Direct-acting antivirals indicated for treatment of hepatitis C (interferon-free) - referral

Current status

European Commission final decision

Overview

 

Direct-acting antivirals for hepatitis C: EMA confirms recommendation to screen for hepatitis B

Further studies needed to assess risk of liver cancer with these medicines

On 15 December 2016, the European Medicines Agency (EMA) confirmed its recommendation to screen all patients for hepatitis B before starting treatment with direct-acting antivirals for hepatitis C; patients infected with both hepatitis B and C viruses must be monitored and managed according to current clinical guidelines. These measures aim to minimise the risk of hepatitis B re-activation with direct-acting antivirals.
Direct-acting antivirals (marketed in the EU as Daklinza, Exviera, Harvoni, Olysio, Sovaldi and Viekirax)1 are important medicines for treating chronic (long term) hepatitis C, a disease of the liver caused by hepatitis C virus.

The review of direct-acting antivirals was carried out by EMA's Pharmacovigilance Risk Assessment Committee (PRAC). It looked into cases of returning signs and symptoms of previously inactive hepatitis B infection (re-activation) when patients were treated with direct-acting antivirals for hepatitis C.

The hepatitis B re-activation is thought to be the consequence of the rapid treatment-induced reduction in hepatitis C virus (as co-infection is known to suppress the hepatitis B virus) and the lack of activity of direct-acting antivirals against hepatitis B virus.

The PRAC recommendation to include a warning in the prescribing information about hepatitis B re-activation and how to minimise it was endorsed by EMA's Committee for Medicinal Products for Human Use (CHMP).

In addition to data on hepatitis B re-activation, EMA also reviewed data suggesting that patients treated with direct-acting antivirals who have previously been treated for liver cancer could be at risk of their cancer returning early.

The CHMP agreed that companies should carry out a study to evaluate the risk of liver cancer returning with direct-acting antivirals. In this context, further research is also needed on the risk of new liver cancers in patients with chronic hepatitis C and cirrhosis (liver scarring) that are treated with direct-acting antivirals.

The CHMP's opinion was passed to the European Commission, which issued a legally binding decision valid throughout the EU.

Information for patients

Direct-acting antiviral medicines (including Daklinza, Exviera, Harvoni, Olysio, Sovaldi and Viekirax) are effective treatments for long-term hepatitis C that can be used without interferons (medicines known to have troublesome side effects).

• If you also have hepatitis B virus infection, direct-acting antivirals for hepatitis C may cause the hepatitis B infection to become active again. Re-activation of hepatitis B may cause serious liver problems.
• You will be tested for hepatitis B before starting treatment with direct-acting antivirals to check if you might be at risk of hepatitis B reactivation.
• If you have both hepatitis B and C virus infections, your doctor will monitor you closely during and after treatment with direct-acting antivirals. You may also receive treatment for hepatitis B.
• Tell your doctor if you have or have had hepatitis B infection. Speak to your doctor if you have any question or concern regarding your treatment.

Information for healthcare professionals

Cases of hepatitis B re-activation (with severe consequences) have been reported in patients co-infected with hepatitis B and C viruses treated with direct-acting antivirals. The frequency of such re-activation appears to be low.

• Hepatitis B re-activation is thought to be caused by the rapid treatment-induced reduction in hepatitis C virus (as co-infection is known to suppress the hepatitis B virus) and the lack of anti-hepatitis B activity of direct-acting antivirals.
• All patients should be screened for hepatitis B before starting treatment with direct-acting antivirals for hepatitis C; patients co-infected with hepatitis B and C must then be monitored and managed according to current clinical guidelines.
• Further studies are needed to evaluate the risk of recurring or newly diagnosed hepatocellular carcinoma in patients treated with direct-acting antivirals. Companies marketing these medicines have been asked to perform a prospective study to assess the risk of recurrence of previously treated hepatocellular carcinoma, and a prospective cohort study in patients with cirrhosis to assess the incidence and type of de novo hepatocellular carcinoma.
• Therapeutic guidelines recommend that, in patients with advanced fibrosis and cirrhosis, surveillance for hepatocellular carcinoma should continue even after sustained viral response has been achieved.

More about the medicines

The review covered the following direct-acting antivirals for treating chronic hepatitis C: Daklinza (daclatasvir), Exviera (dasabuvir), Harvoni (sofosbuvir / ledipasvir), Olysio (simeprevir), Sovaldi (sofosbuvir) and Viekirax (ombitasvir / paritaprevir / ritonavir). Since the start of this review, two other direct-acting antivirals, Epclusa (sofosbuvir / velpatasvir) and Zepatier (elbasvir / grazoprevir), have been authorised in the EU.

Direct-acting antivirals work by blocking the action of proteins which are essential for making new hepatitis C viruses.

More information on these medicines can be found on EMA's website.

More about the procedure

The review of direct-acting antivirals for the treatment of hepatitis C was initiated on 17 March 2016 at the request of the European Commission, under Article 20 of Regulation (EC) No 726/2004. On 14 April 2016 the scope of the review was extended to include the risk of liver cancer, in addition to the potential risk of hepatitis B re-activation.

The review was carried out by the Pharmacovigilance Risk Assessment Committee (PRAC), the committee responsible for the evaluation of safety issues for human medicines, which made a set of recommendations.

The PRAC recommendations were sent to the Committee for Medicinal Products for Human Use (CHMP), responsible for questions concerning medicines for human use, which adopted the Agency's opinion. The CHMP opinion was forwarded to the European Commission, which issued a final legally binding decision applicable in all EU Member States on 23/2/2017.

Direct-acting antivirals for hepatitis C Article-20 procedure - Direct-acting antivirals for hepatitis C: EMA confirms recommendation to screen for hepatitis B

Reference Number: EMA/141732/2017

Key facts

About this medicine

• Approved name:
  Direct-acting antivirals indicated for treatment of hepatitis C (interferon-free)
• International non-proprietary name (INN) or common name:
  • daclatasvir
  • dasabuvir
  • sofosbuvir
  • ledipasvir
  • simeprevir
  • ombitasvir
  • paritaprevir
  • ritonavir
• Associated names:
  • Sovaldi
  • Olysio
  • Viekirax
  • Harvoni
  • Exviera
  • Daklinza

About this procedure

• Current status:
  European Commission final decision
• Reference number:
  EMEA/H/A-20/1438
• Type:
  Article 20 procedures

  This type of procedure is triggered for medicines that have been authorised via the centralised procedure in case of quality, safety or efficacy issues.

• Authorisation model:
  Centrally authorised product(s)
• Decision making model:
  PRAC-CHMP-EC

Key dates and outcomes

• Procedure start date:
  17/03/2016
• PRAC recommendation date:
  01/12/2016
• CHMP opinion date:
  15/12/2016
• EC decision date:
  23/02/2017
• Outcome:
  Risk minimisation measures

All documents

Procedure started

Direct-acting antivirals for hepatitis C Article-20 procedure - Addendum to PRAC list of questions

Reference Number: EMA/PRAC/196081/2016

Direct-acting antivirals for hepatitis C Article-20 procedure - Review started (updated communication)

Reference Number: EMA/263596/2016

Direct-acting antivirals for hepatitis C Article-20 procedure - Addendum to notification

Direct-acting antivirals for hepatitis C Article-20 procedure - Review started

Reference Number: EMA/199242/2016

Direct-acting antivirals for hepatitis C Article-20 procedure - Notification

Direct-acting antivirals for hepatitis C Article-20 procedure - Timetable for the procedure

Reference Number: EMA/PRAC/196120/2016

Direct-acting antivirals for hepatitis C Article-20 procedure - PRAC list of questions

Reference Number: EMA/PRAC/188631/2016

Recommendation provided by Pharmacovigilance Risk Assessment Committee

Direct-acting antivirals for hepatitis C Article-20 procedure - PRAC warns of risk of hepatitis B re-activation with direct-acting antivirals for hepatitis C

Reference Number: EMA/795452/2016

Opinion provided by Committee for Medicinal Products for human Use

Direct-acting antivirals for hepatitis C Article-20 procedure - Annex III

Direct-acting antivirals for hepatitis C Article-20 procedure - Direct-acting antivirals for hepatitis C: EMA confirms recommendation to screen for hepatitis B

Reference Number: EMA/824717/2016

European Commission final decision

Direct-acting antivirals for hepatitis C Article-20 procedure - Direct-acting antivirals for hepatitis C: EMA confirms recommendation to screen for hepatitis B

Reference Number: EMA/141732/2017

Direct-acting antivirals for hepatitis C Article-20 procedure - Sovaldi Annex I-III

Direct-acting antivirals for hepatitis C Article-20 procedure - Olysio Annex I-III

Direct-acting antivirals for hepatitis C Article-20 procedure - Harvoni Annex I-III

Direct-acting antivirals for hepatitis C Article-20 procedure - Viekirax Annex I-III

Direct-acting antivirals for hepatitis C Article-20 procedure - Daklinza Annex I-III

Direct-acting antivirals for hepatitis C Article-20 procedure - Annex IV

Direct-acting antivirals for hepatitis C Article-20 procedure - Exviera Annex I-III

Direct-acting antivirals for hepatitis C Article-20 procedure - PRAC assessment report

AdoptedReference Number: EMA/103226/2017

Direct-acting antivirals for hepatitis C Article-20 procedure - Direct-acting antivirals for hepatitis C: EMA confirms recommendation to screen for hepatitis B

Reference Number: EMA/141732/2017

Description of documents published

Please note that some of the listed documents apply only to certain procedures.

• Overview - lay-language summary of the stage of the procedure
• Notification – a letter from a Member State, the European Commission or the marketing authorisation holder requesting the initiation of the procedure
• Scientific background – further background information from the triggering Member State on the issues leading to the initiation of the procedure (if applicable)
• List of questions – questions agreed by the Committee requesting further information from the marketing authorisation holder(s) / applicant(s) to evaluate the issues identified
• Timetable for the procedure – agreed timeframe to respond to the list of questions, to assess the issues and to adopt a conclusion
• List of medicines concerned by the procedure – medicine(s) / active substance(s) concerned, and marketing authorisation holder(s) / applicant(s)
• List of questions to be addressed by the stakeholders – call for data to be submitted by stakeholders (e.g. healthcare professionals, patient organisations, individual patients) (if applicable)
• Stakeholder submission form – form to be used by stakeholders to submit data (if applicable)
• Scientific conclusions – scientific conclusions of the PRAC and/or CHMP and/or CMDh
• Assessment report – PRAC or CHMP assessment and conclusions on the issues investigated, including divergent positions (if applicable)
• Divergent positions – divergent positions of the CHMP or CMDh members for pharmacovigilance procedures (if applicable)
• Changes to the summary of product characteristics, labelling and package leaflet (amended sections or fully revised version) (if applicable)
• Condition(s) to the marketing authorisation(s) – condition(s) for the safe and effective use of the medicine(s) (if applicable)
• Condition for lifting the suspension – condition to be fulfilled for the suspension of the marketing authorisation(s) to be lifted (if applicable)
• Timetable for implementation of CMDh position – agreed timeframe to submit and finalise the variation(s) implementing the outcome of the procedure (if applicable)

Note that older documents may have different titles.