Consumer medicine information

Daklinza Tablets

Daclatasvir

BRAND INFORMATION

Brand name

Daklinza

Active ingredient

Daclatasvir

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Daklinza Tablets.

What is in this leaflet

Read this leaflet carefully before taking DAKLINZA. This leaflet answers some common questions about DAKLINZA.

It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking DAKLINZA against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What DAKLINZA is used for

DAKLINZA is a trade name (manufacturer's name) for the medicine, daclatasvir. DAKLINZA is a direct acting antiviral agent (DAA) against the hepatitis C virus (HCV). DAKLINZA is an inhibitor of NS5A, which is a protein that is required to form new HCV particles.

You should not take DAKLINZA alone to treat chronic (lasting a long time) hepatitis C infection in adults. DAKLINZA should only be used together with other antiviral medicines such as sofosbuvir, or asunaprevir (SUNVEPRA), or together with SUNVEPRA, peginterferon alfa, and ribavirin.

How DAKLINZA Works

DAKLINZA (in combination with other medicines) works by stopping the HCV from multiplying and infecting liver cells. After you stop taking DAKLINZA, your doctor will monitor your blood for HCV. If HCV is still not detected in your blood at least 12 weeks after stopping treatment, you have what is called a sustained virologic response (SVR), also referred to as virologic cure.

It is not known if DAKLINZA is safe and effective in children under 18 years of age.

Ask your doctor if you have any questions about why DAKLINZA has been prescribed for you.

DAKLINZA is not addictive. This medicine is available only with a doctor's prescription.

Before you take DAKLINZA

It is important that you check the information below before you take DAKLINZA.

When you must not take DAKLINZA

DAKLINZA is sometimes used with peginterferon alfa and ribavirin. Peginterferon alfa and ribavirin may cause birth defects or death of your unborn baby. If you are pregnant or planning to become pregnant, or your sexual partner is pregnant or plans to become pregnant, do not take these medicines. You or your sexual partner should not become pregnant while taking peginterferon alfa and ribavirin, and for 6 months after treatment ends.

  • Two effective forms of birth control must be used, one by each partner, male and female, during treatment and for the 6 months after treatment with peginterferon alfa and ribavirin.
    Talk with your doctor about forms of birth control that may be used during this time.
  • Females must have a negative pregnancy test before starting treatment with peginterferon alfa and ribavirin, every month while being treated, and every month for 6 months after your treatment ends.

If you or your female sexual partner becomes pregnant while taking, or within 6 months after you stop taking, peginterferon alfa and ribavirin, tell your doctor right away.

Do not take DAKLINZA if you have an allergy to it or to any other ingredients in the formulation listed at the end of this leaflet.

Do not take DAKLINZA if you are currently taking any of these medicines:

  • carbamazepine
  • dexamethasone (when administered by injection or taken by mouth)
  • oxcarbazepine
  • phenobarbital
  • phenytoin
  • rifabutin
  • rifampicin
  • St. John's wort (Hypericum perforatum) or a product that contains St. John's wort

If you are not sure if any of these medicines are in the products you are taking, talk to your doctor or pharmacist.

Do not use DAKLINZA after the expiry date printed on the back of the pack. If this medicine is taken after the expiry date has passed, it may not work as well.

Do not take DAKLINZA if the packaging is torn or shows signs of tampering.

Before you start to take DAKLINZA

Tell your doctor if you:

  • have a current or previous infection with the hepatitis B virus
  • have liver problems other than hepatitis C infection
  • have had, or are intending to have, a liver transplant
  • have diabetes
  • have any other medical condition

DAKLINZA should not be used during pregnancy.

Tell your doctor if you are pregnant or intend to become pregnant. It is not known if DAKLINZA will harm your unborn baby.

If you can become pregnant, continue the use of effective contraception for 5 weeks after the end of your treatment with DAKLINZA.

If you are also taking ribavirin, you must follow the contraception instructions under "When you must not take DAKLINZA" above.

Tell your doctor or pharmacist if you are breast-feeding or plan to breast-feed. It is recommended that you do not breast-feed while taking DAKLINZA. It is not known if DAKLINZA passes into breast milk.

If you have not told your doctor about any of the above, tell them before you use DAKLINZA.

As DAKLINZA should only be used together with other antiviral medicines such as sofosbuvir, or SUNVEPRA, or together with SUNVEPRA, peginterferon alfa, and ribavirin, please read the Consumer Medicine Information for the other products prescribed by your doctor before starting DAKLINZA.

Taking other medicines

Be sure to inform your doctor of all medications you are taking including prescribed drugs, over the counter products, natural therapies, vitamin supplements and recreational drugs.

DAKLINZA and other medicines may affect each other. This can cause you to have too much or not enough DAKLINZA or other medicines in your body, which may affect the way DAKLINZA or your other medicines work, or may cause side effects.

Medicines for other conditions:

Tell your doctor if you are taking or starting to take medicines that contain:

  • amiodarone
  • atazanavir. You may need a lower dose of DAKLINZA (30 mg).
  • boceprevir or telaprevir. You may need a lower dose of DAKLINZA (30 mg).
  • clarithromycin, erythromycin. You may need a lower dose of DAKLINZA (30 mg).
  • dabigatran
  • digoxin
  • diltiazem, verapamil
  • efavirenz, etravirine, or nevirapine. You may need a higher dose of DAKLINZA (90 mg).
  • elvitegravir, cobicistat, emtricitabine, or tenofovir disoproxil fumarate. You may need a lower dose of DAKLINZA (30 mg).
  • fluconazole, ketoconazole, itraconazole, posaconazole, or voriconazole. You may need a lower dose of DAKLINZA (30 mg).
  • rosuvastatin, atorvastatin, fluvastatin, simvastatin, pitavastatin, or pravastatin
  • warfarin and other similar medicines called vitamin K antagonists used to thin the blood

Your doctor will be able to advise you about the most appropriate medications to treat your condition. It is important that you tell your doctor or pharmacist about the medicines you are taking, even if they are not listed in this leaflet.

They will be able to provide you with more information than is contained within this leaflet on the medicines you need to be careful with, or should avoid while taking DAKLINZA.

How to take DAKLINZA

DAKLINZA should be given only when prescribed by your doctor. Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

How much to take

Take DAKLINZA exactly as your doctor tells you to take it. Do not change your dose unless your doctor tells you to.

Do not stop taking DAKLINZA without first talking with your doctor. If you think there is a reason to stop taking DAKLINZA, talk with your doctor before doing so.

How to take it

Swallow the tablet whole with a drink such as a glass of water.

When to take DAKLINZA

Take DAKLINZA once each day with or without food.

How long to take it

Continue taking DAKLINZA for as long as your doctor tells you to.

Do not stop taking DAKLINZA unless your doctor tells you to - even if you feel better.

If you forget to take it

If you miss a dose of DAKLINZA and less than 20 hours have passed since you were to take the missed dose, take the missed dose as soon as possible. Take the next dose at your regular time.

If you miss a dose of DAKLINZA and more than 20 hours have passed since you were to take the missed dose, skip the missed dose. Take the next dose at your regular time.

Do not take 2 doses of DAKLINZA at the same time to make up for the missed dose.

If you take too much (overdose)

Immediately call your doctor or the Poisons Information Centre on 131126 in Australia, or go to the Accident and Emergency Centre at your nearest hospital if you or anyone else takes too much DAKLINZA. Do this even if there are no signs of discomfort or poisoning.

While you are using DAKLINZA

Things you must do

  • If you become pregnant while taking DAKLINZA, tell your doctor immediately.
  • If you are about to start taking any new medicines, tell your doctor and pharmacist that you are taking DAKLINZA. DAKLINZA and the other medicine may interfere with each other.
  • If you are taking DAKLINZA together with SUNVEPRA, your doctor may perform additional tests that will determine how well your liver is working. Please read the Consumer Medicine Information for SUNVEPRA.

Things you must not do

  • Do not give DAKLINZA to anyone else, even if they have the same condition as you.
  • Do not use DAKLINZA to treat any other complaints unless your doctor tells you to.
  • Do not stop taking DAKLINZA without checking with your doctor.

Things to be careful of

Be careful driving or operating machinery until you know how DAKLINZA affects you.

Make sure that you visit your doctor regularly throughout your entire course of treatment with DAKLINZA.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking DAKLINZA. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects

Ask your doctor or pharmacist to answer any questions you may have.

The most common side effects when DAKLINZA is taken in combination with SUNVEPRA include:

  • headache
  • tiredness
  • diarrhoea
  • nasal congestion (blocked nose)
  • nausea

The most common side effects when DAKLINZA is taken in combination with sofosbuvir (some patients in studies of this regimen also received ribavirin) include:

  • tiredness
  • headache
  • nausea
  • joint pain
  • diarrhoea

The most common side effects when DAKLINZA is taken in combination with SUNVEPRA, peginterferon alfa, and ribavirin include:

  • tiredness
  • headache
  • itching
  • unusual weakness
  • flu-like symptoms
  • insomnia
  • rash
  • anaemia
  • cough
  • dry skin
  • diarrhoea
  • nausea
  • hair loss
  • irritability
  • fever
  • muscle aches

If any of the following happen, tell your doctor immediately, or go to the Accident and Emergency Centre at your nearest hospital:

  • allergic reaction - swelling of the face, lips, or throat which makes breathing difficult

If you have these side effects, you may have had a serious reaction to DAKLINZA. You may need urgent medical attention or hospitalisation.

This is not a complete list of side effects, other side effects not listed above may also occur in some patients.

Tell your doctor if you notice anything that is making you feel unwell.

Do not be alarmed by this list of possible side effects. You may not experience any of them or only some of them.

After using DAKLINZA

Storage

Store DAKLINZA tablets in a cool dry place where the temperature stays below 30°C.

Keep your tablets in the original container until it is time to take them.

Do not store DAKLINZA or any other medicine in the bathroom or near the kitchen sink. Do not leave it in the car. Heat and dampness can destroy some medicines.

Keep DAKLINZA tablets where children cannot reach them. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking DAKLINZA tablets, or the tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product description

What it looks like

DAKLINZA tablets come in three strengths:

  • DAKLINZA 60 mg tablets are light green biconvex pentagonal debossed with "BMS" on one side and "215" on the other side. Available in packs of 7 and 28 tablets.
  • DAKLINZA 30 mg tablets are green biconvex pentagonal debossed with "BMS" on one side and "213" on the other side. Available in packs of 7 and 28 tablets.

Ingredients

Each capsule contains:

Active ingredients:

  • DAKLINZA 60 mg tablets - 60 mg of daclatasvir as daclatasvir dihydrochloride per tablet
  • DAKLINZA 30 mg tablets - 30 mg of daclatasvir as daclatasvir dihydrochloride per tablet

Other ingredients:

lactose, microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate, and OPADRY Green.

Opadry Green contains hypromellose, titanium dioxide, Macrogol 400, indigo carmine aluminum lake, and iron oxide yellow.

DAKLINZA tablets do not contain gluten or sucrose.

Registration Numbers

DAKLINZA 60 mg - AUST R 222742

DAKLINZA 30 mg - AUST R 222743

Sponsored by

Bristol-Myers Squibb Australia Pty Ltd,
4 Nexus Court, Mulgrave,
Victoria 3170, Australia

This information in no way replaces the advice of your doctor or pharmacist.

Date of Preparation: March 2020

V7.0 27 March 2020

Published by MIMS May 2020

BRAND INFORMATION

Brand name

Daklinza

Active ingredient

Daclatasvir

Schedule

S4

 

1 Name of Medicine

Daclatasvir.

6.7 Physicochemical Properties

Daklinza (daclatasvir), is a highly selective inhibitor of HCV nonstructural protein 5A (NS5A) replication complex. The chemical name for daclatasvir dihydrochloride is carbamic acid, N,N'-[[1,1'- biphenyl]-4,4'-diylbis [1H-imidazole-5,2-diyl-(2S)- 2,1-pyrrolidinediyl [(1S)-1-(1-methylethyl)-2-oxo- 2,1-ethanediyl]]]bis-, C,C'-dimethyl ester, hydrochloride (1:2).
Molecular formula: C40H50N8O6.2HCl. Molecular weight: 738.88 (free base); 811.80 (dihydrochloride salt).

Chemical Structure.


CAS number.

1009119-65-6.

2 Qualitative and Quantitative Composition

Daklinza 30 mg daclatasvir (equivalent to 33 mg daclatasvir dihydrochloride).

Excipients with known effect.

Each 30 mg tablet contains 58 mg of lactose.
Daklinza 60 mg daclatasvir (equivalent to 66 mg daclatasvir dihydrochloride).

Excipients with known effect.

Each 60 mg tablet contains 116 mg of lactose.
Daclatasvir drug substance is white to yellow. Daclatasvir dihydrochloride is freely soluble in water.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Daklinza (daclatasvir) 30 mg tablets are green biconvex pentagonal debossed with "BMS" on one side and "213" on the other side.
Daklinza (daclatasvir) 60 mg tablets are light green biconvex pentagonal debossed with “BMS” on one side and “215” on the other side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacodynamics.

The effect of daclatasvir 60 mg and 180 mg on the QTc interval was evaluated in a randomized, partially blinded, placebo controlled, positive controlled thorough QT study in 56 healthy subjects. Single doses of 60 mg or 180 mg daclatasvir did not have a clinically relevant effect on QTc interval as corrected by Fridericia's method (QTcF). There was no significant relationship between increased daclatasvir plasma concentration and change in QTc. A daclatasvir dose of 180 mg is expected to bracket the highest plasma concentrations expected clinically.

Mechanism of action.

Daclatasvir is a direct acting antiviral agent (DAA) against the hepatitis C virus. Daclatasvir is an inhibitor of NS5A, a multifunctional protein that is an essential component of the HCV replication complex. Daclatasvir inhibits both viral RNA replication and virion assembly. In vitro and computer modelling data indicate that daclatasvir interacts with the N-terminus within domain 1 of the protein, which may cause structural distortions that interfere with NS5A functions.

Antiviral activity.

Daclatasvir is a potent pangenotypic NS5A replication complex inhibitor with effective concentration (50% reduction, EC50) values from picomolar to low nanomolar. EC50 values of daclatasvir range from 0.001 to 1.25 nanomolar in genotype 1a, 1b, 3a, 4a, 5a, and 6a, and from 0.034 to 19 nanomolar in genotype 2a cell based replicon assays. In addition, daclatasvir inhibits infectious genotype 2a (JFH-1) virus with EC50 value of 0.020 nanomolar. In HCV genotype 1a infected subjects, a single 60 mg dose of daclatasvir resulted in a 3.2 log10 IU/mL mean reduction in viral load measured after 24 hours.
Daclatasvir showed additive to synergistic interactions with interferon alfa, HCV NS3 protease inhibitors, HCV NS5B non-nucleoside inhibitors, and HCV NS5B nucleoside analogs in combination studies using the cell based HCV replicon system. No antagonism of antiviral activity was observed.

Resistance.

In cell culture.

Substitutions conferring daclatasvir resistance in HCV genotypes 1-6 were selected in the cell based replicon system and observed in the N-terminal 100 amino acid region of NS5A. L31V and Y93H were frequently observed resistance substitutions in genotype 1b, while M28T, L31V/M, Q30E/H/R, and Y93C/H/N were frequently observed resistance substitutions in genotype 1a. Single amino acid substitutions generally conferred low level resistance (EC50 < 1 nanomolar for L31V, Y93H) for genotype 1b, and higher levels of resistance for genotype 1a (up to 350 nanomolar for Y93N). Resistance patterns observed in the clinic are very similar to patterns generated in vitro except that linked substitutions are more complex in clinical specimens.
The majority of wild type HCV genotype 2a contain a pre-existing resistance substitution (L31M) with EC50 values of 9 to 19 nanomolar. The most resistant variants with a single amino acid substitution were F28S (EC50 > 500 nanomolar) for genotype 2a, Y93H (EC50 > 680 nanomolar) for genotype 3a, L31F (EC50 6.9 nanomolar) for genotype 5a, and P32L (EC50 250 nanomolar) for genotype 6a. In genotype 4, amino acid substitutions at 30 and 93 (EC50 < 16 nanomolar) were frequently selected.

In clinical studies.

Effect of baseline HCV polymorphisms on treatment response.

Analyses were conducted to explore the association between naturally occurring baseline NS5A amino acid substitutions (polymorphisms) and treatment outcome. The impact of NS5A polymorphisms is regimen specific.
Daklinza in combination with sofosbuvir. In a pooled analysis of phase 2 and 3 studies where patients received daclatasvir and sofosbuvir with or without ribavirin for 12 or 24 weeks, baseline NS5A polymorphisms at amino acid positions associated with daclatasvir resistance (28, 30, 31 or 93) were detected in 19% (116/605) of patients (32/295 genotype 1a, 15/75 genotype 1b, 33/36 genotype 2, 31/192 genotype 3, 4/6 genotype 4 and 1/1 genotype 6) with available baseline NS5A sequence. These NS5A polymorphisms included M28T/V, Q30E/H/L/R, L31M or Y93C/H/L/N/S in genotype 1a patients; R30K/M/Q, L31M or Y93H in genotype 1b patients; F28L or L31M in genotype 2 patients; M28V, A30E/K/S/T/V, L31M or Y93H in genotype 3 patients; L28M or L30R in genotype 4 patients; and F28M/V and R30S in genotype 6 patients.
Overall SVR12 rates for patients with or without baseline NS5A polymorphisms at 28, 30, 31 or 93 were 88% (102/116) and 96% (469/489), respectively (see Table 5). In patients without cirrhosis, the SVR12 rates in patients with and without baseline NS5A polymorphisms were high: 95% (83/87) and 99% (350/353), respectively. In patients with cirrhosis, SVR12 rates with and without baseline NS5A polymorphisms were 53% (11/21) and 85% (77/91), respectively. Specific baseline NS5A polymorphisms in the 10 patients with cirrhosis who failed were: M28T (n = 1), L31M (n = 2, both Child-Pugh B) and Y93N (n = 1) in patients with genotype 1a; A30K (n = 1), Y93H (n = 3) and A30T (n = 1) in patients with genotype 3; and L31M (n = 1, Child-Pugh C) in a patient with genotype 2. All of the described genotype 1a, genotype 2, and genotype 3 NS5A substitutions confer a greater than 100-fold reduction in daclatasvir activity in vitro, except for A30T which was only detected at baseline and not at failure. For the 14 patients with cirrhosis who failed without noted baseline NS5A polymorphisms, 6 patients had Child-Pugh C liver disease.
The sofosbuvir resistance associated substitution S282T was not detected in the baseline NS5B sequence of any patient in phase 2 or 3 studies by population based sequencing.
In a pooled analysis of 629 patients who received daclatasvir/ sofosbuvir with or without ribavirin in phase 2 and 3 studies, 44 patients (19 with genotype 1a, 2 with genotype 1b, 2 with genotype 2, and 21 with genotype 3) qualified for resistance analysis due to virologic failure or early study discontinuation and having HCV RNA greater than 1,000 IU/mL. Postbaseline NS5A and NS5B sequencing (assay cut-off of 20%) were available for 44/44 and 39/44 patients, respectively.
NS5A resistance associated variants (RAVs) were observed in postbaseline isolates from 37/44 patients (13/19 with genotype 1a, 1/2 with genotype 1b, 2/2 with genotype 2, and 21/21 with genotype 3) not achieving SVR. Thirteen (68%) of the 19 patients with HCV genotype 1a who qualified for resistance testing harboured one or more NS5A RAVs at positions M28, Q30, L31, H58 or Y93. Five of the patients with genotype 1a also had Child-Pugh C liver disease. Two patients had the same NS5A RAVs at baseline and postbaseline (M28T or Y93N). Substitutions at Q30 were most frequently observed (Q30E/H/K/R; 10/19 [52.6%]). Of the 2 patients with genotype 1b who qualified for resistance testing, a deletion at NS5A-P32 was observed in 1 patient. The 2 patients with genotype 2 who qualified for resistance testing had the same NS5A RAVs at baseline and postbaseline (L31M). Of the 21 patients with genotype 3 who qualified for resistance testing, 21 (100%) patients harboured one or more NS5A RAVs at positions 30, 31, 62 or 93. Substitutions at Y93 were most frequently observed (17/21 [81%]) and were observed at baseline in 6 patients and only postbaseline in 11 patients. Among the 7 patients who had no NS5A RAVs at failure, all received daclatasvir/ sofosbuvir for 8 weeks. All of the described genotype 1a Q30 substitutions, genotype 1b P32 deletion, genotype 2 L31M, and genotype 3 Y93H conferred reduced susceptibility to daclatasvir in vitro (fold-change in EC50 values ≥ 900).
Limited data on the persistence of daclatasvir resistance associated substitutions are available.
Daklinza in combination with asunaprevir (Sunvepra). In a pooled analysis of treatment naive and treatment experienced HCV genotype 1b infected subjects from phase 2/3 clinical trials, the efficacy of Daklinza in combination with Sunvepra was reduced in subjects whose virus had NS5A sequence polymorphisms detected at L31 (F, I, M or V) or Y93 (H). The pooled SVR rate in phase 2/3 trials for patients whose virus had L31F/I/M/V or Y93H was 48/119 (40%) compared with 686/742 (93%) for patients whose virus lacked L31F/I/M/V or Y93H polymorphisms. Among 863 HCV genotype 1b infected patients in phase 2/3 clinical trials with available NS5A sequence data, the prevalence of NS5A polymorphisms L31F/I/M/V or Y93H at baseline was 14%; 4% had virus with L31F/I/M/V without Y93H, 10% had virus with Y93H without L31F/I/M/V, and 0.5% had virus with L31F/I/M/V+Y93H. Of 127 virologic failures with baseline NS5A sequence data, 16% had L31F/I/M/V alone, 38% had Y93H alone, and 2% had L31F/I/M/V+Y93H.
Daklinza in combination with Sunvepra, peginterferon alfa, and ribavirin. Of 373 subjects with baseline NS5A sequence data in HALLMARK QUAD (see Section 5.1 Pharmacodynamic Properties, Clinical trials), 42 had pre-existing daclatasvir resistant substitutions. Of these 42 subjects, 38 achieved SVR12, 1 was a nonvirologic failure, and 3 experienced virologic failure (1 genotype 1a had NS5A-L31M and 1 had NS5A-Y93F at baseline; 1 genotype 1b had NS5A-L31M at baseline).

Treatment emergent resistance substitutions in subjects not achieving SVR.

Daklinza in combination with sofosbuvir. Of 211 subjects from study AI444040 treated with Daklinza and sofosbuvir, there was a single genotype 3 subject with virologic relapse. NS5A resistance associated substitutions observed at failure (A30K, S62I) were also detected at baseline [see Section 5.1 Pharmacodynamic Properties, Clinical trials]. NS5B resistance associated substitutions were not detected by standard sequencing methods.
Of 418 subjects treated in the ALLY-1, -2, and -3 trials with Daklinza and sofosbuvir with or without ribavirin for 12 weeks, 33 subjects (12/169 with genotype 1a, 1/44 with genotype 1b, 1/18 with genotype 2, and 19/178 with genotype 3) qualified for resistance analysis due to virologic failure or early study discontinuation and HCV RNA greater than 1000 IU/mL. Postbaseline NS5A and NS5B sequencing (assay cut-off of 20%) were available for 33/33 and 30/33 subjects, respectively. Virus from all 33 subjects at the time of virologic failure harbored one or more of the following NS5A resistance associated substitutions: M28T, Q30H/K/R, L31M/V, H58D/P, or Y93C/N (genotype 1a), L31M (genotype 2), A30K/S, L31I, S62A/L/P/T, or Y93H (genotype 3). The most common NS5A amino acids with resistance substitutions were Q30 (Q30 H/K/R; 75% [9/12]) in GT-1a failures, deletion of P32 (P32X) in a GT-1b failure, and Y93 (Y93H; 89% [17/19]) in GT-3 failures. For NS5B, 5 of 30 subjects at the time of virologic failure had virus with previously reported NS5B resistance associated substitutions: A112T, L159F, or E237G (genotype 1a), S282T (genotype 3).
Daklinza in combination with Sunvepra. In a pooled analysis of HCV genotype 1b infected patients treated with Daklinza and Sunvepra, treatment emergent NS5A amino acid substitutions were detected in the viruses from 116/117 (99%) patients who experienced virologic failure and had available resistance data (see Table 5). Most of these patients (105/117, 90%) had virus with treatment emergent substitutions at NS5A amino acid positions L31 and/or Y93. Of 121 patients with available resistance data for both NS5A and NS3, 95 (79%) patients had virus with both D168 substitutions NS3 and L31 plus Y93H substitutions in NS5A.
Daklinza in combination with Sunvepra, peginterferon alfa, and ribavirin. Treatment emergent NS5A amino acid substitutions were detected in the viruses of 17/17 (100%) HCV genotype 1a infected patients who experienced virologic failure with Daklinza, Sunvepra, peginterferon alfa, and ribavirin (see Table 6); 15/16 (94%) patients with available data had virus with treatment emergent asunaprevir resistance associated substitutions in NS3. Treatment emergent substitutions at NS5A position Q30 were most commonly observed (88%, 15/17). A single HCV genotype 1b infected patient who experienced virologic failure had virus with treatment emergent substitutions in NS5A and NS3.

Persistence of resistance associated substitutions.

Persistence of emergent NS5A resistance associated substitutions was monitored post-treatment in subjects who failed daclatasvir containing regimens in phase 2/3 clinical trials. Among subjects treated with Daklinza and Sunvepra, emergent genotype 1b NS5A resistance associated substitutions remained at detectable levels in all subjects monitored; 31 subjects only monitored at 24 weeks post-treatment and 9 subjects monitored for 36 weeks or more post-treatment. No data on the persistence of daclatasvir resistance associated substitutions are available from study ALLY-3. The long-term clinical impact of virus containing emergent daclatasvir resistant substitutions is unknown.

Cross resistance.

HCV replicons expressing daclatasvir associated resistance substitutions remained fully sensitive to interferon alfa and other anti-HCV agents with different mechanisms of action, such as NS3 protease and NS5B polymerase inhibitors (nucleoside and non-nucleoside).

Clinical trials.

The efficacy of Daklinza in combination with another oral agent has been evaluated in six phase 2/3 studies, in combination with Sunvepra (HALLMARK DUAL and HALLMARK NIPPON) and in combination with sofosbuvir, with or without ribavirin (studies AI444040, ALLY-3 (AI444218), ALLY-2 (AI444216) and ALLY-1 (AI444215)). The efficacy and safety of Daklinza in combination with Sunvepra, peginterferon alfa, and ribavirin was evaluated in the phase 3 HALLMARK QUAD trial. HCV RNA values were measured during the clinical trials using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System. The assay had a lower limit of quantification (LLOQ) of 25 IU per mL except in the HALLMARK NIPPON study, where the LLOQ was 15 IU per mL. SVR (virologic cure) was defined as HCV RNA below the lower limit of quantitation (LLOQ) at post-treatment week 12.

Daklinza in combination with sofosbuvir.

The efficacy and safety of Daklinza in combination with sofosbuvir in the treatment of patients with HCV infection were evaluated in four open label randomized studies (AI444040, ALLY-3, ALLY-2 and ALLY-1).

Study AI444040.

In study AI444040, 211 adults with HCV genotype 1, 2 or 3 infection and without cirrhosis received daclatasvir and sofosbuvir, with or without ribavirin. Among the 167 subjects with HCV genotype 1 infection, 126 were treatment naive and 41 had failed prior therapy with a protease inhibitor (PI) regimen (boceprevir or telaprevir). All 44 subjects with HCV genotype 2 or 3 infection were treatment naive. The dose of Daklinza was 60 mg once daily and the dose of sofosbuvir was 400 mg once daily. Treatment duration was 12 weeks for 82 treatment naive HCV genotype 1 subjects, and 24 weeks for the other 129 subjects (treatment naive HCV genotype 1, 2, or 3 and genotype 1 subjects who had failed prior PI therapy). All subjects were followed for 48 weeks post-treatment. Among the 211 subjects, median age was 54 years (range: 20 to 70); 83% were white, 12% were black, 2% were Asian; and 20% were Hispanic or Latino. The mean score on the FibroTest (a validated noninvasive diagnostic assay for liver fibrosis status) for all 211 subjects was 0.460 (range: 0.03 to 0.89). Conversion of the FibroTest score to the corresponding METAVIR score suggests that 35% of all subjects (49% of subjects with prior PI failure, 30% of subjects with genotype 2 or 3) had F3 or greater liver fibrosis. Most subjects in this study (71%, including 98% of prior PI failures) had IL-28B rs12979860 non-CC genotypes.
SVR was achieved by 99% of subjects with HCV genotype 1, 96% of those with genotype 2, and 89% of those with genotype 3. Response was rapid (more than 97% of subjects had HCV RNA < LLOQ at week 4) and was not influenced by HCV subtype (1a/1b), IL28B genotype, or use of ribavirin. Treatment naive subjects with HCV genotype 1 who received 12 weeks of treatment had a similar response as those treated for 24 weeks.
While the addition of ribavirin to the regimen did not result in an increase in efficacy, the frequencies of adverse reactions commonly associated with ribavirin therapy (rash, cough, anaemia, dyspnoea, insomnia, and anxiety) were higher for subjects in this study who received ribavirin than for subjects who did not.
SVR12 and outcomes in subjects without SVR in AI444040 are shown by patient population in Tables 7 and 8.

Study ALLY-3.

Study ALLY-3 was a confirmatory phase 3 study in which the combination of daclatasvir and sofosbuvir administered for 12 weeks was evaluated in 152 adults infected with HCV genotype 3; 101 patients were treatment naive and 51 patients had failed prior antiviral therapy, including 7 patients who had received sofosbuvir and ribavirin. Median age was 55 years (range: 24 to 73); 90% of patients were white; 4% were black/ African-American; 5% were Asian; 16% were Hispanic or Latino. Most patients (71%) had a high baseline viral load (HCV RNA level ≥ 800,000 IU/mL). Twenty one percent of patients had compensated cirrhosis. Most patients (61%) had IL-28B rs12979860 non-CC genotypes.
SVR12 was achieved by 90% of treatment naive patients and 86% of treatment experienced patients. Response was rapid (viral load at week 4 showed that more than 95% of patients responded to therapy) and was not influenced by IL28B genotype. SVR12 rates were lower among patients with cirrhosis (see Table 9).

Study ALLY-2.

In study ALLY-2, the combination of daclatasvir and sofosbuvir administered for 12 weeks was evaluated in 153 adults with chronic hepatitis C and HIV coinfection; 101 patients were HCV treatment naive and 52 patients had failed prior HCV therapy. Patients with HCV genotype 1, 2, 3, 4, 5, or 6 infection were eligible to enroll, however no patients with genotype 5 or 6 were enrolled. Sixty eight percent of patients had HCV genotype 1a, 15% had HCV genotype 1b, 8% had genotype 2, 7% had genotype 3, and 2% had genotype 4. The dose of daclatasvir was adjusted for concomitant antiretroviral use. Median age was 53 years (range: 24 to 71); 63% of patients were white; 33% were black/ African-American; 1% were Asian; 18% of patients were Hispanic/ Latino. Most patients (80%) had a high baseline viral load (HCV RNA level ≥ 800,000 IU/mL). Sixteen percent of patients had compensated cirrhosis. Most patients (73%) had IL-28B rs12979860 non-CC genotypes. Concomitant HIV therapy included PI based regimens (darunavir + ritonavir, atazanavir + ritonavir, or lopinavir/ ritonavir) for 46% of patients, NNRTI based (efavirenz, nevirapine, or rilpivirine) regimens for 26%; 27% of patients were receiving other HIV therapy, most commonly integrase based (raltegravir or dolutegravir) regimens. Two patients were not receiving treatment for HIV.
The SVR12 rate for the primary endpoint in treatment naive genotype 1 patients was achieved by 96% (80/83) of patients administered daclatasvir and sofosbuvir for 12 weeks in ALLY-2. SVR rates were high regardless of combination antiretroviral therapy (CART). Among treatment naive patients, 98% (46/47) of those receiving a PI based regimen, 100% (28/28) of those receiving an NNRTI regimen, and 92% (23/25) of those receiving another CART regimen achieved SVR. Among treatment experienced patients, 96% (22/23) of those receiving a PI based regimen, 100% (12/12) of those receiving an NNRTI regimen, and 100% (16/16) of those receiving another CART regimen achieved SVR. SVR rates were comparable regardless of age, race, gender, IL28B allele status, or baseline HCV RNA level. Outcomes by prior treatment experience are presented in Table 10.

Study ALLY-1.

In study ALLY-1, the regimen of daclatasvir, sofosbuvir, and ribavirin administered for 12 weeks was evaluated in 113 adults with chronic hepatitis C and Child-Pugh A, B or C cirrhosis (n = 60) or HCV recurrence after liver transplant (n = 53). Patients with HCV genotype 1, 2, 3, 4, 5 or 6 infection were eligible to enroll; however, no patients with genotype 5 were enrolled. Fifty eight percent of patients had HCV genotype 1a, 19% had HCV genotype 1b, 4% had genotype 2, 15% had genotype 3, 4% had genotype 4, and 1% had genotype 6. Patients received daclatasvir 60 mg once daily, sofosbuvir 400 mg once daily, and ribavirin for 12 weeks and were monitored for 24 weeks post-treatment.
Patients in ALLY-1 had a median age of 59 years (range: 19 to 82); 96% of patients were white, 4% were black/ African-American, and 1% were Asian; 34% of patients were Hispanic/ Latino. Most patients (59%) were treatment experienced, and most (71%) had baseline HCV RNA levels greater than or equal to 800,000 IU/mL. Among the 60 patients in the cirrhosis cohort, 20% were Child-Pugh class A, 53% were Child-Pugh class B, and 27% were Child-Pugh class C. Most (55%) of the 53 patients in the postliver transplant cohort had F3 or F4 fibrosis (based on FibroTest results). Most patients (77%) had IL-28B rs12979860 non-CC genotypes.
SVR12 rates for the coprimary endpoints were 82% (37/42) in genotype 1 patients in the cirrhosis cohort and 95% (39/41) in genotype 1 patients in the postliver transplant cohort (see Table 11). SVR rates were comparable regardless of age, race, gender, IL28B allele status, or baseline HCV RNA level. In the cirrhosis cohort, 4 patients with hepatocellular carcinoma underwent liver transplantation after 1-71 days of treatment; 3 of the 4 patients received 12 weeks of postliver transplant treatment extension and 1 patient, treated for 23 days before transplantation, did not receive treatment extension. All 4 patients achieved SVR12.

Daklinza in combination with Sunvepra in subjects with HCV genotype 1b.

HALLMARK DUAL (study AI447028) was a global open label study that included subjects with chronic HCV genotype 1b infection and compensated liver disease who were treatment naive, null or partial responders to peginterferon alfa and ribavirin, or were intolerant of or ineligible to receive interferon based therapy. Subjects in the treatment naive cohort were randomized 2:1 to receive Daklinza 60 mg once daily in combination with Sunvepra 100 mg twice daily for 24 weeks or placebo for 12 weeks (placebo subjects were rolled over into another study and offered treatment with Daklinza in combination with Sunvepra for 24 weeks). Subjects in the null or partial responder and intolerant/ ineligible cohorts were treated with Daklinza 60 mg once daily in combination with Sunvepra 100 mg twice daily for 24 weeks. Subjects were monitored for 24 weeks post-treatment.
Of the 745 treated subjects, in HALLMARK DUAL included in the efficacy analyses, 643 subjects received Daklinza in combination with Sunvepra. These 643 subjects had a median age of 57 years (range: 20 to 79); 48% of the subjects were male; 70% were white, 24% were Asian, 5% were black, and 4% were Hispanic/ Latino. The mean baseline HCV RNA level was 6.4 log10 IU/mL; 32% of the subjects had compensated cirrhosis (Child-Pugh A) and 29% had the IL28B CC genotype. Baseline characteristics of the 102 placebo treated subjects were similar to those of subjects treated with Daklinza in combination with Sunvepra.
SVR, the primary endpoint, and outcomes in subjects without SVR in HALLMARK DUAL are shown by patient population in Table 12. SVR rates for patients with and without baseline NS5A resistance associated polymorphisms are included in the table.
Among subjects who had failed prior therapy, SVR rate was the same (82%) among the 84 subjects with prior partial response and the 119 subjects with prior null response. Response was rapid (95% of subjects had HCV RNA < LLOQ at week 4). There were no differences in antiviral response due to race, gender, IL28B allele, presence or absence of cirrhosis, or age in any of the treatment populations. SVR rates were consistently high across all categories of baseline viral load. Among subjects 65 and older, 88% (117/133) achieved SVR and among subjects 75 years or older, 100% (10/10) achieved SVR.
HALLMARK NIPPON (study AI447026) was an open label study that included Japanese subjects with HCV genotype 1b infection and compensated liver disease who were non-responders (null or partial responders) to interferon alfa or beta and ribavirin or who were intolerant of or ineligible to receive interferon based therapy. Subjects in both the non-responder and intolerant/ ineligible cohorts were treated with Daklinza 60 mg once daily in combination with Sunvepra 100 mg twice daily for 24 weeks and monitored for 24 weeks post-treatment.
The 222 treated subjects in HALLMARK NIPPON had a median age of 63 years (range: 24-75); 35% of the subjects were male. Mean baseline HCV RNA level was 7 log10 IU/mL, and 10% of subjects had compensated cirrhosis (Child-Pugh A). Among 87 subjects in the non-responder cohort, 36 subjects were prior partial responders and 48 subjects were prior null responders to interferon/ ribavirin. Among 135 subjects in the interferon intolerant/ ineligible cohort, 35 subjects were in the intolerant category and 100 in the ineligible. Most of the non-responder cohort had a non-CC IL28B genotype, while most of the intolerant/ ineligible cohort had IL28B genotype CC.
SVR and outcomes for subjects without SVR in HALLMARK NIPPON are shown by patient population in Table 13. SVR rates for patients with and without baseline NS5A resistance associated polymorphisms are included in the table.
In the nonresponder cohort, 78% of prior partial responders and 81% of prior null responders achieved SVR. In the intolerant/ ineligible cohort, 94% of subjects who were intolerant and 86% of those who were ineligible achieved SVR. Response was rapid (96% of subjects had HCV RNA < LLOQ at week 4). Within the prior nonresponder and interferon intolerant/ ineligible populations, there were no differences in antiviral response due to gender, baseline HCV RNA level, IL28B allele, presence or absence of cirrhosis or age. Among subjects 65 years and older, 91% (81/89) achieved SVR and among subjects 75 years or older, 100% (4/4) achieved SVR.

Daklinza in combination with Sunvepra in subjects with HCV genotype 1a.

The efficacy of Daklinza and Sunvepra combination therapy in the treatment of chronic hepatitis C genotype 1a infection has not been established. In a study of Daklinza and Sunvepra combination therapy for 24 weeks in subjects with chronic HCV genotype 1 infection who were prior null responders to peginterferon alfa plus ribavirin, 2 (22%) of the 9 subjects with HCV genotype 1a infection had undetectable HCV RNA at post-treatment week 24.

Daklinza in combination with Sunvepra, peginterferon alfa, and ribavirin in subjects with HCV genotype 1 or 4.

The efficacy and safety of Daklinza in combination with Sunvepra, peginterferon alfa, and ribavirin in the treatment of chronic HCV genotype 1 or 4 infection were evaluated in the single arm, open label phase 3 HALLMARK QUAD study (AI447029) in adults with compensated liver disease who were partial or null responders to therapy with peginterferon alfa 2a or 2b and ribavirin. Subjects received Daklinza 60 mg once daily, Sunvepra 100 mg twice daily, peginterferon alfa-2a 180 microgram subcutaneously once weekly, and ribavirin 1000 mg per day (bodyweight less than 75 kg) or 1200 mg per day (at least 75 kg) in two divided doses for 24 weeks followed by 24 weeks of follow-up after completion of treatment or early discontinuation.
The 398 treated subjects in HALLMARK QUAD had a median age of 53 years (range: 19-76); 69% of the subjects were male; 76% were white, 12% were Asian, 9% were black; 9% were Hispanic/ Latino. The mean baseline HCV RNA level was 6.46 log10 IU/mL; 23% of subjects had compensated cirrhosis (Child-Pugh A); 89% had HCV genotype 1 and 11% had HCV genotype 4; 91% of subjects had non-CC IL28B genotype.
SVR, the primary endpoint, and outcomes in subjects without SVR in HALLMARK QUAD are shown by patient population in Table 14. The demonstrated effectiveness of Daklinza/ Sunvepra/ peginterferon alfa/ ribavirin treatment in HCV genotype 1 and 4 null responders indicates that this regimen is also expected to be effective in HCV genotype 1 and 4 subjects who are treatment naive.
Response was rapid (98% of subjects had HCV RNA < LLOQ at week 4). There were no differences in antiviral response due to gender, age, baseline HCV RNA level, presence or absence of baseline polymorphisms, IL28B allele status, or presence or absence of cirrhosis in any of the treatment populations.

Long-term follow-up.

Limited data are available from an ongoing follow-up study to assess durability of response up to 3 years after treatment with Daklinza. Among 224 subjects who achieved SVR12 with Daklinza and Sunvepra with a median duration of post-SVR12 follow-up of approximately 8.5 months, 1 (< 1%) relapse occurred. No relapses occurred among 28 subjects who achieved SVR12 with Daklinza and sofosbuvir (± ribavirin) with a median duration of post-SVR12 follow-up of approximately 14.5 months or among 30 subjects who achieved SVR12 with Daklinza, Sunvepra, peginterferon alfa, and ribavirin with a median duration of post-SVR12 follow-up of approximately 18 months.

5.2 Pharmacokinetic Properties

The pharmacokinetic properties of daclatasvir were evaluated in healthy adult subjects and in subjects with chronic HCV. Following multiple oral doses of daclatasvir 60 mg once daily in combination with peginterferon alfa and ribavirin in HCV infected subjects, the geometric mean (CV%) daclatasvir Cmax was 1534 (58) nanogram/mL, AUC0-24h was 14122 (70) nanogram.h/mL, and Cmin was 232 (83) nanogram/mL.

Absorption.

Daclatasvir administered as a tablet was readily absorbed following multiple oral doses with peak plasma concentrations occurring between 1 and 2 hours. Daclatasvir Cmax, AUC, and Cmin increased in an approximately dose proportional manner. Steady state was achieved after 4 days of once daily administration. At the 60 mg dose, exposure to daclatasvir was similar between healthy and HCV infected subjects.
In vitro studies with human Caco-2 cells indicated that daclatasvir is a substrate of P-gp. The absolute bioavailability of the tablet formulation is 67%.
In healthy subjects, administration of daclatasvir 60 mg tablet after a high fat meal (approximately 1000 kcal, approximately 50% from fat) decreased daclatasvir Cmax and AUC by 28% and 23%, respectively, compared with administration under fasting conditions. Administration of daclatasvir 60 mg tablet after a light meal (approximately 275 kcal, approximately 15% from fat) resulted in no reduction in daclatasvir exposure (see Section 4.2 Dose and Method of Administration).

Distribution.

At steady state, protein binding of daclatasvir in HCV infected subjects was approximately 99% and independent of dose at the dose range studied (1 mg to 100 mg). In subjects who received daclatasvir 60 mg tablet orally followed by 100 microgram (13C,15N)-daclatasvir intravenous dose, estimated volume of distribution at steady state was 47.1 L. In vitro studies indicate that daclatasvir is actively and passively transported into hepatocytes. The active transport is mediated by OCT1 and other unidentified uptake transporters, but not by organic anion transporter (OAT) 2, sodium taurocholate cotransporting polypeptide (NTCP), or OATPs.

Metabolism.

In vitro studies demonstrate that daclatasvir is a substrate of CYP3A, with CYP3A4 the major CYP isoform responsible for the metabolism. No metabolites circulated at levels more than 5% of the parent concentration.

Excretion.

Following single dose oral administration of 14C-daclatasvir in healthy subjects, 88% of total radioactivity was recovered in faeces (53% as unchanged drug) and 6.6% was excreted in the urine (primarily as unchanged drug). These data indicate that the liver is the major clearance organ for daclatasvir in humans. In vitro studies indicate that daclatasvir is actively and passively transported into hepatocytes. The active transport is mediated by OCT1 and other unidentified uptake transporters. Following multiple dose administration of daclatasvir in HCV infected subjects, the terminal elimination half-life of daclatasvir ranged from 12 to 15 hours. In subjects who received daclatasvir 60 mg tablet orally followed by 100 microgram (13C,15N)- daclatasvir intravenous dose, the total clearance was 4.24 L/h.

Special populations.

Hepatic impairment.

No dose adjustment of Daklinza is necessary for patients with mild (Child-Pugh A), moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment and cirrhosis).
The pharmacokinetics of daclatasvir following a 30 mg single dose were studied in non-HCV infected subjects with mild, moderate, and severe hepatic impairment compared with unimpaired subjects. The Cmax and AUC of total daclatasvir (free and protein bound drug) were lower in subjects with hepatic impairment; however, hepatic impairment did not have a clinically significant effect on the free drug concentrations of daclatasvir.

Renal impairment.

No dose adjustment of Daklinza is necessary for patients with any degree of renal impairment (see Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment). Compared to non-HCV infected subjects with normal renal function (creatinine clearance (CrCl) of 90 mL/min, defined using the Cockcroft-Gault CrCl formula), the AUC of daclatasvir was estimated to be 26.4%, 59.8%, and 79.6% higher in subjects with CrCl values of 60, 30, and 15 mL/min, respectively. Daclatasvir unbound AUC was estimated to be 18.0%, 39.2%, and 51.2% higher for subjects with CrCl values of 60, 30, and 15 mL/min, respectively, relative to subjects with normal renal function. Subjects with endstage renal disease requiring hemodialysis had a 26.9% increase in daclatasvir AUC and a 20.1% increase in unbound AUC compared to subjects with normal renal function. Population pharmacokinetic analysis of data from clinical trials indicated that mild to moderate renal impairment had no clinically meaningful effect on the pharmacokinetics of daclatasvir. Daclatasvir is highly protein bound to plasma proteins and is unlikely to be removed by dialysis.

Elderly patients.

Population pharmacokinetic analysis of data from clinical trials indicated that age had no apparent effect on the pharmacokinetics of daclatasvir.

Paediatric and adolescent.

The pharmacokinetics of daclatasvir in paediatric patients have not been evaluated.

Gender.

Population pharmacokinetic analysis of data from clinical trials indicated that gender had no clinically meaningful effect on the pharmacokinetics of daclatasvir.

Race.

Population pharmacokinetic analysis of data from clinical trials indicated that race had no clinically meaningful effect on the pharmacokinetics of daclatasvir.

5.3 Preclinical Safety Data

Genotoxicity.

Daclatasvir was not mutagenic or clastogenic in an in vitro mutagenesis (Ames bacterial mutagenicity) assay, a chromosome aberration assay in Chinese hamster ovary cells, or in an in vivo oral micronucleus study in rats.
See also the product information for ribavirin and peginterferon alfa.

Carcinogenicity.

Daclatasvir was not carcinogenic in mice or rats at AUC values 8.7 and 4.7-fold the human exposure at the recommended daily human clinical dose of 60 mg/day, respectively.
See also the product information for ribavirin and peginterferon alfa.

4 Clinical Particulars

4.1 Therapeutic Indications

Daklinza is indicated in combination with other medicinal products for the treatment of chronic hepatitis C virus (HCV) infection in adults (see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 4.2 Dose and Method of Administration).

4.3 Contraindications

Daklinza is contraindicated in patients with previously demonstrated hypersensitivity to daclatasvir or any component of the product.
Since Daklinza is used in combination with other medicinal products, the contraindications applicable to those medicinal products are applicable to the combination regimen. Refer to the respective product information for a list of contraindications.
The combination of Daklinza with peginterferon alfa and ribavirin is contraindicated in women who are pregnant or may become pregnant and men whose female partners are pregnant because of the risks of birth defects and foetal death associated with ribavirin (see Section 4.4 Special Warnings and Precautions for Use).
Daklinza is contraindicated in combination with drugs that strongly induce CYP3A4 and thus may lead to lower exposure and loss of efficacy of Daklinza. Contraindicated drugs include, but are not limited to, phenytoin, carbamazepine, oxcarbazepine, phenobarbital, rifampicin, rifabutin, dexamethasone and St John's wort (Hypericum perforatum) (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

General.

Daklinza must not be administered as monotherapy. Daklinza must be administered in combination with other medicinal products for the treatment of chronic HCV infection (see Section 4.1 Therapeutic Indications; Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 4.2 Dose and Method of Administration). Warnings and precautions for other medicinal products in the regimen also apply when coadministered with Daklinza.

Potential for hepatotoxicity with Sunvepra containing regimens.

Drug induced liver injury, in some cases severe, has been observed with Sunvepra containing regimens. See prescribing information for Sunvepra for hepatic monitoring recommendations.
In Daklinza regimens that did not contain Sunvepra, the frequencies of clinically significant ALT or AST elevations were similar to frequencies among patients who received placebo.

Potential for drug interaction with amiodarone.

Severe bradycardia and heart block have been reported in patients receiving amiodarone with Daklinza and sofosbuvir, with or without other medicinal products that lower heart rate. Bradycardia has generally occurred within hours to days. Bradycardia generally resolved after discontinuation of HCV treatment. The mechanism for the bradycardia effect has not been established.
Amiodarone should be coadministered with Daklinza and sofosbuvir only if alternative antiarrhythmic treatments are contraindicated or not tolerated. For patients with no alternative treatment options, close monitoring is recommended. Patients should be continuously monitored in an inpatient setting for the first 48 hours of coadministration, after which outpatient monitoring or self monitoring of the heart rate should occur on a daily basis through at least the first two weeks of treatment.
Due to the long half-life of amiodarone, patients who have discontinued amiodarone just before starting Daklinza and sofosbuvir should also undergo cardiac monitoring as described above.
All patients receiving Daklinza and sofosbuvir in combination with amiodarone should be warned of the symptoms of bradycardia and heart block and advised to seek medical advice urgently should they experience them.
Refer to the amiodarone and sofosbuvir product information. (See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 4.8 Adverse Effects (Undesirable Effects), Postmarketing experience.)

Hepatitis B virus (HBV) reactivation.

Cases of hepatitis B virus (HBV) reactivation, including fatal cases, have been reported during and after treatment HCV with direct acting antiviral agents in HCV/HBV coinfected patients. Screening for current or past HBV infection, including testing for HBV surface antigen (HBsAg) and HBV core antibody (anti-HBc), should be performed in all patients before initiation of treatment with Daklinza.
Patients with serologic evidence of current or past HBV infection should be monitored and treated according to current clinical practice guidelines to manage potential HBV reactivation. Consider initiation of HBV antiviral therapy, if indicated.

Potential for dysglycaemia in patients with diabetes.

Diabetic patients may experience dysglycaemia, including symptomatic hypoglycaemia, during or after treatment with direct-acting antiviral (DAA) agents. This may be due to changes in blood glucose control resulting from changes in liver function following DAA treatment. Close monitoring of blood glucose is recommended during treatment with Daklinza.

Genotype specific activity.

The clinical data to support the use of Daklinza and sofosbuvir in patients infected with HCV genotypes 2, 4, 5 and 6 are limited.

Use in hepatic impairment and cirrhosis.

No dose adjustment of Daklinza is required for patients with mild (Child-Pugh A), moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment (see Section 5.2 Pharmacokinetic Properties, Special populations; Section 5.1 Pharmacodynamic Properties, Clinical trials).

Coinfection with hepatitis B virus (HBV).

The safety and efficacy of Daklinza in the treatment of chronic HCV infection in patients who are coinfected with HBV have not been established (see Section 4.4 Special Warnings and Precautions for Use, Hepatitis B virus (HBV) reactivation).

Use in renal impairment.

No dose adjustment of Daklinza is required for patients with any degree of renal impairment (see Section 5.2 Pharmacokinetic Properties, Special populations).

Retreatment with Daklinza.

The efficacy of Daklinza as part of a retreatment regimen in patients with prior exposure to a NS5A inhibitor has not been established.

Paediatric use.

Safety and effectiveness of Daklinza in paediatric patients less than 18 years of age have not been established.

Use in the elderly.

Of more than 2000 subjects in clinical studies of Daklinza combination therapy, 310 were 65 years and older and 20 were 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. No dose adjustment of Daklinza is required for elderly patients.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Potential for other medicines to affect Daklinza.

Daclatasvir is a substrate of CYP3A4. Therefore, moderate or strong inducers of CYP3A4 may decrease the plasma levels and therapeutic effect of daclatasvir. See Section 4.3 Contraindications for drugs that are contraindicated for use with Daklinza due to potential loss of virologic activity.
Strong inhibitors of CYP3A4 may increase the plasma levels of daclatasvir (see Section 4.2 Dose and Method of Administration, Table 2). Daclatasvir is also a substrate of P-glycoprotein transporter (P-gp), and organic cation transporter (OCT) 1, but coadministration of agents that modify P-gp or OCT-1 activity alone (without concurrent effect on CYP3A4) is unlikely to have a clinically meaningful effect on daclatasvir exposure.

Potential for Daklinza to affect other medicines.

Daclatasvir is an inhibitor of P-glycoprotein transporter (P-gp), organic anion transporting polypeptide (OATP) 1B1 and 1B3, OCT-1 and breast cancer resistance protein (BCRP). Administration of Daklinza may increase systemic exposure to medicinal products that are substrates of P-gp, OATP 1B1 or 1B3, OCT-1 or BCRP, which could increase or prolong their therapeutic effect and adverse reactions. Caution should be used if the medicinal product has a narrow therapeutic range.
Close monitoring of anticoagulation with all vitamin K antagonists (international normalised ratio, INR) is recommended, as liver function may change during treatment with Daklinza causing fluctuation in the INR.

Established and potentially significant drug interactions.

Refer to the respective product information for other medicinal products in the regimen for drug interaction information. The most conservative recommendation should be followed.
Table 2 provides clinical recommendations for established or potentially significant drug interactions between Daklinza and other drugs. Clinically relevant increase in concentration is indicated as an arrow pointing upwards and clinically relevant decrease as an arrow pointing downwards.

Other drugs.

Based on the results of drug interaction studies, no dose adjustment of Daklinza is recommended when Daklinza is given with Sunvepra, cyclosporin, darunavir/ ritonavir, dolutegravir, escitalopram, ethinyloestradiol + levonorgestrel, ethinyloestradiol + norethisterone, famotidine, lopinavir/ ritonavir, buprenorphine/ naloxone, methadone, midazolam, omeprazole, peginterferon alfa, ribavirin, simeprevir, sofosbuvir, tacrolimus, tenofovir.
No clinically relevant effects on the pharmacokinetics of either medicinal product are expected when Daklinza is coadministered with any of the following: PDE-5 inhibitors, medicinal products in the ACE inhibitor class (e.g. enalapril), medicinal products in the angiotensin II receptor antagonist class (e.g. losartan, irbesartan, olmesartan, candesartan, valsartan), abacavir, alprazolam, azithromycin, ciprofloxacin, darunavir/ cobicistat, didanosine, disopyramide, emtricitabine, enfuvirtide, flecainide, lamivudine, maraviroc, mexiletine, mycophenolate mofetil, propafenone, quinidine, raltegravir, rilpirivine, sirolimus, stavudine, triazolam, zidovudine or antacids.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Daclatasvir alone had no effects on fertility in male or female rats. The highest AUC value in unaffected females was 18-fold the exposure at the recommended human dose. In male rats, effects on reproductive endpoints were limited to reduced prostate/ seminal vesicle weights, and minimally increased dysmorphic sperm at 200 mg/kg/day (19-fold the exposure at the recommended human daily clinical dose); however, neither finding adversely affected fertility or the number of viable conceptuses sired.

Use with ribavirin and peginterferon alfa.

Ribavirin caused reversible testicular toxicity in animals; while peginterferon alfa may impair fertility in females. Please refer to product information for ribavirin and peginterferon alfa for additional information.

Use of Daklinza with peginterferon alfa and ribavirin (Category X).

Ribavirin may cause birth defects and/or death of the exposed fetus and animal studies have shown that interferons have abortifacient effects. Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin; and therefore ribavirin is contraindicated in women who are pregnant and in the male partners of women who are pregnant (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, and ribavirin prescribing information). Interferons have abortifacient effects in animals and should be assumed to have abortifacient potential in humans. Refer also to the product information for peginterferon alfa and ribavirin.
Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy.
When Daklinza is used in combination with peginterferon alfa and ribavirin, women of childbearing potential and their male partners must use two forms of effective contraception during treatment and for at least 6 months after treatment has concluded.

Daklinza (Category B3).

There are no adequate and well controlled studies in pregnant women. Studies of daclatasvir in animals have shown both maternal and embryofetal developmental toxicity at AUC levels above the recommended human dose (RHD). Daklinza should not be used during pregnancy or in women of childbearing potential not using contraception. Use of effective contraception should be continued for 5 weeks after completion of treatment.
Daclatasvir crosses the placenta in rats. Embryofetal development studies in rats and rabbits showed embryolethality, reduced fetal bodyweights, and fetal malformations at doses which were maternotoxic (mortality, adverse clinical signs, decreases in bodyweight and food consumption). Fetal malformations in rats included small and misshapen cerebrum, dilated cerebral ventricles, shortened lower jaws, incomplete ossification of parietals and frontals, enlarged fontanels, misshapen and/or fused sternebrae, and supernumerary hindlimb phalanges, at 25 times the RHD AUC. Additional malformations at the high dose were absent or small or malpositioned eyes, dilated olfactory bulbs, imperforate or absent nasal openings, exencephaly, cleft lip and palate, polydactyly of forelimbs and hindlimbs, shortened upper jaw, misshapen tympanic annuli, fused nasals and premaxillae, and alterations to the pectoral girdle, sternebrae, vertebrae and ribs, at 52 times the RHD AUC. Fetal malformations in rabbits involved the ribs, and variations were increased in the head and skull, at 72 times the RHD AUC. At the respective NOAELs for both fetal and maternal toxicity, the daclatasvir AUC was 4 times (rats) and 16 times (rabbits) the RHD AUC. In a study of prenatal and postnatal development in rats, there was neither maternal nor developmental toxicity at doses up to 50 mg/kg/day, associated with AUC values 2.6-fold the RHD AUC. At the highest dose tested (100 mg/kg/day), maternal toxicity included mortality and dystocia; developmental toxicity included slight reductions in offspring viability in the perinatal and neonatal periods; and reductions in birthweight that persisted into adulthood. The AUC value associated with this dose is 4.7-fold the RHD AUC.
 Treatment of rats with daclatasvir during pregnancy and lactation caused decreased pup bodyweight gain (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).
It is not known whether daclatasvir is excreted in human milk. Daclatasvir was excreted into the milk of lactating rats with concentrations 1.7 to 2-fold maternal plasma levels. Mothers should be instructed not to breastfeed if they are taking Daklinza. See also the product information for ribavirin and peginterferon alfa.

4.8 Adverse Effects (Undesirable Effects)

Daklinza must be administered with other drugs for the treatment of HCV infection. Refer to their respective product information for their associated adverse reactions.

Clinical experience.

The overall safety profile of Daklinza is based on data from 1995 patients with chronic HCV infection who received Daklinza once daily in combination with Sunvepra (n = 918), sofosbuvir with or without ribavirin (n = 679, pooled data), or Sunvepra, peginterferon alfa, and ribavirin (n = 398) in 8 clinical trials. Safety experience is presented by regimen.

All oral regimens.

Daklinza in combination with sofosbuvir.

The safety of Daklinza 60 mg once daily in combination with sofosbuvir (with or without ribavirin) was assessed in four open label randomized clinical trials (AI444040, ALLY-3, ALLY-2 and ALLY-1) in 679 subjects with chronic HCV genotype 1, 2, 3, 4, 5, or 6 infection. Subjects were treated for 12 or 24 weeks.
The most common adverse events (frequency of 10% or greater) were fatigue (19%), headache (15%), and nausea (11%). Most adverse events experienced were mild to moderate in severity. Five percent of subjects experienced a serious adverse event. Seventeen subjects discontinued for adverse events.
The frequencies of adverse reactions commonly associated with ribavirin therapy (rash, cough, anaemia, dyspnoea, insomnia, and anxiety) were higher for subjects who received ribavirin than for subjects who did not.

Daklinza in combination with Sunvepra.

The safety of Daklinza 60 mg once daily in combination with Sunvepra was assessed in 918 subjects with chronic HCV infection in four open label clinical trials (HALLMARK DUAL (AI447028), HALLMARK NIPPON (AI447026), AI447017, AI447011). Median duration of study therapy was 24 weeks.
The most common adverse events (frequency of 10% or greater) were headache (23%), fatigue (17%), diarrhoea (15%), nasopharyngitis (14%), and nausea (10%). Most adverse events were mild to moderate in severity.
Six percent of subjects experienced a serious adverse event (SAE). Three percent of subjects discontinued for adverse events; the most common adverse events leading to discontinuation were increased ALT and increased AST.
In the HALLMARK DUAL study during the first 12 weeks of treatment, rates of adverse reactions were similar between subjects treated with placebo and subjects treated with Daklinza in combination with Sunvepra.

Daklinza in combination with Sunvepra, peginterferon alfa, and ribavirin.

The safety of Daklinza 60 mg once daily in combination with Sunvepra, peginterferon alfa, and ribavirin was assessed in 398 subjects with chronic HCV genotype 1 or 4 infection in an open label clinical trial (HALLMARK QUAD (AI447029)). Median duration of study therapy was 24 weeks.
The most common adverse events (frequency of 15% or greater) were fatigue (42%), headache (31%), pruritus (26%), asthenia (24%), influenza-like illness and insomnia (each in 22%), rash (21%), anaemia (19%), cough (18%), dry skin (18%), diarrhoea (18%), nausea (17%), alopecia, irritability, and pyrexia (each in 16%), and myalgia (15%). Most adverse events experienced were mild to moderate in severity.
Six percent of subjects in HALLMARK QUAD experienced an SAE. Five percent of subjects discontinued for adverse events. The most common adverse events leading to discontinuation were rash, malaise, vertigo, and neutropenia.
Adverse events occurring at frequency of 5% or greater in integrated data from 4 studies of Daklinza in combination with Sunvepra, in study AI444040 of Daklinza in combination with sofosbuvir, or in the HALLMARK QUAD study of Daklinza in combination with Sunvepra, peginterferon alfa, and ribavirin are presented in Table 3.

Less common adverse reactions.

Additional adverse reactions observed in clinical trials of Daklinza combination therapy with Sunvepra or sofosbuvir occurring in less than 5% of subjects are eosinophilia and increased AST. These events have been included because of their seriousness or assessment of potential causal relationship to the regimen.

Postmarketing experience.

The following events have been identified during postapproval use of Daklinza.

Hepatobiliary disorders.

Hepatitis B reactivation (see Section 4.4 Special Warnings and Precautions for Use).

Daclatasvir and sofosbuvir regimen when administered with amiodarone.

Cardiac arrhythmias.

Cardiac arrhythmias including severe bradycardia and heart block have been observed in patients receiving amiodarone with Daklinza and sofosbuvir. (See Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.)

Daclatasvir and asunaprevir regimen.

Skin and subcutaneous tissue disorders.

Erythema multiforme.

Laboratory findings.

Selected treatment emergent grade 3-4 laboratory abnormalities observed in HCV infected subjects treated with Daklinza combination therapy are presented in Table 4.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Daklinza is for oral administration and may be taken with or without food.
The recommended dose of Daklinza is 60 mg once daily. Daklinza must be administered in combination with other agents (see Table 1). For specific dose recommendations for other agents in the regimen, refer to the respective prescribing information.
Dosing recommendations in Table 1 include patients coinfected with human immunodeficiency virus (HIV). For dosing recommendations with specific HIV antiviral agents, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions (see Table 2).

Ribavirin dosing guidelines.

The dose of ribavirin, when combined with Daklinza, is weight based (1,000 or 1,200 mg in patients < 75 kg or ≥ 75 kg, respectively). Refer to the prescribing information of ribavirin.

Dose modification, interruption, and discontinuation.

Once therapy is started, dose modification of Daklinza is not recommended. Treatment interruption should be avoided; however, if treatment interruption of any agent in the regimen is necessary because of adverse reactions, Daklinza should not be given as monotherapy.
Discontinuation of therapy is recommended for patients experiencing confirmed virologic breakthrough (greater than 1 log10 IU/mL increase in HCV RNA from nadir).

Concomitant therapy.

Strong inhibitors of cytochrome P450 enzyme 3A4 (CYP3A4).

The dose of Daklinza should be reduced to 30 mg once daily when coadministered with strong inhibitors of CYP3A4 (using the 30 mg tablet; Daklinza tablets should not be broken). See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions. Coadministration with strong or moderate CYP3A4 inhibitors is contraindicated with regimens that include Sunvepra.

Moderate inducers of CYP3A4.

The dose of Daklinza should be increased to 90 mg once daily (using one 60 mg and one 30 mg tablet; Daklinza tablets should not be broken) when coadministered with moderate inducers of CYP3A4 (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Coadministration with moderate CYP3A4 inducers is contraindicated with regimens that include Sunvepra.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.9 Overdose

There is limited clinical experience with overdose of Daklinza. In phase 1 clinical trials, healthy subjects who received up to 100 mg for up to 14 days or single doses up to 200 mg had no unexpected adverse events.
There is no known antidote for overdose of Daklinza. Treatment of overdose with Daklinza should consist of general supportive measures, including monitoring of vital signs and observation of the patient's clinical status. Because daclatasvir is highly protein bound (> 99%) and has a molecular weight greater than 500, dialysis is unlikely to significantly reduce plasma concentrations of the drug.
For information on the management of overdose, contact the Poisons Information Centre on 131 126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Daklinza 30 mg tablets contain the inactive ingredients lactose (58 mg), microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate, and Opadry complete film coating system 03B110005 Green (proprietary ingredient number 109451).
Daklinza 60 mg tablets contain the inactive ingredients lactose (116 mg), microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate, and Opadry complete film coating system 03B110007 Green (proprietary ingredient number 109448).
Opadry green contains hypromellose, titanium dioxide, Macrogol 400, indigo carmine aluminum lake, and iron oxide yellow.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the ARTG. The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Daklinza 30 mg and 60 mg tablets are supplied in PVC/PCTFE (Aclar)/Al blister packs and are available in packs of 7 and 28 tablets.

6.6 Special Precautions for Disposal

In Australia, unwanted medicines can be returned to local pharmacies involved in the Return Unwanted Medicines (RUM) Project.

Summary Table of Changes