Overview

Direct-acting antivirals (DAAs) have been developed to treat hepatitis C virus (HCV) infection by targeting various steps in the HCV lifecycle. These drugs have been proven to produce higher response rates and tend to be less toxic than interferon-based therapies¹.

Background of Safety Issue

The National Pharmaceutical Regulatory Agency (NPRA) received information on this safety issue from the European Medicines Agency (EMA) and Therapeutic Goods Administration (TGA), Australia. The package inserts of combined hormonal contraceptives containing ethinylestradiol will be updated with information related to the drug interaction between ethinylestradiol and the DAAs combination products of paritaprevir/ritonavir/ombitasvir, with or without dasabuvir.

During clinical trials in HCV patients treated with paritaprevir/ritonavir/ombitasvir and dasabuvir with or without ribavirin, elevations of alanine aminotransaminase (ALT) more than five (5) times the upper limit of normal occurred in women using ethinylestradiol-containing medications such as combined hormonal contraceptives². These ALT elevations were asymptomatic, typically occurring within four weeks of treatment initiation, and declined within approximately two weeks of onset without stopping treatment³.

Adverse Drug Reaction Reports

Since year 2000, NPRA has received 31 ADR reports with 66 adverse events suspected to be linked to products containing ethinylestradiol. Commonly adverse events were amenorrhoea, dizziness, nausea and vomiting. None of the adverse events were reported to be related to the concomitant use with ombitasvir/paritaprevir/ritonavir and dasabuvir.

Advice for Healthcare Professionals

• Concomitant use of ethinylestradiol-containing medicines with ombitasvir/paritaprevir/ritonavir and dasabuvir is now contraindicated.
• Female patients on combined contraceptive therapy should be switched to an alternative method of contraception (e.g. progestogen-only contraception or non-hormonal methods) prior to starting therapy with the ombitasvir/paritaprevir/ritonavir and dasabuvir regimen.
• Ethinylestradiol-containing medicines can be restarted two (2) weeks following completion of treatment with ombitasvir/paritaprevir/ritonavir and dasabuvir.
• Please report all suspected adverse drug reactions to NPRA.

A directive [Ruj. Kami: (13) dlm. BPFK/PPP/07/25 Jld. 2] has been issued by NPRA for updates to the local product packaging insert and consumer medication information leaflet (Risalah Maklumat Ubat untuk Pengguna) related to this safety issue. Please refer to the directive for more information. 

References:

1. Badri PS et al. (2016). Drug Interactions with the Direct-Acting Antiviral Combination of Ombitasvir and Paritaprevir-Ritonavir. Antimicrobial Agents and Chemotherapy; (60) Number 1, 105-114.
2. Co-ordination Group for Mutual Recognition and Decentralised Procedures-Human, European Medicines Agency (2017). CMDh Recommendation Combined Hormonal Contraceptives (CHCs) Containing Ethinylestradiol. Doc.Ref.: CMDh/352/2017, 1-3.
3. Therapeutic Goods Administration (2017). Viekira PAK and Viekira PAK-RBV –interaction with ethinylestradiol. Medicines Safety Updates Volume 8 Number 2, 1-5.
4. The Malaysian National ADR database, NPRA [Accessed: May 2017].

DISCLAIMER

This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgement. While reasonable care has been taken to verify the accuracy of the information at the time of publication, the NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.