ZEPATIER
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ZEPATIER (ZEPATIER).
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.
| 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. |
| Molecular Weight | Elbasvir: 882.0 Da, Grazoprevir: 766.9 Da, Ribavirin (component): 244.2 Da |
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. |
| 1st trimester | Contraindicated due to risk of teratogenicity (ribavirin component). Pregnancy must be excluded before initiation and monthly thereafter. |
| 2nd trimester | Contraindicated due to ribavirin component; both elbasvir and grazoprevir show adverse effects in animal reproduction studies. |
| 3rd trimester | Contraindicated; avoid use throughout pregnancy. |
Clinical note
Comprehensive clinical and safety monograph for ZEPATIER (ZEPATIER).
| Placental transfer | Elbasvir and grazoprevir cross the placenta in animal studies; ribavirin component known to accumulate in placental tissue and fetal blood. Human data limited but presumed significant. |
| Breastfeeding | Excretion into human breast milk unknown; due to potential for adverse effects in nursing infants (ribavirin accumulates in milk), breastfeeding is not recommended during therapy and for at least 7 months after last dose (5 half-lives of ribavirin). |
■ 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.
| Serious Effects |
PregnancyWomen of childbearing potential not using effective contraceptionMale partners of pregnant womenConcurrent use of organic anion transporting polypeptide (OATP)1B1/3 inhibitors (e.g., rifampin)Concurrent use of strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, St. John's wort)Severe hepatic impairment (Child-Pugh C)
| 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) |
| Food/Dietary | ZEPATIER can be taken with or without food. No specific food restrictions are required. Grapefruit and grapefruit juice may increase exposure to grazoprevir; although not contraindicated, consider avoiding large quantities. |
Loading safety data…
| Lactation Rating | L5 (Contraindicated) / Avoid |
| 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. |
| Fetal Monitoring | Pregnancy testing before initiation. Monthly pregnancy tests during therapy and for 6 months after completion if ribavirin used. Monitor fetal development via ultrasound if exposure occurs. Monitor maternal hepatic function and viral load. |
| Fertility Effects | Ribavirin causes reversible infertility in males (oligospermia) and may impair female fertility. Grazoprevir/elbasvir: no significant fertility effects in animal studies. Combined regimen: advise use of effective contraception during and for 6 months after treatment in both sexes. |
| Clinical Pearls | ZEPATIER (elbasvir/grazoprevir) is indicated for chronic HCV genotypes 1 or 4. Prior to initiation, test for NS5A resistance-associated substitutions (RASs) in genotype 1a. In patients with genotype 1a and baseline NS5A RASs, treatment duration is 16 weeks with ribavirin. Avoid in moderate to severe hepatic impairment (Child-Pugh B or C). Monitor hepatic function closely. Coadministration with strong CYP3A4 inducers (e.g., rifampin, carbamazepine) is contraindicated. Also contraindicated with OATP1B1/3 inhibitors (e.g., cyclosporine) and certain HIV protease inhibitors (e.g., atazanavir, darunavir, lopinavir). Grazoprevir increases serum creatinine due to OATP2B1 inhibition, but this does not reflect true renal function decline. |
| Patient Advice | Take ZEPATIER exactly as prescribed, one tablet once daily with or without food. · Do not stop or skip doses without consulting your healthcare provider. · Inform your doctor of all medications you take, including over-the-counter drugs and herbal supplements, to avoid serious interactions. · Notify your healthcare provider immediately if you experience symptoms of liver problems: yellowing of skin or eyes, dark urine, pale stools, nausea, vomiting, or right upper abdominal pain. · ZEPATIER may elevate creatinine levels without reflecting kidney damage; your doctor will monitor appropriately. · If you have genotype 1a HCV, your doctor will test for specific resistance mutations to determine the correct treatment duration. · Avoid alcohol during treatment as it can exacerbate liver injury. · Use effective contraception during treatment and for 2 weeks after the last dose if you or your partner can become pregnant. |