Drug Interaction Between Paracetamol and Warfarin

Stroke Clinical Trial

— INPAWA2  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01104337
• Other study ID #: INPAWA2-URT
• Status: Completed
• Phase: Phase 4
• First received: April 12, 2010
• Last updated: April 13, 2010
• Start date: March 2007
• Est. completion date: February 2010

Study information

• Verified date: February 2010
• Source: Hopital Lariboisière
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Ministry of Health
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 45
• Est. completion date: February 2010
• Est. primary completion date: November 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Screening

Related Conditions & MeSH terms

• Antiphospholipid Syndrome
• Atrial Fibrillation
• Deep Venous Thrombosis
• Pulmonary Embolism
• Stroke
• Venous Thrombosis

Intervention

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
• paracetamol
Treatment consisted of two paracetamol 500mg (Doliprane® 500mg, Sanofi-aventis, Paris, France) tablets three times a day
• Placebo
Treatment consisted of two matching placebo tablets three times a day.

Locations

Country	Name	City	State
France	Therapeutic Research Unit, Department of Internal Medicine, Hospital Lariboière	Paris

Sponsors (1)

Lead Sponsor	Collaborator
Hopital Lariboisière

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The mean maximum increase in INR from baseline to Day 10 (INR (max-D1))		10 days	Yes
Secondary	The mean maximum INR (INRmax)		10 days	Yes
Secondary	The time to the first variation of INR observed		10 days	Yes
Secondary	Day 10 - Day 1 differences in factors II, V, VII, AT-III plasma concentrations between groups.		10 days	Yes
Secondary	Day 10 - Day 1 differences in paracetamol plasma concentration between groups.		10 days	Yes
Secondary	Day 10 - Day 1 differences in R(-), S(-)warfarin plasma concentrations between groups.		10 days	Yes
Secondary	Day 10 - Day 1 differences in Gla-type Osteocalcin (Gla-OC) and undercarboxylated Osteocalcin (Glu-OC)plasma concentrations between groups.		10 days	Yes
Secondary	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	Yes