elbasvir/grazoprevir (Rx)

Brand and Other Names:Zepatier
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

elbasvir/grazoprevir

tablet

  • 50mg/100mg

Chronic Hepatitis C Virus (HCV) Infection

Indicated with or without ribavirin for genotypes 1 or 4 infection

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
  • Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with HCV direct acting antivirals (DDAs)

Safety and efficacy not established

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Interactions

Interaction Checker

and elbasvir/grazoprevir

No Results

     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse 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%)
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            Warnings

            Black Box Warnings

            Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with HCV direct acting antivirals (DDAs)

            HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with DDAs and were not receiving HBV antiviral therapy

            Some cases have resulted in fulminant hepatitis, hepatic failure, and death

            Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up

            Initiate appropriate patient management for HBV infection as clinically indicated

            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

            Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV DDAs, and who were not receiving HBV antiviral therapy; HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level (see Black Box Warnings and Dosing Considerations)

            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)

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            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.

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            Pharmacology

            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

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            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)

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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.