Chronic Hepatitis C Severe hepatic impairment (Child-Pugh C) Coadministration with atazanavir or rifampin

Hepatic viral infections (Hepatitis C)

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

Administration: Take with food at the same time once daily Adult Dose: Chronic Hepatitis C Treatment-naïve adults and adolesents with chronic hepatitis C virus (HCV) genotypes 1-6 without cirrhosis or with compensated cirrhosis Treatment-experienced patients with HCV genotype 1 who have been previously treated with a regimen containing either an NS5A inhibitor or an NS3/4A protease inhibitor, but not both 3 tablets (ie, 300 mg/120 mg total dose) PO once daily with food Recommended duration for treatment-naïve patients Genotypes 1-6, no cirrhosis: 8 wk Genotypes 1-6, compensated cirrhosis (Child-Pugh A): 12 wk Recommended duration for treatment-experienced patients No cirrhosis Genotype 1 and NS5A inhibitor prior treatment: 16 wk Genotype 1 and NS3/4A protease inhibitor prior treatment: 12 wk Genotypes 1, 2, 4, 5, or 6 (prior treatment with simeprevir and sofosbuvir, or simeprevir, boceprevir, or telaprevir with pegylated interferon and ribavirin): 8 wk Genotype 3 (prior treatment with simeprevir and sofosbuvir, or simeprevir, boceprevir, or telaprevir with pegylated interferon and ribavirin): 16 wk Compensated cirrhosis (Child-Pugh A) Genotype 1 and NS5A inhibitor prior treatment: 16 wk Genotype 1 and NS3/4A protease inhibitor prior treatment: 12 wk Genotypes 1, 2, 4, 5, or 6 (prior treatment with simeprevir and sofosbuvir, or simeprevir, boceprevir, or telaprevir with pegylated interferon and ribavirin): 12 wk Genotype 3 (prior treatment with simeprevir and sofosbuvir, or simeprevir, boceprevir, or telaprevir with pegylated interferon and ribavirin): 16 wk Hepatic impairment Mild (Child-Pugh A): No dosage adjustment required Moderate (Child-Pugh B): Not recommended Severe (Child-Pugh C): Contraindicated Renal Dose: Renal impairment Mild, moderate, or severe, including patients on dialysis: No dosage adjustment required

Coadministration is contraindicated with rifampin or atazanavir Coadministration is not recommended with carbamazepine, efavirenz, or St John’s wort

Severe hepatic impairment (Child-Pugh C) Coadministration with atazanavir or rifampin

>10% Headache (9-17%) Fatigue (11-14%) Nausea (6-12%) 1-10% Diarrhea (3-7%) Increased bilirubin, ≥2x ULN (3.5%) Pruritus (7%)

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.

Precaution: Hepatitis B virus reactivation in patients coinfected with HCV/HBV may occur

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.

Store at or below 30°C

Hepatic viral infections (Hepatitis C)

Glecaprevir: HCV NS3/4A protease inhibitor; necessary for the proteolytic cleavage of the HCV-encoded polyprotein (into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins) and is essential for viral replication Pibrentasvir: HCV NS5A inhibitor; essential for viral RNA replication and virion assembly

Pregnancy No adequate human data are available to establish whether or not glecaprevir/pibrentasvir poses a risk to pregnancy outcomes Animal studies No adverse developmental effects were observed when glecaprevir and pibrentasvir were administered separately during organogenesis at exposures up to 53 times (rats; glecaprevir) or 51 and 1.5 times (mice and rabbits, respectively; pibrentasvir) the human exposures at the recommended dose Lactation Unknown if distributed in human breast milk When administered to lactating rodents, glecaprevir and pibrentasvir were present in milk, without effect on growth and development observed in the nursing pups Consider the developmental and health benefits of breastfeeding 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