Published: 25 August 2017

Safety Information

Early Warning System - Monitoring Communication

Medsafe emphasises that patients should NOT stop using any medicine or medical device subject to a monitoring communication. If you have any concerns with a medicine or medical device you are using, please contact your health professional. A monitoring communication does not mean that the medicine or medical device causes an adverse event.

Watch out for INR changes when direct-acting antivirals (DAAs) are used concomitantly with warfarin

25 August 2017

Recent evidence indicates that the use of direct-acting antivirals (DAAs) together with warfarin may result in changes in international normalised ratio (INR).  In most cases decreases in INR were reported during concomitant treatment [1-4].

Increase the frequency of INR monitoring during concomitant treatment and make adjustments when necessary.  Frequent monitoring of INR is also required in the post-treatment follow-up period particularly if any warfarin dose adjustment has occurred.

Products Affected

DAA regimens are used for the treatment of chronic hepatitis C infection.  DAAs approved and currently available for use in New Zealand are summarised in Table 1.  In some countries DAAs are marketed under different brand names and in different combinations.  Be aware that patients who have been importing DAA products from overseas may be taking a different combination from those available in New Zealand.

Warfarin (brand names Coumadin and Marevan) is a vitamin K antagonist and is widely used as an anticoagulant.

Table 1: Direct-acting antivirals approved and currently available for use in New Zealand

Product name	Active ingredients	Sponsor
Viekira Pak	ombitasvir/paritaprevir/ritonavir copackaged with dasabuvir	AbbVie
Viekira Pak-RBV	ombitasvir/paritaprevir/ritonavir copackaged with dasabuvir and ribavirin	AbbVie
Harvoni	ledipasvir/sofosbuvir	Gilead
Sovaldi	sofosbuvir	Gilead
Daklinza	daclatasvir	Bristol-Myers Squibb
Sunvepra	asunaprevir	Bristol-Myers Squibb
Zepatier	elbasvir/grazoprevir	Merck Sharp & Dohme

Additional Information

Advice for healthcare professionals:

• Changes in INR may occur in patients receiving warfarin together with a DAA regimen.  In most cases decreases in INR were reported during DAA treatment. 
• Frequently monitor INR values during concomitant treatment and in the post-treatment follow-up period, particularly if the warfarin dose has been adjusted.
• In one recent case [4], the patient’s INR reduced from 2.4 at baseline to 1.2 after two weeks of DAA treatment.  This required a 125% increase in the total weekly warfarin dose to achieve therapeutic INR at 11 weeks.  Thirteen days after completing DAA treatment, the patient’s INR was supratherapeutic at 7.3 and the patient reported minor haematuria.
• The liver produces and modifies many coagulation factors.  Changes in liver function during treatment with DAAs could result in INR changes [5].
• Discuss with your patients the importance of taking DAAs as prescribed to achieve sustained virologic response (SVR) and to help manage any complications that may occur.
• DAAs are known and postulated to interact with a substantial list of medicines.  Consider both pharmacokinetic and pharmacodynamic interactions when prescribing other concomitant medicines.

Due to the many interactions that can occur with DAAs, take care when co-prescribing other medicines metabolised or transported by [6-8]:

• CYP3A4
• OATP family and OCT1
• BRCP
• P-gp
• Glucuronidation (UGT1A1)
• CYP2C19
• CYP1A2.

The University of Liverpool provides a hepatitis drug interactions checker tool that is quick and easy to use.  However, it currently does not list an interaction with warfarin for all DAAs.

Search the hepatitis drug interactions checker tool

Many other medicines also interact with warfarin.  Warfarin is a mixture of enantiomers that are metabolised by different CYP450 enzymes [9,10].  R-warfarin is metabolised primarily by CYP1A2 and CYP3A4 [9,10].  S-warfarin is metabolised primarily by CYP2C9 [9,10].  The efficacy of warfarin is affected primarily when the metabolism of S-warfarin is altered.

Detailed prescribing information and advice can be found in data sheets and consumer medicine information (CMI).

Search for consumer medicine information and data sheets

The overall benefit-risk balance of DAA regimens remains positive.

Regulator Actions

Medsafe is continuing to monitor reports of adverse reactions to DAAs and is working with companies to ensure that all DAA data sheets and CMI contain information on this safety concern.  Medsafe will publish an updated communication if any change in the rate and pattern of occurrence of this issue is identified.

Reporting

Consumers and healthcare professionals are encouraged to send reports  of suspected adverse reactions to the Centre for Adverse Reactions Monitoring (CARM).

Medsafe cannot give advice about an individual’s medical condition.  If you have any concerns about a medicine you are taking, Medsafe encourages you to talk to your healthcare professional.

References

1. DeCarolis, D.D., et al., Evaluation of a Potential Interaction Between New Regimens to Treat Hepatitis C and Warfarin. Ann Pharmacother, 2016. 50(11): p. 909-917.
2. DeCarolis, D.D., Y.C. Chen, and A.D. Westanmo, Evaluation of a Potential Interaction Between New Regimens to Treat Hepatitis C and Warfarin: Twelve-Week Post-treatment Follow-up. Ann Pharmacother, 2017. 51(5): p. 439-440.
3. de Lorenzo-Pinto, A., et al., Decreased INR after acenocoumarol, ombitasvir/paritaprevir/ritonavir and dasabuvir co-administration. J Clin Pharm Ther, 2016. 41(4): p. 444-446.
4. Puglisi, G.M., et al., Paritaprevir/ritonavir/ombitasvir+dasabuvir plus ribavirin therapy and inhibition of the anticoagulant effect of warfarin: a case report. J Clin Pharm Ther, 2017. 42(1): p. 115-118.
5. UpToDate. Hemostatic abnormalities in patients with liver disease. 11 January 2017 [Accessed 8 August 2017]; Available from: www.uptodate.com/contents/hemostatic-abnormalities-in-patients-with-liver-disease.
6. AbbVie Limited. Viekira Pak New Zealand Data Sheet. 19 May 2017 [Accessed 14 August 2017]; Available from: www.medsafe.govt.nz/profs/datasheet/v/viekiraPaktab.pdf.
7. AbbVie Limited. Viekira Pak-RBV New Zealand Data Sheet. 19 May 2017 [Accessed 14 August 2017]; Available from: www.medsafe.govt.nz/profs/datasheet/v/viekirapak-rbvtab.pdf.
8. Gilead Sciences (NZ). Harvoni New Zealand Data Sheet. 5 March 2017 [Accessed 14 August 2017]; Available from: www.medsafe.govt.nz/profs/datasheet/h/HarvoniTab.pdf.
9. GlaxoSmithKline NZ Limited. Marevan New Zealand Data Sheet. 22 February 2017 [Accessed 8 August 2017]; Available from: www.medsafe.govt.nz/profs/Datasheet/m/Marevantab.pdf.
10. Pharmacy Retailing (NZ) Limited t/a Healthcare Logistics. Coumadin New Zealand Data Sheet. 15 November 2010 [Accessed 8 August 2017]; Available from: www.medsafe.govt.nz/profs/Datasheet/c/Coumadintab.pdf.