Daklinza (daclatasvir) Daklinza film-coated tablets - United Kingdom[英国药品]

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Daklinza (daclatasvir) Daklinza film-coated tablets

2014-12-10 00:17:28 来源: 作者: 【大中小】浏览:1402次评论:0条

近日，百时美施贵宝(BMS)丙肝新药Daklinza(daclatasvir)获欧盟批准，联合其他药物，用于所有1、2、3、4基因型慢性丙型肝炎(HCV)成人感染者的治疗。Daklinza是一种强效的泛基因型NS5A复制复合体抑制剂，在临床试验中，当与吉利德明星药Sovaldi组成一种全口服、无干扰素鸡尾酒疗法(Daklinza Sovaldi)时，取得了100%的治愈率，包括伴有晚期肝脏疾病、基因型3 HCV及既往经蛋白酶抑制剂治疗失败的患者群体。
目前，吉利德也在开发一种基于Sovaldi的丙肝鸡尾酒疗法ledipasvir/Sovaldi(LDV/SOF)，百时美Daklinza/Sovaldi鸡尾酒疗法的获批，对吉利德LDV/SOF鸡尾酒疗法形成了直接威胁。
Daklinza/Sovaldi是一种每日一次、全口服、治愈率达100%的丙肝鸡尾酒疗法，为广泛基因型HCV丙肝患者提供了一种潜在治愈的治疗选择，包括一些难治性群体，如既往治疗失败的群体。
与Sovaldi一样，Daklinza与其他口服药物联合用药时，可排除常规注射制剂干扰素为基础的鸡尾酒方案。目前，在美国，吉利德Sovaldi是唯一的统治者，而艾伯维(AbbVie)和默沙东(Merck & Co)各自的全口服鸡尾酒疗法正在等待FDA的批准。
Daklinza是欧盟批准的首个NS5A复合体抑制剂，将与其他产品联用，提供一种较短治疗时间(12或24周)的治疗方案。而目前基于干扰素和利巴韦林(ribavilin)的治疗方案，治疗周期长达48周。Daklinza的获批，适用于欧盟所有28个成员国。此前，欧洲药品管理局人用医药产品委员会(CHMP)已授予Daklinza加速审批资格。
Dakllinza的获批，是基于数个研究的积极数据，包括一项开放标签、随机研究，调查了Daklinza Sovaldi组合疗法治疗基因型1、2、3 HCV感染的疗效，包括对特拉匹韦(telaprevir)或boceprevir无反应及伴有肝纤维化的患者群体。数据表明，Daklinza Sovaldi组合疗法在基因型1 HCV初治患者中的治愈率达到了99%，在既往对特拉匹韦或boceprevir治疗失败的基因型1 HCV群体中的治愈率达100%，在基因型2和基因型3 HCV中的治愈率分别为96%和89%。
此外，Daklinza治疗丙型肝炎的安全性，已在横跨各种不同群体中得到了证明，包括老年患者、伴有晚期肝病群体、肝移植后受者群体及HIV/HCV共感染群体。

1. Name of the medicinal product
Daklinza 30 mg film-coated tablets
Daklinza 60 mg film-coated tablets
2. Qualitative and quantitative composition
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.
3. Pharmaceutical form
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.
4. Clinical particulars
4.1 Therapeutic indications
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.
4.2 Posology and method of administration
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):

Table 1: Recommended regimens and treatment duration for Daklinza combination therapy
HCV genotype and patient population*	Treatment	Duration
Genotype 1 or 4 without cirrhosis	Daklinza + sofosbuvir	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)
Genotype 1 or 4 with compensated cirrhosis	Daklinza + sofosbuvir	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.
Genotype 3 with compensated cirrhosis and/or treatment experienced	Daklinza + sofosbuvir + ribavirin	24 weeks
Genotype 4	Daklinza + peginterferon alfa + ribavirin	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.

* 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.

Table 2: Treatment stopping rules in patients receiving Daklinza in combination with peginterferon alfa and ribavirin with inadequate on-treatment virologic response
HCV RNA	Action
Treatment week 4: >1000 IU/ml	Discontinue Daklinza, peginterferon alfa and ribavirin
Treatment week 12: ≥25 IU/ml	Discontinue Daklinza, peginterferon alfa and ribavirin
Treatment week 24: ≥25 IU/ml	Discontinue peginterferon alfa and ribavirin (treatment with Daklinza is complete at week 24)

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.
4.3 Contraindications
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).
4.4 Special warnings and precautions for use
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.
4.5 Interaction with other medicinal products and other forms of interaction
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.

Table 3: Interactions and dose recommendations with other medicinal products

Medicinal products by therapeutic areas

Interaction

Recommendations concerning coadministration

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)

C_max: 0.88 (0.78, 0.99)

C_min: 0.91 (0.71, 1.16)

↔ GS-331007**

AUC: 1.0 (0.95, 1.08)

C_max: 0.8 (0.77, 0.90)

C_min: 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 Daklinza or sofosbuvir is required.

Protease inhibitors

Boceprevir

Interaction not studied.

Expected due to CYP3A4 inhibition by boceprevir:

↑ Daclatasvir

The dose of Daklinza should be reduced to 30 mg once daily when coadministered 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)

C_max: 1.50 (1.39, 1.62)

C_min: 2.68 (2.42, 2.98)

↑ Simeprevir

AUC: 1.44 (1.32, 1.56)

C_max: 1.39 (1.27, 1.52)

C_min: 1.49 (1.33, 1.67)

No dose adjustment of Daklinza 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)

C_max: 1.46 (1.28, 1.66)

↔ Telaprevir

AUC: 0.94 (0.84, 1.04)

C_max: 1.01 (0.89, 1.14)

↑ Daclatasvir

AUC: 2.15 (1.87, 2.48)

C_max: 1.22 (1.04, 1.44)

↔ Telaprevir

AUC: 0.99 (0.95, 1.03)

C_max: 1.02 (0.95, 1.09)

CYP3A4 inhibition by telaprevir

The dose of Daklinza should be reduced to 30 mg once daily when coadministered 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: ↔*

C_max: ↔*

C_min: ↔*

↔ Peginterferon alfa

C_min: ↔*

↔ Ribavirin

AUC: 0.94(0.80,1.11)

C_max: 0.94 (0.79, 1.11)

C_min: 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 Daklinza, peginterferon alfa, or ribavirin is required.

ANTIVIRALS, HIV or HBV

Protease inhibitors

Atazanavir 300 mg/ritonavir 100 mg once daily

(daclatasvir 20 mg once daily)

↑ Daclatasvir

AUC*: 2.10 (1.95, 2.26)

C_max*: 1.35 (1.24, 1.47)

C_min*: 3.65 (3.25, 4.11)

CYP3A4 inhibition by ritonavir

*results are dose-normalised to 60 mg dose.

The dose of Daklinza should be reduced to 30 mg once daily when coadministered with atazanavir/ritonavir or other strong inhibitors of CYP3A4.

Darunavir/ritonavir

Lopinavir/ritonavir

Interaction not studied.

Expected due to CYP3A4 inhibition by the protease inhibitor:

↑ Daclatasvir

Due to the lack of data, coadministration of Daklinza and darunavir or lopinavir is not recommended.

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)

C_max: 1.06 (0.98, 1.15)

C_min: 1.15 (1.02, 1.30)

↔ Tenofovir

AUC: 1.10 (1.05, 1.15)

C_max: 0.95 (0.89, 1.02)

C_min: 1.17 (1.10, 1.24)

No dose adjustment of Daklinza or tenofovir is required.

Lamivudine

Zidovudine

Emtricitabine

Abacavir

Didanosine

Stavudine

Interaction not studied.

Expected:

↔ Daclatasvir

↔ NRTI

No dose adjustment of Daklinza 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)

C_max*: 0.83 (0.76, 0.92)

C_min*: 0.41 (0.34, 0.50)

Induction of CYP3A4 by efavirenz

*results are dose-normalised to 60 mg dose.

The dose of Daklinza should be increased to 90 mg once daily when coadministered with efavirenz.

Etravirine

Nevirapine

Interaction not studied.

Expected due to CYP3A4 induction by etravirine or nevirapine:

↓ Daclatasvir

Due to the lack of data, coadministration of Daklinza and etravirine or nevirapine is not recommended.

Rilpivirine

Interaction not studied.

Expected:

↔ Daclatasvir

↔ Rilpivirine

No dose adjustment of Daklinza or rilpivirine is required.

Integrase inhibitors

Raltegravir

Dolutegravir

Interaction not studied.

Expected:

↔ Daclatasvir

↔ Integrase inhibitor

No dose adjustment of Daklinza or the integrase inhibitor is required.

Fusion inhibitor

Enfuvirtide

Interaction not studied.

Expected:

↔ Daclatasvir

↔ Enfuvirtide

No dose adjustment of Daklinza or enfuvirtide is required.

CCR5 receptor antagonist

Maraviroc

Interaction not studied.

Expected:

↔ Daclatasvir

↔ Maraviroc

No dose adjustment of Daklinza or maraviroc is required.

Pharmacokinetic enhancer

Cobicistat-containing regimen

Interaction not studied.

Expected due to CYP3A4 inhibition by cobicistat:

↑ Daclatasvir

The dose of Daklinza should be reduced to 30 mg once daily when coadministered with cobicistat or other strong inhibitors of CYP3A4.

ACID REDUCING AGENTS

H₂-receptor antagonists

Famotidine 40 mg single dose

(daclatasvir 60 mg single dose)

↔ Daclatasvir

AUC: 0.82 (0.70, 0.96)

C_max: 0.56 (0.46, 0.67)

C_min: 0.89 (0.75, 1.06)

Increase in gastric pH

No dose adjustment of Daklinza is required.

Proton pump inhibitors

Omeprazole 40 mg once daily

(daclatasvir 60 mg single dose)

↔ Daclatasvir

AUC: 0.84 (0.73, 0.96)

C_max: 0.64 (0.54, 0.77)

C_min: 0.92 (0.80, 1.05)

Increase in gastric pH

No dose adjustment of Daklinza is required.

ANTIBACTERIALS

Clarithromycin

Telithromycin

Interaction not studied.

Expected due to CYP3A4 inhibition by the antibacterial:

↑ Daclatasvir

The dose of Daklinza should be reduced to 30 mg once daily when coadministered with clarithromycin, telithromycin or other strong inhibitors of CYP3A4.

Erythromycin

Interaction not studied.

Expected due to CYP3A4 inhibition by the antibacterial:

↑ Daclatasvir

Administration of Daklinza 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 Daklinza 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 Daklinza in patients receiving dabigatran etexilate or other intestinal P-gp substrates that have a narrow therapeutic range.

Warfarin

Interaction not studied.

Expected:

↔ Daclatasvir

↔ Warfarin

No dose adjustment of Daklinza or warfarin is required.

ANTICONVULSANTS

Carbamazepine

Oxcarbazepine

Phenobarbital

Phenytoin

Interaction not studied.

Expected due to CYP3A4 induction by the anticonvulsant:

↓ Daclatasvir

Coadministration of Daklinza with carbamazepine, oxcarbazepine, phenobarbital, phenytoin or other strong inducers of CYP3A4 is contraindicated (see section 4.3).

ANTIDEPRESSANTS

Selective serotonin reuptake inhibitors

Escitalopram 10 mg once daily

(daclatasvir 60 mg once daily)

↔ Daclatasvir

AUC: 1.12 (1.01, 1.26)

C_max: 1.14 (0.98, 1.32)

C_min: 1.23 (1.09, 1.38)

↔Escitalopram

AUC: 1.05 (1.02, 1.08)

C_max: 1.00 (0.92, 1.08)

C_min: 1.10 (1.04, 1.16)

No dose adjustment of Daklinza or escitalopram is required.

ANTIFUNGALS

Ketoconazole 400 mg once daily

(daclatasvir 10 mg single dose)

↑ Daclatasvir

AUC: 3.00 (2.62, 3.44)

C_max: 1.57 (1.31, 1.88)

CYP3A4 inhibition by ketoconazole

The dose of Daklinza should be reduced to 30 mg once daily when coadministered 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 Daklinza or fluconazole is required.

ANTIMYCOBACTERIALS

Rifampicin 600 mg once daily

(daclatasvir 60 mg single dose)

↓ Daclatasvir

AUC: 0.21 (0.19, 0.23)

C_max: 0.44 (0.40, 0.48)

CYP3A4 induction by rifampicin

Coadministration of Daklinza with rifampicin, rifabutin, rifapentine or other strong inducers of CYP3A4 is contraindicated (see section 4.3).

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)

C_max: 1.65 (1.52, 1.80)

C_min: 1.18 (1.09, 1.28)

P-gp inhibition by daclatasvir

Digoxin should be used with caution when coadministered with Daklinza. 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.

Calcium channel blockers

Diltiazem

Nifedipine

Amlodipine

Interaction not studied.

Expected due to CYP3A4 inhibition by the calcium channel blocker:

↑ Daclatasvir

Administration of Daklinza with any of these calcium channel blockers may result in increased concentrations of daclatasvir. Caution is advised.

Verapamil

Interaction not studied.

Expected due to CYP3A4 and P-gp inhibition by verapamil:

↑ Daclatasvir

Administration of Daklinza with verapamil may result in increased concentrations of daclatasvir. Caution is advised.

CORTICOSTEROIDS

Systemic dexamethasone

Interaction not studied.

Expected due to CYP3A4 induction by dexamethasone:

↓ Daclatasvir

Coadministration of Daklinza with systemic dexamethasone or other strong inducers of CYP3A4 is contraindicated (see section 4.3).

HERBAL SUPPLEMENTS

St. John's wort (Hypericum perforatum)

Interaction not studied.

Expected due to CYP3A4 induction by St. John's wort:

↓ Daclatasvir

Coadministration of Daklinza with St. John's wort or other strong inducers of CYP3A4 is contraindicated (see section 4.3).

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)

C_max: 1.11 (1.02, 1.20)

↔ Norelgestromin

AUC: 1.12 (1.06, 1.17)

C_max: 1.06 (0.99, 1.14)

↔ Norgestrel

AUC: 1.12 (1.02, 1.23)

C_max: 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 Daklinza. 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)

C_max: 1.04 (0.94, 1.15)

C_min: 1.56 (1.41, 1.71)

↔ Cyclosporine

AUC: 1.03 (0.97, 1.09)

C_max: 0.96 (0.91, 1.02)

No dose adjustment of either medicinal product is required when Daklinza is coadministered 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)

C_max: 1.07 (1.02, 1.12)

C_min: 1.10 (1.03, 1.19)

↔ Tacrolimus

AUC: 1.00 (0.88, 1.13)

C_max: 1.05 (0.90, 1.23)

Sirolimus

Mycophenolate mofetil

Interaction not studied.