Co-Administration of Paxlovid and Rinvoq: Critical Drug Interaction Management
Do not co-administer Paxlovid (nirmatrelvir/ritonavir) with Rinvoq (upadacitinib) without temporarily holding the Rinvoq, as ritonavir is a potent CYP3A4 inhibitor and upadacitinib is primarily metabolized via CYP3A4, creating a high risk for serious toxicity from elevated upadacitinib levels. 1
Understanding the Mechanism of Interaction
The ritonavir component in Paxlovid causes potent and rapid inhibition of CYP3A4, the enzyme responsible for metabolizing approximately 60% of available medications. 2, 1 This inhibition occurs quickly and persists throughout the 5-day treatment course, dramatically increasing plasma concentrations of CYP3A4 substrates like upadacitinib. 1
Key pharmacokinetic considerations:
- Ritonavir inhibits CYP3A4 within hours of the first dose and maintains this effect throughout treatment 1
- Upadacitinib (Rinvoq) is a JAK inhibitor metabolized primarily through CYP3A4 1
- CYP3A4 substrates with narrow therapeutic indices require temporary discontinuation or dose adjustment when co-administered with Paxlovid 3
Recommended Management Strategy
Temporarily hold Rinvoq during the 5-day Paxlovid course:
- Discontinue upadacitinib at least 24 hours before starting Paxlovid 1
- Complete the full 5-day course of Paxlovid (nirmatrelvir 300mg + ritonavir 100mg every 12 hours) 4
- Resume Rinvoq 2-3 days after completing Paxlovid to allow CYP3A4 activity to recover 1
This approach is supported by:
- The short 5-day duration of Paxlovid treatment minimizes the interruption of immunosuppressive therapy 4
- Brief interruptions of JAK inhibitors are generally well-tolerated without immediate disease flare 5
- The mortality benefit of Paxlovid (89% relative risk reduction in high-risk patients) outweighs the temporary interruption of Rinvoq 4
Clinical Context for Immunosuppressed Patients
Continuing immunosuppression during COVID-19:
- Steroids or immunosuppressants can be used when potential benefits outweigh risks in COVID-19-positive patients 5, 6
- For immunosuppressed COVID-19-negative patients, no adjustment of immunosuppressant dose is necessary in advance 5, 6
- The effects of immunosuppression on COVID-19 development have not been fully established 5
However, the specific drug interaction risk supersedes general immunosuppression guidance in this case. 1
Monitoring During and After Treatment
During Paxlovid treatment (while Rinvoq is held):
- Monitor for worsening of the underlying inflammatory condition requiring Rinvoq 5
- Assess COVID-19 progression including oxygen saturation, respiratory rate, and symptom severity 3
- Watch for Paxlovid-related adverse events, particularly dysgeusia (5.6%) and diarrhea (3.1%) 4
After resuming Rinvoq:
- Monitor for delayed inflammatory disease flare in the week following Rinvoq resumption 5
- Assess for any cumulative effects from the brief treatment interruption 5
Alternative Considerations if Paxlovid Cannot Be Used
If the drug interaction risk is deemed unacceptable and Rinvoq cannot be safely held:
- Consider alternative COVID-19 treatments without significant CYP3A4 interactions 1
- Remdesivir (if hospitalized) does not have the same interaction profile 7
- Supportive care measures remain appropriate for low-risk COVID-19 6
Critical Pitfalls to Avoid
Do not attempt dose reduction of either medication as a compromise - this provides neither adequate COVID-19 treatment nor safe immunosuppression levels. 1
Do not continue both medications simultaneously - the magnitude of CYP3A4 inhibition by ritonavir makes co-administration with upadacitinib contraindicated due to unpredictable and potentially dangerous elevation of JAK inhibitor levels. 2, 1
Do not delay Paxlovid initiation - efficacy is highest when started within 3-5 days of symptom onset, so the decision to hold Rinvoq must be made promptly. 4