Bristol-Myers Squibb Pharmaceutical Limited

Daklinza 30 mg film-coated tablets

Daklinza 60 mg film-coated tablets

Daklinza 90 mg film-coated tablets

Daklinza 30 mg film-coated tablets

Each film-coated tablet contains daclatasvir dihydrochloride equivalent to 30 mg daclatasvir.

Daklinza 60 mg film-coated tablets

Each film-coated tablet contains daclatasvir dihydrochloride equivalent to 60 mg daclatasvir.

Daklinza 90 mg film-coated tablets

Each film-coated tablet contains daclatasvir dihydrochloride equivalent to 90 mg daclatasvir.

Excipient(s) with known effect

Each 30-mg film-coated tablet contains 58 mg of lactose (as anhydrous).

Each 60-mg film-coated tablet contains 116 mg of lactose (as anhydrous).

Each 90-mg film-coated tablet contains 173 mg of lactose (as anhydrous).

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Daklinza 30 mg film-coated tablets

Green biconvex pentagonal of dimensions 7.2 mm x 7.0 mm, debossed tablet with "BMS" on one side and "213" on the other side.

Daklinza 60 mg film-coated tablets

Light green biconvex pentagonal of dimensions 9.1 mm x 8.9 mm, debossed tablet with "BMS" on one side and "215" on the other side.

Daklinza 90 mg film-coated tablets

Light green biconvex round of dimension 10.16 mm diameter, embossed tablet with "BMS" on one side and "011" on the other side.

Daklinza is indicated in combination with other medicinal products for the treatment of chronic hepatitis C virus (HCV) infection in adults (see sections 4.2, 4.4 and 5.1).

For HCV genotype specific activity, see sections 4.4 and 5.1.

Treatment with Daklinza should be initiated and monitored by a physician experienced in the management of chronic hepatitis C.

Posology

The recommended dose of Daklinza is 60 mg once daily, to be taken orally with or without meals.

Daklinza must be administered in combination with other medicinal products. The Summary of Product Characteristics for the other medicinal products in the regimen should also be consulted before initiation of therapy with Daklinza.

GT: Genotype; CP: Child Pugh

* Includes patients co-infected with human immunodeficiency virus (HIV). For dosing recommendations with HIV antiviral agents, refer to section 4.5.

Daklinza + peginterferon alfa + ribavirin

This regimen is an alternative recommended regimen for patients with genotype 4 infection, without cirrhosis or with compensated cirrhosis. Daklinza is given for 24 weeks, in combination with 24-48 weeks of peginterferon alfa and ribavirin:

- If HCV RNA is undetectable at both treatment weeks 4 and 12, all 3 components of the regimen should be continued for a total duration of 24 weeks.

- If undetectable HCV RNA is achieved, but not at both treatment weeks 4 and 12, Daklinza should be discontinued at 24 weeks and peginterferon alfa and ribavirin continued for a total duration of 48 weeks.

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 Summary of Product Characteristics of ribavirin.

For patients with Child-Pugh A, B, or C cirrhosis or recurrence of HCV infection after liver transplantation, the recommended initial dose of ribavirin is 600 mg daily with food. If the starting dose is well-tolerated, the dose can be titrated up to a maximum of 1,000-1,200 mg daily (breakpoint 75 kg). If the starting dose is not well-tolerated, the dose should be reduced as clinically indicated, based on haemoglobin and creatinine clearance measurements (see Table 2).

Dose modification, interruption and discontinuation

Dose modification of Daklinza to manage adverse reactions is not recommended. If treatment interruption of components in the regimen is necessary because of adverse reactions, Daklinza must not be given as monotherapy.

There are no virologic treatment stopping rules that apply to the combination of Daklinza with sofosbuvir.

Treatment discontinuation in patients with inadequate on-treatment virologic response during treatment with Daklinza, peginterferon alfa and ribavirin

It is unlikely that patients with inadequate on-treatment virologic response will achieve a sustained virologic response (SVR); therefore discontinuation of treatment is recommended in these patients. The HCV RNA thresholds that trigger discontinuation of treatment (i.e. treatment stopping rules) are presented in Table 3.

Dose recommendation for concomitant medicines

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.

Moderate inducers of CYP3A4

The dose of Daklinza should be increased to 90 mg once daily when coadministered with moderate inducers of CYP3A4. See section 4.5.

Missed doses

Patients should be instructed that, if they miss a dose of Daklinza, the dose should be taken as soon as possible if remembered within 20 hours of the scheduled dose time. However, if the missed dose is remembered more than 20 hours after the scheduled dose, the dose should be skipped and the next dose taken at the appropriate time.

Special populations

Elderly

No dose adjustment of Daklinza is required for patients aged ≥65 years (see section 5.2).

Renal impairment

No dose adjustment of Daklinza is required for patients with any degree of renal impairment (see section 5.2).

Hepatic impairment

No dose adjustment of Daklinza is required for patients with mild (Child-Pugh A, score 5-6), moderate (Child-Pugh B, score 7-9) or severe (Child-Pugh C, score ≥10) hepatic impairment (see sections 4.4 and 5.2).

Paediatric population

The safety and efficacy of Daklinza in children and adolescents aged below 18 years have not yet been established. No data are available.

Method of administration

Daklinza is to be taken orally with or without meals. Patients should be instructed to swallow the tablet whole. The film-coated tablet should not be chewed or crushed due the unpleasant taste of the active substance.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Coadministration with medicinal products that strongly induce cytochrome P450 3A4 (CYP3A4) and P-glycoprotein transporter (P-gp) and thus may lead to lower exposure and loss of efficacy of Daklinza. These active substances include but are not limited to phenytoin, carbamazepine, oxcarbazepine, phenobarbital, rifampicin, rifabutin, rifapentine, systemic dexamethasone, and the herbal product St John's wort (Hypericum perforatum).

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 sections 4.1 and 4.2).

Severe bradycardia and heart block

Cases of severe bradycardia and heart block have been observed when Daklinza is used in combination with sofosbuvir and concomitant amiodarone with or without other drugs that lower heart rate. The mechanism is not established.

The concomitant use of amiodarone was limited through the clinical development of sofosbuvir plus direct-acting antivirals (DAAs). Cases are potentially life threatening, therefore amiodarone should only be used in patients on Daklinza and sofosbuvir when other alternative antiarrhythmic treatments are not tolerated or are contraindicated.

Should concomitant use of amiodarone be considered necessary it is recommended that patients are closely monitored when initiating Daklinza in combination with sofosbuvir. Patients who are identified as being at high risk of bradyarrhythmia should be continuously monitored for 48 hours in an appropriate clinical setting.

Due to the long half-life of amiodarone, appropriate monitoring should also be carried out for patients who have discontinued amiodarone within the past few months and are to be initiated on Daklinza in combination with sofosbuvir.

All patients receiving Daklinza and sofosbuvir in combination with amiodarone with or without other drugs that lower heart rate should also be warned of the symptoms of bradycardia and heart block and should be advised to seek medical advice urgently should they experience them.

Genotype-specific activity

Concerning recommended regimens with different HCV genotypes, see section 4.2. Concerning genotype-specific virological and clinical activity, see section 5.1.

Data to support the treatment of genotype 2 infection with Daklinza and sofosbuvir are limited.

Data from study ALLY-3 (AI444218) support a 12-week treatment duration of Daklinza + sofosbuvir for treatment-naïve and -experienced patients with genotype 3 infection without cirrhosis. Lower rates of SVR were observed for patients with cirrhosis (see section 5.1). Data from compassionate use programmes which included patients with genotype 3 infection and cirrhosis, support the use of Daklinza + sofosbuvir for 24 weeks in these patients. The relevance of adding ribavirin to that regimen is unclear (see section 5.1).

The clinical data to support the use of Daklinza and sofosbuvir in patients infected with HCV genotypes 4 and 6 are limited. There are no clinical data in patients with genotype 5 (see section 5.1).

Patients with Child-Pugh C liver disease

The safety and efficacy of Daklinza in the treatment of HCV infection in patients with Child-Pugh C liver disease have been established in the clinical study ALLY-1 (AI444215, Daklinza + sofosbuvir + ribavirin for 12 weeks); however, SVR rates were lower than in patients with Child-Pugh A and B. Therefore, a conservative treatment regimen of Daklinza + sofosbuvir +/- ribavirin for 24 weeks is proposed for patients with Child-Pugh C (see sections 4.2 and 5.1). Ribavirin may be added based on clinical assessment of an individual patient.

HCV/HBV (hepatitis B virus) co-infection

Cases of hepatitis B virus (HBV) reactivation, some of them fatal, have been reported during or after treatment with direct-acting antiviral agents. HBV screening should be performed in all patients before initiation of treatment. HBV/HCV co-infected patients are at risk of HBV reactivation, and should therefore be monitored and managed according to current clinical guidelines.

Retreatment with daclatasvir

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

Pregnancy and contraception requirements

Daklinza should not be used during pregnancy or in women of childbearing potential not using contraception. Use of highly effective contraception should be continued for 5 weeks after completion of Daklinza therapy (see section 4.6).

When Daklinza is used in combination with ribavirin, the contraindications and warnings for that medicinal product are applicable. Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin; therefore, extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients (see the Summary of Product Characteristics for ribavirin).

Interactions with medicinal products

Coadministration of Daklinza can alter the concentration of other medicinal products and other medicinal products may alter the concentration of daclatasvir. Refer to section 4.3 for a listing of medicinal products that are contraindicated for use with Daklinza due to potential loss of therapeutic effect. Refer to section 4.5 for established and other potentially significant drug-drug interactions.

Paediatric population

Daklinza is not recommended for use in children and adolescents aged below 18 years because the safety and efficacy have not been established in this population.

Important information about some of the ingredients in Daklinza

Daklinza contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Contraindications of concomitant use (see section 4.3)

Daklinza is contraindicated in combination with medicinal products that strongly induce CYP3A4 and P-gp, e.g. phenytoin, carbamazepine, oxcarbazepine, phenobarbital, rifampicin, rifabutin, rifapentine, systemic dexamethasone, and the herbal product St John's wort (Hypericum perforatum), and thus may lead to lower exposure and loss of efficacy of Daklinza.

Potential for interaction with other medicinal products

Daclatasvir is a substrate of CYP3A4, P-gp and organic cation transporter (OCT) 1. Strong or moderate inducers of CYP3A4 and P-gp may decrease the plasma levels and therapeutic effect of daclatasvir. Coadministration with strong inducers of CYP3A4 and P-gp is contraindicated while dose adjustment of Daklinza is recommended when coadministered with moderate inducers of CYP3A4 and P-gp (see Table 4). Strong inhibitors of CYP3A4 may increase the plasma levels of daclatasvir. Dose adjustment of Daklinza is recommended when coadministered with strong inhibitors of CYP3A4 (see Table 4). Coadministration of medicines that inhibit P-gp or OCT1 activity is likely to have a limited effect on daclatasvir exposure.

Daclatasvir is an inhibitor of P-gp, organic anion transporting polypeptide (OATP) 1B1, OCT1 and breast cancer resistance protein (BCRP). Administration of Daklinza may increase systemic exposure to medicinal products that are substrates of P-gp, OATP 1B1, OCT1 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 (see Table 4).

Daclatasvir is a very weak inducer of CYP3A4 and caused a 13% decrease in midazolam exposure. However, as this is a limited effect, dose adjustment of concomitantly administered CYP3A4 substrates is not necessary.

Refer to the respective Summary of Product Characteristics for drug interaction information for other medicinal products in the regimen.

Patients treated with vitamin K antagonists

As liver function may change during treatment with Daklinza, a close monitoring of International Normalized Ratio (INR) values is recommended.

Tabulated summary of interactions

Table 4 provides information from drug interaction studies with daclatasvir including clinical recommendations for established or potentially significant drug interactions. Clinically relevant increase in concentration is indicated as “↑”, clinically relevant decrease as “↓”, no clinically relevant change as “↔”. If available, ratios of geometric means are shown, with 90% confidence intervals (CI) in parentheses. The studies presented in Table 4 were conducted in healthy adult subjects unless otherwise noted. The table is not all-inclusive.

No clinically relevant effects on the pharmacokinetics of either medicinal product are expected when daclatasvir 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), disopyramide, propafenone, flecainide, mexilitine, quinidine or antacids.

Paediatric population

Interaction studies have only been performed in adults.

Dizziness has been reported during treatment with Daklinza in combination with sofosbuvir, and dizziness, disturbance in attention, blurred vision and reduced visual acuity have been reported during treatment with Daklinza in combination with peginterferon alfa and ribavirin.

Summary of the safety profile

The overall safety profile of daclatasvir is based on data from 2215 patients with chronic HCV infection who received Daklinza once daily either in combination with sofosbuvir with or without ribavirin (n=679, pooled data) or in combination with peginterferon alfa and ribavirin (n=1536, pooled data) from a total of 14 clinical studies.

Daklinza in combination with sofosbuvir

The most frequently reported adverse reactions were fatigue, headache, and nausea. Grade 3 adverse reactions were reported in less than 1% of patients, and no patients had a Grade 4 adverse reaction. Four patients discontinued the Daklinza regimen for adverse events, only one of which was considered related to study therapy.

Daklinza in combination with peginterferon alfa and ribavirin

The most frequently reported adverse reactions were fatigue, headache, pruritus, anaemia, influenza-like illness, nausea, insomnia, neutropenia, asthenia, rash, decreased appetite, dry skin, alopecia, pyrexia, myalgia, irritability, cough, diarrhoea, dyspnoea and arthralgia. The most frequently reported adverse reactions of at least Grade 3 severity (frequency of 1% or greater) were neutropenia, anaemia, lymphopenia and thrombocytopenia. The safety profile of daclatasvir in combination with peginterferon alfa and ribavirin was similar to that seen with peginterferon alfa and ribavirin alone, including among patients with cirrhosis.

Tabulated list of adverse reactions

Adverse reactions are listed in Table 5 by regimen, system organ class and frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Laboratory abnormalities

In clinical studies of Daklinza in combination with sofosbuvir with or without ribavirin, 2% of patients had Grade 3 haemoglobin decreases; all of these patients received Daklinza + sofosbuvir + ribavirin. Grade 3/4 increases in total bilirubin were observed in 5% of patients (all in patients with HIV co-infection who were receiving concomitant atazanavir, with Child-Pugh A, B, or C cirrhosis, or who were post-liver transplant).

Description of selected adverse reactions

Cardiac arrhythmias

Cases of severe bradycardia and heart block have been observed when Daklinza is used in combination with sofosbuvir and concomitant amiodarone and/or other drugs that lower heart rate (see sections 4.4 and 4.5).

Paediatric population

The safety and efficacy of Daklinza in children and adolescents aged <18 years have not yet been established. No data are available.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: medsafety@hpra.ie

There is limited experience of accidental overdose of daclatasvir in clinical studies. In phase 1 clinical studies, healthy subjects who received up to 100 mg once daily for up to 14 days or single doses up to 200 mg had no unexpected adverse reactions.

There is no known antidote for overdose of daclatasvir. Treatment of overdose with daclatasvir 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 >500, dialysis is unlikely to significantly reduce plasma concentrations of daclatasvir.

Pharmacotherapeutic group: Direct-acting antiviral, ATC code: J05AX14

Mechanism of action

Daclatasvir is an inhibitor of nonstructural protein 5A (NS5A), a multifunctional protein that is an essential component of the HCV replication complex. Daclatasvir inhibits both viral RNA replication and virion assembly.

Antiviral activity in cell culture

Daclatasvir is an inhibitor of HCV genotypes 1a and 1b replication in cell-based replicon assays with effective concentration (50% reduction, EC₅₀) values of 0.003-0.050 and 0.001-0.009 nM, respectively, depending on the assay method. The daclatasvir EC₅₀ values in the replicon system were 0.003-1.25 nM for genotypes 3a, 4a, 5a and 6a, and 0.034-19 nM for genotype 2a as well as 0.020 nM for infectious genotype 2a (JFH-1) virus.

Daclatasvir showed additive to synergistic interactions with interferon alfa, HCV nonstructural protein 3 (NS3) PIs, HCV nonstructural protein 5B (NS5B) non-nucleoside inhibitors, and HCV NS5B nucleoside analogues in combination studies using the cell-based HCV replicon system. No antagonism of antiviral activity was observed.

No clinically relevant antiviral activity was observed against a variety of RNA and DNA viruses, including HIV, confirming that daclatasvir, which inhibits a HCV-specific target, is highly selective for HCV.

Resistance in cell culture

Substitutions conferring daclatasvir resistance in genotypes 1-4 were observed in the N-terminal 100 amino acid region of NS5A in a cell-based replicon system. 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. These substitutions conferred low level resistance (EC₅₀ <1 nM) for genotype 1b, and higher levels of resistance for genotype 1a (EC₅₀ up to 350 nM). The most resistant variants with single amino acid substitution in genotype 2a and genotype 3a were F28S (EC₅₀ >300 nM) and Y93H (EC₅₀ >1,000 nM), respectively. In genotype 4, amino acid substitutions at 30 and 93 (EC₅₀ < 16 nM) were frequently selected.

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 (nucleoside and non-nucleoside) inhibitors.

Clinical efficacy and safety

In clinical studies of daclatasvir in combination with sofosbuvir or with peginterferon alfa and ribavirin, plasma HCV RNA values were measured using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System, with a lower limit of quantification (LLOQ) of 25 IU/ ml. SVR was the primary endpoint to determine the HCV cure rate, which was defined as HCV RNA less than LLOQ at 12 weeks after the end of treatment (SVR12) for studies AI444040, ALLY-1 (AI444215), ALLY-2 (AI444216), ALLY-3 (AI444218), AI444042 and AI444043 and as HCV RNA undetectable at 24 weeks after the end of treatment (SVR24) for study AI444010.

Daclatasvir in combination with sofosbuvir

The efficacy and safety of daclatasvir 60 mg once daily in combination with sofosbuvir 400 mg once daily in the treatment of patients with chronic HCV infection were evaluated in four open-label studies (AI444040, ALLY-1, ALLY-2 and ALLY-3).

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 patients with HCV genotype 1 infection, 126 were treatment-naïve and 41 had failed prior therapy with a PI regimen (boceprevir or telaprevir). All 44 patients with HCV genotype 2 (n=26) or 3 (n=18) infection were treatment-naïve. Treatment duration was 12 weeks for 82 treatment-naïve HCV genotype 1 patients, and 24 weeks for all other patients in the study. The 211 patients had a median age of 54 years (range: 20 to 70); 83% were white; 12% were black/African-American; 2% were Asian; 20% were Hispanic or Latino. The mean score on the FibroTest (a validated non-invasive diagnostic assay) was 0.460 (range: 0.03 to 0.89). Conversion of the FibroTest score to the corresponding METAVIR score suggests that 35% of all patients (49% of patients with prior PI failure, 30% of patients with genotype 2 or 3) had ≥F3 liver fibrosis. Most patients (71%, including 98% of prior PI failures) had IL-28B rs12979860 non-CC genotypes.

SVR12 was achieved by 99% patients with HCV genotype 1, 96% of those with genotype 2 and 89% of those with genotype 3 (see Tables 6 and 7). Response was rapid (viral load at Week 4 showed that more than 97% of patients responded to therapy), and was not influenced by HCV subtype (1a/1b), IL28B genotype, or use of ribavirin. Among treatment-naïve patients with HCV RNA results at both follow-up Weeks 12 and 24, concordance between SVR12 and SVR24 was 99.5% independent of treatment duration.

Treatment-naïve patients with HCV genotype 1 who received 12 weeks of treatment had a similar response as those treated for 24 weeks (Table 6).

^* Patients who had missing data at follow-up Week 12 were considered responders if their next available HCV RNA value was <LLOQ. One treatment-naïve patient was missing both post-treatment Weeks 12 and 24 data.

^* Patients who had missing data at follow-up Week 12 were considered responders if their next available HCV RNA value was <LLOQ. One patient with HCV genotype 2 infection was missing both post-treatment Week 12 and 24 data.

^** The patient with virologic breakthrough met the original protocol definition of confirmed HCV RNA <LLOQ, detectable at treatment Week 8. Relapse was defined as HCV RNA ≥LLOQ during follow-up after HCV RNA <LLOQ at end of treatment. Relapse includes observations through follow-up Week 24.

Advanced cirrhosis and post-liver transplant (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 transplantation (n=53). Patients with HCV genotype 1, 2, 3, 4, 5 or 6 infection were eligible to enroll. Patients received daclatasvir 60 mg once daily, sofosbuvir 400 mg once daily, and ribavirin (600 mg starting dose) for 12 weeks and were monitored for 24 weeks post treatment. Patients demographics and main disease characteristics are summarised in Table 8.

ND: Not determined

SVR12 was achieved by 83% (50/60) of patients in the cirrhosis cohort, with a marked difference between patients with Child-Pugh A or B (92-94%) as compared to those with Child-Pugh C and 94% of patients in the post-liver transplant cohort (Table 9). 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 post-liver transplant treatment extension and 1 patient, treated for 23 days before transplantation, did not receive treatment extension. All 4 patients achieved SVR12.

ND: Not determined

^{* 2 patients had detectable HCV RNA at end of treatment; 1 of these patients achieved SVR.}

HCV/HIV co-infection (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 co-infection; 101 patients were HCV treatment-naïve and 52 patients had failed prior HCV therapy. Patients with HCV genotype 1, 2, 3, 4, 5, or 6 infection were eligible to enroll, including patients with compenstated cirrhosis (Child-Pugh A). The dose of daclatasvir was adjusted for concomitant antiretroviral use. Patient demographics and baseline disease characteristics are summarised in Table 10.

Overall, SVR12 was achieved by 97% (149/153) of patients administered daclatasvir and sofosbuvir for 12 weeks in ALLY-2. SVR rates were >94% across combination antiretroviral therapy (cART) regimens, including boosted-PI-, NNRTI-, and integrase inhibitor (INSTI)-based therapies.

SVR rates were comparable regardless of HIV regimen, age, race, gender, IL28B allele status, or baseline HCV RNA level. Outcomes by prior treatment experience are presented in Table 11.

A third treatment group in study ALLY-2 included 50 HCV treatment-naïve HIV co-infected patients who received daclatasvir and sofosbuvir for 8 weeks. Demographic and baseline characteristics of these 50 patients were generally comparable to those for patients who received 12 weeks of study treatment. The SVR rate for patients treated for 8 weeks was lower with this treatment duration as summarized in Table 11.

^* Mainly interferon-based therapy +/-NS3/4 PI.

^** Cirrhosis was determined by liver biopsy, FibroScan >14.6 kPa, or FibroTest score ≥0.75 and aspartate aminotransferase (AST): platelet ratio index (APRI) >2. For 5 patients, cirrhosis status was indeterminate.

HCV Genotype 3 (ALLY-3)

In study ALLY-3, the combination of daclatasvir and sofosbuvir administered for 12 weeks was evaluated in 152 adults infected with HCV genotype 3; 101 patients were treatment-naïve and 51 patients had failed prior antiviral therapy. 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. The median viral load was 6.42 log₁₀ IU/ml, and 21% of patients had compensated cirrhosis. Most patients (61%) had IL-28B rs12979860 non-CC genotypes.

SVR12 was achieved in 90% of treatment-naïve 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 12).

^* Mainly interferon-based therapy, but 7 patients received sofosbuvir + ribavirin and 2 patients received a cyclophilin inhibitor.

^** Cirrhosis was determined by liver biopsy (METAVIR F4) for 14 patients, FibroScan >14.6 kPa for 11 patients or FibroTest score ≥0.75 and aspartate aminotransferase (AST): platelet ratio index (APRI) >2 for 7 patients. For 11 patients, cirrhosis status was missing or inconclusive (FibroTest score >0.48 to <0.75 or APRI >1 to ≤2).

Compassionate Use

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

Daclatasvir in combination with peginterferon alfa and ribavirin

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

AI444042: Patients received daclatasvir 60 mg once daily (n=82) or placebo (n=42) plus pegIFN/RBV for 24 weeks. Patients in the daclatasvir treatment group who did not have HCV RNA undetectable at both Weeks 4 and 12 and all placebo-treated patients continued pegIFN/RBV for another 24 weeks. Treated patients had a median age of 49 years (range: 20 to 71); 77% of patients were white; 19% were black/African-American; 4% were Hispanic or Latino. Ten percent of patients had compensated cirrhosis, and 75% of patients had IL-28B rs12979860 non-CC genotypes. Treatment outcomes in study AI444042 are presented in Table 13. Response was rapid (at Week 4 91% of daclatasvir-treated patients had HCV RNA <LLOQ). SVR12 rates were higher for patients with the IL-28B CC genotype than for those with non-CC genotypes and for patients with baseline HCV RNA less than 800,000 IU/ml but consistently higher in the daclatasvir-treated patients than for placebo-treated patients in all subgroups.

AI444010: Patients received daclatasvir 60 mg once daily (n=158) or placebo (n=78) plus pegIFN/RBV through Week 12. Patients assigned to daclatasvir 60 mg once-daily treatment group who had HCV RNA <LLOQ at Week 4 and undetectable at Week 10 were then randomised to receive another 12 weeks of daclatasvir 60 mg + pegIFN/RBV or placebo + pegIFN/RBV for a total treatment duration of 24 weeks. Patients originally assigned to placebo and those in the daclatasvir group who did not achieve HCV RNA <LLOQ at Week 4 and undetectable at Week 10 continued pegIFN/RBV to complete 48 weeks of treatment. Treated patients had a median age of 50 years (range: 18 to 67); 79% of patients were white; 13% were black/African-American; 1% were Asian; 9% were Hispanic or Latino. Seven percent of patients had compensated cirrhosis; 92% had HCV genotype 1 (72% 1a and 20% 1b) and 8% had HCV genotype 4; 65% of patients had IL-28B rs12979860 non-CC genotypes.

Treatment outcomes in study AI444010 for patients with HCV genotype 4 are presented in Table 13. For HCV genotype 1, SVR12 rates were 64% (54% for 1a; 84% for 1b) for patients treated with daclatasvir + pegIFN/RBV and 36% for patients treated with placebo + pegIFN/RBV. For daclatasvir-treated patients with HCV RNA results at both follow-up Weeks 12 and 24, concordance of SVR12 and SVR24 was 97% for HCV genotype 1 and 100% for HCV genotype 4.

^* Patients who had missing data at follow-up Week 12 were considered responders if their next available HCV RNA value was <LLOQ.

^** Cirrhosis status was not reported for four patients in the daclatasvir + pegIFN/RBV group.

AI444043: 301 treatment-naïve patients with HCV genotype 1 infection and HIV co-infection (10% with compensated cirrhosis) were treated with daclatasvir in combination with pegIFN/RBV. The dose of daclatasvir was 60 mg once daily, with dose adjustments for concomitant antiretroviral use (see section 4.5). Patients achieving virologic response [HCV RNA undetectable at weeks 4 and 12] completed therapy after 24 weeks while those who did not achieve virologic response received an additional 24 weeks of treatment with pegIFN/RBV, to complete a total of 48 weeks of study therapy. SVR12 was achieved by 74% of patients in this study (genotype 1a: 70%, genotype 1b: 79%).

Long term efficacy data

Limited data are available from an ongoing follow-up study to assess durability of response up to 3 years after treatment with daclatasvir. Among patients who achieved SVR12 with daclatasvir and sofosbuvir (± ribavirin) with a median duration of post-SVR12 follow-up of 15 months, no relapses have occurred. Among patients who achieved SVR12 with daclatasvir + pegIFN/RBV with a median duration of post-SVR12 follow-up of 22 months, 1% of patients relapsed.

Resistance in clinical studies

Frequency of baseline NS5A resistance-associated variants (RAVs)

Baseline NS5A RAVs were frequently observed in clinical studies of daclatasvir. In 9 phase 2/3 studies with daclatasvir in combination with peginterferon alfa + ribavirin or in combination with sofosbuvir +/- ribavirin, the following frequencies of such RAVs were seen at baseline: 7% in genotype 1a infection (M28T, Q30, L31, and/or Y93); 11% in genotype 1b infection (L31 and/or Y93H), 51% in genotype 2 infection (L31M), 8% in genotype 3 infection (Y93H) and 64% in genotype 4 infection (L28 and/or L30).

Daclatasvir in combination with sofosbuvir

Impact of baseline NS5A RAVs on cure rates

The baseline NS5A RAVs described above had no major impact on cure rates in patients treated with sofosbuvir + daclatasvir +/- ribavirin, with the exception of the Y93H RAV in genotype 3 infection (seen in 16/192 [8%] of patients). The SVR12 rate in genotype-3 infected patients with this RAV is reduced (in practice as relapse after end of treatment response), especially in patients with cirrhosis. The overall cure rate for genotype-3 infected patients who were treated for 12 weeks with sofosbuvir + daclatasvir (without ribavirin) in the presence and absence of the Y93H RAV was 7/13 (54%) and 134/145 (92%), respectively. There was no Y93H RAV present at baseline for genotype-3 infected patients treated for 12-weeks with sofosbuvir + daclatasvir + ribavirin, and thus SVR outcomes cannot be assessed.

Emerging resistance

In a pooled analysis of 629 patients who received daclatasvir and sofosbuvir with or without ribavirin in Phase 2 and 3 studies for 12 or 24 weeks,34 patients qualified for resistance analysis due to virologic failure or early study discontinuation and having HCV RNA greater than 1,000 IU/ml. Observed emergent NS5A resistance-associated variants are reported in Table 14.

^* Patient(s) lost to follow-up

^** One patient considered a protocol failure (non-SVR) achieved SVR

^*** NS5A RAVs monitored at amino acid positions are 28, 29, 30, 31, 32, 58, 62, 92, and 93

The sofosbuvir resistance-associated substitution S282T emerged in only 1 non-SVR12 patient infected with genotype 3.

No data are available on the persistence of daclatasvir resistance-associated substitutions beyond 6 months post-treatment in patients treated with daclatasvir and sofosbuvir with/without ribavirin. Emergent daclatasvir resistance-associated substitutions have been shown to persist for 2 years post-treatment and beyond for patients treated with other daclatasvir-based regimens.

Daclatasvir in combination with peginterferon alfa and ribavirin

Baseline NS5A RAVs (at M28T, Q30, L31, and Y93 for genotype 1a; at L31 and Y93 for genotype 1b) increase the risk for non-response in treatment-naive patients infected with genotype 1a and genotype 1b infection. The impact of baseline NS5A RAVs on cure rates of genotype 4 infection is not apparent..

In case of non-response to therapy with daclatasvir + peginterferon alfa + ribavirin, NS5A RAVs generally emerged at failure (139/153 genotype 1a and 49/57 genotype 1b). The most frequently detected NS5A RAVs included Q30E or Q30R in combination with L31M. The majority of genotype 1a failures had emergent NS5A variants detected at Q30 (127/139 [91%]), and the majority of genotype 1b failures had emergent NS5A variants detected at L31 (37/49 [76%]) and/or Y93H (34/49 [69%]). In limited numbers of genotype 4-infected patients with non-response, substitutions L28M and L30H/S were detected at failure.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with daclatasvir in one or more subsets of the paediatric population in the treatment of chronic hepatitis C (see section 4.2 for information on paediatric use).

The pharmacokinetic properties of daclatasvir were evaluated in healthy adult subjects and in patients with chronic HCV. Following multiple oral doses of daclatasvir 60 mg once daily in combination with peginterferon alfa and ribavirin in treatment-naïve patients with genotype 1 chronic HCV, the geometric mean (CV%) daclatasvir C_max was 1534 (58) ng/ml, AUC_0-24h was 14122 (70) ng•h/ml, and C_min was 232 (83) ng/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 C_max, AUC, and C_min increased in a near 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 subjects and HCV-infected patients.

In vitro and in vivo studies showed that daclatasvir is a substrate of P-gp. The absolute bioavailability of the tablet formulation is 67%.

Effect of food on oral absorption

In healthy subjects, administration of daclatasvir 60 mg tablet after a high-fat meal decreased daclatasvir C_max and AUC by 28% and 23%, respectively, compared with administration under fasting conditions. Administration of daclatasvir 60 mg tablet after a light meal resulted in no reduction in daclatasvir exposure.

Distribution

At steady state, protein binding of daclatasvir in HCV-infected patients was approximately 99% and independent of dose at the dose range studied (1 mg to 100 mg). In patients who received daclatasvir 60 mg tablet orally followed by 100 μg [¹³C,¹⁵N]-daclatasvir intravenous dose, estimated volume of distribution at steady state was 47 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.

Daclatasvir is an inhibitor of P-gp, OATP 1B1 and BCRP. In vitro daclatasvir is an inhibitor of renal uptake transporters, OAT1 and 3, and OCT2, but is not expected to have a clinical effect on the pharmacokinetics of substrates of these transporters.

Biotransformation

In vitro and in vivo studies demonstrate that daclatasvir is a substrate of CYP3A, with CYP3A4 being the major CYP isoform responsible for the metabolism. No metabolites circulated at levels more than 5% of the parent concentration. Daclatasvir in vitro did not inhibit (IC₅₀ >40 µM) CYP enzymes 1A2, 2B6, 2C8, 2C9, 2C19, or 2D6.

Elimination

Following single-dose oral administration of ¹⁴C–daclatasvir in healthy subjects, 88% of total radioactivity was recovered in feces (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 patients, the terminal elimination half-life of daclatasvir ranged from 12 to 15 hours. In patients who received daclatasvir 60 mg tablet orally followed by 100 μg [¹³C,¹⁵N]-daclatasvir intravenous dose, the total clearance was 4.24 l/h.

Special populations

Renal impairment

The pharmacokinetics of daclatasvir following a single 60 mg oral dose were studied in non-HCV infected subjects with renal impairment. Daclatasvir unbound AUC was estimated to be 18%, 39% and 51% higher for subjects with creatinine clearance (CLcr) values of 60, 30 and 15 ml/min, respectively, relative to subjects with normal renal function. Subjects with end-stage renal disease requiring haemodialysis had a 27% increase in daclatasvir AUC and a 20% increase in unbound AUC compared to subjects with normal renal function (see section 4.2).

Hepatic impairment

The pharmacokinetics of daclatasvir following a single 30 mg oral dose were studied in non-HCV infected subjects with mild (Child-Pugh A), moderate (Child-Pugh B), and severe (Child-Pugh C) hepatic impairment compared with unimpaired subjects. The C_max 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 (see section 4.2).

Elderly

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

Paediatric population

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

Gender

Population pharmacokinetic analysis identified gender as a statistically significant covariate on daclatasvir apparent oral clearance (CL/F) with female subjects having slightly lower CL/F, but the magnitude of the effect on daclatasvir exposure is not clinically important.

Race

Population pharmacokinetic analysis of data from clinical studies identified race (categories “other” [patients who are not white, black or Asian] and “black”) as a statistically significant covariate on daclatasvir apparent oral clearance (CL/F) and apparent volume of distribution (Vc/F) resulting in slightly higher exposures compared to white patients, but the magnitude of the effect on daclatasvir exposure is not clinically important.

Toxicology

In repeat-dose toxicology studies in animals, hepatic effects (Kupffer-cell hypertrophy/ hyperplasia, mononuclear cell infiltrates and bile duct hyperplasia) and adrenal gland effects (changes in cytoplasmic vacuolation and adrenal cortical hypertrophy/hyperplasia) were observed at exposures similar or slightly higher than the clinical AUC exposure. In dogs, bone marrow hypocellularity with correlating clinical pathology changes were observed at exposures 9-fold the clinical AUC exposure. None of these effects have been observed in humans.

Carcinogenesis and mutagenesis

Daclatasvir was not carcinogenic in mice or in rats at exposures 8-fold or 4-fold, respectively, the clinical AUC exposure. No evidence of mutagenic or clastogenic activity was observed in in vitro mutagenesis (Ames) tests, mammalian mutation assays in Chinese hamster ovary cells, or in an in vivo oral micronucleus study in rats.

Fertility

Daclatasvir had no effects on fertility in female rats at any dose tested. The highest AUC value in unaffected females was 18-fold the clinical AUC exposure. 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; however, neither finding adversely affected fertility or the number of viable conceptuses sired. The AUC associated with this dose in males is 19-fold the clinical AUC exposure.

Embryo-foetal development

Daclatasvir is embryotoxic and teratogenic in rats and rabbits at exposures at or above 4-fold (rat) and 16-fold (rabbit) the clinical AUC exposure. Developmental toxicity consisted of increased embryofoetal lethality, reduced foetal body weights and increased incidence of foetal malformations and variations. In rats, malformations mainly affected the brain, skull, eyes, ears, nose, lip, palate or limbs and in rabbits, the ribs and cardiovascular area. Maternal toxicity including mortality, abortions, adverse clinical signs, decreases in body weight and food consumption was noted in both species at exposures 25-fold (rat) and 72-fold (rabbit) the clinical AUC exposure.

In a study of pre- 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-fold the clinical AUC exposure. At the highest dose (100 mg/kg/day), maternal toxicity included mortality and dystocia; developmental toxicity included slight reductions in offspring viability in the peri- and neonatal periods; and reductions in birth weight that persisted into adulthood. The AUC value associated with this dose is 4-fold the clinical AUC exposure.

Excretion into milk

Daclatasvir was excreted into the milk of lactating rats with concentrations 1.7- to 2-fold maternal plasma levels.

Tablet core

Anhydrous lactose

Microcrystalline cellulose

Croscarmellose sodium

Silicon dioxide (E551)

Magnesium stearate

Tablet film-coat

Hypromellose

Titanium dioxide (E171)

Macrogol 400

Indigo carmine aluminum lake (E132)

Yellow iron oxide (E172)

Not applicable.

Daklinza 30 mg and 60 mg film-coated tablets

30 months

Daklinza 90 mg film-coated tablets

2 years

This medicinal product does not require any special storage conditions.

Polyvinyl Chloride/poly-chloro-tri-fluoro-ethylene (PVC/PCTFE) clear blister/aluminum foil lidding.

Pack size of 28 film-coated tablets in perforated unit dose blisters.

Pack size of 28 film-coated tablets in non-perforated calendar blisters.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Bristol-Myers Squibb Pharma EEIG

Uxbridge Business Park

Sanderson Road

Uxbridge UB8 1DH

United Kingdom

EU/1/14/939/001

EU/1/14/939/002

EU/1/14/939/003

EU/1/14/939/004

EU/1/14/939/005

EU/1/14/939/006

Date of first authorisation: 22 August 2014

23 February 2017

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.