Daklinza - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

3. PHARMACEUTICAL FORM

4.2 Posology and method of administration

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.

Table 1: Recommended treatment for Daklinza interferon-free combination therapy

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).

Table 2: Ribavirin dosing guidelines for coadministration with Daklinza regimen for patients with cirrhosis or post-transplant

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.

s 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

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.

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4.3 Contraindications

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).

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4.4 Special warnings and precautions for use

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-naive and -experienced patients with genotype 3 infec ion 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 vr us) 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.

Retre atm ent 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.

Use in diabetic patients

Diabetics may experience improved glucose control, potentially resulting in symptomatic hypoglycaemia, after initiating HCV DAA treatment. Glucose levels of diabetic patients initiating DAA therapy should be closely monitored, particularly within the first 3 months, and their diabetic medication modified when necessary. The physician in charge of the diabetic care of the patient should be informed when DAA therapy is initiated.

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.

Patients on controlled sodium diet

Daklinza contains less than 1 mmol sodium (23 mg) per maximum dose of 90 mg, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

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 oth er 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.

• Table 4: Interactions and dose recommendations with other medicinal products

  
  

Medicinal products by therapeutic areas

ANTIVIRALS, HCV

Nucleotide analogue polymerase inhibitor

Table 4: Interactions and dose recommendations with other medicinal products

Table 4: Interactions and dose recommendations with other medicinal products

Table 4: Interactions and dose recommendations with other medicinal products

Table 4: Interactions and dose recommendations with other medicinal products

Table 4: Interactions and dose recommendations with other medicinal products

Table 4: Interactions and dose recommendations with other medicinal products

Table 4: Interactions and dose recommendations with other medicinal products

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.

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of daclatasvir in pregnant women.

Studies of daclatasvir in animals have shown embryotoxic and teratogenic effects (see section 5.3). The potential risk for humans is unknown.

Daklinza should not be used during pregnancy or in women of childbearing potential not using contraception (see section 4.4). Use of highly effective contraception should be continued for 5 weeks after completion of Daklinza therapy (see section 4.5).

Since Daklinza is used in combination with other agents, the contraindications and warnings for those medicinal products are applicable.

For detailed recommendations regarding pregnancy and contraception, refer to the Summary of Product Characteristics for ribavirin and peginterferon alfa.

Breast-feeding

It is not known whether daclatasvir is excreted in human milk. Available pharmacokinetic and toxicological data in animals have shown excretion of daclatasvir and metabolites in milk (see section 5.3). A risk to the newborn/infant cannot be excluded. Mothers should be instructed not to breastfeed if they are taking Daklinza.

Fertility

No human data on the effect of daclatasvir on fertility are available.

In rats, no effect on mating or fertility was seen (see section 5.3).

4.7 Effects on ability to drive and use machines

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.

4.8 Undesirable effects

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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, influenzalike 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.

Table 5: Adverse reactions in clinical studies

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 coinfection 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 the national reporting system listed in Appendix V.

4.9 Overdose

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.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Direct-acting antiviral, ATC code: J05AP07

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.

Resist ance 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 the majority of 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. HCV RNA values in the ALLY-3C (AI444379) study were measured using the Roche COBAS® AmpliPrep/COBAS® TaqMan® HCV Test (version 2.0), with an LLOQ of 15 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), ALLY-3C (AI444379), 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 five open-label studies (AI444040, ALLY-1, ALLY-2, ALLY-3, and ALLY-3C).

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-naive and 41 had failed prior therapy with a Pl regimen (boceprevir or telaprevir). All 44 patients with HCV genotype 2 (n=26) or 3 (n=18) infe otic n were treatment-naive. Treatment duration was 12 weeks for 82 treatment-naive 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 METAVlR score suggests that 35% of all patients (49% of patients with prior Pl failure, 30% of patients with genotype 2 or 3) had >F3 liver fibrosis. Most patients (71%, including 98% of prior Pl failures) had lL-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), lL28B genotype, or use of ribavirin. Among treatment-naive 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-naive patients with HCV genotype 1 who received 12 weeks of treatment had a similar response as those treated for 24 weeks (Table 6).

Table 6: Treatment outcomes, daclatasvir in combination with sofosbuvir, HCV genotype 1 in Study AI444040

End of treatment

SVR12 (overall)* 70 (100%)    55 (98%)*    125 (99%)*    21 (100%)    20 (100%)    41 (100%)

Table 6: Treatment outcomes, daclatasvir in combination with sofosbuvir, HCV genotype 1 in Study AI444040

Treatment-naïve

Prior telaprevir or boceprevir failures

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

Table 7: Treatment outcomes, daclatasvir in combination with sofosbuvir for 24 weeks, treatment-naive patients with HCV genotype 2 or 3 in Study AI44 4040

Patients who had mis; ing 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 posttreatment 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.

Table 8: Demographics and main disease characteristics in Study ALLY-1

Post-Liver Transplant N = 53

F3

8 (13%)

13 (25%)

F4

Not reported

CP classes

CP A

CP B

CP C

MELD score mean median Q1, Q3 Min, Max

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. 'nderwent 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.

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-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, 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.

Table 10: Demographics and baselin e chara cteristics in Study ALLY-2

daclatasvir + sofosbuvir

104 (68%)

23 (15%)

13 (8%)

10 (7%)

3 (2%)

Compensated cirrhosis

Concomitant HIV therapy:

PI-based

NNRTI-based

Other

None

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-naive 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.

HCV Genotype 3 (ALLY-3)

In study ALLY-3, the combination of daclatasvir and sofosbuvir administered for 12 weeks was eva'uated in 152 adults infected with HCV genotype 3; 101 patients were treatment-naive 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-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 12).

Table 12: Treatment outcomes, daclatasvir in combination with sofosbuvir for 12 weeks, patients with HCV genotype 3 in Study ALLY-3

>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).

HCV Genotype 3 with compensated cirrhosis (ALLY-3C)

In study ALLY-3C, the combination of daclatasvir, sofosbuvir and ribavirin administered for 24 weeks was evaluated in 78 adults infected with HCV genotype 3 with compensated cirrhosis; the majority of patients were male (57 [73.1%]); median age was 55 years (range 33 to 70); 88.5% were white; 9.0% were Asian; and 2.6% were American Indian or Alaska native; 54 (69.2%) patients were treatment-naive and 24 (30.8%) patients were treatment-experienced. The overall median HCV RNA was 6.38 log10 IU/mL; the majority of patients (59%) had IL-28B rs12979860 non-CC genotypes. Seventy-seven (77 [98.7%]) of treated patients in this study were infected with HCV GT-3a, and 1 patient (1.3%) was infected with HCV GT-3b.

The SVR12 rates were achieved by 88.5% of patients, including 92.6% of treatment-naive and 79.2% of treatment-experienced patients (see Table 13). SVR12 rates were consistently high across most subgroups including gender, age, race, baseline HCV RNA, and IL28B genotype. All 3 HCV/HIV coinfected patients achieved SVR12.

Table 13: Treatment outcomes, daclatasvir in combination with sofosbuvir and ribavirin for 24 weeks, HCV genotype 3 patients with cirrhosis in Study ALLY-3C

Virologic failure

Virologic breakthrough           0                   ­0 0

Table 13: Treatment outcomes, daclatasvir in combination with sofosbuvir and ribavirin for 24 weeks, HCV genotype 3 patients with cirrhosis in Study ALLY-3C

Treatment-experienced N=24

Detectable HCV RNA at end of treatment

Relapse

Non-virologic failure

Other non-responder

No HCV RNA on treatment 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 14. 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.

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%).

,ong term efficacy data

Data are available from a completed follow-up study to assess durability of response for approximately 3 years after treatment with daclatasvir. Among 258 patients who achieved SVR12 with daclatasvir and sofosbuvir (± ribavirin) with a median duration of post-SVR12 follow-up of

38 months, no relapses occurred (with relapses defined as confirmed or last available HCV RNA > LLOQ). Among 302 patients who achieved SVR12 with daclatasvir + pegIFN/RBV with a median duration of post-SVR12 follow-up of 44 months, 2% (n=6) 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 15.

Table 15: Summary of noted newly emergent HCV NS5A substitutions on treatment or during follow-up in treated non-SVR12 subjects infected with HCV genotypes 1 through 3

e patient considered a protocol failure (non-SVR) achieved SVR

5A RAVs monitored at amino acid positions are 28, 29, 30, 31, 32, 58, 62, 92, and 93

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

Emergent daclatasvir resistance-associated substitutions have been shown to persist for 3 years posttreatment and beyond for patients treated with 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).

5.2 Pharmacokinetic properties

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-naive patients with genotype 1 c.ronic HCV, the geometric mean (CV%) daclatasvir Cm,,, was 1534 (58) ng/ml, AUC0–2411 was 14122 (70) ng^h/ml. and Cmin 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 Cmax, AUC, and Cmin 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 Cmax 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 oraiiy followed by 100 p.g [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

olypeptide (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 gM) 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 p.g [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 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 (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.

5.3 Preclinical safety data

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.

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.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Tablet core

Anhydrous lactose Microcrystalline cellulose Croscarmellose sodium Silicon dioxide (E551) Magnesium stearate

T ablet film-coat

Hypromellose

Titanium dioxide (E171)

Macrogol 400

Indigo carmine aluminum lake (E132)

Yellow iron oxide (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

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

6.6 Special precautions for disposal

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

7. MARKETING AUTHORISATION HOLDER

Bristol-Myers Squibb Pharma EEIG Plaza 254

Blanchardstown Corporate Park 2

Dublin 15, D15 T867

Ireland