elbasvir/grazoprevir (elb-as-vir/graz-oh-pre-vir) Zepatier

 Indications

Chronic hepatitis C virus (HCV) genotypes 1 or 4 infection

(with or without ribavirin).

Action

Elbasvir—inhibits the HCV NS5A protein, resulting in

inhibition of viral replication; Grazoprevir—inhibits

the HCV NS3/4A protease, resulting in inhibition of viral

replication. Therapeutic Effects: Decreased levels

of HCV with sustained virologic response and lessened

sequelae of chronic HCV infection.

Pharmacokinetics

Elbasvir

Absorption: Well absorbed following oral administration.

Distribution: Extensively distributed to tissues.

Protein Binding: 99.9%.

Metabolism and Excretion: Partially metabolized

by CYP3A4. 90% excreted in feces and 1% eliminated

in urine.

Half-life: 24 hr.

Grazoprevir

Absorption: Well absorbed following oral administration.

Distribution: Extensively distributed to tissues.

Protein Binding: 98.8%.

Metabolism and Excretion: Partially metabolized

by CYP3A4. 90% excreted in feces and 1% eliminated

in urine.

Half-life: 31 hr.

TIME/ACTION PROFILE (blood levels)

ROUTE ONSET PEAK DURATION

elbasvir (PO) unknown 3 hr 24 hr

grazoprevir

(PO)

unknown 2 hr 24 hr

Contraindications/Precautions

Contraindicated in: Moderate or severe hepatic

impairment (Child-Pugh B or C); Concurrent use of organic

anion transporting polypeptides 1B1/3

(OATP1B1/3) inhibitors, strong CYP3A inducers, or

efavirenz; Situations when ribavirin is contraindicated

(when ribavirin required); OB: Pregnant women or

men whose partners are pregnant (when ribavirin is required;

ribavirin may cause fetal harm); Lactation: Discontinue

sofosbuvir/velpatasvir or discontinue breast

feeding (when ribavirin required).

Use Cautiously in: Patients who are female or of

Asian ancestry (qrisk of liver enzyme elevation); Patients

awaiting liver transplantation or liver transplant

recipients (safety and effectiveness not established);

Receiving immunosuppressant or chemotherapy medications

(qrisk of hepatitis B virus reactivation); OB:

Safety not established (when ribavirin not required);

Lactation: Weigh benefits of breast feeding against possible

adverse effects (when ribavirin not required);

Geri:qrisk of liver enzyme elevation in elderly patients;

Pedi: Safety and effectiveness not established.

Adverse Reactions/Side Effects

Without ribavirin

CNS: headache, insomnia. GI: abdominal pain, diarrhea,

qliver enzymes, nausea. Misc: fatigue, hepatitis

B virus reactivation.

With ribavirin

CNS: depression, headache, irritability. Derm: pruritus,

rash. GI: abdominal pain, hyperbilirubinemia,q

liver enzymes. Hemat: anemia. MS: arthralgia.

Resp: dyspnea. Misc: fatigue, hepatitis B virus reactivation.

Interactions

Drug-Drug: OATP1B1/3 inhibitors, including atazanavir,

cyclosporine, darunavir, lopinavir, saquinavir,

or tipranavir mayqlevels/toxicity of grazoprevir;

concurrent use contraindicated. Strong CYP3A

inducers, including phenytoin, carbamazepine, or

rifampin mayplevels/effectiveness of elbasvir and

grazoprevir; concurrent use contraindicated. Efavirenz

mayplevels/effectiveness of elbasvir and grazoprevir;

concurrent use contraindicated. Moderate

CYP3A inducers, including nafcillin, bosentan,

etravirine, and modafanil mayplevels/effectiveness

of elbasvir and grazoprevir; concurrent use not recommended.

Strong CYP3A inhibitors, including ketoconazole

and cobicistat-containing regimens may

qlevels/toxicity of elbasvir and grazoprevir; concurrent

use not recommended. Mayqlevels/toxicity of tacrolimus;

frequent monitoring of tacrolimus whole blood

concentrations recommended. Mayqlevels/toxicity of

atorvastatin, fluvastatin, lovastatin, rosuvastatin,

and simvastatin; rosuvastatin dose should not exceed

10 mg/day; atorvastatin dose should not exceed 20 mg/

day; use lowest possible dose of fluvastatin, lovastatin,

and simvastatin and monitor closely for myopathy.

Drug-Natural Products: St. John’s wort mayp

levels/effectiveness of elbasvir and grazoprevir; concurrent

use contraindicated.

Route/Dosage

Patients with HCV genotype 1a infection

should be tested for the presence of virus

with NS5A resistance-associated polymorphisms

prior to initiation of therapy

to determine the most appropriate dosage

regimen and duration of therapy

PO (Adults): Genotype 1a: Treatment-naı¨ve or Peginterferon/

ribavirin-experienced without baseline

NS5A polymorphisms—1 tablet once daily for 12 wk;

Genotype 1a: Treatment-naı¨ve or Peg-interferon/ribavirin-

experienced with baseline NS5A polymorphisms—

1 tablet once daily for 16 wk in combination

with ribavirin; Genotype 1b: Treatment-naı¨ve or Peginterferon/ribavirin-experienced—1 tablet once

daily for 12 wk; Genotype 1a or 1b: Peg-interferon/ribavirin/

HCV NS3/4A protease inhibitor-experienced—

1 tablet once daily for 12 wk in combination

with ribavirin; Genotype 4: Treatment-naı¨ve—1 tablet

once daily for 12 wk; Genotype 4: Peg-interferon/

ribavirin-experienced—1 tablet once daily for 16 wk

in combination with ribavirin.

Availability

Tablets: elbasvir 50 mg/grazoprevir 100 mg.