Table 1.

Drug-Drug Interactions With Nirmatrelvir-Ritonavir and Commonly Used Cardiovascular Medications

Druga	NMVr Effect on Drug Level	Effect of Interaction	Recommendation
Antiplatelet agents
Aspirin	None	None	Safe to co-administer with NMVr.
Clopidogrel	Decrease	Increased risk of thrombosis	Recent PCI or history of high-risk PCI: Avoid NMVr or switch to prasugrel with a loading dose while on NMVr. Other patients: Safe to co-administer with NMVr.
Prasugrel	Decrease but with no clinical effect	None	Safe to co-administer with NMVr.
Ticagrelor	Increase	Increased risk of bleeding	Avoid NMVr or switch to prasugrel with a loading dose while on NMVr.
Anticoagulation (AC)
Apixabanc	Increase	Increased risk of bleeding	Cannot be safely adjusted/interrupted if patient is on dialysis: Avoid NMVr. Consider alternative therapies.b For AF: If on 5 mg apixaban twice daily: Start NMVr and decrease dose to 2.5 mg twice daily for a total of 8 days and then resume apixaban at the previous dose. If on 2.5 mg apixaban twice daily: Avoid NMVr or withhold apixaban for 12-24 hours before starting NMVr along with an alternative AC (eg, enoxaparin) for a total of 8 days and then resume apixaban at the previous dose. For VTE: If on 10 mg apixaban twice daily: Start NMVr and decrease apixaban to 5 mg twice daily for a total of 8 days and then resume apixaban at the previous dose. If on 5 mg apixaban twice daily: Start NMVr and decrease apixaban to 2.5 mg twice daily for a total of 8 days and then resume apixaban at the previous dose. If on 2.5 mg apixaban twice daily for VTE prophylaxis: Can continue the same dose while on NMVr (will likely achieve therapeutic levels).
Rivaroxabanc	Increase	Increased risk of bleeding	Cannot be safely adjusted/interrupted: Avoid NMVr. Consider alternative therapies.b Other patients: Withhold rivaroxaban for 24-36 hours before starting NMVr. Use an alternative AC (eg, enoxaparin) for a total of 8 days and then resume rivaroxaban.
Edoxabanc	Increase	Increased risk of bleeding	Cannot be safely adjusted or interrupted: Avoid NMVr. Consider alternative therapies.b If on 60 mg edoxaban daily: Decrease dose by 50% for a total of 8 days from the start of NMVr and then resume edoxaban at the previous dose. If on 30 mg edoxaban daily: Withhold edoxaban when starting NMVr. Use an alternative AC (eg, enoxaparin) for 8 days and then resume edoxaban.
Dabigatranc	Increase	Increased risk of bleeding	Cannot be safely adjusted/interrupted: Avoid NMVr. Consider alternative therapies.b For AF: CrCl >50 mL/min: Decrease dose to 110 mg twice daily for 8 days from the start of NMVr and then resume dabigatran at the previous dose (this dosage is not available in the United States). CrCl 30-50 mL/min: Decrease dose to 75 mg twice daily for 8 days from the start of NMVr and then resume dabigatran at the previous dose. CrCl <30 mL/min: Avoid co-administration of NMVr with dabigatran; consider switching to an alternative AC. For VTE: If on 150 mg dabigatran twice daily: Co-administration with NMVr is not recommended. Withhold dabigatran for 12-24 hours and then start NMVr with an alternative AC (eg, enoxaparin) for a total of 8 days, and then resume dabigatran at the previous dose.
Warfarin	Increase or decrease (most likely decrease)	Variable effect on thrombotic and bleeding risk	May co-administer NMVr with close INR monitoring.
Enoxaparin	None	None	Safe to co-administer with NMVr.
Lipid management
Atorvastatin	Increase	Increased myopathy, liver toxicity	Withhold atorvastatin while on NMVr. Can be resumed 3 days after last dose of NMVr. A lower dose of 10 mg daily is acceptable to continue with NMVr.
Rosuvastatin	Increase	Increased myopathy, liver toxicity	Withhold rosuvastatin while on NMVr. Can be resumed the day after last dose of NMVr. If co-administered with NMVr, a maximum daily dose of 10 mg rosuvastatin is acceptable.
Simvastatin	Increase	Increased myopathy, liver toxicity	Withhold simvastatin 12 hours before the first dose of NMVr. Can resume 5 days after the last dose of NMVr.
Lovastatin	Increase	Increased myopathy, liver toxicity	Withhold lovastatin 12 hours before the first dose of NMVr. Can resume 5 days after the last dose of NMVr.
Pravastatin	None	None	Safe to co-administer with NMVr.
Fluvastatin	None	None	Safe to co-administer with NMVr.
Pitavastatin	None	None	Safe to co-administer with NMVr.
Ezetimibe	Decrease	Decreased efficacy	Safe to co-administer with NMVr.
Fibrates	None	None	Safe to co-administer with NMVr.
Evolocumab	None	None	Safe to co-administer with NMVr.
Alirocumab	None	None	Safe to co-administer with NMVr.
Antianginal drugs
Metoprolol, propranolol, carvedilol, atenolol, esmolol	None	None	Safe to co-administer with NMVr.
Labetolol	Decrease	Reduce antihypertensive effect	Can co-administer NMVr with home blood pressure monitoring.
Nitrates	Decrease	Decreased effect	Safe to co-administer with NMVr.
Ranolazine	Increase	QT prolongation, torsades de pointes	Avoid co-administration of NMVr or temporarily withhold ranolazine while on NMVr.
Heart failure therapy
Lisinopril, enalapril, quinapril, captopril	None	None	Safe to co-administer with NMVr.
Irbesartan	Decrease	Reduced antihypertensive effect	Safe to co-administer with NMVr; interaction is mild. Blood pressure monitoring may be helpful.
Losartan	Increase	Hypotension	Safe to co-administer with NMVr; interaction is mild. Blood pressure monitoring may be helpful.
Valsartan	Increase	Hypotension	Can co-administer with NMVr with blood pressure monitoring. Stop valsartan if hypotension ensues.
Sacubitril/valsartan	Increase	Hypotension	Can co-administer with NMVr with blood pressure monitoring. Stop sacubitril/valsartan if hypotension ensues.
Candesartan	None	None	Safe to co-administer with NMVr.
Telmisartan	None	None	Safe to co-administer with NMVr.
Olmesartan	None	None	Safe to co-administer with NMVr.
Spironolactone	None	None	Safe to co-administer with NMVr.
Eplerenone	Increase	Hyperkalemia	Avoid co-administration and temporarily withhold eplerenone while on NMVr.
Canagliflozin	Decrease	Decreased glycemic control	Safe to co-administer with NMVr, because NMVr is prescribed for a short duration.
Empagliflozin	None	None	Safe to co-administer with NMVr.
Dapagliflozin	None	None	Safe to co-administer with NMVr.
Ivabradine	Increase	Bradycardia	Avoid co-administration or temporarily withhold ivabradine while on NMVr.
Digoxin	Increase	Toxic levels	Based on the patient’s renal function, dose reduction can be advised; however, extreme caution should be exercised with appropriate monitoring of digoxin levels. Alternatively, digoxin can be temporarily withheld while on NMVr.
Furosemide	None	None	Safe to co-administer with NMVr.
Torsemide	Mildly decrease	None	Weak interaction, so safe to co-administer with NMVr.
Hydrochlorothiazide, metolazone, chlorthalidone	None	None	Safe to co-administer with NMVr.
Other antihypertensive agents
Amlodipine	Increase	Hypotension, flushing, and edema	A 50% reduction in the dose of amlodipine is recommended for 8 days when starting NMVr.
Nifedipine, felodipine	Increase	Hypotension, flushing, and edema	Close blood pressure monitoring and/or dose reduction if co-administered with NMVr. Temporarily discontinue if needed. Can be restarted 3 days after the last dose of NMVr.
Diltiazem, verapamil	Increase	Bradycardia, dizziness, hypotension, edema	Close blood pressure monitoring and/or dose reduction if co-administered with NMVr. Temporarily discontinue if needed. Can be restarted 3 days after the last dose of NMVr.
Doxazosin/Terazosin	Increase	Hypotension	Close blood pressure monitoring or temporary discontinuation while on NMVr.
Antiarrhythmic drugs
Amiodarone, dofetilide, flecainide, dronedarone, propafenone, quinidine	Increase	Life-threatening arrhythmias	Co-administration of NMVr is contraindicated. Consider alternative COVID-19 therapiesb or consider withholding antiarrhythmic therapy temporarily if feasible. Amiodarone has prolonged half-life of ∼100 days which precludes the option of temporarily stopping the drug and initiating NMVr.
Sotalol	None	None	Safe to co-administer with NMVr.
Pulmonary hypertension therapy
Ambrisentan	None	None	Safe to co-administer with NMVr.
Bosentan	Increase	Headaches, nausea, and vomiting, liver toxicity	Co-administration with NMVr is contraindicated. Discontinue for at least 36 hours before initiation of NMVr.
Macitentan	Increase	Headaches, nausea, and vomiting, liver toxicity	Co-administration with NMVr is not advised. Discontinue for at least 36 hours before initiation of NMVr.
Sildenafil	Increase	Hypotension, persistent erection, visual disturbances	Do not co-administer NMVr.
Tadalafil	Increase	Hypotension, persistent erection, visual disturbances	Do not co-administer NMVr.
Prostacyclin analogs
Selexipag	None	None	Safe to co-administer with NMVr.
Riociguat	Increase	None	Reduce dose of riociguat to 0.5 mg 3 times a day while co-administering NMVr along with close monitoring for side-effects.
Antiinflammatory drugs
Colchicine	Increase	Toxic levels	Avoid co-administration of NMVr or temporarily withhold colchicine while on NMVr.
Dexamethasone	Increase	Cushing’s syndrome, adrenal suppression	Reduce dose to 50% while taking NMVr and resume full dose 3 days after completion of NMVr. Consider switching to prednisolone or beclomethasone.
Methylprednisone	Increase	Cushing’s syndrome, adrenal suppression	Continue with caution and monitor for side-effects. Consider switching to prednisolone or beclomethasone.
Prednisone	Increase	Cushing’s syndrome, adrenal suppression	Continue with caution and monitor for side-effects. Consider switching to prednisolone or beclomethasone.
Prednisolone	None	No clinically significant effects with short duration of NMVr	Safe to co-administer with NMVr.
Immunosuppressive therapy in heart transplant patients
Cyclosporine	Increase	Toxic levels	NMVr is not recommended in these patients.d
Tacrolimus	Increase	Toxic levels	NMVr is not recommended in these patients.d
Sirolimus	Increase	Toxic levels	NMVr is not recommended in these patients.d

AF = atrial fibrillation; CrCl = creatinine clearance; INR = international normalized ratio; NMVr = nirmatrelvir-ritonavir; PCI = percutaneous coronary intervention; VTE = venous thromboembolism.

^aOnly commonly used drugs are listed here, and it is by no means an exhaustive list of all CV drugs.

^bMonoclonal antibodies against SARS-CoV-2, molnupiravir, remdesivir can be considered based on the clinical scenario after screening for DDIs.

^cWhen considering interrupting oral anticoagulation without substitution, it should be kept in mind that this should be reserved only for those at very low risk for thromboembolism. Low thromboembolic risk: CHA₂DS₂-VASc <3 and/or no history of stroke, VTE more than 1 year earlier, no history of recurrent clots, and no history of severe thrombophilia. Caution must be exercised because active COVID-19 infection, may in itself increase the risk of thromboembolism.

^dSignificant dose reduction is required if co-administered with NMVr. Repeated checks of drug levels of the immunosuppressive agents are required during the 5-day course of NMVr. This is logistically difficult in the setting of active COVID-19 infection and therefore alternative therapies for COVID-19 should be considered.