DaciHep 28Tabs

Daclatasvir

Recommended Retail Price $87

Each tablet contains:

  • Daclatasvir 60 mg

Manufacturer: Natco Pharma Ltd., India

Distributor: Zydus Heptiza, India

 

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Description

Dosage Forms & Strengths

Tablet

  • 30mg
  • 60mg

Hepatitis C

Indicated for use with Sofosbuvir for chronic hepatitis C virus (HCV) genotypes 1 and 3 infection.

Genotype 1

  • Without cirrhosis or with compensated (Child-Pugh A) cirrhosis: 60 mg (plus Sofosbuvir 400 mg) PO qDay for 12 weeks.
  • Decompensated (Child-Pugh B or C) cirrhosis or posttransplant: 60 mg (plus Sofosbuvir 400 mg) PO qDay plus ribavirin for 12 weeks.

Genotype 3

  • Without cirrhosis: 60 mg (plus Sofosbuvir 400 mg) PO qDay for 12 weeks.
  • Compensated (Child-Pugh A) or decompensated (Child-Pugh B or C) cirrhosis, or posttransplant: 60 mg (plus Sofosbuvir 400 mg) PO qDay plus ribavirin for 12 weeks.

Ribavirin dosing

  • HCV genotype 1 or 3 with Child-Pugh B or C cirrhosis or post-transplantation.
    • 600 mg PO qDay initially, increasing up to 1000 mg/day as tolerated.
    • Adjust ribavirin starting dose and on-treatment dose based on hemoglobin and CrCl.
  • HCV genotype 3 with compensated cirrhosis (Child-Pugh A).
    • Weight-based ribavirin dosing of 1000 mg/day (weight <75 kg) or 1200 mg/day (weight ≥75 kg) PO divided BID (with food).

Dosage Modifications

Renal or hepatic impairment (any degree): No dose adjustment required.

Dosage reduction of DaciHep for adverse reactions is not recommended.

CYP inhibitors or inducers.

  • Coadministration with strong CYP3A inhibitors: Decrease dose to 30 mg/day
  • Coadministration with moderate CYP3A inducers: Increase dose to 90 mg/day
  • Coadministration with strong CYP3A inducers: Contraindicated

Dosing Considerations

Reduced sustained virologic response (SVR) rates in HCV genotype 3-infected patients with cirrhosis receiving DaciHep in combination with Sofosbuvir for 12 weeks; optimal duration for patients with cirrhosis is not established.

If Sofosbuvir is permanently discontinued in a patient receiving daclatasvir with Sofosbuvir, then DaciHep should also be discontinued.

NS5A resistance may occur in patients with genotype 1a; consider screening for NS5A polymorphisms at amino acid positions M28, Q30, L31, and Y93 in patients with cirrhosis who are infected with HCV genotype 1a before treatment initiation.

Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with HCV direct acting antivirals (DDAs).

Adverse Effects

>10%

Headache (14%)

Fatigue (14%)

1-10%

Nausea (8%)

Diarrhea (5%)

Elevated lipase, >3 x ULN (2%)

Postmarketing Reports

Cardiac disorders: Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiate treatment with Sofosbuvir in combination with another HCV direct-acting antiviral, including daclatasvir.

Contraindications

When daclatasvir is used in combination with other agents, the contraindications applicable to those agents are applicable to the combination regimen (see ribavirin and Sofosbuvir prescribing information).

Coadministration with drugs that strongly induce CYP3A and, thus, may lead to lower exposure and loss of daclatasvir efficacy.

Contraindicated drugs

  • Anticonvulsants: Carbamazepine, eslicarbazepine, fosphenytoin, phenytoin, oxcarbazepine, pentobarbital, phenobarbital, primidone.
  • Antimycobacterial agents: Rifabutin, rifampin.
  • Herbals: St John’s wort.
  • Other: Dabrafenib, enzalutamide, lumacaftor, mitotane, nevirapine.

Cautions

Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV DDAs, and who were not receiving HBV antiviral therapy; HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level (see Black Box Warnings and Dosing Considerations).

Serious symptomatic bradycardia

  • Serious symptomatic bradycardia may occur in coadministration with Sofosbuvir and amiodarone in combination with another direct acting antiviral (DAA), including daclatasvir.
  • Patients also receiving beta-blockers or those with underlying cardiac comorbidities and/or advanced liver disease may be at higher risk.
  • Coadministration is not recommended.
  • If no alternative exists, inpatient cardiac monitoring is recommended for the first 48 hr and then daily home monitoring for at least the first 2 weeks.
  • Due to amiodarone’s long elimination half-life, patients discontinuing amiodarone just prior to starting Sofosbuvir in combination with daclatasvir should undergo similar cardiac monitoring.

Drug interaction overview

  • Concomitant use with certain other drugs may result in known or potentially significant drug interactions, some of which may lead to loss of therapeutic effect of daclatasvir and possible development of resistance or clinically significant adverse reactions from greater exposures of concomitant drugs or components of daclatasvir.
  • Also see Contraindications and Drug Interactions Checker.
  • Potential for other drugs that affect daclatasvir.
    • Daclatasvir is a substrate of CYP3A.
    • Moderate or strong CYP3A inducers may decrease the plasma levels and therapeutic effect of daclatasvir.
    • Strong CYP3A inducers are contraindicated with daclatasvir (also see Contraindications).
    • Coadministration with moderate CYP3A inducers require a dose increase for daclatasvir (see Dosage Modifications).
    • Strong CYP3A inhibitors may increase daclatasvir systemic exposure requiring a dose reduction for daclatasvir (see Dosage Modifications).
  • Potential for daclatasvir affecting other drugs.
    • Daclatasvir is an inhibitor of P-gp, OATP1B1, OATP1B3, and BCRP.
    • Daclatasvir may increase systemic exposure to drugs that are substrates of P-gp, OATP 1B1 or 1B3, or BCRP, which could increase or prolong their therapeutic effect or increase adverse reactions.
  • Drug without clinically significant interactions with daclatasvir.
    • No clinically relevant changes in exposure were observed for cyclosporine, escitalopram, ethinyl estradiol/norgestimate, methadone, midazolam, tacrolimus, or tenofovir with concomitant use of daclatasvir.
    • No clinically relevant changes in daclatasvir exposure were observed with cyclosporine, escitalopram, famotidine, omeprazole, Sofosbuvir, tacrolimus, or tenofovir.
    • No clinically relevant interaction is anticipated for daclatasvir or the following concomitant medications: peginterferon alfa, ribavirin, or antacids.

Pregnancy

No data in pregnant women are available.

If daclatasvir and Sofosbuvir are administered with ribavirin, the warnings and precautions for ribavirin, in particular the pregnancy avoidance warning, apply to this combination regimen (see ribavirin prescribing information).

Animal studies

  • Studies in rats and rabbits observed no evidence of fetal harm with oral administration of daclatasvir during organogenesis at doses that produced exposures up to 6 and 22 times, respectively, the recommended human dose (RHD) of 60 mg.
  • However, embryofetal toxicity was observed in rats and rabbits at maternally toxic doses that produced exposures of 33 and 98 times the human exposure, respectively, at the RHD of 60 mg.

Lactation

Unknown if distributed in human breast milk.

The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for the drug and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition.

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Pharmacology

Mechanism of Action

Inhibits NS5A, a nonstructural protein encoded by HCV.

Binds to the N-terminus within domain 1 of NS5A, which may cause structural distortions that interfere with NS5A functions, and thereby inhibits both viral RNA replication and virion assembly.

Absorption

Absolute bioavailability: 67%

Peak plasma time: 2 hr

Peak plasma concentration: 182 ng/mL

AUC: 10,973 ng·h/mL

Distribution

Protein bound: 99%

Vd: 47 L

Metabolism

Substrate of CYP3A, with CYP3A4 being the primary CYP isoform responsible for metabolism.

Elimination

Half-life: 12-15 hr

Excretion: 88% feces (53% of the dose as unchanged drug); 6.6% urine (primarily unchanged drug).

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