Glecaprevir And Pibrentasvir

Class: HCV Protease Inhibitors
Chemical Name: (3aR,7S,10S,12R,21E,24aR)-7-tert-butyl-N-((1R,2R)-2-(difluoromethyl)-1-((1-methylcyclopropane-1-sulfonyl)carbamoyl)cyclopropyl)-20,20-difluoro-5,8-dioxo-2,3,3a,5,6,7,8,11,12,20,23,24a-dodecahydro-1H,10H-9,12-methanocyclopenta(18,19)(1,10,17,3,6)trioxadiazacyclononadecino(11,12- b)quinoxaline-10-carboxamide
Molecular Formula: C₃₈H₄₆F₄N₆O₉SC₅₇H₆₅F₅N₁₀O₈
CAS Number: 1365970-03-1
Brands: Mavyret

Medically reviewed on Oct 1, 2018

Introduction

HCV antiviral;¹ fixed combination containing glecaprevir (HCV nonstructural 3/4A [NS3/4A] protease inhibitor) and pibrentasvir (HCV NS5A replication complex inhibitor [NS5A inhibitor]).¹

Uses for Glecaprevir And Pibrentasvir

Chronic HCV Infection

Treatment of chronic HCV genotype 1, 2, 3, 4, 5, or 6 infection in treatment-naive (previously untreated) or previously treated adults without cirrhosis or with compensated cirrhosis, including those with HIV coinfection.^{1 3 4 5 6 7 119}

Treatment of chronic HCV infection is complex and rapidly evolving; consult a specialist to obtain the most up-to-date information.¹¹⁹ Information from the American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America (IDSA) regarding diagnosis and management of HCV infection, including recommendations for initial treatment, is available at [Web].¹¹⁹

Glecaprevir And Pibrentasvir Dosage and Administration

General

• Prior to initiating HCV treatment, test all patients for evidence of current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc).^{1 25 119} (See Risk of HBV Reactivation in Patients Coinfected with HCV and HBV under Cautions.)

• Prior to and during treatment, perform appropriate laboratory tests to evaluate liver function.¹¹⁹ (See Hepatic Impairment under Cautions.)

Administration

Oral Administration

Administer orally once daily with food.¹

Dosage

Available as fixed-combination tablets containing 100 mg of glecaprevir and 40 mg of pibrentasvir.¹

Adults

Treatment of Chronic HCV Infection

HCV Genotype 1, 2, 3, 4, 5, or 6 Infection

Oral

3 tablets (total of 300 mg of glecaprevir and 120 mg of pibrentasvir) once daily.¹ Treatment duration depends on HCV genotype, previous HCV treatment experience, and presence of compensated cirrhosis.¹ (See Tables 1 and 2.)

Previously received HCV regimen containing interferon, peginterferon, ribavirin, and/or sofosbuvir; no previous treatment with HCV NS3/4A protease inhibitors or HCV NS5A inhibitors.¹

In clinical trials, patients previously received HCV regimens containing the fixed combination of ledipasvir and sofosbuvir (ledipasvir/sofosbuvir) or daclatasvir in conjunction with peginterferon and ribavirin.¹

In clinical trials, patients previously received HCV regimens containing simeprevir in conjunction with sofosbuvir or simeprevir (or boceprevir or telaprevir [no longer commercially available]) in conjunction with peginterferon and ribavirin.¹

HCV-infected Individuals Coinfected with HIV

Oral

Dosage and duration of therapy generally same as those recommended for adults without HIV coinfection.^{1 119} (See Specific Drugs under Interactions.)

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): Dosage adjustments not needed.¹

Moderate hepatic impairment (Child-Pugh class B): Not recommended.¹ (See Hepatic Impairment under Cautions.)

Severe hepatic impairment (Child-Pugh class C): Contraindicated.¹

Renal Impairment

Mild, moderate, or severe renal impairment (including hemodialysis patients): Dosage adjustments not needed.¹ Not removed by hemodialysis to any clinically important extent.¹

Geriatric Patients

Dosage adjustments not needed.¹ (See Geriatric Use under Cautions.)

Cautions for Glecaprevir And Pibrentasvir

Contraindications

• Severe hepatic impairment (Child-Pugh class C).¹

• Concomitant use with certain drugs (e.g., atazanavir, rifampin).¹ (See Specific Drugs under Interactions.)

Warnings/Precautions

Warnings

Risk of HBV Reactivation in Patients Coinfected with HCV and HBV

Postmarketing reports of reactivation of HBV infection when DAAs were used for treatment of HCV infection in patients with HBV coinfection;^{1 25} fulminant hepatitis, hepatic failure, and death reported in some cases.^{1 25}

HBV reactivation (abrupt increase in HBV replication manifested as rapid increase in serum HBV DNA levels or detection of HBsAg in an individual who was previously HBsAg negative and anti-HBc positive) reported in patients with HCV and HBV coinfection receiving HCV treatment with a regimen that included HCV DAAs without HBV antiviral therapy.^{1 25} HBV reactivation usually occurred within 4–8 weeks after initiation of HCV treatment.²⁵

Patients with HBV reactivation heterogeneous in terms of HCV genotype and baseline HBV disease.²⁵ Some patients were HBsAg positive; others had serologic evidence of resolved HBV infection (i.e., HBsAg negative and anti-HBc positive).^{1 25}

HBV reactivation also reported in patients receiving certain immunosuppressant or chemotherapeutic drugs;¹ risk of reactivation associated with HCV DAAs may be increased in such patients.¹

Mechanism for HBV reactivation in coinfected patients receiving HCV DAAs unknown.²⁵ Although HCV DAAs not known to cause immunosuppression, HBV reactivation in coinfected patients may result from a complex interplay of host immunologic responses in the setting of infection with 2 hepatitis viruses.²⁵

Prior to initiating treatment with an HCV DAA, including glecaprevir/pibrentasvir, screen all patients for evidence of current or prior HBV infection by measuring HBsAg, anti-HBs, and anti-HBc.^{1 25 119} If there is serologic evidence of HBV infection, measure baseline HBV DNA level.^{25 119}

In all patients with evidence of current or prior HBV infection, monitor for clinical and laboratory signs (i.e., HBsAg, HBV DNA levels, serum aminotransferase and bilirubin concentrations) of hepatitis flare or HBV reactivation during and after treatment with HCV DAAs.^{1 25 119} Initiate appropriate management for HBV infection as clinically indicated ^{1 119}

Advise coinfected patients to immediately contact a clinician if they develop any signs or symptoms of serious liver injury.²⁵ (See Advice to Patients.)

When making decisions regarding HBV monitoring or HBV treatment in coinfected patients, consult a clinician with expertise in managing HBV infection.^{25 119}

Other Warnings and Precautions

Interactions

Concomitant use with certain drugs (i.e., carbamazepine, efavirenz, St. John's wort) may result in clinically important decreases in glecaprevir and pibrentasvir plasma concentrations leading to reduced therapeutic effect of glecaprevir/pibrentasvir.¹ Concomitant use with such drugs not recommended.¹ (See Specific Drugs under Interactions.)

Precautions Related to Fixed Combinations

Consider cautions, precautions, contraindications, and drug interactions associated with both drugs in the fixed combination.¹ Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for both glecaprevir and pibrentasvir.¹

Specific Populations

Pregnancy

Adequate data not available regarding use in pregnant women.¹ In animal studies, no adverse effects on fetal development at glecaprevir or pibrentasvir exposures 53 or 51 times greater, respectively, than human exposures at recommended human dosage.¹

Lactation

Not known whether glecaprevir or pibrentasvir distributed into human milk, affect human milk production, or affect the breast-fed infant.¹

Glecaprevir and pibrentasvir distributed into milk in rodents;¹ no apparent effects on growth and development observed in nursing pups.¹

Consider benefits of breast-feeding and importance of glecaprevir/pibrentasvir to the woman; also consider potential adverse effects on breast-fed child from the drug or underlying maternal condition.¹

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.¹

Geriatric Use

No overall differences in safety and efficacy observed between patients ≥65 years of age and younger adults.¹

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): Dosage adjustments not needed.¹

Moderate hepatic impairment (Child-Pugh class B): Safety and efficacy not established;¹ not recommended.¹

Severe hepatic impairment (Child-Pugh class C): Contraindicated;¹ substantially increased glecaprevir and pibrentasvir AUCs.¹

Renal Impairment

Mild, moderate, and severe renal impairment: Glecaprevir and pibrentasvir AUCs up to 56% higher compared with normal renal function;¹ AUCs not affected by dialysis.¹

HCV-infected individuals with end-stage renal disease (ESRD): Glecaprevir and pibrentasvir AUCs 86 and 54% higher, respectively, compared with normal renal function.¹

Common Adverse Effects

Pruritus,^{1 3 4} headache,^{1 3 5 6 7} fatigue,^{1 3 4 5 6 7} nausea,^{1 3 4 5} diarrhea,^{1 3} asthenia,¹ urinary tract infection.³

Interactions for Glecaprevir And Pibrentasvir

Glecaprevir and pibrentasvir are weak inhibitors of CYP3A and 1A2.¹ Glecaprevir is a substrate of CYP3A.^{1 2}

Glecaprevir and pibrentasvir inhibit P-glycoprotein (P-gp) transport system and are substrates of P-gp.¹

Glecaprevir and pibrentasvir inhibit breast cancer resistance protein (BCRP) and are substrates of BCRP.¹

Glecaprevir and pibrentasvir inhibit organic anion transporting polypeptide (OATP) 1B1 and 1B3.¹ Glecaprevir is a substrate of OATP1B1 and 1B3.¹

Glecaprevir and pibrentasvir are weak inhibitors of UGT1A1.¹

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A, 1A2, 2C9, 2C19, or 2D6: Clinically important pharmacokinetic interactions not expected.¹

CYP3A4 inducers: Possible decreased glecaprevir and pibrentasvir plasma concentrations.¹

Drugs Affecting or Affected by P-glycoprotein Transport System

P-gp substrates: Possible increased concentrations of P-gp substrates.¹

P-gp inducers: Possible decreased glecaprevir and pibrentasvir plasma concentrations.¹

P-gp inhibitors: Possible increased glecaprevir and pibrentasvir plasma concentrations.¹

Drugs Affecting or Affected by Breast Cancer Resistance Protein

BCRP substrates: Possible increased concentrations of BCRP substrates.¹

BCRP inducers: Possible decreased glecaprevir and pibrentasvir plasma concentrations.¹

BCRP inhibitors: Possible increased glecaprevir and pibrentasvir plasma concentrations.¹

Drugs Affecting or Affected by Organic Anion Transporting Polypeptides

OATP1B1 or 1B3 substrates: Possible increased concentrations of these substrates.¹

OATP1B1 or 1B3 inducers: Possible decreased glecaprevir plasma concentrations.¹

OATP1B1 or 1B3 inhibitors: Possible increased glecaprevir plasma concentrations.¹

Drugs Affecting or Affected by Other Membrane Transporters

UGT1A1 or 1A4 substrates: Clinically important pharmacokinetic interactions not expected.¹

Specific Drugs

Glecaprevir And Pibrentasvir Pharmacokinetics

Absorption

Bioavailability

Following oral administration of glecaprevir/pibrentasvir in healthy individuals, peak plasma concentrations of glecaprevir and pibrentasvir occur 5 hours after the dose.¹

Food

Administration of glecaprevir/pibrentasvir with a moderate- to high-fat meal increases glecaprevir exposures by 83–163% and increases pibrentasvir exposures by 40–53% relative to administration in the fasting state.¹

Special Populations

HCV-infected individuals with compensated cirrhosis (Child-Pugh class A): Glecaprevir exposures approximately twofold higher than those reported in individuals with normal hepatic function;¹ pibrentasvir exposures similar to those in individuals with normal hepatic function.¹

HCV-infected individuals with moderate hepatic impairment (Child-Pugh class B): Glecaprevir exposures twofold higher and pibrentasvir exposures 26% higher than those in individuals with normal hepatic function.¹

HCV-infected individuals with severe hepatic impairment (Child-Pugh class C): Glecaprevir exposures 11-fold higher and pibrentasvir exposures 114% higher than those in individuals with normal hepatic function.¹

Mild, moderate, severe, or ESRD without HCV infection: Glecaprevir and pibrentasvir exposures up to 56% higher than those in individuals with normal renal function.¹ In dialysis-dependent individuals, pibrentasvir and glecaprevir exposures similar with or without dialysis (up to 18% difference).¹

HCV-infected individuals with ESRD (with or without dialysis): Glecaprevir and pibrentasvir exposures 86 and 54% higher, respectively, than reported in individuals with normal renal function.¹

Distribution

Plasma Protein Binding

Glecaprevir: 97.5%.¹

Pibrentasvir: >99.9%.¹

Elimination

Metabolism

Glecaprevir: Metabolized to some extent by CYP3A.¹

Pibrentasvir: None.¹

Elimination Route

Glecaprevir: Biliary and fecal excretion.¹ Following a single dose, 92.1% excreted in feces and 0.7% eliminated in urine.¹

Pibrentasvir: Biliary and fecal excretion.¹ Following a single dose, 96.6% excreted in feces; no drug eliminated in urine.¹

Half-life

Glecaprevir: 6 hours.¹

Pibrentasvir: 13 hours.¹

Stability

Storage

Oral

Tablets

≤30°C.¹

Actions and Spectrum

• Glecaprevir/pibrentasvir is a fixed combination containing 2 HCV antivirals.¹ Glecaprevir is an HCV NS3/4A protease inhibitor and pibrentasvir is an HCV NS5A replication complex inhibitor (NS5A inhibitor).¹

• Glecaprevir and pibrentasvir are both direct-acting antivirals (DAAs) with activity against HCV.¹ No in vitro evidence of antagonistic anti-HCV effects between the drugs in replicon studies.¹

• Glecaprevir binds to the active site of HCV NS3/4A protease, thereby blocking enzyme activity essential for viral replication (i.e., blocking cleavage of the HCV-encoded polyproteins into mature forms of NS3, NS4A, NS4B, NS5A, and NS5B).^{1 8} In vitro studies using biochemical assays indicate that glecaprevir has activity against clinical isolates of HCV genotypes 1a, 1b, 2a, 2b, 3a, 4a, 5a, and 6a.¹

• Pibrentasvir inhibits the HCV NS5A protein, which is required for viral replication and virion assembly.¹ In HCV replicon assays, pibrentasvir has shown in vitro activity against laboratory and clinical isolates of HCV genotypes 1a, 1b, 2a, 2b, 3a, 4a, 4b, 4d, 5a, 6a, 6e, and 6p.¹

• Certain amino acid substitutions in NS3/4A protease inhibitor resistance-associated positions of HCV genotypes 1a (e.g., D168F/Y), 1b, 2a, 3a (e.g., Q168R), 4a, and 6a (e.g., D168A/G/H/V/Y) have been selected in cell culture and have been associated with reduced susceptibility to glecaprevir in vitro in replicon studies.¹ Emergence of amino acid substitutions occurred most commonly at NS3 positions A156 or D/Q168.¹ The combination of NS3 resistance-associated substitutions Y56H and D/Q168 resulted in greater reductions in glecaprevir susceptibility.¹ Treatment-emergent NS3 resistance-associated substitutions were detected in clinical trials evaluating glecaprevir/pibrentasvir in patients with HCV genotype 1 (e.g., A156V, V36A/M, Y56H, R155K/T, A156G/T/V, D168A/T) or genotype 3 (e.g., Y56H/N, Q80K/R, A156G, Q168L/R) infection who experienced virologic failure.¹

• Certain amino acid substitutions in NS5A of HCV genotype 1a (e.g., Q30D/deletion, Y93D/H/N, H58D and Y93H, M28G), genotype 1b (e.g., P32-deletion), genotype 2a (e.g., F28S and M31I, P29S and K30G), and genotype 3a (e.g., Y93H) have been selected in cell culture and have been associated with reduced susceptibility to pibrentasvir in vitro in replicon studies.¹ Combinations of these NS5A substitutions often resulted in greater reductions in susceptibility to pibrentasvir compared with a single NS5A substitution.¹ Treatment-emergent NS5A resistance-associated substitutions were detected in clinical trials evaluating glecaprevir/pibrentasvir in patients with HCV genotype 1 (e.g., Q30R, L31M, M28A/G, L28M, P29Q/R, Q30K/R, H58D, Y93H/N) or genotype 3a (e.g., M28G, A30G/K, L31F, P58T, Y93H) infection who experienced virologic failure.¹ Some of these patients also had baseline NS5A polymorphisms at resistance-associated amino acid positions.¹

• Cross-resistance is possible between glecaprevir and other HCV NS3/4A protease inhibitors and between pibrentasvir and other HCV NS5A inhibitors.¹ Cross-resistance not expected between glecaprevir/pibrentasvir and sofosbuvir, peginterferon, or ribavirin.¹

Advice to Patients

• Importance of reading patient information provided by the manufacturer.¹

• Advise patients that the fixed-combination preparation of glecaprevir and pibrentasvir (glecaprevir/pibrentasvir) should be taken once daily with food on a regular dosing schedule.¹

• Importance of taking the recommended dosage of glecaprevir/pibrentasvir for the recommended duration of treatment;¹ importance of not missing doses.¹

• If a dose is missed and remembered <18 hours after the scheduled administration time, take glecaprevir/pibrentasvir as soon as possible and then take the next dose at the usual time.¹ If a dose is missed and remembered >18 hours after the schedule administration time, skip the missed dose and take the next dose at the usual time.¹

• Inform patients that reactivation of HBV infection has occurred in patients being treated for HCV infection who were coinfected with HBV.^{1 25} Importance of informing clinician of any history of HBV infection or other liver problems (e.g., cirrhosis).^{1 25} Importance of immediately contacting a clinician if any signs or symptoms of serious liver injury (e.g., fatigue, weakness, loss of appetite, nausea and vomiting, yellowing of the eyes or skin, light-colored bowel movements) occur.²⁵ (See Risk of HBV Reactivation in Patients Coinfected with HCV and HBV under Cautions.)

• Advise patients that glecaprevir/pibrentasvir may interact with some drugs.¹ Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.¹

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

• Importance of informing patients of other important precautionary information.¹ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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