Drug Interaction Between Paracetamol and Warfarin

Phase 4

Completed

• Conditions: Deep Venous Thrombosis; Pulmonary Embolism; Atrial Fibrillation; Stroke; Antiphospholipid Syndrome
• Interventions: Drug: paracetamol; Drug: Placebo

• Registration Number: NCT01104337
• Lead Sponsor: Hopital Lariboisière

Brief Summary

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

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.

Study Timeline

• Study Start: 2007-03
• Primary Completion: 2008-11
• Status Verified: 2010-02
• Study Completion: 2010-02
• Study First Submitted: 2010-04-12
• Study First Submitted QC: 2010-04-13
• Last Update Submitted: 2010-04-13
• Study First Posted: 2010-04-15
• Last Update Posted: 2010-04-15

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 45

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Paracetamol 3g/d	paracetamol	18 patients on stable warfarin therapy received a 10-day regimen of paracetamol 3g/d
Placebo	Placebo	9 patients on stable warfarin therapy received a 10-day regimen of placebo
Paracetamol 2g/d	paracetamol	18 patients on stable warfarin therapy received a 10-day regimen of paracetamol 2g/d

Primary Outcome Measures

Name	Time	Method
The mean maximum increase in INR from baseline to Day 10 (INR (max-D1))	10 days

Secondary Outcome Measures

Name	Time	Method
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)	10 days	Relation between age and INR (max-D1)is measured using regression analysis.

Trial Locations

Locations (1)

Therapeutic Research Unit, Department of Internal Medicine, Hospital Lariboière; 🇫🇷 Paris, France