LEVERA 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 LEVERA should be initiated and monitored by a physician experienced in the management of chronichepatitis C.

 

Posology

The recommended dose of LEVERA is 60 mg once daily, to be taken orally with orwithout meals.

 

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

 

Table 1: Recommended treatment for LEVERA interferon-freecombination therapy

 

Patient population*	Regimen and duration
HCV GT 1 or 4
Patients without cirrhosis	LEVERA + sofosbuvir for 12 weeks
Patients with cirrhosis   CP A or B         CP C	LEVERA + sofosbuvir + ribavirin for 12 weeks or LEVERA + sofosbuvir (without ribavirin) for 24 weeks   LEVERA + sofosbuvir +/- ribavirin for 24 weeks (see sections 4.4 and 5.1)
HCV GT 3
Patients without cirrhosis	LEVERA + sofosbuvir for 12 weeks
Patients with cirrhosis	LEVERA + sofosbuvir +/- ribavirin for 24 weeks (see section 5.1)
Recurrent HCV infection post-liver transplant (GT 1, 3 or 4)
Patients without cirrhosis	LEVERA + sofosbuvir + ribavirin for 12 weeks (see section 5.1)
Patients with CP A or B cirrhosis GT 1 or 4   GT 3	LEVERA + sofosbuvir + ribavirin for 12 weeks   LEVERA + sofosbuvir +/- ribavirin for 24 weeks
Patients with CP C cirrhosis	LEVERA + sofosbuvir +/- ribavirin for 24 weeks (see sections 4.4 and 5.1)

 

GT: Genotype; CP: Child Pugh

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

 

LEVERA + peginterferon alfa + ribavirin

 

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

 

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

 

-      Ifundetectable HCV RNA is achieved, but not at both treatment weeks 4 and 12, LEVERA should be discontinued at24 weeks and peginterferon alfa and ribavirin continued for a total duration of 48 weeks.

 

 

Ribavirin Dosing Guidelines

 

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

 

For patients with Child-Pugh A, B, or C cirrhosis or recurrence of HCV infection after liver transplantation, therecommended initial dose of ribavirin is 600 mg daily with food.If the starting dose is well-tolerated,the dose can betitrated up to a maximum of1,000-1,200mg 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 co-administration with LEVERA regimen for patients with cirrhosis or post-transplant

 

Laboratory Value/Clinical Criteria	Ribavirin Dosing Guideline
Haemoglobin
>12 g/dL	600 mg daily
> 10 to ≤12 g/dL	400 mg daily
> 8.5 to ≤10 g/dL	200 mg daily
≤8.5 g/dL	Discontinue ribavirin
Creatinine Clearance
>50 mL/min	Follow guidelines above for haemoglobin
>30 to ≤50 mL/min	200 mg every other day
≤30 mL/min or haemodialysis	Discontinue ribavirin

 

 

Dose modification, interruption and discontinuation

 

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

 

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

 

Treatment discontinuation in patients with inadequate on-treatment virologic response during treatment with LEVERA,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 isrecommended in these patients. The HCV RNA thresholds that trigger discontinuation of treatment (i.e. treatment stopping rules) are presented in Table 3.

 

Table 3: Treatment stopping rules in patients receiving LEVERA in combination with peginterferon alfa andribavirin with inadequate on-treatment virologic response

 

HCV RNA	Action
Treatment week 4: >1000 IU/ml	Discontinue LEVERA, peginterferon alfa and ribavirin
Treatment week 12: ≥25 IU/ml	Discontinue LEVERA, peginterferon alfa and ribavirin
Treatment week 24: ≥25 IU/ml	Discontinue peginterferon alfa and ribavirin (treatment with LEVERA is complete at week 24)

 

 

Dose recommendation for concomitant medicines

 

Strong inhibitors of cytochrome P450 enzyme 3A4 (CYP3A4)

 

The dose of LEVERA should be reduced to 30 mg once daily when co-administered with strong inhibitors of CYP3A4.

 

Moderate inducers of CYP3A4

The dose of LEVERA should be increased to 90 mg once daily when co-administered with moderate inducers ofCYP3A4. See section 4.5.

 

Missed doses

 

Patients should be instructed that, if they miss a dose of LEVERA, the dose should be taken as soon as possible ifremembered within 20 hours of the scheduled dose time. However, if the missed dose is remembered more than 20hours 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 LEVERA is required for patients aged ≥65 years (see section 5.2).

 

Renal impairment

 

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

 

Hepatic impairment

 

No dose adjustment of LEVERA is required for patients with mild (Child-PughA, score 56),moderate (Child-PughB,score 79)or severe (Child-PughC, score ≥10) hepatic impairment (see sections 4.4 and 5.2).

 

Paediatric population

 

The safety and efficacy of LEVERA in children and adolescents aged below 18 years have not yet been established. Nodata are available.

 

Method of administration

 

LEVERA is to be taken orally with or without meals. Patients should be instructed to swallow the tablet whole. The film-coatedtablet 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. Co-administration with medicinal products that strongly induce cytochrome P450 3A4 (CYP3A4) and P-glycoproteintransporter (Pgp)and thus may lead to lower exposure and loss of efficacy of LEVERA. These active substancesinclude but are not limited to phenytoin, carbamazepine, oxcarbazepine, phenobarbital, rifampicin, rifabutin, rifapentine,systemic dexamethasone, and the herbal product St John's wort (Hypericum perforatum).

LEVERA must not be administered as monotherapy. LEVERA must be administered in combination with other medicinalproducts 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 LEVERA is used in combination with sofosbuvirand 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 onLEVERA 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 monitoredwhen initiating LEVERA in combination with sofosbuvir. Patients who are identified as being at high risk ofbradyarrhythmia should becontinuously 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 havediscontinued amiodarone within the past few months and are to be initiated on LEVERA in combination with sofosbuvir.

 

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

 

Genotype-specificactivity

 

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

 

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

 

Data from study ALLY3(AI444218) support a 12-weektreatment duration of LEVERA + sofosbuvir for treatment-naïve and experiencedpatients with genotype 3 infection without cirrhosis. Lower rates of SVR were observed for patientswith cirrhosis (see section 5.1). Data from compassionate use programmes which included patients with genotype 3infection and cirrhosis, support the use of LEVERA + sofosbuvir for 24 weeks in these patients. The relevance of addingribavirin to that regimen is unclear (see section 5.1).

 

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

 

Patients with Child-PughC liver disease

 

The safety and efficacy of LEVERA in the treatment of HCV infection in patients with Child-PughC liver disease havebeen established in the clinical study ALLY1(AI444215, LEVERA + sofosbuvir + ribavirin for 12 weeks) ; however, SVR rates were lower than in patients with Child-PughA and B. Therefore, a conservative treatment regimen of LEVERA +sofosbuvir +/ribavirinfor 24 weeks is proposed for patients with Child-PughC (see sections 4.2 and 5.1). Ribavirinmay be added based on clinical assessment of an individual patient.

 

Retreatment with daclatasvir

 

The efficacy of LEVERA as part of a retreatment regimen in patients with prior exposure to a NS5A inhibitor has notbeen established.

 

Pregnancy and contraception requirements

 

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

 

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

 

HCV/HBV (hepatitis B virus) coinfection

 

The safety and efficacy of LEVERA in the treatment of HCV infection in patients who are co-infected with HBV have notbeen investigated.

 

Interactions with medicinal products

 

Co-administration of LEVERA can alter the concentration of other medicinal products and other medicinal products mayalter the concentration of daclatasvir. Refer to section 4.3 for a listing of medicinal products that are contraindicated foruse with LEVERA due to potential loss of therapeutic effect. Refer to section 4.5 for established and other potentiallysignificant drug-druginteractions.

 

Paediatric population

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

 

Important information about some of the ingredients in LEVERA

LEVERA contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiencyor glucose-galactosemalabsorption should not take this medicine.

 

Contraindications of concomitant use (see section 4.3)

 

LEVERA is contraindicated in combination with medicinal products that strongly induce CYP3A4 and Pgp,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 efficacyof LEVERA.

 

Potential for interaction with other medicinal products

 

Daclatasvir is a substrate of CYP3A4, Pgpand organic cation transporter (OCT) 1. Strong or moderate inducers ofCYP3A4 and Pgpmay decrease the plasma levels and therapeutic effect of daclatasvir. Co-administration with stronginducers of CYP3A4 and Pgpis contraindicated while dose adjustment of LEVERA is recommended when

co-administered with moderate inducers of CYP3A4 and Pgp(see Table 4). Strong inhibitors of CYP3A4 may increase the plasma levels of daclatasvir. Dose adjustment of LEVERA is recommended when co-administered with stronginhibitors of CYP3A4 (see Table 4). Co-administration of medicines that inhibit Pgpor OCT1 activity is likely to have alimited effect on daclatasvir exposure.

 

Daclatasvir is an inhibitor of Pgp,organic anion transporting polypeptide (OATP) 1B1, OCT1 and breast cancerresistance protein (BCRP). Administration of LEVERA may increase systemic exposure to medicinal products that aresubstrates of Pgp,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 isa 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 productsin the regimen.

 

Tabulated summary of interactions

 

Table 4 provides information from drug interaction studies with daclatasvir including clinical recommendations forestablished 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 areshown, with 90% confidence intervals (CI) in parentheses. The studies presented in Table 4 were conducted in healthyadult 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	Interaction	Recommendations concerning co-administration
ANTIVIRALS, HCV
Nucleotide analogue polymerase inhibitor
Sofosbuvir 400 mg once daily   (daclatasvir 60 mg once daily)   Study conducted in patients with chronic HCV infection	↔ Daclatasvir*   AUC: 0.95 (0.82, 1.10)   Cmax: 0.88 (0.78, 0.99)   Cmin: 0.91 (0.71, 1.16)   ↔ GS331007**   AUC: 1.0 (0.95, 1.08)   Cmax: 0.8 (0.77, 0.90)   Cmin: 1.4 (1.35, 1.53)   *Comparison for daclatasvir was to a historical reference (data from 3 studies of daclatasvir 60 mg once daily with peginterferon alfa and ribavirin).   **GS331007 is the major circulating metabolite of the prodrug sofosbuvir.	No dose adjustment of LEVERA or sofosbuvir is required.
Protease inhibitors (PIs)
Boceprevir	Interaction not studied.   Expected due to CYP3A4 inhibition by boceprevir:   ↑ Daclatasvir	The dose of LEVERA should be reduced to 30 mg once daily when co-administered with boceprevir or other strong inhibitors of CYP3A4.
Simeprevir 150 mg once daily   (daclatasvir 60 mg once daily)	↑ Daclatasvir   AUC: 1.96 (1.84, 2.10)   Cmax: 1.50 (1.39, 1.62)   Cmin: 2.68 (2.42, 2.98)   ↑ Simeprevir   AUC: 1.44 (1.32, 1.56)   Cmax: 1.39 (1.27, 1.52)   Cmin: 1.49 (1.33, 1.67)	No dose adjustment of LEVERA or simeprevir is required.
Telaprevir 500 mg q12h (daclatasvir 20 mg once daily)                       Telaprevir 750 mg q8h (daclatasvir 20 mg once daily)	↑ Daclatasvir   AUC: 2.32 (2.06, 2.62)   Cmax: 1.46 (1.28, 1.66)   ↔ Telaprevir   AUC: 0.94 (0.84, 1.04)   Cmax: 1.01 (0.89, 1.14)     ↑ Daclatasvir   AUC: 2.15 (1.87, 2.48)   Cmax: 1.22 (1.04, 1.44)   ↔ Telaprevir   AUC: 0.99 (0.95, 1.03)   Cmax: 1.02 (0.95, 1.09)   CYP3A4 inhibition by telaprevir	The dose of LEVERA should be reduced to 30 mg once daily when co-administered with telaprevir or other strong inhibitors of CYP3A4.
Other HCV antivirals
Peginterferon alfa 180 μg once weekly and ribavirin 1000 mg or 1200 mg/day in two divided doses   (daclatasvir 60 mg once daily)   Study conducted in patients with chronic HCV infection	↔ Daclatasvir   AUC: ↔*   Cmax: ↔* Cmin: ↔*   ↔ Peginterferon alfa   Cmin: ↔*   ↔ Ribavirin   AUC: 0.94 (0.80, 1.11)   Cmax: 0.94 (0.79, 1.11)   Cmin: 0.98 (0.82, 1.17)   *PK parameters for daclatasvir when administered with peginterferon alfa and ribavirin in this study were similar to those observed in a study of HCV-infected subjects administered daclatasvir monotherapy for 14 days. PK trough levels for peginterferon alfa in patients who received peginterferon alfa, ribavirin, and daclatasvir were similar to those in patients who received peginterferon alfa, ribavirin, and placebo.	No dose adjustment of LEVERA, peginterferon alfa, or ribavirin is required.
ANTIVIRALS, HIV or HBV
Protease inhibitors (PIs)
Atazanavir 300 mg/ritonavir 100 mg once daily   (daclatasvir 20 mg once daily)	↑ Daclatasvir   AUC*: 2.10 (1.95, 2.26)   Cmax*: 1.35 (1.24, 1.47)   Cmin*: 3.65 (3.25, 4.11)   CYP3A4 inhibition by ritonavir *results are dose-normalized to 60 mg dose.	The dose of LEVERA should be reduced to 30 mg once daily when co-administered with atazanavir/ritonavir, atazanavir/cobicistat or other strong inhibitors of CYP3A4.
Atazanavir/cobicistat	Interaction not studied.   Expected due to CYP3A4 inhibition by atazanavir/cobicistat:   ↑ Daclatasvir
Darunavir 800 mg/ritonavir 100 mg once daily   (daclatasvir 30 mg once daily)	↔ Daclatasvir   AUC: 1.41 (1.32, 1.50)   Cmax: 0.77 (0.70, 0.85)   ↔ Darunavir   AUC: 0.90 (0.73, 1.11)   Cmax: 0.97 (0.80, 1.17)   Cmin: 0.98 (0.67, 1.44)	No dose adjustment of LEVERA 60 mg once daily, darunavir/ritonavir (800/100 mg once daily or 600/100 mg twice daily) or darunavir/cobicistat is required.
Darunavir/cobicistat	Interaction not studied.   Expected:   ↔ Daclatasvir
Lopinavir 400 mg/ritonavir 100 mg twice daily   (daclatasvir 30 mg once daily)	↔ Daclatasvir   AUC: 1.15 (1.07, 1.24)   Cmax: 0.67 (0.61, 0.74)   ↔ Lopinavir*   AUC: 1.15 (0.77, 1.72)   Cmax: 1.22 (1.06, 1.41)   Cmin: 1.54 (0.46, 5.07)   * the effect of 60 mg daclatasvir on lopinavir may be higher.	No dose adjustment of LEVERA 60 mg once daily or lopinavir/ritonavir is required.
Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)
Tenofovir disoproxil fumarate 300 mg once daily   (daclatasvir 60 mg once daily)	↔ Daclatasvir     AUC: 1.10 (1.01, 1.21)   Cmax: 1.06 (0.98, 1.15)   Cmin: 1.15 (1.02, 1.30)   ↔ Tenofovir   AUC: 1.10 (1.05, 1.15)   Cmax: 0.95 (0.89, 1.02)   Cmin: 1.17 (1.10, 1.24)	No dose adjustment of LEVERA or tenofovir is required.
Lamivudine   Zidovudine   Emtricitabine   Abacavir   Didanosine   Stavudine	Interaction not studied.   Expected:   ↔ Daclatasvir   ↔ NRTI	No dose adjustment of LEVERA or the NRTI is required.
Nonnucleoside reverse transcriptase inhibitors (NNRTIs)
Efavirenz 600 mg once daily   (daclatasvir 60 mg once daily/120 mg once daily)	↓ Daclatasvir     AUC*: 0.68 (0.60, 0.78)   Cmax*: 0.83 (0.76, 0.92)   Cmin*: 0.41 (0.34, 0.50)   Induction of CYP3A4 by efavirenz   *results are dose-normalized to 60 mg dose.	The dose of LEVERA should be increased to 90 mg once daily when co-administered with efavirenz.
Etravirine   Nevirapine	Interaction not studied.   Expected due to CYP3A4 induction by etravirine or nevirapine:   ↓ Daclatasvir	Due to the lack of data, co-administration of LEVERA and etravirine or nevirapine is not recommended.
Rilpivirine	Interaction not studied.   Expected:   ↔ Daclatasvir   ↔ Rilpivirine	No dose adjustment of LEVERA or rilpivirine is required.
Integrase inhibitors
Dolutegravir 50 mg once daily   (daclatasvir 60 mg once daily)	↔ Daclatasvir   AUC: 0.98 (0.83, 1.15)   Cmax: 1.03 (0.84, 1.25)   Cmin: 1.06 (0.88, 1.29)   ↑ Dolutegravir   AUC: 1.33 (1.11, 1.59)   Cmax: 1.29 (1.07, 1.57)   Cmin: 1.45 (1.25, 1.68)   Inhibition of Pgp and BCRP by daclatasvir	No dose adjustment of LEVERA or dolutegravir is required.
Raltegravir	Interaction not studied.     Expected:   ↔ Daclatasvir   ↔ Raltegravir	No dose adjustment of LEVERA or raltegravir is required.
Elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate	Interaction not studied for this fixeddose combination tablet.   Expected due to CYP3A4 inhibition bycobicistat:   ↑ Daclatasvir	The dose of LEVERA should be reduced to 30 mg once daily when co-administered with cobicistat or other strong inhibitors of CYP3A4.
Fusion inhibitor
Enfuvirtide	Interaction not studied.   Expected:   ↔ Daclatasvir   ↔ Enfuvirtide	No dose adjustment of LEVERA or enfuvirtide is required.
CCR5 receptor antagonist
Maraviroc	Interaction not studied.   Expected:   ↔ Daclatasvir   ↔ Maraviroc	No dose adjustment of LEVERA or maraviroc is required.
ACID REDUCING AGENTS
H2-receptor antagonists
Famotidine 40 mg single dose   (daclatasvir 60 mg single dose)	↔ Daclatasvir   AUC: 0.82 (0.70, 0.96)   Cmax: 0.56 (0.46, 0.67)   Cmin: 0.89 (0.75, 1.06)   Increase in gastric pH	No dose adjustment of LEVERA is required.
Proton pump inhibitors
Omeprazole 40 mg once daily   (daclatasvir 60 mg single dose)	↔ Daclatasvir   AUC: 0.84 (0.73, 0.96)   Cmax: 0.64 (0.54, 0.77)   Cmin: 0.92 (0.80, 1.05)   Increase in gastric pH	No dose adjustment of LEVERA is required.
ANTIBACTERIALS
Clarithromycin   Telithromycin	Interaction not studied.   Expected due to CYP3A4 inhibition bythe antibacterial:   ↑ Daclatasvir	The dose of LEVERA should be reduced to 30 mg once daily when co-administered with clarithromycin, telithromycin or other strong inhibitors of CYP3A4.
Erythromycin	Interaction not studied.   Expected due to CYP3A4 inhibition bythe antibacterial:   ↑ Daclatasvir	Administration of LEVERA with erythromycin may result in increased concentrations of daclatasvir. Caution is advised.
Azithromycin   Ciprofloxacin	Interaction not studied.   Expected:   ↔ Daclatasvir   ↔ Azithromycin or Ciprofloxacin	No dose adjustment of LEVERA or azithromycin or ciprofloxacin is required.
ANTICOAGULANTS
Dabigatran etexilate	Interaction not studied.   Expected due to inhibition of Pgp by daclatasvir:   ↑ Dabigatran etexilate	Safety monitoring is advised when initiating treatment with LEVERA in patients receiving dabigatran etexilate or other intestinal Pgp substrates that have a narrow therapeutic range.
Warfarin	Interaction not studied.   Expected:   ↔ Daclatasvir   ↔ Warfarin	No dose adjustment of LEVERA or warfarin is required.
ANTICONVULSANTS
Carbamazepine   Oxcarbazepine   Phenobarbital   Phenytoin	Interaction not studied.   Expected due to CYP3A4 induction by the anticonvulsant:   ↓ Daclatasvir	Co-administration of LEVERA with carbamazepine, oxcarbazepine, phenobarbital, phenytoin or other strong inducers of CYP3A4 is contraindicated (see section 4.3).
ANTIDEPRESSANTS
Selective serotonin reuptake inhibitors
Escitalopram 10 mg once daily   (daclatasvir 60 mg once daily)	↔ Daclatasvir   AUC: 1.12 (1.01, 1.26)   Cmax: 1.14 (0.98, 1.32)   Cmin: 1.23 (1.09, 1.38)   ↔Escitalopram   AUC: 1.05 (1.02, 1.08)   Cmax: 1.00 (0.92, 1.08)   Cmin: 1.10 (1.04, 1.16)	No dose adjustment of LEVERA or escitalopram is required.
ANTIFUNGALS
Ketoconazole 400 mg once daily   (daclatasvir 10 mg single dose)	↑ Daclatasvir   AUC: 3.00 (2.62, 3.44)   Cmax: 1.57 (1.31, 1.88)   CYP3A4 inhibition by Ketoconazole	The dose of LEVERA should be reduced to 30 mg once daily when co-administered with ketoconazole or other strong inhibitors of CYP3A4.
Itraconazole   Posaconazole   Voriconazole	Interaction not studied.   Expected due to CYP3A4 inhibition by the antifungal:   ↑ Daclatasvir
Fluconazole	Interaction not studied.   Expected due to CYP3A4 inhibition by the antifungal:   ↑ Daclatasvir   ↔ Fluconazole	Modest increases in concentrations of daclatasvir are expected, but no dose adjustment of LEVERA or fluconazole is required.
ANTIMYCOBACTERIALS
Rifampicin 600 mg once daily   (daclatasvir 60 mg single dose)	↓ Daclatasvir   AUC: 0.21 (0.19, 0.23)   Cmax: 0.44 (0.40, 0.48)   CYP3A4 induction by rifampicin	Co-administration of LEVERA with rifampicin, rifabutin, rifapentine or other strong inducers of CYP3A4 is contraindicated (see section 4.3).
Rifabutin   Rifapentine	nteraction not studied.   Expected due to CYP3A4 induction by the anti-mycobacterial:   ↓ Daclatasvir
CARDIOVASCULAR AGENTS
Antiarrhythmics
Digoxin 0.125 mg once daily   (daclatasvir 60 mg once daily)	↑ Digoxin   AUC: 1.27 (1.20, 1.34)   Cmax: 1.65 (1.52, 1.80)   Cmin: 1.18 (1.09, 1.28)   Pgp inhibition by daclatasvir	Digoxin should be used with caution when co-administered with LEVERA. The lowest dose of digoxin should be initially prescribed. The serum digoxin concentrations should be monitored and used for titration of digoxin dose to obtain the desired clinical effect.
Amiodarone	Interaction not studied.	Use only if no otheralternative is available. Close monitoring is recommended if this medicinal product is administered with LEVERA in combination with sofosbuvir (see sections 4.4 and 4.8).
Calcium channel blockers
Diltiazem   Nifedipine   Amlodipine	Interaction not studied.   Expected due to CYP3A4 inhibition by the calcium channel blocker:   ↑ Daclatasvir	Administration of LEVERA with any of these calcium channel blockers may result in increased concentrations of daclatasvir. Caution is advised.
Verapamil	Interaction not studied.   Expected due to CYP3A4 and Pgp inhibition by verapamil:   ↑ Daclatasvir	Administration of LEVERA with verapamil may result in increased concentrations of daclatasvir. Caution is advised.
CORTICOSTEROIDS
Systemic dexamethasone	Interaction not studied.   Expected due to CYP3A4 induction by dexamethasone:   ↓ Daclatasvir	Co-administration of LEVERA with systemic dexamethasone or other strong inducers of CYP3A4 is contraindicated (see section 4.3).
HERBAL SUPPLEMENTS
St. John's wort (Hypericum perforatum)	Interaction not studied.   Expected due to CYP3A4 induction by St. John's wort:   ↓ Daclatasvir	Co-administration of LEVERA with St. John's wort or other strong inducers of CYP3A4 is contraindicated (see section 4.3).
HORMONAL CONTRACEPTIVES
Ethinylestradiol 35 μg once daily for 21 days + norgestimate 0.180/0.215/0.250 mg once daily for 7/7/7 days   (daclatasvir 60 mg once daily)	↔ Ethinylestradiol   AUC: 1.01 (0.95, 1.07)   Cmax: 1.11 (1.02, 1.20)   ↔ Norelgestromin   AUC: 1.12 (1.06, 1.17)   Cmax: 1.06 (0.99, 1.14)   ↔ Norgestrel   AUC: 1.12 (1.02, 1.23)   Cmax: 1.07 (0.99, 1.16)	An oral contraceptive containing ethinylestradiol 35 μg and norgestimate 0.180/0.215/0.250 mg is recommended with LEVERA. Other oral contraceptives have not been studied.
IMMUNOSUPPRESSANTS
Cyclosporine 400 mg single dose   (daclatasvir 60 mg once daily)	↔ Daclatasvir   AUC: 1.40 (1.29, 1.53)   Cmax: 1.04 (0.94, 1.15)   Cmin: 1.56 (1.41, 1.71)   ↔ Cyclosporine   AUC: 1.03 (0.97, 1.09)   Cmax: 0.96 (0.91, 1.02)	No dose adjustment of either medicinal product is required when LEVERA is co-administered with cyclosporine, tacrolimus, sirolimus or mycophenolate mofetil.
Tacrolimus 5 mg single dose   (daclatasvir 60 mg once daily)	↔ Daclatasvir   AUC: 1.05 (1.03, 1.07)   Cmax: 1.07 (1.02, 1.12)   Cmin: 1.10 (1.03, 1.19)   ↔ Tacrolimus   AUC: 1.00 (0.88, 1.13)   Cmax: 1.05 (0.90, 1.23)
Sirolimus   Mycophenolate mofetil	Interaction not studied.   Expected:   ↔ Daclatasvir   ↔ Immunosuppressant
LIPID LOWERING AGENTS
HMG-CoA reductase inhibitors
Rosuvastatin 10 mg single dose   (daclatasvir 60 mg once daily)	↑ Rosuvastatin   AUC: 1.58 (1.44, 1.74)   Cmax: 2.04 (1.83, 2.26)   Inhibition of OATP 1B1 and BCRP by daclatasvir	Caution should be used when LEVERA is co-administered with rosuvastatin or other substrates of OATP 1B1 or BCRP.
Atorvastatin   Fluvastatin   Simvastatin   Pitavastatin   Pravastatin	Interaction not studied.   Expected due to inhibition of OATP 1B1 and/or BCRP by daclatasvir:   ↑ Concentration of statin
NARCOTIC ANALGESICS
Buprenorphine/naloxone, 8/2 mg to 24/6 mg once daily individualized dose*   (daclatasvir 60 mg once daily)     * Evaluated in opioid-dependent adults on stable buprenorphine/naloxone maintenance therapy.	↔ Daclatasvir   AUC: ↔*   Cmax: ↔*   Cmin: ↔*   ↑ Buprenorphine   AUC: 1.37 (1.24, 1.52)   Cmax: 1.30 (1.03, 1.64)   Cmin: 1.17 (1.03, 1.32)   ↑ Norbuprenorphine   AUC: 1.62 (1.30, 2.02)   Cmax: 1.65 (1.38, 1.99)   Cmin: 1.46 (1.12, 1.89)   *Compared to historical data.	No dose adjustment of LEVERA or buprenorphine may be required, but it is recommended that patients should be monitored for signs of opiate toxicity.
Methadone, 40-120 mg once daily individualized dose*   (daclatasvir 60 mg once daily)   * Evaluated in opioid-dependent adults on stable methadone maintenance therapy.	↔ Daclatasvir   AUC: ↔*   Cmax: ↔*   Cmin: ↔*   ↔ Rmethadone   AUC: 1.08 (0.94, 1.24)   Cmax: 1.07 (0.97, 1.18)   Cmin: 1.08 (0.93, 1.26)   *Compared to historical data.	No dose adjustment of LEVERA or methadone is required.
SEDATIVES
Benzodiazepines
Midazolam 5 mg single dose   (daclatasvir 60 mg once daily)	↔ Midazolam   AUC: 0.87 (0.83, 0.92)   Cmax: 0.95 (0.88, 1.04)	No dose adjustment of midazolam, other benzodiazepines or other CYP3A4 substrates is required when co-administered with LEVERA.
Triazolam   Alprazolam	Interaction not studied.   Expected:   ↔ Triazolam   ↔ Alprazolam

 

 

 

No clinically relevant effects on the pharmacokinetics of either medicinal product are expected when daclatasvir isco-administered with any of the following: PDE5inhibitors, 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.

 

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 riskfor humans is unknown.

 

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

 

Since LEVERA is used in combination with other agents, the contraindications and warnings for those medicinalproducts are applicable.

 

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

 

Breast-feeding

 

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

 

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).

Dizziness has been reported during treatment with LEVERA in combination withsofosbuvir, and dizziness, disturbance in attention, blurred vision and reduced visual acuity have been reported during treatment with LEVERA in combinationwith 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 receivedLEVERA once daily either in combination with sofosbuvir with or without ribavirin (n=679, pooled data) or in combinationwith peginterferon alfa and ribavirin (n=1536, pooled data) from a total of 14 clinical studies.

 

LEVERA in combination with sofosbuvir

 

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

 

LEVERA in combination with peginterferon alfa and ribavirin

 

The most frequently reported adverse reactions were fatigue, headache, pruritus, anaemia, influenza-likeillness,nausea, insomnia, neutropenia, asthenia, rash, decreased appetite, dry skin, alopecia, pyrexia, myalgia, irritability,cough, diarrhoea, dyspnoea andarthralgia. 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 andribavirin 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 eachfrequency grouping, adverse reactions are presented in order of decreasing seriousness.

 

Table 5: Adverse reactions in clinical studies

 

System Organ Class	Adverse Reactions
Frequency	LEVERA +sofosbuvir + ribavirin N=203	LEVERA +sofosbuvir N=476
Blood and lymphatic system disorders
very common	anaemia
Metabolism and nutrition disorders
common	decreased appetite
Psychiatric disorders
common	insomnia, irritability	insomnia
Nervous system disorders
very common	headache	headache
common	dizziness, migraine	dizziness, migraine
Vascular disorders
common	hot flush
Respiratory, thoracic and mediastinal disorders
common	dyspnoea, dyspnoea exertional, cough, nasal congestion
Gastrointestinal disorders
very common	nausea
common	diarrhoea, vomiting, abdominal pain, gastro-oesophageal reflux disease, constipation, dry mouth, flatulence	nausea, diarrhoea, abdominal pain
Skin and subcutaneous tissue disorders
common	rash, alopecia, pruritus, dry skin
Musculoskeletal and connective tissue disorders
common	arthralgia, myalgia	arthralgia, myalgia
General disorders and administration site conditions
very common	fatigue	fatigue

 

Laboratory abnormalities

 

In clinical studies of LEVERA in combination with sofosbuvir with or without ribavirin, 2% of patients had Grade 3haemoglobin decreases; all of these patients receivedLEVERA + sofosbuvir + ribavirin. Grade 3/4 increases in total bilirubin were observed in 5% of patients (all in patients with HIV coinfectionwho were receiving concomitant

atazanavir, with Child-PughA, B, or C cirrhosis, or who were post-livertransplant).

 

Description of selected adverse reactions

 

Cardiac arrhythmias

 

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

 

Paediatric population

 

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

 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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:

 

To report any side effect(s):  The National Pharmacovigilance and Drug Safety Centre (NPC) o Fax: +966-11-205-7662 o Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340. o Reporting hotline: 19999. o E-mail: npc.drug@sfda.gov.sa o Website: https://ade.sfda.gov.sa

 

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

 

There is no known antidote for overdose of daclatasvir. Treatment of overdose with daclatasvir should consist of generalsupportive measures, including monitoring of vital signs, and observation of the patient's clinical status. Becausedaclatasvir is highly protein bound (99%) and has a molecular weight >500, dialysis is unlikely to significantly reduce

plasma concentrations of daclatasvir.

Pharmacotherapeutic group: Direct-actingantiviral, ATC code: J05AX14

 

Mechanism of action

 

Daclatasvir is an inhibitor of nonstructural protein 5A (NS5A), a multifunctional protein that is an essential component ofthe 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 effectiveconcentration (50% reduction, EC50) values of 0.003-0.050and 0.001-0.009nM, respectively, depending on the assaymethod. The daclatasvir EC50 values in the replicon system were 0.003-1.25nM for genotypes 3a, 4a, 5a and 6a, and0.034-19nM for genotype 2a as well as 0.020 nM for infectious genotype 2a (JFH1)

virus.

 

Daclatasvir showed additive to synergistic interactions with interferon alfa, HCV nonstructural protein 3 (NS3) PIs, HCVnonstructural protein 5B (NS5B) nonnucleoside

inhibitors, and HCV NS5B nucleoside analogues in combination studiesusing the cell-basedHCV 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 14were observed in the N-terminal100 amino acid regionof NS5A in a cell-basedreplicon system. L31V and Y93H were frequently observed resistance substitutions in genotype1b, 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 forgenotype 1a (EC50 up to 350 nM). The most resistant variants with single amino acid substitution in genotype 2a andgenotype 3a were F28S (EC50 >300 nM) and Y93H (EC50 >1,000 nM), respectively. In genotype 4, amino acidsubstitutions at 30 and 93 (EC50 < 16 nM) were frequently selected.

 

Cross-resistance

 

HCV replicons expressing daclatasvir-associatedresistance substitutions remained fully sensitive to interferon alfa andother anti-HCVagents with different mechanisms of action, such as NS3 protease and NS5B polymerase (nucleosideand nonnucleoside)

inhibitors.

 

Clinical efficacy and safety

In clinical studies of daclatasvir in combination with sofosbuvir or with peginterferon alfa and ribavirin, plasma HCV RNAvalues were measured using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System, with alower limit of quantification (LLOQ) of 25 IU/ ml. SVR was the primary endpoint to determine the HCV cure rate, whichwas defined as HCV RNA less than LLOQ at 12 weeks after the end of treatment (SVR12) for studies AI444040, ALLY1(AI444215), ALLY2(AI444216), ALLY3

(AI444218), AI444042 and AI444043 and as HCV RNA undetectable at 24weeks 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 thetreatment of patients with chronic HCV infection wereevaluated in four open-label studies (AI444040, ALLY1,ALLY2and ALLY3).

 

In study AI444040, 211 adults with HCV genotype 1, 2, or 3 infection and without cirrhosis received daclatasvir andsofosbuvir, with or without ribavirin. Among the 167 patients with HCV genotype 1 infection, 126 were treatment-naïveand 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-naïveHCV genotype 1patients, and 24 weeks for all otherpatients 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 scoreon the FibroTest (a validated noninvasivediagnostic assay) was 0.460 (range: 0.03 to 0.89). Conversion of theFibroTest score to the corresponding METAVIR score suggests that 35% of all patients (49% of patients with prior PIfailure, 30% of patients with genotype 2 or 3) had ≥F3 liver fibrosis. Most patients (71%, including 98% of prior PI failures) had IL28Brs12979860 non-CCgenotypes.

 

SVR12 was achieved by 99% patients with HCV genotype 1, 96% of those withgenotype 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 patientsresponded to therapy), and was not influenced by HCV subtype (1a/1b), IL28B genotype, or use of ribavirin. Among

treatment-naïvepatients with HCV RNA results at both follow-upWeeks 12 and 24, concordance between SVR12 andSVR24 was 99.5% independent of treatment duration.

 

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

 

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

 

	Treatment-naïve			Prior telaprevir or boceprevir failures
	daclatasvir + sofosbuvir       N=70	daclatasvir + sofosbuvir + ribavirin   N=56	All           N=126	daclatasvir + sofosbuvir       N=21	daclatasvir + sofosbuvir + ribavirin   N=20	All           N=41
End of treatment   HCV RNA undetectable	70 (100%)	56 (100%)	126 (100%)	19 (91%)	19 (95%)	38 (93%)
SVR12 (overall)*	70 (100%)	55 (98%)*	125 (99%)*	21 (100%)	20 (100%)	41 (100%)
12 weeks treatment duration	41/41 (100%)	40/41 (98%)	81/82 (99%)	-	-	-
24 weeks treatment duration	29/29 (100%)	15/15 (100%)	44/44 (100%)	21 (100%)	20 (100%)	41 (100%)
≥ F3 liver fibrosis	-	-	41/41 (100%)	-	-	20/20 (100%)

 

* Patients who had missing data at follow-upWeek 12 were considered responders if their next available HCV RNAvalue was <LLOQ. One treatment-naïvepatient was missing both post-treatment Weeks 12 and 24 data.

 

Table 7: Treatment outcomes, daclatasvir in combination with sofosbuvir for 24 weeks, treatment-naïvepatientswith HCV genotype 2 or 3 in Study AI444040

 

 

	Genotype 2			Genotype 3
	daclatasvir + sofosbuvir     N=17	daclatasvir + sofosbuvir + ribavirin   N=9	All Genotype2       N=26	daclatasvir + sofosbuvir     N=13	daclatasvir + sofosbuvir + ribavirin   N=5	All Genotype 3       N=18
End of treatment   HCV RNA undetectable	17 (100%)	9 (100%)	26 (100%)	11 (85%)	5 (100%)	16 (89%)
SVR12*	17 (100%)	8 (89%)*	25 (96%)*	11 (85%)	5 (100%)	16 (89%)
≥ F3 liver fibrosis			8/8 (100%)			5/5 (100%)
Virologic failure
Virologic breakthrough**	0	0	0	1 (8%)	0	1 (6%)
Relapse**	0	0	0	1/11 (9%)	0	1/16 (6%)

 

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

 

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

 

Advanced cirrhosis and post-livertransplant (ALLY1)

 

In study ALLY1,the regimen of daclatasvir, sofosbuvir, and ribavirin administered for 12 weeks was evaluated in 113adults with chronic hepatitis C and Child-PughA, 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 60mg once daily, sofosbuvir 400 mg once daily, and ribavirin (600 mg starting dose) for 12 weeks and were monitored for24 weeks post treatment. Patients demographics and main disease characteristics are summarized in Table 8.

 

Table 8: Demographics and main disease characteristics in Study ALLY1

	Cirrhotic cohort   N = 60	Post-Liver Transplant   N = 53
Age (years): median (range)   Race: White Black/African American           Other	58 (1975)   57 (95%) 3 (5%) 0	59 (2282)   51 (96%) 1 (2%) 1 (2%)
HCV genotype: 1a 1b 2 3 4 6	34 (57%) 11 (18%) 5 (8%) 6 (10%) 4 (7%) 0	31 (58%) 10 (19%) 0 11 (21%) 0 1 (2%)
Fibrosis stage F0 F1 F2 F3 F4 Not reported	0 1 (2%) 3 (5%) 8 (13%) 48 (80%) 0	6 (11%) 10 (19%) 7 (13%) 13 (25%) 16 (30%) 1 (2%)
CP classes CP A CP B CP C	12 (20%) 32 (53%) 16 (27%)	ND
MELD score mean median Q1, Q3    Min, Max	13.3 13.0 10, 16 8, 27	ND

 

ND: Not determined

 

SVR12 was achieved by 83% (50/60) of patients in the cirrhosis cohort, with a marked difference between patients withChild-PughA or B (92-94%)as compared to those with Child-PughC and 94% of patients in the post-livertransplantcohort (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 oftreatment; 3 of the 4 patients received 12 weeks of post-livertransplant treatment extension and 1 patient, treated for23 days before transplantation, did not receive treatment extension. All 4 patients achieved SVR12.

 

Table 9: Treatment outcomes, daclatasvir in combination with sofosbuvir and ribavirin for 12 weeks, patientswith cirrhosis or HCV recurrence after liver transplantation, Study ALLY1

 

	Cirrhotic cohort N=60		Post-Liver Transplant N=53
End of treatment   HCV RNA undetectable	58/60 (97%)		53/53 (100%)
	SVR12	Relapse	SVR12	Relapse
All patients	50/60 (83%)	9/58* (16%)	50/53 (94%)	3/53 (6%)
Cirrhosis			ND	ND
CP A	11/12 (92%)	1/12 (8%)
CP B	30/32 (94%)	2/32 (6%)
CP C	9/16 (56%)	6/14 (43%)
Genotype 1	37/45 (82%)	7/45 (16%)	39/41 (95%)	2/41 (5%)
1a	26/34 (77%)	7/33 (21%)	30/31 (97%)	1/31 (3%)
1b	11/11 (100%)	0%	9/10 (90%)	1/10 (10%)
Genotype 2	4/5 (80%)	1/5 (20%)	-	-
Genotype 3	5/6 (83%)	1/6 (17%)	10/11 (91%)	1/11 (9%)
Genotype 4	4/4 (100%)	0%	-	-
Genotype 6	-	-	1/1 (100%)	0%

 

ND: Not determined

 

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

 

HCV/HIV co-infection(ALLY2)

 

In study ALLY2,the combination of daclatasvir and sofosbuvir administered for 12 weeks was evaluated in 153 adultswith chronic hepatitis C and HIV coinfection;101 patients were HCV treatment-naïveand 52 patients had failed priorHCV therapy. Patients with HCV genotype 1, 2, 3, 4, 5, or 6 infection were eligible to enroll, including patients withcompensated cirrhosis (Child-PughA). The dose of daclatasvir was adjusted for concomitant antiretroviral use. Patientdemographics and baseline disease characteristics are summarized in Table 10.

 

Table 10: Demographics and baseline characteristics in Study ALLY2

 

Patient disposition	daclatasvir + sofosbuvir   12 weeks   N = 153
Age (years): median (range)	53 (24-71)
Race: White Black/African American Other	97 (63%) 50 (33%) 6 (4%)
HCV genotype: 1a 1b 2 3 4	104 (68%) 23 (15%) 13 (8%) 10 (7%) 3 (2%)
Compensated cirrhosis	24 (16%)
Concomitant HIV therapy: PI-based NNRTI-based                        Other                        None	70 (46%) 40 (26%) 41 (27%) 2 (1%)

 

Overall, SVR12 was achieved by 97% (149/153) of patients administered daclatasvir and sofosbuvir for 12 weeks inALLY2.SVR rates were >94% across combinationantiretroviral therapy (cART) regimens, including boosted-PI,NNRTI,and integrase inhibitor (INSTI)-basedtherapies.

 

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

 

A third treatment group in study ALLY2included 50 HCV treatment-naïveHIV co-infectedpatients who receiveddaclatasvir and sofosbuvir for 8 weeks. Demographic and baseline characteristics of these 50 patients were generallycomparable to those for patients who received 12 weeks of study treatment. The SVR rate for patients treated for 8weeks was lower with this treatment duration as summarized in Table 11.

 

Table 11: Treatment outcomes, daclatasvir in combination with sofosbuvir in patients with HCV/HIV coinfectionin Study ALLY2

 

	8 weeks therapy	12 weeks therapy
	HCV Treatment-naïve   N=50	HCV Treatment-naïve   N=101	HCV Treatment-experienced*   N=52
End of treatment   HCV RNA undetectable	50/50 (100%)	100/101 (99%)	52/52 (100%)
SVR12	38/50 (76%)	98/101 (97%)	51/52 (98%)
No cirrhosis**	34/44 (77%)	88/90 (98%)	34/34 (100%)
With cirrhosis**	3/5 (60%)	8/9 (89%)	14/15 (93%)
Genotype 1	31/41 (76%)	80/83 (96%)	43/44 (98%)
1a	28/35 (80%)	68/71 (96%)	32/33 (97%)
1b	3/6 (50%)	12/12 (100%)	11/11 (100%)
Genotype 2	5/6 (83%)	11/11 (100%)	2/2 (100%)
Genotype 3	2/3 (67%)	6/6 (100%)	4/4 (100%)
Genotype 4	0	1/1 (100%)	2/2 (100%)
Virologic failure
Detectable HCV RNA at end of treatment	0	1/101 (1%)	0
Relapse	10/50 (20%)	1/100 (1%)	1/52 (2%)
Missing post-treatment data	2/50 (4%)	1/101 (1%)	0

 

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

 

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

 

HCV Genotype 3 (ALLY3)

 

In study ALLY3,the combination of daclatasvir and sofosbuvir administered for 12 weeks was evaluated in 152 adultsinfected with HCV genotype 3; 101 patients were treatment-naïveand 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% wereAsian; 16% were Hispanic or Latino. The median viral load was 6.42 log10 IU/ml, and 21% of patients had compensatedcirrhosis. Most patients (61%) had IL-28Brs12979860 non-CCgenotypes.

 

SVR12 was achieved in 90% of treatment-naïvepatients and 86% of Treatment-experiencedpatients. Response wasrapid (viral load at Week 4 showed that more than 95% of patients responded to therapy) and was not influenced byIL28B 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 HCVgenotype 3 in Study ALLY3

 

	Treatment-naïve   N=101	Treatment-experienced* N=51	Total   N=152
End of treatment   HCV RNA undetectable	100 (99%)	51 (100%)	151 (99%)
SVR12	91 (90%)	44 (86%)	135 (89%)
No cirrhosis**	73/75 (97%)	32/34 (94%)	105/109 (96%)
With cirrhosis**	11/19 (58%)	9/13 (69%)	20/32 (63%)
Virologic failure
Virologic breakthrough	0	0	0
Detectable HCV RNA at end of treatment	1 (1%)	0	1 (0.7%)
Relapse	9/100 (9%)	7/51 (14%)	16/151 (11%)

 

* Mainly interferon-basedtherapy, but 7 patients received sofosbuvir + ribavirin and 2 patients received a cyclophilininhibitor.

 

** Cirrhosis was determined by liver biopsy (METAVIR F4) for 14 patients, FibroScan >14.6 kPa for 11 patients orFibroTest score ≥0.75 and aspartate aminotransferase (AST): platelet ratio index (APRI) >2 for 7 patients. For 11patients, 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 leftuntreated were treated under compassionate use programmes. Patients with genotype 3 infection were treated withdaclatasvir + sofosbuvir +/-ribavirin

for 12 or 24 weeks, where the longer treatment duration was associated with alower risk for relapse (around 5%) in a preliminary analysis. The relevance of including ribavirin as part of the 24-weekregimen is unclear. In one cohort the majority of patients were treated with daclatasvir + sofosbuvir + ribavirin for 12weeks. The relapse rate was around 15%, and similar for patients with Child-PughA, B and C. The programmes do notallow for a direct comparison of efficacy between the 12and24-weekregimens.

 

Daclatasvir in combination with peginterferon alfa and ribavirin

 

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

WithHIV.

 

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 allplacebo-treatedpatients 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. Tenpercent of patients had compensated cirrhosis, and 75% of patients had IL28Brs12979860 non-CCgenotypes.

Treatment outcomes in study AI444042 are presented in Table 13. Response was rapid (at Week 4 91% of daclatasvir-treatedpatients had HCV RNA <LLOQ). SVR12 rates were higher for patients with the IL28BCC genotype than forthose with non-CC

genotypes and for patients with baseline HCV RNA less than 800,000 IU/ml but consistently higherin 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 Week12. 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 orplacebo + pegIFN/RBV for a total treatment duration of 24 weeks. Patients originally assigned to placebo and those inthe daclatasvir group who did not achieve HCV RNA <LLOQ at Week 4 and undetectable at Week 10 continuedpegIFN/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 percentof patients had compensated cirrhosis; 92% had HCV genotype 1 (72% 1a and 20% 1b) and 8% had HCV genotype 4;65% of patients had IL28Brs12979860 non-CC genotypes.

 

Treatment outcomes in study AI444010 for patients with HCV genotype 4 are presented in Table 13. For HCV genotype1, SVR12 rates were 64% (54% for 1a; 84% for 1b) for patients treated with daclatasvir + pegIFN/RBV and 36% forpatients treated with placebo + pegIFN/RBV. For daclatasvir-treated patients with HCV RNA results at both follow-upWeeks 12 and 24, concordance of SVR12 and SVR24 was 97% for HCV genotype 1 and 100% for HCV genotype 4.

 

Table 13: Treatment outcomes, daclatasvir in combination with peginterferon alfa and ribavirin (pegIFN/RBV),treatment-naïvepatients with HCV genotype 4

 

	Study AI444042		Study AI444010
	daclatasvir + pegIFN/RBV   N=82	pegIFN/RBV     N=42	daclatasvir + pegIFN/RBV   N=12	pegIFN/RBV     N=6
End of treatment   HCV RNA undetectable	74 (90%)	27 (64%)	12 (100%)	4 (67%)
SVR12*	67 (82%)	18 (43%)	12 (100%)	3 (50%)
No cirrhosis	56/69 (81%)**	17/38 (45%)	12/12 (100%)	3/6 (50%)
With cirrhosis	7/9 (78%)**	1/4 (25%)	0	0
Virologic failure
On-treatment virologic failure	8 (10%)	15 (36%)	0	0
Relapse	2/74 (3%)	8/27 (30%)	0	1/4 (25%)

 

* Patients who had missing data at follow-upWeek 12 were considered responders if their next available HCV RNAvalue was <LLOQ.

 

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

 

AI444043: 301 treatment-naïvepatients with HCV genotype 1 infection and HIV coinfection(10% with compensatedcirrhosis) 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 achievingvirologic response [HCVRNA undetectable at weeks 4 and 12] completed therapy after 24 weeks while those who did not achieve virologicresponse received an additional 24 weeks of treatment with pegIFN/RBV, to complete a total of 48 weeks of studytherapy. 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-upstudy to assess durability of response up to 3 years after treatmentwith daclatasvir. Among patients who achieved SVR12 with daclatasvir and sofosbuvir (± ribavirin) with a medianduration of post-SVR12 follow-upof 15 months, no relapses have occurred. Among patients who achieved SVR12 withdaclatasvir + pegIFN/RBV with a median duration of post-SVR12

follow-upof 22 months, 1% of patients relapsed.

 

Resistance in clinical studies

 

Frequency of baseline NS5A resistance-associatedvariants (RAVs)

 

Baseline NS5A RAVs were frequently observed in clinical studies of daclatasvir. In 9 phase 2/3 studies with daclatasvirin combination with peginterferon alfa + ribavirin or in combination with sofosbuvir +/-ribavirin,the following frequenciesof such RAVs were seen at baseline: 7% in genotype 1a infection (M28T, Q30, L31, and/or Y93) ; 11% in genotype 1binfection (L31 and/or Y93H), 51% in genotype 2 infection (L31M), 8% in genotype 3 infection (Y93H) and 64% ingenotype 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 genotype3

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-3infected 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-weekswith 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 3studies for 12 or 24 weeks,34 patients qualified for resistance analysis due to virologic failure or early studydiscontinuation and having HCV RNA greater than 1,000 IU/ml. Observed emergent NS5A resistance-associated

variants are reported in Table 14.

 

Table 14: Summary of noted newly emergent HCV NS5A substitutions on treatment or during follow-upintreated non-SVR12subjects infected with HCV genotypes 1 through 3

 

Category/ Substitution, n (%)	Genotype 1a   N=301	Genotype 1b   N=79	Genotype 2   N=44	Genotype 3   N=197
Non-responders (non-SVR12)	14*	1	2*	21**
with baseline and post-baseline sequence	12	1	1	20
with emergent NS5A RAVs***	10 (83%)	1 (100%)	0	16 (80%)
M28: T	2 (17%)	--	--	0
Q30: H, K, R	9 (75%)	--	--	--
L31: I, M, V	2 (17%)	0	0	1 (5%)
P32-deletion	0	1 (100%)	0	0
H58: D, P	2 (17%)	--	--	--
S62: L	--	--	--	2 (10%)
Y93: C, H, N	2 (17%)	0	0	11 (55%)

 

* 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 genotype3.

 

No data are available on the persistence of daclatasvir resistance-associated substitutions beyond 6 months post-treatmentin patients treated with daclatasvir and sofosbuvirwith/without ribavirin. Emergent daclatasvir resistance-associated substitutions have been shown to persist for 2 years post-treatmentand beyond for patients treated withother 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 riskfor nonresponsein treatment-naïve patients infected with genotype 1a and genotype 1b infection. The impact ofbaseline NS5A RAVs on curerates of genotype 4 infection is not apparent.

 

In case of nonresponseto therapy with daclatasvir + peginterferon alfa + ribavirin, NS5A RAVs generally emerged atfailure (139/153 genotype 1a and 49/57 genotype 1b). The most frequently detected NS5A RAVs included Q30E orQ30R in combination withL31M. 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-infectedpatients with nonresponse,substitutions L28Mand 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 ormore subsets of the paediatric population in the treatment of chronic hepatitis C (see section 4.2 for information onpaediatric use).

 

The pharmacokinetic properties of daclatasvir were evaluated in healthy adult subjects and in patients with chronicHCV. Following multiple oral doses of daclatasvir 60 mg once daily in combination with peginterferon alfa and ribavirin intreatment-naïve

patients with genotype 1 chronic HCV, the geometric mean (CV%) daclatasvir Cmax was 1534 (58)ng/ml, AUC024hwas 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 concentrationsoccurring between 1 and 2 hours.

 

Daclatasvir Cmax, AUC, and Cmin increased in a near dose-proportionalmanner. Steady state was achieved after 4 daysof once-dailyadministration. At the 60 mg dose, exposure to daclatasvir was similar between healthy subjects andHCV-infected

patients.

 

In vitro and in vivo studies showed that daclatasvir is a substrate of Pgp.The absolute bioavailability of the tabletformulation is 67%.

 

Effect of food on oral absorption

 

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

 

Distribution

 

At steady state, protein binding of daclatasvir in HCV-infectedpatients wasapproximately 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 by100 μg [13C,15N]-daclatasvirintravenous dose, estimated volume of distribution at steady state was 47 l. In vitrostudies indicate that daclatasvir is actively and passively transported intohepatocytes. 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 Pgp,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 thesetransporters.

 

Biotransformation

 

In vitro and in vivo studies demonstrate that daclatasvir is a substrate of CYP3A, with CYP3A4 being the major CYPisoform 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-doseoral administration of 14C–daclatasvir in healthy subjects, 88% of total radioactivity wasrecovered in feces (53% as unchanged drug) and 6.6% was excreted in the urine (primarily as unchanged drug). Thesedata 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 otherunidentified uptake transporters. Following multiple-dose

administration of daclatasvir in HCV-infectedpatients, theterminal elimination half-life

of daclatasvir ranged from 12 to 15 hours. In patients who received daclatasvir 60 mg tabletorally followed by 100 μg [13C,15N]-daclatasvirintravenous 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-HCVinfected subjects withrenal impairment. Daclatasvir unbound AUC was estimated to be 18%, 39% and 51% higher for subjects with creatinineclearance (CLcr) values of 60, 30 and 15 ml/min, respectively, relative to subjects with normal renal function. Subjectswith end-stagerenal disease requiring haemodialysis had a 27% increase in daclatasvir AUC and a 20% increase inunbound 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-HCVinfected subjects withmild (Child-PughA), moderate (Child-PughB), and severe (Child-PughC) hepatic impairment compared with unimpairedsubjects. The Cmax and AUC of total daclatasvir (free and protein-bounddrug) were lower in subjects with hepaticimpairment; however, hepatic impairment did not have a clinicallysignificant 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 thepharmacokinetics 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 oralclearance (CL/F) with female subjects having slightly lower CL/F, but the magnitude of the effect on daclatasvirexposure is not clinically important.

 

Race

 

Population pharmacokinetic analysis of data from clinical studies identified race (categories “other” [patients who are notwhite, 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 themagnitude of the effect on daclatasvir exposure is not clinically important.

 

Toxicology

 

In repeat-dose

toxicology studies in animals, hepatic effects (Kupffer-cellhypertrophy/ hyperplasia, mononuclear cellinfiltrates and bile duct hyperplasia) and adrenal gland effects (changes in cytoplasmic vacuolation and adrenal corticalhypertrophy/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-foldthe clinicalAUC 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-foldor 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 femaleswas 18-foldthe clinical AUC exposure. In male rats, effects on reproductive endpoints were limited to reducedprostate/seminal vesicle weights, and minimally increased dysmorphic sperm at 200 mg/kg/day; however, neitherfinding adversely affected fertility or the number of viable conceptuses sired. The AUC associated with this dose inmales is 19-foldthe clinical AUC exposure.

 

Embryo-foetaldevelopment

 

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 bodyweights and increased incidence of foetal malformations and variations. In rats, malformations mainly affected thebrain, skull, eyes, ears, nose, lip, palate or limbs and in rabbits, the ribs andcardiovascular area. Maternal toxicity including mortality, abortions, adverse clinical signs, decreases in body weight and food consumption was noted in bothspecies at exposures 25-fold(rat) and 72-fold(rabbit) the clinical AUC exposure.

 

In a study of pre- andpostnatal development in rats, there was neither maternal nor developmental toxicity at doses upto 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 viabilityin the peri- andneonatal periods; and reductions in birth weight that persisted into adulthood. The AUC value associatedwith this dose is 4-foldthe clinical AUC exposure.

 

Excretion into milk

 

Daclatasvir was excreted into the milk of lactating rats with concentrations 1.7- to2-fold

maternal plasma levels.

Name of Ingredients	30mg Unit Dose (mg)	60mg Unit Dose (mg)
Daclatasvir Dihydrochloride	33.000	66.000
Avicel pH 112	29.000	58.000
Lactose Anhydrous NF D.C.	85.250	170.500
Croscarmellose Sodium Type A	4.650	9.300
Magnesium Stearate	1.550	3.100
Colloidal Silicon Dioxide	1.550	3.100
Opadry 03B110007 Green	4.650	9.300
Purified Water BP	Qs.	Qs.
Total	159.650	319.300

Not applicable.

LEVERA 30 mg film-coated tablets 24 months/2 years. LEVERA 60 mg film-coated tablets 36 months/3 years.

This medicinal product does not require any special storage conditions.

 

Do not store above 30°C.

Reel OPA/AL/PVC with Aluminum Foil.

 

LEVERA 30 mg and 60 mg: Pack size of 28 film-coated tablets.

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

 

No Special Disposal