Warfarin with Nirmatrelvir Interaction Details
Brand Names Associated with Warfarin
- Coumadin®
- Jantoven®
- Warfarin
Medical Content Editor Dr. Brian Staiger, PharmD
Last updated
Nov 07, 2023
Interaction Effect
Variable plasma warfarin concentration
Interaction Summary
Concomitant administration of nirmatrelvir/ritonavir and warfarin may result in variable warfarin plasma concentrations. Closely monitor INR if coadministration with warfarin is necessary. Consider surveillance of INR for up to 2 weeks following discontinuation of nirmatrelvir/ritonavir .
Severity
Moderate
Onset
Delayed
Evidence
Probable
How To Manage Interaction
Concomitant administration of nirmatrelvir/ritonavir and warfarin may result in variable warfarin plasma concentrations. Closely monitor INR if coadministration with warfarin is necessary. Consider surveillance of INR for up to 2 weeks following discontinuation of nirmatrelvir/ritonavir .
Mechanism Of Interaction
Altered warfarin metabolism
Literature Reports
A) In a physiologically-based pharmacokinetic (PBPK) modeling study (N=100), simulated coadministration of ritonavir with warfarin was estimated to decrease INR in general population subjects (range, 20 to 65 years) and in geriatric subjects (range, 65 to 85 years) compared with rivaroxaban use alone; INR decrease was more profound in older subjects. Following ritonavir treatment, INR was estimated to return to pretreatment levels by week 2. The simulated ritonavir dosage was 100 mg twice daily for 5 days (consistent with nirmatrelvir/ritonavir dosing for COVID-19) and warfarin was 5 mg daily; nirmatrelvir was not incorporated into the simulation due to low drug interaction potential. Ritonavir causes mechanism-based inactivation of CYP3A4 and induces CYP2C9; warfarin is metabolized by both enzymes .
B) A case report described suboptimal international normalized ratio (INR) values with the concomitant use of ritonavir in a 66-year-old man stabilized on warfarin. The patient was prescribed warfarin 3.75 mg to 5 mg daily to maintain an INR within optimal range (2 to 3.5) following a mitral valve replacement due to endocarditis. Two months after discharge, the patient was restarted on a previously effective HAART regimen including zidovudine, lamivudine, and lopinavir/ritonavir (400 mg/100 mg twice a day). Over the next several days, lopinavir plasma trough concentration was 4580 nanogram/mL and an increasing warfarin dose (up to 10 mg/day) was necessary to maintain an optimal INR. Two years later, the patient's treatment regimen was replaced with zidovudine-lamivudine-abacavir plus tenofovir, and the warfarin dose was reduced back to 3.75 mg to 5 mg/day .
C) A case report described decreased international normalized ratio (INR) values with the concomitant use of lopinavir/ritonavir in a 42-year-old male stabilized on warfarin. The patient, who had been treated with warfarin since receiving aortic valve replacement 12 years earlier, was hospitalized with chills and shortness of breath on exertion. His INR was maintained between 2 and 3 with a warfarin dose of 5.5 mg/day. During his hospital stay, he was initiated on co-trimoxazole for pneumonia, fluconazole and citalopram. The patient tested HIV positive and had a baseline CD4 cell count of 150 x 10(6)/L. Five days after discharge, his INR was 4.4. Subsequently, warfarin was withheld for 1 dose and reinitiated at alternating doses of 3 mg/day and 3.5 mg/day, and INR values were 3.8 and 2.1 at 3 days and 2 weeks, respectively. One month after discharge, antiretroviral therapy (zidovudine, lamivudine, and lopinavir/ritonavir) was initiated. Repeated testing rendered INR values between 1.1 and 1.3. Beginning at his 1-month follow-up visit, repeat testing was performed again over the next few weeks revealing INR values between 1 and 1.3. Patient non-adherence and changes in diet were ruled out as causes for decreased INR values. His warfarin dose was titrated to 11 mg/day over several months during which time his INR remained subtherapeutic. Following referral for anticoagulation management 1 month later, his INR stabilized between 2 and 3 with a warfarin dose of 13 mg/day. After receiving antiretroviral therapy for 7 months, his INR value was 2.6 and his CD4 cell count had risen to 330 x 10(6)/L with an HIV viral load less than 50 copies/mL. Induction of CYP2C9-mediated warfarin metabolism by lopinavir/ritonavir was suggested as a possible mechanism .
D) A case report described deep vein thrombosis and pulmonary emboli caused by anti-cardiolipin antibody syndrome with the concomitant use of ritonavir and warfarin in a 41-year-old HIV positive male. The patient was hospitalized and treated with heparin intravenously, and was discharged on warfarin 10 mg daily with an INR of 2.4 to 3. His HIV medications at the time included efavirenz and abacavir. Because of an increasing viral load, therapy was changed to liquid ritonavir 400 mg twice daily, nelfinavir 750 mg three times daily, and zidovudine/lamivudine twice daily. Over the next five days, the patient's INR increased from 2.5 to 10.4, with no clinical signs of bleeding. Despite three injections of vitamin K, the patient developed another deep vein thrombosis and again was hospitalized for intravenous heparin therapy. During this hospitalization, the INR and warfarin dose were extremely difficult to stabilize, and he was discharged on warfarin 30 mg daily with an INR of 2.5. Three days later, the INR had increased to 10.4. The patient confessed to not taking or reducing the dose of his ritonavir at home due to nausea and vomiting. Review of his hospital records also showed that the patient had occasionally refused his ritonavir, explaining the difficulty in establishing a warfarin dose while hospitalized. Ritonavir therapy was discontinued, and the warfarin dose was stabilized at 15 mg daily with an INR between 2.5 and 3 .
E) A case report described an unexpected decrease in warfarin effect after initiation of treatment with ritonavir in a 27-year-old female. The patient who had advanced HIV was started on warfarin after being diagnosed with a thrombosis of the inferior vena cava. She was already taking trimethoprim/sulfamethoxazole (TMP/SMX), rifabutin, didanosine, megestrol, ethinyl estradiol and levonorgestrel. Her INR was stabilized at a dose of 12.5 mg warfarin daily. After 8 weeks, the didanosine and rifabutin were discontinued, and ritonavir, clarithromycin, and zidovudine were started. Testing revealed a decreased INR requiring increased warfarin doses over the next five weeks. After discontinuing only the ritonavir, the patient's INR more than tripled within one week. The authors theorized that the changes may have been due to more than just a simple interaction between ritonavir and warfarin, but may have been the result of a complex, multi-drug interaction .
Warfarin Overview
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Warfarin is used to prevent blood clots from forming or growing larger in your blood and blood vessels. It is prescribed for people with certain types of irregular heartbeat, people with prosthetic (replacement or mechanical) heart valves, and people who have suffered a heart attack. Warfarin is also used to treat or prevent venous thrombosis (swelling and blood clot in a vein) and pulmonary embolism (a blood clot in the lung). Warfarin is in a class of medications called anticoagulants ('blood thinners'). It works by decreasing the clotting ability of the blood.
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Definitions
Severity Categories
Contraindicated
These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.
Major
This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.
Moderate
This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.
Minor
While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.
Onset
Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.
Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.
Evidence
Level of documentation of the interaction.
Established: The interaction is documented and substantiated in peer-reviewed medical literature.
Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.
How To Manage The Interaction
Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.
It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.
Mechanism Of Interaction
The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.
Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.
Where Does Our Information Come From?
Information for our drug interactions is compiled from several drug compendia, including:
The prescribing information for each drug, as published on DailyMED, is also used.
Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.
The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.