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Mavyret

Generic Name: Glecaprevir And Pibrentasvir
Class: HCV Protease Inhibitors
Chemical Name: methyl N-[(2S,3R)-1-[(2S)-2-[6-[(2R,5R)-1-[3,5-difluoro-4-[4-(4-fluorophenyl)piperidin-1-yl]phenyl]-5-[6-fluoro-2-[(2S)-1-[(2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoyl]pyrrolidin-2-yl]-3H-benzimidazol-5-yl]pyrrolidin-2-yl]-5-fluoro-1H-benzimidazol-2-yl]pyrrolidin-1-yl]-3-methoxy-1-oxobutan-2-yl]carbamate
Molecular Formula: C57H65F5N10O8C38H46F4N6O9S
CAS Number: 1353900-92-1

Warning

WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS COINFECTED WITH HCV AND HBV1

See full prescribing information for complete boxed warning. 1

Hepatitis B virus (HBV) reactivation has been reported, in some cases resulting in fulminant hepatitis, hepatic failure, and death. 1

Introduction

Glecaprevir and pibrentasvir is a fixed combination containing 2 hepatitis C virus (HCV) antivirals; glecaprevir is an HCV NS3/4A protease inhibitor and pibrentasvir is an HCV NS5A inhibitor.1

Uses for Mavyret

Glecaprevir and pibrentasvir has the following uses:

The fixed combination of glecaprevir and pibrentasvir 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). Glecaprevir and pibrentasvir 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. 1

Mavyret Dosage and Administration

General

Glecaprevir and pibrentasvir is available in the following dosage form(s) and strength(s):

Tablets: 100 mg glecaprevir and 40 mg pibrentasvir. 1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

  • Testing Prior to the Initiation of Therapy: Test all patients for HBV infection by measuring HBsAg and anti-HBc. 1

  • Recommended Dosage: Three tablets (total daily dose: glecaprevir 300 mg and pibrentasvir 120 mg) taken orally once daily with food. 1

  • See recommended treatment duration in tables below. 1

Table 1: Recommended Duration for Treatment-Naïve Patients

HCV Genotype

Treatment Duration: No Cirrhosis

Treatment Duration: Compensated Cirrhosis (Child-Pugh A)

1, 2, 3, 4, 5, or 6

8 weeks

12 weeks

Table 2: Recommended Duration for Treatment-Experienced Patients

HCV Genotype

Patients Previously Treated With a Regimen Containing:

Treatment Duration: No Cirrhosis

Treatment Duration: Compensated Cirrhosis (Child-Pugh A)

1

An NS5A inhibitor without prior treatment with an NS3/4A protease inhibitor

16 weeks

16 weeks

An NS3/4A protease inhibitor without prior treatment with an NS5A inhibitor

12 weeks

12 weeks

1, 2, 4, 5, or 6

PRS

8 weeks

12 weeks

3

PRS

16 weeks

16 weeks

In clinical trials, subjects were treated with prior regimens containing ledipasvir and sofosbuvir or daclatasvir with pegylated interferon and ribavirin.

In clinical trials, subjects were treated with prior regimens containing simeprevir and sofosbuvir, or simeprevir, boceprevir, or telaprevir with pegylated interferon and ribavirin.

PRS=Prior treatment experience with regimens containing interferon, pegylated interferon, ribavirin, and/or sofosbuvir, but no prior treatment experience with an HCV NS3/4A PI or NS5A inhibitor.

  • HCV/HIV-1 co-infection and patients with any degree of renal impairment: Follow the dosage recommendations in the tables above. 1

  • Hepatic Impairment: glecaprevir and pibrentasvir is not recommended in patients with moderate hepatic impairment (Child-Pugh B); and is contraindicated in patients with severe hepatic impairment (Child-Pugh C). 1

Cautions for Mavyret

Contraindications

  • Patients with severe hepatic impairment (Child-Pugh C).1

  • Coadministration with atazanavir or rifampin.1

Warnings/Precautions

Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV

Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct-acting antivirals, and who were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure and death. Cases have been reported in patients who are HBsAg positive and also in patients with serologic evidence of resolved HBV infection (i.e., HBsAg negative and anti-HBc positive). HBV reactivation has also been reported in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV direct-acting antivirals may be increased in these patients.1

HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level. In patients with resolved HBV infection reappearance of HBsAg can occur. Reactivation of HBV replication may be accompanied by hepatitis, i.e., increase in aminotransferase levels and, in severe cases, increases in bilirubin levels, liver failure, and death can occur.1

Test all patients for evidence of current or prior HBV infection by measuring HBsAg and anti- HBc before initiating HCV treatment with glecaprevir and pibrentasvir. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with glecaprevir and pibrentasvir and during post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.1

Risk of Reduced Therapeutic Effect Due to Concomitant Use of Glecaprevir and Pibrentasvir with Carbamazepine, Efavirenz Containing Regimens, or St. John’s Wort

Carbamazepine, efavirenz, and St. John’s wort may significantly decrease plasma concentrations of glecaprevir and pibrentasvir, leading to reduced therapeutic effect of glecaprevir and pibrentasvir. The use of these agents with glecaprevir and pibrentasvir is not recommended.1

Specific Populations

Pregnancy

No adequate human data are available to establish whether or not glecaprevir and pibrentasvir poses a risk to pregnancy outcomes. In animal reproduction studies, no adverse developmental effects were observed when the components of 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 of glecaprevir and pibrentasvir. No definitive conclusions regarding potential developmental effects of glecaprevir could be made in rabbits, since the highest achieved glecaprevir exposure in this species was only 7% (0.07 times) of the human exposure at the recommended dose. There were no effects with either compound in rodent pre/post-natal developmental studies in which maternal systemic exposures (AUC) to glecaprevir and pibrentasvir were approximately 47 and 74 times, respectively, the exposure in humans at the recommended dose.1

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.1

Glecaprevir was administered orally to pregnant rats (up to 120 mg/kg/day) and rabbits (up to 60 mg/kg/day) during the period of organogenesis (gestation days [GD] 6 to 18, and GD 7 to 19, respectively). No adverse embryo-fetal effects were observed in rats at dose levels up to 120 mg/kg/day (53 times the exposures in humans at the recommended human dose [RHD]). In rabbits, the highest glecaprevir exposure achieved was 7% (0.07 times) of the exposure in humans at RHD. As such, data in rabbits during organogenesis are not available for glecaprevir systemic exposures at or above the exposures in humans at the RHD. In the pre/post-natal developmental study in rats, glecaprevir was administered orally (up to 120 mg/kg/day) from GD 6 to lactation day 20. No effects were observed at maternal exposures 47 times the exposures in humans at the RHD.1

Pibrentasvir was administered orally to pregnant mice and rabbits (up to 100 mg/kg/day) during the period of organogenesis (GD 6 to 15, and GD 7 to 19, respectively). No adverse embryo-fetal effects were observed at any studied dose level in either species. The systemic exposures at the highest doses were 51 times (mice) and 1.5 times (rabbits) the exposures in humans at the RHD. In the pre/post-natal developmental study in mice, pibrentasvir was administered orally (up to 100 mg/kg/day) from GD 6 to lactation day 20. No effects were observed at maternal exposures approximately 74 times the exposures in humans at the RHD.1

Lactation

It is not known whether the components of glecaprevir and pibrentasvir 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 glecaprevir and pibrentasvir 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 glecaprevir and pibrentasvir and any potential adverse effects on the breastfed child from glecaprevir and pibrentasvir or from the underlying maternal condition. 1

No significant effects of glecaprevir or pibrentasvir on growth and post-natal development were observed in nursing pups at the highest doses tested (120 mg/kg/day for glecaprevir and 100 mg/kg/day for pibrentasvir). Maternal systemic exposure (AUC) to glecaprevir and pibrentasvir was approximately 47 or 74 times the exposure in humans at the RHD. Systemic exposure in nursing pups on post-natal day 14 was approximately 0.6 to 2.2 % of the maternal exposure for glecaprevir and approximately one quarter to one third of the maternal exposure for pibrentasvir. Glecaprevir or pibrentasvir was administered (single dose; 5 mg/kg oral) to lactating rats, 8 to 12 days post parturition. Glecaprevir in milk was 13 times lower than in plasma and pibrentasvir in milk was 1.5 times higher than in plasma. Parent drug (glecaprevir or pibrentasvir) represented the majority (>96%) of the total drug-related material in milk.1

Pediatric Use

Safety and effectiveness of glecaprevir and pibrentasvir in children less than 18 years of age have not been established.1

Geriatric Use

In clinical trials of glecaprevir and pibrentasvir, 328 subjects were age 65 years and over (14% of the total number of subjects in the Phase 2 and 3 clinical trials) and 47 subjects were age 75 and over (2%). No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects. No dosage adjustment of glecaprevir and pibrentasvir is warranted in geriatric patients.1

Renal Impairment

No dosage adjustment of glecaprevir and pibrentasvir is required in patients with mild, moderate or severe renal impairment, including those on dialysis.1

Hepatic Impairment

No dosage adjustment of glecaprevir and pibrentasvir is required in patients with mild hepatic impairment (Child-Pugh A). Glecaprevir and pibrentasvir 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. Glecaprevir and pibrentasvir is contraindicated in patients with severe hepatic impairment (Child-Pugh C) due to higher exposures of glecaprevir and pibrentasvir.1

Common Adverse Effects

In subjects receiving glecaprevir and pibrentasvir, the most commonly reported adverse reactions (greater than 10%) are headache and fatigue. 1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

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 glecaprevir and pibrentasvir is not recommended. 1

Consult the full prescribing information prior to and during treatment for potential drug interactions.1

Actions and Spectrum

Mechanism of Action

Glecaprevir and pibrentasvir is a fixed-dose combination of glecaprevir and pibrentasvir, which are direct-acting antiviral agents against the hepatitis C virus.1

Spectrum

Glecaprevir is an inhibitor of the HCV NS3/4A protease, which is 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. In a biochemical assay, glecaprevir inhibited the proteolytic activity of recombinant NS3/4A enzymes from clinical isolates of HCV genotypes 1a, 1b, 2a, 2b, 3a, 4a, 5a, and 6a with IC50 values ranging from 3.5 to 11.3 nM. 1

Pibrentasvir is an inhibitor of HCV NS5A, which is essential for viral RNA replication and virion assembly. The mechanism of action of pibrentasvir has been characterized based on cell culture antiviral activity and drug resistance mapping studies.1

Evaluation of combination of glecaprevir and pibrentasvir showed no antagonism in antiviral activity in HCV genotype 1 replicon cell culture assays.1

Resistance

In Cell Culture: Selection of HCV genotype 1a, 1b, 2a, 3a, 4a or 6a replicons for reduced susceptibility to glecaprevir resulted in the emergence of amino acid substitutions most commonly at NS3 positions A156 or D/Q168. Individual substitutions at NS3 amino acid position A156 introduced into HCV replicons by site-directed mutagenesis generally caused the greatest reductions (>100-fold) in susceptibility to glecaprevir. Individual substitutions at NS3 position D/Q168 had varying effects on glecaprevir susceptibility depending on HCV genotype/subtype and specific amino acid change, with the greatest reductions (>30-fold) observed in genotypes 1a (D168F/Y), 3a (Q168R) and 6a (D168A/G/H/V/Y). Combinations of NS3 Y56H plus D/Q168 substitutions resulted in greater reductions in glecaprevir susceptibility. An NS3 Q80R substitution in genotype 3a caused a 21-fold reduction in glecaprevir susceptibility, while Q80 substitutions in genotypes 1a and 1b (including genotype 1a Q80K) did not reduce glecaprevir susceptibility. Individual amino acid substitutions associated with resistance to other HCV protease inhibitors at positions 36, 43, 54, 55, 56, 155, 166, or 170 in NS3 generally did not reduce susceptibility to glecaprevir. Selection of HCV genotype 1a, 2a or 3a replicons for reduced susceptibility to pibrentasvir resulted in the emergence of amino acid substitutions at known NS5A inhibitor resistance-associated positions, including Q30D/deletion, Y93D/H/N or H58D +Y93H in genotype 1a replicons, F28S + M31I or P29S + K30G in genotype 2a replicons, and Y93H in genotype 3a replicons. The majority of individual amino acid substitutions associated with resistance to other HCV NS5A inhibitors at positions 24, 28, 30, 31, 58, 92, or 93 in NS5A did not reduce susceptibility to pibrentasvir. Individual NS5A amino acid substitutions that reduced susceptibility to pibrentasvir include M28G or Q30D in a genotype 1a replicon (244- and 94-fold, respectively), and P32-deletion in a genotype 1b replicon (1,036-fold). Some combinations of two or more NS5A inhibitor resistance-associated amino acid substitutions may result in greater reductions in pibrentasvir susceptibility.1

In Clinical Studies: In pooled analyses of NS3/4A PI- and NS5A inhibitor-naïve subjects who received glecaprevir and pibrentasvir for 8, 12, or 16 weeks in Phase 2 and 3 clinical studies, treatment-emergent resistance analyses were conducted for 22 subjects who experienced virologic failure (2 with genotype 1, 2 with genotype 2, 18 with genotype 3 infection). No subjects with HCV genotype 4, 5 or 6 infection experienced virologic failure. Among the two genotype 1-infected subjects who experienced virologic failure, both subjects had a subtype 1a infection. One subject had treatment-emergent substitutions A156V in NS3, and Q30R, L31M and H58D in NS5A (Q30R and L31M were also detected at a low frequency at baseline). One subject had treatment-emergent Q30R and H58D (while Y93N was present at baseline and post-treatment) in NS5A. Among the two genotype 2-infected subjects who experienced virologic failure, both subjects had a subtype 2a infection, and no treatment-emergent substitutions were observed in NS3 or NS5A. Among the 18 genotype 3-infected subjects who experienced virologic failure, treatment-emergent NS3 substitutions Y56H/N, Q80K/R, A156G, or Q168L/R were observed in 11 subjects. A166S or Q168R were present at baseline and post-treatment in 5 subjects. Treatment-emergent NS5A substitutions M28G, A30G/K, L31F, P58T, or Y93H were observed in 16 subjects, and 13 subjects had A30K (n=9) or Y93H (n=5) at baseline and post-treatment. Treatment-emergent resistance analyses were conducted for 11 HCV genotype 1 infected subjects (10 genotype 1a, 1 genotype 1b) with prior NS3/4A PI or NS5A inhibitor treatment experience who experienced virologic failure with glecaprevir and pibrentasvir with or without ribavirin in the MAGELLAN-1 study. Treatment-emergent NS3 substitutions V36A/M, Y56H, R155K/T, A156G/T/V, or D168A/T were observed in 73% (8/11) of subjects. Nine of 10 subjects (90%, not including one subject missing NS5A data at failure) had treatment-emergent NS5A substitutions M28A/G (or L28M for genotype 1b), P29Q/R, Q30K/R, H58D or Y93H/N. All 11 subjects also had NS5A inhibitor resistance-associated substitutions detected at baseline, and 7/11 had NS3 PI resistance-associated substitutions detected at baseline (see Cross-Resistance for the effect of baseline resistance-associated substitutions on treatment response for NS3/4A PI or NS5A inhibitor treatment-experienced patients).1

Cross-Resistance: Based on resistance patterns observed in cell culture replicon studies and HCV-infected subjects, cross-resistance is possible between glecaprevir and other HCV NS3/4A PIs, and between pibrentasvir and other HCV NS5A inhibitors. Cross-resistance is not expected between glecaprevir and pibrentasvir and sofosbuvir, pegylated interferon or ribavirin. In the MAGELLAN-1 study, HCV genotype 1-infected subjects who had failed prior treatment with NS3/4A protease and/or NS5A inhibitors were treated with glecaprevir and pibrentasvir for 12 or 16 weeks. Baseline sequences were analyzed by next generation sequencing at a 15% detection threshold. Among 23 NS3/4A PI-experienced/NS5A inhibitor-naïve subjects who received glecaprevir and pibrentasvir for 12 weeks in MAGELLAN-1 (excluding 2 non-virologic failure subjects), 2 subjects each had baseline NS3 R155K or D168E/V substitutions; all 23 subjects achieved SVR12. Among NS5A inhibitor-experienced/PI-naïve subjects who received glecaprevir and pibrentasvir for 16 weeks, baseline NS5A resistance-associated substitutions [R30Q (n=1), Y93H/N (n=5), M28A+Q30R (n=1), Q30H+Y93H (n=1), Q30R+L31M (n=2), L31M+H58P (n=1)], were detected in 73% (11/15) of subjects with available data, of whom 91% (10/11) achieved SVR12. The non-SVR12 subject experienced on-treatment virologic failure and had a genotype 1a infection with baseline NS5A Q30R and L31M substitutions.1

Advice to Patients

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information). 1

Inform patients that HBV reactivation can occur in patients coinfected with HBV during or after treatment of HCV infection. Advise patients to tell their healthcare provider if they have a history of hepatitis B virus infection.1

Inform patients that glecaprevir and pibrentasvir may interact with some drugs; therefore, patients should be advised to report to their healthcare provider the use of any prescription, non-prescription medication or herbal products.1

Advise patients to take glecaprevir and pibrentasvir recommended dosage (three tablets) once daily with food as directed. Inform patients that it is important not to miss or skip doses and to take glecaprevir and pibrentasvir for the duration that is recommended by the physician.1

If a dose is missed and it is less than 18 hours from the usual time that glecaprevir and pibrentasvir should have been taken, advise the patient to take the dose as soon as possible and then to take the next dose at the usual time.1

If a dose is missed and it is more than 18 hours from the usual time that glecaprevir and pibrentasvir should have been taken, advise the patient not to take the missed dose and to take the next dose at the usual time.1

Additional Information

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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.

Glecaprevir and Pibrentasvir

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablet, Film Coated

40 mg pibrentasvir, 100 mg glecaprevir

Mavyret

AbbVie Inc.

AHFS Drug Information. © Copyright 2017, Selected Revisions August 14, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. AbbVie Inc. Mavyret (Glecaprevir and Pibrentasvir) ORAL prescribing information. 2017 Aug.

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