Drug Interaction Between Paracetamol and Warfarin (INPAWA2)

April 13, 2010 updated by: Hopital Lariboisière

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

45

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
      • Paris, France, 75010
        • Therapeutic Research Unit, Department of Internal Medicine, Hospital Lariboière

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Screening
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Hopital Lariboisière

Investigators

  • Principal Investigator: Stephane Mouly, MD, PhD, Therapeutic Research Unit, Department of Internal Medicine, Hospital Lariboisière, Paris, France
  • Principal Investigator: Guy Simoneau, MD, Therapeutic Research Unit, Department of Internal Medicine, Hospital Lariboisière, Paris, France

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

March 1, 2007

Primary Completion (Actual)

November 1, 2008

Study Completion (Actual)

February 1, 2010

Study Registration Dates

First Submitted

April 12, 2010

First Submitted That Met QC Criteria

April 13, 2010

First Posted (Estimate)

April 15, 2010

Study Record Updates

Last Update Posted (Estimate)

April 15, 2010

Last Update Submitted That Met QC Criteria

April 13, 2010

Last Verified

February 1, 2010

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • INPAWA2-URT

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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