This is a fixed-dose combination of glecaprevir, a hepatitis C virus (HCV) NS3/4A protease inhibitor, and pibrentasvir, an HCV NS5A inhibitor, and is indicated for the treatment of patients with chronic HCV genotype (GT) 1, 2, 3, 4, 5 or 6 infection without cirrhosis and with compensated cirrhosis (Child-Pugh A). This is also indicated for the treatment of adult patients with HCV genotype 1 infection, who previously have been treated with a regimen containing an HCV NS5A inhibitor or an NS3/4A protease inhibitor, but not both.

Glecaprevir is an inhibitor of the HCV NS3/4A protease, which is a viral enzyme necessary for the proteolytic cleavage of the HCV encoded polyprotein into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins. These multifunctional proteins, including NS3, are essential for viral replication. The N-terminal of NS3 protein confers serine protease activity, whileThe C-terminus of NS3 encodes a DExH/D-box RNA helicase which hydyolyzes NTP as an energy source to unwind double-stranded RNA in a 3′ to 5′ direction during replication of viral genomic RNA. NS4A is a cofactor for NS3 that directs the localization of NS3 and modulates its enzymatic activities. Glecaprevir disrupts the intracellular processes of the viral life cycle through inhibiting the NS3/4A protease activity of cleaving downstream junctions of HCV polypeptide and proteolytic processing of mature structural protein.

NS5A is a phosphoprotein that plays an essential role in replication, assembly and maturation of infectious viral proteins. The basal phosphorylated form of NS5A, which is maintained by C-terminal serine cluster, is key in ensuring its interaction with the viral capsid protein, or the core protein. By blocking this interaction, pibrentasvir inhibits the assembly of proteins and production of mature HCV particles. NS5A also interacts with viral and cellular proteins to form the HCV replicase complex, and supports the RNA replication of HCV

Testing Prior to the Initiation of Therapy: Test all patients for HBV infection by measuring HBsAg and anti-HBc.

Recommended dosage: Three tablets (total daily dose: glecaprevir 300 mg and pibrentasvir 120 mg) taken orally once daily with food.

See recommended treatment duration in tables below-

Treatment-Naïve Patients: HCV Genotype 1, 2, 3, 4, 5, or 6

• No Cirrhosis: 8 weeks
• Compensated Cirrhosis (Child-Pugh A): 12 weeks

Treatment-Experienced Patients: HCV Genotype 1

• Patients Previously Treated With a Regimen Containing: An NS5A inhibitor without prior treatment with an NS3/4A protease inhibitor
• No Cirrhosis: 16 weeks
• Compensated Cirrhosis (Child-Pugh A): 16 weeks

Treatment-Experienced Patients: HCV Genotype 1

• Patients Previously Treated With a Regimen Containing: An NS3/4A PI without prior treatment with an NS5A inhibitor
• No Cirrhosis: 12 weeks
• Compensated Cirrhosis (Child-Pugh A): 12 weeks

Treatment-Experienced Patients: HCV Genotype 1, 2, 4, 5 or 6

• Patients Previously Treated With a Regimen Containing: PRS
• No Cirrhosis: 8 weeks
• Compensated Cirrhosis (Child-Pugh A): 12 weeks

Treatment-Experienced Patients: HCV Genotype 3

• Patients Previously Treated With a Regimen Containing: PRS
• No Cirrhosis: 16 weeks
• Compensated Cirrhosis (Child-Pugh A): 16 weeks

Carbamazepine, efavirenz, and St. John’s wort may decrease concentrations of glecaprevir and pibrentasvir. Coadministration of carbamazepine, efavirenz containing regimens, and St. John’s wort with this preparation is not recommended.

Patients with severe hepatic impairment (Child-Pugh C). Coadministration with atazanavir and rifampin

In subjects receiving this preparation, the most commonly reported adverse reactions (greater than 10%) are headache and fatigue.

No adequate human data are available to establish whether or not this preparation poses a risk to pregnancy outcomes. It is not known whether the components of this preparation are excreted in human breast milk, affect human milk production, or have effects on the breastfed infant. When administered to lactating rodents, the components of this preparation were present in milk, without effect on growth and development observed in the nursing pups. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for this preparation and any potential adverse effects on the breastfed child from this preparation or from the underlying maternal condition.

Risk of Hepatitis B Virus Reactivation: Test all patients for evidence of current or prior HBV infection before initiation of HCV treatment. Monitor HCV/HBV coinfected patients for HBV reactivation and hepatitis flare during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.

Renal Impairment: No dosage adjustment is required in patients with mild, moderate or severe renal impairment, including those on dialysis

Hepatic Impairment: No dosage adjustment is required in patients with mild hepatic impairment (Child-Pugh A). This is not recommended in patients with moderate hepatic impairment (Child-Pugh B). Safety and efficacy have not been established in HCV-infected patients with moderate hepatic impairment. This is contraindicated in patients with sev.

In case of overdose, the patient should be monitored for any signs and symptoms of toxicities. Appropriate symptomatic treatment should be instituted immediately. Glecaprevir and pibrentasvir are not significantly removed by hemodialysis.

Hepatic viral infections (Hepatitis C)

Store at or below 30°C