Elbasvir/grazoprevir (Zepatier)

Classes: HCV NS5A Inhibitors; HCV NS3/4A Protease Inhibitors

elbasvir/grazoprevir, a tablet 50mg/100mg.

Indicated with or without ribavirin for treatment of chronic hepatitis C virus (HCV) genotypes 1 or 4 infection in adults

1 tablet PO q day.

Treatment duration and whether to take with or without ribavirin are dependent on genotypes and other patient variables.

Genotypes 1a
Treatment-naïve or PegIFN/RBV-experienced without baseline NS5A polymorphisms: elbasvir/grazoprevir for 12 wk.

Treatment-naïve or PegIFN/RBV-experienced with baseline NS5A polymorphisms: elbasvir/grazoprevir plus weight-based ribavirin for 16 wk

Genotype 1b
Treatment-naïve or PegIFN/RBV-experienced: elbasvir/grazoprevir for 12 wk.

Genotypes 1a or 1b
PegIFN/RBV/PI-experienced: elbasvir/grazoprevir plus weight-based ribavirin for 12 wk

Genotype 4
Treatment-naïve: elbasvir/grazoprevir for 12 wk
Peg/IFN/RBV-experienced: elbasvir/grazoprevir plus weight-based ribavirin for 16 wk.

No dosage adjustment is required for patients with any degree of renal impairment including patients on hemodialysis.

Mild (Child-Pugh A) hepatic impairment-No dosage adjustment required.

With moderate-to-severe (Child Pugh B or C) liver impairment it is contraindicated.

Test for NS5A resistance in HCV genotype 1a infected patients to determine dosage regimen and duration prior to initiating therapy.

In clinical trials, patients with genotype 1a who received elbasvir/grazoprevir for 12 weeks showed a lower sustained virologic response (SVR12) rate with ≥1 baseline NS5A resistance-associated polymorphisms at amino acid positions.

elbasvir/grazoprevir contraindicated because of interactions with:

atazanavir

carbamazepine

cyclosporine

dabrafenib

darunavir

dexamethasone

efavirenz

enzalutamide

eslicarbazepine acetate

fosphenytoin

lopinavir

lumacaftor/ivacaftor

mitotane

nevirapine

oxcarbazepine

pentobarbital

phenobarbital

phenytoin

primidone

rifabutin

rifampin

rifapentine

saquinavir

st john’s wort

tipranavir

Serious interactions suggesting use alternatives

armodafinil

bosentan

clobazam

cobicistat

elvitegravir/cobicistat/emtricitabine/tenofovir

etravirine

ketoconazole

modafinil

nafcillin

osimertinib

Significant reactions requiring close monitoring:

atorvastatin

fluvastatin

lovastatin

rosuvastatin

simvastatin

sofosbuvir/velpatasvir

tacrolimus

Adverse effects less than10%.

Fatigue 11%.

Headache 10%.

Treatment associated side effects include:

Fatigue (5%)

Abdominal pain (2%)

Diarrhea (2%)

Irritability (1%)

Depression (1%)

Treatment-experienced plus ribavirin effects:

Anemia (8%)

Headache (6%)

Fatigue (4%)

Dyspnea (4%)

Rash or pruritus (4%)

Irritability (3%)

Abdominal pain (2%)

Depression (2%)

Arthralgia (2%)

Contraindications: patients with moderate or severe hepatic impairment (Child Pugh B or C) because of significantly increased grazoprevir plasma concentration and risk of increased ALT levels

If administered with ribavirin, the contraindications to ribavirin also apply to this combination regimen.

Organic anion transporting polypeptides inhibitors, strong CYP3A inducers, and efavirenz

OATP1B1/3 inhibitors contraindicated with elbasvir/grazoprevir

May increase the risk of ALT elevations owing to a significant increase in grazoprevir plasma concentrations caused by OATP1B1/3 inhibition
HIV medications: atazanavir, darunavir, lopinavir, saquinavir, tipranavir

Strong CYP3A inducers contraindicated with elbasvir/grazoprevir.

May lead to loss of virologic response to elbasvir/grazoprevir owing to significant decreases in elbasvir and grazoprevir plasma concentrations caused by strong CYP3A induction.

Anticonvulsants: carbamazepine, phenytoin

Antimycobacterials: rifampin
Herbals: St John’s wort

HIV medications: efavirenz

As it may increase ALT levels; measuring liver enzymes periodically is indicated

Unknown if distributed in human breast milk

Elbasvir: Inhibitor of HCV NS5A, which is essential for viral RNA replication and virion assembly

Grazoprevir: Inhibitor of HCV NS3/4A protease, which is necessary for the proteolytic cleavage of the HCV-encoded polyprotein and is essential for viral replication

Peak plasma time: 3 hr (elbasvir); 2 hr (grazoprevir)

Peak plasma concentration: 121 ng/mL (elbasvir); 165 ng/mL (grazoprevir)

AUC: 1920 ng·hr/mL (elbasvir); 1420 ng·hr/mL (grazoprevir)

Protein bound: >99.9% (elbasvir); >98.8% (grazoprevir)

Elbasvir and grazoprevir are partially eliminated by oxidative metabolism, primarily by CYP3A

Excretion: >90% feces; <1% urine

Oral Administration

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