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Elbasvir and Grazoprevir

Pronunciation

(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.

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 (CHC) with or without cirrhosis (monoinfection or coinfection with HIV-1): Oral: One tablet (elbasvir 50 mg/grazoprevir 100 mg) once daily.

Genotype 1a:

Treatment naive or peginterferon alfa + ribavirin treatment-experienced without baseline NS5A polymorphisms: One tablet once daily for 12 weeks

Treatment naive or peginterferon alfa + ribavirin treatment-experienced with baseline NS5A polymorphisms: One tablet once daily with concomitant ribavirin for 16 weeks

Peginterferon alfa + ribavirin + NS3/4A protease inhibitor treatment-experienced: One tablet once daily with concomitant ribavirin for 12 weeks. Note: Optimal duration of treatment in patients with one or more baseline NS5A resistance-associated polymorphisms at positions 28, 30, 31 and 93 has not been established.

Genotype 1b:

Treatment naive or peginterferon alfa + ribavirin treatment-experienced: One tablet once daily for 12 weeks

Peginterferon alfa + ribavirin + NS3/4A protease inhibitor treatment-experienced: One tablet once daily with concomitant ribavirin for 12 weeks

Genotype 4:

Treatment naive: One tablet once daily for 12 weeks

Peginterferon alfa + ribavirin treatment-experienced: One tablet once daily with concomitant ribavirin for 16 weeks

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

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 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

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

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

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

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

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

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

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

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

Topotecan: BCRP/ABCG2 Inhibitors may increase the serum concentration of Topotecan. Consider therapy modification

Adverse Reactions

>10%:

Central nervous system: Fatigue (7% to 11%), headache (11%)

Gastrointestinal: Nausea (5% to 11%)

1% to 10%:

Central nervous system: Insomnia (3% to 5%), dizziness (2% to 3%), irritability (1% to 2%), anxiety (1%), depression (1%)

Dermatologic: Night sweats (2%), pruritus (2%), alopecia (1%)

Gastrointestinal: Diarrhea (2% to 5%), abdominal pain (2%), constipation (2%), decreased appetite (2%), dyspepsia (2%), flatulence (2%), upper abdominal pain (2%), vomiting (1% to 2%), xerostomia (1% to 2%)

Hepatic: Increased serum bilirubin (≤2%), increased serum ALT (≤1%; may be increased in females, patients of Asian descent, and older adults)

Neuromuscular & skeletal: Weakness (4%), increased creatine phosphokinase (2%), myalgia (2%), arthralgia (≤2%)

Otic: Tinnitus (2%)

<1% (Limited to important or life-threatening): Reactivation of HBV (FDA Safety Alert Dec. 8, 2016)

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. The safety of treating hepatitis C during pregnancy has not been established; current guidelines recommend delaying pregnancy until HCV antiviral treatment is completed (AASLD/IDSA 2016).

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, vomiting, 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.

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