Daclatasvir is used in combination with Sofosbuvir to treat chronic hepatitis C virus (HCV) infection in adults.

Daclatasvir is a direct-acting antiviral agent (DAA) that works against the hepatitis C virus (HCV). It inhibits NS5A, a nonstructural protein made by HCV. Daclatasvir attaches to the N-terminus of NS5A and blocks both viral RNA replication and the assembly of new virus particles. Studies of Daclatasvir-resistant viruses, biochemical tests, and computer models show that it interacts with Domain 1 at the N-terminus of NS5A, which may change the protein’s structure and prevent it from functioning properly.

The recommended dose of Daclatasvir is 60 mg once daily, to be taken orally with or without meals.

Daclatasvir must be administered in combination with other medicinal products. The Summary of Product Characteristics for the other medicinal products in the regimen should also be consulted before initiation of therapy with Daclatasvir. Recommended regimens and treatment duration are provided in table below:

For the regimen of Daclatasvir+Sofosbuvir, data for 12-week treatment duration are available only for treatment-naïve patients with genotype 1 infection. For Daclatasvir+Sofosbuvir with or without Ribavirin, data are available for patients with advanced liver disease (≥F3) without cirrhosis. The recommended use of Daclatasvir+Sofosbuvir in genotype 4 is based on extrapolation from genotype 1. For the regimen of Daclatasvir+Peginterferon alfa + Ribavirin, data are available for treatment-naïve patients.

• The dose of Ribavirin, when combined with Daclatasvir, is weight-based (1,000 or 1,200 mg in patients <75 kg or ≥75 kg, respectively).
• Dose modification, interruption and discontinuation: Dose modification of Daclatasvir to manage adverse reactions is not recommended. If treatment interruption of components in the regimen is necessary because of adverse reactions, Daclatasvir must not be given as monotherapy.
• There are no virologic treatment stopping rules that apply to the combination of Daclatasvir with Sofosbuvir.
• Treatment discontinuation in patients with inadequate on-treatment virologic response during treatment with Daclatasvir, Peginterferon alfa and Ribavirin.

Dose recommendation for concomitant medicines:

• Strong inhibitors of cytochrome P450 enzyme 3A4 (CYP3A4): The dose of Daclatasvir should be reduced to 30 mg once daily when coadministered with strong inhibitors of CYP3A4.
• Moderate inducers of CYP3A4: The dose of Daclatasvir should be increased to 90 mg once daily when coadministered with moderate inducers of CYP3A4.
• Missed doses: Patients should be instructed that, if they miss a dose of Daclatasvir, the dose should be taken as soon as possible if remembered within 20 hours of the scheduled dose time. However, if the missed dose is remembered more than 20 hours after the scheduled dose, the dose should be skipped and the next dose taken at the appropriate time.

Potential for Other Drugs to Affect Daclatasvir : Daclatasvir is a substrate of CYP3A. Therefore moderate or strong inducers of CYP3A may reduce the plasma levels and effectiveness of Daclatasvir. Strong inhibitors of CYP3A such as clarithromycin itraconazole ketoconazole or ritonavir may increase the plasma levels of Daclatasvir.

Potential for Daclatasvir to Affect Other Drugs : Daclatasvir is an inhibitor of P-glycoprotein transporter (P-gp) organic anion transporting polypeptide (OATP) 1B1 and 1B3 and breast cancer resistance protein (BCRP). Giving Daclatasvir may increase exposure to medicines that are substrates of P-gp OATP 1B1 1B3 or BCRP which could increase or prolong their effects or side effects.

Daclatasvir should not be used with drugs that strongly induce CYP3A because they can reduce the levels and effectiveness of Daclatasvir. Contraindicated drugs include but are not limited to anticonvulsants such as phenytoin and carbamazepine antimycobacterial agents such as rifampin and herbal products like St Johns wort (Hypericum perforatum).

The following serious adverse reactions have been reported for Daclatasvir especially when given with Sofosbuvir and Amiodarone. Serious symptomatic bradycardia may occur. Symptoms can include fainting or near-fainting dizziness or lightheadedness feeling unwell weakness tiredness shortness of breath chest pain confusion or memory problems. Patients should seek medical attention immediately if these symptoms appear.

No data are available on the use of Daclatasvir in pregnant women to determine any drug-related risk. It is also unknown whether Daclatasvir passes into human breast milk affects the breastfed infant or changes milk production. Use only if clearly needed and prescribed by a doctor.

There is a potential risk of adverse effects or reduced virologic response due to drug interactions. Concomitant use of Daclatasvir with other medications may lead to clinically significant interactions, which can result in:

• Reduced therapeutic effectiveness of Daclatasvir and possible development of resistance
• Dosage adjustments of either Daclatasvir or co-administered drugs
• Increased risk of clinically significant adverse reactions due to higher exposure of Daclatasvir or other drugs

Serious symptomatic bradycardia with Sofosbuvir and Amiodarone: Cases of symptomatic bradycardia, including those requiring pacemaker intervention, have been reported when Amiodarone is used together with Sofosbuvir in combination with another direct-acting antiviral such as Daclatasvir. Patients receiving Sofosbuvir with Daclatasvir who require Amiodarone therapy (when no alternative is available) should undergo appropriate cardiac monitoring.

Elderly: No dose adjustment of Daclatasvir is needed for patients aged 65 years or older.

Renal Impairment: Daclatasvir does not require dose adjustment for patients with any degree of kidney problems.

Hepatic Impairment: No dose adjustment is required for patients with mild (Child-Pugh A score 5-6) moderate (Child-Pugh B score 7-9) or severe (Child-Pugh C score ≥10) liver impairment.

Pediatric Population: The safety and effectiveness of Daclatasvir in children and adolescents under 18 years have not been established. No data are available.

There is no known antidote for Daclatasvir overdose. Treatment should focus on general supportive care, including monitoring vital signs and observing the patient’s clinical condition. Because Daclatasvir is highly protein-bound (more than 99%), dialysis is unlikely to significantly reduce its plasma levels.

Hepatic viral infections (Hepatitis C)

Store Daclatasvir at room temperature below 30 degrees Celsius. Protect from light and keep out of reach of children.