Daklinza

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 

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This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Daklinza 30 mg film-coated tablets 
Daklinza 60 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Daklinza 30 mg film-coated tablets 
 
Each film-coated tablet contains daclatasvir dihydrochloride equivalent to 30 mg daclatasvir. 
 
Daklinza 60 mg film-coated tablets 
 
Each film-coated tablet contains daclatasvir dihydrochloride equivalent to 60 mg daclatasvir. 
 
Excipient(s) with known effect 
 
Each 30-mg film-coated tablet contains 58 mg of lactose (as anhydrous). 
Each 60-mg film-coated tablet contains 116 mg of lactose (as anhydrous). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet). 
 
Daklinza 30 mg film-coated tablets 
 
Green biconvex pentagonal of dimensions 7.2 mm x 7.0 mm, debossed tablet with "BMS" on one side 
and "213" on the other side. 
 
Daklinza 60 mg film-coated tablets 
 
Light green biconvex pentagonal of dimensions 9.1 mm x 8.9 mm, debossed tablet with "BMS" on one 
side and "215" on the other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Daklinza is indicated in combination with other medicinal products for the treatment of chronic 
hepatitis C virus (HCV) infection in adults (see sections 4.2, 4.4 and 5.1). 
 
For HCV genotype specific activity, see sections 4.4 and 5.1. 
 
4.2 Posology and method of administration 
 
Treatment with Daklinza should be initiated and monitored by a physician experienced in the 
management of chronic hepatitis C. 

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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  

Patient population* Regimen and duration 

HCV GT 1 or 4 

Patients without cirrhosis Daklinza + sofosbuvir for 12 weeks 

Patients with cirrhosis 

CP A or B 

 

 

Daklinza + sofosbuvir + ribavirin for 12 weeks 

or 

Daklinza + sofosbuvir (without ribavirin) for 24 weeks 

 

CP C Daklinza + sofosbuvir +/- ribavirin for 24 weeks 

(see sections 4.4 and 5.1) 

HCV GT 3 

Patients without cirrhosis Daklinza + sofosbuvir for 12 weeks 

Patients with cirrhosis Daklinza + sofosbuvir +/- ribavirin for 24 weeks 

(see section 5.1) 

Recurrent HCV infection post-liver transplant (GT 1, 3 or 4) 

Patients without cirrhosis Daklinza + sofosbuvir + ribavirin for 12 weeks  

(see section 5.1) 

Patients with CP A or B cirrhosis 

GT 1 or 4 

GT 3 

 

Daklinza + sofosbuvir + ribavirin for 12 weeks 

Daklinza + sofosbuvir +/- ribavirin for 24 weeks 

Patients with CP C cirrhosis Daklinza + sofosbuvir +/- ribavirin for 24 weeks 

(see sections 4.4 and 5.1) 
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. 

 

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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 

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 Daklinza to manage adverse reactions is not recommended. If treatment 
interruption of components in the regimen is necessary because of adverse reactions, Daklinza must 
not be given as monotherapy. 
There are no virologic treatment stopping rules that apply to the combination of Daklinza with 
sofosbuvir. 
 
Treatment discontinuation in patients with inadequate on-treatment virologic response during 
treatment with Daklinza, peginterferon alfa and ribavirin 
It is unlikely that patients with inadequate on-treatment virologic response will achieve a sustained 
virologic response (SVR); therefore discontinuation of treatment is recommended in these patients. 
The HCV RNA thresholds that trigger discontinuation of treatment (i.e. treatment stopping rules) are 
presented in Table 3. 
 
Table 3: Treatment stopping rules in patients receiving Daklinza in combination with 

peginterferon alfa and ribavirin with inadequate on-treatment virologic response 

HCV RNA Action 

Treatment week 4: >1000 IU/ml Discontinue Daklinza, peginterferon alfa and ribavirin 

Treatment week 12: ≥25 IU/ml Discontinue Daklinza, peginterferon alfa and ribavirin 

Treatment week 24: ≥25 IU/ml Discontinue peginterferon alfa and ribavirin (treatment with 
Daklinza is complete at week 24) 

 
Dose recommendation for concomitant medicines 
Strong inhibitors of cytochrome P450 enzyme 3A4 (CYP3A4) 

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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. 
 
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). 
 
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 

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only be used in patients on Daklinza and sofosbuvir when other alternative antiarrhythmic treatments 
are not tolerated or are contraindicated. 
 
Should concomitant use of amiodarone be considered necessary it is recommended that patients are 
closely monitored when initiating Daklinza in combination with sofosbuvir. Patients who are 
identified as being at high risk of bradyarrhythmia should be continuously monitored for 48 hours in 
an appropriate clinical setting. 
 
Due to the long half-life of amiodarone, appropriate monitoring should also be carried out for patients 
who have discontinued amiodarone within the past few months and are to be initiated on Daklinza in 
combination with sofosbuvir. 
 
All patients receiving Daklinza and sofosbuvir in combination with amiodarone with or without other 
drugs that lower heart rate should also be warned of the symptoms of bradycardia and heart block and 
should be advised to seek medical advice urgently should they experience them. 
 
Genotype-specific activity 
Concerning recommended regimens with different HCV genotypes, see section 4.2. Concerning 
genotype-specific virological and clinical activity, see section 5.1. 
Data to support the treatment of genotype 2 infection with Daklinza and sofosbuvir are limited. 
 
Data from study ALLY-3 (AI444218) support a 12-week treatment duration of Daklinza + sofosbuvir 
for treatment-naïve and -experienced patients with genotype 3 infection without cirrhosis. Lower rates 
of SVR were observed for patients with cirrhosis (see section 5.1). Data from compassionate use 
programmes which included patients with genotype 3 infection and cirrhosis, support the use of 
Daklinza + sofosbuvir for 24 weeks in these patients. The relevance of adding ribavirin to that regimen 
is unclear (see section 5.1). 
The clinical data to support the use of Daklinza and sofosbuvir in patients infected with HCV 
genotypes 4 and 6 are limited. There are no clinical data in patients with genotype 5 (see section 5.1). 
 
Patients with Child-Pugh C liver disease 
The safety and efficacy of Daklinza in the treatment of HCV infection in patients with Child-Pugh C 
liver disease have been established in the clinical study ALLY-1 (AI444215, Daklinza + sofosbuvir + 
ribavirin for 12 weeks); however, SVR rates were lower than in patients with Child-Pugh A and B. 
Therefore, a conservative treatment regimen of Daklinza + sofosbuvir +/- ribavirin for 24 weeks is 
proposed for patients with Child-Pugh C (see sections 4.2 and 5.1). Ribavirin may be added based on 
clinical assessment of an individual patient. 
 
HCV/HBV (hepatitis B virus) co-infection 
Cases of hepatitis B virus (HBV) reactivation, some of them fatal, have been reported during or after 
treatment with direct-acting antiviral agents. HBV screening should be performed in all patients before 
initiation of treatment. HBV/HCV co-infected patients are at risk of HBV reactivation, and should 
therefore be monitored and managed according to current clinical guidelines. 
 
Retreatment with daclatasvir 
The efficacy of Daklinza as part of a retreatment regimen in patients with prior exposure to a NS5A 
inhibitor has not been established. 
 
Pregnancy and contraception requirements 
Daklinza should not be used during pregnancy or in women of childbearing potential not using 
contraception. Use of highly effective contraception should be continued for 5 weeks after completion 
of Daklinza therapy (see section 4.6). 
When Daklinza is used in combination with ribavirin, the contraindications and warnings for that 
medicinal product are applicable. Significant teratogenic and/or embryocidal effects have been 
demonstrated in all animal species exposed to ribavirin; therefore, extreme care must be taken to avoid 
pregnancy in female patients and in female partners of male patients (see the Summary of Product 
Characteristics for ribavirin).  

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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 other medicinal products  
Daclatasvir is a substrate of CYP3A4, P-gp and organic cation transporter (OCT) 1. Strong or 
moderate inducers of CYP3A4 and P-gp may decrease the plasma levels and therapeutic effect of 
daclatasvir. Coadministration with strong inducers of CYP3A4 and P-gp is contraindicated while dose 
adjustment of Daklinza is recommended when coadministered with moderate inducers of CYP3A4 
and P-gp (see Table 4). Strong inhibitors of CYP3A4 may increase the plasma levels of daclatasvir. 
Dose adjustment of Daklinza is recommended when coadministered with strong inhibitors of CYP3A4 
(see Table 4). Coadministration of medicines that inhibit P-gp or OCT1 activity is likely to have a 
limited effect on daclatasvir exposure. 
 
Daclatasvir is an inhibitor of P-gp, organic anion transporting polypeptide (OATP) 1B1, OCT1 and 
breast cancer resistance protein (BCRP). Administration of Daklinza may increase systemic exposure 
to medicinal products that are substrates of P-gp, OATP 1B1, OCT1 or BCRP, which could increase 
or prolong their therapeutic effect and adverse reactions. Caution should be used if the medicinal 
product has a narrow therapeutic range (see Table 4). 
 
Daclatasvir is a very weak inducer of CYP3A4 and caused a 13% decrease in midazolam exposure. 
However, as this is a limited effect, dose adjustment of concomitantly administered CYP3A4 
substrates is not necessary. 
 
Refer to the respective Summary of Product Characteristics for drug interaction information for other 
medicinal products in the regimen. 
 

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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 

Interaction Recommendations concerning 
coadministration 

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) 
 
↔ GS-331007** 
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). 
**GS-331007 is the major circulating 
metabolite of the prodrug sofosbuvir. 

No dose adjustment of Daklinza 
or sofosbuvir is required.  

Protease inhibitors (PIs) 

Boceprevir Interaction not studied. 
Expected due to CYP3A4 inhibition by 
boceprevir: 
↑ Daclatasvir 
 

The dose of Daklinza should be 
reduced to 30 mg once daily 
when coadministered 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 Daklinza 
or simeprevir is required. 

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Table 4: Interactions and dose recommendations with other medicinal products 

Medicinal products by 
therapeutic areas 

Interaction Recommendations concerning 
coadministration 

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 Daklinza should be 
reduced to 30 mg once daily 
when coadministered 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 Daklinza, 
peginterferon alfa, or ribavirin is 
required. 

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Table 4: Interactions and dose recommendations with other medicinal products 

Medicinal products by 
therapeutic areas 

Interaction Recommendations concerning 
coadministration 

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-normalised to 60 mg 
dose. 

The dose of Daklinza should be 
reduced to 30 mg once daily 
when coadministered 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 Daklinza 
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 Daklinza 
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 Daklinza 
or tenofovir is required.  

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Table 4: Interactions and dose recommendations with other medicinal products 

Medicinal products by 
therapeutic areas 

Interaction Recommendations concerning 
coadministration 

Lamivudine 
Zidovudine 
Emtricitabine 
Abacavir 
Didanosine 
Stavudine 

Interaction not studied. 
Expected: 
↔ Daclatasvir  
↔ NRTI  
 

No dose adjustment of Daklinza 
or the NRTI is required. 

Non-nucleoside 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-normalised to 60 mg 
dose. 

The dose of Daklinza should be 
increased to 90 mg once daily 
when coadministered with 
efavirenz. 

Etravirine 
Nevirapine 

Interaction not studied. 
Expected due to CYP3A4 induction by 
etravirine or nevirapine: 
↓ Daclatasvir 

Due to the lack of data, 
coadministration of Daklinza 
and etravirine or nevirapine is 
not recommended. 

Rilpivirine Interaction not studied. 
Expected: 
↔ Daclatasvir  
↔ Rilpivirine 

No dose adjustment of Daklinza 
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 P-gp and BCRP by 
daclatasvir 

No dose adjustment of Daklinza 
or dolutegravir is required. 

Raltegravir 
 

Interaction not studied. 
Expected: 
↔ Daclatasvir  
↔ Raltegravir 

No dose adjustment of Daklinza 
or raltegravir is required. 

Elvitegravir, cobicistat, 
emtricitabine, tenofovir 
disoproxil fumarate 

Interaction not studied for this fixed 
dose combination tablet. 
Expected due to CYP3A4 inhibition by 
cobicistat: 
↑ Daclatasvir 

The dose of Daklinza should be 
reduced to 30 mg once daily 
when coadministered with 
cobicistat or other strong 
inhibitors of CYP3A4. 

Fusion inhibitor 
Enfuvirtide  Interaction not studied. 

Expected: 
↔ Daclatasvir  
↔ Enfuvirtide 

No dose adjustment of Daklinza 
or enfuvirtide is required. 

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Table 4: Interactions and dose recommendations with other medicinal products 

Medicinal products by 
therapeutic areas 

Interaction Recommendations concerning 
coadministration 

CCR5 receptor antagonist 
Maraviroc  Interaction not studied. 

Expected: 
↔ Daclatasvir  
↔ Maraviroc 

No dose adjustment of Daklinza 
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 Daklinza 
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 Daklinza 
is required. 

ANTIBACTERIALS 

Clarithromycin 
Telithromycin 

Interaction not studied. 
Expected due to CYP3A4 inhibition by 
the antibacterial: 
↑ Daclatasvir  
 

The dose of Daklinza should be 
reduced to 30 mg once daily 
when coadministered with 
clarithromycin, telithromycin or 
other strong inhibitors of 
CYP3A4. 

Erythromycin Interaction not studied. 
Expected due to CYP3A4 inhibition by 
the antibacterial: 
↑ Daclatasvir  

Administration of Daklinza 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 Daklinza 
or azithromycin or ciprofloxacin 
is required. 

ANTICOAGULANTS 

Dabigatran etexilate Interaction not studied. 
Expected due to inhibition of P-gp by 
daclatasvir: 
↑ Dabigatran etexilate 

Safety monitoring is advised 
when initiating treatment with 
Daklinza in patients receiving 
dabigatran etexilate or other 
intestinal P-gp substrates that 
have a narrow therapeutic range. 

Warfarin or other vitamin K 
antagonists 

Interaction not studied. 
Expected: 
↔ Daclatasvir  
↔ Warfarin 

No dose adjustment of Daklinza 
or warfarin is required. Close 
monitoring of INR values is 
recommended with all vitamin 
K antagonists. This is due to 
liver function that may change 
during treatment with Daklinza. 

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Table 4: Interactions and dose recommendations with other medicinal products 

Medicinal products by 
therapeutic areas 

Interaction Recommendations concerning 
coadministration 

ANTICONVULSANTS 

Carbamazepine 
Oxcarbazepine 
Phenobarbital 
Phenytoin 
 

Interaction not studied. 
Expected due to CYP3A4 induction by 
the anticonvulsant: 
↓ Daclatasvir 

Coadministration of Daklinza 
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 Daklinza 
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 Daklinza should be 
reduced to 30 mg once daily 
when coadministered 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 Daklinza 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 

Coadministration of Daklinza 
with rifampicin, rifabutin, 
rifapentine or other strong 
inducers of CYP3A4 is 
contraindicated (see section 4.3). 

Rifabutin 
Rifapentine 

Interaction not studied. 
Expected due to CYP3A4 induction by 
the antimycobacterial: 
↓ Daclatasvir  Me

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Table 4: Interactions and dose recommendations with other medicinal products 

Medicinal products by 
therapeutic areas 

Interaction Recommendations concerning 
coadministration 

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) 
 
 
P-gp inhibition by daclatasvir 

Digoxin should be used with 
caution when coadministered 
with Daklinza. 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 other alternative 
is available. Close monitoring is 
recommended if this medicinal 
product is administered with 
Daklinza 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 Daklinza 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 P-gp 
inhibition by verapamil: 
↑ Daclatasvir 

Administration of Daklinza 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 

Coadministration of Daklinza 
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 

Coadministration of Daklinza 
with St. John’s wort or other 
strong inducers of CYP3A4 is 
contraindicated (see section 4.3). 

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Table 4: Interactions and dose recommendations with other medicinal products 

Medicinal products by 
therapeutic areas 

Interaction Recommendations concerning 
coadministration 

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 Daklinza. 
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 Daklinza is 
coadministered 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 
Daklinza is coadministered 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  
 

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Table 4: Interactions and dose recommendations with other medicinal products 

Medicinal products by 
therapeutic areas 

Interaction Recommendations concerning 
coadministration 

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 Daklinza 
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: ↔* 
 
↔ R-methadone 
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 Daklinza 
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 coadministered with 
Daklinza. 

Triazolam 
Alprazolam 

Interaction not studied. 
Expected: 
↔ Triazolam 
↔ Alprazolam 

 
No clinically relevant effects on the pharmacokinetics of either medicinal product are expected when 
daclatasvir is coadministered with any of the following: PDE-5 inhibitors, medicinal products in the 
ACE inhibitor class (e.g. enalapril), medicinal products in the angiotensin II receptor antagonist class 
(e.g. losartan, irbesartan, olmesartan, candesartan, valsartan), disopyramide, propafenone, flecainide, 
mexilitine, quinidine or antacids. 
 
Paediatric population 
Interaction studies have only been performed in adults. 
 

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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 
 
Summary of the safety profile 
The overall safety profile of daclatasvir is based on data from 2215 patients with chronic HCV 
infection who received Daklinza once daily either in combination with sofosbuvir with or without 
ribavirin (n=679, pooled data) or in combination with peginterferon alfa and ribavirin (n=1536, pooled 
data) from a total of 14 clinical studies. 
 
Daklinza in combination with sofosbuvir 
The most frequently reported adverse reactions were fatigue, headache, and nausea. Grade 3 adverse 
reactions were reported in less than 1% of patients, and no patients had a Grade 4 adverse reaction. 
Four patients discontinued the Daklinza regimen for adverse events, only one of which was considered 
related to study therapy. 
 
Daklinza in combination with peginterferon alfa and ribavirin 
The most frequently reported adverse reactions were fatigue, headache, pruritus, anaemia, influenza-
like illness, nausea, insomnia, neutropenia, asthenia, rash, decreased appetite, dry skin, alopecia, 
pyrexia, myalgia, irritability, cough, diarrhoea, dyspnoea and arthralgia. The most frequently reported 
adverse reactions of at least Grade 3 severity (frequency of 1% or greater) were neutropenia, anaemia, 
lymphopenia and thrombocytopenia. The safety profile of daclatasvir in combination with 
peginterferon alfa and ribavirin was similar to that seen with peginterferon alfa and ribavirin alone, 
including among patients with cirrhosis. 
 
Tabulated list of adverse reactions 
Adverse reactions are listed in Table 5 by regimen, system organ class and frequency: very common 
(≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) 

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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 

System Organ Class Adverse Reactions 
Frequency Daklinza +sofosbuvir + 

ribavirin 
N=203 

Daklinza +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, 
gastrooesophageal 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 Daklinza in combination with sofosbuvir with or without ribavirin, 2% of patients 
had Grade 3 haemoglobin decreases; all of these patients received Daklinza + sofosbuvir + ribavirin. 
Grade 3/4 increases in total bilirubin were observed in 5% of patients (all in patients with HIV co-
infection who were receiving concomitant atazanavir, with Child-Pugh A, B, or C cirrhosis, or who 
were post-liver transplant). 
 
Description of selected adverse reactions 
Cardiac arrhythmias 
Cases of severe bradycardia and heart block have been observed when Daklinza is used in 
combination with sofosbuvir and concomitant amiodarone and/or other drugs that lower heart rate (see 
sections 4.4 and 4.5). 
 
Paediatric population 
The safety and efficacy of Daklinza in children and adolescents aged <18 years have not yet been 
established. No data are available. 
 

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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. 
 
Resistance in cell culture 
Substitutions conferring daclatasvir resistance in genotypes 1-4 were observed in the N-terminal 100 
amino acid region of NS5A in a cell-based replicon system. L31V and Y93H were frequently 
observed resistance substitutions in genotype 1b, while M28T, L31V/M, Q30E/H/R, and Y93C/H/N 
were frequently observed resistance substitutions in genotype 1a. These substitutions conferred low 
level resistance (EC50 <1 nM) for genotype 1b, and higher levels of resistance for genotype 1a (EC50 
up to 350 nM). The most resistant variants with single amino acid substitution in genotype 2a and 
genotype 3a were F28S (EC50 >300 nM) and Y93H (EC50 >1,000 nM), respectively. In genotype 4, 
amino acid substitutions at 30 and 93 (EC50 < 16 nM) were frequently selected. 
 
Cross-resistance 
HCV replicons expressing daclatasvir-associated resistance substitutions remained fully sensitive to 
interferon alfa and other anti-HCV agents with different mechanisms of action, such as NS3 protease 
and NS5B polymerase (nucleoside and non-nucleoside) inhibitors. 

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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-naïve and 41 had failed prior therapy with a PI regimen (boceprevir or 
telaprevir). All 44 patients with HCV genotype 2 (n=26) or 3 (n=18) infection were treatment-naïve. 
Treatment duration was 12 weeks for 82 treatment-naïve HCV genotype 1 patients, and 24 weeks for 
all other patients in the study. The 211 patients had a median age of 54 years (range: 20 to 70); 83% 
were white; 12% were black/African-American; 2% were Asian; 20% were Hispanic or Latino. The 
mean score on the FibroTest (a validated non-invasive diagnostic assay) was 0.460 (range: 0.03 to 
0.89). Conversion of the FibroTest score to the corresponding METAVIR score suggests that 35% of 
all patients (49% of patients with prior PI failure, 30% of patients with genotype 2 or 3) had ≥F3 liver 
fibrosis. Most patients (71%, including 98% of prior PI failures) had IL-28B rs12979860 non-CC 
genotypes. 
 
SVR12 was achieved by 99% patients with HCV genotype 1, 96% of those with genotype 2 and 89% 
of those with genotype 3 (see Tables 6 and 7). Response was rapid (viral load at Week 4 showed that 
more than 97% of patients responded to therapy), and was not influenced by HCV subtype (1a/1b), 
IL28B genotype, or use of ribavirin. Among treatment-naïve patients with HCV RNA results at both 
follow-up Weeks 12 and 24, concordance between SVR12 and SVR24 was 99.5% independent of 
treatment duration.  
Treatment-naïve patients with HCV genotype 1 who received 12 weeks of treatment had a similar 
response as those treated for 24 weeks (Table 6). 
 
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%) -- -- -- 

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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 

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

 
Table 7: Treatment outcomes, daclatasvir in combination with sofosbuvir for 24 weeks, 

treatment-naïve patients with HCV genotype 2 or 3 in Study AI444040 

 Genotype 2 Genotype 3 

 daclatasvir 
+ sofosbuvir  

N=17 

daclatasvir 
+ sofosbuvir 
+ ribavirin 

N=9 

All 
Genotype 2 

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 RNA value was <LLOQ. One patient with HCV genotype 2 infection was missing both post-
treatment Week 12 and 24 data. 

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

 
Advanced cirrhosis and post-liver transplant (ALLY-1) 
In study ALLY-1, the regimen of daclatasvir, sofosbuvir, and ribavirin administered for 12 weeks was 
evaluated in 113 adults with chronic hepatitis C and Child-Pugh A, B or C cirrhosis (n=60) or HCV 
recurrence after liver transplantation (n=53). Patients with HCV genotype 1, 2, 3, 4, 5 or 6 infection 
were eligible to enroll. Patients received daclatasvir 60 mg once daily, sofosbuvir 400 mg once daily, 
and ribavirin (600 mg starting dose) for 12 weeks and were monitored for 24 weeks post treatment. 
Patients demographics and main disease characteristics are summarised in Table 8. 
 
Table 8: Demographics and main disease characteristics in Study ALLY-1 

 Cirrhotic cohort 
N = 60 

Post-Liver Transplant 
N = 53 

Age (years): median (range) 58 (19-75) 59 (22-82) 
Race: White 57 (95%) 51 (96%) 

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

 Cirrhotic cohort 
N = 60 

Post-Liver Transplant 
N = 53 

 Black/African 
American 

3 (5%) 1 (2%) 

 Other 0 1 (2%) 

HCV genotype:  
 1a 

 
34 (57%) 

 
31 (58%) 

 1b 11 (18%) 10 (19%) 
 2 5 (8%) 0 
 3 6 (10%) 11 (21%) 
 4 4 (7%) 0 
 6 0 1 (2%) 

Fibrosis stage   
 F0 0 6 (11%) 
 F1 1 (2%) 10 (19%) 
 F2 3 (5%) 7 (13%) 
 F3 8 (13%) 13 (25%) 
 F4 48 (80%) 16 (30%) 
Not reported 0 1 (2%) 

CP classes  ND 
  CP A 12 (20%)  
  CP B 32 (53%)  
  CP C 16 (27%)  

MELD score  ND 
 mean 13.3  
 median 13.0  
 Q1, Q3 10, 16  
 Min, Max 8, 27  

ND: Not determined 
 
SVR12 was achieved by 83% (50/60) of patients in the cirrhosis cohort, with a marked difference 
between patients with Child-Pugh A or B (92-94%) as compared to those with Child-Pugh C and 94% 
of patients in the post-liver transplant cohort (Table 9). SVR rates were comparable regardless of age, 
race, gender, IL28B allele status, or baseline HCV RNA level. In the cirrhosis cohort, 4 patients with 
hepatocellular carcinoma underwent liver transplantation after 1–71 days of treatment; 3 of the 
4 patients received 12 weeks of post-liver transplant treatment extension and 1 patient, treated for 
23 days before transplantation, did not receive treatment extension. All 4 patients achieved SVR12. 
 
Table 9: Treatment outcomes, daclatasvir in combination with sofosbuvir and ribavirin for 

12 weeks, patients with cirrhosis or HCV recurrence after liver transplantation, 
Study ALLY-1 

 Cirrhotic cohort 

N=60 

Post-LiverTransplant 

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%)   

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Table 9: Treatment outcomes, daclatasvir in combination with sofosbuvir and ribavirin for 
12 weeks, patients with cirrhosis or HCV recurrence after liver transplantation, 
Study ALLY-1 

 Cirrhotic cohort 

N=60 

Post-LiverTransplant 

N=53 

 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 (ALLY-2) 
In study ALLY-2, the combination of daclatasvir and sofosbuvir administered for 12 weeks was 
evaluated in 153 adults with chronic hepatitis C and HIV co-infection; 101 patients were HCV 
treatment-naïve and 52 patients had failed prior HCV therapy. Patients with HCV genotype 1, 2, 3, 4, 
5, or 6 infection were eligible to enroll, including patients with compenstated cirrhosis (Child-
Pugh A). The dose of daclatasvir was adjusted for concomitant antiretroviral use. Patient 
demographics and baseline disease characteristics are summarised in Table 10. 
 
Table 10: Demographics and baseline characteristics in Study ALLY-2 

Patient disposition 
daclatasvir + sofosbuvir 

12 weeks 
N = 153 

Age (years): median (range) 53 (24-71) 

Race: 
 White 

 
97 (63%) 

 Black/African American 50 (33%) 
 Other 6 (4%) 

HCV genotype: 
 1a 

 
104 (68%) 

 1b 23 (15%) 
 2 13 (8%) 
 3 10 (7%) 
 4 3 (2%) 

Compensated cirrhosis 24 (16%) 

Concomitant HIV therapy: 
 PI-based 

 
70 (46%) 

 NNRTI-based 40 (26%) 
 Other 41 (27%) 
 None 2 (1%) 

 
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. 

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SVR rates were comparable regardless of HIV regimen, age, race, gender, IL28B allele status, or 
baseline HCV RNA level. Outcomes by prior treatment experience are presented in Table 11. 
 
A third treatment group in study ALLY-2 included 50 HCV treatment-naïve HIV co-infected patients 
who received daclatasvir and sofosbuvir for 8 weeks. Demographic and baseline characteristics of 
these 50 patients were generally comparable to those for patients who received 12 weeks of study 
treatment. The SVR rate for patients treated for 8 weeks was lower with this treatment duration as 
summarized in Table 11. 
 
Table 11: Treatment outcomes, daclatasvir in combination with sofosbuvir in patients 

with HCV/HIV co-infection in Study ALLY-2 

 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 

 1b 
28/35 (80%) 

3/6 (50%) 

68/71 (96%) 

12/12 (100%) 

32/33 (97%) 

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 aspartate 

aminotransferase (AST): platelet ratio index (APRI) >2. For 5 patients, cirrhosis status was indeterminate. 
 
HCV Genotype 3 (ALLY-3) 
In study ALLY-3, the combination of daclatasvir and sofosbuvir administered for 12 weeks was 
evaluated in 152 adults infected with HCV genotype 3; 101 patients were treatment-naïve and 
51 patients had failed prior antiviral therapy. Median age was 55 years (range: 24 to 73); 90% of 
patients were white; 4% were black/African-American; 5% were Asian; 16% were Hispanic or Latino. 
The median viral load was 6.42 log10 IU/ml, and 21% of patients had compensated cirrhosis. Most 
patients (61%) had IL-28B rs12979860 non-CC genotypes. 
 
SVR12 was achieved in 90% of treatment-naïve patients and 86% of treatment-experienced patients. 
Response was rapid (viral load at Week 4 showed that more than 95% of patients responded to 
therapy) and was not influenced by IL28B genotype. SVR12 rates were lower among patients with 
cirrhosis (see Table 12). 
 

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

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

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

 
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-naïve 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-naïve 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 co-
infected 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 

 
Treatment-naïve 

N=54 

Treatment-
experienced 

N=24 

Total 

N=78 

End of treatment 

HCV RNA undetectable 
54/54 (100.0%) 21/24 (87.5%) 75/78 (96.2%) 

Responder (SVR12) 50/54 (92.6%) 19/24 (79.2%) 69/78 (88.5%)* 

Non-responder (non-SVR12) 4/54 (7.4%) 5/24 (20.8%) 9/78 (11.5%) 

  Virologic failure    

Virologic breakthrough 0 0 0 

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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-naïve 

N=54 

Treatment-
experienced 

N=24 

Total 

N=78 

Detectable HCV RNA 
at end of treatment 

0 2/24 (8.3%) 2/78 (2.6%) 

Relapse 0 2/21 (9.5%) 2/75 (2.7%) 

  Non-virologic failure    

Other non-responder** 4/54 (7.4%) 0 4/78 (5.1%) 

No HCV RNA on 
treatment 

0 1/24 (4.2%) 1/78 (1.3%) 

*    One treatment-experienced patient achieved SVR12 per local HCV RNA results. 
**  Other non-responders included 4  patients with HCV  RNA < LLOQ target not detected (TND) at end of 

treatment, but who were lost to follow-up at post-treatment Week 12 and subsequent time points, and 
1 patient who had no on-treatment HCV RNA results due to early discontinuation.  

 
Compassionate Use 
Patients with HCV infection (across genotypes) at high risk of decompensation or death within 
12 months if left untreated were treated under compassionate use programmes. Patients with 
genotype 3 infection were treated with daclatasvir + sofosbuvir +/- ribavirin for 12 or 24 weeks, where 
the longer treatment duration was associated with a lower risk for relapse (around 5%) in a preliminary 
analysis. The relevance of including ribavirin as part of the 24-week regimen is unclear. In one cohort 
the majority of patients were treated with daclatasvir + sofosbuvir + ribavirin for 12 weeks. The 
relapse rate was around 15%, and similar  for patients with Child-Pugh A, B and C. The programmes 
do not allow for a direct comparison of efficacy between the 12- and 24-week regimens. 
 
Daclatasvir in combination with peginterferon alfa and ribavirin 
AI444042 and AI444010 were randomised, double-blind studies that evaluated the efficacy and safety 
of daclatasvir in combination with peginterferon alfa and ribavirin (pegIFN/RBV) in the treatment of 
chronic HCV infection in treatment-naïve adults with compensated liver disease (including cirrhosis). 
AI444042 enrolled patients with HCV genotype 4 infection and AI444010 enrolled patients with 
either genotype 1 or 4. AI444043 was an open-label, single-arm study of daclatasvir with 
pegIFN/RBV in treatment-naïve adults with chronic HCV genotype 1 infection who were co-infected 
with HIV. 
 
AI444042: Patients received daclatasvir 60 mg once daily (n=82) or placebo (n=42) plus pegIFN/RBV 
for 24 weeks. Patients in the daclatasvir treatment group who did not have HCV RNA undetectable at 
both Weeks 4 and 12 and all placebo-treated patients continued pegIFN/RBV for another 24 weeks. 
Treated patients had a median age of 49 years (range: 20 to 71); 77% of patients were white; 19% 
were black/African-American; 4% were Hispanic or Latino. Ten percent of patients had compensated 
cirrhosis, and 75% of patients had IL-28B rs12979860 non-CC genotypes. Treatment outcomes in 
study AI444042 are presented in Table 14. Response was rapid (at Week 4 91% of daclatasvir-treated 
patients had HCV RNA <LLOQ). SVR12 rates were higher for patients with the IL-28B CC genotype 
than for those with non-CC genotypes and for patients with baseline HCV RNA less than 
800,000 IU/ml but consistently higher in the daclatasvir-treated patients than for placebo-treated 
patients in all subgroups. 
 
AI444010: Patients received daclatasvir 60 mg once daily (n=158) or placebo (n=78) plus 
pegIFN/RBV through Week 12. Patients assigned to daclatasvir 60 mg once-daily treatment group 
who had HCV RNA <LLOQ at Week 4 and undetectable at Week 10 were then randomised to receive 
another 12 weeks of daclatasvir 60 mg + pegIFN/RBV or placebo + pegIFN/RBV for a total treatment 
duration of 24 weeks. Patients originally assigned to placebo and those in the daclatasvir group who 
did not achieve HCV RNA <LLOQ at Week 4 and undetectable at Week 10 continued pegIFN/RBV 

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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. 
 
Table 14: Treatment outcomes, daclatasvir in combination with peginterferon alfa and 

ribavirin (pegIFN/RBV), treatment-naïve patients with HCV genotype 4 

 

Study AI444042  Study AI444010 

daclatasvir + 
pegIFN/RBV 

N=82 

pegIFN/RB
V 

N=42  

daclatasvir + 
pegIFN/RBV 

N=12 

pegIFN/RB
V 

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 

With cirrhosis 

56/69 (81%)** 

7/9 (78%)** 

17/38 (45%) 

1/4 (25%) 

 12/12 (100%) 

0 

3/6 (50%) 

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-up Week 12 were considered responders if their next available 

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

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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 

Category/ Substitution, n (%) 
Genotype 1a Genotype 1b Genotype 2 Genotype 3 

N=301 N=79 N=44 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 genotype 3. 
Emergent daclatasvir resistance-associated substitutions have been shown to persist for 3 years post-
treatment 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 

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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-naïve patients with genotype 1 chronic HCV, the 
geometric mean (CV%) daclatasvir Cmax was 1534 (58) ng/ml, AUC0-24h 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 orally followed by 100 μg [13C,15N]-daclatasvir intravenous dose, estimated volume of 
distribution at steady state was 47 l. In vitro studies indicate that daclatasvir is actively and passively 
transported into hepatocytes. The active transport is mediated by OCT1 and other unidentified uptake 
transporters, but not by organic anion transporter (OAT) 2, sodium-taurocholate cotransporting 
polypeptide (NTCP), or OATPs. 
 
Daclatasvir is an inhibitor of P-gp, OATP 1B1 and BCRP. In vitro daclatasvir is an inhibitor of renal 
uptake transporters, OAT1 and 3, and OCT2, but is not expected to have a clinical effect on the 
pharmacokinetics of substrates of these transporters. 
 
Biotransformation 
In vitro and in vivo studies demonstrate that daclatasvir is a substrate of CYP3A, with CYP3A4 being 
the major CYP isoform responsible for the metabolism. No metabolites circulated at levels more than 
5% of the parent concentration. Daclatasvir in vitro did not inhibit (IC50 >40 µM) CYP enzymes 1A2, 
2B6, 2C8, 2C9, 2C19, or 2D6.  

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Elimination 
Following single-dose oral administration of 14C–daclatasvir in healthy subjects, 88% of total 
radioactivity was recovered in feces (53% as unchanged drug) and 6.6% was excreted in the urine 
(primarily as unchanged drug). These data indicate that the liver is the major clearance organ for 
daclatasvir in humans. In vitro studies indicate that daclatasvir is actively and passively transported 
into hepatocytes. The active transport is mediated by OCT1 and other unidentified uptake transporters. 
Following multiple-dose administration of daclatasvir in HCV-infected patients, the terminal 
elimination half-life of daclatasvir ranged from 12 to 15 hours. In patients who received daclatasvir 
60 mg tablet orally followed by 100 μg [13C,15N]-daclatasvir intravenous dose, the total clearance was 
4.24 l/h. 
 
Special populations 
Renal impairment 
The pharmacokinetics of daclatasvir following a single 60 mg oral dose were studied in non-HCV 
infected subjects with renal impairment. Daclatasvir unbound AUC was estimated to be 18%, 39% and 
51% higher for subjects with creatinine clearance (CLcr) values of 60, 30 and 15 ml/min, respectively, 
relative to subjects with normal renal function. Subjects with end-stage renal disease requiring 
haemodialysis had a 27% increase in daclatasvir AUC and a 20% increase in unbound AUC compared 
to subjects with normal renal function (see section 4.2). 
 
Hepatic impairment 
The pharmacokinetics of daclatasvir following a single 30 mg oral dose were studied in non-HCV 
infected subjects with mild (Child-Pugh A), moderate (Child-Pugh B), and severe (Child-Pugh C) 
hepatic impairment compared with unimpaired subjects. The 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. 

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Carcinogenesis and mutagenesis 
Daclatasvir was not carcinogenic in mice or in rats at exposures 8-fold or 4-fold, respectively, the 
clinical AUC exposure. No evidence of mutagenic or clastogenic activity was observed in in vitro 
mutagenesis (Ames) tests, mammalian mutation assays in Chinese hamster ovary cells, or in an in vivo 
oral micronucleus study in rats.  
 
Fertility 
Daclatasvir had no effects on fertility in female rats at any dose tested. The highest AUC value in 
unaffected females was 18-fold the clinical AUC exposure. In male rats, effects on reproductive 
endpoints were limited to reduced prostate/seminal vesicle weights, and minimally increased 
dysmorphic sperm at 200 mg/kg/day; however, neither finding adversely affected fertility or the 
number of viable conceptuses sired. The AUC associated with this dose in males is 19-fold the clinical 
AUC exposure. 
 
Embryo-foetal development 
Daclatasvir is embryotoxic and teratogenic in rats and rabbits at exposures at or above 4-fold (rat) and 
16-fold (rabbit) the clinical AUC exposure. Developmental toxicity consisted of increased 
embryofoetal lethality, reduced foetal body weights and increased incidence of foetal malformations 
and variations. In rats, malformations mainly affected the brain, skull, eyes, ears, nose, lip, palate or 
limbs and in rabbits, the ribs and cardiovascular area. Maternal toxicity including mortality, abortions, 
adverse clinical signs, decreases in body weight and food consumption was noted in both species at 
exposures 25-fold (rat) and 72-fold (rabbit) the clinical AUC exposure. 
 
In a study of pre- and postnatal development in rats, there was neither maternal nor developmental 
toxicity at doses up to 50 mg/kg/day, associated with AUC values 2-fold the clinical AUC exposure. 
At the highest dose (100 mg/kg/day), maternal toxicity included mortality and dystocia; 
developmental toxicity included slight reductions in offspring viability in the peri- and neonatal 
periods; and reductions in birth weight that persisted into adulthood. The AUC value associated with 
this dose is 4-fold the clinical AUC exposure. 
 
Excretion into milk 
Daclatasvir was excreted into the milk of lactating rats with concentrations 1.7- to 2-fold maternal 
plasma levels.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
Anhydrous lactose 
Microcrystalline cellulose 
Croscarmellose sodium 
Silicon dioxide (E551) 
Magnesium stearate 
 
Tablet film-coat 
Hypromellose 
Titanium dioxide (E171) 
Macrogol 400 
Indigo carmine aluminum lake (E132) 
Yellow iron oxide (E172) 
 
6.2 Incompatibilities 
 
Not applicable. 

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6.3 Shelf life 
 
30 months 
 
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 lidding. 
Pack size of 28 film-coated tablets in perforated unit dose blisters. 
Pack size of 28 film-coated tablets in non-perforated calendar blisters. 
 
Not all pack sizes may be marketed. 
 
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 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/14/939/001 
EU/1/14/939/002 
EU/1/14/939/003 
EU/1/14/939/004 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 22 August 2014 
 
 
10. DATE OF REVISION OF THE TEXT 
 
{MM/YYYY} 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
  

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ANNEX II 
 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 

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A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Bristol-Myers Squibb S.r.l. 
Loc. Fontana del Ceraso 
03012 Anagni (FR) 
Italy  
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE  
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
 Periodic safety update reports 
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT   
 
 Risk Management Plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted: 

 At the request of the European Medicines Agency; 
 Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 
 Obligation to conduct post-authorisation measures 
 
The MAH shall complete, within the stated timeframe, the below measures: 
 

Description Due date 
In order to evaluate the recurrence of hepatocellular carcinoma associated with 
Daklinza, the MAH shall conduct and submit the results of a prospective safety 
study using data deriving from a cohort of a well-defined group of patients, based 
on an agreed protocol.  The final study report shall be submitted by:  

Q2 2023 

 
 
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ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  

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A. LABELLING 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON TEXT 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Daklinza 30 mg film-coated tablets 
daclatasvir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 30 mg of daclatasvir (as dihydrochloride). 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. 
See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
28 film-coated tablets 
28 x 1 film-coated tablet 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
 
 

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10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bristol-Myers Squibb Pharma EEIG 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/14/939/001 28 tablets (calendar pack) 
EU/1/14/939/002 28 x 1 tablet 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
Daklinza 30 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
UNIT DOSE BLISTER (PERFORATED) TEXT 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Daklinza 30 mg tablets 
daclatasvir 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
BMS 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 

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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
CALENDAR BLISTER (NON-PERFORATED) TEXT 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Daklinza 30 mg tablets 
daclatasvir 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Bristol-Myers Squibb Pharma EEIG 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
Monday Tuesday Wednesday Thursday Friday Saturday Sunday 
 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON TEXT 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Daklinza 60 mg film-coated tablets 
daclatasvir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 60 mg of daclatasvir (as dihydrochloride). 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. 
See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
28 film-coated tablets 
28 x 1 film-coated tablet 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
 
 

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10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bristol-Myers Squibb Pharma EEIG 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/14/939/003 28 tablets (calendar pack) 
EU/1/14/939/004 28 x 1 tablet 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
Daklinza 60 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
UNIT DOSE BLISTER (PERFORATED) TEXT 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Daklinza 60 mg tablets 
daclatasvir 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
BMS 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 

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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
CALENDAR BLISTER (NON-PERFORATED) TEXT 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Daklinza 60 mg tablets 
daclatasvir 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Bristol-Myers Squibb Pharma EEIG 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
Monday Tuesday Wednesday Thursday Friday Saturday Sunday 
 

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B. PACKAGE LEAFLET 

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Package leaflet: Information for the patient 
 

Daklinza 30 mg film-coated tablets 
Daklinza 60 mg film-coated tablets 

daclatasvir 
 

This medicine is subject to additional monitoring. This will allow quick identification of new 
safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects. 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
 Keep this leaflet. You may need to read it again.  
 If you have any further questions, ask your doctor or pharmacist. 
 This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
 If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
1. What Daklinza is and what it is used for 
2. What you need to know before you take Daklinza 
3. How to take Daklinza 
4. Possible side effects 
5. How to store Daklinza 
6. Contents of the pack and other information 
 
 
1. What Daklinza is and what it is used for 
 
Daklinza contains the active ingredient daclatasvir. It is used to treat adults with hepatitis C, an 
infectious disease that affects the liver, caused by the hepatitis C virus. 
 
This medicine works by stopping the hepatitis C virus from multiplying and infecting new cells. This 
lowers the amount of hepatitis C virus in your body and removes the virus from your blood over a 
period of time. 
 
Daklinza must always be used together with other medicines against hepatitis C infection and must 
never be used by itself.  
 
It is very important that you also read the package leaflets for the other medicines that you will be 
taking with Daklinza. If you have any questions about your medicines, please ask your doctor or 
pharmacist. 
 
 
2. What you need to know before you take Daklinza 
 
Do not take Daklinza 
 if you are allergic to daclatasvir or any of the other ingredients of this medicine (listed in section 6 

of this leaflet) 
 if you are taking (by mouth or other ways that affect the whole body) any of the following 

medicines 
- phenytoin, carbamazepine, oxcarbazepine or phenobarbital, used to treat epileptic seizures 
- rifampicin, rifabutin or rifapentine, antibiotics used to treat tuberculosis 
- dexamethasone, a steroid used to treat allergic and inflammatory diseases 
- medicines containing St. John’s wort (Hypericum perforatum, a herbal preparation). 
 

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These medicines lower the effect of Daklinza and may result in your treatment not working. If 
you take any of these medicines, tell your doctor immediately. 

 
Since Daklinza must always be used in combination with other medicines against hepatitis C infection, 
please make sure that you read the "Do not take" section of the package leaflets for these medicines. If 
you are unsure of any information in the package leaflets, please contact your doctor or pharmacist. 
 
Warnings and precautions 
Talk to your doctor or pharmacist before taking Daklinza. 
 
Tell your doctor if any of the following applies: 
 you currently take, or have taken in the last few months, the medicine amiodarone to treat 

irregular heartbeats (your doctor may consider alternative treatments if you have taken this 
medicine) 

 you have a current or previous infection with the hepatitis B virus, since your doctor may want to 
monitor you more closely 

 your liver is damaged and not functioning properly (decompensated liver disease) 
 you have diabetes. You may need closer monitoring of your blood glucose levels and/or 

adjustment of your diabetes medication after starting Daklinza. Some diabetic patients have 
experienced low sugar levels in the blood (hypoglycaemia) after starting treatment with medicines 
like Daklinza. 

 
Tell your doctor immediately if you are taking any medicines for heart problems and during treatment 
you experience: 
 Shortness of breath 
 Light-headedness 
 Palpitations 
 Fainting 
 
Children and adolescents 
Daklinza is not recommended for patients below 18 years of age. Daklinza has not yet been studied in 
children and adolescents. 
 
Other medicines and Daklinza 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. This is because Daklinza may affect the way some medicines work. In addition some 
medicines may affect the way Daklinza works. Your doctor may need to adjust the dose of Daklinza or 
you may not be able to take Daklinza with certain medicines.  
 
Do not take Daklinza if you are taking any of the following medicines: 
 phenytoin, carbamazepine, oxcarbazepine or phenobarbital, used to treat epileptic seizures 
 rifampicin, rifabutin or rifapentine, antibiotics used to treat tuberculosis 
 dexamethasone, a steroid used to treat allergic and inflammatory diseases 
 medicines containing St. John’s wort (Hypericum perforatum, a herbal preparation). 
These medicines lower the effect of Daklinza so your treatment will not work. If you take any of these 
medicines, tell your doctor immediately. 
 
Tell your doctor or pharmacist if you take any of the following medicines: 
 amiodarone or digoxin, used to treat irregular heart beats 
 atazanavir/ritonavir, atazanavir/cobicistat, elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil 

fumarate combination tablet, etravirine, nevirapine or efavirenz, used to treat HIV infection 
 boceprevir or telaprevir, used to treat hepatitis C infection 
 clarithromycin, telithromycin or erythromycin, used to treat bacterial infections 
 warfarin and other similar medicines called vitamin K antagonists used to thin the blood. Your 

doctor may need to increase the frequency of your blood tests to check how well your blood can 
clot. 

 dabigatran etexilate, used to to prevent blood clots 

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 ketoconazole, itraconazole, posaconazole or voriconazole, used to treat fungal infections 
 verapamil, diltiazem, nifedipine or amlodipine, used to decrease blood pressure 
 rosuvastatin, atorvastatin, fluvastatin, simvastatin, pitavastatin or pravastatin, used to lower blood 

cholesterol 
 oral contraceptives 
With some of these medicines, your doctor may need to adjust your dose of Daklinza. 
 
Pregnancy and contraception  
Tell your doctor if you are pregnant, think you may be pregnant or are planning to become pregnant. If 
you become pregnant, stop taking Daklinza and tell your doctor immediately. 
 
If you are pregnant you must not take Daklinza. 
If you can become pregnant, use effective contraception during and for 5 weeks after your treatment 
with Daklinza. 
 
Daklinza is sometimes used together with ribavirin. Ribavirin can harm your unborn baby. It is 
therefore very important that you (or your partner) do not become pregnant during this treatment. 
 
Breast-feeding 
It is not known whether Daklinza passes into human breast milk. You should not breastfeed during 
treatment with Daklinza. 
 
Driving and using machines 
Some patients have reported dizziness, difficulty concentrating, and vision problems while taking 
Daklinza with other medicines for their hepatitis C infection. If you have any of these side effects, do 
not drive or use any tools or machines. 
 
Daklinza contains lactose 
If you have been told by your doctor that you have an intolerance to some sugars (e.g. lactose), talk to 
your doctor before taking Daklinza. 
 
Daklinza contains sodium 
This medicine contains less than 1 mmol sodium (23 mg) per maximum dose of 90 mg, that is to say 
essentially ‘sodium-free’. 
 
 
3. How to take Daklinza 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 
 
Recommended dose 
The recommended dose of Daklinza is 60 mg once a day. Swallow the tablet whole. Do not chew or 
crush the tablet as it has a very unpleasant taste. Daklinza can be taken with or without a meal. 
 
Some other medicines can interact with Daklinza, affecting the levels of Daklinza in your body. If you 
are taking any of these medicines, your doctor may decide to change your daily dose of Daklinza to 
ensure that the treatment is safe and effective for you. 
 
Since Daklinza must always be used with other medicines against hepatitis C infection, please read the 
package leaflets for these medicines. If you have any questions, ask your doctor or pharmacist. 
 
How long to take Daklinza 
Make sure you take Daklinza for as long as your doctor has told you to take it. 
 
The duration of your treatment with Daklinza will be either 12 or 24 weeks. The duration of your 
treatment will depend on whether you have previously received treatment for your hepatitis C 

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infection, the condition of your liver, and what other medicines you will take with Daklinza. You may 
have to take your other medicines for different lengths of time. 
 
If you take more Daklinza than you should 
If you accidentally take more Daklinza tablets than your doctor recommended, contact your doctor at 
once or contact the nearest hospital for advice. Keep the tablet blister with you so that you can easily 
describe what you have taken. 
 
If you forget to take Daklinza 
It is important not to miss a dose of this medicine.  
If you do miss a dose:  
 and you notice within 20 hours of the time you usually take Daklinza, you must take the tablet as 

soon as possible. Then take the next dose at your usual time.  
 and you notice 20 hours or more after the time you usually take Daklinza, wait and take the next 

dose at your usual time. Do not take a double dose (two doses close together).  
 
If you stop taking Daklinza 
It is important that you continue to take Daklinza during the whole treatment period. Otherwise the 
medicine may not work against the hepatitis C virus. Do not stop taking Daklinza unless your 
doctor told you to stop. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
When Daklinza is used together with sofosbuvir (without ribavirin), the following side effects have 
been reported. 
 
Very common (may affect more than 1 in 10 people): 
 headache, fatigue 
 
Common (may affect up to 1 in 10 people): 
 difficulty sleeping 
 dizziness 
 migraine 
 nausea (feeling sick), diarrhoea, abdominal pain 
 joint pain, aching or tender muscles, not caused by exercise 
 
When Daklinza is used together with sofosbuvir and ribavirin, the following side effects have been 
reported. 
 
Very common (may affect more than 1 in 10 people): 
 headache, nausea (feeling sick), fatigue 
 reduction in red blood cells (anaemia) 
 
Common (may affect up to 1 in 10 people): 
 decreased appetite 
 difficulty sleeping, irritability 
 dizziness 
 migraine 
 shortness of breath, cough, nasal congestion (blocked nose) 
 hot flush 
 dry skin, unusual hair loss or thinning, rash, itching 

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 diarrhoea, vomiting, abdominal pain, constipation, heartburn, excessive gas in the stomach or 
bowel 

 dry mouth 
 joint pain, aching or tender muscles, not caused by exercise 
 
When Daklinza is used together with peginterferon alfa and ribavirin the reported side effects are the 
same as those listed in the package leaflets for these medicines. The most common of these side 
effects are listed below. 
 
Very common (may affect more than 1 in 10 people): 
 decreased appetite 
 difficulty sleeping 
 headache 
 shortness of breath 
 nausea 
 fatigue 
 flu-like illness, fever 
 itching, dry skin, unusual hair loss or thinning, rash 
 diarrhoea 
 cough 
 joint pain, aching or tender muscles, not caused by exercise, unusual weakness 
 irritability 
 reduction in red blood cells (anaemia), reduction in white blood cells 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store Daklinza 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and blister after "EXP". 
The expiry date refers to the last day of that month. 
 
This medicine does not require any special storage conditions. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Daklinza contains  
 The active substance is daclatasvir. Each film-coated tablet contains 30 mg or 60 mg daclatasvir 

(as dihydrochloride) 
 The other ingredients are 

- Tablet core: anhydrous lactose (see section 2), microcrystalline cellulose, croscarmellose 
sodium, silicon dioxide (E551) and magnesium stearate 

- Film-coating: hypromellose, titanium dioxide (E171), macrogol 400, indigo carmine 
aluminum lake (E132), yellow iron oxide (E172) 

 
What Daklinza looks like and contents of the pack 

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Daklinza 30 mg: the film-coated tablet is green, biconvex, pentagonal shape with "BMS" debossed on 
one side and "213" on the other side. 
 
Daklinza 60 mg: the film-coated tablet is light green, biconvex, pentagonal shape with "BMS" 
debossed on one side and "215" on the other side. 
 
Daklinza 30 mg and 60 mg film-coated tablets are available in packs of 28 tablets in non-perforated 
calendar blisters and perforated unit dose blisters. 
 
Not all packages may be marketed in your country. 
 
Marketing Authorisation Holder 
Bristol-Myers Squibb Pharma EEIG 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 

Manufacturer 
Bristol-Myers Squibb S.r.l. 
Loc. Fontana del Ceraso 
03012 Anagni (FR) 
Italy 

 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
Belgique/België/Belgien 
N.V. Bristol-Myers Squibb Belgium S.A. 
Tél/Tel: + 32 2 352 76 11 
 

Lietuva 
Bristol-Myers Squibb Kft. 
Tel: +370 52 369140 
 

България 
Bristol-Myers Squibb Kft. 
Teл.: + 359 800 12 400 
 

Luxembourg/Luxemburg 
N.V. Bristol-Myers Squibb Belgium S.A. 
Tél/Tel: + 32 2 352 76 11 
 

Česká republika 
Bristol-Myers Squibb spol. s r.o. 
Tel: + 420 221 016 111 
 

Magyarország 
Bristol-Myers Squibb Kft. 
Tel.: + 36 1 9206 550 
 

Danmark 
Bristol-Myers Squibb 
Tlf: + 45 45 93 05 06 
 

Malta 
BRISTOL-MYERS SQUIBB S.R.L. 
Tel: + 39 06 50 39 61 
 

Deutschland 
Bristol-Myers Squibb GmbH & Co. KGaA 
Tel: + 49 89 121 42-0 
 

Nederland 
Bristol-Myers Squibb B.V. 
Tel: + 31 (0)30 300 2222 
 

Eesti 
Bristol-Myers Squibb Kft. 
Tel: +372 640 1030 
 

Norge 
Bristol-Myers Squibb Norway Ltd 
Tlf: + 47 67 55 53 50 
 

Ελλάδα 
BRISTOL-MYERS SQUIBB A.E. 
Τηλ: + 30 210 6074300 
 

Österreich 
Bristol-Myers Squibb GesmbH 
Tel: + 43 1 60 14 30 
 

España 
BRISTOL-MYERS SQUIBB, S.A. 
Tel: + 34 91 456 53 00 
 

Polska 
BRISTOL-MYERS SQUIBB POLSKA SP. Z O.O. 
Tel.: + 48 22 5796666 
 

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France 
Bristol-Myers Squibb SARL 
Tél: + 33 (0)1 58 83 84 96 
 

Portugal 
Bristol-Myers Squibb Farmacêutica Portuguesa, 
S.A. 
Tel: + 351 21 440 70 00 
 

Hrvatska 
Bristol-Myers Squibb spol. s r.o. 
TEL: +385 1 2078 508 
 

România 
Bristol-Myers Squibb Kft. 
Tel: + 40 (0)21 272 16 00 
 

Ireland 
Bristol-Myers Squibb Pharmaceuticals uc 
Tel: + 353 (0)1 483 3625 
 

Slovenija 
Bristol-Myers Squibb spol. s r.o. 
Tel: +386 1 2355 100 
 

Ísland 
Bristol-Myers Squibb AB hjá Vistor hf. 
Sími: + 354 535 7000 
 

Slovenská republika 
Bristol-Myers Squibb spol. s r.o. 
Tel: + 421 2 59298411 
 

Italia 
BRISTOL-MYERS SQUIBB S.R.L. 
Tel: + 39 06 50 39 61 
 

Suomi/Finland 
Oy Bristol-Myers Squibb (Finland) Ab 
Puh/Tel: + 358 9 251 21 230 
 

Κύπρος 
BRISTOL-MYERS SQUIBB A.E. 
Τηλ: + 357 800 92666 
 

Sverige 
Bristol-Myers Squibb AB 
Tel: + 46 8 704 71 00 
 

Latvija 
Bristol-Myers Squibb Kft. 
Tel: +371 67708347 
 

United Kingdom 
Bristol-Myers Squibb Pharmaceuticals Ltd 
Tel: + 44 (0800) 731 1736 
 

This leaflet was last revised in <{MM/YYYY}>. 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 

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	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETINGAUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE ANDEFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET