Drug-Drug Interactions Between Ritonavir-Boosted Nirmatrelvir (Paxlovid) and Concomitant Medications
Last Updated: September 26, 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. 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 July 31, 2022 (internal communication, August 2022).
b The FDA EUA 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 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 those conjugated to the drug monomethyl auristatin E (or vedotin). These include 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. After the last dose is administered, most of the interaction potential resolves within 2 to 3 days, although resolution may take longer in adults of advanced age.1
Longer treatment courses of ritonavir-boosted nirmatrelvir are not authorized by the current Food and Drug Administration (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. The guidance in this document is based on the drug-drug interaction potential of the FDA-authorized 5-day course of ritonavir-boosted nirmatrelvir.
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 select outpatient medications that are not expected to have clinically relevant interactions with ritonavir-boosted nirmatrelvir.
- Box 2 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:
Consider consulting with an expert (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 drug-drug interaction when choosing management strategies for patients who will be receiving ritonavir-boosted nirmatrelvir. Potential strategies include:
- Increasing monitoring for potential adverse reactions 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.
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 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|
|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.|
|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 Ontario COVID-19 Science Advisory Table for monitoring guidance and dose adjustment information as needed.i|
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.
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; P-gp = P-glycoprotein
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- 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.