DACTASVIR

DACTASVIR
Packing3 blister packs of 10 tablets/1 bottle of 30 tablets
Shelf life36 months
CompositionDaclatasvir 60 mg
Posology and pharmaceutical formFilm-coated tablet

Summary of product characteristic

Indications, posology and method of administration

Package: 3 blister packs of 10 tablets/1 bottle of 30 tablets
Shelf life: 36 months
Composition and strength: Daclatasvir 60 mg
Pharmaceutical form: Film-coated tablet

THERAPEUTIC INDICATIONS
Daclatasvir is indicated in combination with other medicinal products for the treatment of chronic hepatitis C virus (HCV) infection in adults.
POSOLOGY AND METHOD OF ADMINISTRATION
Treatment with daclatasvir should be initiated and monitored by a physician experienced in the management of chronic hepatitis C.
Posology
The recommended dose of daclatasvir is 60 mg once daily, to be taken orally with or without meals.
Daclatasvir 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 daclatasvir.

Table 1: Recommended treatment for daclatasvir interferon-free combination therapy
Patient population*	*Regimen and duration*
HCV GT 1 or 4
Patients without cirrhosis	Daclatasvir + sofosbuvir for 12 weeks.
Patients with cirrhosis Child Pugh A or B	Daclatasvir + sofosbuvir + ribavirin for 12 weeks hoặc Daclatasvir + sofosbuvir (without ribavirin) for 24 weeks.
Child Pugh C	Daclatasvir + sofosbuvir +/- ribavirin for 24 weeks.
HCV GT 3
Patients without cirrhosis	Daclatasvir + sofosbuvir for 12 weeks.
Patients with cirrhosis	Daclatasvir + sofosbuvir +/- ribavirin for 24 weeks.
Recurrent HCV infection post-liver transplant (GT 1, 3 or 4)
Patients without cirrhosis	Daclatasvir + sofosbuvir + ribavirin for 12 weeks.
Patients with Child Pugh A or B cirrhosis GT 1 or 4 GT 3	Daclatasvir + sofosbuvir + ribavirin for 12 weeks. Daclatasvir + sofosbuvir +/- ribavirin for 24 weeks.
Patients with Child Pugh C cirrhosis	Daclatasvir + sofosbuvir +/- ribavirin for 24 weeks.
GT: Genotype * Includes patients co-infected with human immunodeficiency virus (HIV). For dosing recommendations with HIV antiviral agents

Daclatasvir + peginterferon alfa + ribavirin:
This regimen is an alternative recommended regimen for patients with genotype 4 infection, without cirrhosis or with compensated cirrhosis. Daclatasvir 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, daclatasvir should be discontinued at 24 weeks and peginterferon alfa and ribavirin continued for a total duration of 48 weeks.
Ribavirin Dosing Guidelines
The dose of ribavirin, when combined with daclatasvir, 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 daclatasvir regimen for patients with cirrhosis or post-transplant
*Laboratory Value/Clinical Criteria*	*Ribavirin Dosing Guideline*
Hemoglobin
> 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	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 daclatasvir to manage adverse reactions is not recommended. If treatment interruption of components in the regimen is necessary because of adverse reactions, daclatasvir must not be given as monotherapy.
There are no virologic treatment stopping rules that apply to the combination of daclatasvir with sofosbuvir.
Treatment discontinuation in patients with inadequate on-treatment virologic response during treatment with daclatasvir, 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 daclatasvir in combination with peginterferon alfa and ribavirin with inadequate on-treatment virologic response
*HCV RNA*	*Action*
Treatment week 4: > 1000 IU/ml	Discontinue daclatasvir, peginterferon alfa and ribavirin.
Treatment week 12: ≥ 25 IU/ml	Discontinue daclatasvir, peginterferon alfa and ribavirin.
Treatment week 24: ≥ 25 IU/ml	Discontinue peginterferon alfa and ribavirin (treatment with daclatasvir is complete at week 24).

Dose recommendation for concomitant medicines
Strong inhibitors of cytochrome P450 enzyme 3A4 (CYP3A4)
The dose of daclatasvir should be reduced to 30 mg once daily when coadministered with strong inhibitors of CYP3A4.
Moderate inducers of CYP3A4
The dose of daclatasvir should be increased to 90 mg once daily when coadministered with moderate inducers of CYP3A4.
Missed doses
Patients should be instructed that, if they miss a dose of daclatasvir, 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 daclatasvir is required for patients aged ≥ 65 years.
Renal impairment
No dose adjustment of daclatasvir is required for patients with any degree of renal impairment.
Hepatic impairment
No dose adjustment of daclatasvir 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.
Paediatric population
The safety and efficacy of daclatasvir in children and adolescents aged below 18 years have not yet been established. No data are available.
Method of administration
Daclatasvir 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.
CONTRAINDICATIONS
Hypersensitivity to the active substance or to any of the excipients.
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 daclatasvir. 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).

This information is for reference only. Please read the leaflet inside.

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