Elbasvir and grazoprevir: Pediatric drug information

(For additional information see "Elbasvir and grazoprevir: Drug information" and see "Elbasvir and grazoprevir: Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)

ALERT: US 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.

Brand Names: US

Zepatier

Brand Names: Canada

Zepatier [DSC]

Therapeutic Category

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

Dosing: Pediatric

Chronic hepatitis C, genotype 1a

Chronic hepatitis C, genotype 1a:

Children ≥12 years of age or weighing ≥30 kg and Adolescents: Elbasvir 50 mg and grazoprevir 100 mg per tablet:

Treatment-naive or peginterferon alfa + ribavirin treatment–experienced without baseline NS5A resistance-associated substitutions (RASs) for elbasvir: Oral: 1 tablet once daily for 12 weeks.

Treatment-naive or peginterferon alfa + ribavirin treatment-experienced with baseline NS5A RASs for elbasvir: Oral: 1 tablet once daily for 16 weeks in combination with ribavirin.

Peginterferon alfa + ribavirin + NS3/4A protease inhibitor treatment-experienced: Oral: 1 tablet once daily for 12 weeks in combination with ribavirin. Note: The optimal treatment regimen for peginterferon alfa + ribavirin + NS3/4A protease inhibitor treatment-experienced patients with NS5A RASs at positions 28, 30, 31, or 93 has not been established.

Chronic hepatitis C, genotype 1b

Chronic hepatitis C, genotype 1b:

Children ≥12 years of age or weighing ≥30 kg and Adolescents: Elbasvir 50 mg and grazoprevir 100 mg per tablet:

Treatment-naive or peginterferon alfa + ribavirin treatment-experienced: Oral: 1 tablet once daily for 12 weeks.

Peginterferon alfa + ribavirin + NS3/4A protease inhibitor treatment-experienced: Oral: 1 tablet once daily for 12 weeks in combination with ribavirin.

Chronic hepatitis C, genotype 4

Chronic hepatitis C, genotype 4:

Children ≥12 years of age or weighing ≥30 kg and Adolescents: Elbasvir 50 mg and grazoprevir 100 mg per tablet:

Treatment-naive: Oral: 1 tablet once daily for 12 weeks.

Peginterferon alfa + ribavirin treatment-experienced: Oral: 1 tablet once daily for 16 weeks in combination with ribavirin.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

Children ≥12 years or weighing ≥30 kg and Adolescents:

Any degree of renal impairment: No dosage adjustment necessary.

Hemodialysis: No dosage adjustment necessary.

Dosing: Hepatic Impairment: Pediatric

Preexisting hepatic impairment:

Children ≥12 years or weighing ≥30 kg and Adolescents:

Mild impairment: No dosage adjustment necessary.

Moderate or severe impairment: Use is contraindicated.

History of prior hepatic decompensation: Use is contraindicated.

Hepatotoxicity during treatment:

Children ≥12 years or weighing ≥30 kg and Adolescents:

ALT >10 times ULN: Consider discontinuing therapy if ALT levels remain persistently >10 times ULN.

Any ALT elevation accompanied by signs/symptoms of hepatic inflammation or increasing conjugated bilirubin, alkaline phosphatase, or INR: Discontinue therapy.

Hepatic decompensation/failure: Discontinue therapy.

Dosing: Adult

(For additional information see "Elbasvir and grazoprevir: Drug information")

Note: Compensated cirrhosis is defined as Child-Pugh class A (AASLD/IDSA 2021).

Chronic hepatitis C

Chronic hepatitis C:

Genotype 1a:

Note: Prior to initiating therapy, NS5A resistance-associated substitution (RAS) testing may be useful to determine if clinically important resistance exists necessitating use of an alternative regimen (AASLD/IDSA 2021).

Treatment-naive without cirrhosis (alternative agent): Oral: 1 tablet (elbasvir 50 mg/grazoprevir 100 mg) once daily for 12 weeks (AASLD/IDSA 2021).

Post kidney transplantation, treatment-naive or nondirect-acting antiviral–experienced patients without cirrhosis or with compensated cirrhosis (alternative agent): Oral: 1 tablet (elbasvir 50 mg/grazoprevir 100 mg) once daily for 12 weeks. Note: Reserve use for patients without baseline NS5A RASs for elbasvir (AASLD/IDSA 2021).

Genotype 1b:

Treatment-naive without cirrhosis or with compensated cirrhosis: Oral: 1 tablet (elbasvir 50 mg/grazoprevir 100 mg) once daily for 12 weeks; 8 weeks may be considered for patients with mild fibrosis without cirrhosis (AASLD/IDSA 2021).

Genotype 4:

Treatment-naive without cirrhosis or with compensated cirrhosis: Oral: 1 tablet (elbasvir 50 mg/grazoprevir 100 mg) once daily for 12 weeks (AASLD/IDSA 2021).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

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: Adult

Preexisting hepatic impairment:

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

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

Hepatotoxicity during treatment:

Asymptomatic increases in ALT <10-fold: Closely monitor with repeat testing every 2 weeks. If persistent elevation remains, consider stopping therapy (AASLD/IDSA 2021).

<10-fold increase in ALT from baseline with weakness, nausea, vomiting, jaundice, or significantly increased bilirubin, alkaline phosphatase, or INR: Discontinue direct-acting antiviral (AASLD/IDSA 2021).

≥10-fold increase in ALT from baseline at any time during treatment: Discontinue direct-acting antiviral therapy, especially with signs and symptoms of liver inflammation or increasing conjugated bilirubin, alkaline phosphatase, or INR (AASLD/IDSA 2021).

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

>10%: Nervous system: Fatigue (11%)

1% to 10%:

Hepatic: Increased serum alanine aminotransferase (1%)

Nervous system: Headache (10%)

<1%:

Hematologic & oncologic: Decreased hemoglobin

Hepatic: Increased serum bilirubin

Frequency not defined: Hepatic: Acute hepatic failure (FDA Safety Alert, August 28, 2019), severe hepatic disease (FDA Safety Alert, August 28, 2019)

Postmarketing:

Hypersensitivity: Angioedema

Infection: Reactivation of HBV

Contraindications

Moderate or severe hepatic impairment (Child-Pugh class B or C); history of prior hepatic decompensation; concurrent use with OATP1B1/3 inhibitors that are known or expected to significantly increase grazoprevir plasma concentrations and strong inducers of 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.

Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more 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.

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 INR.

Disease-related concerns:

• Diabetes: Rapid reduction in hepatitis C viral load during direct-acting antiviral (DAA) therapy for hepatitis C may lead to improvement in glucose metabolism in patients with diabetes, potentially resulting in symptomatic hypoglycemia if antidiabetic agents are continued at the same dose. Monitor for changes in glucose tolerance and inform patients of the risk of hypoglycemia during DAA therapy, particularly within the first 3 months. Modification of antidiabetic therapy may be necessary (Ciancio 2018; Dawood 2017; Hum 2017).

• Hepatic impairment: Cases of hepatic decompensation and failure, some fatal, have been reported in patients without cirrhosis and in patients with baseline cirrhosis with and without moderate or severe liver impairment (Child-Pugh class B or C). Use is contraindicated in moderate or severe impairment (Child-Pugh class B or C) and with a history of prior hepatic decompensation. Monitor hepatic function tests and for signs and symptoms of hepatic decompensation more frequently in patients with compensated cirrhosis (Child-Pugh class A) or evidence of advanced liver disease (eg, portal hypertension); discontinue if hepatic decompensation or failure develops.

• 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.

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.

Dosage Forms: US

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

Tablet, Oral:

Zepatier: Elbasvir 50 mg and grazoprevir 100 mg

Generic Equivalent Available: US

Pricing: US

Tablets (Zepatier Oral)

50-100 mg (per each): $312.00

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Tablet, Oral:

Zepatier: Elbasvir 50 mg and grazoprevir 100 mg [DSC]

Administration: Pediatric

Oral: Administer without regard to meals.

Administration: Adult

Oral: Administer without regard to meals.

Storage/Stability

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.

Use

Treatment of chronic hepatitis C virus (HCV) genotype 1 or 4 infection; used with ribavirin in certain patient populations (FDA approved in pediatric patients ≥12 years of age or weighing ≥30 kg and adults).

Metabolism/Transport Effects

Substrate of CYP3A4 (major), OATP1B1/1B3 (SLCO1B1/1B3), P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits BCRP/ABCG2, CYP3A4 (weak), OATP1B1/1B3 (SLCO1B1/1B3)

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Alpelisib: BCRP/ABCG2 Inhibitors may increase the serum concentration of Alpelisib. Management: Avoid coadministration of BCRP/ABCG2 inhibitors and alpelisib due to the potential for increased alpelisib concentrations and toxicities. If coadministration cannot be avoided, closely monitor for increased alpelisib adverse reactions. Risk D: Consider therapy modification

ALPRAZolam: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ALPRAZolam. Risk C: Monitor therapy

Antidiabetic Agents: Direct Acting Antiviral Agents (HCV) may enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy

Asciminib: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy

Asunaprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Asunaprevir. Risk X: Avoid combination

Atazanavir: May increase the serum concentration of Elbasvir and Grazoprevir. Risk X: Avoid combination

Atogepant: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Atogepant. Management: For episodic migraine, the recommended atogepant dose is 10 mg or 30 mg once daily if given with OATP1B1/1B3 inhibitors. For chronic migraine, the recommended atogepant dose is 30 mg once daily with OATP1B1/1B3 inhibitors. Risk D: Consider therapy modification

Atorvastatin: Elbasvir and Grazoprevir may increase the serum concentration of Atorvastatin. Management: Limit the adult dose of atorvastatin to a maximum of 20 mg/day when used together with elbasvir and grazoprevir. Use the lowest atorvastatin dose necessary and monitor closely for evidence of statin-related toxicities such as myalgia or myopathy. Risk D: Consider therapy modification

Berotralstat: BCRP/ABCG2 Inhibitors may increase the serum concentration of Berotralstat. Management: Decrease the berotralstat dose to 110 mg daily when combined with BCRP inhibitors. Risk D: Consider therapy modification

Brincidofovir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Brincidofovir. Management: Consider alternatives to OATP1B/1B3 inhibitors in patients treated with brincidofovir. If coadministration is required, administer OATP1B1/1B3 inhibitors at least 3 hours after brincidofovir and increase monitoring for brincidofovir adverse reactions. Risk D: Consider therapy modification

Cladribine: BCRP/ABCG2 Inhibitors may increase the serum concentration of Cladribine. Management: Avoid concomitant use of BCRP inhibitors during the 4 to 5 day oral cladribine treatment cycles whenever possible. If combined, consider dose reduction of the BCRP inhibitor and separation in the timing of administration. Risk D: Consider therapy modification

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

Cobicistat: May increase the serum concentration of Elbasvir and Grazoprevir. Risk X: Avoid combination

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

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

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Elbasvir and Grazoprevir. Risk C: Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Elbasvir and Grazoprevir. Management: Consider alternatives to this combination when possible. If combined, monitor for increased elbasvir/grazoprevir toxicities, including ALT elevations. Risk D: Consider therapy modification

Darunavir: May increase the serum concentration of Elbasvir and Grazoprevir. Risk X: Avoid combination

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

Efavirenz: May decrease the serum concentration of Elbasvir and Grazoprevir. Risk X: Avoid combination

Elagolix: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Elagolix. Risk X: Avoid combination

Elagolix, Estradiol, and Norethindrone: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Elagolix, Estradiol, and Norethindrone. Specifically, concentrations of elagolix may be increased. Risk X: Avoid combination

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

Finerenone: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Finerenone. Risk C: Monitor therapy

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

Fluvastatin: Elbasvir and Grazoprevir may increase the serum concentration of Fluvastatin. Risk C: Monitor therapy

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

Ixabepilone: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Ixabepilone. Risk C: Monitor therapy

Ketoconazole (Systemic): May increase the serum concentration of Elbasvir and Grazoprevir. Risk X: Avoid combination

Lemborexant: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lemborexant. Management: The maximum recommended dosage of lemborexant is 5 mg, no more than once per night, when coadministered with weak CYP3A4 inhibitors. Risk D: Consider therapy modification

Leniolisib: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk X: 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. Risk D: Consider therapy modification

Lonafarnib: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lonafarnib. Management: Avoid concurrent use of lonafarnib with weak CYP3A4 inhibitors. If concurrent use is unavoidable, reduce the lonafarnib dose to or continue at a dose of 115 mg/square meter. Monitor for evidence of arrhythmia, syncope, palpitations, or similar effects. Risk D: Consider therapy modification

Lopinavir: May increase the serum concentration of Elbasvir and Grazoprevir. Risk X: Avoid combination

Lovastatin: Elbasvir and Grazoprevir may increase the serum concentration of Lovastatin. Risk C: Monitor therapy

Midazolam: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Midazolam. Risk C: Monitor therapy

Momelotinib: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Momelotinib. Risk C: Monitor therapy

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

OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors: May increase the serum concentration of Elbasvir and Grazoprevir. Risk X: Avoid combination

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

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

Pretomanid: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy

Red Yeast Rice: Elbasvir and Grazoprevir may increase the serum concentration of Red Yeast Rice. Risk C: Monitor therapy

Revefenacin: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentrations of the active metabolite(s) of Revefenacin. Risk X: Avoid combination

RifAMPin: May increase the serum concentration of Elbasvir and Grazoprevir. RifAMPin may decrease the serum concentration of Elbasvir and Grazoprevir. Risk X: Avoid combination

Rosuvastatin: Elbasvir and Grazoprevir may increase the serum concentration of Rosuvastatin. Management: Initiate rosuvastatin at 5 mg daily and limit the rosuvastatin dose to a maximum of 10 mg per day during coadministration with elbasvir/grazoprevir. Monitor closely for evidence of rosuvastatin toxicities (eg, myopathy, rhabdomyolysis). Risk D: Consider therapy modification

Saquinavir: May increase the serum concentration of Elbasvir and Grazoprevir. Risk X: Avoid combination

Simvastatin: Elbasvir and Grazoprevir may increase the serum concentration of Simvastatin. Risk C: Monitor therapy

Sirolimus (Conventional): CYP3A4 Inhibitors (Weak) may increase the serum concentration of Sirolimus (Conventional). Risk C: Monitor therapy

Sirolimus (Protein Bound): CYP3A4 Inhibitors (Weak) may increase the serum concentration of Sirolimus (Protein Bound). Management: Reduce the dose of protein bound sirolimus to 56 mg/m² when used concomitantly with a weak CYP3A4 inhibitor. Risk D: Consider therapy modification

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

Tacrolimus (Systemic): Direct Acting Antiviral Agents (HCV) may decrease the serum concentration of Tacrolimus (Systemic). Direct Acting Antiviral Agents (HCV) may increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy

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

Taurursodiol: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Taurursodiol. Risk X: Avoid combination

Tipranavir: May increase the serum concentration of Elbasvir and Grazoprevir. Risk X: Avoid combination

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

Triazolam: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Triazolam. Risk C: Monitor therapy

Trofinetide: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Management: Avoid concurrent use with OATP1B1/1B3 substrates for which small changes in exposure may be associated with serious toxicities. Monitor for evidence of an altered response to any OATP1B1/1B3 substrate if used together with trofinetide. Risk D: Consider therapy modification

Ubrogepant: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Ubrogepant. Management: In patients taking weak CYP3A4 inhibitors, the initial and second dose (given at least 2 hours later if needed) of ubrogepant should be limited to 50 mg. Risk D: Consider therapy modification

Ubrogepant: BCRP/ABCG2 Inhibitors may increase the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 50 mg and second dose (at least 2 hours later if needed) of 50 mg when used with a BCRP inhibitor. Risk D: Consider therapy modification

Vitamin K Antagonists (eg, warfarin): Direct Acting Antiviral Agents (HCV) may diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Voclosporin: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy

Voxilaprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Voxilaprevir. Risk X: Avoid combination

Zavegepant: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Zavegepant. Risk X: Avoid combination

Reproductive Considerations

Patients with hepatitis C virus (HCV) infection should be treated before considering pregnancy to optimize maternal health and reduce the risk of HCV transmission (AASLD/IDSA 2021).

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

Pregnancy Considerations

Outcome data following maternal use of direct-acting antiviral (DAA) medications during pregnancy are limited. Use of a DAA is not currently recommended for the purpose of reducing mother to child transmission of hepatitis C virus due to a lack of safety and efficacy data. The decision to continue treatment in a patient who becomes pregnant while taking a DAA should be individualized after considering the potential benefits and risks of therapy. DAA medications should not be initiated during pregnancy outside of clinical trials until safety and efficacy data are available (AASLD/IDSA 2021; SMFM [Dotters-Katz 2021]).

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

Monitoring Parameters

Management of hepatitis C virus (HCV) infection requires extensive monitoring; refer to current guidelines for additional guidance including disease state monitoring and response to abnormal laboratory parameters (AASLD/IDSA 2021).

Baseline (AASLD/IDSA 2021; manufacturer's labeling):

Within 6 months prior to starting antiviral therapy: CBC, INR, hepatic function (eg, albumin, total and direct bilirubin, ALT, AST, alkaline phosphatase), SCr, calculated GFR.

Prior to starting antiviral therapy (no specific time frame): HCV genotype and subtype; quantitative HCV viral load. In genotype 1a patients, assess HCV virus for presence of NS5A resistance-associated polymorphisms. Hepatitis B surface antigen (HBsAG), hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc); HIV testing; pregnancy test in individuals who can become pregnant.

During and after therapy (AASLD/IDSA 2021; manufacturer's labeling):

LFTs (treatment week 8; test again at week 12 [if treatment duration 16 weeks]; also monitor as clinically indicated).

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 posttreatment follow-up. In patients with diabetes, monitor blood glucose and for signs/symptoms of hypoglycemia.

Mechanism of Action

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.

Pharmacokinetics (Adult Data Unless Noted)

Absorption: Not affected by meals.

Bioavailability: Elbasvir: 32%; Grazoprevir: 27%

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

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

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

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

Half-life elimination: Elbasvir: ~24 hours; Grazoprevir: ~31 hours

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

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

Brand Names: International

International Brand Names by Country

For country code abbreviations (show table)

(AE) United Arab Emirates: Zepatier;
(AR) Argentina: Zepatier;
(AT) Austria: Zepatier;
(AU) Australia: Zepatier;
(BE) Belgium: Zepatier;
(BG) Bulgaria: Zepatier;
(BR) Brazil: Zepatier;
(CH) Switzerland: Zepatier;
(CL) Chile: Zepatier;
(CO) Colombia: Zepatier;
(CZ) Czech Republic: Zepatier;
(DE) Germany: Zepatier;
(DO) Dominican Republic: Zepatier;
(EE) Estonia: Zepatier;
(EG) Egypt: Zepatier;
(ES) Spain: Zepatier;
(FI) Finland: Zepatier;
(FR) France: Zepatier;
(GB) United Kingdom: Zepatier;
(GR) Greece: Zepatier;
(HK) Hong Kong: Zepatier;
(HR) Croatia: Zepatier;
(HU) Hungary: Zepatier;
(IE) Ireland: Zepatier;
(IT) Italy: Zepatier;
(KR) Korea, Republic of: Zepatier;
(LT) Lithuania: Zepatier;
(LV) Latvia: Zepatier;
(MX) Mexico: Zepatier;
(MY) Malaysia: Zepatier;
(NL) Netherlands: Zepatier;
(NO) Norway: Zepatier;
(NZ) New Zealand: Zepatier;
(PE) Peru: Zepatier;
(PL) Poland: Zepatier;
(PR) Puerto Rico: Zepatier;
(PT) Portugal: Zepatier;
(QA) Qatar: Zepatier;
(RO) Romania: Zepatier;
(RU) Russian Federation: Zepatier;
(SA) Saudi Arabia: Zepatier;
(SE) Sweden: Zepatier;
(SG) Singapore: Zepatier;
(SI) Slovenia: Zepatier;
(SK) Slovakia: Zepatier;
(TH) Thailand: Zepatier;
(TW) Taiwan: Zepatier

American Association for the Study of Liver Diseases (AASLD), Infectious Diseases Society of America (IDSA). HCV guidance: recommendations for testing, managing, and treating hepatitis C. https://www.hcvguidelines.org. Updated October 5, 2021. Accessed March 28, 2022.
Ciancio A, Bosio R, Bo S, et al. Significant improvement of glycemic control in diabetic patients with HCV infection responding to direct-acting antiviral agents. J Med Virol. 2018;90(2):320-327. doi:10.1002/jmv.24954. [PubMed 28960353]
Dawood AA, Nooh MZ, Elgamal AA. Factors associated with improved glycemic control by direct-acting antiviral agent treatment in Egyptian type 2 diabetes mellitus patients with chronic hepatitis C genotype 4. Diabetes Metab J. 2017;41(4):316-321. doi: 10.4093/dmj.2017.41.4.316. [PubMed 28868829]
Dotters-Katz SK, Kuller JA, Hughes BL. Society for Maternal-Fetal Medicine consult series #56: hepatitis C in pregnancy-updated guidelines: replaces consult number 43, November 2017. Am J Obstet Gynecol. 2021;225(3):B8-B18. doi:10.1016/j.ajog.2021.06.008 [PubMed 34116035]
FDA Drug Safety Communication. FDA warns about rare occurrence of serious liver injury with use of hepatitis C medicines Mavyret, Zepatier, and Vosevi in some patients with advanced liver disease. Food and Drug Administration website. https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-rare-occurrence-serious-liver-injury-use-hepatitis-c-medicines-mavyret-zepatier-and. Published August 28, 2019. Accessed September 6, 2019.
FDA Safety Alert. MedWatch. Direct-acting antiviral for hepatitis C: drug safety communication – risk of hepatitis B reactivating. Food and Drug Administration website. Available at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm523690.htm. Accessed December 8, 2016.
Hum J, Jou JH, Green PK, et al. Improvement in Glycemic Control of Type 2 Diabetes After Successful Treatment of Hepatitis C Virus. Diabetes Care. 2017;40(9):1173-1180. doi: 10.2337/dc17-0485. [PubMed 28659309]
Zepatier (elbasvir and grazoprevir) [prescribing information]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp; January 2022.
Zepatier (elbasvir/grazoprevir) [product monograph]. Kirkland, Quebec, Canada: Merck Canada Inc; March 2021.

Topic 134746 Version 29.0

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Elbasvir and grazoprevir: Pediatric drug information