Grazoprevir

(in ZEPATIER)

Open Grazoprevir in the interactive console ↗

Pronunciation: graz-OE-pre-veer

Grazoprevir ballicule: receptor binding, kinetics and half-life diagram — Mechanism of action: Grazoprevir ballicule

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 itSensitive OATP1B and CYP3A substrate, so it is contraindicated with OATP1B inhibitors and strong CYP3A inducers, and genotype 1a warrants baseline NS5A resistance testing.

Pearls

First-line for genotype 1b or 4; alternative for 1a.
Contraindicated even in Child-Pugh B cirrhosis.
Monitor ALT; late elevations track higher grazoprevir exposure.

Grazoprevir molecular structure (skeletal formula) — Molecular structure: Grazoprevir

Principal riskBoxed warning (as Zepatier): risk of hepatitis B virus reactivation in patients coinfected with HCV and HBV.

Classes and tags

Clinical profile

Therapeutic safety burden2 / 4

Overdose danger1 / 4

Weight-gain liability0 / 4

Sedation liability0 / 4

QT / Torsades0 / 4

Direct muscarinic antagonism0 / 4

FDA label

Read the full label on DailyMed ↗

BOXED WARNING HBV reactivation in HCV/HBV co-infected patients — test all patients (HBsAg, anti-HBc) before starting; monitor during and after treatment; fulminant hepatitis, hepatic failure and death reported

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

Available strengths

tab 50/100 mg

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

Cost

Grazoprevir ((IN ZEPATIER))

Strength		#/mo	generic $/mo	CostPlus
50/100 mg	tab	30 qd		not offered

NADAC is a voluntary CMS survey of what retail community pharmacies pay for the drugs they stock. Grazoprevir is dispensed outside retail pharmacies, so it rarely appears on surveyed invoices.

Other forms: Elbasvir ((in ZEPATIER))

Open Grazoprevir in the interactive console ↗

Self-check

Which HCV genotype warrants baseline NS5A resistance testing with grazoprevir here?
Genotype 1a.
Which partner is fixed with grazoprevir in Zepatier?
Elbasvir.