Daclatasvir with sofosbuvir, with or without ribavirin, for chronic hepatitis C

• Daclatasvir is a direct-acting antiviral (DAA) agent
  It selectively inhibits HCV viral replication by targeting the hepatitis C virus (HCV) NS5A protein; it is used in combination with the HCV NS5B RNA polymerase inhibitor sofosbuvir.¹

• PBS listed as an interferon-free, all-oral combination treatment for HCV genotypes 1 and 3
  In combination with sofosbuvir for HCV genotypes 1 or 3, or in combination with sofosbuvir plus ribavirin for patients with cirrhosis and infection with HCV genotype 1. ²
• High rates of sustained virological response in patients with genotype 1 or 3 infection
  Demonstrated in treatment-naïve and treatment-experienced patients with or without cirrhosis, and in those co-infected with HIV-1.^{3, 4}

• Available on the General Schedule (S85) and S100 Highly Specialised Drugs program
  Community pharmacists can only dispense prescriptions written under the General Schedule, not those written under S100 arrangements.⁵

Authority required (written or by phone)

From 1 March 2016 daclatasvir (Daklinza), became available on the PBS General Schedule ‘Section 85’ and Section 100 (S100) Highly Specialised Drugs (HSD) Program for oral combination treatment with sofosbuvir for patients who are 18 years or older with:⁵

• genotype 1 HCV – for 12 weeks in patients without cirrhosis who are treatment-naïve, 12 or 24 weeks for those without cirrhosis who are treatment-experienced, or 24 weeks for those without cirrhosis who are treatment-naïve or treatment-experienced
• genotype 3 HCV – in treatment-naïve or treatment-experienced patients without cirrhosis for 12 weeks, and in treatment-naïve or -experienced patients with cirrhosis for 24 weeks.⁵

Daclatasvir is also available on the General Schedule and S100 HSD program as a combination treatment with sofosbuvir and ribavirin for 12 weeks in treatment-naïve or -experienced patients who are 18 years or older with genotype 1 HCV and cirrhosis.⁵

At the time of Authority application, the hepatitis C virus genotype and patient’s cirrhotic status (non-cirrhotic or cirrhotic) must be provided, and evidence of chronic hepatitis C infection (repeatedly testing positive for antibody to HCV [anti-HCV positive] and for hepatitis C virus ribonucleic acid [HCV RNA positive] and the hepatitis C virus genotype must be documented in the patient’s medical records.

PBS patient and prescriber eligibility is the same whether the medicines is prescribed under the PBS General Schedule or the HSD program.⁵

As well as daclatasvir and sofosbuvir, with or without ribavirin, three additional all-oral HCV treatment combinations were also identified in the recommended prescribing matrix for PBS listing from 1 March 2016, as follows:⁵

• ledipasvir with sofosbuvir (see the separate NPS RADAR review Ledipasvir with sofosbuvir fixed-dose combination for chronic hepatitis C)
• sofosbuvir with ribavirin (see the Sofosbuvir treatment combinations for chronic hepatitis C RADAR review)
• sofosbuvir with peginterferon alfa-2a and ribavirin (see the interferon wrap-up).⁵

May be prescribed by specialists or GPs

Gastroenterologists, hepatologists or infectious-disease physicians experienced in the treatment of chronic hepatitis C infection can prescribe daclatasvir on the PBS. Other health professionals, including GPs, can also prescribe daclatasvir under the PBS, provided that it is done in consultation (by phone, mail, email, or videoconference) with one of these specialists.⁵

Community pharmacists can only dispense under the General Schedule

Daclatasvir will not be available under the new S100 HSD Community Access arrangements introduced on 1 July 2015. Approved pharmacists in the community will be able to dispense when a prescription is issued under the General Schedule. However, if the prescription has been written under S100 HSD arrangements in a public hospital, approved pharmacists in the community will not be able to dispense.

Daclatasvir is a direct-acting antiviral (DAA) agent that selectively inhibits the HCV non-structural protein NS5A, an essential component of the HCV replication complex.¹

Daclatasvir is an oral tablet used as a component of a combination HCV antiviral treatment regimen, and can be used in combination with sofosbuvir, with or without ribavirin, to treat chronic HCV infection.

Use in a combination antiviral regimen for patients with genotype 1 or 3 HCV infection

PBS-listed daclatasvir is suitable for patients with genotype 1 or genotype 3 HCV infection in combination antiviral treatment regimens with sofosbuvir, with or without ribavirin depending on the HCV genotype and treatment history.⁵ Refer to the section ‘Where does it fit’ for detailed place in therapy.

There are limited data to support the use of daclatasvir in patients with genotype 2 HCV infection,¹ and it is not PBS listed for this use.⁵

Available for use in patients with decompensated liver disease

Although the manufacturer’s product information states that daclatasvir combination regimens have not been studied in patients with decompensated cirrhosis,¹ the PBS-listed HCV treatment regimens for daclatasvir do not distinguish between patients with compensated versus decompensated cirrhosis.^{2, 7}

Available for use in patients co-infected with HIV or hepatitis B virus

Although the manufacturer’s product information states that safety and efficacy of daclatasvir treatment regimens for the treatment of chronic HCV infection has not been established in patients who are co-infected with HIV or hepatitis B virus (HBV),¹ treatment regimens for chronic HCV infection in these populations should be the same as those used for HCV mono-infection.⁷

Careful assessment of potential interactions with concurrent medicines should be used to guide selection of an appropriate direct-acting antiviral (DAA) treatment regimen. Australian consensus recommendations direct practitioners to the University of Liverpool’s Hepatitis Drug Interactions website.⁷

Not for use during pregnancy

There are no adequate and well-controlled trials to support using daclatasvir in pregnant women. Ensure women of childbearing potential use contraception during, and for 5 weeks after completing, treatment involving daclatasvir.

Because ribavirin is contraindicated in pregnancy, when using daclatasvir in combination with ribavirin, extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients, for 6 months after completion of therapy.¹

Australian Consensus recommendations recommend daclatasvir and sofosbuvir, with or without ribavirin, as a first-line option for treatment of patients with chronic genotype 1 or genotype 3 hepatitis C infection.⁷ Patients with compensated and decompensated cirrhosis are also eligible for PBS-listed daclatasvir combination treatment regimens.⁷

Daclatasvir is PBS listed with sofosbuvir as a 12- or 24-week interferon- and ribavirin-free treatment regimen for both treatment-naïve and treatment-experienced patients 18 years or older with genotype 1 or 3 HCV infection regardless of their cirrhotic or non-cirrhotic status, or as a 12-week interferon-free regimen with sofosbuvir and ribavirin for treatment-naïve or -experienced patients aged 18 years or older with genotype 1 HCV infection and cirrhosis.⁵

Although daclatasvir is approved by the Therapeutic Goods Administration for use with asunaprevir or with peginterferon alfa and ribavirin,¹ these combinations are not PBS listed.⁵ Daclatasvir should not be used as monotherapy.¹

The contraindications applicable to the other individual antiviral agents are applicable when used in combination with daclatasvir. Refer to the respective Product Information for sofosbuvir or ribavirin for a list of contraindications for these medicines.¹

As well as daclatasvir and sofosbuvir, with or without ribavirin, three additional HCV treatment combinations were also listed on the PBS for treatment of chronic hepatitis C from 1 March 2016:⁵

• ledipasvir with sofosbuvir (see Ledipasvir with sofosbuvir fixed-dose combination for chronic hepatitis C)
• sofosbuvir with ribavirin (see Sofosbuvir treatment combinations for chronic hepatitis C)
• sofosbuvir with peginterferon alfa-2a and ribavirin (see interferon wrap-up).

The PBAC considered that the appropriate comparator should be ‘no treatment’, as many HCV patients are not undertaking therapy because of adverse effects associated with current interferon-based therapies.⁶

For the purposes of PBS listing the results of a single non-comparative open label trial were considered by the PBAC.⁴ The PBAC accepted this study as sufficient evidence of clinical effectiveness of daclatasvir in achieving SVR, while noting the limitations of the study, including the small sample size.⁶

Combination treatment with daclatasvir for 12 weeks achieves high rates of SVR for genotype 1 and 3 HCV infection

In the study considered by the PBAC, patients infected with HCV genotypes 1, 2 or 3 but without cirrhosis were randomly assigned, in a 1:1:1 ratio to receive treatment as follows:⁴

• combination of daclatasvir and sofosbuvir for 23 weeks following treatment with sofosbuvir alone during a 1-week run-in period, or
• combination of daclatasvir and sofosbuvir for 24 weeks, or
• combination of daclatasvir, sofosbuvir and ribavirin for 24 weeks.

Of the 211 patients who received daclatasvir, 44 were infected with genotype 2 or 3 HCV and 167 had genotype 1 infection, with mostly treatment-naïve treatment history.

After 12 weeks an overall SVR was achieved by 98% of patients infected with HCV genotype 1 and 91% of patients infected with genotypes 2 and 3.⁴ The submission noted the numerically lower SVR rate seen in patients with genotype 2 and 3 compared with genotype 1 infection.⁶

High rates of SVR (95% to 100%) were also observed in treatment-experienced patients who received daclatasvir with sofosbuvir (with or without ribavirin) for 24 weeks; however, this included only 41 patients who had previously experienced virological failure with telaprevir or boceprevir and peginterferon alfa–ribavirin combination treatment.⁴

Two other small studies have established similarly high rates of SVR after 12 weeks, mostly against genotype 1 infection in patients without cirrhosis who were co-infected with HIV-1 in both treatment-naïve and treatment-experienced groups,³ as well as in genotype 3 infection in mostly treatment-naïve patients without cirrhosis.⁹ In the latter study, 86% of 51 treatment-experienced patients achieved SVR.

Follow the prescribing matrix outlined by the PBAC

The PBAC has outlined a prescribing matrix based on treatment history and HCV genotype for antiviral treatment regimens that are supported by evidence and available for PBS rebate.

The PBAC noted that evidence of clinical efficacy for daclatasvir with sofosbuvir was insufficient in the following groups:⁶

• treatment-experienced patients with HCV genotypes 2–6
• patients with documented cirrhosis
• treatment-naïve patients with HCV genotype 4, 5 or 6
• patients with HIV or HBV co-infection.⁹

While some clinical efficacy was observed in patients with cirrhosis in one study, the proportion of patients achieving SVR was lower than for patients without cirrhosis.⁹ Another study showed similar rates of SVR in patients with and without cirrhosis; however, this was in a population of patients co-infected with HIV.³ Both these studies were limited by the small number of patients with cirrhosis studied.

Read more about the new hepatitis C medicines available on the PBS.

There were insufficient data to reliably determine the safety profile of daclatasvir with sofosbuvir, especially with respect to uncommon or rare treatment-related adverse events.⁶

Combination treatment with daclatasvir is well tolerated

In the pivotal trial involving 211 patients, two (< 1%) discontinued during treatment and 15 patients (7.1%) experienced serious adverse events during the treatment period (including five events of overdose with no clinically significant effects). The most common adverse events were fatigue (37%), headache (29%) and nausea (19%).⁴

The most common grade 3 or 4 laboratory abnormalities were low phosphorus and elevated glucose levels.⁴

Other trials showed a similarly low rate of serious adverse events and discontinuations.^{3, 9}

For information about reporting adverse reactions to the TGA, or to report suspected adverse reactions online, see the TGA website.

Read more about the efficacy and safety of daclatasvir in Australian Prescriber.

Potential drug interaction with amiodarone

Severe bradycardia and heart block have been reported in patients using amiodarone who underwent HCV antiviral treatment with daclatasvir and sofosbuvir, regardless of whether other medicines that lower heart rate were being used. Bradycardia resolved after discontinuation of HCV treatment.

Consider an alternative antiarrhythmic treatment. For patients with no alternative treatment options, warn patients of the symptoms of bradycardia and heart block. Closely monitor cardiac activity when co-administering amiodarone with daclatasvir and sofosbuvir.¹

Contraindicated in combination with strong CYP3A4 inducers

Do not use daclatasvir in combination with drugs that strongly induce CYP3A4, as these may lead to lower exposure and loss of efficacy of daclatasvir.

Contraindicated medicines include, but are not limited to, phenytoin, carbamazepine, oxcarbazepine, phenobarbital, rifampicin, rifabutin, dexamethasone and St John’s wort.¹

A dose adjustment is required when daclatasvir is used in combination with moderate inducers of CYP3A4 (see Dosing issues).¹

The PBAC recommended the listing of daclatasvir in combination with sofosbuvir for treatment of genotype 1 chronic hepatitis C (CHC) in treatment-naïve patients without cirrhosis, based on acceptable cost effectiveness over no treatment.⁶

The listing of daclatasvir in combination with sofosbuvir for the treatment of genotype 3 CHC was also recommended on the basis of acceptable cost-effectiveness over no treatment.⁶

However, following the recommendation to list sofosbuvir-containing regimens, the PBAC considered these sofosbuvir-containing regimens to be the appropriate comparator for all other oral HCV treatments because they were likely to become the standard of care, while accepting that the listing of daclatasvir could only progress if sofosbuvir is available on the PBS.⁶

The PBAC considered that the SVR achieved with 12 weeks’ combination treatment with daclatasvir and sofosbuvir was non-inferior in comparative efficacy with that of:⁶

• ledipasvir with sofosbuvir fixed-dose combination in treatment-naïve patients with genotype 1 CHC but no cirrhosis
• sofosbuvir and ribavirin treatment over 24 weeks in treatment-naïve patients with genotype 3 CHC but no cirrhosis.

Daclatasvir is for oral administration and may be taken with or without food. The recommended dose is 60 mg once daily taken in a combination antiviral regimen with other medicines.¹ For specific dosing recommendations for other medicines taken with daclatasvir in an antiviral regimen, refer to the respective Product Information.

Daclatasvir is not for use as monotherapy

Avoid treatment interruption after therapy with daclatasvir has started. If treatment interruption of any agent used in combination with daclatasvir is necessary, discontinue daclatasvir.¹

Dose adjustment required if co-administered with moderate inducers or strong inhibitors of CYP3A4

A 30 mg daclatasvir tablet is also available for use when dose adjustment is required.

Daclatasvir is a substrate of CYP3A, and the major CYP isoform responsible for its metabolism is CYP3A4.¹

The dose of daclatasvir should be increased to 90 mg once daily when used in combination with moderate inducers of CYP3A4.¹ Moderate CYP3A4 inducers include, but are not limited to, bosentan, modafinil and efavirenz.¹⁰ Note that strong inducers of CYP3A4 are contraindicated with daclatasvir (see Safety issues).¹

Strong inhibitors of CYP3A4 may increase the plasma levels of daclatasvir, and the dose of daclatasvir should be reduced to 30 mg once daily when administered concomitantly with strong inhibitors of CYP3A4.¹ These include, but are not limited to, boceprevir, clarithromycin and ketoconazole.¹⁰

Discontinue treatment if virological breakthrough is confirmed

Australian Consensus Recommendations do not mandate testing for HCV RNA during antiviral treatment; however, they note it may be considered when there is a concern over non-adherence to treatment, and for patients with cirrhosis.⁷

If a patient experiences an increase in HCV RNA (from nadir) of greater than 1 log 10 IU/mL, it is recommended daclatasvir be discontinued. The effectiveness of treatment with daclatasvir in patients with prior exposure to an NS5A inhibitor has not been established.¹

No dose adjustment required for renal or hepatic impairment

When administering daclatasvir in patients with mild, moderate or severe hepatic or renal impairment, no dose adjustment is needed.¹ However, the safety of sofosbuvir has not been assessed in patients with severe renal impairment (eGFR < 30 mL/min/1.73m²) or end-stage renal disease requiring haemodialysis, and there are no data to support use of sofosbuvir in patients with severe renal failure.¹¹ Combination treatment with daclatasvir and sofosbuvir should therefore not be used in these patients.

No dose adjustment required for older people

Clinical trials of daclatasvir have included cohorts of patients 65 years and older, with no differences in safety or efficacy observed compared with younger people. No dose adjustment of daclatasvir is advised at this time.¹

Advise patients talking daclatasvir with sofosbuvir, with or without ribavirin, as follows.⁸

• Daclatasvir should not be taken alone to treat chronic hepatitis C. It should be used together with other antiviral medicines such as sofosbuvir, with or without ribavirin, which are also PBS listed.
• Daclatasvir is sometimes used with ribavirin, which may cause birth defects or death of your unborn baby. If you are pregnant or are planning to become pregnant or your sexual partner is pregnant or plans to become pregnant, do not take these medicines.
• Do not take daclatasvir if you are currently taking any of these medicines:
  • carbamazepine
  • dexamethasone
  • oxcarbazepine
  • phenobarbital
  • phenytoin
  • rifabutin
  • rifampicin
  • St John’s wort.
  If you are unsure, talk to your doctor or pharmacist.

Discuss the daclatasvir (Daklinza) Consumer Medicine Information (CMI) leaflet with the patient, especially when daclatasvir is used in combinations that are not PBS listed and therefore not considered here (eg, with Sunvepra or Pegasys-RBV).