Dosing and uses of Zepatier (grazoprevir/elbasvir)
Adult dosage forms and strengths
elbasvir/grazoprevir
tablet
- 50mg/100mg
Chronic Hepatitis C
Indicated with or without ribavirin for treatment of chronic hepatitis C virus (HCV) genotypes 1 or 4 infection in adults
1 tablet PO qDay; treatment duration and whether to take with or without ribavirin are dependent on genotypes and other patient variable
Treatment regimen and duration of therapy
- Patients with or without cirrhosis
- 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
Dosage modifications
Renal impairment
- No dosage adjustment is required for patients with any degree of renal impairment including patients on hemodialysis
- Refer to the ribavirin prescribing information for dose in patients with CrCl ≤50 mL/min
Hepatic impairment
- Mild (Child-Pugh A): No dosage adjustment required
- Moderate-to-severe (Child Pugh B or C): Contraindicated
Dosing Considerations
Testing prior to initiating therapy
- Test for NS5A resistance in HCV genotype 1a infected patients to determine dosage regimen and duration
- 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 28, 30, 31, or 93
- Obtain hepatic laboratory testing prior to and during treatment
Pediatric dosage forms and strengths
Safety and efficacy not established
Zepatier (grazoprevir/elbasvir) adverse (side) effects
>10%
Fatigue, treatment-naïve (11%)
1-10%
Headache, treatment-naïve (10%)
Treatment-experienced
- Fatigue (5%)
- Abdominal pain (2%)
- Diarrhea (2%)
- Irritability (1%)
- Depression (1%)
Treatment-experienced plus ribavirin
- Anemia (8%)
- Headache (6%)
- Fatigue (4%)
- Dyspnea (4%)
- Rash or pruritus (4%)
- Irritability (3%)
- Abdominal pain (2%)
- Depression (2%)
- Arthralgia (2%)
Warnings
Black box warnings
Direct-acting antivirals (DDAs) may reactivate hepatitis B virus (HBV) in patients who have a current or previous HBV infection while being treated for hepatitis C virus
In a few cases, HBV reactivation in patients treated with DAA medicines resulted in serious liver problems or death
Patients should be screened for evidence of current or prior HBV infection before starting treatment with DAAs, and monitored for HBV flare-ups or reactivation during DAA treatment and posttreatment follow-up
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 (refer to ribavirin prescribing information)
Organic anion transporting polypeptides 1B1/3 (OATP1B1/3) inhibitors, strong CYP3A inducers, and efavirenz
OATP1B1/3 inhibitors contraindicated with elbasvir/grazoprevir
- Not a comprehensive list
- 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
- Immunosuppressants: cyclosporine
Strong CYP3A inducers contraindicated with elbasvir/grazoprevir
- Not a comprehensive list 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
Cautions
May increase ALT levels; measure liver enzymes prior to therapy, at treatment week 8, and as clinically indicated; for patients receiving 16 weeks of therapy, additional hepatic laboratory testing should be performed at treatment week 12
Warnings and precautions (including pregnancy) for ribavirin apply if coadministered
Risk of adverse reactions or reduced therapeutic effect caused by drug interactions (see Contraindications and Drug Interactions)
Pregnancy
Pregnancy
No adequate human data are available
In animal reproduction studies, no evidence of adverse developmental outcomes was observed with elbasvir or grazoprevir at exposures greater than those in humans at the recommended human dose
Note: Ribavirin is contraindicated in pregnant women and men whose female partners are pregnant
Lactation
Unknown if distributed in human breast milk
Consider the developmental and health benefits of breastfeeding, along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Zepatier (grazoprevir/elbasvir)
Mechanism of action
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 (into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins) and is essential for viral replication
Absorption
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)
Distribution
Protein bound: >99.9% (elbasvir); >98.8% (grazoprevir)
Vd: 680 L (elbasvir); 1250 L (grazoprevir)
Metabolism
Elbasvir and grazoprevir are partially eliminated by oxidative metabolism, primarily by CYP3A
No circulating metabolites of either elbasvir or grazoprevir were detected in human plasma
Elimination
Excretion: >90% feces; <1% urine
Administration
Oral Administration
May take with or without food
Storage
Store at 20-25°C (68-77°F); excursions permitted between 15-30°C (59-86°F)
