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)
|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||Diabetes medications||Pain medications |
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 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.
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:
- Tables with guidance on managing specific drug-drug interactions:
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.
|Prescribe Alternative COVID-19 Therapy|
|For these medications, management strategies are not possible or feasible, or the risks outweigh the potential benefits.|
|Anticonvulsants||Cardiovascular agents||Pain medications|
|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||Lipid-modifying agents||Erectile dysfunction medications|
|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||Erectile dysfunction medications||Pain medications|
|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||Cardiovascular agents||Pain medications|
a Reduced 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.
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
- 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.