Drug Interaction Between Paracetamol and Warfarin

Study Overview
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Brief Summary
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The objective of this study is to investigate whether paracetamol, given at therapeutic doses (2g/day and 3 g/day), may potentiate the anticoagulant effect of warfarin.

Detailed Description
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Paracetamol is recommended as a first-line analgesic and antipyretic therapy in patients receiving short- and long-term oral anticoagulation, especially elderly patient.However,Increased INR was previously observed in patients treated with warfarin and paracetamol given at the maximum recommended dose (4g/day). To date, the mechanism of this interaction has not been determined.A recent in vitro study suggested that the toxic metabolite N-acetyl-para-benzoquinoneimine (NAPQI) appeared to interfere with vitamin K-dependent γ-carboxylase (VKD-carb) and vitamin K epoxide reductase (VKOR) activites12. The question remaining to be dealt with is whether this in vitro observation can explain the in vivo paracetamol-warfarin interaction. We aim to evaluate the effect of paracetamol at the most widely used doses 2 and 3g/day on INR in stable patients treated with warfarin in a double blind randomized placebo-controlled trial and to identify the mechanism involved in this interaction in vivo.

Official Title
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Dose-dependent Drug-drug Interaction Between Paracetamol and Warfarin in Adults Receiving Long-term Oral Anticoagulants: A Randomized Controlled Trial

Conditions
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Deep Venous Thrombosis, Pulmonary Embolism, Atrial Fibrillation, Stroke, Antiphospholipid Syndrome

Intervention / Treatment
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* Drug: paracetamol
* Drug: paracetamol
* Drug: Placebo


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 at 2 to 9 mg for more than 30 days Aged 18 years or older Laboratory values (hemoglobin, blood cell counts, albumin, blood ionogram, complementary hemostasis parameters and aspartate, alanine transaminases (AST and ALT))remained within normal limits Exclusion Criteria: Any treatment change within 7 days before enrollment Any paracetamol intake within the last 14 days Drug allergy Concomitant drug ( 5-fluorouracile, acetylsalicylic acid, non steroidal anti-inflammatory drugs, chloramphenicol, diflunisal, miconazole) St John's wort treatment Pregnancy

Ages Eligible for Study
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Minimum Age: 18 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: Screening
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Paracetamol 2g/d<br>18 patients on stable warfarin therapy received a 10-day regimen of paracetamol 2g/d | Drug: paracetamol<br>* Treatment consisted of two paracetamol 500mg (Doliprane® 500mg, Sanofi-aventis, Paris, France) tablets twice a day along with two matching placebo tablets once daily<br>|
| Experimental: Paracetamol 3g/d<br>18 patients on stable warfarin therapy received a 10-day regimen of paracetamol 3g/d | Drug: paracetamol<br>* Treatment consisted of two paracetamol 500mg (Doliprane® 500mg, Sanofi-aventis, Paris, France) tablets three times a day<br>|
| Placebo Comparator: Placebo<br>9 patients on stable warfarin therapy received a 10-day regimen of placebo | Drug: Placebo<br>* Treatment consisted of two matching placebo tablets three times a day.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The mean maximum increase in INR from baseline to Day 10 (INR (max-D1)) |  | 10 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The mean maximum INR (INRmax) |  | 10 days | 
| The time to the first variation of INR observed |  | 10 days | 
| Day 10 - Day 1 differences in factors II, V, VII, AT-III plasma concentrations between groups. |  | 10 days | 
| Day 10 - Day 1 differences in paracetamol plasma concentration between groups. |  | 10 days | 
| Day 10 - Day 1 differences in R(-), S(-)warfarin plasma concentrations between groups. |  | 10 days | 
| Day 10 - Day 1 differences in Gla-type Osteocalcin (Gla-OC) and undercarboxylated Osteocalcin (Glu-OC)plasma concentrations between groups. |  | 10 days | 
| Relation between age and the mean maximum increase in INR from baseline to Day 10 (INR (max-D1) | Relation between age and INR (max-D1)is measured using regression analysis. | 10 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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paracetamol, warfarin, drug interaction, pathogenic mechanism