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Elbasvir and Grazoprevir

Medically reviewed on Nov 15, 2018

Pronunciation

See also: Harvoni

(ELB as vir & graz OH pre vir)

Index Terms

  • Grazoprevir and Elbasvir

Dosage Forms

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

Tablet, Oral:

Zepatier: Elbasvir 50 mg and grazoprevir 100 mg

Brand Names: U.S.

  • Zepatier

Pharmacologic Category

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

Pharmacology

Elbasvir is an inhibitor of HCV NS5A, which is essential for viral replication and virion assembly.

Grazoprevir is an inhibitor of 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.

Absorption

Not affected by meals.

Distribution

Elbasvir: Distribution into most tissue including hepatic; Grazoprevir: Predominantly hepatic distribution

Vd: Elbasvir: ~680 L; Grazoprevir: ~1,250 L

Metabolism

Elbasvir, Grazoprevir: Hepatic (partial oxidative metabolism via CYP3A); metabolites not detected in plasma

Excretion

Feces (>90%); urine (<1%)

Time to Peak

Elbasvir: Median: 3 hours (range: 3 to 6 hours); Grazoprevir: Median: 2 hours (range: 30 minutes to 3 hours)

Half-Life Elimination

Elbasvir: ~24 hours; Grazoprevir: ~31 hours

Protein Binding

Elbasvir: >99.9% (albumin, alpha-1 acid glycoprotein); Grazoprevir: 98.8% (albumin, alpha-1 acid glycoprotein)

Use: Labeled Indications

Chronic hepatitis C: Treatment of chronic hepatitis C virus (HCV) genotype 1 or 4 infection in adults; used with ribavirin in certain patient populations.

Off Label Uses

Chronic hepatitis C (genotype 3)

Based on the American Association for the Study of Liver Diseases/Infectious Diseases Society of America (AASLD/IDSA 2017) Recommendations for Testing, Managing, and Treating Hepatitis C guidelines, elbasvir/grazoprevir, in combination with sofosbuvir, is an effective and recommended treatment of genotype 3 HCV in peginterferon/ribavirin treatment-experienced patients with compensated cirrhosis (Child-Pugh class A). Hepatitis C treatment guidelines are constantly changing with the advent of new treatment therapies and information; consult current clinical practice guidelines for the most recent treatment recommendations.

Contraindications

Moderate or severe hepatic impairment (Child-Pugh class B or C); concurrent use with organic anion transporting polypeptides 1B1/3 (OATP1B1/3) inhibitors that are known or expected to significantly increase grazoprevir plasma concentrations and strong inducers of cytochrome P450 3A (CYP3A). Concurrent use of drugs that are contraindicated include, but are not necessarily limited to: Atazanavir, carbamazepine, cyclosporine, darunavir, efavirenz, lopinavir, phenytoin, rifampin, saquinavir, St John's wort, tipranavir. If used with ribavirin, contraindications of ribavirin also apply. See ribavirin prescribing information.

Canadian labeling (not in US labeling): Hypersensitivity to elbasvir, grazoprevir, or any component of the formulation. If used with sofosbuvir, contraindications of sofosbuvir also apply. See sofosbuvir prescribing information.

Dosing: Adult

Chronic hepatitis C (genotype 1a or 1b) (monoinfection or coinfection with HIV-1): Oral:

Genotype 1a:

Treatment naive or peginterferon alfa + ribavirin treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh class A) without baseline NS5A polymorphisms: One tablet once daily for 12 weeks

Treatment naive or peginterferon alfa + ribavirin treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh class A) with baseline NS5A polymorphisms (alternative agent): One tablet once daily with concomitant ribavirin for 16 weeks (AASLD/IDSA 2017)

Peginterferon alfa + ribavirin + NS3/4A protease inhibitor treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh class A) and without baseline NS5A polymorphisms (alternative agent): One tablet once daily with concomitant ribavirin for 12 weeks (AASLD/IDSA 2017)

Peginterferon alfa + ribavirin + NS3/4A protease inhibitor treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh class) and with baseline NS5A polymorphisms (alternative agent): One tablet once daily with concomitant ribavirin for 16 weeks (AASLD/IDSA 2017)

Genotype 1b:

Treatment naive or peginterferon alfa + ribavirin treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh class A): One tablet once daily for 12 weeks

Peginterferon + ribavirin + NS3/4A protease inhibitor treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh class A) (alternative agent): One tablet once daily with concomitant ribavirin for 12 weeks (AASLD/IDSA 2017)

Chronic hepatitis C (genotype 3) (off-label use): Oral: Peginterferon alfa + ribavirin treatment-experienced with compensated cirrhosis (Child-Pugh class A): One tablet once daily with concomitant sofosbuvir for 12 weeks (AASLD/IDSA 2017)

Chronic hepatitis C (genotype 4): Oral:

Treatment naive without cirrhosis or with compensated cirrhosis (Child-Pugh class A): One tablet once daily for 12 weeks

Peginterferon alfa + ribavirin treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh class A) who experienced virologic relapse after prior peginterferon/ribavirin therapy: One tablet once daily for 12 weeks (AASLD/IDSA 2017)

Peginterferon alfa + ribavirin treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh class A) who experienced prior on-treatment failure while on peginterferon/ribavirin (alternative agent): One tablet once daily with concomitant ribavirin for 16 weeks (AASLD/IDSA 2017)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

CrCl >50 mL/minute: No dosage adjustment necessary.

CrCl ≤50 mL/minute: No dosage adjustment necessary. If used with concomitant ribavirin, refer to ribavirin monograph for dosage adjustments.

End-stage renal disease (ESRD) and hemodialysis (not removed by hemodialysis): No dosage adjustment necessary.

Dosing: Hepatic Impairment

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

Moderate or severe impairment (Child-Pugh class B or C): Use is contraindicated.

Administration

Oral: Administer without regard to meals.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). Keep in original blister pack until time of use; protect from moisture.

Drug Interactions

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

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

Atazanavir: May increase the serum concentration of Grazoprevir. Avoid combination

AtorvaSTATin: Grazoprevir may increase the serum concentration of AtorvaSTATin. Management: Limit the dose of atorvastatin to a maximum of 20 mg/day when used together with elbasvir and grazoprevir. Monitor closely for evidence of statin-related toxicities such as myalgia or myopathy. Consider therapy modification

AtorvaSTATin: Elbasvir may increase the serum concentration of AtorvaSTATin. Management: Limit the dose of atorvastatin to a maximum of 20 mg/day when used together with elbasvir and grazoprevir. Monitor closely for evidence of statin-related toxicities such as myalgia or myopathy. Consider therapy modification

Ceritinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of ceritinib with a narrow therapeutic index CYP3A substrate (eg, alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus) should be avoided when possible. Exceptions are discussed separately. Monitor therapy

Cobicistat: May increase the serum concentration of Grazoprevir. Avoid combination

Cobicistat: May increase the serum concentration of Elbasvir. Avoid combination

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CycloSPORINE (Systemic): May increase the serum concentration of Grazoprevir. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Grazoprevir. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Elbasvir. Avoid combination

CYP3A4 Inducers (Strong): May decrease the serum concentration of Grazoprevir. Avoid combination

CYP3A4 Inducers (Strong): May decrease the serum concentration of Elbasvir. Avoid combination

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Consider therapy modification

Darunavir: May increase the serum concentration of Grazoprevir. Avoid combination

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

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

Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Efavirenz: May decrease the serum concentration of Elbasvir. Avoid combination

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

Fluvastatin: Elbasvir may increase the serum concentration of Fluvastatin. Monitor therapy

Fluvastatin: Grazoprevir may increase the serum concentration of Fluvastatin. Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Ketoconazole (Systemic): May increase the serum concentration of Elbasvir. Avoid combination

Ketoconazole (Systemic): May increase the serum concentration of Grazoprevir. 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 Grazoprevir. Avoid combination

Lovastatin: Elbasvir may increase the serum concentration of Lovastatin. Monitor therapy

Lovastatin: Grazoprevir may increase the serum concentration of Lovastatin. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

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

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

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

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

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

Pitolisant: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant. Consider therapy modification

RifAMPin: May decrease the serum concentration of Grazoprevir. Conversely, single doses of Rifampin may increase Grazoprevir concentrations. Avoid combination

Rosuvastatin: Grazoprevir may increase the serum concentration of Rosuvastatin. Management: Limit the dose of rosuvastatin to a maximum of 10 mg/day when used together with elbasvir and grazoprevir. Monitor closely for evidence of statin-related toxicities such as myalgia or myopathy. Consider therapy modification

Rosuvastatin: Elbasvir may increase the serum concentration of Rosuvastatin. Management: Limit the dose of rosuvastatin to a maximum of 10 mg/day when used together with elbasvir and grazoprevir. Monitor closely for evidence of statin-related toxicities such as myalgia or myopathy. Consider therapy modification

Saquinavir: May increase the serum concentration of Grazoprevir. Avoid combination

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simvastatin: Elbasvir may increase the serum concentration of Simvastatin. Monitor therapy

Simvastatin: Grazoprevir may increase the serum concentration of Simvastatin. Monitor therapy

St John's Wort: May decrease the serum concentration of Grazoprevir. Avoid combination

St John's Wort: May decrease the serum concentration of Elbasvir. Avoid combination

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tacrolimus (Systemic): Grazoprevir may increase the serum concentration of Tacrolimus (Systemic). Monitor therapy

Talazoparib: BCRP/ABCG2 Inhibitors may increase the serum concentration of Talazoparib. Monitor therapy

Tipranavir: May increase the serum concentration of Grazoprevir. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

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

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

Warfarin: Grazoprevir may enhance the anticoagulant effect of Warfarin. Monitor therapy

Adverse Reactions

>10%:

Central nervous system: Fatigue (11%), headache (10% to 11%)

Gastrointestinal: Nausea (11%)

1% to 10%: Hepatic: Increased serum alanine aminotransferase (1% to 2%)

<1%, postmarketing, and/or case reports: Angioedema, decreased hemoglobin, increased serum bilirubin, reactivation of HBV

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. 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 coinfected patients for hepatitis flare or HBV reactivation during HCV treatment and posttreatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.

Warnings/Precautions

Concerns related to adverse effects:

• ALT elevations: ALT elevations (>5 times ULN) have been observed generally at week 8 or beyond; changes have been mostly asymptomatic and resolved with ongoing or completed therapy. Females, Asian patients, and patients ≥65 years of age may be at greater risk for ALT changes. Patients should report fatigue, weakness, decreased appetite, nausea/vomiting, jaundice, or discolored feces. Monitor liver function tests prior to therapy, at treatment week 8, and as clinically indicated. Consider discontinuing therapy if ALT levels remain persistently >10 times ULN. Discontinue therapy if accompanied by signs/symptoms of hepatic inflammation or increasing conjugated bilirubin, alkaline phosphatase, or international normalized ratio (INR).

Disease-related concerns:

• Hepatic impairment: Use is contraindicated in moderate or severe impairment (Child-Pugh class B or 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.

Other warnings/precautions:

• Resistance testing prior to treatment initiation in HCV genotype 1a: Testing patients with HCV genotype 1a infection for the presence of virus with NS5A resistance-associated polymorphisms is recommended prior to treatment initiation to determine regimen and duration. Sustained virologic response rates were lower after 12 weeks in genotype 1a-infected patients with one or more baseline NS5A resistance-associated polymorphisms at amino acid positions 28, 30, 31, or 93.

Monitoring Parameters

Hepatic function (baseline, treatment week 8 and week 12 [if treatment duration is 16 weeks] and as clinically indicated). 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. In genotype 1a patients, testing for the presence of virus with NS5A resistance-associated polymorphisms is recommended prior to treatment initiation.

Serum HCV-RNA at baseline, weeks 4, 8, 12, during treatment follow up, and when clinically indicated

Pregnancy Considerations

Adverse events have not been observed in animal reproduction studies.

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]).

If used in combination with ribavirin, all warnings related to the use of ribavirin and pregnancy and/or contraception should be followed. Refer to the ribavirin monograph for additional information.

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 nausea, diarrhea, headache, or insomnia. 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) or severe loss of strength and energy (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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