Adult: As combination therapy with other antiviral treatment regimen in patients with chronic HCV genotype 1 (1a or 1b), and 3: 60 mg once daily. Treatment duration may vary depending on genotype and treatment regimen used (refer to detailed product guideline).
Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines identified IL28B or also known as IFN-lambda/IFNL3 genotype as the strongest baseline predictor of response to treatment regimens containing peginterferon alfa for HCV genotype 1. Since daclatasvir is used as part of certain combination treatment regimens for HCV, IL28B genotype may be considered relevant. According to 4 genome-wide association studies, polymorphisms in or near the IL28B gene in individuals of different ethnic groups significantly impacts the response to HCV treatment, role in pathogenesis, and outcome of HCV infection. IL28B variants with the most data in influencing HCV therapy are rs12979860 and rs8099917.
Carriers of IL28B gene rs12979860 variant
Patients with chronic hepatitis C with CC genotype may have an increased response to daclatasvir, peginterferon alfa-2a, peginterferon alfa-2b, and ribavirin while those with CT and TT genotypes may have decreased response to daclatasvir, peginterferon alfa-2a, peginterferon alfa-2b, and ribavirin. The sustained virologic response 24 (SVR24) rates are higher in individuals treated with the combination of daclatasvir and peginterferon alfa/ribavirin as compared to those receiving peginterferon alfa/ribavirin alone across all IL28B genotypes and regardless of viral subtypes. Other genetic and clinical factors may influence the response to daclatasvir therapy.
Although several studies were conducted to identify the impact of IL28B with HCV, there is still no evidence suggesting dose adjustment to daclatasvir treatment according to IL28B status. IL28B genotype testing prior to initiating daclatasvir has not been addressed by currently available references.
May be taken with or without food.
Hypersensitivity. Pregnancy (especially in combination with ribavirin and peginterferon alfa) and lactation. Concomitant use with strong CYP3A4 and P-glycoprotein (P-gp) inducers (e.g. carbamazepine, phenytoin, rifampicin, systemic dexamethasone, St. John’s wort). Contraindications of other concurrently used agents (e.g. ribavirin) are applicable (refer to respective detailed product guideline).
Patients with underlying cardiac comorbidities, diabetes mellitus, advanced hepatic disease, hepatitis B co-infection. Not intended for use as a monotherapy. Patients taking moderate CYP3A4 inducers or strong CYP3A4 inhibitors. Hepatic impairment.
Blood and lymphatic system disorders: Anaemia, neutropenia, thrombocytopenia, leucopenia, lymphopenia. Ear and labyrinth disorders: Vertigo, tinnitus. Eye disorders: Dry eye, blurred vision, reduced visual acuity. Gastrointestinal disorders: Nausea, diarrhoea, vomiting, abdominal pain, constipation, dry mouth, flatulence, GERD. General disorders and admin site conditions: Irritability, fatigue, asthenia, influenza-like illness, pyrexia. Investigations: Weight decreased, increased ALT, AST and blood bilirubin. Metabolism and nutrition disorders: Decreased appetite. Musculoskeletal and connective tissue disorders: Myalgia, arthralgia. Nervous system disorders: Headache, dizziness, migraine, disturbance in attention. Psychiatric disorders: Insomnia, depression, anxiety, sleep disorder, libido decreased, mood swings. Respiratory, thoracic and mediastinal disorders: Nasopharyngitis, dyspnoea, nasal congestion, cough. Skin and subcutaneous tissue disorders: Rash, pruritus, alopecia, dry skin. Vascular disorders: Hot flush, hypertension. Potentially Fatal: Hepatitis B virus reactivation resulting in fulminant hepatitis and hepatic failure.
Patient Counseling Information
This drug may cause dizziness, disturbance in attention, blurred vision, and reduced visual acuity, if affected, do not drive or operate machinery.
Perform pregnancy test prior to treatment initiation. Within 12 weeks prior to treatment initiation, obtain HCV genotype and subtype, quantitative HCV viral load, CBC, INR, LFTs (e.g. albumin, ALT, AST, alkaline phosphatase, total and direct bilirubin), and calculated GFR. Perform screening for NS5A polymorphisms at amino acid positions M28, Q30, L31, and Y93 in genotype 1a patients with cirrhosis; hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc). Monitor CBC, serum creatinine, calculated GFR during treatment; LFTs after 4 weeks of therapy and as clinically indicated; quantitative HCV viral load testing after 4 weeks of therapy then at 12 weeks after treatment completion. Monitor for clinical and laboratory signs of hepatitis flare or hepatitis B virus (HBV) reactivation in patients with serologic evidence of HBV infection during and post-treatment follow-up. For concomitant use with amiodarone, or patients who discontinued amiodarone prior to initiating daclatasvir and sofosbuvir combination, perform cardiac monitoring for the 1st 48 hours of co-administration (in-patient setting), or monitor heart rate daily for at least the 1st 2 weeks of treatment (out-patient or self-monitoring).
May decrease plasma levels and therapeutic effect with moderate CYP3A4 inducers (e.g. efavirenz, etravirine, nevirapine, bosentan, nafcillin). Increased risk of severe liver injury with asunaprevir-containing regimen. Increased plasma concentrations with strong CYP3A4 inhibitors (e.g. boceprevir, telaprevir, atazanavir, cobicistat, ritonavir, erythromycin, clarithromycin, ketoconazole, itraconazole). May increase systemic exposures and prolong therapeutic effects of P-gp substrates (e.g. dabigatran, digoxin), organic anion transporting polypeptide (OATP) 1B1 or 1B3 and breast cancer resistance protein (BCRP) substrates (e.g. HMG-CoA reductase inhibitors). May cause symptomatic hypoglycaemia with antidiabetic agents. May diminish the anticoagulant effects of vitamin K antagonists (e.g. warfarin). Potentially Fatal: Concomitant use with sofosbuvir and amiodarone increases the risk of severe symptomatic bradycardia and heart block. Decreased plasma levels and therapeutic effect with strong CYP3A4 or P-gp inducers (e.g. phenytoin, carbamazepine, oxcarbazepine, phenobarbital, rifampicin, rifabutin, rifapentine, systemic dexamethasone).
Avoid St. John’s wort as it decreases the plasma levels and therapeutic effect of daclatasvir. Decreased plasma concentration and exposure with high-fat meals.
Description: Daclatasvir is an inhibitor of non-structural protein 5A (NS5A), an essential component of hepatitis C virus (HCV) replication complex. It binds to the N-terminus within the Domain 1 of HCV, thereby inhibiting both viral RNA replication and virion assembly. Pharmacokinetics: Absorption: Readily absorbed from the gastrointestinal tract. Decreased plasma concentration and exposure with high-fat meals. Bioavailability: 67%. Time to peak plasma concentration: 1-2 hours. Distribution: Plasma protein binding: Approx 99%. Metabolism: Metabolised in the liver primarily by CYP3A4 isoenzyme. Excretion: Via faeces (88%, 53% as unchanged drug); urine (6.6%, mainly as unchanged drug). Elimination half-life: Approx 12-15 hours.