Each film coated tablet contains:                

Daclatasvir dihydrochloride ................................................................. 65.92 mg

Equivalent to daclatasvir ........................................................................... 60 mg

Inactive ingredients: 

Lactose monohydrate, povidone K25, croscarmellose sodium, colloidal silicon dioxide (Aerosil 200), microcrystalline cellulose (Avicel PH 101), microcrystalline cellulose (Avicel PH 102), magnesium stearate, opadry II white.

Dacladazin is indicated in combination with other medicinal products for the treatment of chronic hepatitis C virus (HCV) infection in adults.

For HCV genotype specific activity, see Warnings and Precautions.

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

Dosage:

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

Dacladazin 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 Dacladazin.

Table 1: Recommended treatment for Dacladazin Interferon-free Combination Therapy.

GT: Genotype; CP: Child Pugh

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

Dacladazin + Peginterferon alfa + Ribavirin:

This regimen is an alternative recommended regimen for patients with genotype 4 infection, without cirrhosis or with compensated cirrhosis. Dacladazin 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, Dacladazin 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 Dacladazin, 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 co-administration with Dacladazin regimen for patients with cirrhosis or post-transplant.

Dose Modification, Interruption and Discontinuation:

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

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

Treatment Discontinuation in patients with inadequate on-treatment virologic response during treatment with Dacladazin, 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 Dacladazin in combination with Peginterferon alfa and Ribavirin with inadequate on-treatment virologic response.

Dose Recommendation for Concomitant Medicines:

Strong inhibitors of cytochrome P450 enzyme 3A4 (CYP3A4):

The dose of Dacladazin should be reduced to 30 mg once daily when coadministered with strong inhibitors of CYP3A4.

Moderate inducers of CYP3A4:

The dose of Dacladazin 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 Dacladazin, 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 Dacladazin is required for patients aged ≥ 65 years.

Renal impairment:

No dose adjustment of Dacladazin is required for patients with any degree of renal impairment.

Hepatic impairment:

No dose adjustment of Dacladazin 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.

Pediatric population:

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

Administration:

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

Hypersensitivity to the active substance or to any of the excipients.

Co-administration 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 Dacladazin. 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).

Dacladazin must not be administered as monotherapy. Dacladazin must be administered in combination with other medicinal products for the treatment of chronic HCV infection.

Severe Bradycardia and Heart block:

Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone is co-administered with sofosbuvir in combination with an investigational agent (NS5A inhibitor) or simeprevir. A fatal cardiac arrest was reported in a patient receiving a sofosbuvir-containing regimen (ledipasvir/sofosbuvir). Bradycardia has generally occurred within hours to days, but cases have been observed up to 2 weeks after initiating HCV treatment. Patients also taking beta-blockers, or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with co-administration of amiodarone. Bradycardia generally resolved after discontinuation of HCV treatment. The mechanism for this effect is unknown.

Co-administration of amiodarone with sofosbuvir in combination with another direct acting antiviral (DAA) is not recommended. For patients taking amiodarone who have no other alternative, viable treatment options and who will be co-administered sofosbuvir and another DAA:

- Counsel patients about the risk of serious symptomatic bradycardia.

- Cardiac monitoring in an in-patient setting for the first 48 hours of co-administration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment.

Patients who are taking sofosbuvir in combination with another DAA who need to start amiodarone therapy due to no other alternative, viable treatment options should undergo similar cardiac monitoring as outlined above.

Due to amiodarone’s long half-life, patients discontinuing amiodarone just prior to starting sofosbuvir in combination with a DAA should also undergo similar cardiac monitoring as outlined above.

Patients who develop signs or symptoms of bradycardia should seek medical evaluation immediately. Symptoms may include near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pains, confusion or memory problems.

Genotype-specific activity:

Concerning recommended regimens with different HCV genotypes, see Dosage and Administration.

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

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

The clinical data to support the use of daclatasvir and sofosbuvir in patients infected with HCV genotypes 4 and 6 are limited. There are no clinical data in patients with genotype 5.

Patients with Child-Pugh C liver disease:

The safety and efficacy of daclatasvir in the treatment of HCV infection in patients with Child-Pugh C liver disease have been established (daclatasvir + 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 daclatasvir + sofosbuvir +/- ribavirin for 24 weeks is proposed for patients with Child-Pugh C. 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 daclatasvir as part of a retreatment regimen in patients with prior exposure to a NS5A inhibitor has not been established.

Pregnancy and Contraception requirements:

Dacladazin 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 Dacladazin therapy.

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

Interactions with Medicinal products:

Co-administration of daclatasvir can alter the concentration of other medicinal products and other medicinal products may alter the concentration of daclatasvir. Refer to Contraindications section for a listing of medicinal products that are contraindicated for use with daclatasvir due to potential loss of therapeutic effect. Refer to Drug Interactions section for established and other potentially significant drug-drug interactions.

Pediatric population:

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

Important information about some of the ingredients in Dacladazin:

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

Contraindications of Concomitant use:

Dacladazin 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 daclatasvir.

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. Co-administration with strong inducers of CYP3A4 and P-gp is contraindicated while dose adjustment of daclatasvir is recommended when co-administered 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 Dacladazin is recommended when co-administered with strong inhibitors of CYP3A4 (see Table 4). Co-administration 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 daclatasvir may increase systemic exposure to medicinal products that are substrates of P-gp, OATP 1B1, OCT1 or BCRP, which could increase or prolong their therapeutic effect and adverse reactions. Caution should be used if the medicinal product has a narrow therapeutic range (see Table 4).

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

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

Patients treated with Vitamin K antagonists:

As liver function may change during treatment with daclatasvir, 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.

No clinically relevant effects on the pharmacokinetics of either medicinal product are expected when daclatasvir is co-administered 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.

Pediatric population:

Interaction studies have only been performed in adults.

Pregnancy:

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

The potential risk for humans is unknown.

Dacladazin 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 Dacladazin therapy.

Since Dacladazin 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.

Lactation:

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. A risk to the newborn/infant cannot be excluded. Mothers should be instructed not to breastfeed if they are taking Dacladazin.

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

Daclatasvir 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 daclatasvir regimen for adverse events, only one of which was considered related to study therapy.

Daclatasvir in combination with peginterferon alfa and ribavirin:

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

Tabulated list of adverse reactions:

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

Table 5: Adverse Reactions in Clinical studies.

Laboratory abnormalities:

In clinical studies of daclatasvir in combination with sofosbuvir with or without ribavirin, 2% of patients had Grade 3 haemoglobin decreases; all of these patients received daclatasvir + 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 daclatasvir is used in combination with sofosbuvir and concomitant amiodarone and/or other drugs that lower heart rate.

Postmarketing Experience:

Cardiac Disorders: 

Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiate treatment with sofosbuvir in combination with another HCV direct-acting antiviral.

Pediatric population:

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

Reporting of suspected adverse reactions:

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the National Reporting System:

E-mail: PV.Center@eda.mohealth.gov.eg 

Tel.: (+2) 02 23684288-- 23648769--- 23640368 ext. 1303

Fax: (+2) 02 23684194

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.

Pharmacodynamic properties:

Pharmacotherapeutic group: Direct-acting antiviral.

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.

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.

Pediatric population:

The European Medicines Agency has deferred the obligation to submit the results of studies with daclatasvir in one or more subsets of the pediatric population in the treatment of chronic hepatitis C.

Pharmacokinetic properties:

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.

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.

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.

Elderly:

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

Pediatric population:

The pharmacokinetics of daclatasvir in pediatric 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. 

Store in a dry place at a temperature not exceeding 30^°C.

Dacladazin Film coated Tablets: Box containing 2 strips of 14 film coated tablets each.