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

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

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

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

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

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

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

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

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.)

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.)

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

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

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

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

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

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.)