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Elbasvir and Grazoprevir

Class: HCV Replication Complex Inhibitors
Chemical Name: N,N′-[[(6S)-6-Phenyl-6H-indolo[1,2-c][1,3]benzoxazine-3,10-diyl]bis[1H-imidazole-5,2-diyl-(2S)-2,1-pyrrolidinediyl[(1S)-1-(1-methylethyl)-2-oxo-2,1-ethanediyl]]]bis-carbamic acid, C,C′-dimethyl ester
Molecular Formula: C49H55N9O7C38H50N6O9S•H2O
CAS Number: 1370468-36-2
Brands: Zepatier

Medically reviewed by Drugs.com. Last updated on April 6, 2020.

Warning

    Risk of HBV Reactivation in Patients Coinfected with HCV and HBV
  • HBV reactivation, including cases resulting in fulminant hepatitis, hepatic failure, and death, reported in patients coinfected with HCV and HBV who were receiving or had completed treatment with HCV direct-acting antivirals (DAAs) and were not receiving HBV antiviral therapy. (See Risk of HBV Reactivation in Patients Coinfected with HCV and HBV under Cautions.)

  • Test all patients for evidence of current or prior HBV infection before initiating fixed combination of elbasvir and grazoprevir (elbasvir/grazoprevir).

  • Monitor patients coinfected with HCV and HBV for hepatitis flare or HBV reactivation during and after HCV treatment. Initiate appropriate management for HBV infection as clinically indicated.

Introduction

Antiviral; fixed combination containing elbasvir (HCV NS5A replication complex inhibitor [NS5A inhibitor]) and grazoprevir (HCV NS3/4A protease inhibitor).

Uses for Elbasvir and Grazoprevir

Chronic HCV Infection

Treatment of chronic HCV genotype 1 or genotype 4 infection in treatment-naive (have not previously received HCV treatment) or previously treated adults without cirrhosis or with compensated cirrhosis (Child-Pugh class A), including those with HIV coinfection.

Used alone or in conjunction with ribavirin, depending on HCV genotype and certain patient factors (e.g., previous treatment experience, presence of baseline polymorphisms).

Efficacy of 12-week elbasvir/grazoprevir regimen for treatment of HCV genotype 1a infection reduced when 1 or more NS5A resistance-associated polymorphisms at certain amino acid positions (28, 30, 31, 93) are present at baseline. Screening for NS5A resistance-associated polymorphisms recommended prior to initiation of treatment in patients with HCV genotype 1a infection. (See General under Dosage and Administration.)

Treatment of chronic HCV infection is complex and rapidly evolving; consult a specialist to obtain the most up-to-date information. Information from the American Association for the Study of Liver Diseases (AASLD), Infectious Diseases Society of America (IDSA), and International Antiviral Society–USA (IAS–USA) regarding diagnosis and management of HCV infection, including recommendations for initial treatment, is available at [Web].

Elbasvir and Grazoprevir Dosage and Administration

General

  • For treatment of chronic HCV infection, elbasvir/grazoprevir is used alone or in conjunction with ribavirin.

  • Base specific regimen and duration of treatment on HCV genotype and certain patient factors (e.g., previous treatment experience, presence of baseline polymorphisms). Relapse rates after treatment are affected by baseline patient and viral factors and differ between treatment regimens and treatment duration for certain subgroups.

  • HCV genotype 1a infection: Screening for presence of HCV NS5A resistance-associated polymorphisms recommended prior to initiation of treatment to determine appropriate treatment regimen and treatment duration.

  • Prior to initiating HCV treatment, test all patients for evidence of current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc). (See Risk of HBV Reactivation in Patients Coinfected with HCV and HBV under Cautions.)

  • Prior to and during treatment, perform appropriate laboratory tests to evaluate liver function. (See Hepatic Effects under Cautions.)

Administration

Oral Administration

Administer orally once daily without regard to food.

Dosage

Available as fixed-combination tablets containing 50 mg of elbasvir and 100 mg of grazoprevir (elbasvir/grazoprevir).

Adults

Treatment of Chronic HCV Infection
HCV Genotype 1a Infection
Oral

1 tablet (elbasvir 50 mg and grazoprevir 100 mg) once daily.

Use alone in patients without baseline NS5A polymorphisms who are treatment-naive or previously treated with peginterferon alfa and ribavirin; use in conjunction with ribavirin in those with baseline NS5A polymorphisms or in those previously treated with peginterferon alfa, ribavirin, and an HCV protease inhibitor. Treatment duration of 12 weeks recommended in most patients; treatment duration of 16 weeks recommended in those with baseline NS5A polymorphisms. (See Table 1.)

Previously treated defined as patients who failed treatment with peginterferon alfa and ribavirin.

NS5A resistance-associated polymorphisms at amino acid positions 28, 30, 31, or 93.

Use weight-based ribavirin dosage in patients with Clcr >50 mL/minute (800 mg daily in those <66 kg, 1 g daily in those 66–80 kg, 1.2 g daily in those 81–105 kg, 1.4 g daily in those >105 kg); give ribavirin daily dosage in 2 divided doses with food.

Previously treated with an HCV protease inhibitor defined as patients who failed treatment with a regimen of peginterferon alfa, ribavirin, and an HCV NS3/4A protease inhibitor (e.g., boceprevir, simeprevir, telaprevir; no longer commercially available).

The optimal elbasvir/grazoprevir-based regimen and duration of treatment not established for patients with HCV genotype 1a infection who were previously treated with peginterferon alfa, ribavirin, and an HCV protease inhibitor and have 1 or more baseline NS5A resistance-associated polymorphisms at positions 28, 30, 31, and 93.

Table 1. Recommended Treatment Regimen and Duration of Elbasvir/Grazoprevir for HCV Genotype 1a Infection in Adults without Cirrhosis or with Compensated Cirrhosis.1

Patient Type

Multiple-drug Regimen

Duration of Treatment

Treatment-naive or previously treated without baseline NS5A polymorphisms

Elbasvir/grazoprevir

12 weeks

Treatment-naive or previously treated with baseline NS5A polymorphisms

Elbasvir/grazoprevir with ribavirin

16 weeks

Previously treated with an HCV protease inhibitor,

Elbasvir/grazoprevir with ribavirin

12 weeks

HCV Genotype 1b Infection
Oral

1 tablet (elbasvir 50 mg and grazoprevir 100 mg) once daily.

Use alone in patients who are treatment-naive or previously treated with peginterferon alfa and ribavirin; use in conjunction with ribavirin in those previously treated with peginterferon alfa, ribavirin, and an HCV protease inhibitor. Treatment duration of 12 weeks recommended. (See Table 2.)

Previously treated defined as patients who failed treatment with peginterferon alfa and ribavirin.

Previously treated with an HCV protease inhibitor defined as patients who failed treatment with a regimen of peginterferon alfa, ribavirin, and an HCV NS3/4A protease inhibitor (e.g., boceprevir, simeprevir, telaprevir; no longer commercially available).

Use weight-based ribavirin dosage in patients with Clcr >50 mL/minute (800 mg daily in those <66 kg, 1 g daily in those 66–80 kg, 1.2 g daily in those 81–105 kg, 1.4 g daily in those >105 kg); give ribavirin daily dosage in 2 divided doses with food.

Table 2. Recommended Treatment Regimen and Duration of Elbasvir/Grazoprevir for HCV Genotype 1b Infection in Adults without Cirrhosis or with Compensated Cirrhosis.1

Patient Type

Multiple-drug Regimen

Duration of Treatment

Treatment-naive or previously treated

Elbasvir/grazoprevir

12 weeks

Previously treated with an HCV protease inhibitor

Elbasvir/grazoprevir with ribavirin

12 weeks

HCV Genotype 4 Infection
Oral

1 tablet (elbasvir 50 mg and grazoprevir 100 mg) once daily.

Use alone in patients who are treatment-naive; use in conjunction with ribavirin in those previously treated with peginterferon alfa and ribavirin. Treatment duration of 12 weeks recommended in treatment-naive patients; treatment duration of 16 weeks recommended in those previously treated with peginterferon alfa and ribavirin. (See Table 3.)

Previously treated defined as patients who failed treatment with peginterferon alfa and ribavirin.

Use weight-based ribavirin dosage in patients with Clcr >50 mL/minute (800 mg daily in those <66 kg, 1 g daily in those 66–80 kg, 1.2 g daily in those 81–105 kg, 1.4 g daily in those >105 kg); give ribavirin daily dosage in 2 divided doses with food.

Table 3. Recommended Treatment Regimen and Duration of Elbasvir/Grazoprevir for HCV Genotype 4 Infection in Adults without Cirrhosis or with Compensated Cirrhosis.1

Patient Type

Multiple-drug Regimen

Duration of Treatment

Treatment-naive

Elbasvir/grazoprevir

12 weeks

Previously treated

Elbasvir/grazoprevir with ribavirin

16 weeks

HCV-infected with HIV Coinfection.
Oral

HCV genotype 1 or 4: Use same elbasvir/grazoprevir dosage and same HCV genotype-specific multiple-drug regimen and duration of treatment recommended for HCV-infected patients without HIV coinfection. (See Table 1, Table 2, and Table 3.)

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): Dosage adjustments not needed. Monitor for signs and symptoms of hepatic decompensation. (See Hepatic Impairment under Cautions.)

Moderate or severe hepatic impairment (Child-Pugh class B or C) or any history of hepatic decompensation: Contraindicated. (See Hepatic Impairment under Cautions.)

Renal Impairment

Mild, moderate, or severe renal impairment, including those requiring hemodialysis: Dosage adjustments not needed. (See Renal Impairment under Cautions.)

Geriatric Patients

Dosage adjustments not needed. (See Geriatric Use under Cautions.)

Cautions for Elbasvir and Grazoprevir

Contraindications

  • Moderate or severe hepatic impairment (Child-Pugh class B or C) or any history of hepatic decompensation. (See Hepatic Impairment under Cautions.)

  • Concomitant use with certain drugs (e.g., inhibitors of organic anion transporting polypeptide [OATP] 1B1 and 1B3, potent inducers of CYP3A, efavirenz). (See Interactions.)

  • If elbasvir/grazoprevir used in conjunction with ribavirin, the contraindications to ribavirin also apply. (See Precautions Related to Fixed Combinations and Multiple-drug Treatment Regimens under Cautions.)

Warnings/Precautions

Warnings

Risk of HBV Reactivation in Patients Coinfected with HCV and HBV

Postmarketing reports of reactivation of HBV infection when DAAs were used for treatment of HCV infection in patients with HBV coinfection; fulminant hepatitis, hepatic failure, and death reported in some cases.

HBV reactivation (abrupt increase in HBV replication manifested as rapid increase in serum HBV DNA levels or detection of HBsAg in an individual who was previously HBsAg negative and anti-HBc positive) reported in patients with HCV and HBV coinfection receiving HCV treatment with a regimen that included HCV DAAs without interferon alfa. HBV reactivation usually occurred within 4–8 weeks after initiation of HCV treatment.

Patients with HBV reactivation heterogeneous in terms of HCV genotype and baseline HBV disease. Some patients were HBsAg positive; others had serologic evidence of resolved HBV infection (i.e., HBsAg negative and anti-HBc positive).

HBV reactivation also reported in patients receiving certain immunosuppressant or chemotherapeutic drugs; risk of reactivation associated with HCV DAAs may be increased in such patients.

Mechanism for HBV reactivation in coinfected patients receiving HCV DAAs unknown. Although HCV DAAs not known to cause immunosuppression, HBV reactivation in coinfected patients may result from a complex interplay of host immunologic responses in the setting of infection with 2 hepatitis viruses.

Prior to initiating treatment with an HCV DAA, including elbasvir/grazoprevir, screen all patients for evidence of current or prior HBV infection by measuring HBsAg, anti-HBs, and anti-HBc. Initiate appropriate management for HBV infection as clinically indicated.

In all patients with evidence of current or prior HBV infection, monitor for clinical and laboratory signs (i.e., HBsAg, HBV DNA levels, serum aminotransferase and bilirubin concentrations) of hepatitis flare or HBV reactivation during and after treatment with HCV DAAs. Initiate appropriate management for HBV infection as clinically indicated.

Advise coinfected patients to immediately contact a clinician if they develop any signs or symptoms of serious liver injury. (See Advice to Patients.)

When making decisions regarding HBV monitoring or HBV treatment in coinfected patients, consult a clinician with expertise in managing HBV infection.

Other Warnings/Precautions

Risk of Hepatic Decompensation or Failure in Patients with Evidence of Advanced Liver Disease

Postmarketing reports of hepatic decompensation or failure, including some fatalities, in patients receiving HCV treatment regimens containing an HCV NS3/4A protease inhibitor, including elbasvir/grazoprevir. Data insufficient to estimate frequency of such events; causal relationship not established. Hepatic decompensation or failure usually occurred within first 4 weeks of HCV treatment.

Many of the reported cases of hepatic decompensation or failure occurred in patients with evidence of advanced liver disease with moderate or severe hepatic impairment (Child-Pugh class B or C) prior to initiation of HCV treatment. Some cases occurred in patients reported as noncirrhotic or as having compensated cirrhosis with mild liver impairment (Child-Pugh class A) at baseline, but with a history of a decompensation event or evidence of portal hypertension or decreased platelet counts at baseline. Some cases also reported in patients who had confounding factors (e.g., serious liver-related comorbidities).

If elbasvir/grazoprevir used in patients who have compensated cirrhosis (Child-Pugh class A) or evidence of advanced liver disease (e.g., portal hypertension), perform hepatic function tests as clinically indicated and monitor for signs and symptoms of hepatic decompensation (e.g., jaundice, ascites, hepatic encephalopathy, variceal hemorrhage).

Discontinue elbasvir/grazoprevir in patients who develop evidence of hepatic decompensation or failure. (See Contraindications under Cautions.)

Advise patients to contact a clinician if they develop any signs or symptoms of worsening liver disease. (See Advice to Patients.)

Hepatic Effects

Increased ALT concentrations (>5 times ULN) reported in 1% of patients in clinical trials. Generally occurs at ≥8 weeks after initiation of treatment (mean onset 10 weeks; range 6–12 weeks); typically asymptomatic and resolved with ongoing treatment or completion of treatment. Increased rates of late-onset ALT elevations reported in patients with increased grazoprevir plasma concentrations and in certain patient groups (e.g., ≥65 years of age, Asian descent, females). Incidence of late-onset ALT elevations apparently not affected by presence of cirrhosis or treatment duration.

Increased bilirubin (>2.5 times ULN) reported in 6% of patients in clinical trials receiving elbasvir/grazoprevir in conjunction with ribavirin compared with <1% of patients receiving elbasvir/grazoprevir alone. Bilirubin increases were predominately indirect bilirubin and typically not associated with increased ALT concentrations.

Perform hepatic laboratory testing prior to treatment, at treatment week 8, at treatment week 12 (in those receiving 16 weeks of therapy), and as clinically indicated.

Consider discontinuance of elbasvir/grazoprevir if ALT concentrations remain persistently >10 times ULN. Discontinue if ALT elevations are accompanied by signs or symptoms of liver inflammation or increasing conjugated bilirubin, alkaline phosphatase, or INR. Advise patients to immediately contact clinician if onset of fatigue, weakness, lack of appetite, nausea and vomiting, jaundice, or discolored feces is observed.

Interactions

Concomitant use of elbasvir/grazoprevir and certain drugs is contraindicated or not recommended. Some drug interactions may result in loss of therapeutic effect and possible development of resistance to elbasvir/grazoprevir; other interactions may lead to adverse reactions from increased exposures of concomitant drugs or elbasvir/grazoprevir.

Consider potential for drug interactions prior to and during treatment. Review concomitant drugs during treatment; monitor patient for adverse reactions associated with the concomitant drugs. (See Interactions.)

Precautions Related to Fixed Combinations and Multiple-drug Treatment Regimens

Consider cautions, precautions, contraindications, and drug interactions associated with both drugs in the fixed combination. Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for both elbasvir and grazoprevir.

When elbasvir/grazoprevir is used in conjunction with ribavirin, consider that ribavirin may cause fetal toxicity and/or death. Extreme care must be taken to avoid pregnancy in female patients and female partners of male patients receiving a ribavirin-containing regimen. Obtain a negative pregnancy test for female patients of childbearing potential immediately prior to initiating ribavirin; perform pregnancy tests monthly during and for 6 months after ribavirin treatment is completed. Women of childbearing potential (and their male partners) and male patients (and their female partners) must use at least 2 forms of effective contraception during and for 6 months after ribavirin treatment is completed.

Specific Populations

Pregnancy

Adequate data regarding use of elbasvir/grazoprevir in pregnant women not available. In animal studies using elbasvir or grazoprevir, no evidence of fetal harm at exposures greater than those attained with recommended human dosage.

When used in conjunction with ribavirin, consider that ribavirin is contraindicated in pregnant women and male partners of pregnant women. (See Precautions Related to Fixed Combinations and Multiple-drug Treatment Regimens under Cautions.)

Lactation

Not known whether elbasvir/grazoprevir distributes into human milk, affects human milk production, or affects breast-fed infant; both elbasvir and grazoprevir are distributed into milk in rats.

Consider benefits of breast-feeding and importance of the drug to the woman; also consider potential adverse effects on the breast-fed child from the drug or underlying maternal condition.

When used in conjunction with ribavirin, consider potential for adverse reactions to ribavirin in nursing infants and discontinue nursing or the ribavirin-containing regimen. (See Precautions Related to Fixed Combinations and Multiple-drug Treatment Regimens under Cautions.)

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.

Geriatric Use

Increased rate of late-onset ALT elevations reported in adults ≥65 years of age.

Elbasvir and grazoprevir AUCs reported in individuals ≥65 years of age increased compared with AUCs reported in younger adults.

Hepatic Impairment

Mild hepatic impairment or compensated cirrhosis (Child-Pugh class A): Monitor for signs and symptoms of hepatic decompensation (e.g., jaundice, ascites, hepatic encephalopathy, variceal hemorrhage).

Moderate or severe hepatic impairment (Child-Pugh class B or C) or any history of hepatic decompensation: Contraindicated. Postmarketing reports of hepatic decompensation or failure in such patients. (See Risk of Hepatic Decompensation or Failure in Patients with Evidence of Advanced Liver Disease under Cautions.)

Efficacy and safety not established in liver transplant recipients or pretransplant patients.

Mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C) without HCV infection: Elbasvir AUCs similar but grazoprevir AUCs increased (12-fold higher in those with severe hepatic impairment) compared with AUCs in individuals with normal hepatic function.

Compensated cirrhosis in HCV-infected adults: Elbasvir AUCs similar but grazoprevir AUCs slightly higher compared with those reported in HCV-infected adults without cirrhosis.

Renal Impairment

Severe renal impairment (including those requiring dialysis): Increased elbasvir and grazoprevir exposures compared with exposures in individuals without severe renal impairment. Not considered clinically important.

Elbasvir and grazoprevir not removed by hemodialysis; unlikely to be removed by peritoneal dialysis.

Race

Asians: Higher rate of late-onset ALT elevations reported in clinical trials. Elbasvir and grazoprevir AUCs estimated to be increased by 15 and 50%, respectively, compared with AUCs reported in Caucasians; dosage adjustments not needed based on race.

Black or African American individuals: Estimated elbasvir and grazoprevir exposures are comparable to those in Caucasians.

Gender

Females: Higher rate of late-onset ALT elevations reported in clinical trials. Elbasvir and grazoprevir AUCs estimated to be increased by 50 and 30%, respectively, compared with AUCs reported in males; dosage adjustments not needed based on gender.

Common Adverse Effects

Elbasvir/grazoprevir: Headache, fatigue, insomnia, dizziness, nausea, diarrhea, upper respiratory tract infection, arthralgia.

Elbasvir/grazoprevir in conjunction with ribavirin: Fatigue, headache, asthenia, nausea, vomiting, diarrhea, constipation, upper abdominal pain, insomnia, anemia, decreased hemoglobin concentrations, elevated bilirubin concentrations, elevated triacylglycerol lipase concentrations.

Interactions for Elbasvir and Grazoprevir

Elbasvir and grazoprevir are substrates of CYP3A; grazoprevir is a weak inhibitor of CYP3A. Elbasvir and grazoprevir inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, and 2D6.

Elbasvir inhibits P-gp transport system; elbasvir and grazoprevir are substrates of P-gp.

Elbasvir and grazoprevir inhibit intestinal breast cancer resistance protein (BCRP).

Grazoprevir is a substrate and inhibitor of OATP1B1 and 1B3.

The following drug interactions based on studies using elbasvir/grazoprevir, elbasvir alone, or grazoprevir alone, or are predicted drug interactions that may occur with elbasvir/grazoprevir. When elbasvir/grazoprevir is used, consider interactions associated with both drugs in the fixed combination.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Potent CYP3A inducers: Possible pharmacokinetic interactions (decreased elbasvir and grazoprevir concentrations and possible loss of therapeutic effect); concomitant use contraindicated.

Moderate CYP3A inducers: Possible pharmacokinetic interactions (decreased elbasvir and grazoprevir concentrations and possible reduced therapeutic effect); concomitant use not recommended.

Potent CYP3A inhibitors: Possible pharmacokinetic interactions (increased elbasvir and grazoprevir concentrations); concomitant use not recommended.

Drugs Affecting or Affected by Breast Cancer Resistance Protein

BCRP substrates: Possible pharmacokinetic interactions (increased concentrations of BCRP substrate).

Drugs Affecting or Affected by Organic Anion Transport Polypeptides

OATP1B1 or 1B3 inhibitors: Possible pharmacokinetic interactions (increased grazoprevir concentrations); concomitant use contraindicated with drugs known or suspected to increase grazoprevir concentrations.

Specific Drugs

Drug

Interaction

Comments

Antacids

Dosage adjustments not needed if used concomitantly with antacids

Anticonvulsants (carbamazepine, phenytoin)

Carbamazepine, phenytoin: Possible decreased elbasvir and grazoprevir concentrations; possible loss of virologic response to the HCV antiviral

Carbamazepine, phenytoin: Concomitant use contraindicated

Antidiabetic agents

Altered blood glucose control resulting in serious symptomatic hypoglycemia reported when DAAs used in diabetic patients receiving antidiabetic agents

Frequently monitor glucose concentrations; dosage adjustment of antidiabetic agent may be needed

Antifungals, azoles (ketoconazole)

Ketoconazole: Increased elbasvir and grazoprevir concentrations and AUC; may increase risk of hepatotoxicity

Concomitant use not recommended

Antimycobacterials, rifamycins (rifampin)

Rifampin: Multiple doses result in clinically important decreases in grazoprevir concentrations and is expected to result in clinically important decreases in elbasvir concentrations; may lead to loss of virologic response to the HCV antiviral

Concomitant use contraindicated

Antiretrovirals, HIV entry and fusion inhibitors

Maraviroc: No effect on maraviroc pharmacokinetics expected

Maraviroc: Dosage adjustments not needed

Antiretrovirals, HIV integrase inhibitors (INSTIs)

Bictegravir: No effect on bictegravir pharmacokinetics expected

Dolutegravir: No clinically important effects on elbasvir, grazoprevir, or dolutegravir pharmacokinetics

Cobicistat-boosted elvitegravir: Increased elbasvir and grazoprevir concentrations expected

Fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (EVG/c/FTC/TDF): Increased elbasvir and grazoprevir concentrations

Fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate (EVG/c/FTC/TAF): Possible increased elbasvir and grazoprevir concentrations

Raltegravir: No clinically important effects on elbasvir, grazoprevir, or raltegravir pharmacokinetics

Bictegravir: Dosage adjustments not needed

Dolutegravir: Dosage adjustments not needed

Cobicistat-boosted elvitegravir, including EVG/c/FTC/TDF or EVG/c/FTC/TAF: Concomitant use with elbasvir/grazoprevir not recommended

Raltegravir: Dosage adjustments not needed

Antiretrovirals, HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs)

Doravirine: No clinically important effect on pharmacokinetics of elbasvir or grazoprevir; possible increased doravirine AUC

Efavirenz: Substantially decreased elbasvir and grazoprevir concentrations; possible loss of virologic response to the HCV antiviral

Etravirine: Possible decreased elbasvir and grazoprevir concentrations; possible reduced therapeutic effect of the HCV antiviral

Nevirapine: Decreased elbasvir and grazoprevir concentrations expected

Rilpivirine: No clinically important effects on elbasvir, grazoprevir, or rilpivirine pharmacokinetics

Doravirine: Dosage adjustments not needed

Efavirenz: Concomitant use contraindicated

Etravirine: Concomitant use not recommended

Nevirapine: Concomitant use not recommended

Rilpivirine: Dosage adjustments not needed

Antiretrovirals, HIV nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs)

Abacavir: Clinically important pharmacokinetic interactions not expected

Emtricitabine: Clinically important pharmacokinetic interactions not expected

Lamivudine: Clinically important pharmacokinetic interactions not expected

TDF: No clinically important effects on elbasvir, grazoprevir, or tenofovir pharmacokinetics

TDF: Dosage adjustments not needed

Antiretrovirals, HIV protease inhibitors (PIs)

Ritonavir-boosted atazanavir: Increased elbasvir concentrations and substantially increased grazoprevir concentrations; may increase risk of ALT elevations

Ritonavir-boosted darunavir: Increased elbasvir concentrations and substantially increased grazoprevir concentrations; may increase risk of ALT elevations

Fixed combination of lopinavir and ritonavir (lopinavir/ritonavir): Increased elbasvir concentrations and substantially increased grazoprevir concentrations; may increase risk of ALT elevations

Ritonavir: Increased grazoprevir concentrations

Saquinavir: Substantially increased grazoprevir concentrations expected; may increase risk of ALT elevations

Tipranavir: Substantially increased grazoprevir concentrations expected; may increase risk of ALT elevations

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Concomitant use with elbasvir/grazoprevir contraindicated

Ritonavir-boosted or cobicistat-boosted darunavir: Concomitant use with elbasvir/grazoprevir contraindicated

Lopinavir/ritonavir: Concomitant use contraindicated

Saquinavir or ritonavir-boosted saquinavir: Concomitant use with elbasvir/grazoprevir contraindicated

Ritonavir-boosted tipranavir: Concomitant use with elbasvir/grazoprevir contraindicated

Benzodiazepines (midazolam)

Midazolam: Increased midazolam exposures

Bosentan

Possible decreased elbasvir and grazoprevir concentrations; possible reduced therapeutic effect of the HCV antiviral

Concomitant use not recommended

Buprenorphine

Fixed combination of buprenorphine and naloxone (buprenorphine/naloxone): No clinically important effects on elbasvir or grazoprevir pharmacokinetics

Dosage adjustments not needed

Corticosteroids (prednisone)

Prednisone: No clinically important effects on elbasvir, grazoprevir, or prednisone pharmacokinetics

Dosage adjustments not needed

Digoxin

No clinically important effects on digoxin pharmacokinetics

Dosage adjustments not needed

Entecavir

Clinically important pharmacokinetic interactions not expected

Estrogens/progestins

Oral contraceptive containing ethinyl estradiol and levonorgestrel: No clinically important effects on pharmacokinetics of ethinyl estradiol or levonorgestrel

Dosage adjustments not needed

Histamine H2-receptor antagonists (famotidine)

Famotidine: No clinically important effects on elbasvir or grazoprevir pharmacokinetics

Histamine H2-receptor antagonists: Dosage adjustments not needed

HMG-CoA reductase inhibitors (statins)

Atorvastatin: Increased atorvastatin concentrations and AUC

Fluvastatin, lovastatin, simvastatin: Possible increased statin concentrations

Pitavastatin, pravastatin: No clinically important effects on pitavastatin or pravastatin pharmacokinetics

Rosuvastatin: Increased rosuvastatin concentrations and AUC

Atorvastatin: Do not exceed atorvastatin dosage of 20 mg once daily

Fluvastatin, lovastatin, simvastatin: Use lowest necessary statin dosage; monitor for statin-associated adverse effects (e.g., myopathy)

Pitavastatin, pravastatin: Dosage adjustments not needed

Rosuvastatin: Do not exceed rosuvastatin dosage of 10 mg once daily

Immunosuppressants (cyclosporine, tacrolimus)

Cyclosporine: Increased elbasvir concentrations and AUC; substantially increased grazoprevir concentrations and AUC; may increase risk of ALT elevations

Tacrolimus: Increased tacrolimus concentrations; no effect on elbasvir and grazoprevir concentrations

Cyclosporine: Concomitant use contraindicated

Tacrolimus: Frequently monitor tacrolimus whole blood concentrations, renal function, and tacrolimus-associated adverse effects

Methadone

No clinically important effects on elbasvir or grazoprevir pharmacokinetics

Dosage adjustments not needed

Modafinil

Possible decreased elbasvir and grazoprevir concentrations; possible reduced therapeutic effect of the HCV antiviral

Concomitant use not recommended

Montelukast

No clinically important effects on montelukast pharmacokinetics

Mycophenolate mofetil

No clinically important effects on elbasvir, grazoprevir, or mycophenolic acid pharmacokinetics

Dosage adjustments not needed

Nafcillin

Possible decreased elbasvir and grazoprevir concentrations; possible reduced therapeutic effect of the HCV antiviral

Concomitant use not recommended

Phosphate binders (calcium acetate, sevelamer)

Calcium acetate, sevelamer: No clinically important effects on elbasvir or grazoprevir pharmacokinetics

Phosphate binders: Dosage adjustments not needed

Proton-pump inhibitors (pantoprazole)

Pantoprazole: No clinically important effects on elbasvir or grazoprevir pharmacokinetics

Proton-pump inhibitors: Dosage adjustments not needed

Ribavirin

No clinically important effects on elbasvir or grazoprevir pharmacokinetics

No in vitro evidence of antagonistic anti-HCV effects

Dosage adjustments not needed

Sofosbuvir

No clinically important effects on sofosbuvir pharmacokinetics

Dosage adjustments not needed

St. John's wort (Hypericum perforatum)

Substantially decreased elbasvir and grazoprevir concentrations; may lead to loss of virologic response to the HCV antiviral

Concomitant use contraindicated

Warfarin

INR fluctuations reported in patients receiving elbasvir/grazoprevir

Frequently monitor INR; warfarin dosage adjustment may be needed

Elbasvir and Grazoprevir Pharmacokinetics

Absorption

Bioavailability

Following oral administration of elbasvir/grazoprevir in HCV-infected adults, peak plasma concentrations of elbasvir and grazoprevir occur approximately 3 and 2 hours, respectively, after the dose.

Steady-state concentrations of elbasvir and grazoprevir attained within approximately 6 days with once-daily administration.

Elbasvir: Pharmacokinetics similar in healthy and HCV-infected adults; exposures increase in a dose-proportional manner over dosage range of 5–200 mg once daily.

Grazoprevir: Exposures approximately twofold higher in HCV-infected adults compared with healthy adults; studies using grazoprevir dosages of 10–800 mg once daily in HCV-infected adults indicate peak plasma concentrations and AUC increase in a more-than-dose-proportional manner.

Concomitant use of elbasvir and grazoprevir does not have a clinically important effect on pharmacokinetics of either drug compared with administration alone.

Food

Elbasvir and grazoprevir: Effect of food not considered clinically important.

Administration of elbasvir/grazoprevir with a high-fat meal (approximately 900 kcal, 500 kcal from fat) in healthy individuals decreases elbasvir AUC and peak plasma concentrations by approximately 11 and 15%, respectively, and increases grazoprevir AUC and peak plasma concentrations by approximately 1.5- and 2.8-fold, respectively, relative to administration in the fasting state.

Special Populations

Elbasvir: In individuals with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C) without HCV infection, no clinically important differences in AUCs compared with individuals with normal hepatic function.

Grazoprevir: In individuals with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C) without HCV infection, AUCs increased by 1.7-, 5-, or 12-fold, respectively, compared with individuals with normal hepatic function.

Elbasvir: In individuals with severe renal impairment (not dependent on dialysis) or individuals requiring hemodialysis, AUCs increased by 46 or 25%, respectively, compared with individuals without severe renal impairment.

Grazoprevir: In individuals with severe renal impairment (not dependent on dialysis) or individuals requiring hemodialysis, AUCs increased by 40 or 10%, respectively, compared with individuals without severe renal impairment.

Adults ≥65 years of age: Elbasvir and grazoprevir AUCs estimated to be increased by 16 and 45%, respectively, compared with AUCs in younger adults.

Asians: Elbasvir and grazoprevir AUCs estimated to be increased by 15 and 50%, respectively, compared with Caucasians.

Black or African Americans: Elbasvir and grazoprevir AUCs comparable to those in Caucasians.

Females: Elbasvir and grazoprevir AUCs estimated to be increased by 50 and 30%, respectively, compared with males.

Distribution

Extent

Elbasvir: Distributes into most tissues, including the liver, based on preclinical studies.

Grazoprevir: Distributes principally into the liver, based on preclinical studies; distribution into liver probably facilitated by active transport through OATP1B1 and 1B3.

Plasma Protein Binding

Elbasvir: 99.9%.

Grazoprevir: 98.8%.

Elimination

Metabolism

Elbasvir and grazoprevir both partially eliminated by oxidative metabolism, principally by CYP3A.

Elimination Route

Elbasvir and grazoprevir: >90% of dose excreted in feces; <1% excreted in urine.

Half-life

Elbasvir: Approximately 24 hours in HCV-infected adults.

Grazoprevir: Approximately 31 hours in HCV-infected adults.

Special Populations

Elbasvir and grazoprevir: Not removed by hemodialysis; removal by peritoneal dialysis unlikely since highly bound to plasma protein.

Stability

Storage

Oral

Film-coated Tablets

20–25°C (may be exposed to 15–30°C).

Protect from moisture by storing in original blister package until used.

Actions and Spectrum

  • Elbasvir/grazoprevir is a fixed combination of 2 HCV antivirals. Elbasvir is an HCV NS5A replication complex inhibitor (NS5A inhibitor) and grazoprevir is an HCV NS3/4A protease inhibitor.

  • Elbasvir and grazoprevir are both direct-acting antivirals (DAAs) with activity against HCV. No in vitro evidence of antagonistic anti-HCV effects between the drugs in HCV replicon studies.

  • Elbasvir targets HCV NS5A protein, which is required for viral replication and virion assembly. In vitro studies using cell-based replicon assays indicate elbasvir has activity against HCV genotypes 1a, 1b, and 4.

  • Grazoprevir inhibits HCV NS3/4A protease, which is required for viral replication. Inhibition of NS3/4A protease prevents proteolytic cleavage of the HCV-encoded polyprotein to form mature forms of NS3, NS4A, NS4B, NS5A, and NS5B. In vitro studies using cell-based replicon assays indicate grazoprevir has activity against HCV genotypes 1a, 1b, and 4.

  • Certain amino acid substitutions in NS5A of HCV genotypes 1a, 1b, and 4 selected in cell culture and associated with reduced susceptibility to elbasvir in vitro in replicon studies. Single M28A/G/T, Q30D/E/H/K/R, L31M/V, H28D, and Y93C/H/N substitutions in HCV genotype 1a replicons confer reduced susceptibility to elbasvir; single L28M, L31F, and Y93H substitutions in HCV genotype 1b replicons are associated with reduced susceptibility to elbasvir. In HCV genotype 4 replicons, single L30S, M31V, and Y93H substitutions are associated with reduced susceptibility to elbasvir. In general, combinations of elbasvir resistance-associated substitutions further reduce elbasvir antiviral activity in HCV genotypes 1a, 1b, and 4 replicons. In phase 2 and 3 clinical trials, treatment-emergent amino acid substitutions in NS5A were detected in patients with HCV genotype 1a infection (M28A/G/T, Q30H/K/R/Y, L31F/M/V, H58D, Y93H/N/S), HCV genotype 1b infection (L28M, L31F/V, Y93H), or HCV genotype 4 infection (L28S/T, M31I/V, P58D, Y93H) experiencing virologic failure.

  • Certain amino acid substitutions in NS3 of HCV genotypes 1a, 1b, and 4 selected in cell culture and associated with reduced susceptibility to grazoprevir in vitro in replicon studies. Single Y56H, R155K, A156G/T/V, and D168A/E/G/N/S/V/Y substitutions in HCV genotype 1a replicons confer reduced susceptibility to grazoprevir; single F43S, Y56F, V107I, A156S/T/V, and D168A/G/V substitutions in HCV genotype 1b replicons confer reduced susceptibility to grazoprevir. In HCV genotype 4 replicons, single D168A/V substitutions are associated with reduced susceptibility to grazoprevir. In general, combinations of grazoprevir resistance-associated substitutions further reduce grazoprevir antiviral activity in HCV genotypes 1a, 1b, and 4 replicons. In phase 2 and 3 clinical trials, treatment-emergent amino acid substitutions in NS3 were detected in patients with HCV genotype 1a infection (V36L/M, Y56H, V107I, R155I/K, A156G/T/V, V158A, D168A/G/N/V/Y), HCV genotype 1b infection (Y56F, V107I, A156T), or HCV genotype 4 infection (A156M/T/V, D168A/G, V170I) experiencing virologic failure.

  • Possible cross-resistance among HCV NS5A inhibitors and among HCV NS3/4A protease inhibitors. Efficacy of elbasvir/grazoprevir not established in patients who failed previous treatment with a regimen that included an HCV NS5A inhibitor. Only limited data available regarding efficacy of elbasvir/grazoprevir in patients who failed previous treatment with a regimen of peginterferon alfa, ribavirin, and an HCV NS3/4A protease inhibitor (e.g., boceprevir, simeprevir, telaprevir; no longer commercially available) and have HCV NS3 resistance-associated substitutions at baseline prior to administration of elbasvir/grazoprevir. Elbasvir and grazoprevir active against HCV with amino acid substitutions associated with resistance to HCV NS5B polymerase inhibitors.

Advice to Patients

  • Importance of reading patient information provided by the manufacturer.

  • Advise patients to take elbasvir/grazoprevir once daily (with or without food) on a regular dosing schedule.

  • Importance of taking the recommended dosage of elbasvir/grazoprevir for the recommended duration of treatment; importance of not missing or skipping doses.

  • Inform patients that reactivation of HBV infection has occurred in coinfected patients being treated for HCV infection. Importance of informing clinician of any history of HBV infection or other liver problems (e.g., cirrhosis). Importance of immediately contacting a clinician if any signs or symptoms of serious liver injury (e.g., fatigue, weakness, loss of appetite, nausea and vomiting, yellowing of the eyes or skin, light-colored bowel movements) occur. (See Risk of HBV Reactivation in Patients Coinfected with HCV and HBV under Cautions.)

  • Advise patients to immediately contact a clinician if they have symptoms of worsening liver problems (e.g., nausea, vomiting, yellowing of skin or white part of the eyes, bleeding or bruising more easily than normal, confusion, loss of appetite, diarrhea, dark or brown urine, dark or bloody stools, abdominal swelling, pain in upper right side of stomach area, sleepiness, vomiting of blood). (See Risk of Hepatic Decompensation or Failure in Patients with Evidence of Advanced Liver Disease under Cautions.)

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. If used in conjunction with ribavirin, advise men and women of importance of using 2 forms of effective contraception during and for 6 months after ribavirin therapy. (See Precautions Related to Fixed Combinations and Multiple-drug Treatment Regimens under Cautions.)

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Elbasvir and Grazoprevir

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

Elbasvir 50 mg and Grazoprevir 100 mg

Zepatier

Merck

AHFS DI Essentials™. © Copyright 2021, Selected Revisions April 6, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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