Ketoconazole with Warfarin Interaction Details
Brand Names Associated with Ketoconazole
- Ketoconazole
- Nizoral®
Brand Names Associated with Warfarin
- Coumadin®
- Jantoven®
- Warfarin
Medical Content Editor Dr. Brian Staiger, PharmD
Last updated
Dec 02, 2023
Interaction Effect
An increased risk of bleeding
Interaction Summary
Ketoconazole is a potent CYP3A4 inhibitor and concomitant use with warfarin (a CYP3A4 substrate) may result in increased warfarin exposure and effect (ie, increased INR and risk of bleeding). In a nested case-control study of continuous warfarin users aged 65 years or older, there was 4.5-fold increase in risk of bleeding requiring hospitalization with exposure to azole antifungals, including ketoconazole . If ketoconazole therapy is required in a patient taking warfarin, more frequent monitoring of INR is recommended, especially when ketoconazole is initiated and discontinued . Dose adjustments of one or both agents may also be warranted .
Severity
Major
Onset
Delayed
Evidence
Probable
How To Manage Interaction
Concomitant use of ketoconazole and warfarin should be approached with caution as this may result in increased INR and thereby increase the risk for bleeding. When possible, substitute ketoconazole with an antifungal with a low-risk profile for bleeding. If concomitant use of ketoconazole and warfarin is required, more frequent monitoring of the patient's INR is recommended, especially during initiation and discontinuation of ketoconazole . Dose adjustments of one or both agents may also be warranted .
Mechanism Of Interaction
Disruption of vitamin K synthesis; inhibition of CYP3A4-mediated warfarin metabolism
Literature Reports
A) Initiation of antibiotics in patients on continuous warfarin therapy resulted in a significantly increased risk of serious bleeding requiring hospitalization according to a nested case-control study of United States Medicare part D beneficiaries aged 65 years and older (n=38,762). Patients on warfarin who received any antibiotic were twice as likely to be hospitalized for bleeding compared with matched controls on warfarin who were not exposed to antibiotics (adjusted odds ratio (aOR), 2.01; 95% CI, 1.62 to 2.5). Additionally, continuous-warfarin users were twice as likely to have a bleeding event that required hospitalization within 60 days of antibiotic exposure compared with non-exposure. Antibiotic exposure greater than 60 days from the index bleed was not significantly associated with increased risk of bleeding. Specific antibiotics with the highest bleeding risk were azole antifungals (aOR, 4.57; 95% CI, 1.9 to 11.03), followed by cotrimoxazole (aOR, 2.7; 95% CI, 1.46 to 5.05), cephalosporins (aOR, 2.45; 95% CI, 1.52 to 3.95), penicillins (aOR, 1.92; 95% CI, 1.21 to 2.07), macrolides (aOR, 1.86; 95% CI, 1.08 to 3.21), and quinolones (aOR, 1.69; 95% CI, 1.09 to 2.62) .
B) Ketoconazole has been reported to potentiate the anticoagulant effect of warfarin in a single case study. A 75-year-old woman stabilized on warfarin for 3 years was administered ketoconazole 200 mg twice daily for a chronic vaginal thrush infection. Three weeks after treatment, the patient was noted to have spontaneous bleeding and a decrease in her coagulation control. The patient had received no other drugs and had normal liver function tests and CBC. Treatment consisted of stopping ketoconazole therapy and reducing the warfarin dosage. Warfarin control was reestablished at her previous dosage level over the next 3 weeks .
C) It is recommended that patients treated with warfarin may need a reduction in dosage by approximately one-third with concurrent administration of ketoconazole .
D) No hypoprothrombinemic interaction was found in 2 volunteers who received 200 mg ketoconazole plus 7.5 mg to 15 mg warfarin for 3 weeks .
Ketoconazole Overview
-
Ketoconazole is used to treat fungal infections when other medications are not available or cannot be tolerated. Ketoconazole should not be used to treat fungal meningitis (infection of the membranes surrounding the brain and spinal cord caused by a fungus) or fungal nail infections. Ketoconazole is in a class of antifungals called imidazoles. It works by slowing the growth of fungi that cause infection.
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.