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Glecaprevir and Pibrentasvir

Pronunciation

(glek A pre vir & pi BRENT as vir)

Index Terms

  • ABT-493 and ABT-530
  • Pibrentasvir and Glecaprevir

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Mavyret: Glecaprevir 100 mg and pibrentasvir 40 mg

Brand Names: U.S.

  • Mavyret

Pharmacologic Category

  • Antihepaciviral, NS3/4A Protease Inhibitor (Anti-HCV)
  • Antihepaciviral, NS5A Inhibitor
  • NS3/4A Inhibitor
  • NS5A Inhibitor

Pharmacology

Glecaprevir is an inhibitor of hepatitis C virus (HCV) NS3/4A protease, 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 is an inhibitor of HCV NS5A, essential for viral RNA replication and virion assembly.

Metabolism

Glecaprevir: Secondary to CYP3A

Excretion

Glecaprevir: Feces (92.1%), urine (0.7%); Pibrentasvir: Feces (96.6%)

Time to Peak

5 hours

Half-Life Elimination

Glecaprevir: 6 hours; Pibrentasvir: 13 hours

Protein Binding

Glecaprevir: 97.5%; Pibrentasvir: >99.9%

Special Populations: Hepatic Function Impairment

Glecaprevir AUC was 100% higher in Child-Pugh class B patients, and increased to 11-fold in Child-Pugh class C patients. Pibrentasvir AUC was 26% higher in Child-Pugh class B patients, and 114% higher in Child-Pugh class C patients.

Use: Labeled Indications

Chronic hepatitis C: Treatment of chronic hepatitis C virus (HCV) genotype 1, 2, 3, 4, 5, or 6 infection in adults without cirrhosis or with compensated cirrhosis (Child-Pugh class A); HCV genotype 1 infection in adults previously treated with a regimen containing an HCV NS5A inhibitor or an NS3/4A protease inhibitor, but not both

Contraindications

Severe hepatic impairment (Child-Pugh class C); coadministration with atazanavir or rifampin

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to glecaprevir, pibrentasvir, or any component of the formulation; coadministration with atorvastatin, dabigatran, ethinyl estradiol, or simvastatin.

Dosing: Adult

Chronic hepatitis C (HCV monoinfected or HCV/HIV co-infected patients): Without cirrhosis or with compensated cirrhosis (Child-Pugh class A): Oral:

Treatment-naive patients:

Genotype 1, 2, 3, 4, 5, or 6: Three tablets once daily for 8 weeks (without cirrhosis) or 12 weeks (with compensated cirrhosis [Child-Pugh class A]).

Treatment-experienced patients:

Genotype 1: Prior treatment with an NS5A inhibitor containing regimen without an NS3/4A protease inhibitor (alternative regimen): Three tablets once daily for 16 weeks (AASLD/IDSA 2017)

Genotype 1: Prior treatment with an NS3/4A protease inhibitor containing regimen without an NS5A inhibitor: Three tablets once daily for 12 weeks

Genotype 1, 2, 4, 5, or 6: Prior treatment with regimens containing interferon (including pegylated formulations) and/or ribavirin but no prior treatment with an NS3/4A protease inhibitor or NS5A inhibitor: Three tablets once daily for 8 weeks (without cirrhosis) or 12 weeks (with compensated cirrhosis [Child-Pugh class A]) (AASLD/IDSA 2017)

Genotype 1 or 2: Prior treatment with regimens containing sofosbuvir, but no prior treatment with an NS3/4A protease inhibitor or NS5A inhibitor: Three tablets once daily for 12 weeks without cirrhosis or with compensated cirrhosis (Child-Pugh class A) (AASLD/IDSA 2017)

Genotype 3: Prior treatment with regimens containing interferon (including pegylated formulations), ribavirin, and/or sofosbuvir, but no prior treatment with an NS3/4A protease inhibitor or NS5A inhibitor (alternative regimen): Three tablets once daily for 16 weeks (AASLD/IDSA 2017)

Liver transplant recipients:

Genotypes 1, 2, 3, 4, 5, or 6: Treatment-naive and experienced without cirrhosis or with compensated cirrhosis (Child-Pugh class A; alternative regimen for compensated cirrhosis): Three tablets once daily for 12 weeks (AASLD/IDSA 2017)

Kidney transplant recipients:

Genotypes 1, 2, 3, 4, 5, or 6: Treatment-naive and experienced without cirrhosis or with compensated cirrhosis (Child-Pugh class A): Three tablets once daily for 12 weeks (AASLD/IDSA 2017)

Missed dose: If <18 hours from the usual dosage time, administer dose as soon as possible, then administer next dose at usual dosage time. If >18 hours from the usual dosage time, skip the missed dose and administer the next dose at usual dosage time

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

No dosage adjustment necessary.

Dosing: Hepatic Impairment

Mild impairment (Child-Pugh class A): No dosage adjustment necessary

Moderate impairment (Child-Pugh class B): Use is not recommended

Severe impairment (Child-Pugh class C): Use is contraindicated

Administration

Administer orally with food.

Storage

Store at ≤30°C (86°F).

Drug Interactions

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Per US labeling: reduce afatinib by 10mg if not tolerated. Per Canadian labeling: avoid combination if possible; if used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. Consider therapy modification

ARIPiprazole: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

Asunaprevir: OATP1B1/SLCO1B1 Inhibitors may increase the serum concentration of Asunaprevir. Avoid combination

Atazanavir: May increase the serum concentration of Glecaprevir and Pibrentasvir. Avoid combination

AtorvaSTATin: Glecaprevir and Pibrentasvir may increase the serum concentration of AtorvaSTATin. Avoid combination

Betrixaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Betrixaban. Management: Decrease the betrixaban dose to an initial single dose of 80 mg followed by 40 mg once daily if combined with a P-glycoprotein inhibitor. Consider therapy modification

Bilastine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bilastine. Management: Consider alternatives when possible; bilastine should be avoided in patients with moderate to severe renal insufficiency who are receiving p-glycoprotein inhibitors. Consider therapy modification

Brentuximab Vedotin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy

CarBAMazepine: May decrease the serum concentration of Glecaprevir and Pibrentasvir. Avoid combination

Celiprolol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Celiprolol. Monitor therapy

CloZAPine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of CloZAPine. Monitor therapy

Cobicistat: May increase the serum concentration of Glecaprevir and Pibrentasvir. Monitor therapy

Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. See full monograph for details. Consider therapy modification

CycloSPORINE (Systemic): May increase the serum concentration of Glecaprevir and Pibrentasvir. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Glecaprevir and Pibrentasvir. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Glecaprevir and Pibrentasvir. Monitor therapy

Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Management: Dabigatran dose reductions may be needed. Specific recommendations vary considerably according to US vs Canadian labeling, specific P-gp inhibitor, renal function, and indication for dabigatran treatment. Refer to full monograph or dabigatran labeling. Consider therapy modification

Darunavir: May increase the serum concentration of Glecaprevir and Pibrentasvir. Avoid combination

Digoxin: Glecaprevir and Pibrentasvir may increase the serum concentration of Digoxin. Management: Measure serum digoxin concentrations before initiating glecaprevir/pibrentasvir. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 50% or by modifying the dosing frequency; continue monitoring during concomitant therapy. Consider therapy modification

Dofetilide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Dofetilide. Monitor therapy

DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. Consider therapy modification

Efavirenz: May decrease the serum concentration of Glecaprevir and Pibrentasvir. Avoid combination

Eltrombopag: May increase the serum concentration of OATP1B1/SLCO1B1 Substrates. Monitor therapy

Eltrombopag: May increase the serum concentration of BCRP/ABCG2 Substrates. Monitor therapy

Ethinyl Estradiol: May enhance the adverse/toxic effect of Glecaprevir and Pibrentasvir. Specifically, the risk for ALT elevation may be increased with this combination. Avoid combination

Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Monitor therapy

Flibanserin: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Flibanserin. Monitor therapy

Gemfibrozil: May increase the serum concentration of OATP1B1/SLCO1B1 Substrates. See separate drug interaction monographs for agents listed as exceptions. Monitor therapy

Grazoprevir: OATP1B1/SLCO1B1 Inhibitors may increase the serum concentration of Grazoprevir. Avoid combination

HMG-CoA Reductase Inhibitors (Statins): Glecaprevir and Pibrentasvir may increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Management: Use the lowest statin dose possible if combined with glecaprevir/pibrentasvir and monitor for increased statin effects/toxicities. Avoid concomitant use with atorva-, simva-, or lovastatin. Limit rosuvastatin to 10 mg daily and reduce pravastatin dose 50% Consider therapy modification

Irinotecan Products: UGT1A1 Inhibitors may increase serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, concentrations of SN-38 may be increased. UGT1A1 Inhibitors may increase the serum concentration of Irinotecan Products. Avoid combination

Lomitapide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lomitapide. Management: Patients on lomitapide 5 mg/day may continue that dose. Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half. The lomitapide dose may then be titrated up to a max adult dose of 30 mg/day. Consider therapy modification

Lopinavir: May increase the serum concentration of Glecaprevir and Pibrentasvir. Avoid combination

Lovastatin: Glecaprevir and Pibrentasvir may increase the serum concentration of Lovastatin. Avoid combination

Naldemedine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naldemedine. Monitor therapy

Naloxegol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol. Monitor therapy

NiMODipine: CYP3A4 Inhibitors (Weak) may increase the serum concentration of NiMODipine. Monitor therapy

Osimertinib: May increase the serum concentration of BCRP/ABCG2 Substrates. Monitor therapy

PAZOPanib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

PAZOPanib: BCRP/ABCG2 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of Glecaprevir and Pibrentasvir. Monitor therapy

P-glycoprotein/ABCB1 Substrates: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Avoid combination

Prucalopride: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride. Monitor therapy

Ranolazine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ranolazine. Monitor therapy

Regorafenib: May increase the serum concentration of BCRP/ABCG2 Substrates. Monitor therapy

RifAMPin: May decrease the serum concentration of Glecaprevir and Pibrentasvir. RifAMPin may increase the serum concentration of Glecaprevir and Pibrentasvir. Specifically, a single dose of rifampin may increase glecaprevir/pibrentasvir concentrations, while chronic daily use of rifampin may decrease glecaprevir/pibrentasvir concentrations. Avoid combination

RifAXIMin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin. Monitor therapy

Rolapitant: May increase the serum concentration of BCRP/ABCG2 Substrates. Management: Monitor patients receiving rolapitant for increased exposure to and/or effects of BCRP/ABCG2 substrates. Use the lowest effective rosuvastatin dose when used in combination with rolapitant. Monitor therapy

Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Avoid combination

Simvastatin: Glecaprevir and Pibrentasvir may increase the serum concentration of Simvastatin. Avoid combination

St John's Wort: May decrease the serum concentration of Glecaprevir and Pibrentasvir. Avoid combination

Tacrolimus (Systemic): Glecaprevir and Pibrentasvir may increase the serum concentration of Tacrolimus (Systemic). Monitor therapy

Tedizolid: May increase the serum concentration of BCRP/ABCG2 Substrates. Monitor therapy

Teriflunomide: May increase the serum concentration of BCRP/ABCG2 Substrates. Monitor therapy

Teriflunomide: May increase the serum concentration of OATP1B1/SLCO1B1 Substrates. Monitor therapy

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use is necessary, initiate tizanidine at an adult dose of 2 mg and increase in 2 to 4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

Tolvaptan: May increase the serum concentration of OATP1B1/SLCO1B1 Substrates. Consider therapy modification

Tolvaptan: May increase the serum concentration of OATP1B3/SLCO1B3 Substrates. Consider therapy modification

Tolvaptan: May increase the serum concentration of BCRP/ABCG2 Substrates. Consider therapy modification

Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Avoid combination

Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations. Consider therapy modification

VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination

Voxilaprevir: OATP1B1/SLCO1B1 Inhibitors may increase the serum concentration of Voxilaprevir. Avoid combination

Voxilaprevir: May increase the serum concentration of BCRP/ABCG2 Substrates. Avoid combination

Adverse Reactions

>10%

Central nervous system: Headache (9% to 17%), fatigue (11% to 14%)

Gastrointestinal: Nausea (6% to 12%)

1% to 10%:

Gastrointestinal: Diarrhea (3% to 7%)

Hepatic: Increased serum bilirubin (4%; 2x ULN)

ALERT: U.S. Boxed Warning

Hepatitis B virus reactivation:

Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with glecaprevir and pibrentasvir. HBV reactivation has been reported in hepatitis C virus (HCV)/HBV coinfected patients who were undergoing or had completed treatment with HCV direct-acting antivirals and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Monitor HCV/HBV co-infected patients for hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.

Warnings/Precautions

Disease-related concerns:

• Hepatic impairment: Use is not recommended in patients with moderate impairment (Child-Pugh class B); use is contraindicated in patients with severe impairment (Child-Pugh class C).

• Hepatitis B virus reactivation: [US Boxed Warning]: Hepatitis B virus (HBV) reactivation has been reported in hepatitis C virus (HCV)/HBV coinfected patients who were receiving or had completed treatment with HCV direct-acting antivirals and were not receiving HBV antiviral therapy; some cases have resulted in fulminant hepatitis, hepatic failure, and death. Test all patients for evidence of current or prior HBV infection prior to initiation of treatment; monitor HCV/HBV co-infected patients for hepatitis flare or HBV reactivation during treatment and post-treatment follow-up. Initiate treatment for HBV infection as clinically indicated. HBV reactivation has been reported in HBsAg positive patients and in patients with serologic evidence of resolved HBV infection (ie, HBsAg negative and anti-HBc positive) and is characterized by an abrupt increase in HBV replication manifested as a rapid increase in serum HBV DNA level; reappearance of HBsAg may occur in patients with resolved HBV infection. Risk of HBV reactivation may be increased in patients receiving certain immunosuppressants or chemotherapeutic agents.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustments, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Monitoring Parameters

Baseline (within 12 weeks prior to starting antiviral therapy) CBC, INR, hepatic function panel (albumin, total and direct bilirubin, ALT, AST, and alkaline phosphatase), and calculated GFR; repeat CBC, serum creatinine, calculated GFR, and hepatic function panel after 4 weeks of therapy and as clinically indicated; baseline (at any time prior to starting therapy) hepatitis C virus (HCV) genotype and subtype and quantitative HCV viral load; repeat quantitative HCV viral load testing (after 4 weeks of therapy and at 12 weeks after completion of therapy). If quantitative HCV viral load is detectable at treatment week 4, repeat testing is recommended after 2 additional weeks of treatment (treatment week 6) (AASLD/IDSA 2017). Hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) prior to initiation; in patients with serologic evidence of hepatitis B virus (HBV) infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during treatment and during post-treatment follow-up.

Pregnancy Considerations

Adverse events were not observed in animal reproduction studies with glecaprevir or pibrentasvir as individual agents.

Treatment of hepatitis C is not currently recommended to treat maternal infection or to decrease the risk of mother-to-child transmission during pregnancy (Tran 2016). HCV-infected females of childbearing potential should consider postponing pregnancy until therapy is complete to reduce the risk of HCV transmission (AASLD/IDSA 2017). When HCV infection is detected during pregnancy, treatment should be deferred until after delivery. Direct-acting antiviral medications should not be used in pregnant females outside of clinical trials until safety and efficacy information is available (SMFM [Hughes 2017]).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, loss of strength and energy, nausea, or diarrhea. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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