my advice to patients will be to stop the 4 statins listed below as soon as COVID-19 is diagnosed and resume them 7 days after stopping the Paxlovid.

Calcium Channel Blockers

These drugs are predominantly utilized for hypertension, thus if levels increase blood pressure can drop too low. We sometimes utilize diltiazem also for atrial fibrillation or premature beats and higher levels of diltiazem could result in both lower blood pressure and heart rate.

If Paxlovid is started in a patient on a CCB, the most reasonable approach (supervised by a physician) would be to cut the dose in half and have the patient monitor the BP at home during the 5 days of Paxlovid and for 3-5 days after.

Blood Thinners

Most patients with atrial fibrillation are taking either warfarin or one of the newer oral anticoagulants (NOACs). Those on warfarin have to be wary of any new medication and should have their INR checked to monitor levels.

Of the multiple NOACs, rivaroxaban (Xarelto) is the only one that should be stopped according to the FDA.

Apixaban (Eliquis) is the blood thinner I most often use in my patients with atrial fibrillation. While it is not mentioned by the FDA document the manufacturer has recommended when co-administering with another preparation containing ritonavir a dose reduction to 2.5 mg twice a day. If the patient is already on a 2.5 mg dose, concurrent use should be avoided.

Other Considerations

Much of what was reviewed in a detailed article from June of 2021 entitled “Lopinavir-Ritonavir in SARS-CoV-2 Infection and Drug-Drug Interactions with Cardioactive Medications” is relevant to Paxlovid and cardioactive medications

The drug interactions with ritonavir range from insignificant to mild to strong. There are some differences from the NIH recommendations in the chart below.

Note that caution is recommended if a patient is on the antiplatelet drug clopidogrel (Plavix) and Ticagrelor is contraindicated. These drugs (plus aspirin) are essential in the early months after placement of a drug-eluting coronary stent. Consultation with a cardiologist is mandatory before stopping them.

Some beta-blockers, commonly used for a variety of indications by cardiologists are on the caution/monitor category as are two angiotensin receptor blockers, widely used for hypertension.

Based on this information, I think it makes sense to monitor heart rate and blood pressure twice daily on any cardiac patient taking Paxlovid and adjust medications accordingly.

Ranolazine, an antianginal drug I almost never prescribe but frequently stop is contraindicated with Paxlovid. Similarly, ivabradine, a drug I’ve never prescribed is contraindicated.

We still have some patients with permanent atrial fibrillation on digoxin and I would advise halving the dosage for 10 days and monitoring heart rate for them if Paxlovid started.

These substantial and highly significant drug interactions mean that cardiac patients and their physicians must review medications carefully before beginning a course of Paxlovid.

Interactionably Yours,

-ACP