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Daclatasvir

Medically reviewed by Drugs.com. Last updated on May 5, 2020.

Pronunciation

(dak LAT as vir)

Index Terms

  • Daclatasvir Dihydrochloride

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Tablet, Oral:

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

Brand Names: U.S.

  • Daklinza [DSC]

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 Uses

Chronic 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 (without cirrhosis or with compensated cirrhosis). 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 2018).

Peginterferon/ribavirin-experienced patients without cirrhosis (alternative agent): 60 mg once daily with concomitant sofosbuvir for 12 weeks (AASLD/IDSA 2018).

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 ribavirin-ineligible, 60 mg once daily with concomitant sofosbuvir for 24 weeks (AASLD/IDSA 2018).

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 (AASLD/IDSA 2018).

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 log10 IU/mL increase in HCV RNA from nadir).

Chronic hepatitis C (genotype 2) (off-label use): Oral:

Treatment-naive without cirrhosis (alternative agent): 60 mg once daily with concomitant sofosbuvir for 12 weeks (AASLD/IDSA 2018).

Treatment-naive with compensated (Child-Pugh class A) cirrhosis (alternative agent): 60 mg once daily with concomitant sofosbuvir for 16 to 24 weeks (AASLD/IDSA 2018).

Peginterferon/ribavirin-experienced without cirrhosis (alternative agent): 60 mg once daily with concomitant sofosbuvir for 12 weeks (AASLD/IDSA 2018).

Peginterferon/ribavirin-experienced with compensated (Child-Pugh class A) cirrhosis (alternative agent): 60 mg once daily with concomitant sofosbuvir for 16 to 24 weeks (AASLD/IDSA 2018).

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 (AASLD/IDSA 2018).

Liver transplant recipients (treatment-naive and -experienced) without cirrhosis: 60 mg once daily with concomitant sofosbuvir and ribavirin for 12 weeks (AASLD/IDSA 2018).

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 (AASLD/IDSA 2018).

Kidney transplant recipients (treatment-naive and -experienced) with or without compensated (Child-Pugh class A) cirrhosis (alternative agent): 60 mg once daily with sofosbuvir and ribavirin for 12 weeks (AASLD/IDSA 2018).

Chronic hepatitis C (genotype 3):

Treatment-naive without cirrhosis (alternative agent): 60 mg once daily with concomitant sofosbuvir for 12 weeks (AASLD/IDSA 2018).

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 2018).

Peginterferon/ribavirin-experienced patients without cirrhosis (alternative agent): 60 mg once daily with concomitant sofosbuvir for 12 weeks (AASLD/IDSA 2018).

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 2018).

Liver transplant recipients (treatment-naive and -experienced) without cirrhosis: 60 mg once daily with concomitant sofosbuvir and ribavirin for 12 weeks (AASLD/IDSA 2018).

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 (AASLD/IDSA 2018).

Kidney transplant recipients (treatment-naive and -experienced) with or without compensated (Child-Pugh class A) cirrhosis (alternative agent): 60 mg once daily with sofosbuvir and ribavirin for 12 weeks (AASLD/IDSA 2018).

Chronic hepatitis C (genotype 4) (off-label use): 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 (AASLD/IDSA 2018).

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 (AASLD/IDSA 2018).

Chronic hepatitis C (genotype 5 or 6) (off-label use): 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 (AASLD/IDSA 2018).

Kidney transplant recipients (treatment-naive and -experienced) with or without compensated (Child-Pugh class A) cirrhosis (alternative agent): 60 mg once daily with sofosbuvir and ribavirin for 12 weeks (AASLD/IDSA 2018).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Geriatric

Refer to adult dosing.

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

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

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: If combined, administer the P-gp inhibitor simultaneously with, or after, the dose of afatinib. Monitor closely for signs and symptoms of afatinib toxicity and if the combination is not tolerated, reduce the afatinib dose by 10 mg. Consider therapy modification

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

Alpelisib: BCRP/ABCG2 Inhibitors may increase the serum concentration of Alpelisib. Management: Avoid coadministration of BCRP/ABCG2 inhibitors and alpelisib due to the potential for increased alpelisib concentrations and toxicities. If coadministration cannot be avoided, closely monitor for increased alpelisib adverse reactions. Consider therapy modification

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

Antidiabetic Agents: Direct Acting Antiviral Agents (HCV) may enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

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

Asunaprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Asunaprevir. Avoid combination

Betrixaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Betrixaban. Management: Decrease adult betrixaban dose to an initial single dose of 80 mg followed by 40 mg once daily if combined with a P-gp inhibitor. Avoid concomitant use of betrixaban and P-gp inhibitors in patients with severe renal impairment (CrCL less than 30 mL/min). Consider therapy modification

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

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

Cladribine: BCRP/ABCG2 Inhibitors may increase the serum concentration of Cladribine. Management: Avoid concomitant use of BCRP inhibitors during the 4 to 5 day oral cladribine treatment cycles whenever possible. If combined, consider dose reduction of the BCRP inhibitor and separation in the timing of administration. Consider therapy modification

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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-gp inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. See interaction 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. Monitor therapy

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

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

Digoxin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Digoxin. Management: Measure digoxin serum concentrations before initiating treatment with these P-glycoprotein (P-gp) inhibitors. Reduce digoxin concentrations by either reducing the digoxin dose by 15% to 30% or by modifying the dosing frequency. Consider therapy modification

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

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

Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: Exceptions to this monograph are discussed in separate Lexi-Interact monographs. Monitor therapy

Elagolix: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Elagolix. Avoid combination

Elagolix, Estradiol, and Norethindrone: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Elagolix, Estradiol, and Norethindrone. Specifically, concentrations of elagolix may be increased. Avoid combination

Eluxadoline: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Eluxadoline. Management: Decrease the eluxadoline dose to 75 mg twice daily if combined with OATP1B1/1B3 inhibitors and monitor patients for increased eluxadoline effects/toxicities. Consider therapy modification

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

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

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

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

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

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

Grazoprevir: OATP1B1/1B3 (SLCO1B1/1B3) 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

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

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

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

Lefamulin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin tablets with P-glycoprotein/ABCB1 inhibitors. If concomitant use is required, monitor for lefamulin adverse effects. Consider therapy modification

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

Morphine (Systemic): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Morphine (Systemic). Monitor therapy

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

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 if used with nevirapine. Consider therapy modification

Ozanimod: BCRP/ABCG2 Inhibitors may increase serum concentrations of the active metabolite(s) of Ozanimod. Avoid combination

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

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

Revefenacin: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentrations of the active metabolite(s) of Revefenacin. Avoid combination

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

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

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

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

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

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

Sirolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Sirolimus. Management: Avoid concurrent use of sirolimus with P-glycoprotein (P-gp) inhibitors when possible and alternative agents with lesser interaction potential with sirolimus should be considered. Monitor for increased sirolimus concentrations/toxicity if combined. Consider therapy modification

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

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

Talazoparib: BCRP/ABCG2 Inhibitors may increase the serum concentration of Talazoparib. Monitor therapy

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

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

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

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

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

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

Ubrogepant: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 50 mg and second dose (at least 2 hours later if needed) of 50 mg when used with a P-gp inhibitor. Consider therapy modification

Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring concomitant treatment with P-glycoprotein (P-gp) inhibitors. Resume the previous venetoclax dose 2 to 3 days after discontinuation of a P-gp inhibitor. Consider therapy modification

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

Vitamin K Antagonists (eg, warfarin): Direct Acting Antiviral Agents (HCV) may diminish the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Voxilaprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Voxilaprevir. Avoid combination

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.

• Diabetes: Rapid reduction in hepatitis C viral load during direct-acting antiviral (DAA) therapy for hepatitis C may lead to improvement in glucose metabolism in patients with diabetes, potentially resulting in symptomatic hypoglycemia if antidiabetic agents are continued at the same dose. Monitor for changes in glucose tolerance and inform patients of the risk of hypoglycemia during DAA therapy, particularly within the first 3 months. Modification of antidiabetic therapy may be necessary (Ciancio 2018; Dawood 2017; Hum 2017).

• 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.

Other warnings/precautions:

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

Monitoring Parameters

Baseline (within 12 weeks prior to treatment initiation) CBC, INR, hepatic function (albumin, total and direct bilirubin, ALT, AST, alkaline phosphatase), calculated GFR; baseline (obtain any time prior to treatment initiation) HCV genotype and subtype, quantitative HCV viral load. During treatment, monitor 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) (AASLD/IDSA 2018). 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.

In patients with diabetes, monitor blood glucose and for signs/symptoms of hypoglycemia (Ciancio 2018; Dawood 2017; Hum 2017).

Reproductive Considerations

If used in combination with ribavirin, all warnings related to the use of ribavirin and contraception should be followed.

HCV-infected females of childbearing potential should consider postponing pregnancy until therapy is complete to reduce the risk of HCV transmission (AASLD/IDSA 2018).

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 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). 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

What is this drug used for?

• It is used to treat long-term hepatitis C infections.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Headache

• Nausea

• Diarrhea

• Trouble sleeping

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin

• Low blood sugar like dizziness, headache, fatigue, feeling weak, shaking, fast heartbeat, confusion, increased hunger, or sweating

• Severe loss of strength and energy

• Shortness of breath

• Slow heartbeat

• Chest pain

• Confusion

• Trouble with memory

• Fatigue

• Weakness

• Dizziness

• Passing out

• Pale skin

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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