MyDekla

Daclatasvir.

Daclatasvir film-coated tablets 30 mg (MyDekla 30): Each film coated tablet contains: Daclatasvir Dihydrochloride equivalent to Daclatasvir 30 mg.
Excipient(s) with known effect: Each 30 mg film-coated tablet contains 58 mg of lactose (as anhydrous).
Daclatasvir film-coated tablets 60 mg (MyDekla 60): Each film coated tablet contains: Daclatasvir Dihydrochloride equivalent to Daclatasvir 60 mg.
Each 60 mg film-coated tablet contains 116 mg of lactose (as anhydrous).
Excipients/Inactive Ingredients: Core Tablet: Lactose Anhydrous, Silicified Microcrystalline cellulose, Croscarmellose Sodium, Silica Colloidal anhydrous, Magnesium Stearate.
Film-Coat: 30 mg: Opadry green 03B510054, 60 mg: Opadry green 03B510052 (Hypromellose, Iron Oxide Yellow, FD&C Blue # 2 - Indigo Carmine Aluminium Lake, Macrogols, Titanium Dioxide & FD&C Blue # 2 - Indigo Carmine AL 3% to 5%).

Pharmacotherapeutic group: Direct-acting antiviral. ATC code: J05AX14. Zimbabwe Pharmacological classification: 7.13 - Antivirals. Namibia Pharmacological Classification: 20.2.8 - Antiviral agents.
Pharmacology: 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.
Pharmacodynamics: Clinical safety and efficacy: Evaluation of safety and efficacy of Daclatasvir in combination with sofosbuvir or with peginterferon alfa and ribavirin were based on published paper for studies AI444040, ALLY-1 (AI444215), ALLY-2 (AI444216), ALL Y-3 (AI4442 l 8), ALL Y-3+ (AI444326), AI444042, AI444043, and AI444010.
Daclatasvir in combination with sofosbuvir: The efficacy and safety of daclatasvir 60 mg once daily in combination with sofosbuvir 400 mg once daily inthe treatment of patients with chronic HCV infection were evaluated in two open-label studies (Al444040,ALLY-1, ALLY-2 and ALLY-3).
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 Pl 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 5 and 6). 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 (l a/ lb), 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 1 and 2). (See Table 1 and Table 2.)


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Advanced cirrhosis and post-liver transplant (ALLY-1): In study ALL Y-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 3 and 4. (See Table 3 and Table 4.)


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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 5). 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. (See Table 5.)


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HCV/HIV co-infection (ALLY-2): In study ALL Y-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 emoll, including patients with compensated cirrhosis (Child-Pugh A). The dose of daclatasvir was adjusted for concomitant antiretroviral use. Patient demographics and baseline disease characteristics are summarised in Table 6. (See Table 6.)


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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 (INSTl)-based therapies.
SVR rates were comparable regardless of HIV regimen, age, race, gender, IL28B allele status, or baseline HCV RNA level. Outcomes by prior treatment experience are presented in Table 7.
A third treatment group in study ALL Y-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 7. (See Table 7.)


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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 rsl2979860 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 8.)


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In study ALLY-3+, the combination of daclatasvir and sofosbuvir administered for 12 weeks or 16 weeks was evaluated in 50 adults infected with HCV genotype 3; 14 patients with advanced fibrosis and 36 patients with compensated cirrhosis.
SVR12 was 90% overall (45 of 50): 88% (21 of 24) in the 12-week (91% observed) and 92% (24 of 26) in the 16-week group. All patients with advanced fibrosis achieved SVR12. SVR12 in patients with cirrhosis was 86% overall (31 of 36): 83% (15 of 18) in the 12-week (88% observed) and 89% (16 of 18) in the 16-week group; for treatment-experienced patients with cirrhosis, these values were 87% (26 of 30), 88% (14 of 16; 93% observed), and 86% (12 of 14), respectively.
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 rsl2979860 non-CC genotypes. Treatment outcomes in study AI444042 are presented in Table 8. 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=l58) 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 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% la and 20% lb) and 8% had HCV genotype 4; 65% of patients had IL-28B rsl2979860 non-CC genotypes.
Treatment outcomes in study AI444010 for patients with HCV genotype 4 are presented in Table 8. For HCV genotype 1, SVR12 rates were 64% (54% for la; 84% for lb) 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. (See Table 9.)


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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 Interactions). 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 la: 70%, genotype lb: 79%).
Long term efficacy data: Limited data are available from an ongoing follow-up study to assess durability of response up to 3 years after treatment with daclatasvir. Among patients who achieved SVR12 with daclatasvir and sofosbuvir (± ribavirin) with a median duration of post-SVR12 follow-up of 15 months, no relapses have occurred. Among patients who achieved SVR12 with daclatasvir + pegIFN/RBV with a median duration of post SVR12 follow-up of 22 months, 1 % of patients relapsed.
Resistance in clinical studies: Frequency of baseline NS5A resistance-associated variants (RAVs): Baseline NS5A RAVs were frequently observed in clinical studies of daclatasvir. In 9 phase 2/3 studies with daclatasvir in combination with peginterferon alfa + ribavirin or in combination with sofosbuvir +/- ribavirin, the following frequencies of such RAVs were seen at baseline: 7% in genotype la infection (M28T, Q30, L31, and/or Y93), 11% in genotype lb 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 as previously mentioned 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 curerate 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 10. (See Table 10.)


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The sofosbuvir resistance-associated substitution S282T emerged in only 1 non-SVR12 patient infected with genotype 3. No data are available on the persistence of daclatasvir resistance-associated substitutions beyond 6 months post-treatment in patients treated with daclatasvir and sofosbuvir with/without ribavirin. Emergent daclatasvir resistance-associated substitutions have been shown to persist for 2 years posttreatment and beyond for patients treated with other daclatasvir-based regimens.
Daclatasvir in combination with peginterferon alfa and ribavirin: Baseline NS5A RAVs (at M28T, Q30, 131, 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 la 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 la and 49/57 genotype lb). 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 lb 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.
Pharmacokinetics: According to published paper literature, 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, OATl 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, 2Cl9, 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 OCTl 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 Dosage & Administration).
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 Dosage & Administration).
Elderly: Population pharmacokinetic analysis of data from clinical studies indicated that age had no apparent effect on the pharmacokinetics of daclatasvir. Data on patients ≥65 years are limited (see Precautions).
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.

Daclatasvir is indicated: In combination with sofosbuvir, with or without ribavirin, for the treatment of chronic hepatitis C virus (HCV) infection genotype 1 or 3 in adults.
In combination with pegIFN/RBV for the treatment of chronic hepatitis C virus (HCV) infection genotype 4 in adults.

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.
Recommended regimens and treatment duration are provided in Table 11 as follows (see Pharmacology: Pharmacodynamics under Actions and Precautions): See Table 11.


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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).
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 12. (See Table 12.)


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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 co-administered with strong inhibitors of CYP3A4.
Moderate inducers of CYP3A4: The dose of Daclatasvir should be increased to 90 mg once daily when co-administered with moderate inducers of CYP3A4. See Interactions.
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 (see Pharmacology: Pharmacokinetics under Actions and Precautions).
Renal Impairment: No dose adjustment of Daclatasvir is required for patients with any degree of renal impairment (see Pharmacology: Pharmacokinetics under Actions).
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. Daclatasvir has not been studied in patients with decompensated cirrhosis (see Pharmacology: Pharmacokinetics under Actions and Precautions).
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.

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.

Hypersensitivity to the active substance or to any of the excipients listed in Description. 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 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).

Daclatasvir must not be administered as monotherapy. Daclatasvir must be administered in combination with other medicinal products for the treatment of chronic HCV infection (see Indications/Uses and Dosage & Administration).
General: The safety and efficacy of the combination of Daclatasvir and sofosbuvir have been evaluated in a number of patients with cirrhosis in clinical studies. Further clinical studies with the combination are ongoing.
Severe bradycardia and heart block: Cases of severe bradycardia and heart block have been observed when Daclatasvir is used in combination with sofosbuvir and concomitant amiodarone with or without other drugs that lower heart rate. The mechanism is not established. The concomitant use of amiodarone was limited through the clinical development of sofosbuvir plus direct-acting antivirals (DAAs). Cases are potentially life threatening, therefore amiodarone should only be used in patients on Daclatasvir 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 Daclatasvir 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 Daclatasvir in combination with sofosbuvir. All patients receiving Daclatasvir 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: The clinical data to support the use of daclatasvir and sofosbuvir in patients infected with HCV genotype 2, 4, 5, and 6 are limited.
Hepatitis B Virus (HBV) Reactivation: Cases of hepatitis B virus (HCV) reactivation, including fatal cases, have been reported during and after treatment of HCV with direct-acting anti viral agent in HCV/HBV co-infected patients. Screening for current or past HBV infection, including testing for HBV surface antigen (HBsAg) and HBV core antibody (anti-HBc), should be performed in all patients before initiation of treatment with DACLATASVIR. Patients with serologic evidence of current or past HBV infection should be monitored and treated according to current clinical practice guideline to manage potential HBV reactivation. Consider initiation of HBV antiviral therapy, if indicated.
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 in the clinical study ALL Y-1 (AI444215, 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 (see Pharmacology: Pharmacodynamics under Actions and Dosage & Administration). Ribavirin may be added based on clinical assessment of an individual patient.
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.
HCV/HBV (hepatitis B virus) co-infection: The safety and efficacy of Daclatasvir in the treatment of HCV infection in patients who are co-infected with HBV have not been investigated.
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 for a listing of medicinal products that are contraindicated for use with Daclatasvir due to potential loss of therapeutic effect. Refer to Interactions for established and other potentially significant drug-drug interactions.
Important information about some of the ingredients in Daclatasvir: Daclatasvir contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Effect on Ability to Drive and Use Machines: 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 Daclatasvir in combination with peginterferon alfa and ribavirin.
Pregnancy and contraception requirements: Daclatasvir 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 Daclatasvir therapy.
When Daclatasvir 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).
Paediatric population: Daclatasvir 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.

Pregnancy: There are no data from the use of daclatasvir in pregnant women.
Studies of daclatasvir in animals have shown embryotoxic and teratogenic effects. The potential risk for humans is unknown. Daclatasvir should not be used during pregnancy or in women of childbearing potential not using contraception (see Precautions). Use of highly effective contraception should be continued for 5 weeks after completion of Daclatasvir therapy (see Interactions). Since Daclatasvir 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. A risk to the newborn/infant cannot be excluded. Mothers should be instructed not to breastfeed if they are taking Daclatasvir.
Fertility: No human data on the effect of daclatasvir on fertility are available. In rats, no effect on mating or fertility was seen.

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 13 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. (See Table 13.)


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Laboratory abnormalities: In clinical studies of Daclatasvir in combination with sofosbuvir with or without ribavirin, one patient had a Grade 3 haemoglobin decrease; this patient was in a ribavirin treatment group. Laboratory abnormalities among patients treated with Daclatasvir, peginterferon alfa and ribavirin were similar to those among patients treated with placebo, peginterferon and ribavirin.
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 (see Precautions and Interactions).
Paediatric 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.

Contraindications of concomitant use (see Contraindications): Daclatasvir is contraindicated in combination with medicinal products that strongly induce CYP3A4 and Pgp, e.g. phenytoin, carbamazepine, oxcarbazepine, phenobarbital, rifampicin, rifabutin, rifapentine, systemic dexamethasone, and the herbal product St John's wort (Hypericum perforatum), and thus may lead to lower exposure and loss of 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. Coadministration 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 13). Strong inhibitors of CYP3A4 may increase the plasma levels of daclatasvir. Dose adjustment of Daclatasvir is recommended when co-administered with strong inhibitors of CYP3A4 (see Table 12). 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 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 12).
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.
Tabulated summary of interactions: Table 14 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 14 were conducted in healthy adult subjects unless otherwise noted. The table is not all-inclusive. (See Tables 14a-14d.)


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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.
Paediatric population: Interaction studies have only been performed in adults.

Special precautions for disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Do not store above 30°C. Store in original container.
Shelf Life: Mydekla 30: 24 months.
Mydekla 60: 24 months.

Antivirals

J05AP07 - daclatasvir ; Belongs to the class of antivirals for treatment of HCV infections. Used in the treatment of hepatitis C viral infections.

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