Official Title: “Pharmacodynamic Drug Interaction Between Warfarin and Amoxicillin-Clavulanic Acid”

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.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Crossover Assignment, Pharmacodynamics Study

Study Primary Completion Date: September 2009

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

Intervention(s) in this Clinical Trial

• Drug: Firstly : Amoxicillin-Clavulanic acid and secondly : Placebo
  • Amoxicillin : 2g twice daily Clavulanic acid : 125 mg twice daily
• Drug: Firstly : Placebo and secondly : Amoxicillin-Clavulanic acid
  • Amoxicillin : 2g twice daily Clavulanic acid : 125mg twice daily seven consecutive days

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • Order 1 : Firstly Amoxicillin-Acid clavulanic, and Secondly Placebo
• Experimental: 2
  • Order 2 : Firstly Placebo, and Secondly Amoxicillin-Acid clavulanic

Primary Measures

• INR at day one and seven (delta Day7-Day1)
  • Time Frame: 7 days
    Safety Issue?: Yes

Secondary Measures

• % 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
  • Time Frame: 7 days for each period
    Safety Issue?: No

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

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 80 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Assistance Publique - Hôpitaux de Paris

Overall Clinical Trial Officials and Contacts

Stephane MD MOULY, MD, PhD Principal Investigator Assistance Publique - Hôpitaux de Paris  

Information obtained from ClinicalTrials.gov on November 20, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00603317

Study ID Number: P051056

ClinicalTrials.gov Identifier: NCT00603317

Health Authority: France: Ministry of Health