Warfarin with Dicloxacillin Interaction Details

Brand Names Associated with Warfarin

Brand Names Associated with Dicloxacillin

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Nov 07, 2023

Interaction Effect

Decreased INR/prothrombin time and anticoagulant effectiveness

Interaction Summary

Concomitant use of dicloxacillin and warfarin may significantly decrease INR and decrease warfarin efficacy , likely due to increased CYP2C9-mediated metabolism of warfarin by dicloxacillin . If concomitant use is required, monitor INR more frequently when starting, stopping, or changing dose of the antibiotic , and continue for 3 weeks after dicloxacillin discontinuation . An increase in warfarin dosage may be necessary during and for several weeks after dicloxacillin discontinuation. If possible, substitute an antibiotic with a lower risk of interaction with warfarin .

Severity

Major

Onset

Delayed

Evidence

Established

How To Manage Interaction

Concomitant use of dicloxacillin and warfarin may significantly decrease INR and decrease warfarin efficacy , likely due to increased CYP2C9-mediated metabolism of warfarin by dicloxacillin . If concomitant use is required, monitor INR more frequently when starting, stopping, or changing dose of the antibiotic , and continue for 3 weeks after dicloxacillin discontinuation . An increase in warfarin dosage may be necessary during and for several weeks after dicloxacillin discontinuation. If possible, substitute an antibiotic with a lower risk of interaction with warfarin .

Mechanism Of Interaction

Induction of CYP2C9-mediated metabolism of warfarin

Literature Reports

A) In a propensity score matched cohort study of patients who received warfarin for atrial fibrillation or mechanical heart valves (n=111,637 patients), treatment with dicloxacillin (53,035 episodes) compared with phenoxymethylpenicillin (144,727 episodes) significantly increased 21-day (days 7 to 28) risk of ischemic stroke and systemic embolism (2.3 vs 1.1 events per 1000; HR, 2.17; 95% CI, 1.56 to 3.02) following initiation of each exposure. In a secondary analysis, treatment with dicloxacillin also significantly increased 21-day risk of ischemic stroke and systemic embolism compared with no antibiotic use (2.3 vs 0.8 events per 1000; HR, 2.92; 95% CI, 2.02 to 4.22). Additionally, the increased risk of ischemic stroke and systemic embolism decreased over time following the index date in the combined dicloxacillin or flucloxacillin group (day 29 to 60 HR, 1.4; day 61 to 120 HR, 1.43). Episodes of dicloxacillin/flucloxacillin were matched 1:1 to episodes of phenoxymethylpenicillin and to randomly selected episodes of no antibiotic use in this study .

B) Following coadministration with dicloxacillin, the AUC(0 to 24 hours) geometric mean ratio was significantly reduced for omeprazole (0.33; 95% CI, 0.24 to 0.45), tolbutamide (0.73; 95% CI, 0.65 to 0.81), and midazolam (0.54; 95% CI, 0.41 to 0.72) in a clinical pharmacokinetic cross-over study of healthy men (n=12; median age, 22 years), indicating that dicloxacillin is an inducer of CYP2C19-, CYP2C9-, and CYP3A4-mediated drug metabolism. Patients received a 5 drug cocktail of midazolam (CYP3A4 substrate; 2.5 mg buccal), tolbutamide (CYP2C9 substrate; 500 mg), omeprazole (CYP2C19 substrate; 20 mg), caffeine (CYP1A2 substrate; 200 mg) and dextromethorphan (CYP2D6 substrate; 30 mg) before and after 10 days of treatment with 1 g dicloxacillin 3 times daily. Caution should be used if dicloxacillin is coadministered with narrow therapeutic window drugs that are metabolized by CYP2C19, CYP2C9, or CYP3A4 .

C) In a retrospective study of patients who received warfarin, mainly for atrial fibrillation or mechanical heart values (n=519), treatment with dicloxacillin significantly decreased mean INR from baseline to 2 to 4 weeks after initiation (mean INR decrease, 0.62; 95% CI, 0.5 to 0.74). The mean INR prior to dicloxacillin exposure was 2.59 (95% CI, 2.5 to 2.68) compared with 1.97 (95% CI, 1.9 to 2.05) 2 to 4 weeks after dicloxacillin exposure. A total of 61% of patients experienced subtherapeutic INR levels (less than 2) within 2 to 4 weeks after dicloxacillin treatment .

D) A 73-year-old man, previously stable on chronic warfarin therapy for atrial fibrillation, experienced repeated subtherapeutic INR values during concomitant dicloxacillin therapy for recurrent cellulitis. For over 3 years, the patient achieved therapeutic INR values (goal INR, 2 to 3) at weekly warfarin dosages of 35 to 40 mg/week, with 35 of 47 INR values within the target range. Of 12 INR values outside the target range, 7 were supra-therapeutic (INR, 3.03 to 4.09) and 5 were subtherapeutic. All subtherapeutic INR values occurred during or within 2 weeks of finishing a course of dicloxacillin. On 2 occasions he received dicloxacillin 500 mg every 6 hours for 10 days and a third course for 30 days. When interviewed about each low INR value, the patient reported no changes in dietary vitamin K intake or warfarin adherence issues, and he denied other medication changes. In response to the low INR values noted during or within 2 weeks of concurrent dicloxacillin, the patient's warfarin dosage was increased incrementally up to 50 to 60 mg/week. Despite this 71.4% increase in weekly warfarin dosage, the patient’s INR remained subtherapeutic for several weeks after dicloxacillin was stopped. Application of the Naranjo probability criteria rated the interaction between dicloxacillin and warfarin as definite .

E) A 41-year-old man who received warfarin 22 mg per week for recurrent DVT was started on dicloxacillin 500 mg 4 times daily for 10 days for cellulitis of the left foot. His prothrombin time (PT) decreased from 20.4 seconds at baseline to 16.9 seconds on day 5 of dicloxacillin therapy. This represented a 17% decrease. The PT returned to baseline some time between 9 and 22 days after dicloxacillin was discontinued .

F) A retrospective review of 7 patients who were on concurrent warfarin and dicloxacillin therapy was conducted. All patients were required to have received stable doses of warfarin for at least 2 weeks prior to the start of dicloxacillin therapy and could have no changes in medications known to inhibit or induce the metabolism of warfarin within the past 2 weeks. Five of the seven patients experienced a fall in their prothrombin time (PT) large enough to require an increase in their warfarin dose. The decrease in PT appeared to occur within 4 to 5 days after the initiation of dicloxacillin .

Warfarin Overview

• 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.

Dicloxacillin Overview

• Dicloxacillin is used to treat infections caused by certain types of bacteria. Dicloxacillin is in a class of medications called penicillins. It works by killing bacteria.

• Antibiotics such as dicloxacillin will not work for colds, flu, or other viral infections. Using antibiotics when they are not needed increases your risk of getting an infection later that resists antibiotic treatment.

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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:

• Gold Standard Drug Database
• Micromedex
• Lexicomp
• DrugBank

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.