Daklinza 30 mg film-coated tablets
Daklinza 60 mg film-coated tablets
Each film-coated tablet contains daclatasvir dihydrochloride equivalent to 30 mg or 60 mg daclatasvir.
Excipient(s) with known effect:
Each 30-mg film-coated tablet contains 58 mg of lactose (as anhydrous).
Each 60-mg film-coated tablet contains 116 mg of lactose (as anhydrous).
For the full list of excipients, see section 6.1.
Film-coated tablet (tablet).
30 mg: Green biconvex pentagonal of dimensions 7.2 mm x 7.0 mm, debossed tablet with "BMS" on one side and "213" on the other side.
60 mg: Light green biconvex pentagonal of dimensions 9.1 mm x 8.9 mm, debossed tablet with “BMS” on one side and “215” on the other side.
Daklinza is indicated in combination with other medicinal products for the treatment of chronic hepatitis C virus (HCV) infection in adults (see sections 4.2, 4.4 and 5.1).
For HCV genotype specific activity, see sections 4.4 and 5.1.
Treatment with Daklinza should be initiated and monitored by a physician experienced in the management of chronic hepatitis C.
Posology
The recommended dose of Daklinza is 60 mg once daily, to be taken orally with or without meals.
Daklinza must be administered in combination with other medicinal products. The Summary of Product Characteristics for the other medicinal products in the regimen should also be consulted before initiation of therapy with Daklinza.
Recommended regimens and treatment duration are provided in Table 1 below (see sections 4.4 and 5.1):
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Table 1: Recommended regimens and treatment duration for Daklinza combination therapy
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HCV genotype and patient population*
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Treatment
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Duration
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Genotype 1 or 4 without cirrhosis
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Daklinza + sofosbuvir
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12 weeks
Consider prolongation of treatment to 24 weeks for patients with prior treatment including a NS3/4A protease inhibitor (see sections 4.4 and 5.1)
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Genotype 1 or 4 with compensated cirrhosis
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Daklinza + sofosbuvir
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24 weeks
Shortening treatment to 12 weeks may be considered for previously untreated patients with cirrhosis and positive prognostic factors such as IL28B CC genotype and/or low baseline viral load.
Consider adding ribavirin for patients with very advanced liver disease or with other negative prognostic factors such as prior treatment experience.
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Genotype 3 with compensated cirrhosis and/or treatment experienced
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Daklinza + sofosbuvir + ribavirin
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24 weeks
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Genotype 4
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Daklinza + peginterferon alfa + ribavirin
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24 weeks of Daklinza in combination with 24-48 weeks of peginterferon alfa and ribavirin.
If the patient has HCV RNA 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 the patient achieves HCV RNA undetectable, but not at both treatment weeks 4 and 12, Daklinza should be discontinued at 24 weeks and peginterferon alfa and ribavirin continued for a total duration of 48 weeks.
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* For the regimen of Daklinza + sofosbuvir, data for 12-week treatment duration are available only for treatment-naïve patients with genotype 1 infection. For Daklinza + sofosbuvir with or without ribavirin, data are available for patients with advanced liver disease (≥F3) without cirrhosis (see sections 4.4 and 5.1). The recommended use of Daklinza + sofosbuvir in genotype 4 is based on extrapolation from genotype 1. For the regimen of Daklinza + peginterferon alfa + ribavirin, data are available for treatment-naïve patients (see section 5.1).
The dose of ribavirin, when combined with Daklinza, is weight-based (1,000 or 1,200 mg in patients <75 kg or ≥75 kg, respectively).
Dose modification, interruption and discontinuation
Dose modification of Daklinza to manage adverse reactions is not recommended. If treatment interruption of components in the regimen is necessary because of adverse reactions, Daklinza must not be given as monotherapy.
There are no virologic treatment stopping rules that apply to the combination of Daklinza with sofosbuvir.
Treatment discontinuation in patients with inadequate on-treatment virologic response during treatment with Daklinza, peginterferon alfa and ribavirin
It is unlikely that patients with inadequate on-treatment virologic response will achieve a sustained virologic response (SVR); therefore discontinuation of treatment is recommended in these patients. The HCV RNA thresholds that trigger discontinuation of treatment (i.e. treatment stopping rules) are presented in Table 2.
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Table 2: Treatment stopping rules in patients receiving Daklinza in combination with peginterferon alfa and ribavirin with inadequate on-treatment virologic response
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HCV RNA
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Action
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Treatment week 4: >1000 IU/ml
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Discontinue Daklinza, peginterferon alfa and ribavirin
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Treatment week 12: ≥25 IU/ml
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Discontinue Daklinza, peginterferon alfa and ribavirin
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Treatment week 24: ≥25 IU/ml
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Discontinue peginterferon alfa and ribavirin (treatment with Daklinza is complete at week 24)
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Dose recommendation for concomitant medicines
Strong inhibitors of cytochrome P450 enzyme 3A4 (CYP3A4)
The dose of Daklinza should be reduced to 30 mg once daily when coadministered with strong inhibitors of CYP3A4.
Moderate inducers of CYP3A4
The dose of Daklinza should be increased to 90 mg once daily when coadministered with moderate inducers of CYP3A4. See section 4.5.
Missed doses
Patients should be instructed that, if they miss a dose of Daklinza, the dose should be taken as soon as possible if remembered within 20 hours of the scheduled dose time. However, if the missed dose is remembered more than 20 hours after the scheduled dose, the dose should be skipped and the next dose taken at the appropriate time.
Special populations
Elderly
No dose adjustment of Daklinza is required for patients aged ≥65 years (see sections 4.4 and 5.2).
Renal impairment
No dose adjustment of Daklinza is required for patients with any degree of renal impairment (see section 5.2).
Hepatic impairment
No dose adjustment of Daklinza is required for patients with mild (Child-Pugh A, score 5-6), moderate (Child-Pugh B, score 7-9) or severe (Child-Pugh C, score ≥10) hepatic impairment. Daklinza has not been studied in patients with decompensated cirrhosis (see sections 4.4 and 5.2).
Paediatric population
The safety and efficacy of Daklinza in children and adolescents aged below 18 years have not yet been established. No data are available.
Method of administration
Daklinza is to be taken orally with or without meals. Patients should be instructed to swallow the tablet whole. The film-coated tablet should not be chewed or crushed due the unpleasant taste of the active substance.
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Coadministration with medicinal products that strongly induce cytochrome P450 3A4 (CYP3A4) and P-glycoprotein transporter (P-gp) and thus may lead to lower exposure and loss of efficacy of Daklinza. These active substances include but are not limited to phenytoin, carbamazepine, oxcarbazepine, phenobarbital, rifampicin, rifabutin, rifapentine, systemic dexamethasone, and the herbal product St John's wort (Hypericum perforatum).
Daklinza must not be administered as monotherapy. Daklinza must be administered in combination with other medicinal products for the treatment of chronic HCV infection (see sections 4.1 and 4.2).
General
The safety and efficacy of the combination of Daklinza and sofosbuvir have been eva luated in one study of limited size that did not include patients with cirrhosis. Further clinical studies with the combination are ongoing.
Genotype-specific activity
Concerning recommended regimens with different HCV genotypes, see section 4.2. Concerning genotype-specific virological and clinical activity, see section 5.1.
Due to limited experience using sofosbuvir in combination with Daklinza in patients with genotype 1 infection and compensated cirrhosis, there are uncertainties concerning the most appropriate way to use Daklinza (duration, role of ribavirin) in such patients.
Due to limitations in the pivotal study many uncertainties remain regarding the most effective way to use Daklinza for treatment of genotypes 2 and 3 infection, and how to tailor regimens according to important factors potentially affecting the virological response.
Although not studied in patients with genotype 4 infection, the combination of Daklinza and sofosbuvir is expected to yield similar activity for genotype 4 as observed for genotype 1, based on in vitro antiviral activity and available clinical data with Daklinza in combination with peginterferon and ribavirin (see section 5.1).
Daklinza has not been studied in patients with HCV genotypes 5 and 6, and no regimen recommendation can be given.
Decompensated liver disease
The safety and efficacy of Daklinza in the treatment of HCV infection in patients with decompensated liver disease have not been established.
Retreatment with daclatasvir
The efficacy of Daklinza as part of a retreatment regimen in patients with prior exposure to a NS5A inhibitor has not been established.
Pregnancy and contraception requirements
Daklinza should not be used during pregnancy or in women of childbearing potential not using contraception. Use of highly effective contraception should be continued for 5 weeks after completion of Daklinza therapy (see section 4.6).
When Daklinza is used in combination with ribavirin, the contraindications and warnings for that medicinal product are applicable. Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin; therefore, extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients (see the Summary of Product Characteristics for ribavirin).
Organ transplant patients
The safety and efficacy of Daklinza in the treatment of HCV infection in patients who are pre-, peri-, or post-liver transplant or other organ transplant patients have not been established.
HCV/HIV (human immunodeficiency virus) co-infection
The safety and efficacy of Daklinza in the treatment of HCV infection in patients who are co-infected with HIV have not been established.
HCV/HBV (hepatitis B virus) co-infection
The safety and efficacy of Daklinza in the treatment of HCV infection in patients who are co-infected with HBV have not been investigated.
Elderly
Clinical data in patients aged ≥65 years are limited. In clinical studies of Daklinza in combination with sofosbuvir or with peginterferon alfa and ribavirin, no differences in responses were observed between elderly and younger patients.
Interactions with medicinal products
Coadministration of Daklinza can alter the concentration of other medicinal products and other medicinal products may alter the concentration of daclatasvir. Refer to section 4.3 for a listing of medicinal products that are contraindicated for use with Daklinza due to potential loss of therapeutic effect. Refer to section 4.5 for established and other potentially significant drug-drug interactions.
Paediatric population
Daklinza is not recommended for use in children and adolescents aged below 18 years because the safety and efficacy have not been established in this population.
Important information about some of the ingredients in Daklinza
Daklinza contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Contraindications of concomitant use (see section 4.3)
Daklinza is contraindicated in combination with medicinal products that strongly induce CYP3A4 and P-gp, e.g. phenytoin, carbamazepine, oxcarbazepine, phenobarbital, rifampicin, rifabutin, rifapentine, systemic dexamethasone, and the herbal product St John's wort (Hypericum perforatum), and thus may lead to lower exposure and loss of efficacy of Daklinza.
Potential for interaction with other medicinal products
Daclatasvir is a substrate of CYP3A4 and P-gp. Strong or moderate inducers of CYP3A4 and P-gp may decrease the plasma levels and therapeutic effect of daclatasvir. Coadministration with strong inducers of CYP3A4 and P-gp is contraindicated while dose adjustment of Daklinza is recommended when coadministered with moderate inducers of CYP3A4 and P-gp (see Table 3). Strong inhibitors of CYP3A4 may increase the plasma levels of daclatasvir. Dose adjustment of Daklinza is recommended when coadministered with strong inhibitors of CYP3A4 (see Table 3). Coadministration of medicines that inhibit P-gp activity is likely to a have limited effect on daclatasvir exposure.
Daclatasvir is an inhibitor of P-gp, organic anion transporting polypeptide (OATP) 1B1, organic cation transporter (OCT)1 and breast cancer resistance protein (BCRP). Administration of Daklinza may increase systemic exposure to medicinal products that are substrates of P-gp, OATP 1B1, OCT1 or BCRP, which could increase or prolong their therapeutic effect and adverse reactions. Caution should be used if the medicinal product has a narrow therapeutic range (see Table 3).
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 3 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 3 were conducted in healthy adult subjects unless otherwise noted. The table is not all-inclusive.
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Table 3: Interactions and dose recommendations with other medicinal products
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Medicinal products by therapeutic areas
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Interaction
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Recommendations concerning coadministration
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ANTIVIRALS, HCV
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Nucleotide analogue polymerase inhibitor
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Sofosbuvir 400 mg once daily
(daclatasvir 60 mg once daily)
Study conducted in patients with chronic HCV infection
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↔ 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.
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No dose adjustment of Daklinza or sofosbuvir is required.
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Protease inhibitors
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Boceprevir
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Interaction not studied.
Expected due to CYP3A4 inhibition by boceprevir:
↑ Daclatasvir
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The dose of Daklinza should be reduced to 30 mg once daily when coadministered with boceprevir or other strong inhibitors of CYP3A4.
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Simeprevir 150 mg once daily
(daclatasvir 60 mg once daily)
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↑ 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)
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No dose adjustment of Daklinza or simeprevir is required.
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Telaprevir 500 mg q12h
(daclatasvir 20 mg once daily)
Telaprevir 750 mg q8h
(daclatasvir 20 mg once daily)
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↑ 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
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The dose of Daklinza should be reduced to 30 mg once daily when coadministered with telaprevir or other strong inhibitors of CYP3A4.
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Other HCV antivirals
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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
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↔ 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.
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No dose adjustment of Daklinza, peginterferon alfa, or ribavirin is required.
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ANTIVIRALS, HIV or HBV
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Protease inhibitors
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Atazanavir 300 mg/ritonavir 100 mg once daily
(daclatasvir 20 mg once daily)
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↑ 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.
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The dose of Daklinza should be reduced to 30 mg once daily when coadministered with atazanavir/ritonavir or other strong inhibitors of CYP3A4.
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Darunavir/ritonavir
Lopinavir/ritonavir
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Interaction not studied.
Expected due to CYP3A4 inhibition by the protease inhibitor:
↑ Daclatasvir
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Due to the lack of data, coadministration of Daklinza and darunavir or lopinavir is not recommended.
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Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)
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Tenofovir disoproxil fumarate 300 mg once daily
(daclatasvir 60 mg once daily)
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↔ 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)
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No dose adjustment of Daklinza or tenofovir is required.
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Lamivudine
Zidovudine
Emtricitabine
Abacavir
Didanosine
Stavudine
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Interaction not studied.
Expected:
↔ Daclatasvir
↔ NRTI
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No dose adjustment of Daklinza or the NRTI is required.
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Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
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Efavirenz 600 mg once daily
(daclatasvir 60 mg once daily/120 mg once daily)
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↓ 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.
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The dose of Daklinza should be increased to 90 mg once daily when coadministered with efavirenz.
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Etravirine
Nevirapine
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Interaction not studied.
Expected due to CYP3A4 induction by etravirine or nevirapine:
↓ Daclatasvir
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Due to the lack of data, coadministration of Daklinza and etravirine or nevirapine is not recommended.
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Rilpivirine
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Interaction not studied.
Expected:
↔ Daclatasvir
↔ Rilpivirine
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No dose adjustment of Daklinza or rilpivirine is required.
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Integrase inhibitors
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Raltegravir
Dolutegravir
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Interaction not studied.
Expected:
↔ Daclatasvir
↔ Integrase inhibitor
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No dose adjustment of Daklinza or the integrase inhibitor is required.
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Fusion inhibitor
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Enfuvirtide
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Interaction not studied.
Expected:
↔ Daclatasvir
↔ Enfuvirtide
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No dose adjustment of Daklinza or enfuvirtide is required.
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CCR5 receptor antagonist
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Maraviroc
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Interaction not studied.
Expected:
↔ Daclatasvir
↔ Maraviroc
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No dose adjustment of Daklinza or maraviroc is required.
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Pharmacokinetic enhancer
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Cobicistat-containing regimen
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Interaction not studied.
Expected due to CYP3A4 inhibition by cobicistat:
↑ Daclatasvir
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The dose of Daklinza should be reduced to 30 mg once daily when coadministered with cobicistat or other strong inhibitors of CYP3A4.
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ACID REDUCING AGENTS
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H2-receptor antagonists
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Famotidine 40 mg single dose
(daclatasvir 60 mg single dose)
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↔ 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
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No dose adjustment of Daklinza is required.
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Proton pump inhibitors
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Omeprazole 40 mg once daily
(daclatasvir 60 mg single dose)
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↔ 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
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No dose adjustment of Daklinza is required.
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ANTIBACTERIALS
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Clarithromycin
Telithromycin
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Interaction not studied.
Expected due to CYP3A4 inhibition by the antibacterial:
↑ Daclatasvir
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The dose of Daklinza should be reduced to 30 mg once daily when coadministered with clarithromycin, telithromycin or other strong inhibitors of CYP3A4.
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Erythromycin
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Interaction not studied.
Expected due to CYP3A4 inhibition by the antibacterial:
↑ Daclatasvir
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Administration of Daklinza with erythromycin may result in increased concentrations of daclatasvir. Caution is advised.
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Azithromycin
Ciprofloxacin
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Interaction not studied.
Expected:
↔ Daclatasvir
↔ Azithromycin or Ciprofloxacin
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No dose adjustment of Daklinza or azithromycin or ciprofloxacin is required.
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ANTICOAGULANTS
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Dabigatran etexilate
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Interaction not studied.
Expected due to inhibition of P-gp by daclatasvir:
↑ Dabigatran etexilate
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Safety monitoring is advised wh |
