Drug-Drug Interactions Between Ritonavir-Boosted Nirmatrelvir (Paxlovid) and Concomitant Medications

Last Updated: May 13, 2022

Ritonavir, a strong cytochrome P450 (CYP) 3A4 inhibitor and a P-glycoprotein inhibitor, is coadministered with nirmatrelvir to increase the blood concentration of nirmatrelvir, thereby making it effective against SARS-CoV-2. Ritonavir may also increase blood concentrations of certain concomitant medications. Because ritonavir-boosted nirmatrelvir (Paxlovid) is the only highly effective oral antiviral for the treatment of COVID-19, drug interactions that can be safely managed should not preclude the use of this medication.

Clinicians should be aware that many commonly used medications can be safely coadministered with ritonavir-boosted nirmatrelvir despite its drug-drug interaction potential. Box 1 includes commonly prescribed medications that are not expected to have clinically relevant interactions with ritonavir-boosted nirmatrelvir.

Box 1. Commonly Prescribed Outpatient Medications Not Expected to Have Clinically Relevant Interactions With Ritonavir-Boosted Nirmatrelvir (Paxlovid)

Box 1. Commonly Prescribed Outpatient Medications Not Expected to Have Clinically Relevant Interactions With Ritonavir-Boosted Nirmatrelvir (Paxlovid)
Medications Without Clinically Relevant Interactions
These commonly prescribed medications may be coadministered without dose adjustment and without increased monitoring.^a This list is not inclusive of all noninteracting medications within each drug category.
Acid reducing agents Famotidine Omeprazole Pantoprazole Allergy medications Cetirizine Diphenhydramine Loratadine Anti-infective agents Azithromycin Hydroxychloroquine Cardiovascular agents Aspirin Atenolol Carvedilol Furosemide Hydrochlorothiazide Irbesartan Isosorbide Dinitrate Lisinopril Losartan Metoprolol Prasugrel	Diabetes medications Empagliflozin Insulin Metformin Pioglitazone Immunosuppressants Methotrexate Mycophenolate Prednisone Lipid-modifying agents Ezetimibe Pitavastatin Pravastatin Neuropsychiatric agents Amitriptyline Bupropion Citalopram Duloxetine Escitalopram Fluoxetine Gabapentin Lorazepam Nortriptyline Olanzapine Paroxetine Sertraline Venlafaxine	Pain medications Acetaminophen Aspirin Codeine Ibuprofen Naproxen Respiratory medications Corticosteroids (inhaled) Formoterol Montelukast Miscellaneous Allopurinol Contraceptives (oral)^b Donepezil Enoxaparin Finasteride Levothyroxine Ondansetron
^aThis list is primarily based on the most common medication searches by U.S. users on the Liverpool COVID-19 Drug Interactions website between January 1 and April 13, 2022 (internal communication, April 2022). The Liverpool website classifies these medications as those that have no interaction or weak interaction with ritonavir-boosted nirmatrelvir. ^b The Food and Drug Administration Emergency Use Authorization for ritonavir-boosted nirmatrelvir suggests that individuals who use contraceptive products containing ethinyl estradiol consider using a backup, nonhormonal contraceptive method because coadministration may result in low ethinyl estradiol levels. However, the low level is not expected to be clinically significant during 5 days of therapy. The progestin concentration of a combined hormonal contraceptive is expected to remain similar or increase with coadministration, which would maintain the effectiveness of the oral contraceptive.

Medications That Have Clinically Relevant Drug-Drug Interactions With Ritonavir-Boosted Nirmatrelvir

Clinicians should be aware that, in some cases, drug-drug interactions with ritonavir-boosted nirmatrelvir may lead to serious or life-threatening drug toxicities. The recommended treatment course of ritonavir-boosted nirmatrelvir for COVID-19 is 5 days. After the last dose is administered, most of the interaction potential resolves within 2 to 3 days, although resolution may take longer in elderly adults.¹

Ritonavir-boosted nirmatrelvir should not be given within 2 weeks of administering a strong CYP3A4 inducer (e.g., St. John’s wort, rifampin). Ritonavir-boosted nirmatrelvir is contraindicated in this setting, because strong CYP3A4 inducers may reduce the concentrations of nirmatrelvir and ritonavir, rendering the treatment ineffective against SARS-CoV-2. Alternative treatment for COVID-19 should be prescribed.

Identifying Drug-Drug Interactions

Before prescribing ritonavir-boosted nirmatrelvir, carefully review the patient’s concomitant medications, including over-the-counter medicines, herbal supplements, and recreational drugs.

Consult 1 or more of the following resources for information on identifying and managing drug-drug interactions:

Quick reference lists:
- Box 1 lists commonly prescribed outpatient medications that are not expected to have clinically relevant interactions with ritonavir-boosted nirmatrelvir.
- Box 2 lists medications that have clinically relevant drug-drug interactions with ritonavir-boosted nirmatrelvir.
Web-based drug-drug interaction checker:
- The Liverpool COVID-19 Drug Interactions website
Tables with guidance on managing specific drug-drug interactions:
- The Ontario COVID-19 Science Advisory Table
- The Food and Drug Administration Emergency Use Authorization fact sheet and checklist for ritonavir-boosted nirmatrelvir

Consider expert consultation (e.g., with a pharmacist, an HIV specialist, or the patient’s specialist providers), especially for patients receiving highly specialized therapies or drugs prone to concentration-dependent toxicities, such as certain anticonvulsant, anticoagulant, antiarrhythmic, chemotherapeutic, neuropsychiatric, and immunosuppressant drugs.

Management Strategies for Drug-Drug Interactions

Consider the magnitude and significance of the potential interaction when choosing management strategies for patients who are to receive ritonavir-boosted nirmatrelvir. Potential strategies include:

Temporarily withholding the concomitant medication,
Increasing monitoring for potential adverse reactions to the concomitant medication,
Adjusting the dose of the concomitant medication,
Using an alternative to the concomitant medication, or
Using alternative COVID-19 therapies (see Therapeutic Management of Nonhospitalized Adults With COVID-19).

Use the chosen strategy for the 5-day duration of ritonavir-boosted nirmatrelvir treatment and for at least 2 to 3 days after treatment completion. The strategy may need to continue for a longer duration if ritonavir-boosted nirmatrelvir is initiated in an elderly patient or if the interacting medication has a long half-life.

Box 2. Outpatient Medications That Have Clinically Relevant Drug-Drug Interactions With Ritonavir-Boosted Nirmatrelvir (Paxlovid)

Not all medications that may interact with ritonavir-boosted nirmatrelvir are included in Box 2. Deviation from the recommended strategies may be appropriate in certain clinical scenarios.

Box 2. Outpatient Medications That Have Clinically Relevant Drug-Drug Interactions With Ritonavir-Boosted Nirmatrelvir (Paxlovid)
Prescribe Alternative COVID-19 Therapy
For these medications, management strategies are not possible or feasible, or the risks outweigh the potential benefits.
Anticonvulsants Carbamazepine Phenobarbital Phenytoin Primidone Anti-infective agents Glecaprevir/pibrentasvir Rifampin Rifapentine Immunosuppressants Voclosporin	Cardiovascular agents Amiodarone Clopidogrel^a,b Disopyramide Dofetilide Dronedarone Eplerenone Flecainide Ivabradine Propafenone Quinidine Neuropsychiatric agents Clozapine Lumateperone Lurasidone Midazolam (oral) Pimozide	Pain medications Meperidine (pethidine) Pulmonary hypertension medications Sildenafil Tadalafil Vardenafil Miscellaneous Bosentan Certain chemotherapeutic agents^c Ergot derivatives Lumacaftor/ivacaftor St. John’s wort Tolvaptan
Temporarily Withhold Concomitant Medication, If Clinically Appropriate
Withhold these medications during ritonavir-boosted nirmatrelvir treatment and for at least 2–3 days after treatment completion. They may need to be withheld for longer if the patient is elderly or the medication has a long half-life. If withholding is not clinically appropriate, use an alternative concomitant medication or COVID-19 therapy.
Anticoagulants Rivaroxaban^d Anti-infective agents Erythromycin BPH medications Alfuzosin Silodosin Cardiovascular agents Aliskiren Ranolazine Ticagrelor^b Vorapaxar Immunosuppressants^f Everolimus Sirolimus Tacrolimus	Lipid-modifying agents Atorvastatin^e Lomitapide Lovastatin^e Rosuvastatin^e Simvastatin^e Migraine medications Eletriptan Rimegepant Ubrogepant Neuropsychiatric agents Clonazepam^g Clorazepate^g Diazepam^g Estazolam^g Flurazepam^g Suvorexant Triazolam^g	Erectile dysfunction medications Avanafil Respiratory medications Salmeterol Miscellaneous Certain chemotherapeutic agents^c Colchicine^h Finerenone Flibanserin Naloxegol
Adjust Concomitant Medication Dose and Monitor for Adverse Effects
Consult the Liverpool COVID-19 Drug Interactions website or the Ontario COVID-19 Science Advisory Table for specific dosing recommendations.ⁱ If the dose of the concomitant medication cannot be adjusted, withhold the medication (if clinically appropriate) or use an alternative concomitant medication or COVID-19 therapy.
Anticoagulants Apixaban Dabigatran Edoxaban Anti-infective agents Clarithromycin Itraconazole Ketoconazole Maraviroc Rifabutin BPH medications Tamsulosin Cardiovascular agents Cilostazol Digoxin Mexiletine Diabetes medications Saxagliptin	Erectile dysfunction medications Sildenafil Tadalafil Vardenafil Immunosuppressants^f Cyclosporine Neuropsychiatric agents Alprazolam^g Aripiprazole Brexpiprazole Buspirone Cariprazine Chlordiazepoxide^g Clobazam^g Iloperidone Pimavanserin Quetiapine Trazodone	Pain medications Fentanyl Hydrocodone Oxycodone Pulmonary hypertension medications Riociguat Miscellaneous Certain chemotherapeutic agents^c Darifenacin Elexacaftor/tezacaftor/ ivacaftor Eluxadoline Ivacaftor Tezacaftor/ivacaftor
Continue Concomitant Medication and Monitor for Adverse Effects
Pre-emptive dose adjustment is not required but may be considered. Educate patients on potential adverse effects. Consult the Liverpool COVID-19 Drug Interactions website or the Ontario COVID-19 Science Advisory Table for monitoring guidance and dose adjustment information if needed.ⁱ
Anticoagulants Warfarin Anti-infective agents Cobicistat or ritonavir-boosted antiretrovirals Isavuconazole Posaconazole Voriconazole BPH medications Doxazosin Terazosin Diabetes medications Glyburide	Cardiovascular agents Amlodipine Diltiazem Felodipine Nifedipine Sacubitril Valsartan Verapamil Neuropsychiatric agents Haloperidol Hydroxyzine Mirtazapine Risperidone Ziprasidone Zolpidem	Pain medications Buprenorphine Hydromorphone Methadone Morphine Tramadol
^aReduced effectiveness of clopidogrel is likely. It may be acceptable to continue clopidogrel if the benefit of ritonavir-boosted nirmatrelvir treatment outweighs the risk of reduced clopidogrel effectiveness. ^b For patients at very high risk of thrombosis (e.g., received a coronary stent within the past 6 weeks), consider prescribing an alternative antiplatelet (e.g., prasugrel) or an alternative COVID-19 therapy. ^c Ritonavir-boosted nirmatrelvir may increase concentrations of some chemotherapeutic agents, leading to an increased potential for drug toxicities. Some chemotherapeutic agents may decrease the effectiveness of ritonavir-boosted nirmatrelvir. Please refer to the FDA EUA ritonavir-boosted nirmatrelvir fact sheet and the prescribing information for the chemotherapeutic agent and consult the patient’s specialist provider. The University Health Network/Kingston Health Sciences Centre is an additional resource for evaluating drug-drug interactions for chemotherapeutic agents. ^d For patients at high risk of arterial or venous thrombosis (e.g., had a stroke within the past 3 months with a CHA₂DS₂-VASc score of 7–9 or a pulmonary embolism within the past month), consult the primary or specialty provider and consider using an alternative anticoagulant or COVID-19 therapy. ^e For lovastatin and simvastatin, withhold at least 12 hours before initiation of ritonavir-boosted nirmatrelvir, during treatment, and for 5 days after treatment completion. For atorvastatin and rosuvastatin, withhold at the beginning of treatment with ritonavir-boosted nirmatrelvir and resume after completion of the 5-day course. If withholding a statin is not clinically appropriate (e.g., the patient had a recent myocardial infarction), the doses of atorvastatin and rosuvastatin can be adjusted and continued, and lovastatin and simvastatin should be switched to an alternative statin. ^f Consult a patient’s specialist providers before coadministering these immunosuppressants and ritonavir-boosted nirmatrelvir. These immunosuppressants have significant drug-drug interaction potential with ritonavir, and close monitoring may not be feasible. Alternative COVID-19 therapy may need to be considered. See the American Society of Transplantation statement for more information. ^g Abrupt discontinuation or rapid dose reduction of benzodiazepines may precipitate an acute withdrawal reaction.² The risk is greatest for patients who have been using high doses of benzodiazepines over an extended period. ^h For patients with severe hepatic or renal impairment, coadministration of colchicine and ritonavir-boosted nirmatrelvir is contraindicated due to the potential for serious or life-threatening reactions. ⁱ For medications not included on the Liverpool COVID-19 Drug Interactions website or the Ontario COVID-19 Science Advisory Table, refer to the medication’s FDA label for information on coadministration with ritonavir or other strong CYP3A4 and/or P-gp inhibitors. Key: BPH = benign prostatic hyperplasia; CHA₂DS₂-VASc = congestive heart failure, hypertension, age, diabetes, stroke, vascular disease; CYP = cytochrome P450; EUA = Emergency Use Authorization; FDA = Food and Drug Administration; P-gp = P-glycoprotein

References

Stader F, Khoo S, Stoeckle M, et al. Stopping lopinavir/ritonavir in COVID-19 patients: duration of the drug interacting effect. J Antimicrob Chemother. 2020;75(10):3084-3086. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32556272.
Food and Drug Administration. FDA requiring Boxed Warning updated to improve safe use of benzodiazepine drug class. 2020. Available at: https://www.fda.gov/media/142368/download.