Drug-Drug Interactions Between Ritonavir-Boosted Nirmatrelvir (Paxlovid) and Concomitant Medications
Last Updated: March 6, 2023
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.
Before prescribing ritonavir-boosted nirmatrelvir (Paxlovid) to treat patients with mild to moderate COVID-19, carefully review the patient’s concomitant medications, including over-the-counter medicines, herbal supplements, and recreational drugs. Because ritonavir-boosted nirmatrelvir 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. Select Outpatient Medications Not Expected to Have Clinically Relevant Interactions With Ritonavir-Boosted Nirmatrelvir (Paxlovid)
This is not a comprehensive list of all the medications that are not expected to have clinically relevant interactions with ritonavir-boosted nirmatrelvir.a
|Medications Without Clinically Relevant Interactions|
|These 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 Reducers||Immunosuppressants||Pain |
a This 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 December 31, 2022 (internal communication, January 2023).
b Coadministering contraceptive products that contain ethinyl estradiol with ritonavir-boosted nirmatrelvir may result in lower ethinyl estradiol concentrations. The FDA EUA for ritonavir-boosted nirmatrelvir suggests that individuals who use these types of contraceptive products should consider using an additional nonhormonal contraceptive method. However, the lower ethinyl estradiol concentrations are not expected to be clinically significant during the 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.
c Ritonavir-boosted nirmatrelvir interacts with certain conjugated monoclonal antibodies, such as ado-trastuzumab emtansine, brentuximab vedotin, enfortumab vedotin, polatuzumab vedotin, and tisotumab vedotin. Before coadministering ritonavir-boosted nirmatrelvir and any of these conjugated monoclonal antibodies, refer to the drug’s FDA prescribing information and consult with the patient’s specialist providers as needed.
Key: EUA = Emergency Use Authorization; FDA = Food and Drug Administration
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. CYP3A4 inhibition occurs rapidly, with maximum inhibition occurring within 48 hours of ritonavir initiation.1 After treatment is completed and ritonavir is discontinued, 70% to 90% of CYP3A4 inhibition resolves within 2 to 3 days.2 The time to resolution of inhibition varies based on factors such as the patient’s age; therefore, resolution may take longer in some individuals, such as in adults of advanced age.
Nirmatrelvir and ritonavir are CYP3A4 substrates. 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 the delayed offset of enzyme induction may reduce the concentrations of nirmatrelvir and ritonavir, rendering the treatment ineffective against SARS-CoV-2. Alternative treatment for COVID-19 should be prescribed.
Ritonavir is an inducer of certain drug-metabolizing enzymes and drug transporters. However, when ritonavir is used for 5 days, its induction properties are less likely to be clinically relevant than when the drug is used chronically (e.g., in people who take HIV protease inhibitors).3 The guidance in this document is based on the drug-drug interaction potential of the Food and Drug Administration (FDA)-authorized 5-day course of ritonavir-boosted nirmatrelvir. Longer treatment courses of ritonavir-boosted nirmatrelvir are not authorized by the current FDA Emergency Use Authorization (EUA), and there are insufficient data on the efficacy of administering a second treatment course in cases where SARS-CoV-2 viral rebound is suspected.
Identifying Drug-Drug Interactions
Consult the following resources for information on identifying and managing drug-drug interactions.
- Quick reference lists:
- Box 1 above lists select outpatient medications that are not expected to have clinically relevant interactions with ritonavir-boosted nirmatrelvir.
- Box 2 below lists select outpatient medications that have clinically relevant drug-drug interactions with ritonavir-boosted nirmatrelvir.
- Web-based drug-drug interaction checker:
- Tables with guidance on managing specific drug-drug interactions:
- The University of Waterloo/University of Toronto drug interaction guide
- The FDA EUA fact sheet and checklist for ritonavir-boosted nirmatrelvir
Management Strategies for Drug-Drug Interactions
Consider the magnitude and significance of the potential drug-drug interaction when choosing management strategies for patients who will be receiving ritonavir-boosted nirmatrelvir. Potential strategies include:
- Increasing monitoring for potential adverse events to the concomitant medication.
- Adjusting the dose of the concomitant medication.
- Temporarily withholding the concomitant medication.
- Using an alternative to the concomitant medication.
- 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 adult of advanced age or if the interacting medication has a long half-life.
Consider consulting with an expert (e.g., a pharmacist or the patient’s specialist providers) when treating patients who are receiving highly specialized therapies or drugs that are prone to concentration-dependent toxicities, such as certain anticonvulsant, anticoagulant, antiarrhythmic, chemotherapeutic, neuropsychiatric, and immunosuppressant drugs.
The decision to prescribe ritonavir-boosted nirmatrelvir to patients who are receiving calcineurin and mammalian target of rapamycin inhibitors should always be made in consultation with the patient’s specialist providers. Ritonavir-boosted nirmatrelvir may be prescribed safely to select patients if an expert in managing the interaction is available and close therapeutic drug monitoring is logistically feasible. Otherwise, an alternative therapy for COVID-19 should be considered. See the American Society of Transplantation statement for more information.
Interactions between ritonavir-boosted nirmatrelvir and chemotherapeutic agents should also be managed in consultation with the patient’s specialist providers. For guidance on managing these interactions, refer to the FDA EUA fact sheet and the prescribing information for the chemotherapeutic agent. The University Health Network/Kingston Health Sciences Centre provides an additional resource for evaluating drug-drug interactions between ritonavir-boosted nirmatrelvir and chemotherapeutic agents.
Patients should be counseled about ritonavir-boosted nirmatrelvir’s drug-drug interaction potential and the signs and symptoms of potential adverse effects. If ritonavir-boosted nirmatrelvir is prescribed to patients who take certain recreational drugs, those patients will require counseling and careful monitoring for adverse effects.
Box 2. Select 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.
|Prescribe Alternative COVID-19 Therapy|
|For these medications, management strategies are not possible or feasible, or the risks outweigh the potential benefits.|
|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 an adult of advanced age or if the medication has a long half-life. If withholding is not clinically appropriate, use an alternative concomitant medication or COVID-19 therapy.|
|Adjust Concomitant Medication Dose and Monitor for Adverse Effects|
|Reduce the dose and/or extend the dosing interval of the concomitant medication. Consult the Liverpool COVID-19 Drug Interactions website or the University of Waterloo/University of Toronto drug interaction guide for specific dosing recommendations.j 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.|
|Continue Concomitant Medication and Monitor for Adverse Effects|
|Pre-emptive dose adjustment is not required but may be considered based on an individualized assessment of the patient’s risk for adverse reactions. Educate patients about potential adverse effects. Consult the Liverpool COVID-19 Drug Interactions website or the University of Waterloo/University of Toronto drug interaction guide for monitoring guidance and dose adjustment information as needed.j|
a Reduced effectiveness of clopidogrel is likely. It may be acceptable to continue clopidogrel if the benefits of using ritonavir-boosted nirmatrelvir outweigh the risk of reduced clopidogrel effectiveness.
b For patients at very high risk of thrombosis (e.g., those who received a coronary stent within the past 6 weeks), consider prescribing an alternative antiplatelet (e.g., prasugrel, if clinically appropriate) or an alternative COVID-19 therapy.
c Some PDE5 inhibitors are used to treat both PAH and erectile dysfunction; however, the doses used to treat PAH are higher than those used for erectile dysfunction. Because of this, and because PDE5 inhibitors are used chronically in patients with PAH, coadministration with ritonavir-boosted nirmatrelvir is contraindicated in these patients. PDE5 inhibitors can be coadministered with ritonavir-boosted nirmatrelvir in patients with erectile dysfunction, though the dose of the PDE5 inhibitor should be adjusted.
d 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 fact sheet for ritonavir-boosted nirmatrelvir 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.
e For patients who are at high risk of arterial or venous thrombosis (e.g., those who 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 (e.g., LMWH) or an alternative COVID-19 therapy. For patients with a lower risk of arterial or venous thrombosis, clinicians may consider administering low-dose aspirin while rivaroxaban is being withheld.
f The use of another COVID-19 therapy may need to be considered. These immunosuppressants have significant drug-drug interaction potential with ritonavir, and they should not be used if close monitoring, including therapeutic drug monitoring, is not feasible. Consult a patient’s specialist providers before coadministering these immunosuppressants with ritonavir-boosted nirmatrelvir. See the American Society of Transplantation statement for more information.
g Withhold lovastatin and simvastatin for at least 12 hours before initiating ritonavir-boosted nirmatrelvir, during treatment, and for 5 days after treatment completion. Withhold atorvastatin and rosuvastatin 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., because the patient recently had a myocardial infarction), clinicians can reduce the doses of atorvastatin and rosuvastatin and continue treatment. However, lovastatin and simvastatin should be switched to an alternative statin.
h The guidance on managing drug-drug interactions between certain benzodiazepines and ritonavir-boosted nirmatrelvir can vary significantly between product information resources. Note that abrupt discontinuation or rapid dose reduction of benzodiazepines may precipitate an acute withdrawal reaction.4 The risk is greatest for patients who have been using high doses of benzodiazepines over an extended period.
i Do not coadminister this medication with ritonavir-boosted nirmatrelvir in patients with hepatic or renal impairment.
j For medications that are not included on the Liverpool COVID-19 Drug Interactions website or in the University of Waterloo/University of Toronto drug interaction guide, refer to the FDA labels for information on coadministering these medications with ritonavir or other strong CYP3A4 and/or P-gp inhibitors (e.g., ketoconazole).
k Dexamethasone exposure is expected to increase 2.60-fold when dexamethasone is coadministered with ritonavir-boosted nirmatrelvir.5 Clinicians should weigh the risks and benefits of continuing the patient’s normal dose of dexamethasone (while monitoring for AEs) versus decreasing the dose. Patients who are receiving higher doses of dexamethasone will be at a greater risk of AEs.
l Patients should take ritonavir-boosted nirmatrelvir at least 3 hours after receipt of brincidofovir.
m Ritonavir-boosted nirmatrelvir interacts with certain conjugated monoclonal antibodies, such as ado-trastuzumab emtansine, brentuximab vedotin, enfortumab vedotin, polatuzumab vedotin, and tisotumab vedotin. Before coadministering ritonavir-boosted nirmatrelvir and any of these conjugated monoclonal antibodies, refer to the drug’s FDA prescribing information and consult with the patient’s specialist providers as needed.
Key: AE = adverse effect; 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; LMWH = low-molecular-weight heparin; PAH = pulmonary arterial hypertension; PDE5 = phosphodiesterase 5; P-gp = P-glycoprotein
- Katzenmaier S, Markert C, Riedel KD, et al. Determining the time course of CYP3A inhibition by potent reversible and irreversible CYP3A inhibitors using a limited sampling strategy. Clin Pharmacol Ther. 2011;90(5):666-673. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21937987.
- 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.
- University of Liverpool. Evaluating the interaction risk of COVID-19 therapies. 2022. Available at: https://covid19-druginteractions.org/prescribing_resources. Accessed February 13, 2022.
- 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.
- Li M, Zhu L, Chen L, Li N, Qi F. Assessment of drug-drug interactions between voriconazole and glucocorticoids. J Chemother. 2018;30(5):296-303. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30843777.