Daklinza - patient leaflet, side effects, dosage

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer(s) responsible for batch release

Bristol-Myers Squibb S.r.l.

Loc. Fontana del Ceraso

03012 Anagni (FR) Italy

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2).

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION

Periodic safety update reports

The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European s web-portal.

D. CONDITIONS OR RESTRICTIONS WITH REGA EFFECTIVE USE OF THE MEDICINAL PROD

Risk Management Plan (RMP)

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP.

An updated RMP should be submitted:

• At the request of the European Medicines Agency;
• Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.
• Obligation to conduct post-authorisation measures

The MAH shall complete, within the stated timeframe, the below measures:

Desciioi-on	Due date
In order to evaluate the recurrence of hepatocellular carcinoma associated with Dak’inza, the MAH 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. The final study report shall be submitted by:	Q2 2023

• 9. SPECIAL STORAGE CONDITIONS

• 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

  UNIT DOSE BLISTER (PERFORATED) TEXT

  
  

  BMS

  EXP

  Lot

  Daklinza 30 mg tablets daclatasvir

  2. NAME OF THE MARKETING AUTHORISATION HOLDER

  3. EXPIRY DATE

  4. BATCH NUMBER

  1. NAME OF THE MEDICINAL PRODUCT

  5. OTHER

  
  

  CALENDAR BLISTER (NON-PERFORATED) TEXT

  
  

  1. NAME OF THE MEDICINAL PRODUCT

  
  

  Daklinza 30 mg tablets daclatasvir

  
  

  2. NAME OF THE MARKETING AUTHORISATION HOLDER

  
  

  Bristol-Myers Squibb Pharma EEIG

  
  

  3. EXPIRY DATE

  
  

  EXP

  
  

  4. BATCH NUMBER

  
  

  Lot

  
  

  5. OTHER

  
  
  
  
  
  

  OUTER CARTON TEXT

  
  

  1. NAME OF THE MEDICINAL PRODUCT

  
  

  Daklinza 60 mg film-coated tablets daclatasvir

  
  

  2. STATEMENT OF ACTIVE SUBSTANCE(S)

  
  

  Each film-coated tablet contains 60 mg of daclatasvir (as dihydrochloride).

  
  

  3. LIST OF EXCIPIENTS

  
  

  Contains lactose.

  See package leaflet for further information.

  
  

  4. PHARMACEUTICAL FORM AND CONTENTS

  
  

  28 film-coated tablets

  28 × 1 film-coated tablet

  
  
  
  

  5. METHOD AND ROUTE(S) OF ADML ISTRATION

  
  

  Read the package leaflet before use. Oral use.

  
  

  6. SPECIAL WARNING x

  
  

  THE MEDICINAL PRODUCT MUST BE STORED OUT

  
  

  OF THE SIGHT AND P E/v^Ii OF CHILDREN

  
  

  Keep out of the si

  ach of children.

  
  

  EXPIRY DATE

  EXP

  
  

• 9. SPECIAL STORAGE CONDITIONS

• 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

  UNIT DOSE BLISTER (PERFORATED) TEXT

  
  

  BMS

  EXP

  Lot

  Daklinza 60 mg tablets daclatasvir

  2. NAME OF THE MARKETING AUTHORISATION HOLDER

  3. EXPIRY DATE

  4. BATCH NUMBER

  1. NAME OF THE MEDICINAL PRODUCT

  5. OTHER

  
  

  CALENDAR BLISTER (NON-PERFORATED) TEXT

  
  

  1. NAME OF THE MEDICINAL PRODUCT

  
  

  Daklinza 60 mg tablets daclatasvir

  
  

  2. NAME OF THE MARKETING AUTHORISATION HOLDER

  
  

  Bristol-Myers Squibb Pharma EEIG

  
  

  3. EXPIRY DATE

  
  

  EXP

  
  

  4. BATCH NUMBER

  
  

  Lot

  
  

  5. OTHER

  
  
  
  
  
  

Package leaflet: Information for the patient

Daklinza 30 mg film-coated tablets

Daklinza 60 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.

What you need to know before you take Daklinza o 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 doct monitor you more closely

your liver is damaged and not functioning properly (decompensated liver disease) you have diabetes. You may need closer monitoring of your blood glucose levels and/or adjustment of your diabetes medication after starting Daklinza. Some diabetic patients have experienced low sugar levels in the blood (hypoglycaemia) after starting treatment with medicines like Daklinza.

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 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, c arbamazepine, 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.

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 trea with Daklinza.

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

3. How to take Dakli

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

nsure 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 table 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 ta 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 yo

4. Possible side effects

Like all medicines, this medicine can cause side effects, alt

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 i

difficulty sleeping dizziness

migraine

nausea (feeling sic

diarrhoea, abdominal pain

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

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 comm 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 Th. s 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 or 60 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 30 mg and 60 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 Bristol-Myers Squibb Pharma EEIG Plaza 254

Blanchardstown Corporate Park 2

Dublin 15, D15 T867

Ireland

Österreich

Bristol-Myers Squibb GesmbH

Tel: + 43 1 60 14 30

Polska

B ristol-M yers S quibb P olska S p. z o. o.

Tel.: + 48 22 5796666

Portugal

Bristol-Myers Squibb Farmacêutica Portuguesa, S.A.

Tel: + 351 21 440 70 00

Detailed information on this medicine is available on the European Medicines Agency web site:

52

One treatment-experienced patient achieved SVR12 per local HCV RNA results.

Other non-responders included 4 patients with HCV RNA < LLOQ target not detected (TND) at end of treatment, but who were lost to follow-up at post-treatment Week 12 and subsequent time points, and 1 patient who had no on-treatment HCV RNA results due to early discontinuation.

Compassionate Use hi h i k f d i d h ihi

Patients with HCV infection (across genotypes) at high risk of decompensation or death within

12 months if left untreated were treated under compassionate use programmes. Patients with genotype 3 infection were treated with daclatasvir + sofosbuvir +/- ribavirin for 12 or 24 weeks, where the longer treatment duration was associated with a lower risk for relapse (around 5%) in a preliminary analysis. The relevance of including ribavirin as part of the 24-week regimen is unclear. In one cohort the majority of patients were treated with daclatasvir + sofosbuvir + ribavirin for 12 weeks. The relapse rate was around 15%, and similar for patients with Child-Pugh A, B and C. The programmes do not allow for a direct comparison of efficacy between the 12– and 24-week regimens.

Daclatasvir in combination with peginterferon alfa and ribavirin

AI444042 and AI444010 were randomised, double-blind studies that evaluated the efficacy and safety of daclatasvir in combination with peginterferon alfa and ribavirin (pegIFN/RBV) in the treatment of chronic HCV infection in treatment-naïve adults with compensated liver disease (including cirrhosis). AI444042 enrolled patients with HCV genotype 4 infection and AI444010 enrolled patients with either genotype 1 or 4. AI444043 was an open-label, single-arm study of daclatasvir with pegIFN/RBV in treatment-naïve adults with chronic HCV genotype 1 infection who were co-infected with HIV.

AI444042: Patients received daclatasvir 60 mg once daily (n=82) or placebo (n=42) plus pegIFN/RBV for 24 weeks. Patients in the daclatasvir treatment group who did not have HCV RNA undetectable at both Weeks 4 and 12 and all placebo-treated patients continued pegIFN/RBV for another 24 weeks. Treated patients had a median age of 49 years (range: 20 to 71); 77% of patients were white; 19% were black/African-American; 4% were Hispanic or Latino. Ten percent of patients had compensated cirrhosis, and 75% of patients had IL-28B rs12979860 non-CC genotypes. Treatment outcomes in study AI444042 are presented in Table 14. Response was rapid (at Week 4 91% of daclatasvir-treated patients had HCV RNA <LLOQ). SVR12 rates were higher for patients with the IL-28B CC genotype than for those with non-CC genotypes and for patients with baseline HCV RNA less than 800,000 IU/ml but consistently higher in the daclatasvir-treated patients than for placebo-treated patients in all subgroups.

AI444010: Patients received daclatasvir 60 mg once daily (n=158) or placebo (n=78) plus pegIFN/RBV through Week 12. Patients assigned to daclatasvir 60 mg once-daily treatment group who had HCV RNA <LLOQ at Week 4 and undetectable at Week 10 were then randomised to receive another 12 weeks of daclatasvir 60 mg + pegIFN/RBV or placebo + pegIFN/RBV for a total treatment duration of 24 weeks. Patients originally assigned to placebo and those in the daclatasvir group who did not achieve HCV RNA <LLOQ at Week 4 and undetectable at Week 10 continued pegIFN/RBV