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药品使用说明书

【通用名称】：达卡他韦

【批准文号】：进口药品注册证号：-

【英文名称】：DAKLINZA

【商品名称】：DAKLINZA

【剂型】：片剂

【形状】：

    60 mg daclatasvir(等于66 mg daclatasvir二盐酸盐)，浅绿色，双凸

【功能主治】：

    DAKLINZA是适用为与索非布韦使用为有慢性丙型肝炎病毒(HCV)基因型3感染患者的治疗。使用的限制：在HCV基因型3-感染有硬化患者接受DAKLINZA与索非布韦联用共12周，持续病毒学反应(SVR)率减低。

【规格/中西药品】：60mg，30mg

【用法用量】：

   1.推荐剂量：DAKLINZA的推荐剂量是60 mg，口服，每天1次与索非布韦联用共12周。DAKLINZA可有或无食物服用。尚未确定对有硬化患者DAKLINZA达卡他韦和索非布韦的最佳时间[见临床研究(14)]。对索非布韦特异性推荐剂量，参考相关处方资料。

2.由于药物相互作用剂量修饰对与DAKLINZA共同给药前其他药物参考药物相互作用和禁忌证节。细胞色素P450酶3A(CYP3A的强抑制剂：减低DAKLINZA剂量至30 mg每天1次当与强CYP3A抑制剂共同给药时用30 mg片[见药物相互作用(7)]。中度CYP3A诱导剂：当共同给药与中度CYP3A诱导剂增加DAKLINZA的剂量至90 mg每天1次利用适当的片组合(三片30 mg片或一片60 mg和一片30 mg片)[见药物相互作用(7)]。强CYP3A诱导剂：DAKLINZA是禁忌与强CYP3A诱导剂联用[见禁忌证(4)]。建议对不良反应不减低DAKLINZA剂量。

3.治疗的终止一例接受DAKLINZA与索非布韦患者如永久地终止索非布韦，然后DAKLINZA也应被终止。

【不良反应】：

   在说明书其它处描述以下严重不良反应：当与索非布韦和胺碘酮共同给药严重症状性心动过缓。

1.临床试验经验因为临床试验是在广泛不同情况下进行的，临床试验观察到不良反应率不能与另一种药临床试验发生率直接比较而且可能不反映实践中观察到的发生率。在临床试验约1900例有慢性HCV感染受试者曾被用推荐剂量DAKLINZA与其它抗-HCV药物联用治疗。在ALLY-3试验中，152例未治疗过和经历治疗有HCV基因型3感染受试者被用DAKLINZA 60 mg每天1次与索非布韦联用治疗共12周。最常见不良反应(频数10%或更大)是头痛和疲乏。所有不良反应严重程度是轻度至中度。一例受试者经受严重不良事件被认为与DAKLINZA无关，和没有受试者为不良事件终止治疗。表2中展示不良反应被认为至少可能与治疗有关和发生在频数5%或更大。达卡他韦达卡他韦Daklinza(daclatasvir)片使用说明书2015年第一版实验室异常脂肪酶升高：在ALLY-3中2%受试者观察到暂时，无症状脂肪酶升高大于正常上限(ULN)3倍。

2.上市后经验心脏病：在开始服用胺碘酮与索非布韦联用与另一个HCV直接作用抗病毒药，包括DAKLINZA治疗患者曾报道严重症状性心动过缓。

【禁忌】：

   DAKLINZA是禁忌与强烈地诱导CYP3A药物联用和，从而，可能导致DAKLINZA的较低暴露和丧失疗效。禁忌药物包括，但不限于在表1中列举[见药物相互作用(7)和临床药理学(12.3)]。Daklinza(daclatasvir)片使用说明书2015年第一版。

【注意事项】：

   1.由于药物相互作用不良反应或丧失病毒学反应的风险DAKLINZA和其他药物的同时使用可能导致已知或潜在地显著药物相互作用，其中有些可能导致以下[见禁忌证(4)和药物相互作用(7)]：丧失DAKLINZA的治疗效应和发生耐药性可能，同时药物或DAKLINZA达卡他韦的剂量调整，来自同时药物或DAKLINZA更大暴露临床上显著不良反应可能性。见表1由于丧失疗效和发生耐药性可能禁忌与DAKLINZA药物[见禁忌证(4)]。见表3对预防或处理其他其他可能性步骤和已知显著药物相互作用[见药物相互作用(7)]。DAKLINZA治疗前和期间考虑对药物相互作用潜能，DAKLINZA治疗期间审查同时用药，和监视伴随同时药物不良反应。

2.当共同给药与索非布韦和胺碘酮严重症状性心动过缓当胺碘酮是与索非布韦联用与另外一个HCV直接作用抗病毒药，包括DAKLINZA共同给药时曾报道症状性心动过缓的上市后病例和需要起搏器干预病例。一例在接受一个含索非布韦方案患者(ledipasvir/索非布韦)报道致命性心脏骤停。心动过缓一般地发生在小时至天内，但曾观察到直至开始HCV治疗后2周。还服用β受体阻滞剂患者或患有心脏合并症和/或晚期肝病患者可能是处在与胺碘酮的共同给药对症状性心动过缓风险增加。HCV治疗的终止后心动过缓一般解决。不知道这个心动过缓效应的机制。建议胺碘酮不与DAKLINZA与索非布韦联用的共同给药。对服用胺碘酮无另外治疗选择患者和将被与DAKLINZA和索非布韦共同给药：与患者商讨关于严重症状性心动过缓的风险。建议共同给药的头48小时监视患者情况，其后应在每天基础上门诊患者或自我-监视心率直至至少治疗头2周。正在服用索非布韦与DAKLINZA达卡他韦联用患者由于无其他治疗选择需要开始胺碘酮治疗应进行相似心脏监视如上概述。由于胺碘酮的长消除半衰期，开始索非布韦与DAKLINZA联用之前患者终止胺碘酮还应进行上述相似的心脏监视。发生心动过缓体征或症状患者应寻求立即医学评价。症状可能包括接近-昏厥或昏厥，眩晕或头重脚轻，乏力，软弱，过度劳累，气短，胸痛，混乱，或记忆问题。

【药物相互作用】：

   1.对其他药物影响DAKLINZA潜能Daclatasvir是CYP3A的底物。因此，中度或强诱导剂of CYP3A may decrease the plasma levels和therapeutic effect of daclatasvir[见剂量和给药方法(2.2)，禁忌证(4)，和表3]。CYP3A的强抑制剂(如，克拉霉素[clarithromycin]，伊曲康唑[itraconazole]，酮康唑[ketoconazole]，利托那韦[ritonavir])可能增加daclatasvir的血浆水平。

2.对DAKLINZA影响其他药物潜能Daclatasvir是一种P-糖蛋白转运蛋白(P-gp)，有机阴离子转运多肽(OATP)1B1和1B3，和乳癌耐药性蛋白(BCRP)的抑制剂。DAKLINZA的给药可能增加对P-gp，OATP 1B1或1B3，或BCRP的底物医药产品的全身暴露，可能增加或延长它们的治疗作用或不良反应。

3.已确定和潜在地显著药物相互作用对索非布韦药物相互作用资料参考处方资料。应该遵循最保守的建议。表3提供DAKLINZA达卡他韦和其他药物间对已确定或潜在地显著药物相互作用的临床建议[见禁忌证(4)]。在浓度临床上相关增加以“↑”指示和临床上相关减低以“↓”指示，Daklinza(daclatasvir)片使用说明书2015年第一版

【质量检验报告摘录】：

 

Daclatasvir

Medically reviewed on Sep 10, 2018

 

 

Pronunciation

See also: Mavyret

(dak LAT as vir)

Index Terms

· Daclatasvir Dihydrochloride

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Daklinza: 30 mg, 60 mg, 90 mg [contains fd&c blue #2 aluminum lake]

Brand Names: U.S.

· Daklinza

Pharmacologic Category

· Antihepaciviral, NS5A Inhibitor

· NS5A Inhibitor

Pharmacology

Daclatasvir binds to the N-terminus within Domain 1 of HCV nonstructural protein 5A (NS5A) and inhibits viral RNA replication and virion assembly.

Distribution

Vdss: 47 L

Metabolism

Primarily via CYP3A4

Excretion

Feces (88%, 53% unchanged); urine (6.6%, primarily unchanged)

Time to Peak

Plasma: ≤2 hours

Half-Life Elimination

~12 to 15 hours

Protein Binding

~99%

Use: Labeled Indications

Chronic hepatitis C: Treatment of chronic hepatitis C virus (HCV) genotype 1 or genotype 3 infection in combination with sofosbuvir, with or without ribavirin

Limitations of use: Sustained virologic response rates are reduced in HCV genotype 3-infected patients with cirrhosis receiving daclatasvir in combination with sofosbuvir for 12 weeks.

Off Label UsesChronic hepatitis C (genotype 2)

Based on the American Association for the Study of Liver Diseases/Infectious Diseases Society of America (AASLD/IDSA) Recommendations for Testing, Managing, and Treating Hepatitis C guidelines, daclatasvir, in combination with sofosbuvir, is an effective and recommended alternative for the treatment of HCV in patients with genotype 2, in either treatment-naive patients or peginterferon/ribavirin treatment-experienced patients (unable to tolerate preferred regimens). Daclatasvir, in combination with sofosbuvir (with or without ribavirin), is also an effective and recommended regimen in patients with decompensated cirrhosis and, in combination with sofosbuvir and ribavirin, in liver transplant patients with or without compensated or decompensated cirrhosis. In addition, daclatasvir, in combination with sofosbuvir and ribavirin, may be used in kidney transplant recipients with or without compensated cirrhosis. Hepatitis C treatment guidelines are constantly changing with the advent of new treatment therapies and information; consult current clinical practice guidelines for the most recent treatment recommendations.

Chronic hepatitis C (genotype 4)

Based on the AASLD/IDSA Recommendations for Testing, Managing, and Treating Hepatitis C guidelines, daclatasvir, in combination with sofosbuvir (with or without ribavirin), is effective and recommended for the treatment of HCV in patients with genotype 4 who have decompensated cirrhosis. Daclatasvir, in combination with sofosbuvir and ribavirin, is also an effective and recommended alterative regimen for liver transplant patients, with or without compensated cirrhosis. Hepatitis C treatment guidelines are constantly changing with the advent of new treatment therapies and information; consult current clinical practice guidelines for the most recent treatment recommendations.

Chronic hepatitis C (genotype 5 or 6)

Based on the AASLD/IDSA Recommendations for Testing, Managing, and Treating Hepatitis C guidelines, daclatasvir, in combination with sofosbuvir and ribavirin, is an effective and recommended alterative regimen for liver transplant patients, with or without compensated cirrhosis. In addition, daclatasvir, in combination with sofosbuvir and ribavirin, may be used in kidney transplant recipients with or without compensated cirrhosis. Hepatitis C treatment guidelines are constantly changing with the advent of new treatment therapies and information; consult current clinical practice guidelines for the most recent treatment recommendations.

Contraindications

Concurrent use of strong CYP3A inducers (eg, carbamazepine, phenytoin, rifampin, St John's wort). When used in combination with other agents (eg, ribavirin), the contraindications to those agents also apply (refer to respective labeling information).

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to daclatasvir or any component of the formulation; concurrent use with strong inducers of CYP3A4 and P-glycoprotein (P-gp)

Dosing: Adult

Note: Discontinue daclatasvir if other antihepaciviral therapy is permanently discontinued. Not indicated as monotherapy.

Chronic hepatitis C (genotype 1a or 1b): Oral:

Treatment-naive without cirrhosis (alternative agent): 60 mg once daily with concomitant sofosbuvir for 12 weeks (AASLD/IDSA 2017).

Peginterferon/ribavirin-experienced patients without cirrhosis (alternative agent): 60 mg once daily with concomitant sofosbuvir for 12 weeks (AASLD/IDSA 2017).

Decompensated (Child-Pugh class B or C) cirrhosis: 60 mg once daily with concomitant sofosbuvir and ribavirin for 12 weeks. For patients who are ribavirin-ineligible, 60 mg once daily with concomitant sofosbuvir for 24 weeks (AASLD/IDSA 2017).

Liver transplant recipients with or without compensated (Child-Pugh class A) cirrhosis (alternative agent): 60 mg once daily with concomitant sofosbuvir and ribavirin for 12 weeks (AASLD/IDSA 2017).

When used concomitantly with asunaprevir [Canadian product] for patients with genotype 1b (with or without compensated cirrhosis), the recommended duration of therapy is 24 weeks; when used concomitantly with asunaprevir, peginterferon alfa, and ribavirin in patients with genotypes 1 or 4 (with or without compensated cirrhosis), the recommended duration of therapy is 24 weeks. (Sunvepra Canadian labeling 2017). Note: Discontinuation of therapy is recommended for virologic breakthrough (>1 log10IU/mL increase in HCV RNA from nadir).

Chronic hepatitis C (genotype 2) (off-label use; AASLD/IDSA 2017): Oral:

Treatment-naive without cirrhosis (alternative agent): 60 mg once daily with concomitant sofosbuvir for 12 weeks

Treatment-naive with compensated (Child-Pugh class A) cirrhosis (alternative agent): 60 mg once daily with concomitant sofosbuvir for 16 to 24 weeks

Peginterferon/ribavirin-experienced without cirrhosis (alternative agent): 60 mg once daily with concomitant sofosbuvir for 12 weeks

Peginterferon/ribavirin-experienced with compensated (Child-Pugh class A) cirrhosis (alternative agent): 60 mg once daily with concomitant sofosbuvir for 16 to 24 weeks

Patients with decompensated (Child-Pugh class B or C) cirrhosis: 60 mg once daily with concomitant sofosbuvir and ribavirin for 12 weeks. For patients who are not eligible for ribavirin, 60 mg once daily with concomitant sofosbuvir for 24 weeks.

Liver transplant recipients (treatment-naive and -experienced) without cirrhosis: 60 mg once daily with concomitant sofosbuvir and ribavirin for 12 weeks

Liver transplant recipients (treatment-naive and -experienced) with compensated (Child-Pugh class A) or decompensated (Child-Pugh class B or C) cirrhosis: 60 mg once daily with concomitant sofosbuvir and ribavirin for 12 weeks

Kidney transplant recipients with or without compensated (Child-Pugh class A) cirrhosis (alternative agent): 60 mg once daily with sofosbuvir and ribavirin for 12 weeks

Chronic hepatitis C (genotype 3):

Treatment-naive without cirrhosis (alternative agent): 60 mg once daily with concomitant sofosbuvir for 12 weeks (AASLD/IDSA 2017)

Treatment-naive with compensated (Child-Pugh class A) cirrhosis (alternative agent): 60 mg once daily with concomitant sofosbuvir, with or without ribavirin, for 24 weeks (AASLD/IDSA 2017)

Peginterferon/ribavirin-experienced patients without cirrhosis (alternative agent): 60 mg once daily with concomitant sofosbuvir for 12 weeks (AASLD/IDSA 2017)

Patients with decompensated cirrhosis: 60 mg once daily with concomitant sofosbuvir and ribavirin for 12 weeks. For patients who are not eligible for ribavirin, 60 mg once daily with concomitant sofosbuvir for 24 weeks (AASLD/IDSA 2017)

Liver transplant recipients (treatment-naive and -experienced) without cirrhosis: 60 mg once daily with concomitant sofosbuvir and ribavirin for 12 weeks

Liver transplant recipients (treatment-naive and -experienced) with compensated (Child-Pugh class A) or decompensated (Child-Pugh class B or C) cirrhosis: 60 mg once daily with concomitant sofosbuvir and ribavirin for 12 weeks

Kidney transplant recipients with or without compensated (Child-Pugh class A) cirrhosis (alternative agent): 60 mg once daily with sofosbuvir and ribavirin for 12 weeks (AASLD/IDSA 2017)

Chronic hepatitis C (genotype 4) (off-label use; AASLD/IDSA 2017): Oral:

Patients with decompensated (Child-Pugh class B or C) cirrhosis: 60 mg once daily with concomitant sofosbuvir and ribavirin for 12 weeks. If ribavirin-ineligible, 60 mg once daily with concomitant sofosbuvir for 24 weeks.

Liver transplant recipients (treatment-naive and -experienced) with or without compensated (Child-Pugh class A) cirrhosis (alternative agent): 60 mg once daily with concomitant sofosbuvir and ribavirin for 12 weeks.

Chronic hepatitis C (genotype 5 or 6) (off-label use; AASLD/IDSA 2017): Oral:

Liver transplant recipients (treatment-naive and -experienced) with or without compensated (Child-Pugh class A) cirrhosis (alternative agent): 60 mg once daily with concomitant sofosbuvir and ribavirin for 12 weeks.

Kidney transplant recipients with or without compensated (Child-Pugh class A) cirrhosis (alternative agent): 60 mg once daily with sofosbuvir and ribavirin for 12 weeks (AASLD/IDSA 2017)

Dosage adjustment with concomitant medications:

Strong inhibitors of CYP3A and certain HIV antiviral agents: 30 mg once daily

Moderate CYP3A inducers or nevirapine: 90 mg once daily

Strong CYP3A inducers: Concomitant use is contraindicated.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

No dosage adjustment necessary.

Dosing: Hepatic Impairment

Child-Pugh class A, B, or C: No dosage adjustment necessary.

Administration

Oral: Administer with or without food.

Storage

Store at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F).

Drug Interactions

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Per US labeling: reduce afatinib by 10mg if not tolerated. Per Canadian labeling: avoid combination if possible; if used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. Consider therapy modification

Amiodarone: Daclatasvir may enhance the bradycardic effect of Amiodarone. Avoid combination

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).Monitor therapy

Asunaprevir: OATP1B1/SLCO1B1 Inhibitors may increase the serum concentration of Asunaprevir. Avoid combination

Betrixaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Betrixaban. Management: Decrease the betrixaban dose to an initial single dose of 80 mg followed by 40 mg once daily if combined with a P-glycoprotein inhibitor. Consider therapy modification

Bilastine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bilastine. Management: Consider alternatives when possible; bilastine should be avoided in patients with moderate to severe renal insufficiency who are receiving p-glycoprotein inhibitors. Consider therapy modification

Brentuximab Vedotin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy

Buprenorphine: Daclatasvir may increase the serum concentration of Buprenorphine. Monitor therapy

Celiprolol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Celiprolol. Monitor therapy

Ceritinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of ceritinib with a narrow therapeutic index CYP3A substrate (eg, alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus) should be avoided when possible. Monitor therapy

Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. See full monograph for details. Consider therapy modification

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Daclatasvir. Management: Increase the daclatasvir dose to 90 mg once daily if used with a moderate CYP3A4 inducer. Consider therapy modification

CYP3A4 Inducers (Strong): May decrease the serum concentration of Daclatasvir. Avoid combination

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Daclatasvir. Management: Decrease the daclatasvir dose to 30 mg once daily if combined with a strong CYP3A4 inhibitor. No dose adjustment is needed when daclatasvir is used with darunavir/cobicistat. Consider therapy modification

Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Management: Dabigatran dose reductions may be needed. Specific recommendations vary considerably according to US vs Canadian labeling, specific P-gp inhibitor, renal function, and indication for dabigatran treatment. Refer to full monograph or dabigatran labeling.Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).Monitor therapy

Dexamethasone (Systemic): May decrease the serum concentration of Daclatasvir. Management: US labeling recommends increasing the daclatasvir dose to 90 mg once daily if used with dexamethasone. Canadian labeling states that the combination of daclatasvir and dexamethasone is contraindicated.Consider therapy modification

Digoxin: Daclatasvir may increase the serum concentration of Digoxin. Management: See full interaction monograph for details. Consider therapy modification

DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. Consider therapy modification

Elagolix: OATP1B1/SLCO1B1 Inhibitors may increase the serum concentration of Elagolix. Avoid combination

Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus.Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).Monitor therapy

Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Grazoprevir: OATP1B1/SLCO1B1 Inhibitors may increase the serum concentration of Grazoprevir. Avoid combination

HMG-CoA Reductase Inhibitors (Statins): Daclatasvir may increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Naldemedine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naldemedine.Monitor therapy

Naloxegol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol. Monitor therapy

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).Monitor therapy

Nevirapine: May decrease the serum concentration of Daclatasvir. Management: Increase the daclatasvir dose to 90 mg once daily. Consider therapy modification

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).Monitor therapy

PAZOPanib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

PAZOPanib: BCRP/ABCG2 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

P-glycoprotein/ABCB1 Substrates: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Exceptions: Loperamide. Monitor therapy

Pitolisant: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant. Consider therapy modification

Prucalopride: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride.Monitor therapy

Ranolazine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ranolazine.Monitor therapy

Rifapentine: May decrease the serum concentration of Daclatasvir. Management: US labeling recommends increasing the daclatasvir dose to 90 mg once daily if used with rifapentine. Canadian labeling states that the combination of daclatasvir and rifapentine is contraindicated. Consider therapy modification

RifAXIMin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin. Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Avoid combination

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).Monitor therapy

St John's Wort: May decrease the serum concentration of Daclatasvir. Avoid combination

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tacrolimus (Systemic): Daclatasvir may decrease the serum concentration of Tacrolimus (Systemic). Specifically, this decrease in tacrolimus concentrations may occur with continued prolonged combination therapy. Daclatasvir may increase the serum concentration of Tacrolimus (Systemic). Specifically, this increase in tacrolimus concentrations may occur during the first week of combined therapy. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).Monitor therapy

Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Avoid combination

Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations.Consider therapy modification

VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination

Voxilaprevir: OATP1B1/SLCO1B1 Inhibitors may increase the serum concentration of Voxilaprevir. Avoid combination

Warfarin: Daclatasvir may enhance the anticoagulant effect of Warfarin. Monitor therapy

Adverse Reactions

All adverse drug reactions are from combination therapy trials with sofosbuvir.

>10%:

Central nervous system: Fatigue (14% to 15%), headache (12% to 14%)

Gastrointestinal: Nausea (8% to 15%)

Hematologic & Oncologic: Anemia (20%)

1% to 10%:

Central nervous system: Drowsiness (5%), insomnia (3%)

Dermatologic: Skin rash (8%)

Gastrointestinal: Diarrhea (3% to 5%), increased serum lipase (>3x ULN, transient)

<1%, postmarketing, and/or case reports: Reactivation of HBV (FDA Safety Alert Dec. 8, 2016)

ALERT: U.S. Boxed Warning

Hepatitis B virus reactivation:

Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with daclatasvir. HBV reactivation has been reported in hepatitis C virus (HCV)/HBV coinfected patients who were undergoing or had completed treatment with HCV direct-acting antivirals and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up. Initiate appropriate management for HBV infection as clinically indicated.

Warnings/Precautions

Concerns related to adverse effects:

• Bradycardia: When used in combination with sofosbuvir and amiodarone, symptomatic bradycardia (eg, near-fainting, dizziness, lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion, memory problems) has been reported; pacemaker intervention may be required. Bradycardia generally occurs within hours or days but has been observed up to 2 weeks after treatment initiation. Risk factors include concomitant beta blocker use, underlying cardiac morbidities, and/or advanced hepatic disease. Patients receiving amiodarone (with no alternate treatment options) and initiating daclatasvir and sofosbuvir treatment, and patients on daclatasvir and sofosbuvir treatment who are initiating amiodarone therapy should have inpatient cardiac monitoring for the first 48 hours of amiodarone coadministration and daily outpatient self-monitoring through at least the first 2 weeks of treatment. Patients discontinuing amiodarone just prior to starting daclatasvir and sofosbuvir treatment should also undergo similar cardiac monitoring procedures. Bradycardia usually resolves after HCV treatment discontinuation.

Disease-related concerns:

• Cardiovascular disease: Patients with underlying cardiac morbidities and also taking concomitant amiodarone are at increased risk for symptomatic bradycardia; use with caution and monitor for bradycardia.

• Hepatic disease: Patients with advanced hepatic disease and also taking concomitant amiodarone are at increased risk for symptomatic bradycardia; use with caution. Sustained virologic response rates are reduced in HCV genotype 3-infected patients with cirrhosis. Optimal duration of treatment for HCV genotype 3-infected patients with cirrhosis or HCV genotype 1 patients with Child-Pugh class C cirrhosis has not been established.

• Hepatitis B virus reactivation: [US Boxed Warning]: Hepatitis B virus (HBV) reactivation has been reported in hepatitis C virus (HCV)/HBV coinfected patients who were receiving or had completed treatment with HCV direct-acting antivirals and were not receiving HBV antiviral therapy; some cases have resulted in fulminant hepatitis, hepatic failure, and death. Test all patients for evidence of current or prior HBV infection prior to initiation of daclatasvir; monitor HCV/HBV co-infected patients for hepatitis flare or HBV reactivation during treatment and post-treatment follow-up. Initiate treatment for HBV infection as clinically indicated. HBV reactivation has been reported in HBsAg positive patients and in patients with serologic evidence of resolved HBV infection (ie, HBsAg negative and anti-HBc positive) and is characterized by an abrupt increase in HBV replication manifested as a rapid increase in serum HBV DNA level; reappearance of HBsAg may occur in patients with resolved HBV infection. Risk of HBV reactivation may be increased in patients receiving certain immunosuppressants or chemotherapeutic agents.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Appropriate use: Do not use as monotherapy; use only in combination with other antihepatitis C virus drugs.

Monitoring Parameters

Manufacturer’s labeling: Hepatic function at baseline and periodically when clinically indicated during treatment. Prior to treatment initiation in genotype 1a patients with cirrhosis, consider screening for the presence of NS5A polymorphisms at amino acid positions M28, Q30, L31, and Y93 in patients with cirrhosis. Hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) prior to initiation; in patients with serologic evidence of hepatitis B virus (HBV) infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during treatment and during post-treatment follow-up. If used in combination with amiodarone or in patients who discontinued amiodarone just prior to initiating sofosbuvir in combination with daclatasvir, inpatient cardiac monitoring for the first 48 hours of coadministration, then outpatient self-monitoring of heart rate daily through at least the first 2 weeks of treatment.

Alternate recommendations (AASLD/IDSA 2017):

Baseline (within 12 weeks prior to starting antiviral therapy): CBC, INR, hepatic function panel (albumin, total and direct bilirubin, ALT, AST, and alkaline phosphatase), calculated GFR

Baseline (at any time prior to starting antiviral therapy): HCV genotype and subtype, quantitative HCV viral load

During therapy: CBC, serum creatinine, calculated GFR, hepatic function panel (after 4 weeks of therapy and as clinically indicated); quantitative HCV viral load testing (after 4 weeks of therapy and at 12 weeks after completion of therapy). If quantitative HCV viral load is detectable at treatment week 4, repeat testing is recommended after 2 additional weeks of treatment (treatment week 6).

Pregnancy Considerations

Daclatasvir must not be used as monotherapy. If used in combination with ribavirin, use is contraindicated in pregnant females and males whose female partners are pregnant. All warnings related to the use of ribavirin and pregnancy and/or contraception should be followed.

Treatment of hepatitis C is not currently recommended to treat maternal infection or to decrease the risk of mother-to-child transmission during pregnancy (Tran 2016). HCV-infected females of childbearing potential should consider postponing pregnancy until therapy is complete to reduce the risk of HCV transmission (AASLD/IDSA 2017). When HCV infection is detected during pregnancy, treatment should be deferred until after delivery. Direct-acting antiviral medications should not be used in pregnant females outside of clinical trials until safety and efficacy information is available (SMFM [Hughes 2017]).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, loss of strength and energy, or nausea. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

 

 

来源

https://www.drugs.com/ppa/daclatasvir.html