ZEPATIER

Clinical safety rating: caution

Comprehensive clinical and safety monograph for ZEPATIER (ZEPATIER).

How it works

ZEPATIER is a fixed-dose combination of elbasvir, an HCV NS5A inhibitor, and grazoprevir, an HCV NS3/4A protease inhibitor. Elbasvir inhibits HCV NS5A, disrupting viral replication and assembly. Grazoprevir inhibits the HCV NS3/4A serine protease, preventing cleavage of the HCV polyprotein into mature viral proteins.

What the body does with it

Metabolism	Elbasvir is metabolized primarily by CYP3A. Grazoprevir is metabolized primarily by CYP3A. Mild oxidation and glucuronidation are minor pathways.
Excretion	Elbasvir: primarily biliary/fecal (≥90% as metabolites, <1% unchanged in urine). Grazoprevir: primarily biliary/fecal (≥90% as metabolites, <1% unchanged in urine). Renal elimination is negligible for both.
Half-life	Elbasvir: terminal half-life approximately 24 hours. Grazoprevir: terminal half-life approximately 31 hours. The prolonged half-lives support once-daily dosing and allow for sustained viral suppression.
Protein binding	Elbasvir: ≥99.9% bound, primarily to albumin and α1-acid glycoprotein. Grazoprevir: 98.8% bound, primarily to albumin and α1-acid glycoprotein.
Volume of Distribution	Elbasvir: apparent Vd approximately 4.5 L/kg (high, indicating extensive tissue distribution). Grazoprevir: apparent Vd approximately 19 L/kg (very high, likely due to binding to plasma proteins and tissue uptake).
Bioavailability	Elbasvir: absolute bioavailability not determined in humans; oral absorption is high. Grazoprevir: absolute bioavailability approximately 27% after oral administration; absorption is enhanced with food (high-fat meal increases AUC by 1.5-fold).
Onset of Action	Oral: Reductions in HCV RNA are detectable within hours of first dose; clinical virologic response (≥2 log10 drop) is seen within 1-2 days.
Duration of Action	Duration of antiviral effect persists for the full 24-hour dosing interval due to half-lives. The recommended treatment duration is 12-16 weeks for most genotypes, with sustained virologic response (SVR) assessed 12 weeks post-treatment.

Classification & Brands

Dosing & administration

One tablet (elbasvir 50 mg/grazoprevir 100 mg) orally once daily.

Dosage form	TABLET
Renal impairment	No dose adjustment required for any degree of renal impairment including end-stage renal disease on dialysis.
Liver impairment	Contraindicated in moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment. No dose adjustment required in mild (Child-Pugh A) hepatic impairment.
Pediatric use	Not approved for use in pediatric patients; safety and efficacy not established.
Geriatric use	No dose adjustment required; however, clinical studies indicate similar safety and efficacy as in younger adults, but caution is warranted due to potential age-related comorbidities.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for ZEPATIER (ZEPATIER).

Breastfeeding	No data on human milk excretion. M/P ratio unknown. Ribavirin accumulates in breast milk and is contraindicated during breastfeeding. Grazoprevir/elbasvir: animal studies show excretion in milk; potential for adverse effects. Avoid breastfeeding during treatment and for 7 days after last dose.
Teratogenic Risk	ZEPATIER (grazoprevir/elbasvir) is contraindicated in pregnancy due to the ribavirin component in some regimens. Ribavirin is teratogenic in all trimesters, causing fetal malformations and embryolethality. Grazoprevir/elbasvir alone has no adequate human data, but animal studies show no teratogenicity. However, combination with ribavirin mandates avoidance in pregnancy.

Warnings & precautions

■ FDA Black Box Warning

Risk of hepatitis B virus (HBV) reactivation in patients coinfected with HCV and HBV, which may result in fulminant hepatitis, hepatic failure, and death. Test all patients for evidence of current or prior HBV infection before initiating treatment.

Side Effect Profile

Serious Effects

Absolute Contraindications

["Moderate or severe hepatic impairment (Child-Pugh B or C)","Use with strong CYP3A inducers (e.g., rifampin, St. John's wort, carbamazepine, phenytoin)","Use with certain HIV medications (e.g., efavirenz, etravirine, nevirapine, atazanavir/ritonavir, lopinavir/ritonavir, darunavir/ritonavir, tipranavir/ritonavir)","Use with cyclosporine"]

Clinical Precautions

Precautions

["Risk of hepatitis B virus reactivation","Hepatic decompensation with use in patients with moderate or severe hepatic impairment (Child-Pugh B or C)","Elevation of total bilirubin and/or ALT levels","Risk of adverse reactions due to drug interactions (e.g., strong CYP3A inducers/inhibitors)"]

Clinical Tips & Counseling

Drug interactions

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ZEPATIER

Clinical safety rating: caution

Comprehensive clinical and safety monograph for ZEPATIER (ZEPATIER).

How it works

What the body does with it

Metabolism	Elbasvir is metabolized primarily by CYP3A. Grazoprevir is metabolized primarily by CYP3A. Mild oxidation and glucuronidation are minor pathways.
Excretion	Elbasvir: primarily biliary/fecal (≥90% as metabolites, <1% unchanged in urine). Grazoprevir: primarily biliary/fecal (≥90% as metabolites, <1% unchanged in urine). Renal elimination is negligible for both.
Half-life	Elbasvir: terminal half-life approximately 24 hours. Grazoprevir: terminal half-life approximately 31 hours. The prolonged half-lives support once-daily dosing and allow for sustained viral suppression.
Protein binding	Elbasvir: ≥99.9% bound, primarily to albumin and α1-acid glycoprotein. Grazoprevir: 98.8% bound, primarily to albumin and α1-acid glycoprotein.
Volume of Distribution	Elbasvir: apparent Vd approximately 4.5 L/kg (high, indicating extensive tissue distribution). Grazoprevir: apparent Vd approximately 19 L/kg (very high, likely due to binding to plasma proteins and tissue uptake).
Bioavailability	Elbasvir: absolute bioavailability not determined in humans; oral absorption is high. Grazoprevir: absolute bioavailability approximately 27% after oral administration; absorption is enhanced with food (high-fat meal increases AUC by 1.5-fold).
Onset of Action	Oral: Reductions in HCV RNA are detectable within hours of first dose; clinical virologic response (≥2 log10 drop) is seen within 1-2 days.
Duration of Action	Duration of antiviral effect persists for the full 24-hour dosing interval due to half-lives. The recommended treatment duration is 12-16 weeks for most genotypes, with sustained virologic response (SVR) assessed 12 weeks post-treatment.

Classification & Brands

Dosing & administration

One tablet (elbasvir 50 mg/grazoprevir 100 mg) orally once daily.

Dosage form	TABLET
Renal impairment	No dose adjustment required for any degree of renal impairment including end-stage renal disease on dialysis.
Liver impairment	Contraindicated in moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment. No dose adjustment required in mild (Child-Pugh A) hepatic impairment.
Pediatric use	Not approved for use in pediatric patients; safety and efficacy not established.
Geriatric use	No dose adjustment required; however, clinical studies indicate similar safety and efficacy as in younger adults, but caution is warranted due to potential age-related comorbidities.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for ZEPATIER (ZEPATIER).

Breastfeeding	No data on human milk excretion. M/P ratio unknown. Ribavirin accumulates in breast milk and is contraindicated during breastfeeding. Grazoprevir/elbasvir: animal studies show excretion in milk; potential for adverse effects. Avoid breastfeeding during treatment and for 7 days after last dose.
Teratogenic Risk	ZEPATIER (grazoprevir/elbasvir) is contraindicated in pregnancy due to the ribavirin component in some regimens. Ribavirin is teratogenic in all trimesters, causing fetal malformations and embryolethality. Grazoprevir/elbasvir alone has no adequate human data, but animal studies show no teratogenicity. However, combination with ribavirin mandates avoidance in pregnancy.