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Daklinza (daclatasvir dihydrochloride) – Package leaflet - J05AX14

Updated on site: 06-Oct-2017

Medication nameDaklinza
ATC CodeJ05AX14
Substancedaclatasvir dihydrochloride
ManufacturerBristol-Myers Squibb Pharma EEIG

Package leaflet: Information for the patient

Daklinza 30 mg film-coated tablets Daklinza 60 mg film-coated tablets Daklinza 90 mg film-coated tablets daclatasvir

This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects.

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1.What Daklinza is and what it is used for

2.What you need to know before you take Daklinza

3.How to take Daklinza

4.Possible side effects

5.How to store Daklinza

6.Contents of the pack and other information

1.What Daklinza is and what it is used for

Daklinza contains the active ingredient daclatasvir. It is used to treat adults with hepatitis C, an infectious disease that affects the liver, caused by the hepatitis C virus.

This medicine works by stopping the hepatitis C virus from multiplying and infecting new cells. This lowers the amount of hepatitis C virus in your body and removes the virus from your blood over a period of time.

Daklinza must always be used together with other medicines against hepatitis C infection and must never be used by itself.

It is very important that you also read the package leaflets for the other medicines that you will be taking with Daklinza. If you have any questions about your medicines, please ask your doctor or pharmacist.

2. What you need to know before you take Daklinza

Do not take Daklinza

if you are allergic to daclatasvir or any of the other ingredients of this medicine (listed in section 6 of this leaflet)

if you are taking (by mouth or other ways that affect the whole body) any of the following medicines

-phenytoin, carbamazepine, oxcarbazepine or phenobarbital, used to treat epileptic seizures

-rifampicin, rifabutin or rifapentine, antibiotics used to treat tuberculosis

-dexamethasone, a steroid used to treat allergic and inflammatory diseases

-medicines containing St. John’s wort (Hypericum perforatum, a herbal preparation).

These medicines lower the effect of Daklinza and may result in your treatment not working. If you take any of these medicines, tell your doctor immediately.

Since Daklinza must always be used in combination with other medicines against hepatitis C infection, please make sure that you read the "Do not take" section of the package leaflets for these medicines. If you are unsure of any information in the package leaflets, please contact your doctor or pharmacist.

Warnings and precautions

Talk to your doctor or pharmacist before taking Daklinza.

Tell your doctor if any of the following applies:

you currently take, or have taken in the last few months, the medicine amiodarone to treat irregular heartbeats (your doctor may consider alternative treatments if you have taken this medicine)

you have a current or previous infection with the hepatitis B virus, since your doctor may want to monitor you more closely

your liver is damaged and not functioning properly (decompensated liver disease)

Tell your doctor immediately if you are taking any medicines for heart problems and during treatment you experience:

Shortness of breath

Light-headedness

Palpitations

Fainting

Children and adolescents

Daklinza is not recommended for patients below 18 years of age. Daklinza has not yet been studied in children and adolescents.

Other medicines and Daklinza

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This is because Daklinza may affect the way some medicines work. In addition some medicines may affect the way Daklinza works. Your doctor may need to adjust the dose of Daklinza or you may not be able to take Daklinza with certain medicines.

Do not take Daklinza if you are taking any of the following medicines:

phenytoin, carbamazepine, oxcarbazepine or phenobarbital, used to treat epileptic seizures

rifampicin, rifabutin or rifapentine, antibiotics used to treat tuberculosis

dexamethasone, a steroid used to treat allergic and inflammatory diseases

medicines containing St. John’s wort (Hypericum perforatum, a herbal preparation).

These medicines lower the effect of Daklinza so your treatment will not work. If you take any of these medicines, tell your doctor immediately.

Tell your doctor or pharmacist if you take any of the following medicines:

amiodarone or digoxin, used to treat irregular heart beats

atazanavir/ritonavir, atazanavir/cobicistat, elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate combination tablet, etravirine, nevirapine or efavirenz, used to treat HIV infection

boceprevir or telaprevir, used to treat hepatitis C infection

clarithromycin, telithromycin or erythromycin, used to treat bacterial infections

warfarin and other similar medicines called vitamin K antagonists used to thin the blood. Your doctor may need to increase the frequency of your blood tests to check how well your blood can clot.

dabigatran etexilate, used to to prevent blood clots

ketoconazole, itraconazole, posaconazole or voriconazole, used to treat fungal infections

verapamil, diltiazem, nifedipine or amlodipine, used to decrease blood pressure

rosuvastatin, atorvastatin, fluvastatin, simvastatin, pitavastatin or pravastatin, used to lower blood cholesterol

oral contraceptives

With some of these medicines, your doctor may need to adjust your dose of Daklinza.

Pregnancy and contraception

Tell your doctor if you are pregnant, think you may be pregnant or are planning to become pregnant. If you become pregnant, stop taking Daklinza and tell your doctor immediately.

If you are pregnant you must not take Daklinza.

If you can become pregnant, use effective contraception during and for 5 weeks after your treatment with Daklinza.

Daklinza is sometimes used together with ribavirin. Ribavirin can harm your unborn baby. It is therefore very important that you (or your partner) do not become pregnant during this treatment.

Breast-feeding

It is not known whether Daklinza passes into human breast milk. You should not breastfeed during treatment with Daklinza.

Driving and using machines

Some patients have reported dizziness, difficulty concentrating, and vision problems while taking Daklinza with other medicines for their hepatitis C infection. If you have any of these side effects, do not drive or use any tools or machines.

Daklinza contains lactose

If you have been told by your doctor that you have an intolerance to some sugars (e.g. lactose), talk to your doctor before taking Daklinza.

3.How to take Daklinza

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

Recommended dose

The recommended dose of Daklinza is 60 mg once a day. Swallow the tablet whole. Do not chew or crush the tablet as it has a very unpleasant taste. Daklinza can be taken with or without a meal.

Some other medicines can interact with Daklinza, affecting the levels of Daklinza in your body. If you are taking any of these medicines, your doctor may decide to change your daily dose of Daklinza to ensure that the treatment is safe and effective for you.

Since Daklinza must always be used with other medicines against hepatitis C infection, please read the package leaflets for these medicines. If you have any questions, ask your doctor or pharmacist.

How long to take Daklinza

Make sure you take Daklinza for as long as your doctor has told you to take it.

The duration of your treatment with Daklinza will be either 12 or 24 weeks. The duration of your treatment will depend on whether you have previously received treatment for your hepatitis C infection, the condition of your liver, and what other medicines you will take with Daklinza. You may have to take your other medicines for different lengths of time.

If you take more Daklinza than you should

If you accidentally take more Daklinza tablets than your doctor recommended, contact your doctor at once or contact the nearest hospital for advice. Keep the tablet blister with you so that you can easily describe what you have taken.

If you forget to take Daklinza

It is important not to miss a dose of this medicine.

If you do miss a dose:

and you notice within 20 hours of the time you usually take Daklinza, you must take the tablet as soon as possible. Then take the next dose at your usual time.

and you notice 20 hours or more after the time you usually take Daklinza, wait and take the next dose at your usual time. Do not take a double dose (two doses close together).

If you stop taking Daklinza

It is important that you continue to take Daklinza during the whole treatment period. Otherwise the medicine may not work against the hepatitis C virus. Do not stop taking Daklinza unless your doctor told you to stop.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4.Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

When Daklinza is used together with sofosbuvir (without ribavirin), the following side effects have been reported.

Very common (may affect more than 1 in 10 people):

headache, fatigue

Common (may affect up to 1 in 10 people):

difficulty sleeping

dizziness

migraine

nausea (feeling sick), diarrhoea, abdominal pain

joint pain, aching or tender muscles, not caused by exercise

When Daklinza is used together with sofosbuvir and ribavirin, the following side effects have been reported.

Very common (may affect more than 1 in 10 people):

headache, nausea (feeling sick), fatigue

reduction in red blood cells (anaemia)

Common (may affect up to 1 in 10 people):

decreased appetite

difficulty sleeping, irritability

dizziness

migraine

shortness of breath, cough, nasal congestion (blocked nose)

hot flush

dry skin, unusual hair loss or thinning, rash, itching

diarrhoea, vomiting, abdominal pain, constipation, heartburn, excessive gas in the stomach or bowel

dry mouth

joint pain, aching or tender muscles, not caused by exercise

When Daklinza is used together with peginterferon alfa and ribavirin the reported side effects are the same as those listed in the package leaflets for these medicines. The most common of these side effects are listed below.

Very common (may affect more than 1 in 10 people):

decreased appetite

difficulty sleeping

headache

shortness of breath

nausea

fatigue

flu-like illness, fever

itching, dry skin, unusual hair loss or thinning, rash

diarrhoea

cough

joint pain, aching or tender muscles, not caused by exercise, unusual weakness

irritability

reduction in red blood cells (anaemia), reduction in white blood cells

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

5.How to store Daklinza

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and blister after "EXP". The expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Daklinza contains

The active substance is daclatasvir. Each film-coated tablet contains 30 mg, 60 mg or 90 mg daclatasvir (as dihydrochloride)

The other ingredients are

-Tablet core: anhydrous lactose (see section 2), microcrystalline cellulose, croscarmellose sodium, silicon dioxide (E551) and magnesium stearate

-Film-coating: hypromellose, titanium dioxide (E171), macrogol 400, indigo carmine aluminum lake (E132), yellow iron oxide (E172)

What Daklinza looks like and contents of the pack

Daklinza 30 mg: the film-coated tablet is green, biconvex, pentagonal shape with "BMS" debossed on one side and "213" on the other side.

Daklinza 60 mg: the film-coated tablet is light green, biconvex, pentagonal shape with "BMS" debossed on one side and "215" on the other side.

Daklinza 90 mg: the film-coated tablet is light green, biconvex, round shape with "BMS" embossed on one side and "011" on the other side

Daklinza 30 mg, 60 mg and 90 mg film-coated tablets are available in packs of 28 tablets in non- perforated calendar blisters and perforated unit dose blisters.

Not all packages may be marketed in your country.

Marketing Authorisation Holder

Manufacturer

Bristol-Myers Squibb Pharma EEIG

Bristol-Myers Squibb S.r.l.

Uxbridge Business Park

Loc. Fontana del Ceraso

Sanderson Road

03012 Anagni (FR)

Uxbridge UB8 1DH

Italy

United Kingdom

 

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

Belgique/België/Belgien

Lietuva

N.V. Bristol-Myers Squibb Belgium S.A.

Bristol-Myers Squibb Gyógyszerkereskedelmi Kft.

Tél/Tel: + 32 2 352 76 11

Tel: +370 52 369140

България

Luxembourg/Luxemburg

Bristol-Myers Squibb Gyógyszerkereskedelmi Kft. N.V. Bristol-Myers Squibb Belgium S.A.

Teл.: + 359 800 12 400

Tél/Tel: + 32 2 352 76 11

Česká republika

Magyarország

Bristol-Myers Squibb spol. s r.o.

Bristol-Myers Squibb Gyógyszerkereskedelmi Kft.

Tel: + 420 221 016 111

Tel.: + 36 1 301 9700

Danmark

Malta

Bristol-Myers Squibb

BRISTOL-MYERS SQUIBB S.R.L.

Tlf: + 45 45 93 05 06

Tel: + 39 06 50 39 61

Deutschland

Nederland

Bristol-Myers Squibb GmbH & Co. KGaA

Bristol-Myers Squibb B.V.

Tel: + 31 (0)30 300 2222

Eesti

Norge

Bristol-Myers Squibb Gyógyszerkereskedelmi Kft. Bristol-Myers Squibb Norway Ltd

Tel: +372 640 1030

Tlf: + 47 67 55 53 50

Ελλάδα

Österreich

BRISTOL-MYERS SQUIBB A.E.

Bristol-Myers Squibb GesmbH

Τηλ: + 30 210 6074300

Tel: + 43 1 60 14 30

España

Polska

BRISTOL-MYERS SQUIBB, S.A.

BRISTOL-MYERS SQUIBB POLSKA SP. Z O.O.

Tel: + 34 91 456 53 00

Tel.: + 48 22 5796666

France

Portugal

Bristol-Myers Squibb SARL

Bristol-Myers Squibb Farmacêutica Portuguesa,

Tél: + 33 (0)1 58 83 84 96

S.A.

 

Tel: + 351 21 440 70 00

Hrvatska

România

Bristol-Myers Squibb spol. s r.o.

Bristol-Myers Squibb Gyógyszerkereskedelmi Kft.

TEL: +385 1 2078 508

Tel: + 40 (0)21 272 16 00

Ireland

Slovenija

Bristol-Myers Squibb Pharmaceuticals

Bristol-Myers Squibb spol. s r.o.

Tel: + 353 (1 800) 749 749

Tel: +386 1 2355 100

Ísland

Slovenská republika

Vistor hf.

Bristol-Myers Squibb spol. s r.o.

Sími: + 354 535 7000

Tel: + 421 2 59298411

Italia

Suomi/Finland

BRISTOL-MYERS SQUIBB S.R.L.

Oy Bristol-Myers Squibb (Finland) Ab

Tel: + 39 06 50 39 61

Puh/Tel: + 358 9 251 21 230

Κύπρος

Sverige

BRISTOL-MYERS SQUIBB A.E.

Bristol-Myers Squibb AB

Τηλ: + 357 800 92666

Tel: + 46 8 704 71 00

Latvija

United Kingdom

Bristol-Myers Squibb Gyógyszerkereskedelmi Kft. Bristol-Myers Squibb Pharmaceuticals Ltd

Tel: +371 67708347

Tel: + 44 (0800) 731 1736

Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu.

ANNEX IV

SCIENTIFIC CONCLUSIONS

Scientific conclusions

Hepatitis В virus (HBV) and hepatitis C virus (HCV) co-infection is not uncommon due to overlapping transmission modes. HCV infection is known to cause suppression of HBV replication in co-infected patients. The virological and immunological aspects of HBV/HCV co-infection are not fully comprehended. Although liver disease activity and progression are generally more severe in the presence of double infection, HBV replication is often suppressed in the presence of HCV coinfection. The European Association for the Study of the Liver (EASL) recommendations on treatment of hepatitis C makes reference to the potential risk of HBV reactivation during or after HCV clearance.

Direct-acting antiviral agents (DAAs) target specific non-structural proteins of the hepatitis C virus and result in disruption of viral replication and infection. Given their increased potency against HCV and lack of anti-HBV activity, the risk of HBV reactivation may be greater with newer HCV treatment regimens than with the previously approved interferon-based HCV treatments. Literature cases (Balagopal et al., 2015; Collins et al., 2015; Ende et al., 2015) described HCV viral load in patients treated with direct acting antivirals (DAA) in interferon-free regimens, and further cases have been identified in EudraVigilance. Some of the cases identified with DAAs had serious outcomes, with worsening of hepatic status and at least one case where the patient required liver transplantation.

HBV replication after starting treatment with DAAs for HCV infection is not currently described in the product information of currently authorised products and in view of the seriousness of the events described, the need for intervention on HBV replication and the biological plausibility of the replication it was considered that further investigation was warranted. The current referral procedure was triggered by the European Commission (EC) to allow further investigation of the risk of hepatitis B virus replication after starting treatment with DAAs and recommend any appropriate measure to minimise the risk.

Following the initiation of this review, results from a study (Reig et al. 2016) performed between October 2014 and December 2015 in Hepatology Units of four University Spanish hospitals in patients with chronic hepatitis C and a history of hepatocellular carcinoma (HCC) treated with DAAs suggested unexpected early HCC recurrence.

It was considered that in addition to the hepatitis B virus reactivation, the risk of hepatocellular carcinoma should also be further investigated and that consideration should be given for adequate measures to optimise the safe and effective use of these medicinal products. The European Commission therefore extended the scope of the procedure in April 2016 to allow consideration of other data to assess the risk of hepatocellular carcinoma and its impact on the benefit-risk balance for all DAAs in the treatment of chronic hepatitis C.

As both requests for the triggered procedure result from the evaluation of data resulting from pharmacovigilance activities, the EC requested the opinion to be adopted by the Committee for Medicinal Products for Human Use (CHMP) on the basis of a recommendation of the Pharmacovigilance Risk Assessment Committee (PRAC).

Overall summary of the scientific evaluation by the PRAC

In its assessment, the PRAC considered all the data submitted by the MAHs, as well as literature and additional information from a scientific advisory group in relation to the risk of hepatitis B reactivation and to the recurrence and occurrence of hepatocellular carcinoma.

Hepatitis B virus reactivation

With regards to the risk of hepatitis B reactivation, since chronic hepatitis B infection (HbsAg+) was generally considered an exclusion criterion and the collection of data regarding HBV serology and

DNA was not mandatory in the development programme of DAAs agents, there is limited information on hepatitis B reactivation obtainable from the completed clinical trials. Therefore data on HBV reactivation with DAAs mostly arose post-marketing.

The available data provide evidence that the reactivation of HBV replication may occur in the context of the treatment of chronic HCV active infection with any form of effective treatment in patients co- infected with HBV and HCV. The reactivation may occur mostly in subjects with detectable HBsAg and active HBV replication of any level, as evaluated by measurable levels of HBV-DNA, but may also occur in subjects without detectable HBsAg though with detectable anti-HBc antibody, of which a small percentage may also present with variable levels of active HBV replication.

Although severe and even fatal cases of HBV reactivation have been described in the literature, the available data indicate that reactivation of HBV replication may mostly be mild and without clinical consequences. The impact of chronic HCV infection characteristics, such as HCV genotype, viral load and histopathologic staging, on the risk of occurrence of HBV reactivation could not be clarified from the available data. It may be assumed however that patients with more advanced liver disease may have a higher risk of severe clinical complications should HBV reactivation occur. Generally, the reactivation occurred shortly after the initiation of treatment in a pattern that implies a correlation with the rapid decrease in HCV viral load which characterises the viral load dynamics with DAAs.

Overall, the PRAC was of the view that evidence exists of a risk of HBV reactivation in HBV/HCV co-infected patients treated with DAAs and therefore HBV reactivation in co-infected patients should be considered as an important identified risk which should be closely monitored through routine risk minimisation activities.

In order to minimise the risk of HBV reactivation, the PRAC recommended that all patients should be screened for HBV infection before initiation of treatment with DAAs and that patients presenting a co- infection HBV/HCV should be monitored and managed according to current clinical guidelines. The product information should reflect these recommendations and inform healthcare professionals about this risk. In addition, patients should be advised to contact their doctor if they have ever been infected with HBV as close monitoring is required.

Hepatocellular carcinoma

With regards to the review of HCC with DAAs, MAHs were requested to perform a comprehensive review of all available data from clinical trials, observational studies, spontaneous reports and published literature on HCC in patients with chronic hepatitis C after treatment with DAAs.

A study from Reig et al. (2016) showed a signal of HCC recurrence in patients treated with DAAs; similar results were obtained by Conti et al. (2016). Other published data from larger cohorts did not support the findings (Pol et al, 2016). However, these cohorts were either not designed for assessing HCC recurrence, as is the case of the ANRS CO22 HEPATHER cohort, or included a limited number of patients with a previous HCC reaching complete radiological response and subsequently treated with DAAs as in the ANRS CO12 CirVir cohort.

Overall, the PRAC considered that further studies were warranted to further characterise the risk of HCC recurrence associated with DAAs, in order to address remaining uncertainties about this potential risk and conclude on the need for any additional advice on clinical management. Taking all available data into account, the PRAC was of the view that MAHs should conduct and submit the results of a prospective safety study using data deriving from a cohort of a well-defined group of patients, based on an agreed protocol setting out criteria for entry and follow-up of patients in terms of timing and method for screening. The protocol of this study shall be submitted to the PRAC by 15 June 2017 and the final study results by Q4 2019.

Based on the findings of Reig et al, concerns on the development of de novo HCC in cirrhotic HCV patients treated with DAA were also raised, as these patients may harbour not yet diagnosed HCC.

Clinical trial data on incidence of new on-set HCC show higher point estimates for HCC after reaching SVR with IFN-free regimens compared to IFN-containing regimens, also when stratifying by presence of cirrhosis. However, the difficulty of fully controlling confounding in this non-randomised comparison was recognised. Still, it was considered that the impact of DAAs therapies on the incidence and type of de novo HCC should be further investigated by the MAHs through a prospective cohort study to be conducted in HCV infected patients with compensated cirrhosis (CPT-A) without history of HCC and treated with DAAs. The research should capture prospectively the known risk factors for HCC and the periodic image testing for HCC diagnosis, according to current European clinical guidelines (EASL). A feasibility assessment of the use of existing data sources for this purpose should be submitted for PRAC assessment by 15 June 2017. Should the use of existing data sources not show feasible, a proposal for a prospective collection of data should be provided.

The PRAC was also of the view that ‘emergence of hepatocellular carcinoma’ and ‘recurrence of hepatocellular carcinoma’ should be considered as important potential risks. In addition, ‘patients with previous HCC’ should be considered as missing information, since this population was excluded from available clinical trials. The RMP of the relevant medicinal products will be updated accordingly.

In conclusion, the PRAC considered that the benefit-risk balance of DAAs-containing products remained favourable subject to the amendments of the terms of the marketing authorisations.

Grounds for PRAC recommendation

Whereas,

The PRAC considered the procedure under Article 20 of Regulation (EC) No 726/2004 resulting from pharmacovigilance data for direct-acting antiviral agents (DAAs) indicated in the treatment chronic hepatitis C.

The PRAC reviewed the totality of the data submitted in writing and during the oral explanations by the marketing authorisation holders in relation to the risk of hepatitis B reactivation and to the concerns raised following reports of hepatocellular carcinoma in patients using DAAs, as well as the outcome of the meeting of the scientific advisory group on HIV/Viral diseases.

Concerning HBV reactivation, the PRAC concluded that available data provide evidence of a risk of HBV reactivation in patients co-infected with HBV/HCV treated for chronic hepatitis C with DAAs. The PRAC was of the view that all patients should be screened for hepatitis B virus infection before initiation of treatment with DAAs. Patients with HBV/HCV co-infection should be monitored during and after treatment according to current clinical guidelines. The product information will include a warning to inform about the risk of hepatitis B reactivation and reflect these recommendations.

Concerning the risk of recurrence of HCC in patients using DAAs, the PRAC considered that further data are required on the impact of DAAs treatment on the incidence of HCC recurrence. All MAHs of DAAs shall conduct a prospective safety study in a well-defined group of patients based on an agreed protocol setting out criteria for entry and follow-up. A joint study is encouraged.

The PRAC was also of the opinion that the impact of DAAs treatment on the incidence and type of de novo hepatocellular carcinoma should be further investigated though a prospective cohort study in HCV infected patients with cirrhosis. A joint study is encouraged.

In view of the above, the PRAC considers that the benefit-risk balance of direct-acting antivirals remains favourable subject to the amendments to the terms of the marketing authorisations.

The PRAC, as a consequence, recommends the variation to the terms of the marketing authorisations for Daklinza, Exviera, Harvoni, Olysio, Sovaldi and Viekirax.

CHMP opinion and detailed explanation of the scientific grounds for the differences from the PRAC recommendation

Having reviewed the PRAC recommendation, the CHMP agreed with the overall scientific conclusions and grounds for recommendation.

In accordance with the PRAC recommendation, in order to evaluate the recurrence of hepatocellular carcinoma associated with direct-acting antivirals, the MAHs shall conduct and submit the results of a prospective safety study using data deriving from a cohort of a well-defined group of patients, based on an agreed protocol setting out criteria for entry and follow-up of patients in terms of timing and method for screening.

After further consideration of the timelines proposed for the submission of the final study report and taking into account that the protocol is due to be submitted by 15 June 2017, the CHMP was of the opinion that the date for the submission of the final study report should be postponed to Q2 2021 in order to allow sufficient time for agreement on a joint protocol and for collection of sufficient data to adequately respond to the scientific question.

The wording of the condition to the marketing authorisation has been amended accordingly. In addition, interim results should be submitted for PRAC assessment by Q4 2019.

The RMP should be updated accordingly within 3 months of this CHMP opinion.

Overall conclusion

The CHMP, as a consequence, considers that the benefit-risk balance of Daklinza, Exviera, Harvoni, Olysio, Sovaldi and Viekirax remains favourable subject to the amendments to the product information and to the conditions described above.

Therefore the CHMP recommends the variation to the terms of the marketing authorisations for Daklinza, Exviera, Harvoni, Olysio, Sovaldi and Viekirax.

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