Drug Interaction Between Paracetamol and Warfarin (INPAWA2)

This study has been completed.
Sponsor:
Information provided by:
Hopital Lariboisière
ClinicalTrials.gov Identifier:
NCT01104337
First received: April 12, 2010
Last updated: April 13, 2010
Last verified: February 2010
  Purpose

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.


Condition Intervention Phase
Deep Venous Thrombosis
Pulmonary Embolism
Atrial Fibrillation
Stroke
Antiphospholipid Syndrome
Drug: paracetamol
Drug: Placebo
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Screening
Official Title: Dose-dependent Drug-drug Interaction Between Paracetamol and Warfarin in Adults Receiving Long-term Oral Anticoagulants: A Randomized Controlled Trial

Resource links provided by NLM:


Further study details as provided by Hopital Lariboisière:

Primary Outcome Measures:
  • The mean maximum increase in INR from baseline to Day 10 (INR (max-D1)) [ Time Frame: 10 days ] [ Designated as safety issue: Yes ]

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


Enrollment: 45
Study Start Date: March 2007
Study Completion Date: February 2010
Primary Completion Date: November 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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
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 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.

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01104337

Locations
France
Therapeutic Research Unit, Department of Internal Medicine, Hospital Lariboière
Paris, France, 75010
Sponsors and Collaborators
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
  More Information

No publications provided

Responsible Party: Pr Stephane Mouly, Therapeutic Research Unit, Department of Internal Medicine, Hospital Lariboisière, Paris,France
ClinicalTrials.gov Identifier: NCT01104337     History of Changes
Other Study ID Numbers: INPAWA2-URT
Study First Received: April 12, 2010
Last Updated: April 13, 2010
Health Authority: France: Ministry of Health

Keywords provided by Hopital Lariboisière:
paracetamol
warfarin
drug interaction
pathogenic mechanism

Additional relevant MeSH terms:
Antiphospholipid Syndrome
Atrial Fibrillation
Pulmonary Embolism
Thrombosis
Venous Thromboembolism
Venous Thrombosis
Arrhythmias, Cardiac
Autoimmune Diseases
Cardiovascular Diseases
Embolism
Embolism and Thrombosis
Heart Diseases
Immune System Diseases
Lung Diseases
Pathologic Processes
Respiratory Tract Diseases
Thromboembolism
Vascular Diseases
Acetaminophen
Warfarin
Analgesics
Analgesics, Non-Narcotic
Anticoagulants
Antipyretics
Central Nervous System Agents
Hematologic Agents
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Sensory System Agents

ClinicalTrials.gov processed this record on October 29, 2014