Skip to Content

Daclatasvir Dihydrochloride

Class: HCV Replication Complex Inhibitors
Chemical Name: N,N′ - [[1,1′ - Biphenyl] - 4,4′ - diylbis[1H - imidazole - 5,2 - diyl - (2S) - 2,1 - pyrrolidinediyl[(1S) - 1 - (1 - methylethyl) - 2 - oxo - 2,1 - ethanediyl]]]bis - carbamic acid, C,C′-dimethyl ester, hydrochloride (1:2)
Molecular Formula: C40H50N8O6•2HCl
CAS Number: CAS-1009119-65-6
Brands: Daklinza

Warning(s)

Special Alerts:

[Posted 10/04/2016]

AUDIENCE: Infectious Disease, Gastroenterology, Patient

ISSUE: The FDA is warning about the risk of hepatitis B virus (HBV) becoming an active infection again in any patient who has a current or previous infection with HBV and is treated with certain direct-acting antiviral (DAA) medicines for hepatitis C virus. In a few cases, HBV reactivation in patients treated with DAA medicines resulted in serious liver problems or death. HBV reactivation usually occurred within 4-8 weeks.

As a result, FDA is requiring a Boxed Warning, our most prominent warning, about the risk of HBV reactivation to be added to the drug labels of these DAAs directing health care professionals to screen and monitor for HBV in all patients receiving DAA treatment. This warning will also be included in the patient information leaflet or Medication Guides for these medicines.

BACKGROUND: Direct-acting antiviral medicines are used to treat chronic hepatitis C virus (HCV) infection, an infection that can last a lifetime. These medicines reduce the amount of HCV in the body by preventing HCV from multiplying, and in most cases, they cure HCV. Without treatment, HCV can lead to serious liver problems including cirrhosis, liver cancer, and death (see List of Direct-Acting Antivirals in the FDA Drug Safety Communication, available at: ).

FDA identified 24 cases of HBV reactivation reported to FDA and from the published literature in HCV/HBV co-infected patients treated with DAAs during the 31 months from November 22, 2013 to July 18, 2016. This number includes only cases submitted to FDA, so there are likely additional cases about which FDA is unaware. Of the cases reported, two patients died and one required a liver transplant. HBV reactivation was not reported as an adverse event in the clinical trials submitted for the DAA approvals because patients with HBV co-infection were excluded from the trials. See the data summary section in the Drug Safety Communication, available at: , for more detailed information.

RECOMMENDATION: Health care professionals should screen all patients for evidence of current or prior HBV infection before starting treatment with DAAs, and monitor patients using blood tests for HBV flare-ups or reactivation during treatment and post-treatment follow-up.

Patients should tell your health care professional if you have a history of hepatitis B infection or other liver problems before being treated for hepatitis C. Do not stop taking your DAA medicine without first talking to your health care professional. Stopping treatment early could result in your virus becoming less responsive to certain hepatitis C medicines. Read the patient information leaflet or Medication Guide that comes with each new prescription because the information may have changed. Contact your health care professional immediately if you develop fatigue, weakness, loss of appetite, nausea and vomiting, yellow eyes or skin, or light-colored stools, as these may be signs of serious liver problems.

For more information visit the FDA website at: and .

Introduction

Antiviral;1 11 HCV NS5A replication complex inhibitor (NS5A inhibitor).1 11

Uses for Daclatasvir Dihydrochloride

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Chronic HCV Infection

Treatment of chronic HCV genotype 1 or genotype 3 infection in treatment-naive (previously untreated) or previously treated adults, including those with cirrhosis (compensated or decompensated), liver transplant recipients, and those with HIV coinfection.1 119

Treatment of chronic HCV genotype 2 infection;10 119 only limited data available.10 119

Must be used in conjunction with other antivirals;1 119 do not use alone.1 119

Usually used in a multiple-drug regimen that includes sofosbuvir (with or without ribavirin).1 119

Efficacy of daclatasvir and sofosbuvir (with or without ribavirin) for treatment of HCV genotype 1a infection is reduced in cirrhotic patients with NS5A polymorphisms M28, Q30, L31, or Y93 at baseline.1 8 Consider screening for NS5A polymorphisms prior to initiation of treatment in cirrhotic patients with HCV genotype 1a infection.1 (See General under Dosage and Administration.)

Efficacy of daclatasvir and sofosbuvir (with or without ribavirin) is reduced in cirrhotic patients with HCV genotype 3 infection compared with those without cirrhosis.1 2

Treatment of chronic HCV infection is complex and rapidly evolving; consult a specialist to obtain the most up-to-date information.119 Information from the American Association for the Study of Liver Diseases (AASLD), Infectious Diseases Society of America (IDSA), and International Antiviral Society–USA (IAS–USA) regarding diagnosis and management of HCV infection, including recommendations for initial treatment, is available at .119

Daclatasvir Dihydrochloride Dosage and Administration

General

  • Must be used in conjunction with other antivirals;1 do not use alone.1

  • Specific multiple-drug regimen and duration of treatment depend on HCV genotype and patient population.1 119

  • If sofosbuvir is permanently discontinued in a patient receiving daclatasvir, also discontinue daclatasvir.1

  • HCV genotype 1a infection in patients with cirrhosis: Consider screening for presence of NS5A polymorphisms at M28, Q30, L31, and Y93 prior to initiation of multiple-drug regimen of daclatasvir and sofosbuvir (with or without ribavirin).1

Administration

Oral Administration

Administer orally once daily without regard to food.1

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Available as daclatasvir dihydrochloride;1 dosage expressed in terms of daclatasvir.1

Daclatasvir dosage may need to be reduced if used concomitantly with certain CYP3A inhibitors or daclatasvir dosage may need to be increased if used with certain CYP3A inducers (see Specific Drugs under Interactions).1 Do not reduce daclatasvir dosage because of adverse effects.1

Adults

Treatment of Chronic HCV Infection
HCV Genotype 1 Infection
Oral

Noncirrhotic or with compensated cirrhosis (Child-Pugh class A): 60 mg once daily in conjunction with sofosbuvir for a duration of 12 weeks.1

Decompensated cirrhosis (Child-Pugh class B or C): 60 mg once daily in conjunction with sofosbuvir and ribavirin.1 Usual treatment duration is 12 weeks, but optimal duration not established in those with Child-Pugh class C cirrhosis.1 Some experts recommend duration of 24 weeks for treatment of genotype 1a or 1b infection in cirrhotic patients.119

HCV Genotype 3 Infection
Oral

Noncirrhotic: 60 mg once daily in conjunction with sofosbuvir for a duration of 12 weeks.1

Compensated cirrhosis (Child-Pugh class A) or decompensated cirrhosis (Child-Pugh class B or C): 60 mg once daily in conjunction with sofosbuvir and ribavirin.1 Usual treatment duration is 12 weeks, but optimal duration not established in those with Child-Pugh class C impairment.1 Some experts recommend duration of 24 weeks for treatment of genotype 3 infection in cirrhotic patients.119

HCV Genotype 2 Infection
Oral

Some experts recommend 60 mg once daily in conjunction with sofosbuvir for a duration of 12 weeks;119 some patients (e.g., those with cirrhosis) may benefit from treatment duration of 24 weeks.119

Liver Transplant Recipients
Oral

Chronic HCV genotype 1 or genotype 3 infection: 60 mg once daily in conjunction with sofosbuvir and ribavirin.1 Usual treatment duration is 12 weeks.1

HCV-infected Coinfected with HIV
Oral

Generally, use the same daclatasvir dosage recommended for treatment of HCV infection in patients without HIV infection;1 119 consider that daclatasvir dosage may need to be increased or decreased when used concomitantly with certain HIV antiretroviral agents.1 119 (See Specific Drugs under Interactions.)

Multiple-drug regimen and duration of treatment are the same as those for patients without HIV infection.1

Special Populations

Hepatic Impairment

Mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C): Dosage adjustments not needed.1

Renal Impairment

Mild, moderate, or severe renal impairment: Dosage adjustments not needed.1

Geriatric Patients

Dosage adjustments not needed.1

Cautions for Daclatasvir Dihydrochloride

Contraindications

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • Concomitant use with certain drugs that are potent inducers of CYP3A (e.g., carbamazepine, phenytoin, rifampin, St. John's wort [Hypericum perforatum]).1 (See Interactions.)

  • Because daclatasvir must be used in conjunction with other antivirals, consider contraindications for all antivirals included in the multiple-drug regimen.1 (See Precautions Related to Multiple-drug Treatment Regimens under Cautions.)

  • Daclatasvir used in conjunction with sofosbuvir and ribavirin is contraindicated in women who are or may become pregnant and in male partners of pregnant women.1 (See Precautions Related to Multiple-drug Treatment Regimens under Cautions.)

Warnings/Precautions

Cardiovascular Effects

Postmarketing reports of symptomatic bradycardia, including cases requiring pacemaker intervention, in patients receiving amiodarone concomitantly with HCV treatment regimen containing sofosbuvir in conjunction with another HCV direct-acting antiviral (DAA), including daclatasvir.1 23 Fatal cardiac arrest reported in one patient.1

In most reported cases, bradycardia occurred within hours to days after HCV treatment initiated in patients receiving amiodarone (also has been observed up to 2 weeks after initiation of HCV treatment) and resolved after HCV treatment discontinued.1 Mechanism for this adverse cardiovascular effect unknown.1

Patients who may be at increased risk for symptomatic bradycardia if amiodarone used concomitantly with an HCV treatment regimen containing sofosbuvir with another DAA include those also receiving a β-adrenergic blocking agent, those with underlying cardiac comorbidities, and/or those with advanced liver disease.1

Concomitant use of amiodarone with an HCV treatment regimen containing sofosbuvir with daclatasvir is not recommended.1

If there are no alternative HCV treatment options and regimen of sofosbuvir and daclatasvir must be used in a patient receiving amiodarone, advise patient about the risk of serious bradycardia before initiating HCV treatment.1 Perform cardiac monitoring in an inpatient setting during first 48 hours of concomitant use of these drugs;1 heart rate monitoring should then be performed daily (outpatient or self-monitoring) through at least the first 2 weeks of concomitant use.1 Similar cardiac monitoring recommended in patients who discontinued amiodarone just prior to initiation of a regimen containing sofosbuvir with daclatasvir or if there are no other treatment options and amiodarone must be initiated in a patient already receiving sofosbuvir and daclatasvir.1

Advise patients receiving amiodarone concomitantly with a regimen containing sofosbuvir and daclatasvir to immediately contact a clinician if signs or symptoms of bradycardia (e.g., near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion, memory problems) develop.1

Interactions

Concomitant use of daclatasvir and certain drugs may result in clinically important drug interactions.1 These drug interactions may result in loss of therapeutic effect and possible development of resistance to daclatasvir, require dosage adjustments of the concomitant drugs or daclatasvir, and lead to adverse reactions from increased exposures of concomitant drugs or daclatasvir.1

Consider potential drug interactions prior to and during therapy.1 Review drugs used concomitantly with daclatasvir during course of treatment;1 monitor patient for adverse reactions associated with these drugs.1 (See Interactions.)

Precautions Related to Multiple-drug Treatment Regimens

Daclatasvir must be used in conjunction with other antivirals.1 Consider cautions, precautions, contraindications, and drug interactions associated with each drug in the multiple-drug regimen.1 Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for each drug.1

When used in conjunction with sofosbuvir and ribavirin,1 consider that ribavirin may cause fetal toxicity and/or death.349 377 Extreme care must be taken to avoid pregnancy in female patients and female partners of male patients receiving a ribavirin-containing regimen.349 377 Obtain a negative pregnancy test for female patients of childbearing potential immediately prior to initiating ribavirin;349 377 perform pregnancy tests monthly during and for 6 months after ribavirin treatment is completed.349 377 Women of childbearing potential (and their male partners) and male patients (and their female partners) must use at least 2 forms of effective contraception during and for 6 months after ribavirin treatment is completed.349 377

Specific Populations

Pregnancy

Adequate data not available regarding use of daclatasvir in pregnant women.1

Consider benefits and risks when prescribing daclatasvir in pregnant women.1

When used in conjunction with sofosbuvir and ribavirin, consider that ribavirin is contraindicated in pregnant women and male partners of pregnant women.349 377 (See Precautions Related to Multiple-drug Treatment Regimens under Cautions.)

Lactation

Not known whether daclatasvir distributed into human milk;1 distributed into milk in rats.1

Consider benefits of breast-feeding and importance of daclatasvir to the woman;1 also consider potential adverse effects on the breast-fed child from the drugs or from underlying maternal condition.1

When used in conjunction with sofosbuvir and ribavirin,1 consider potential for adverse reactions to ribavirin in nursing infants and discontinue nursing or the ribavirin-containing regimen.349 377 (See Precautions Related to Multiple-drug Treatment Regimens under Cautions.)

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.1

Geriatric Use

No clinically important differences in safety or efficacy of daclatasvir in patients ≥65 years of age compared with younger adults.1

Hepatic Impairment

Dosage adjustments not needed in patients with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C).1

Renal Impairment

Dosage adjustments not needed in patients with any degree of renal impairment.1

Common Adverse Effects

Headache,1 2 fatigue,1 2 nausea,1 2 diarrhea,1 2 abdominal pain,2 arthralgia.2 insomnia,2 somnolence,1 dizziness,1 anemia,1 rash.1

Interactions for Daclatasvir Dihydrochloride

Daclatasvir is a substrate of CYP3A.1

Inhibits breast cancer resistance protein (BCRP).1

Inhibits organic anion transporting polypeptide (OATP) 1B1 and 1B3.1

Inhibitor and substrate of P-glycoprotein (P-gp) transport.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Moderate or potent CYP3A inducers: Concomitant use with daclatasvir may decrease daclatasvir concentrations and may result in loss of therapeutic effect of the HCV antiviral.1

Potent CYP3A inhibitors: Concomitant use with daclatasvir may increase daclatasvir concentrations.1

Drugs Affecting or Affected by Breast Cancer Resistance Protein

BCRP substrates: Concomitant use with daclatasvir may increase concentrations of the BCRP substrate.1

Drugs Affecting or Affected by Organic Anion Transport Polypeptides

OATP1B1 or OATB1B3 substrates: Concomitant use with daclatasvir may increase concentrations of the OATP1B1 or OATB1B3 substrate.1

Drugs Affecting or Affected by P-glycoprotein Transport

P-gp substrates: Concomitant use with daclatasvir may increase concentrations of the P-gp substrate.1

Specific Drugs

Drug

Interaction

Comments

Antacids

No clinically important pharmacokinetic interactions expected1

Antiarrhythmic agents (amiodarone, digoxin)

Amiodarone: Concomitant use with regimen containing sofosbuvir and daclatasvir may result in serious symptomatic bradycardia (mechanism unknown);1 23 effect on amiodarone and daclatasvir concentrations unknown1

Digoxin: Increased digoxin concentrations1

Amiodarone: Concomitant use with regimen containing sofosbuvir and daclatasvir not recommended;1 if concomitant use required, patient counseling and cardiac monitoring required1 (see Cardiovascular Effects under Cautions)

Digoxin: Monitor serum digoxin concentrations before and during concomitant therapy;1 if daclatasvir initiated in a patient receiving digoxin, reduce digoxin dosage by approximately 15–30% or modify dosing frequency;1 if digoxin initiated in a patient receiving daclatasvir, use lowest appropriate digoxin dosage and adjust if necessary based on concentration1

Anticonvulsants (e.g., carbamazepine, phenytoin)

Carbamazepine, phenytoin: Decreased daclatasvir concentrations possible;1 may result in decreased HCV antiviral effect1

Carbamazepine, phenytoin: Concomitant use contraindicated1

Antifungals, azoles (fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole)

Fluconazole: Increased daclatasvir concentrations expected;1 not considered clinically important1

Itraconazole, ketoconazole, posaconazole, voriconazole: Increased daclatasvir concentrations reported or expected due to potent CYP3A inhibition by the antifungal agent1

Fluconazole: Dosage adjustment not needed1

Itraconazole, ketoconazole, posaconazole, voriconazole: Use daclatasvir dosage of 30 mg once daily1

Antimycobacterials, rifamycins (rifampin, rifapentine)

Rifampin: Substantially decreased daclatasvir concentrations;1 may result in decreased HCV antiviral effect1

Rifapentine: Decreased daclatasvir concentrations expected due to moderate CYP3A induction by rifapentine1

Rifampin: Concomitant use contraindicated1

Rifapentine: Use daclatasvir dosage of 90 mg once daily1

Atazanavir

Ritonavir-boosted atazanavir: Increased daclatasvir concentrations due to potent CYP3A inhibition by ritonavir-boosted atazanavir1 7

Cobicistat-boosted atazanavir: Increased daclatasvir concentrations possible1

Ritonavir-boosted or cobicistat-boosted atazanavir: Use daclatasvir dosage of 30 mg once daily1 7

Unboosted atazanavir: Dosage adjustments not needed1

Benzodiazepines (midazolam)

Midazolam: No clinically important effects on pharmacokinetics of midazolam1

Bosentan

Decreased daclatasvir concentrations expected due to moderate CYP3A induction by bosentan1

Use daclatasvir dosage of 90 mg once daily1

Buprenorphine

Buprenorphine or fixed combination of buprenorphine/naloxone: Increased buprenorphine and norbuprenorphine concentrations1

Dosage adjustments of buprenorphine or buprenorphine/naloxone not needed;1 monitor closely for sedation and adverse cognitive effects1

Calcium-channel blocking agents (diltiazem, verapamil)

Diltiazem, verapamil: Increased daclatasvir concentrations expected;1 not considered clinically important1

Diltiazem, verapamil: Dosage adjustments not needed1

Ciprofloxacin

Increased daclatasvir concentrations expected due to moderate CYP3A inhibition by ciprofloxacin;1 not considered clinically important1

Dosage adjustments not needed1

Corticosteroids (dexamethasone)

Dexamethasone: Decreased daclatasvir concentrations expected due to moderate CYP3A induction by the corticosteroid1

Use daclatasvir dosage of 90 mg once daily1

Dabigatran

Increased dabigatran concentrations expected1

Concomitant use not recommended in certain patients with renal impairment;1 consult recommendations from the manufacturer of dabigatran1

Darunavir

Ritonavir-boosted darunavir: Increased daclatasvir concentrations due to moderate CYP3A inhibition by ritonavir-boosted darunavir;1 not considered clinically important1

Cobicistat-boosted darunavir: Increased daclatasvir concentrations possible1

Ritonavir-boosted or cobicistat-boosted darunavir: Dosage adjustments not needed1

Dolutegravir

No clinically important pharmacokinetic interactions1

Efavirenz

Decreased daclatasvir concentrations due to moderate CYP3A induction by efavirenz1 7

Use daclatasvir dosage of 90 mg once daily1 7

Elvitegravir

Fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (EVG/c/FTC/TDF): Possible increased daclatasvir concentrations1

EVG/c/FTC/TDF: Use daclatasvir dosage of 30 mg once daily1

Estrogens/progestins

No clinically important pharmacokinetic interaction when used with ethinyl estradiol in conjunction with norgestimate1 6

Etravirine

Decreased daclatasvir concentrations expected due to moderate CYP3A induction by etravirine1

Use daclatasvir dosage of 90 mg once daily1

Fosamprenavir

Increased daclatasvir concentrations expected due to moderate CYP3A inhibition by fosamprenavir;1 not considered clinically important1

Dosage adjustments not needed1

Histamine H2-receptor antagonists (famotidine)

Famotidine: No clinically important changes in daclatasvir pharmacokinetics expected1

HMG-CoA reductase inhibitors (statins)

Atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin: Increased statin concentrations reported or expected1

Atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin: Monitor for statin-associated adverse effects (e.g., myopathy)1

Immunosuppressants (cyclosporine, tacrolimus)

Cyclosporine, tacrolimus: No clinically important changes in pharmacokinetics of either drug1

Indinavir

Increased daclatasvir concentrations expected due to potent CYP3A inhibition by indinavir1

Use daclatasvir dosage of 30 mg once daily1

Interferons

Interferon alfa: No in vitro evidence of antagonistic anti-HCV effects1

Peginterferon alfa: No clinically important pharmacokinetic interactions expected1

Lopinavir

Fixed combination of lopinavir/ritonavir: Decreased daclatasvir concentrations and AUC;1 not considered clinically important1

Macrolides (clarithromycin, erythromycin, telithromycin)

Clarithromycin, telithromycin: Increased daclatasvir concentrations expected due to potent CYP3A inhibition by the macrolide1

Erythromycin: Increased daclatasvir concentrations expected due to moderate CYP3A inhibition by erythromycin;1 not considered clinically important1

Clarithromycin, telithromycin: Use daclatasvir dosage of 30 mg once daily1

Erythromycin: Dosage adjustments not needed1

Methadone

No clinically important changes in methadone pharmacokinetics expected1

Modafinil

Decreased daclatasvir concentrations expected due to moderate CYP3A induction by modafinil1

Use daclatasvir dosage of 90 mg once daily1

Nafcillin

Decreased daclatasvir concentrations expected due to moderate CYP3A induction by nafcillin1

Use daclatasvir dosage of 90 mg once daily1

Nefazodone

Increased daclatasvir concentrations expected due to potent CYP3A inhibition by nefazodone1

Use daclatasvir dosage of 30 mg once daily1

Nelfinavir

Increased daclatasvir concentrations expected due to potent CYP3A inhibition by nelfinavir1

Use daclatasvir dosage of 30 mg once daily1

Nevirapine

Decreased daclatasvir concentrations expected due to moderate CYP3A induction by etravirine1

Use daclatasvir dosage of 90 mg once daily1

Proton-pump inhibitors (omeprazole)

Omeprazole: No clinically important changes in the pharmacokinetics of daclatasvir1

Ribavirin

No clinically important pharmacokinetic interactions expected1

Rilpivirine

No clinically important pharmacokinetic interactions expected1

Saquinavir

Increased daclatasvir concentrations expected due to potent CYP3A inhibition by saquinavir1

Use daclatasvir dosage of 30 mg once daily1

Selective serotonin-reuptake inhibitors (escitalopram)

Escitalopram: No clinically important changes in pharmacokinetics of either drug1

Simeprevir

Increased daclatasvir concentrations and AUC and increased simeprevir concentrations and AUC1

No in vitro evidence of antagonistic anti-HCV effects between daclatasvir and HCV NS3/4A protease inhibitors1

Sofosbuvir

No clinically important changes in daclatasvir pharmacokinetics1

No in vitro evidence of antagonistic anti-HCV effects between daclatasvir and HCV NS5B polymerase inhibitors1

St. John's wort

Decreased daclatasvir exposures expected; may lead to loss of HCV antiviral effect1

Concomitant use contraindicated1

Tenofovir

Tenofovir disoproxil fumarate: No clinically important changes in the pharmacokinetics of either drug1 7

Daclatasvir Dihydrochloride Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability is 67%.1

Food

In healthy adults, administration of 60-mg tablet with high-fat, high-caloric meal decreases peak plasma concentrations and AUC by 28 and 23%, respectively, relative to administration in the fasting state.1

Administration with low-fat, low-caloric meal does not affect daclatasvir exposures.1

Plasma Concentrations

Peak plasma concentrations occur within 2 hours after an oral dose in HCV-infected individuals.1 Exposures increase in dose-proportional manner.1

Steady-state concentrations attained after approximately 4 days of once-daily administration.1

Special Populations

Mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C) without HCV infection: AUC of total daclatasvir (free and protein bound) after single 30-mg oral dose decreased by 43, 38, or 36%, respectively, and AUC of unbound daclatasvir decreased by 40, 2, or 5%, respectively, compared with individuals with normal hepatic function.1

Renal impairment without HCV infection: Predicted AUC of total daclatasvir after single 60-mg oral dose in individuals with Clcr of 60, 30, or 15 mL/minute increased by 26, 60, or 80%, respectively, and predicted AUC of unbound daclatasvir increased by 18, 39, or 51%, respectively, compared with individuals with normal renal function.1

End-stage renal disease requiring dialysis: Observed AUC of total or unbound daclatasvir increased by 27 or 20%, respectively, compared with individuals with normal renal function.1

AUC in HCV-infected females estimated to be increased by 30% compared with HCV-infected males;1 not considered clinically important.1

Population pharmacokinetic analysis indicates that age (range 18–79 years) and race do not have clinically important effects on daclatasvir exposures.1

Distribution

Plasma Protein Binding

Approximately 99%.1

Elimination

Metabolism

Metabolized principally by CYP3A4.1

Elimination Route

Following single 25-mg oral dose in healthy individuals, 6.6% eliminated in urine (principally as unchanged drug) and 88% excreted in feces (53% as unchanged daclatasvir).1

Half-life

Terminal elimination half-life approximately 12–15 hours.1

Special Populations

Unlikely to be removed by dialysis.1

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1

Actions and Spectrum

  • HCV NS5A replication complex inhibitor (NS5A inhibitor).1 11 Direct-acting antiviral (DAA) with activity against HCV.1 11

  • Binds to N-terminus of domain 1 of NS5A protein, which plays a vital role RNA replication.1 3 4 Binding leads to structural distortions and interferes with NS5A interactions with membranes and cell proteins, thereby inhibiting RNA replication and virion assembly.1 3

  • In vitro studies using cell-based replicon assays indicate daclatasvir is active against HCV genotypes 1a, 1b, and 3;1 3 5 also has in vitro activity against HCV genotypes 2, 4, 5 and 6.4

  • Certain amino acid substitutions in NS5A of HCV genotype 1a, 1b, and 3a have been selected in cell culture and are associated with reduced susceptibility to daclatasvir in vitro in replicon studies.1 HCV genotype 1a with M28T, Q30E, Q30H, Q30R, L31V, Y93C, Y93H, or Y93N substitutions and HCV genotype 1b with L31V and Y93H single substitutions, L31M/Y93H and L31V/Y93H combination substitutions or a P32-deletion (P32X) has reduced susceptibility to the drug.1 HCV genotype 3a expressing A30K, L31F, L311, or Y93H substitutions have reduced susceptibility to daclatasvir.1 5 In patients receiving daclatasvir with sofosbuvir (with or without ribavirin) for treatment of HCV genotype 1a infection, treatment-emergent Q30 (Q30H/K/R) most frequently associated with virologic failure or relapse.1 In those with HCV genotype 3 infection, Y93H most common NS5A substitution associated with virologic failure.1

  • Cross-resistance between daclatasvir and other HCV NS5A inhibitors expected.1 Impact of previous daclatasvir treatment on efficacy of other HCV NS5A inhibitors not evaluated;1 efficacy of daclatasvir in conjunction with sofosbuvir not evaluated in patients who failed previous treatment that included a different NS5A inhibitor.1 Cross-resistance between daclatasvir and other classes of HCV DAAs not expected.1

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • Importance of using daclatasvir in conjunction with sofosbuvir (with or without ribavirin);1 do not use alone.1

  • Advise patient to take daclatasvir once daily with or without food.1

  • If a regimen of daclatasvir in conjunction with sofosbuvir (with or without ribavirin) is used in a patient receiving amiodarone, advise the patient about the risk of serious symptomatic bradycardia and the importance of immediately contacting a clinician if signs or symptoms of bradycardia (e.g., near-fainting or fainting, dizziness, lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion, memory problems) occur.1

  • Inform patients that the effect of HCV treatment on transmission of HCV is unknown;1 appropriate precautions should be taken to prevent transmission of the virus during treatment or in the event of treatment failure.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 If used in multiple-drug regimen that includes ribavirin, advise men and women of importance of using 2 forms of effective contraception during and for 6 months after ribavirin therapy.349 377 (See Precautions Related to Multiple-drug Treatment Regimens under Cautions.)

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Daclatasvir Dihydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

30 mg (of daclatasvir)

Daklinza

Bristol-Myers Squibb

60 mg (of daclatasvir)

Daklinza

Bristol-Myers Squibb

AHFS DI Essentials. © Copyright 2016, Selected Revisions June 9, 2016. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Bristol-Myers Squibb. Daklinza (daclatasvir ) tablets prescribing information. Princeton, NJ; 2016 Feb.

2. Nelson DR, Cooper JN, Lalezari JP et al. All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III study. Hepatology. 2015; 61:1127-35. [PubMed 25614962]

3. Degasperi E, Aghemo A, Colombo M. Daclatasvir for the treatment of chronic hepatitis C. Expert Opin Pharmacother. 2015; 16:2679-88. [PubMed 26549010]

4. Wang C, Jia L, O'Boyle DR et al. Comparison of daclatasvir resistance barriers on NS5A from hepatitis C virus genotypes 1 to 6: implications for cross-genotype activity. Antimicrob Agents Chemother. 2014; 58:5155-63. [PubMed 24936600]

5. Wang C, Valera L, Jia L et al. In vitro activity of daclatasvir on hepatitis C virus genotype 3 NS5A. Antimicrob Agents Chemother. 2013; 57:611-3. [PubMed 23089758]

6. Bifano M, Sevinsky H, Hwang C et al. Effect of the coadministration of daclatasvir on the pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and norgestimate. Antivir Ther. 2014; 19:511-9. [PubMed 24343001]

7. Bifano M, Hwang C, Oosterhuis B et al. Assessment of pharmacokinetic interactions of the HCV NS5A replication complex inhibitor daclatasvir with antiretroviral agents: ritonavir-boosted atazanavir, efavirenz and tenofovir. Antivir Ther. 2013; 18:931-40. [PubMed 23963204]

8. Poordad F, Schiff ER, Vierling JM et al. Daclatasvir With Sofosbuvir and Ribavirin for HCV Infection With Advanced Cirrhosis or Post-Liver Transplant Recurrence. Hepatology. 2016; :. [PubMed 26754432]

9. Wyles DL, Ruane PJ, Sulkowski MS et al. Daclatasvir plus Sofosbuvir for HCV in Patients Coinfected with HIV-1. N Engl J Med. 2015; 373:714-25. [PubMed 26196502]

10. Mangia A, Arleo A, Copetti M et al. The combination of daclatasvir and sofosbuvir for curing genotype 2 patients who cannot tolerate ribavirin. Liver Int. 2016; :. [PubMed 26786792]

11. Belema M, Nguyen VN, Bachand C et al. Hepatitis C virus NS5A replication complex inhibitors: the discovery of daclatasvir. J Med Chem. 2014; 57:2013-32. [PubMed 24521299]

23. US Food and Drug Administration. FDA drug safety communication: FDA warns of serious slowing of the heart rate when antiarrhythmic drug amiodarone is used with hepatitis C treatments containing sofosbuvir (Harvoni) or Sovaldi in combination with another direct acting antiviral. 2015 Mar 24. From FDA website.

119. American Association for the Study of Liver Diseases (AASLD). Recommendations for testing, managing, and treating hepatitis C. From the AASLD website. Accessed 2016 Mar 1.

349. Merck Sharp & Dohme Corporation. Rebetol (ribavirin) capsules and oral solution prescribing information. Whitehouse Station, NJ; 2013 Nov.

377. Genentech. Copegus (ribavirin) tablets prescribing information. South San Francisco, CA; 2013 Feb.

Hide