Warfarin with Bosentan Interaction Details
Brand Names Associated with Warfarin
- Coumadin®
- Jantoven®
- Warfarin
Brand Names Associated with Bosentan
- Bosentan
- Tracleer®
Medical Content Editor Dr. Brian Staiger, PharmD
Last updated
Nov 07, 2023
Interaction Effect
Reduced warfarin efficacy
Interaction Summary
Bosentan may significantly decrease the anticoagulant properties of warfarin. Bosentan was shown to cause a significant increase in the elimination of R- and S-warfarin and a subsequent decrease in the anticoagulant properties of warfarin when compared to placebo. Bosentan induces cytochrome P450 3A4 enzymes, which are responsible for R-warfarin metabolism. However, because the effect on S-warfarin was similar in magnitude, it is suspected that bosentan may also be capable of inducing cytochrome P450 2C9 . The plasma concentrations of S-warfarin (a CYP2C9 substrate) and R-warfarin (a CYP3A4 substrate) were decreased by 29% and 38%, respectively, during concomitant therapy with bosentan 500 mg twice daily for 6 days. According to the manufacturer, clinical studies involving concomitant administration of bosentan and warfarin in subjects with pulmonary arterial hypertension did not demonstrate clinically relevant changes in INR or warfarin dose (baseline vs. end of the clinical studies). The need to change the warfarin dose during the clinical trials due to changes in INR or due to adverse events was similar among bosentan- and placebo-treated patients .
Severity
Moderate
Onset
Delayed
Evidence
Probable
How To Manage Interaction
In patients receiving oral anticoagulation with warfarin, the prothrombin time (PT) or international normalized ratio (INR) should be closely monitored with the addition or withdrawal of treatment with bosentan, and should be reassessed periodically during concurrent therapy. Adjustments of the warfarin dose may be necessary in order to maintain the desired level of anticoagulation.
Mechanism Of Interaction
Induction of cytochrome P450 3A4, and possibly 2C9, enzyme activity by bosentan
Literature Reports
A) Twelve healthy male subjects participated in a double-blind, randomized, placebo-controlled study to determine the effects of bosentan on the pharmacodynamics and pharmacokinetics of warfarin. Each study participant received placebo or bosentan 500 mg twice daily for ten days, with a single oral dose of warfarin 26 mg being administered on the morning of day 6. Bosentan treatment caused a statistically significant reduction in the area under the concentration-time curve (AUC) and the oral clearance of both warfarin enantiomers. The mean AUC of R-warfarin was decreased by 38% (from 97,200 mcg/h/L to 59,500 mcg/h/L) and the mean AUC of S-warfarin decreased by 29% (from 63,100 mcg/h/L to 44,600 mcg/h/L). Maximum concentration (Cmax) was not significantly different between the placebo phase and the warfarin phase, indicating that bosentan has no effect on the absorption of warfarin. The half-life of both R- and S-warfarin was reduced from 50.9 hours to 32.1 hours and from 37.7 hours to 25.1 hours, respectively, by bosentan administration. Pharmacodynamically, bosentan therapy resulted in a 23% decrease in the average maximum prothrombin time, which parallels the decrease in S-warfarin plasma concentrations .
B) Decreased International Normalized Ratio (INR) occurred 10 days after initiation of bosentan therapy in a patient stabilized on warfarin therapy. A 35-year-old African American female with a history of PAH was stabilized on 27.5 mg/week warfarin. Bosentan 62.5 mg twice daily was initiated for management of PAH. After 10 days of bosentan therapy, the INR was subtherapeutic at 1.7 and remained decreased over the next 5 weeks despite an increase of the warfarin dose at weekly intervals by a total of 1.8-fold to 57.5 mg/week. Bosentan was increased 4 weeks after initiation to the maintenance dose of 125 mg twice daily. After 5 weeks of dosage increases, the INR became supratherapeutic for 3 weeks, resulting in a subsequent dosage decrease. The resultant warfarin dose required to maintain a therapeutic INR was 45 mg/week, a 63.6% dosage increase after the initiation of bosentan. No adverse effects were experienced due to INR values outside the targeted range. In this case, bosentan significantly decreased the anticoagulant properties of warfarin .
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.
Bosentan Overview
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Bosentan is used to treat pulmonary arterial hypertension (PAH, high blood pressure in the vessels that carry blood to the lungs) in adults and children 3 years of age and older. Bosentan may improve the ability to exercise and slow the worsening of symptoms in patients with PAH. Bosentan is in a class of medications called endothelin receptor antagonists. It works by stopping the action of endothelin, a natural substance that causes blood vessels to narrow and prevents normal blood flow in people who have PAH.
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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.