Grazoprevir
(in ZEPATIER)
What it isHCV NS3/4A protease inhibitor, marketed only in the fixed-dose combination Zepatier with elbasvir.
Why this oneProvides a curative, ribavirin-free 12-week regimen for chronic HCV genotypes 1 and 4, usable even in severe renal impairment or dialysis.
What limits itA sensitive OATP1B and CYP3A substrate, so it is contraindicated with OATP1B inhibitors and strong CYP3A inducers, and genotype 1a warrants baseline NS5A resistance testing.
FDA label
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| FDA dosing | Population | Start | Target | Max |
|---|---|---|---|---|
| Chronic HCV GT1a, treatment-naive or PegIFN/RBV-experienced, WITHOUT baseline NS5A polymorphisms | adults & peds >=12 y or >=30 kg | 1 tablet (elbasvir 50 mg / grazoprevir 100 mg) QD x 12 wk | 1 tablet QD x 12 wk | 1 tablet QD |
| Chronic HCV GT1a WITH baseline NS5A polymorphisms (positions 28/30/31/93) | adults & peds >=12 y or >=30 kg | 1 tablet QD + weight-based ribavirin x 16 wk | 1 tablet QD + RBV x 16 wk | 1 tablet QD |
| Chronic HCV GT1b, treatment-naive or PegIFN/RBV-experienced | adults & peds >=12 y or >=30 kg | 1 tablet QD x 12 wk | 1 tablet QD x 12 wk | 1 tablet QD |
| Chronic HCV GT1a or 1b, PegIFN/RBV/protease-inhibitor-experienced | adults & peds >=12 y or >=30 kg | 1 tablet QD + ribavirin x 12 wk | 1 tablet QD + RBV x 12 wk | 1 tablet QD |
| Chronic HCV GT4, treatment-naive | adults & peds >=12 y or >=30 kg | 1 tablet QD x 12 wk | 1 tablet QD x 12 wk | 1 tablet QD |
| Chronic HCV GT4, PegIFN/RBV-experienced | adults & peds >=12 y or >=30 kg | 1 tablet QD + ribavirin x 16 wk | 1 tablet QD + RBV x 16 wk | 1 tablet QD |
Renal No adjustment needed (any degree of renal impairment, incl. hemodialysis); adjust ribavirin per its label if CrCl <=50 mL/min
Hepatic Mild (Child-Pugh A): no adjustment. Moderate/severe (Child-Pugh B/C) or any prior hepatic decompensation: CONTRAINDICATED
Ribavirin co-administration required in some regimens (see table); ribavirin contraindications/warnings then also apply
Instructions
- Take with or without food
- Before starting: test all patients for HBV (HBsAg + anti-HBc)
- GT1a: test for baseline NS5A resistance-associated polymorphisms to set regimen/duration
- Hepatic labs before treatment, at week 8 (and week 12 if 16-wk course), and as indicated
- HCV/HIV-1 co-infection: same regimens as mono-infection
Contraindications
- Moderate or severe hepatic impairment (Child-Pugh B/C) or any history of hepatic decompensation
- OATP1B1/3 inhibitors that significantly raise grazoprevir levels (atazanavir, darunavir, lopinavir, saquinavir, tipranavir, cyclosporine) — ALT-elevation risk
- Strong CYP3A inducers (phenytoin, carbamazepine, rifampin, St. John's wort) and efavirenz — loss of virologic response
- If given with ribavirin, all ribavirin contraindications apply (incl. pregnancy)
Cautions
- HBV reactivation in HCV/HBV co-infected patients — can cause fulminant hepatitis, hepatic failure, death; test and monitor (boxed)
- Late ALT elevations (~1%, at/after wk 8; higher in females, Asians, age >=65) — monitor hepatic labs; discontinue if ALT >10x ULN persists or with signs of liver inflammation
- Hepatic decompensation/failure (incl. fatal) reported with NS3/4A protease-inhibitor regimens — monitor; discontinue if decompensation develops
- Significant drug interactions via CYP3A/OATP1B1/3 — review co-medications
Adverse reactions
- ZEPATIER x12 wk: fatigue, headache, nausea (>=5%)
- With ribavirin x16 wk: anemia, headache (moderate/severe >=5%)
- Late ALT elevations ~1%; bilirubin elevation and hemoglobin decline mainly with ribavirin
- Postmarketing: angioedema, hepatic decompensation/failure
Pregnancy No adequate human data (animal studies: no adverse developmental effects); if given with ribavirin, regimen is CONTRAINDICATED in pregnancy and in men whose partners are pregnant
Lactation Unknown if present in human milk (present in rat milk, no pup effects); weigh benefit vs risk; with ribavirin, ribavirin lactation guidance applies
⚠ BOXED WARNING
- Hepatitis B virus reactivation
Principal riskBoxed warning (as Zepatier): risk of hepatitis B virus reactivation in patients coinfected with HCV and HBV.
Classes and tags
Clinical profile
Mechanism of action: Grazoprevir ballicule
