Composition
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.
Therapeutic Indications
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.
Dosage and Administration
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.
Patient Population* | Regimen and Duration |
HCV GT 1 or 4 |
Patients without cirrhosis | Dacladazin + sofosbuvir for 12 weeks. |
Patients with cirrhosis CP A or B
|
Dacladazin + sofosbuvir + ribavirin for 12 weeks or Dacladazin + sofosbuvir (without ribavirin) for 24 weeks. |
CP C | Dacladazin + sofosbuvir +/- ribavirin for 24 weeks. |
HCV GT 3 |
Patients without cirrhosis | Dacladazin + sofosbuvir for 12 weeks. |
Patients with cirrhosis | Dacladazin + sofosbuvir +/- ribavirin for 24 weeks. |
Recurrent HCV Infection Post-liver Transplant (GT 1, 3 or 4) |
Patients without cirrhosis | Dacladazin + sofosbuvir + ribavirin for 12 weeks. |
Patients with cirrhosis CP A or B GT 1 or 4 GT 3 |
Dacladazin + sofosbuvir + ribavirin for 12 weeks. Dacladazin + sofosbuvir +/- ribavirin for 24 weeks. |
Patients with cirrhosis CP C |
Dacladazin + sofosbuvir +/- ribavirin for 24 weeks. |
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.
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 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.
HCV RNA | Action |
Treatment week 4: > 1000 IU/ml | Discontinue Dacladazin, peginterferon alfa and ribavirin. |
Treatment week 12: ≥ 25 IU/ml | Discontinue Dacladazin, peginterferon alfa and ribavirin. |
Treatment week 24: ≥ 25 IU/ml | Discontinue peginterferon alfa and ribavirin (treatment with Dacladazin is complete at week 24). |
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.
Contraindications
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).
Warnings and Precautions
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.
Drug Interactions
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.
Medicinal products by Therapeutic areas | Interaction | Recommendations concerning Co-administration |
ANTIVIRALS, HCV |
Nucleotide analogue polymerase inhibitor |
Sofosbuvir 400 mg once daily (daclatasvir 60 mg once daily) Study conducted in patients with chronic HCV infection
| ↔ Daclatasvir* AUC: 0.95 (0.82, 1.10) Cmax: 0.88 (0.78, 0.99) Cmin: 0.91 (0.71, 1.16) ↔ 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 Dacladazin or sofosbuvir is required.
|
Protease inhibitors (PIs) |
Boceprevir
| Interaction not studied. Expected due to CYP3A4 inhibition by boceprevir: ↑ Daclatasvir | The dose of Dacladazin should be reduced to 30 mg once daily when co-administered with boceprevir or other strong inhibitors of CYP3A4. |
Simeprevir 150 mg once daily (daclatasvir 60 mg once daily) | ↑ Daclatasvir AUC: 1.96 (1.84, 2.10) Cmax: 1.50 (1.39, 1.62) Cmin: 2.68 (2.42, 2.98) ↑ Simeprevir AUC: 1.44 (1.32, 1.56) Cmax: 1.39 (1.27, 1.52) Cmin: 1.49 (1.33, 1.67) | No dose adjustment of Dacladazin or simeprevir is required. |
Telaprevir 500 mg q12h (daclatasvir 20 mg once daily)
Telaprevir 750 mg q8h (daclatasvir 20 mg once daily) | ↑ Daclatasvir AUC: 2.32 (2.06, 2.62) Cmax: 1.46 (1.28, 1.66) ↔ Telaprevir AUC: 0.94 (0.84, 1.04) Cmax: 1.01 (0.89, 1.14) ↑ Daclatasvir AUC: 2.15 (1.87, 2.48) Cmax: 1.22 (1.04, 1.44) ↔ Telaprevir AUC: 0.99 (0.95, 1.03) Cmax: 1.02 (0.95, 1.09) CYP3A4 inhibition by telaprevir. | The dose of Dacladazin should be reduced to 30 mg once daily when co-administered with telaprevir or other strong inhibitors of CYP3A4. |
Other HCV Antivirals |
Peginterferon alfa 180 µg once weekly and ribavirin 1000 mg or 1200 mg/day in two divided doses (daclatasvir 60 mg once daily) Study conducted in patients with chronic HCV infection. | ↔ Daclatasvir AUC: ↔ ∗ Cmax: ↔ ∗ Cmin: ↔ ∗ ↔ Peginterferon alfa Cmin: ↔ ∗ ↔ Ribavirin AUC: 0.94 (0.80, 1.11) Cmax: 0.94 (0.79, 1.11) Cmin: 0.98 (0.82, 1.17) *PK parameters for daclatasvir when administered with peginterferon alfa and ribavirin in this study were similar to those observed in a study of HCV-infected subjects administered daclatasvir monotherapy for 14 days. PK trough levels for peginterferon alfa in patients who received peginterferon alfa, ribavirin, and daclatasvir were similar to those in patients who received peginterferon alfa, ribavirin, and placebo.
| No dose adjustment of Dacladazin, peginterferon alfa, or ribavirin is required.
|
ANTIVIRALS, HIV or HBV |
Protease inhibitors (PIs) |
Atazanavir 300 mg/ ritonavir 100 mg once daily (daclatasvir 20 mg once daily) | ↑ Daclatasvir AUC*: 2.10 (1.95, 2.26) Cmax*: 1.35 (1.24, 1.47) Cmin*: 3.65 (3.25, 4.11) CYP3A4 inhibition by ritonavir. *Results are dose-normalised to 60 mg dose. | The dose of Dacladazin should be reduced to 30 mg once daily when co-administered with atazanavir/ritonavir, atazanavir/cobicistat or other strong inhibitors of CYP3A4. |
Atazanavir/Cobicistat | Interaction not studied. Expected due to CYP3A4 inhibition by atazanavir/cobicistat: ↑ Daclatasvir |
Darunavir 800 mg/ ritonavir 100 mg once daily (daclatasvir 30 mg once daily) | ↔ Daclatasvir AUC: 1.41 (1.32, 1.50) Cmax: 0.77 (0.70, 0.85) ↔ Darunavir AUC: 0.90 (0.73, 1.11) Cmax: 0.97 (0.80, 1.17) Cmin: 0.98 (0.67, 1.44) | No dose adjustment of Dacladazin 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 Dacladazin 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 Dacladazin or tenofovir is required.
|
Lamivudine Zidovudine Emtricitabine Abacavir Didanosine Stavudine | Interaction not studied. Expected: ↔ Daclatasvir ↔ NRTI | No dose adjustment of Dacladazin 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 Dacladazin should be increased to 90 mg once daily when co-administered with efavirenz. |
Etravirine Nevirapine
| Interaction not studied. Expected due to CYP3A4 induction by etravirine or nevirapine: ↓ Daclatasvir | Due to the lack of data, co-administration of Dacladazin and etravirine or nevirapine is not recommended. |
Rilpivirine
| Interaction not studied. Expected: ↔ Daclatasvir ↔ Rilpivirine | No dose adjustment of Dacladazin 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 Dacladazin or dolutegravir is required. |
Raltegravir
| Interaction not studied. Expected: ↔ Daclatasvir ↔ Raltegravir | No dose adjustment of Dacladazin 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 Dacladazin should be reduced to 30 mg once daily when co-administered with cobicistat or other strong inhibitors of CYP3A4. |
Fusion inhibitor |
Enfuvirtide
| Interaction not studied. Expected: ↔ Daclatasvir ↔ Enfuvirtide | No dose adjustment of Dacladazin or enfuvirtide is required. |
CCR5 receptor antagonist |
Maraviroc
| Interaction not studied. Expected: ↔ Daclatasvir ↔ Maraviroc | No dose adjustment of Dacladazin 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 Dacladazin 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 Dacladazin is required. |
ANTIBACTERIALS |
Clarithromycin Telithromycin | Interaction not studied. Expected due to CYP3A4 inhibition by the antibacterial: ↑ Daclatasvir | The dose of Dacladazin should be reduced to 30 mg once daily when co-administered with clarithromycin, telithromycin or other strong inhibitors of CYP3A4. |
Erythromycin
| Interaction not studied. Expected due to CYP3A4 inhibition by the antibacterial: ↑ Daclatasvir | Administration of Dacladazin 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 Dacladazin 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 Dacladazin 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 Dacladazin 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 Dacladazin. |
ANTICONVULSANTS |
Carbamazepine Oxcarbazepine Phenobarbital Phenytoin | Interaction not studied. Expected due to CYP3A4 induction by the anticonvulsant: ↓ Daclatasvir | Co-administration of Dacladazin with carbamazepine, oxcarbazepine, phenobarbital, phenytoin or other strong inducers of CYP3A4 is contraindicated. |
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 Dacladazin 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 Dacladazin should be reduced to 30 mg once daily when co-administered with ketoconazole or other strong inhibitors of CYP3A4. |
Itraconazole Posaconazole Voriconazole
| Interaction not studied. Expected due to CYP3A4 inhibition by the antifungal: ↑ Daclatasvir |
Fluconazole
| Interaction not studied. Expected due to CYP3A4 inhibition by the antifungal: ↑ Daclatasvir ↔ Fluconazole | Modest increases in concentrations of daclatasvir are expected, but no dose adjustment of Dacladazin or fluconazole is required. |
ANTIMYCOBACTERIALS |
Rifampicin 600 mg once daily (daclatasvir 60 mg single dose)
| ↓ Daclatasvir AUC: 0.21 (0.19, 0.23) Cmax: 0.44 (0.40, 0.48) CYP3A4 induction by rifampicin. | Co-administration of Dacladazin with rifampicin, rifabutin, rifapentine or other strong inducers of CYP3A4 is contraindicated. |
Rifabutin Rifapentine | Interaction not studied. Expected due to CYP3A4 induction by the antimycobacterial: ↓ Daclatasvir |
CARDIOVASCULAR AGENTS |
Antiarrhythmics |
Digoxin 0.125 mg once daily (daclatasvir 60 mg once daily)
| ↑ Digoxin AUC: 1.27 (1.20, 1.34) Cmax: 1.65 (1.52, 1.80) Cmin: 1.18 (1.09, 1.28) P-gp inhibition by daclatasvir. | Digoxin should be used with caution when co-administered with Dacladazin. 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.
| Co-administration of amiodarone with sofosbuvir in combination with another DAA may result in serious symptomatic bradycardia. The mechanism of this effect is unknown. Co-administration of amiodarone with sofosbuvir in combination with another DAA is not recommended; if co-administration is required, cardiac monitoring is recommended. Use only if no other alternative is available. Close monitoring is recommended if this medicinal product is administered with Dacladazin in combination with sofosbuvir. |
Calcium channel blockers |
Diltiazem Nifedipine Amlodipine
| Interaction not studied. Expected due to CYP3A4 inhibition by the calcium channel blocker: ↑ Daclatasvir | Administration of Dacladazin with any of these calcium channel blockers may result in increased concentrations of Dacladazin. Caution is advised. |
Verapamil
| Interaction not studied. Expected due to CYP3A4 and P-gp inhibition by verapamil: ↑ Daclatasvir | Administration of Dacladazin with verapamil may result in increased concentrations of Dacladazin. Caution is advised. |
CORTICOSTEROIDS |
Systemic dexamethasone
| Interaction not studied. Expected due to CYP3A4 induction by dexamethasone: ↓ Daclatasvir | Co-administration of Dacladazin with systemic dexamethasone or other strong inducers of CYP3A4 is contraindicated. |
HERBAL SUPPLEMENTS |
St. John's wort (Hypericum perforatum) | Interaction not studied. Expected due to CYP3A4 induction by St. John's wort: ↓ Daclatasvir | Co-administration of Dacladazin with St. John's wort or other strong inducers of CYP3A4 is contraindicated. |
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 Dacladazin. 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 Dacladazin is co-administered with cyclosporine, tacrolimus, sirolimus or mycophenolate mofetil. |
Tacrolimus 5 mg single dose (daclatasvir 60 mg once daily) | ↔ Daclatasvir AUC: 1.05 (1.03, 1.07) Cmax: 1.07 (1.02, 1.12) Cmin: 1.10 (1.03, 1.19) ↔ Tacrolimus AUC: 1.00 (0.88, 1.13) Cmax: 1.05 (0.90, 1.23) |
Sirolimus Mycophenolate mofetil | Interaction not studied. Expected: ↔ Daclatasvir ↔ Immunosuppressant |
LIPID LOWERING AGENTS |
HMG-CoA reductase inhibitors |
Rosuvastatin 10 mg single dose (daclatasvir 60 mg once daily) | ↑ Rosuvastatin AUC: 1.58 (1.44, 1.74) Cmax: 2.04 (1.83, 2.26) Inhibition of OATP 1B1 and BCRP by daclatasvir | Caution should be used when Dacladazin is co-administered with rosuvastatin or other substrates of OATP 1B1 or BCRP. |
Atorvastatin Fluvastatin Simvastatin Pitavastatin Pravastatin | Interaction not studied. Expected due to inhibition of OATP 1B1 and/or BCRP by daclatasvir: ↑ Concentration of statin. |
NARCOTIC ANALGESICS |
Buprenorphine/naloxone, 8/2 mg to 24/6 mg once daily individualized dose* (daclatasvir 60 mg once daily) * Evaluated in opioid-dependent adults on stable buprenorphine/naloxone maintenance therapy. | ↔ Daclatasvir AUC: ↔ * Cmax: ↔ * Cmin: ↔ * ↑ Buprenorphine AUC: 1.37 (1.24, 1.52) Cmax: 1.30 (1.03, 1.64) Cmin: 1.17 (1.03, 1.32) ↑ Norbuprenorphine AUC: 1.62 (1.30, 2.02) Cmax: 1.65 (1.38, 1.99) Cmin: 1.46 (1.12, 1.89) | No dose adjustment of Dacladazin 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 Dacladazin or methadone is required.
|
SEDATIVES |
Benzodiazepines |
Midazolam 5 mg single dose (daclatasvir 60 mg once daily) | ↔ Midazolam AUC: 0.87 (0.83, 0.92) Cmax: 0.95 (0.88, 1.04) | No dose adjustment of midazolam, other benzodiazepines or other CYP3A4 substrates is required when co-administered with Dacladazin. |
Triazolam Alprazolam
| Interaction not studied. Expected: ↔ Triazolam ↔ Alprazolam |
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 and Lactation
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.
Effects on ability to drive and to 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 faclatasvir in combination with peginterferon alfa and ribavirin.
Undesirable Effects
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.
System Organ Class | Adverse Reactions |
Frequency | Daclatasvir +sofosbuvir + ribavirin | Daclatasvir +sofosbuvir |
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, exertional dyspnoea, 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 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
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.
Pharmacological Properties
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.
Storage
Store in a dry place at a temperature not exceeding 30°C.
Packaging
Dacladazin Film coated Tablets: Box containing 2 strips of 14 film coated tablets each.