Daclatasvir (Daklinza) is a direct-acting oral antiviral drug that is used to treat patients with chronic hepatitis C. It is usually given in combination with other antiviral drugs like sofosbuvir.

Daclatasvir (Daklinza) Uses:

• Chronic hepatitis C:

  • Used for the 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 Use of Daclatasvir in Adults:

  • Used for chronic hepatitis C (genotype 2)
  • Used for chronic hepatitis C (genotype 4)
  • Used for chronic hepatitis C (genotype 5 or 6)

Daclatasvir (Daklinza) Dose in Adults

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

Daclatasvir (Daklinza) Dose in the treatment of chronic hepatitis C (genotype 1a or 1b): Oral:

• Treatment-naive without cirrhosis (alternative agent):

  • 60 mg once a day with concomitant sofosbuvir for 12 weeks.

• Peginterferon/ribavirin-experienced patients without cirrhosis (alternative agent):

  • 60 mg once a day with concomitant sofosbuvir for 12 weeks.

• Decompensated (Child-Pugh class B or C) cirrhosis:

  • 60 mg once a day with concomitant sofosbuvir and ribavirin for 12 weeks.
  • For patients who are ribavirin-ineligible, 60 mg once in a day with concomitant sofosbuvir for 24 weeks.

• Liver transplant recipients with or without compensated (Child-Pugh class A) cirrhosis (alternative agent):

  • 60 mg once a day with concomitant sofosbuvir and ribavirin for 12 weeks.
  • 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.
• Note: Discontinuation of therapy is considered for virologic breakthrough ( more than 1 log IU/mL increase in HCV RNA from nadir).

Daclatasvir (Daklinza) Dose in the treatment of chronic hepatitis C (genotype 2) (off-label use; AASLD/IDSA 2017): Oral:

• Treatment-naive without cirrhosis (alternative agent):

  • 60 mg once a day with concomitant sofosbuvir for 12 weeks

• Treatment-naive with compensated (Child-Pugh class A) cirrhosis (alternative agent):

  • 60 mg once a day with concomitant sofosbuvir for 16 to 24 weeks

• Peginterferon/ribavirin-experienced without cirrhosis (alternative agent):

  • 60 mg once a day with concomitant sofosbuvir for 12 weeks

• Peginterferon/ribavirin-experienced with compensated (Child-Pugh class A) cirrhosis (alternative agent):

  • 60 mg once a day with concomitant sofosbuvir for 16 to 24 weeks
  • Patients with decompensated (Child-Pugh class B or C) cirrhosis:
    • 60 mg once a day with concomitant sofosbuvir and ribavirin for 12 weeks.
    • For patients who are not eligible for ribavirin, 60 mg once a day with concomitant sofosbuvir for 24 weeks.

• Liver transplant recipients (treatment-naive and -experienced) without cirrhosis:

  • 60 mg once in a day 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 a day 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 a day with sofosbuvir and ribavirin for 12 weeks

Daclatasvir (Daklinza) Dose in the treatment of chronic hepatitis C (genotype 3):

• Treatment-naive without cirrhosis (alternative agent):

  • 60 mg once a day with concomitant sofosbuvir for 12 weeks.

• Treatment-naive with compensated (Child-Pugh class A) cirrhosis (alternative agent):

  • 60 mg once a day with concomitant sofosbuvir, with or without ribavirin, for 24 weeks.

• Peginterferon/ribavirin-experienced patients without cirrhosis (alternative agent):

  • 60 mg once a day with concomitant sofosbuvir for 12 weeks.

• Patients with decompensated cirrhosis:

  • 60 mg once a day 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 a day 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 a day 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 a day with sofosbuvir and ribavirin for 12 weeks.

Dose in the treatment of 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 a day with concomitant sofosbuvir and ribavirin for 12 weeks. If ribavirin-ineligible, 60 mg once in a day 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 a day with concomitant sofosbuvir and ribavirin for 12 weeks.

Daclatasvir (Daklinza) Dose in the treatment of 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 a day 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 a day with sofosbuvir and ribavirin for 12 weeks.

Daclatasvir (Daklinza) Dosage adjustment with concomitant medications:

• Strong inhibitors of CYP3A and certain HIV antiviral agents:
  • 30 mg once a day
• Moderate CYP3A inducers or nevirapine:
  • 90 mg once a day
• Strong CYP3A inducers:
  • Concomitant use is contraindicated.

Use in children:

Not indicated.

Daclatasvir (Daklinza) Pregnancy Risk Category: N

• Daclatasvir must not be used as monotherapy.
• Use is contraindicated in pregnant females and males whose female partners are pregnant if used in combination with ribavirin.
• All warnings related to the use of ribavirin and pregnancy and/or 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.
• Treatment of hepatitis C is not currently recommended to treat maternal infection or to decrease the risk of mother-to-child transmission during pregnancy.
• 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.

Daclatasvir use during breastfeeding:

• It is not known if daclatasvir is present in breast milk.
• Breastfeeding is not linked to the spread of the hepatitis C virus; however, breastfeeding is not recommended if nipples are cracked or bleeding (milk should be expressed and discarded).
• In the presence of HIV co-infection breastfeeding is not recommended.
• According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.

Daclatasvir (Daklinza) Dose in Kidney Disease:

No dosage adjustment required.

Daclatasvir (Daklinza) Dose in Liver disease:

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

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

Common Side Effects of Daclatasvir (Daklinza):

• Central nervous system:

  • Fatigue
  • Headache

• Gastrointestinal:

  • Nausea

• Hematologic & Oncologic:

  • Anemia

Less Common Side Effects of Daclatasvir (Daklinza):

• Central nervous system:

  • Drowsiness
  • Insomnia

• Dermatologic:

  • Skin rash

• Gastrointestinal:

  • Diarrhea
  • Increased serum lipase

Contraindications to Daclatasvir (Daklinza):

• Concurrent use of strong CYP3A inducers (eg, rifampin, carbamazepine, phenytoin St John's wort).
• When used in combination with other agents for example 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.

Warnings and Precautions

• Bradycardia:

  • Bradycardia generally occurs within hours or days but has been observed up to 2 weeks after treatment initiation.
  • When used in combination with sofosbuvir and amiodarone, symptomatic bradycardia for example:
    • lightheadedness,
    • near-fainting,
    • dizziness,
    • malaise,
    • weakness,
    • excessive tiredness,
    • shortness of breath,
    • memory problems,
    • chest pain, and
    • confusion has been reported;
  • pacemaker intervention may be required.
  • Risk factors include concomitant beta-blocker use, underlying cardiac morbidities, and/or advanced hepatic disease.
  • Patients discontinuing amiodarone just prior to starting daclatasvir and sofosbuvir treatment should also undergo similar cardiac monitoring procedures
  • Patients receiving amiodarone (with no alternative 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.
  • Bradycardia usually resolves after HCV treatment discontinuation.

• Cardiovascular disease:

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

• Diabetes:

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

• Hepatic disease:

  • The optimal duration of treatment for HCV genotype 3-infected patients with cirrhosis or HCV genotype 1 patient with Child-Pugh class C cirrhosis has not been established.
  • 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.

• 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 (i.e. HBsAg negative and anti-HBC positive. It is characterized by an abrupt increase in HBV replication characterized by a rapid increase in serum HBV DNA levels.
  • The risk of HBV reactivation may be increased in patients receiving immunosuppressants or chemotherapeutic drugs.
  • 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:

• Baseline (within 12 weeks prior to starting antiviral therapy):
  • CBC, INR, hepatic function panel (albumin, total and direct bilirubin, ALT, AST, and alkaline phosphatase), and calculated GFR.
• Baseline (at any time prior to starting antiviral therapy):
  • HCV genotype and subtype, quantitative HCV viral load.

Daclatasvir: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Daclatasvir (Daklinza) Monitoring Parameters:

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).
• In patients with diabetes, monitor blood glucose and for signs/symptoms of hypoglycemia.

How to administer Daclatasvir (Daklinza)?

Oral: Administer with or without food.

Mechanism of action of Daclatasvir (Daklinza):

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

Protein binding:

• ~99%

Metabolism:

• Primarily via CYP3A4

Bioavailability:

• 67%

Half-life elimination:

• ~12 to 15 hours

Time to peak, plasma:

• 2 hours or less than 2 hours

Excretion:

• Feces (88 percent, 53 percent unchanged);
• urine (6.6 percent, primarily unchanged)

International Brand Names of Daclatasvir:

• Daklinza
• Mydekla
• Virodacla
• Zetaciver
• Augidacla
• Daclacef
• Daclavir
• Javidacla

Daclatasvir Brand Names in Pakistan:

• Mydacla (Mydekla) 60 mg: Mylan/ AGP Pharma
• Daclit 60 mg: Genix Pharma
• Daclaget 60 mg: Getz Pharma
• Clavir 60 mg: Hilton Pharma
• Dakvir 60 mg: Pharmevo Pharma
• Daclata 60 mg: Highnoon Pharma
• Dacriva 60 mg: CCL Pharma
• Maclinza 60 mg: Macter Pharma