Pharmacodynamic Drug Interaction Between Warfarin and Amoxicillin-clavulanic Acid

Study Overview
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Brief Summary
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Several case reports indicate that the use of the antibiotic combination amoxicillin and clavulanic acid (AM-CLAVAC) can interact with warfarin pharmacodynamics. However, fever per se might also be responsible of these warfarin overdose reports, as well as the use of high dose paracetamol. The aim of the present study is to determine if AM-CLAVAC can increase the pharmacodynamics of warfarin among patients at steady state Double blinded cross over controlled study vs placebo performed in 12 evaluable patients treated with warfarin with an INR target 2 to 3 and a stable INR and a stable dose.

Detailed Description
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Double blinded cross over controlled study vs placebo performed in 12 evaluable patients treated with warfarin with an INR target 2 to 3 and a stable INR and a stable dose One period : seven consecutive days of amoxicillin(2g twice daily)- clavulanic acid (125 mg twice daily) association Wash out period of at least 4 weak with the return to a stable INR and warfarin dose One period : seven consecutive days of placebo twice daily Main outcome INR delta Day7-Day

Official Title
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Pharmacodynamic Drug Interaction Between Warfarin and Amoxicillin-clavulanic Acid

Conditions
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Oral Anticoagulation, Deep Venous Thrombosis, Atrial Fibrillation, Pulmonary Embolism

Intervention / Treatment
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* Drug: Firstly : Amoxicillin-Clavulanic acid and secondly : Placebo
* Drug: Firstly : Placebo and secondly : Amoxicillin-Clavulanic acid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: patients treated with warfarin (target INR 2 to 3) stable anticoagulation (3 consecutive INR in the target) stable dose no infection normal CRP age >18 years normal transaminase levels Exclusion Criteria: drug allergy penicillin allergy Alzheimer cancer thyroid disease gastro intestinal chronic disease frequent nausea or vomiting Cirrhosis chronic renal failure (GFR<60 ml/min) frequent intake of paracetamol or NSAID addict to drugs or alcool St John's wort treatment or grapefruit juice intake concomitant drugs (amiodarone, cimetidine, SSRI, clofibrate, fenofibrate, diltiazem, fluconazole, itraconazole, isoniazide, voriconazole, métronidazole, miconazole , omeprazole, glucocorticoids, zileuton, ritonavir, rifampicin, carbamazepine, phenytoin, phenobarbital) antibiotic use during the 3 last weeks pregnancy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Order 1 : Firstly Amoxicillin-Acid clavulanic, and Secondly Placebo | Drug: Firstly : Amoxicillin-Clavulanic acid and secondly : Placebo<br>* Amoxicillin : 2g twice daily Clavulanic acid : 125 mg twice daily<br>|
| Experimental: 2<br>Order 2 : Firstly Placebo, and Secondly Amoxicillin-Acid clavulanic | Drug: Firstly : Placebo and secondly : Amoxicillin-Clavulanic acid<br>* Amoxicillin : 2g twice daily Clavulanic acid : 125mg twice daily seven consecutive days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| INR at day one and seven (delta Day7-Day1) |  | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| % of patients with an INR>3.5 during each study period mean INR during each study period effect of VKORC1 genetic polymorphism trough blood concentrations of S and R warfarin at day1 and day7 (delta) during each study period |  | 7 days for each period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Warfarin, Drug interaction, Pharmacogenetics, Amoxicillin, Clavulanic acid