Elbasvir / grazoprevir

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# Black Box Warning

# Overview
Elbasvir / grazoprevir is a combination of a hepatitis C virus NS5A inhibitor and a Hepatitis C virus NS3/4A protease inhibitor that is FDA approved for the treatment of chronic HCV genotype 1 or 4 infection in adults. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include fatigue, headache, and nausea.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
Elbasvir and grazoprevir is indicated for the treatment of chronic hepatitis C virus (HCV) genotype 1 or 4 infection in adults. Elbasvir and grazoprevir is indicated for use with ribavirin in certain patient populations.
Dosing Information
- Elbasvir and grazoprevir is a two-drug, fixed-dose combination product containing 50 mg of elbasvir and 100 mg of grazoprevir in a single tablet.
- The recommended dosage of elbasvir and grazoprevir is one tablet taken orally once daily with or without food.
- Elbasvir and grazoprevir is used in combination with ribavirin in certain patient populations (see TABLE 1). When administered with elbasvir and grazoprevir, the recommended dosage of ribavirin in patients without renal impairment is weight-based administered in two divided doses with food. For further information on ribavirin dosing and dosage modifications, refer to the ribavirin prescribing information.
- Treatment Regimen and Duration of Therapy
Relapse rates are affected by baseline host and viral factors and differ between treatment regimens and durations for certain subgroups
TABLE 1 below provides the recommended elbasvir and grazoprevir treatment regimen and duration based on the patient population and genotype in HCV mono-infected and HCV/HIV-1 co-infected patients with or without cirrhosis and with or without renal impairment including patients receiving hemodialysis.
- Relapse rates are affected by baseline host and viral factors and differ between treatment regimens and durations for certain subgroups
- TABLE 1 below provides the recommended elbasvir and grazoprevir treatment regimen and duration based on the patient population and genotype in HCV mono-infected and HCV/HIV-1 co-infected patients with or without cirrhosis and with or without renal impairment including patients receiving hemodialysis.
- Renal Impairment
No dosage adjustment of elbasvir and grazoprevir is recommended in patients with any degree of renal impairment including patients on hemodialysis. Administer elbasvir and grazoprevir with or without ribavirin according to the recommendations in TABLE 1. Refer to the ribavirin tablet prescribing information for the correct ribavirin dosage for patients with CrCl less than or equal to 50 mL per minute.
- No dosage adjustment of elbasvir and grazoprevir is recommended in patients with any degree of renal impairment including patients on hemodialysis. Administer elbasvir and grazoprevir with or without ribavirin according to the recommendations in TABLE 1. Refer to the ribavirin tablet prescribing information for the correct ribavirin dosage for patients with CrCl less than or equal to 50 mL per minute.
- Hepatic Impairment
No dosage adjustment of elbasvir and grazoprevir is recommended in patients with mild hepatic impairment (Child-Pugh A). Elbasvir and grazoprevir is contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh B or C).
- No dosage adjustment of elbasvir and grazoprevir is recommended in patients with mild hepatic impairment (Child-Pugh A). Elbasvir and grazoprevir is contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh B or C).

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Elbasvir and grazoprevir in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Elbasvir and grazoprevir in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Elbasvir / grazoprevir FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Elbasvir and grazoprevir in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Elbasvir and grazoprevir in pediatric patients.

# Contraindications
- Elbasvir and grazoprevir is contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh B or C) due to the expected significantly increased grazoprevir plasma concentration and the increased risk of alanine aminotransferase (ALT) elevations.
- Elbasvir and grazoprevir is contraindicated with inhibitors of organic anion transporting polypeptides 1B1/3 (OATP1B1/3) that are known or expected to significantly increase grazoprevir plasma concentrations, strong inducers of cytochrome P450 3A (CYP3A), and efavirenz.
- If elbasvir and grazoprevir is administered with ribavirin, the contraindications to ribavirin also apply to this combination regimen. Refer to the ribavirin prescribing information for a list of contraindications for ribavirin.

# Warnings
- Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV
Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals, and who were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure and death. Cases have been reported in patients who are HBsAg positive and also in patients with serologic evidence of resolved HBV infection (i.e., HBsAg negative and anti-HBc positive). HBV reactivation has also been reported in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV direct-acting antivirals may be increased in these patients.
HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level. In patients with resolved HBV infection reappearance of HBsAg can occur. Reactivation of HBV replication may be accompanied by hepatitis, i.e., increases in aminotransferase levels and, in severe cases, increases in bilirubin levels, liver failure, and death can occur.
Test all patients for evidence of current or prior HBV infection by measuring HBsAg and anti-HBc before initiating HCV treatment with elbasvir and grazoprevir. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with elbasvir and grazoprevir and during post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.
- Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals, and who were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure and death. Cases have been reported in patients who are HBsAg positive and also in patients with serologic evidence of resolved HBV infection (i.e., HBsAg negative and anti-HBc positive). HBV reactivation has also been reported in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV direct-acting antivirals may be increased in these patients.
- HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level. In patients with resolved HBV infection reappearance of HBsAg can occur. Reactivation of HBV replication may be accompanied by hepatitis, i.e., increases in aminotransferase levels and, in severe cases, increases in bilirubin levels, liver failure, and death can occur.
- Test all patients for evidence of current or prior HBV infection by measuring HBsAg and anti-HBc before initiating HCV treatment with elbasvir and grazoprevir. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with elbasvir and grazoprevir and during post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.
- Increased Risk of ALT Elevations
During clinical trials with elbasvir and grazoprevir with or without ribavirin, 1% of subjects experienced elevations of ALT from normal levels to greater than 5 times the upper limit of normal (ULN), generally at or after treatment week 8. ALT elevations were typically asymptomatic and most resolved with ongoing or completion of therapy. Higher rates of late ALT elevations occurred in the following subpopulations: female sex (2% ), Asian race (2% ), and age 65 years or older (2% )
Hepatic laboratory testing should be performed 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.
Patients should be instructed to consult their healthcare professional without delay if they have onset of fatigue, weakness, lack of appetite, nausea and vomiting, jaundice, or discolored feces.
Consider discontinuing elbasvir and grazoprevir if ALT levels remain persistently greater than 10 times the ULN.
Discontinue elbasvir and grazoprevir if ALT elevation is accompanied by signs or symptoms of liver inflammation or increasing conjugated bilirubin, alkaline phosphatase, or INR.
- During clinical trials with elbasvir and grazoprevir with or without ribavirin, 1% of subjects experienced elevations of ALT from normal levels to greater than 5 times the upper limit of normal (ULN), generally at or after treatment week 8. ALT elevations were typically asymptomatic and most resolved with ongoing or completion of therapy. Higher rates of late ALT elevations occurred in the following subpopulations: female sex (2% ), Asian race (2% ), and age 65 years or older (2% )
- Hepatic laboratory testing should be performed 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.
- Patients should be instructed to consult their healthcare professional without delay if they have onset of fatigue, weakness, lack of appetite, nausea and vomiting, jaundice, or discolored feces.
- Consider discontinuing elbasvir and grazoprevir if ALT levels remain persistently greater than 10 times the ULN.
- Discontinue elbasvir and grazoprevir if ALT elevation is accompanied by signs or symptoms of liver inflammation or increasing conjugated bilirubin, alkaline phosphatase, or INR.
- Risks Associated with Ribavirin Combination Treatment
If elbasvir and grazoprevir is administered with ribavirin, the warnings and precautions for ribavirin, including the pregnancy avoidance warning, also apply to this combination regimen. Refer to the ribavirin prescribing information for a full list of warnings and precautions for ribavirin
- If elbasvir and grazoprevir is administered with ribavirin, the warnings and precautions for ribavirin, including the pregnancy avoidance warning, also apply to this combination regimen. Refer to the ribavirin prescribing information for a full list of warnings and precautions for ribavirin
- Risk of Adverse Reactions or Reduced Therapeutic Effect Due to Drug Interactions
The concomitant use of elbasvir and grazoprevir and certain drugs may result in known or potentially significant drug interactions, some of which may lead to:
Possible clinically significant adverse reactions from greater exposure of concomitant drugs or components of elbasvir and grazoprevir.
Significant decrease of elbasvir and grazoprevir plasma concentrations which may lead to reduced therapeutic effect of elbasvir and grazoprevir and possible development of resistance.
See TABLES 2 and 6 for steps to prevent or manage these known or potentially significant drug interactions, including dosing recommendations.
- The concomitant use of elbasvir and grazoprevir and certain drugs may result in known or potentially significant drug interactions, some of which may lead to:
Possible clinically significant adverse reactions from greater exposure of concomitant drugs or components of elbasvir and grazoprevir.
Significant decrease of elbasvir and grazoprevir plasma concentrations which may lead to reduced therapeutic effect of elbasvir and grazoprevir and possible development of resistance.
- Possible clinically significant adverse reactions from greater exposure of concomitant drugs or components of elbasvir and grazoprevir.
- Significant decrease of elbasvir and grazoprevir plasma concentrations which may lead to reduced therapeutic effect of elbasvir and grazoprevir and possible development of resistance.
- See TABLES 2 and 6 for steps to prevent or manage these known or potentially significant drug interactions, including dosing recommendations.

# Adverse Reactions

## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
If elbasvir and grazoprevir is administered with ribavirin, refer to the prescribing information for ribavirin for a description of ribavirin-associated adverse reactions.
The safety of elbasvir and grazoprevir was assessed based on 2 placebo-controlled trials and 7 uncontrolled Phase 2 and 3 clinical trials in approximately 1700 subjects with chronic hepatitis C virus infection with compensated liver disease (with or without cirrhosis)
- Adverse Reactions with elbasvir and grazoprevir in Treatment-Naive Subjects
C-EDGE TN was a Phase 3 randomized, double-blind, placebo-controlled trial in 421 treatment-naive (TN) subjects with HCV infection who received elbasvir and grazoprevir or placebo one tablet once daily for 12 weeks. Adverse reactions (all intensity) occurring in C-EDGE TN in at least 5% of subjects treated with elbasvir and grazoprevir for 12 weeks are presented in TABLE 3. In subjects treated with elbasvir and grazoprevir who reported an adverse reaction, 73% had adverse reactions of mild severity. The type and severity of adverse reactions in subjects with compensated cirrhosis were comparable to those seen in subjects without cirrhosis. No subjects treated with elbasvir and grazoprevir or placebo had serious adverse reactions. The proportion of subjects treated with elbasvir and grazoprevir or placebo who permanently discontinued treatment due to adverse reactions was 1% in each group.This image is provided by the National Library of Medicine.C-EDGE COINFECTION was a Phase 3 open-label trial in 218 treatment-naive HCV/HIV co-infected subjects who received elbasvir and grazoprevir one tablet once daily for 12 weeks. Adverse reactions (all intensity) reported in C-EDGE COINFECTION in at least 5% of subjects treated with elbasvir and grazoprevir for 12 weeks were fatigue (7%), headache (7%), nausea (5%), insomnia (5%), and diarrhea (5%). No subjects reported serious adverse reactions or discontinued treatment due to adverse reactions. No subjects switched their antiretroviral therapy regimen due to loss of plasma HIV-1 RNA suppression. Median increase in CD4+ T-cell counts of 31 cells per mm3 was observed at the end of 12 weeks of treatment.
- C-EDGE TN was a Phase 3 randomized, double-blind, placebo-controlled trial in 421 treatment-naive (TN) subjects with HCV infection who received elbasvir and grazoprevir or placebo one tablet once daily for 12 weeks. Adverse reactions (all intensity) occurring in C-EDGE TN in at least 5% of subjects treated with elbasvir and grazoprevir for 12 weeks are presented in TABLE 3. In subjects treated with elbasvir and grazoprevir who reported an adverse reaction, 73% had adverse reactions of mild severity. The type and severity of adverse reactions in subjects with compensated cirrhosis were comparable to those seen in subjects without cirrhosis. No subjects treated with elbasvir and grazoprevir or placebo had serious adverse reactions. The proportion of subjects treated with elbasvir and grazoprevir or placebo who permanently discontinued treatment due to adverse reactions was 1% in each group.This image is provided by the National Library of Medicine.C-EDGE COINFECTION was a Phase 3 open-label trial in 218 treatment-naive HCV/HIV co-infected subjects who received elbasvir and grazoprevir one tablet once daily for 12 weeks. Adverse reactions (all intensity) reported in C-EDGE COINFECTION in at least 5% of subjects treated with elbasvir and grazoprevir for 12 weeks were fatigue (7%), headache (7%), nausea (5%), insomnia (5%), and diarrhea (5%). No subjects reported serious adverse reactions or discontinued treatment due to adverse reactions. No subjects switched their antiretroviral therapy regimen due to loss of plasma HIV-1 RNA suppression. Median increase in CD4+ T-cell counts of 31 cells per mm3 was observed at the end of 12 weeks of treatment.
- Adverse Reactions with elbasvir and grazoprevir with or without Ribavirin in Treatment-Experienced Subjects
C-EDGE TE was a Phase 3 randomized, open-label trial in treatment-experienced (TE) subjects. Adverse reactions of moderate or severe intensity reported in C-EDGE TE in at least 2% of subjects treated with elbasvir and grazoprevir one tablet once daily for 12 weeks or elbasvir and grazoprevir one tablet once daily with ribavirin for 16 weeks are presented in TABLE 4. No subjects treated with elbasvir and grazoprevir without ribavirin for 12 weeks reported serious adverse reactions or discontinued treatment due to adverse reactions. The proportion of subjects treated with elbasvir and grazoprevir with ribavirin for 16 weeks with serious adverse reactions was 1%. The proportion of subjects treated with elbasvir and grazoprevir with ribavirin for 16 weeks who permanently discontinued treatment due to adverse reactions was 3%. The type and severity of adverse reactions in subjects with cirrhosis were comparable to those seen in subjects without cirrhosis.This image is provided by the National Library of Medicine.The type and severity of adverse reactions with elbasvir and grazoprevir with or without ribavirin in 10 treatment-experienced subjects with HCV/HIV co-infected were comparable to those reported in subjects without HIV co-infected. Median increase in CD4+ T-cell counts of 32 cells/mm3 was observed at the end of 12 weeks of treatment with elbasvir and grazoprevir alone. In subjects treated with elbasvir and grazoprevir with ribavirin for 16 weeks, CD4+ T-cell counts decreased a median of 135 cells per mm3 at the end of treatment. No subjects switched their antiretroviral therapy regimen due to loss of plasma HIV-1 RNA suppression. No subject experienced an AIDS-related opportunistic infection.
C-SALVAGE was a Phase 2 open-label trial in 79 PegIFN/RBV/PI-experienced subjects. Adverse reactions of moderate or severe intensity reported in C-SALVAGE in at least 2% of subjects treated with elbasvir and grazoprevir once daily with ribavirin for 12 weeks were fatigue (3%) and insomnia (3%). No subjects reported serious adverse reactions or discontinued treatment due to adverse reactions.
- C-EDGE TE was a Phase 3 randomized, open-label trial in treatment-experienced (TE) subjects. Adverse reactions of moderate or severe intensity reported in C-EDGE TE in at least 2% of subjects treated with elbasvir and grazoprevir one tablet once daily for 12 weeks or elbasvir and grazoprevir one tablet once daily with ribavirin for 16 weeks are presented in TABLE 4. No subjects treated with elbasvir and grazoprevir without ribavirin for 12 weeks reported serious adverse reactions or discontinued treatment due to adverse reactions. The proportion of subjects treated with elbasvir and grazoprevir with ribavirin for 16 weeks with serious adverse reactions was 1%. The proportion of subjects treated with elbasvir and grazoprevir with ribavirin for 16 weeks who permanently discontinued treatment due to adverse reactions was 3%. The type and severity of adverse reactions in subjects with cirrhosis were comparable to those seen in subjects without cirrhosis.This image is provided by the National Library of Medicine.The type and severity of adverse reactions with elbasvir and grazoprevir with or without ribavirin in 10 treatment-experienced subjects with HCV/HIV co-infected were comparable to those reported in subjects without HIV co-infected. Median increase in CD4+ T-cell counts of 32 cells/mm3 was observed at the end of 12 weeks of treatment with elbasvir and grazoprevir alone. In subjects treated with elbasvir and grazoprevir with ribavirin for 16 weeks, CD4+ T-cell counts decreased a median of 135 cells per mm3 at the end of treatment. No subjects switched their antiretroviral therapy regimen due to loss of plasma HIV-1 RNA suppression. No subject experienced an AIDS-related opportunistic infection.
- C-SALVAGE was a Phase 2 open-label trial in 79 PegIFN/RBV/PI-experienced subjects. Adverse reactions of moderate or severe intensity reported in C-SALVAGE in at least 2% of subjects treated with elbasvir and grazoprevir once daily with ribavirin for 12 weeks were fatigue (3%) and insomnia (3%). No subjects reported serious adverse reactions or discontinued treatment due to adverse reactions.
- Adverse Reactions with elbasvir and grazoprevir in Subjects with Severe Renal Impairment including Subjects on Hemodialysis
The safety of elbasvir and grazoprevir in comparison to placebo in subjects with severe renal impairment (Stage 4 or Stage 5 chronic kidney disease, including subjects on hemodialysis) and chronic hepatitis C virus infection with compensated liver disease (with or without cirrhosis) was assessed in 235 subjects (C-SURFER). The adverse reactions (all intensity) occurring in at least 5% of subjects treated with elbasvir and grazoprevir for 12 weeks are presented in TABLE 5. In subjects treated with elbasvir and grazoprevir who reported an adverse reaction, 76% had adverse reactions of mild severity. The proportion of subjects treated with elbasvir and grazoprevir or placebo with serious adverse reactions was less than 1% in each treatment arm, and less than 1% and 3% of subjects, respectively, permanently discontinued treatment due to adverse reactions in each treatment arm.
- The safety of elbasvir and grazoprevir in comparison to placebo in subjects with severe renal impairment (Stage 4 or Stage 5 chronic kidney disease, including subjects on hemodialysis) and chronic hepatitis C virus infection with compensated liver disease (with or without cirrhosis) was assessed in 235 subjects (C-SURFER). The adverse reactions (all intensity) occurring in at least 5% of subjects treated with elbasvir and grazoprevir for 12 weeks are presented in TABLE 5. In subjects treated with elbasvir and grazoprevir who reported an adverse reaction, 76% had adverse reactions of mild severity. The proportion of subjects treated with elbasvir and grazoprevir or placebo with serious adverse reactions was less than 1% in each treatment arm, and less than 1% and 3% of subjects, respectively, permanently discontinued treatment due to adverse reactions in each treatment arm.
- Laboratory Abnormalities in Subjects Receiving elbasvir and grazoprevir with or without Ribavirin
Serum ALT Elevations: During clinical trials with elbasvir and grazoprevir with or without ribavirin, regardless of treatment duration, 1% (12/1599) of subjects experienced elevations of ALT from normal levels to greater than 5 times the ULN, generally at or after treatment week 8 (mean onset time 10 weeks, range 6-12 weeks). These late ALT elevations were typically asymptomatic. Most late ALT elevations resolved with ongoing therapy with elbasvir and grazoprevir or after completion of therapy. The frequency of late ALT elevations was higher in subjects with higher grazoprevir plasma concentrations. The incidence of late ALT elevations was not affected by treatment duration. Cirrhosis was not a risk factor for late ALT elevations.
Serum Bilirubin Elevations: During clinical trials with elbasvir and grazoprevir with or without ribavirin, regardless of treatment duration, elevations in bilirubin at greater than 2.5 times ULN were observed in 6% of subjects receiving elbasvir and grazoprevir with ribavirin compared to less than 1% in those receiving elbasvir and grazoprevir alone. These bilirubin increases were predominately indirect and generally observed in association with ribavirin co-administration. Bilirubin elevations were typically not associated with serum ALT elevations.
Decreased Hemoglobin: During clinical trials with elbasvir and grazoprevir with or without ribavirin, the mean change from baseline in hemoglobin levels in subjects treated with elbasvir and grazoprevir for 12 weeks was 0.3 g per dL and with elbasvir and grazoprevir with ribavirin for 16 weeks was approximately 2.2 g per dL. Hemoglobin declined during the first 8 weeks of treatment, remained low during the remainder of treatment, and normalized to baseline levels during follow-up. Less than 1% of subjects treated with elbasvir and grazoprevir with ribavirin had hemoglobin levels decrease to less than 8.5 g per dL during treatment. No subjects treated with elbasvir and grazoprevir alone had a hemoglobin level less than 8.5 g per dL.
- Serum ALT Elevations: During clinical trials with elbasvir and grazoprevir with or without ribavirin, regardless of treatment duration, 1% (12/1599) of subjects experienced elevations of ALT from normal levels to greater than 5 times the ULN, generally at or after treatment week 8 (mean onset time 10 weeks, range 6-12 weeks). These late ALT elevations were typically asymptomatic. Most late ALT elevations resolved with ongoing therapy with elbasvir and grazoprevir or after completion of therapy. The frequency of late ALT elevations was higher in subjects with higher grazoprevir plasma concentrations. The incidence of late ALT elevations was not affected by treatment duration. Cirrhosis was not a risk factor for late ALT elevations.
- Serum Bilirubin Elevations: During clinical trials with elbasvir and grazoprevir with or without ribavirin, regardless of treatment duration, elevations in bilirubin at greater than 2.5 times ULN were observed in 6% of subjects receiving elbasvir and grazoprevir with ribavirin compared to less than 1% in those receiving elbasvir and grazoprevir alone. These bilirubin increases were predominately indirect and generally observed in association with ribavirin co-administration. Bilirubin elevations were typically not associated with serum ALT elevations.
- Decreased Hemoglobin: During clinical trials with elbasvir and grazoprevir with or without ribavirin, the mean change from baseline in hemoglobin levels in subjects treated with elbasvir and grazoprevir for 12 weeks was 0.3 g per dL and with elbasvir and grazoprevir with ribavirin for 16 weeks was approximately 2.2 g per dL. Hemoglobin declined during the first 8 weeks of treatment, remained low during the remainder of treatment, and normalized to baseline levels during follow-up. Less than 1% of subjects treated with elbasvir and grazoprevir with ribavirin had hemoglobin levels decrease to less than 8.5 g per dL during treatment. No subjects treated with elbasvir and grazoprevir alone had a hemoglobin level less than 8.5 g per dL.

## Postmarketing Experience
There is limited information regarding Elbasvir / grazoprevir Postmarketing Experience in the drug label.

# Drug Interactions
- Potential for Drug Interactions
Grazoprevir is a substrate of OATP1B1/3 transporters. Co-administration of elbasvir and grazoprevir with OATP1B1/3 inhibitors that are known or expected to significantly increase grazoprevir plasma concentrations is contraindicated.
Elbasvir and grazoprevir are substrates of CYP3A and P-gp, but the role of intestinal P-gp in the absorption of elbasvir and grazoprevir appears to be minimal. Co-administration of moderate or strong inducers of CYP3A with elbasvir and grazoprevir may decrease elbasvir and grazoprevir plasma concentrations, leading to reduced therapeutic effect of elbasvir and grazoprevir. Co-administration of elbasvir and grazoprevir with strong CYP3A inducers or efavirenz is contraindicated, and TABLE 2. Co-administration of elbasvir and grazoprevir with moderate CYP3A inducers is not recommended, and TABLE 6. Co-administration of elbasvir and grazoprevir with strong CYP3A inhibitors may increase elbasvir and grazoprevir concentrations. Co-administration of elbasvir and grazoprevir with certain strong CYP3A inhibitors is not recommended.
- Grazoprevir is a substrate of OATP1B1/3 transporters. Co-administration of elbasvir and grazoprevir with OATP1B1/3 inhibitors that are known or expected to significantly increase grazoprevir plasma concentrations is contraindicated.
- Elbasvir and grazoprevir are substrates of CYP3A and P-gp, but the role of intestinal P-gp in the absorption of elbasvir and grazoprevir appears to be minimal. Co-administration of moderate or strong inducers of CYP3A with elbasvir and grazoprevir may decrease elbasvir and grazoprevir plasma concentrations, leading to reduced therapeutic effect of elbasvir and grazoprevir. Co-administration of elbasvir and grazoprevir with strong CYP3A inducers or efavirenz is contraindicated, and TABLE 2. Co-administration of elbasvir and grazoprevir with moderate CYP3A inducers is not recommended, and TABLE 6. Co-administration of elbasvir and grazoprevir with strong CYP3A inhibitors may increase elbasvir and grazoprevir concentrations. Co-administration of elbasvir and grazoprevir with certain strong CYP3A inhibitors is not recommended.
- Established and other Potentially Significant Drug Interactions
If dose adjustments of concomitant medications are made due to treatment with elbasvir and grazoprevir, doses should be readjusted after administration of elbasvir and grazoprevir is completed.
TABLE 6 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with either elbasvir and grazoprevir, the components of elbasvir and grazoprevir (elbasvir  and grazoprevir ) as individual agents, or are predicted drug interactions that may occur with elbasvir and grazoprevir.
- If dose adjustments of concomitant medications are made due to treatment with elbasvir and grazoprevir, doses should be readjusted after administration of elbasvir and grazoprevir is completed.
- TABLE 6 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with either elbasvir and grazoprevir, the components of elbasvir and grazoprevir (elbasvir  and grazoprevir ) as individual agents, or are predicted drug interactions that may occur with elbasvir and grazoprevir.
- Drugs without Clinically Significant Interactions with Elbasvir and Grazoprevir
The interaction between the components of elbasvir and grazoprevir (elbasvir or grazoprevir) or elbasvir and grazoprevir and the following drugs were evaluated in clinical studies, and no dose adjustments are needed when elbasvir and grazoprevir is used with the following drugs individually: acid reducing agents (proton pump inhibitors, H2 blockers, antacids), buprenorphine/naloxone, digoxin, dolutegravir, methadone, mycophenolate mofetil, oral contraceptive pills, phosphate binders, pitavastatin, pravastatin, prednisone, raltegravir, ribavirin, rilpivirine, tenofovir disoproxil fumarate, and sofosbuvir.
No clinically relevant drug-drug interaction is expected when elbasvir and grazoprevir is co-administered with abacavir, emtricitabine, entecavir, and lamivudine.
- The interaction between the components of elbasvir and grazoprevir (elbasvir or grazoprevir) or elbasvir and grazoprevir and the following drugs were evaluated in clinical studies, and no dose adjustments are needed when elbasvir and grazoprevir is used with the following drugs individually: acid reducing agents (proton pump inhibitors, H2 blockers, antacids), buprenorphine/naloxone, digoxin, dolutegravir, methadone, mycophenolate mofetil, oral contraceptive pills, phosphate binders, pitavastatin, pravastatin, prednisone, raltegravir, ribavirin, rilpivirine, tenofovir disoproxil fumarate, and sofosbuvir.
- No clinically relevant drug-drug interaction is expected when elbasvir and grazoprevir is co-administered with abacavir, emtricitabine, entecavir, and lamivudine.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA):
- Risk Summary
No adequate human data are available to establish whether or not elbasvir and grazoprevir poses a risk to pregnancy outcomes. In animal reproduction studies, no evidence of adverse developmental outcomes was observed with the components of elbasvir and grazoprevir (elbasvir or grazoprevir) at exposures greater than those in humans at the recommended human dose (RHD) . During organogenesis in the rat and rabbit, systemic exposures (AUC) were approximately 10 and 18 times (for elbasvir) and 117 and 41 times (for grazoprevir), respectively, the exposure in humans at the RHD. In rat pre/postnatal developmental studies, maternal systemic exposures (AUC) to elbasvir and grazoprevir were approximately 10 and 78 times, respectively, the exposure in humans at the RHD.
The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
If elbasvir and grazoprevir is administered with ribavirin, the combination regimen is contraindicated in pregnant women and in men whose female partners are pregnant. Refer to the ribavirin prescribing information for more information on use in pregnancy.
- No adequate human data are available to establish whether or not elbasvir and grazoprevir poses a risk to pregnancy outcomes. In animal reproduction studies, no evidence of adverse developmental outcomes was observed with the components of elbasvir and grazoprevir (elbasvir or grazoprevir) at exposures greater than those in humans at the recommended human dose (RHD) . During organogenesis in the rat and rabbit, systemic exposures (AUC) were approximately 10 and 18 times (for elbasvir) and 117 and 41 times (for grazoprevir), respectively, the exposure in humans at the RHD. In rat pre/postnatal developmental studies, maternal systemic exposures (AUC) to elbasvir and grazoprevir were approximately 10 and 78 times, respectively, the exposure in humans at the RHD.
- The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
- If elbasvir and grazoprevir is administered with ribavirin, the combination regimen is contraindicated in pregnant women and in men whose female partners are pregnant. Refer to the ribavirin prescribing information for more information on use in pregnancy.
- Data
Animal data
Elbasvir: Elbasvir was administered orally at up to 1000 mg/kg/day to pregnant rats and rabbits on gestation days 6 to 20 and 7 to 20, respectively, and also to rats on gestation day 6 to lactation/post-partum day 20. No effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed at up to the highest dose tested. Systemic exposures (AUC) to elbasvir were approximately 10 (rats) and 18 (rabbits) times the exposure in humans at the RHD. In both species, elbasvir has been shown to cross the placenta, with fetal plasma concentrations of up to 0.8% (rabbits) and 2.2% (rats) that of maternal concentrations observed on gestation day 20.
Grazoprevir: Grazoprevir was administered to pregnant rats (oral doses up to 400 mg/kg/day) and rabbits (intravenous doses up to 100 mg/kg/day) on gestation days 6 to 20 and 7 to 20, respectively, and also to rats (oral doses up to 400 mg/kg/day) on gestation day 6 to lactation/post-partum day 20. No effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed at up to the highest dose tested. Systemic exposures (AUC) to grazoprevir were 78 (rats) and 41 (rabbits) times the exposure in humans at the RHD. In both species, grazoprevir has been shown to cross the placenta, with fetal plasma concentrations of up to 7% (rabbits) and 89% (rats) that of maternal concentrations observed on gestation day 20.
- Animal data
Elbasvir: Elbasvir was administered orally at up to 1000 mg/kg/day to pregnant rats and rabbits on gestation days 6 to 20 and 7 to 20, respectively, and also to rats on gestation day 6 to lactation/post-partum day 20. No effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed at up to the highest dose tested. Systemic exposures (AUC) to elbasvir were approximately 10 (rats) and 18 (rabbits) times the exposure in humans at the RHD. In both species, elbasvir has been shown to cross the placenta, with fetal plasma concentrations of up to 0.8% (rabbits) and 2.2% (rats) that of maternal concentrations observed on gestation day 20.
Grazoprevir: Grazoprevir was administered to pregnant rats (oral doses up to 400 mg/kg/day) and rabbits (intravenous doses up to 100 mg/kg/day) on gestation days 6 to 20 and 7 to 20, respectively, and also to rats (oral doses up to 400 mg/kg/day) on gestation day 6 to lactation/post-partum day 20. No effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed at up to the highest dose tested. Systemic exposures (AUC) to grazoprevir were 78 (rats) and 41 (rabbits) times the exposure in humans at the RHD. In both species, grazoprevir has been shown to cross the placenta, with fetal plasma concentrations of up to 7% (rabbits) and 89% (rats) that of maternal concentrations observed on gestation day 20.
- Elbasvir: Elbasvir was administered orally at up to 1000 mg/kg/day to pregnant rats and rabbits on gestation days 6 to 20 and 7 to 20, respectively, and also to rats on gestation day 6 to lactation/post-partum day 20. No effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed at up to the highest dose tested. Systemic exposures (AUC) to elbasvir were approximately 10 (rats) and 18 (rabbits) times the exposure in humans at the RHD. In both species, elbasvir has been shown to cross the placenta, with fetal plasma concentrations of up to 0.8% (rabbits) and 2.2% (rats) that of maternal concentrations observed on gestation day 20.
- Grazoprevir: Grazoprevir was administered to pregnant rats (oral doses up to 400 mg/kg/day) and rabbits (intravenous doses up to 100 mg/kg/day) on gestation days 6 to 20 and 7 to 20, respectively, and also to rats (oral doses up to 400 mg/kg/day) on gestation day 6 to lactation/post-partum day 20. No effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed at up to the highest dose tested. Systemic exposures (AUC) to grazoprevir were 78 (rats) and 41 (rabbits) times the exposure in humans at the RHD. In both species, grazoprevir has been shown to cross the placenta, with fetal plasma concentrations of up to 7% (rabbits) and 89% (rats) that of maternal concentrations observed on gestation day 20.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Elbasvir / grazoprevir in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Elbasvir / grazoprevir during labor and delivery.

### Nursing Mothers
- Risk Summary
It is not known whether elbasvir and grazoprevir is present in human breast milk, affects human milk production, or has effects on the breastfed infant. When administered to lactating rats, the components of elbasvir and grazoprevir (elbasvir and grazoprevir) were present in milk, without effects on growth and development observed in nursing pups.
The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for elbasvir and grazoprevir and any potential adverse effects on the breastfed child from elbasvir and grazoprevir or from the underlying maternal condition.
If elbasvir and grazoprevir is administered with ribavirin, the information for ribavirin with regard to nursing mothers also applies to this combination regimen. Refer to the ribavirin prescribing information for information on use during lactation.
- It is not known whether elbasvir and grazoprevir is present in human breast milk, affects human milk production, or has effects on the breastfed infant. When administered to lactating rats, the components of elbasvir and grazoprevir (elbasvir and grazoprevir) were present in milk, without effects on growth and development observed in nursing pups.
- The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for elbasvir and grazoprevir and any potential adverse effects on the breastfed child from elbasvir and grazoprevir or from the underlying maternal condition.
- If elbasvir and grazoprevir is administered with ribavirin, the information for ribavirin with regard to nursing mothers also applies to this combination regimen. Refer to the ribavirin prescribing information for information on use during lactation.
- Data
Elbasvir: No effects of elbasvir on growth and postnatal development were observed in nursing pups at up to the highest dose tested. Maternal systemic exposure (AUC) to elbasvir was approximately 10 times the exposure in humans at the RHD. Elbasvir was excreted into the milk of lactating rats following oral administration (1000 mg/kg/day) from gestation day 6 to lactation day 14, with milk concentrations approximately 4 times that of maternal plasma concentrations observed 2 hours post-dose on lactation day 14.
Grazoprevir: No effects of grazoprevir on growth and postnatal development were observed in nursing pups at up to the highest dose tested. Maternal systemic exposure (AUC) to grazoprevir was approximately 78 times the exposure in humans at the RHD. Grazoprevir was excreted into the milk of lactating rats following oral administration (up to 400 mg/kg/day) from gestation day 6 to lactation day 14, with milk concentrations of 54 and 87% that of maternal plasma concentrations observed 2 and 8 hours post-dose, respectively, on lactation day 14.
- Elbasvir: No effects of elbasvir on growth and postnatal development were observed in nursing pups at up to the highest dose tested. Maternal systemic exposure (AUC) to elbasvir was approximately 10 times the exposure in humans at the RHD. Elbasvir was excreted into the milk of lactating rats following oral administration (1000 mg/kg/day) from gestation day 6 to lactation day 14, with milk concentrations approximately 4 times that of maternal plasma concentrations observed 2 hours post-dose on lactation day 14.
- Grazoprevir: No effects of grazoprevir on growth and postnatal development were observed in nursing pups at up to the highest dose tested. Maternal systemic exposure (AUC) to grazoprevir was approximately 78 times the exposure in humans at the RHD. Grazoprevir was excreted into the milk of lactating rats following oral administration (up to 400 mg/kg/day) from gestation day 6 to lactation day 14, with milk concentrations of 54 and 87% that of maternal plasma concentrations observed 2 and 8 hours post-dose, respectively, on lactation day 14.

### Pediatric Use
Safety and efficacy in pediatric patients have not been established in pediatric patients less than 18 years of age.

### Geriatic Use
Clinical trials of elbasvir and grazoprevir with or without ribavirin included 187 subjects aged 65 years and over. Higher elbasvir and grazoprevir plasma concentrations were observed in subjects aged 65 years and over. A higher rate of late ALT elevations was observed in subjects aged 65 years and over in clinical trials. However, no dosage adjustment of elbasvir and grazoprevir is recommended in geriatric patients.

### Gender
Higher elbasvir and grazoprevir plasma concentrations were observed in females compared to males. Females experienced a higher rate of late ALT elevations in clinical trials. However, no dose adjustment of elbasvir and grazoprevir is recommended based on gender.

### Race
Higher elbasvir and grazoprevir plasma concentrations were observed in Asians compared to Caucasians. Asians experienced a higher rate of late ALT elevations in clinical trials. However, no dose adjustment of elbasvir and grazoprevir is recommended based on race/ethnicity.

### Renal Impairment
No dosage adjustment of elbasvir and grazoprevir is recommended in patients with any degree of renal impairment including patients receiving hemodialysis. Administer elbasvir and grazoprevir with or without ribavirin according to recommendations in TABLE 1. Refer to the prescribing information for ribavirin tablets for renal dosage adjustment of ribavirin in patients with CrCl less than or equal to 50 mL per minute.

### Hepatic Impairment
No dosage adjustment of elbasvir and grazoprevir is recommended in patients with mild hepatic impairment (Child-Pugh A). Elbasvir and grazoprevir is contraindicated in patients with moderate hepatic impairment (Child-Pugh B) due to the lack of clinical safety and efficacy experience in HCV-infected Child-Pugh B patients, and in patients with severe hepatic impairment (Child-Pugh C) due to a 12-fold increase in grazoprevir exposure in non-HCV infected Child-Pugh C subjects. 
The safety and efficacy of elbasvir and grazoprevir have not been established in patients awaiting liver transplant or in liver transplant recipients.

### Females of Reproductive Potential and Males
If elbasvir and grazoprevir is administered with ribavirin, the information for ribavirin with regard to pregnancy testing, contraception, and infertility also applies to this combination regimen. Refer to ribavirin prescribing information for additional information.

### Immunocompromised Patients
There is no FDA guidance one the use of Elbasvir / grazoprevir in patients who are immunocompromised.

# Administration and Monitoring

### Administration
Testing Prior to the Initiation of Therapy
- Testing for HBV Infection
Test all patients for evidence of current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating HCV treatment with elbasvir and grazoprevir.
- Test all patients for evidence of current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating HCV treatment with elbasvir and grazoprevir.
- NS5A Resistance Testing in HCV Genotype 1a-Infected Patients
Testing patients with HCV genotype 1a infection for the presence of virus with NS5A resistance-associated polymorphisms is recommended prior to initiation of treatment with elbasvir and grazoprevir to determine dosage regimen and duration, TABLE 1. In subjects receiving elbasvir and grazoprevir for 12 weeks, sustained virologic response (SVR12) rates were lower in genotype 1a-infected patients with one or more baseline NS5A resistance-associated polymorphisms at amino acid positions 28, 30, 31, or 93.
- Testing patients with HCV genotype 1a infection for the presence of virus with NS5A resistance-associated polymorphisms is recommended prior to initiation of treatment with elbasvir and grazoprevir to determine dosage regimen and duration, TABLE 1. In subjects receiving elbasvir and grazoprevir for 12 weeks, sustained virologic response (SVR12) rates were lower in genotype 1a-infected patients with one or more baseline NS5A resistance-associated polymorphisms at amino acid positions 28, 30, 31, or 93.
- Hepatic Laboratory Testing
Obtain hepatic laboratory testing prior to and during treatment with elbasvir and grazoprevir
- Obtain hepatic laboratory testing prior to and during treatment with elbasvir and grazoprevir

### Monitoring
There is limited information regarding Elbasvir / grazoprevir Monitoring in the drug label.

# IV Compatibility
There is limited information regarding the compatibility of Elbasvir / grazoprevir and IV administrations.

# Overdosage
- Human experience of overdose with elbasvir and grazoprevir is limited. No specific antidote is available for overdose with elbasvir and grazoprevir. In case of overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted.
- Hemodialysis does not remove elbasvir or grazoprevir since elbasvir and grazoprevir are highly bound to plasma protein

# Pharmacology

## Mechanism of Action
- Elbasvir and grazoprevir is a fixed-dose combination of elbasvir and grazoprevir which are direct-acting antiviral agents against the hepatitis C virus
- Elbasvir and grazoprevir combines two direct-acting antiviral agents with distinct mechanisms of action and non-overlapping resistance profiles to target HCV at multiple steps in the viral lifecycle.
- Elbasvir is an inhibitor of HCV NS5A, which is essential for viral RNA replication and virion assembly. The mechanism of action of elbasvir has been characterized based on cell culture antiviral activity and drug resistance mapping studies.
- Grazoprevir is an inhibitor of the 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. In a biochemical assay, grazoprevir inhibited the proteolytic activity of the recombinant HCV genotype 1a, 1b, and 4a NS3/4A protease enzymes with IC50 values of 7 pM, 4 pM, and 62 pM, respectively.

## Structure
Elbasvir:
- The IUPAC name for elbasvir is Dimethyl N,N'-(benzoxazine-3,10-diyl]bis{1H-imidazole-5,2-diyl-(2S)-pyrrolidine-2,1-diyl})dicarbamate.
- It has a molecular formula of C49H55N9O7 and a molecular weight of 882.02. It has the following structural formula:
Elbasvir is practically insoluble in water (less than 0.1 mg per mL) and very slightly soluble in ethanol (0.2 mg per mL), but is very soluble in ethyl acetate and acetone.
Grazoprevir:
The IUPAC name for grazoprevir is (1aR,5S,8S,10R,22aR)-N--2-ethenylcyclopropyl]-14-methoxy-5-(2-methylpropan-2-yl)-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropadioxadiazacyclononadecinoquinoxaline-8-carboxamide.
It has a molecular formula of C38H50N6O9S and a molecular weight of 766.90. It has the following structural formula:
Grazoprevir is practically insoluble in water (less than 0.1 mg per mL) but is freely soluble in ethanol and some organic solvents (e.g., acetone, tetrahydrofuran and N,N-dimethylformamide).

## Pharmacodynamics
Cardiac Electrophysiology
- Thorough QT studies have been conducted for elbasvir and grazoprevir.
- The effect of elbasvir 700 mg on QTc interval was evaluated in a randomized, single-dose, placebo- and active-controlled (moxifloxacin 400 mg) 3-period crossover thorough QT trial in 42 healthy subjects. At a concentration 3 to 4 times the therapeutic concentration, elbasvir does not prolong QTc to any clinically relevant extent.
- The effect of grazoprevir 1600 mg (16 times the approved dose) on QTc interval was evaluated in a randomized, single-dose, placebo- and active-controlled (moxifloxacin 400 mg) 3-period crossover thorough QT trial in 41 healthy subjects. At a concentration 40 times the therapeutic concentration, grazoprevir does not prolong QTc to any clinically relevant extent.

## Pharmacokinetics
The pharmacokinetic properties of elbasvir and grazoprevir have been evaluated in non-HCV-infected adult subjects and in HCV-infected adult subjects. Elbasvir pharmacokinetics were similar in healthy subjects and HCV-infected subjects and were approximately dose-proportional over the range of 5-100 mg once daily. Grazoprevir oral exposures are approximately 2-fold greater in HCV-infected subjects as compared to healthy subjects. Grazoprevir pharmacokinetics increased in a greater than dose-proportional manner over the range of 10-800 mg once daily in HCV-infected subjects. Ribavirin co-administration with elbasvir and grazoprevir had no clinically relevant impact on plasma AUC and Cmax of elbasvir and grazoprevir compared to administration of elbasvir and grazoprevir alone. The geometric mean steady-state pharmacokinetic parameter values for elbasvir and grazoprevir in non-cirrhotic HCV-infected subjects are provided in TABLE 7. Following once daily administration of elbasvir and grazoprevir to HCV-infected subjects, elbasvir and grazoprevir reached steady state within approximately 6 days.
- Absorption
Following administration of elbasvir and grazoprevir to HCV-infected subjects, elbasvir peak concentrations occur at a median Tmax of 3 hours (range of 3 to 6 hours); grazoprevir peak concentrations occur at a median Tmax of 2 hours (range of 30 minutes to 3 hours). The absolute bioavailability of elbasvir is estimated to be 32%, and grazoprevir is estimated to be 27%.
Effect of Food
Relative to fasting conditions, the administration of a single dose of elbasvir and grazoprevir with a high-fat (900 kcal, 500 kcal from fat) meal to healthy subjects resulted in decreases in elbasvir AUC0-inf and Cmax of approximately 11% and 15%, respectively, and increases in grazoprevir AUC0-inf and Cmax of approximately 1.5-fold and 2.8-fold, respectively. These differences in elbasvir and grazoprevir exposure are not clinically relevant; therefore, elbasvir and grazoprevir may be taken without regard to food.
- Following administration of elbasvir and grazoprevir to HCV-infected subjects, elbasvir peak concentrations occur at a median Tmax of 3 hours (range of 3 to 6 hours); grazoprevir peak concentrations occur at a median Tmax of 2 hours (range of 30 minutes to 3 hours). The absolute bioavailability of elbasvir is estimated to be 32%, and grazoprevir is estimated to be 27%.
- Effect of Food
Relative to fasting conditions, the administration of a single dose of elbasvir and grazoprevir with a high-fat (900 kcal, 500 kcal from fat) meal to healthy subjects resulted in decreases in elbasvir AUC0-inf and Cmax of approximately 11% and 15%, respectively, and increases in grazoprevir AUC0-inf and Cmax of approximately 1.5-fold and 2.8-fold, respectively. These differences in elbasvir and grazoprevir exposure are not clinically relevant; therefore, elbasvir and grazoprevir may be taken without regard to food.
- Relative to fasting conditions, the administration of a single dose of elbasvir and grazoprevir with a high-fat (900 kcal, 500 kcal from fat) meal to healthy subjects resulted in decreases in elbasvir AUC0-inf and Cmax of approximately 11% and 15%, respectively, and increases in grazoprevir AUC0-inf and Cmax of approximately 1.5-fold and 2.8-fold, respectively. These differences in elbasvir and grazoprevir exposure are not clinically relevant; therefore, elbasvir and grazoprevir may be taken without regard to food.
- Distribution
Elbasvir and grazoprevir are extensively bound (greater than 99.9% and 98.8%, respectively) to human plasma proteins. Both elbasvir and grazoprevir bind to human serum albumin and 1-acid glycoprotein. Estimated apparent volume of distribution values of elbasvir and grazoprevir are approximately 680 L and 1250 L, respectively, based on population pharmacokinetic modeling.
In preclinical distribution studies, elbasvir distributes into most tissues including the liver; whereas grazoprevir distributes predominantly to the liver likely facilitated by the active transport through the OATP1B1/3 liver uptake transporter.
- Elbasvir and grazoprevir are extensively bound (greater than 99.9% and 98.8%, respectively) to human plasma proteins. Both elbasvir and grazoprevir bind to human serum albumin and 1-acid glycoprotein. Estimated apparent volume of distribution values of elbasvir and grazoprevir are approximately 680 L and 1250 L, respectively, based on population pharmacokinetic modeling.
- In preclinical distribution studies, elbasvir distributes into most tissues including the liver; whereas grazoprevir distributes predominantly to the liver likely facilitated by the active transport through the OATP1B1/3 liver uptake transporter.
- Elimination
The geometric mean apparent terminal half-life for elbasvir (50 mg) and grazoprevir (100 mg) is approximately 24 and 31 hours, respectively, in HCV-infected subjects.
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.
Excretion
The primary route of elimination of elbasvir and grazoprevir is through feces with almost all (greater than 90%) of radiolabeled dose recovered in feces compared to less than 1% in urine.
- The geometric mean apparent terminal half-life for elbasvir (50 mg) and grazoprevir (100 mg) is approximately 24 and 31 hours, respectively, in HCV-infected subjects.
- 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.
- 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.
- Excretion
The primary route of elimination of elbasvir and grazoprevir is through feces with almost all (greater than 90%) of radiolabeled dose recovered in feces compared to less than 1% in urine.
- The primary route of elimination of elbasvir and grazoprevir is through feces with almost all (greater than 90%) of radiolabeled dose recovered in feces compared to less than 1% in urine.
- Specific Populations
Pediatric Population
The pharmacokinetics of elbasvir and grazoprevir in pediatric patients less than 18 years of age have not been established.
Geriatric Population
In population pharmacokinetic analyses, elbasvir and grazoprevir AUCs are estimated to be 16% and 45% higher, respectively, in subjects at least 65 years of age compared to subjects less than 65 years of age.
Gender
In population pharmacokinetic analyses, elbasvir and grazoprevir AUCs are estimated to be 50% and 30% higher, respectively, in females compared to males.
Weight/BMI
In population pharmacokinetic analyses, there was no effect of weight on elbasvir pharmacokinetics. Grazoprevir AUC is estimated to be 15% higher in a 53-kg subject compared to a 77-kg subject. This change is not clinically relevant for grazoprevir.
Race/Ethnicity
In population pharmacokinetic analyses, elbasvir and grazoprevir AUCs are estimated to be 15% and 50% higher, respectively, for Asians compared to Caucasians. Population pharmacokinetics estimates of exposure of elbasvir and grazoprevir were comparable between Caucasians and Black/African Americans.
Renal Impairment
In population pharmacokinetic analyses, elbasvir AUC was 25% higher in hemodialysis-dependent subjects and 46% higher in non-dialysis-dependent subjects with severe renal impairment compared to elbasvir AUC in subjects without severe renal impairment. In population pharmacokinetic analysis in HCV-infected subjects, grazoprevir AUC was 10% higher in hemodialysis-dependent subjects and 40% higher in non-dialysis-dependent subjects with severe renal impairment compared to grazoprevir AUC in subjects without severe renal impairment. Elbasvir and grazoprevir are not removed by hemodialysis. Elbasvir and grazoprevir are unlikely to be removed by peritoneal dialysis as both are highly protein bound.
Overall, changes in exposure of elbasvir and grazoprevir in HCV-infected subjects with renal impairment with or without hemodialysis are not clinically relevant.
Hepatic Impairment
The pharmacokinetics of elbasvir and grazoprevir were evaluated in non-HCV-infected subjects with mild hepatic impairment (Child-Pugh Category A , score of 5-6), moderate hepatic impairment (Child-Pugh Category B , score of 7-9) and severe hepatic impairment (Child-Pugh Category C , score of 10-15). In addition, the pharmacokinetics of elbasvir and grazoprevir were also evaluated in HCV-infected subjects including CP-A subjects with compensated cirrhosis.
Relative to non-HCV-infected subjects with normal hepatic function, no clinically relevant differences in elbasvir AUC values were observed in non-HCV-infected subjects with mild, moderate, or severe hepatic impairment. In population pharmacokinetic analyses, elbasvir steady-state AUC was similar in HCV-infected subjects with compensated cirrhosis compared to HCV-infected, non-cirrhotic subjects.
Relative to non-HCV-infected subjects with normal hepatic function, grazoprevir AUC values were higher by 1.7-fold, 5-fold, and 12-fold in non-HCV-infected subjects with mild, moderate, and severe hepatic impairment, respectively. In population pharmacokinetic analyses, grazoprevir steady-state AUC values were higher by 1.65-fold in HCV-infected subjects with compensated cirrhosis compared to HCV-infected, non-cirrhotic subjects.
- Pediatric Population
The pharmacokinetics of elbasvir and grazoprevir in pediatric patients less than 18 years of age have not been established.
- The pharmacokinetics of elbasvir and grazoprevir in pediatric patients less than 18 years of age have not been established.
- Geriatric Population
In population pharmacokinetic analyses, elbasvir and grazoprevir AUCs are estimated to be 16% and 45% higher, respectively, in subjects at least 65 years of age compared to subjects less than 65 years of age.
- In population pharmacokinetic analyses, elbasvir and grazoprevir AUCs are estimated to be 16% and 45% higher, respectively, in subjects at least 65 years of age compared to subjects less than 65 years of age.
- Gender
In population pharmacokinetic analyses, elbasvir and grazoprevir AUCs are estimated to be 50% and 30% higher, respectively, in females compared to males.
- In population pharmacokinetic analyses, elbasvir and grazoprevir AUCs are estimated to be 50% and 30% higher, respectively, in females compared to males.
- Weight/BMI
In population pharmacokinetic analyses, there was no effect of weight on elbasvir pharmacokinetics. Grazoprevir AUC is estimated to be 15% higher in a 53-kg subject compared to a 77-kg subject. This change is not clinically relevant for grazoprevir.
- In population pharmacokinetic analyses, there was no effect of weight on elbasvir pharmacokinetics. Grazoprevir AUC is estimated to be 15% higher in a 53-kg subject compared to a 77-kg subject. This change is not clinically relevant for grazoprevir.
- Race/Ethnicity
In population pharmacokinetic analyses, elbasvir and grazoprevir AUCs are estimated to be 15% and 50% higher, respectively, for Asians compared to Caucasians. Population pharmacokinetics estimates of exposure of elbasvir and grazoprevir were comparable between Caucasians and Black/African Americans.
- In population pharmacokinetic analyses, elbasvir and grazoprevir AUCs are estimated to be 15% and 50% higher, respectively, for Asians compared to Caucasians. Population pharmacokinetics estimates of exposure of elbasvir and grazoprevir were comparable between Caucasians and Black/African Americans.
- Renal Impairment
In population pharmacokinetic analyses, elbasvir AUC was 25% higher in hemodialysis-dependent subjects and 46% higher in non-dialysis-dependent subjects with severe renal impairment compared to elbasvir AUC in subjects without severe renal impairment. In population pharmacokinetic analysis in HCV-infected subjects, grazoprevir AUC was 10% higher in hemodialysis-dependent subjects and 40% higher in non-dialysis-dependent subjects with severe renal impairment compared to grazoprevir AUC in subjects without severe renal impairment. Elbasvir and grazoprevir are not removed by hemodialysis. Elbasvir and grazoprevir are unlikely to be removed by peritoneal dialysis as both are highly protein bound.
Overall, changes in exposure of elbasvir and grazoprevir in HCV-infected subjects with renal impairment with or without hemodialysis are not clinically relevant.
- In population pharmacokinetic analyses, elbasvir AUC was 25% higher in hemodialysis-dependent subjects and 46% higher in non-dialysis-dependent subjects with severe renal impairment compared to elbasvir AUC in subjects without severe renal impairment. In population pharmacokinetic analysis in HCV-infected subjects, grazoprevir AUC was 10% higher in hemodialysis-dependent subjects and 40% higher in non-dialysis-dependent subjects with severe renal impairment compared to grazoprevir AUC in subjects without severe renal impairment. Elbasvir and grazoprevir are not removed by hemodialysis. Elbasvir and grazoprevir are unlikely to be removed by peritoneal dialysis as both are highly protein bound.
- Overall, changes in exposure of elbasvir and grazoprevir in HCV-infected subjects with renal impairment with or without hemodialysis are not clinically relevant.
- Hepatic Impairment
The pharmacokinetics of elbasvir and grazoprevir were evaluated in non-HCV-infected subjects with mild hepatic impairment (Child-Pugh Category A , score of 5-6), moderate hepatic impairment (Child-Pugh Category B , score of 7-9) and severe hepatic impairment (Child-Pugh Category C , score of 10-15). In addition, the pharmacokinetics of elbasvir and grazoprevir were also evaluated in HCV-infected subjects including CP-A subjects with compensated cirrhosis.
Relative to non-HCV-infected subjects with normal hepatic function, no clinically relevant differences in elbasvir AUC values were observed in non-HCV-infected subjects with mild, moderate, or severe hepatic impairment. In population pharmacokinetic analyses, elbasvir steady-state AUC was similar in HCV-infected subjects with compensated cirrhosis compared to HCV-infected, non-cirrhotic subjects.
Relative to non-HCV-infected subjects with normal hepatic function, grazoprevir AUC values were higher by 1.7-fold, 5-fold, and 12-fold in non-HCV-infected subjects with mild, moderate, and severe hepatic impairment, respectively. In population pharmacokinetic analyses, grazoprevir steady-state AUC values were higher by 1.65-fold in HCV-infected subjects with compensated cirrhosis compared to HCV-infected, non-cirrhotic subjects.
- The pharmacokinetics of elbasvir and grazoprevir were evaluated in non-HCV-infected subjects with mild hepatic impairment (Child-Pugh Category A , score of 5-6), moderate hepatic impairment (Child-Pugh Category B , score of 7-9) and severe hepatic impairment (Child-Pugh Category C , score of 10-15). In addition, the pharmacokinetics of elbasvir and grazoprevir were also evaluated in HCV-infected subjects including CP-A subjects with compensated cirrhosis.
- Relative to non-HCV-infected subjects with normal hepatic function, no clinically relevant differences in elbasvir AUC values were observed in non-HCV-infected subjects with mild, moderate, or severe hepatic impairment. In population pharmacokinetic analyses, elbasvir steady-state AUC was similar in HCV-infected subjects with compensated cirrhosis compared to HCV-infected, non-cirrhotic subjects.
- Relative to non-HCV-infected subjects with normal hepatic function, grazoprevir AUC values were higher by 1.7-fold, 5-fold, and 12-fold in non-HCV-infected subjects with mild, moderate, and severe hepatic impairment, respectively. In population pharmacokinetic analyses, grazoprevir steady-state AUC values were higher by 1.65-fold in HCV-infected subjects with compensated cirrhosis compared to HCV-infected, non-cirrhotic subjects.
- Drug Interaction Studies
Drug interaction studies were performed in healthy adults with elbasvir, grazoprevir, or co-administered elbasvir and grazoprevir and drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interactions. TABLE 8 summarizes the effects of co-administered drugs on the exposures of the individual components of elbasvir and grazoprevir (elbasvir and grazoprevir). TABLE 9 summarizes the effects of the individual components of elbasvir and grazoprevir on the exposures of the co-administered drugs. For information regarding clinical recommendations.
Elbasvir and grazoprevir are substrates of CYP3A and P-gp, but the role of intestinal P-gp in the absorption of elbasvir and grazoprevir appears to be minimal. Co-administration of moderate and strong CYP3A inducers with elbasvir and grazoprevir may decrease elbasvir and grazoprevir plasma concentrations, leading to reduced therapeutic effect of elbasvir and grazoprevir. Co-administration of strong CYP3A4 inhibitors with elbasvir and grazoprevir may increase elbasvir and grazoprevir plasma concentrations.
Grazoprevir is a substrate of OATP1B1/3. Co-administration of elbasvir and grazoprevir with drugs that inhibit OATP1B1/3 transporters may result in a clinically relevant increase in grazoprevir plasma concentrations.
Elbasvir is not a CYP3A inhibitor in vitro and grazoprevir is a weak CYP3A inhibitor in humans. Co-administration with grazoprevir resulted in a 34% increase in plasma exposure of midazolam and a 43% increase in plasma exposure of tacrolimus (see TABLES 6 and 9). Elbasvir inhibited P-gp in vitro, but no clinically relevant increases in concentrations of digoxin (a P-gp substrate; see TABLE 9) were observed by co-administration of elbasvir. Grazoprevir is not a P-gp inhibitor in vitro. Elbasvir and grazoprevir are inhibitors of the drug transporter breast cancer resistance protein (BCRP) at the intestinal level in humans and may increase plasma concentrations of co-administered BCRP substrates.
Clinically significant drug interactions with elbasvir and grazoprevir as an inhibitor of other CYP enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6), UGT1A1, esterases (CES1, CES2, and CatA), organic anion transporters (OAT)1 and OAT3, and organic cation transporter (OCT)2, are not expected, and multiple-dose administration of elbasvir or grazoprevir is unlikely to induce the metabolism of drugs metabolized by CYP1A2, CYP2B6, or CYP3A based on in vitro data.
- Drug interaction studies were performed in healthy adults with elbasvir, grazoprevir, or co-administered elbasvir and grazoprevir and drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interactions. TABLE 8 summarizes the effects of co-administered drugs on the exposures of the individual components of elbasvir and grazoprevir (elbasvir and grazoprevir). TABLE 9 summarizes the effects of the individual components of elbasvir and grazoprevir on the exposures of the co-administered drugs. For information regarding clinical recommendations.
- Elbasvir and grazoprevir are substrates of CYP3A and P-gp, but the role of intestinal P-gp in the absorption of elbasvir and grazoprevir appears to be minimal. Co-administration of moderate and strong CYP3A inducers with elbasvir and grazoprevir may decrease elbasvir and grazoprevir plasma concentrations, leading to reduced therapeutic effect of elbasvir and grazoprevir. Co-administration of strong CYP3A4 inhibitors with elbasvir and grazoprevir may increase elbasvir and grazoprevir plasma concentrations.
- Grazoprevir is a substrate of OATP1B1/3. Co-administration of elbasvir and grazoprevir with drugs that inhibit OATP1B1/3 transporters may result in a clinically relevant increase in grazoprevir plasma concentrations.
- Elbasvir is not a CYP3A inhibitor in vitro and grazoprevir is a weak CYP3A inhibitor in humans. Co-administration with grazoprevir resulted in a 34% increase in plasma exposure of midazolam and a 43% increase in plasma exposure of tacrolimus (see TABLES 6 and 9). Elbasvir inhibited P-gp in vitro, but no clinically relevant increases in concentrations of digoxin (a P-gp substrate; see TABLE 9) were observed by co-administration of elbasvir. Grazoprevir is not a P-gp inhibitor in vitro. Elbasvir and grazoprevir are inhibitors of the drug transporter breast cancer resistance protein (BCRP) at the intestinal level in humans and may increase plasma concentrations of co-administered BCRP substrates.
- Clinically significant drug interactions with elbasvir and grazoprevir as an inhibitor of other CYP enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6), UGT1A1, esterases (CES1, CES2, and CatA), organic anion transporters (OAT)1 and OAT3, and organic cation transporter (OCT)2, are not expected, and multiple-dose administration of elbasvir or grazoprevir is unlikely to induce the metabolism of drugs metabolized by CYP1A2, CYP2B6, or CYP3A based on in vitro data.
These images are provided by the National Library of Medicine.
These images are provided by the National Library of Medicine.

## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Carcinogenesis and Mutagenesis
Elbasvir and grazoprevir were not genotoxic in a battery of in vitro or in vivo assays, including microbial mutagenesis, chromosomal aberration in Chinese Hamster Ovary cells, and in in vivo rat micronucleus assays.
Carcinogenicity studies with elbasvir or grazoprevir have not been conducted.
If elbasvir and grazoprevir is administered in a regimen containing ribavirin, the information for ribavirin on carcinogenesis and mutagenesis also applies to this combination regimen. Refer to the ribavirin prescribing information for information on carcinogenesis and mutagenesis.
- Elbasvir and grazoprevir were not genotoxic in a battery of in vitro or in vivo assays, including microbial mutagenesis, chromosomal aberration in Chinese Hamster Ovary cells, and in in vivo rat micronucleus assays.
- Carcinogenicity studies with elbasvir or grazoprevir have not been conducted.
- If elbasvir and grazoprevir is administered in a regimen containing ribavirin, the information for ribavirin on carcinogenesis and mutagenesis also applies to this combination regimen. Refer to the ribavirin prescribing information for information on carcinogenesis and mutagenesis.
- Impairment of Fertility
No effects on mating, female or male fertility, or early embryonic development were observed in rats at up to the highest dose tested. Systemic exposures (AUC) to elbasvir and grazoprevir were approximately 8 and 114 times, respectively, the exposure in humans at the recommended human dose.
If elbasvir and grazoprevir  is administered with ribavirin, the information for ribavirin on impairment of fertility also applies to this combination regimen. Refer to the ribavirin prescribing information for information on impairment of fertility.
- No effects on mating, female or male fertility, or early embryonic development were observed in rats at up to the highest dose tested. Systemic exposures (AUC) to elbasvir and grazoprevir were approximately 8 and 114 times, respectively, the exposure in humans at the recommended human dose.
- If elbasvir and grazoprevir  is administered with ribavirin, the information for ribavirin on impairment of fertility also applies to this combination regimen. Refer to the ribavirin prescribing information for information on impairment of fertility.

# Clinical Studies
Overview of Clinical Trials
- The efficacy of elbasvir and grazoprevir was assessed in 2 placebo-controlled trials and 4 uncontrolled Phase 2 and 3 clinical trials in 1401 subjects with genotype (GT) 1, 4, or 6 chronic hepatitis C virus infection with compensated liver disease (with or without cirrhosis). An overview of the 6 trials (n=1373) contributing to the assessment of efficacy in genotype 1 or 4 is provided in TABLE 12. C-EDGE TN, C-EDGE COINFECTION, C-SCAPE, and C-EDGE TE also included subjects with genotype 6 HCV infection (n=28). Because elbasvir and grazoprevir is not indicated for genotype 6 infection, results in patients with genotype 6 infection are not included in Clinical Studies (14).
- Elbasvir and grazoprevir was administered once daily by mouth in these trials. For subjects who received ribavirin (RBV), the RBV dosage was weight-based (less than 66 kg = 800 mg per day, 66 to 80 kg = 1000 mg per day, 81 to 105 kg = 1200 mg per day, greater than 105 kg = 1400 mg per day) administered by mouth in two divided doses with food.
- Sustained virologic response (SVR) was the primary endpoint in all trials and was defined as HCV RNA less than lower limit of quantification (LLOQ) at 12 weeks after the cessation of treatment (SVR12). Serum HCV RNA values were measured during these clinical trials using the COBAS AmpliPrep/COBAS Taqman HCV test (version 2.0) with an LLOQ of 15 HCV RNA IU per mL, with the exception of C-SCAPE where the assay had an LLOQ of 25 HCV RNA IU per mL.
Clinical Trials in Treatment-Naive Subjects with Genotype 1 HCV (C-EDGE TN and C-EDGE COINFECTION)
- The efficacy of elbasvir and grazoprevir in treatment-naive subjects with genotype 1 chronic hepatitis C virus infection with or without cirrhosis was demonstrated in the C-EDGE TN and C-EDGE COINFECTION trials.
- C-EDGE TN was a randomized, double-blind, placebo-controlled trial in treatment-naive subjects with genotype 1 or 4 infection with or without cirrhosis. Subjects were randomized in a 3:1 ratio to: elbasvir and grazoprevir for 12 weeks (immediate treatment group) or placebo for 12 weeks followed by open-label treatment with elbasvir and grazoprevir for 12 weeks (deferred treatment group). Among subjects with genotype 1 infection randomized to the immediate treatment group, the median age was 55 years (range: 20 to 78); 56% of the subjects were male; 61% were White; 20% were Black or African American; 8% were Hispanic or Latino; mean body mass index was 26 kg/m2; 72% had baseline HCV RNA levels greater than 800,000 IU per mL; 24% had cirrhosis; 67% had non-C/C IL28B alleles (CT or TT); and 55% had genotype 1a and 45% had genotype 1b chronic HCV infection.
- C-EDGE COINFECTION was an open-label, single-arm trial in treatment-naive HCV/HIV-1 co-infected subjects with genotype 1 or 4 infection with or without cirrhosis. Subjects received elbasvir and grazoprevir for 12 weeks. Among subjects with genotype 1 infection, the median age was 50 years (range: 21 to 71); 85% of the subjects were male; 75% were White; 19% were Black or African American; 6% were Hispanic or Latino; mean body mass index was 25 kg per m2; 59% had baseline HCV RNA levels greater than 800,000 IU per mL; 16% had cirrhosis; 65% had non-C/C IL28B alleles (CT or TT); and 76% had genotype 1a, 23% had genotype 1b, and 1% had genotype 1-Other chronic HCV infection.
- TABLE 13 presents treatment outcomes for elbasvir and grazoprevir in treatment-naive subjects with genotype 1 infection from C-EDGE TN (immediate treatment group) and C-EDGE COINFECTION. For treatment outcomes for elbasvir and grazoprevir  in genotype 4 infection.
- Treatment-Experienced Subjects who Failed Prior PegIFN with RBV Therapy (C-EDGE TE)
C-EDGE TE was a randomized, open-label comparative trial in subjects with genotype 1 or 4 infection, with or without cirrhosis, with or without HCV/HIV-1 co-infected, who had failed prior therapy with PegIFN + RBV therapy. Subjects were randomized in a 1:1:1:1 ratio to one of the following treatment groups: elbasvir and grazoprevir for 12 weeks, elbasvir and grazoprevir + RBV for 12 weeks, elbasvir and grazoprevir for 16 weeks, or elbasvir and grazoprevir + RBV for 16 weeks. Among subjects with genotype 1 infection, the median age was 57 years (range: 19 to 77); 64% of the subjects were male; 67% were White; 18% were Black or African American; 9% were Hispanic or Latino; mean body mass index was 28 kg/m2; 78% had baseline HCV RNA levels greater than 800,000 IU/mL; 34% had cirrhosis; 79% had non-C/C IL28B alleles (CT or TT); and 60% had genotype 1a, 39% had genotype 1b, and 1% had genotype 1-Other chronic HCV infection.
Treatment outcomes in genotype 1 subjects treated with elbasvir and grazoprevir for 12 weeks or elbasvir and grazoprevir with RBV for 16 weeks are presented in TABLE 14. Treatment outcomes with elbasvir and grazoprevir with RBV for 12 weeks or without RBV for 16 weeks are not shown because these regimens are not recommended in PegIFN/RBV-experienced genotype 1 patients. For treatment outcomes for elbasvir and grazoprevir in genotype 4 infection.
- C-EDGE TE was a randomized, open-label comparative trial in subjects with genotype 1 or 4 infection, with or without cirrhosis, with or without HCV/HIV-1 co-infected, who had failed prior therapy with PegIFN + RBV therapy. Subjects were randomized in a 1:1:1:1 ratio to one of the following treatment groups: elbasvir and grazoprevir for 12 weeks, elbasvir and grazoprevir + RBV for 12 weeks, elbasvir and grazoprevir for 16 weeks, or elbasvir and grazoprevir + RBV for 16 weeks. Among subjects with genotype 1 infection, the median age was 57 years (range: 19 to 77); 64% of the subjects were male; 67% were White; 18% were Black or African American; 9% were Hispanic or Latino; mean body mass index was 28 kg/m2; 78% had baseline HCV RNA levels greater than 800,000 IU/mL; 34% had cirrhosis; 79% had non-C/C IL28B alleles (CT or TT); and 60% had genotype 1a, 39% had genotype 1b, and 1% had genotype 1-Other chronic HCV infection.
- Treatment outcomes in genotype 1 subjects treated with elbasvir and grazoprevir for 12 weeks or elbasvir and grazoprevir with RBV for 16 weeks are presented in TABLE 14. Treatment outcomes with elbasvir and grazoprevir with RBV for 12 weeks or without RBV for 16 weeks are not shown because these regimens are not recommended in PegIFN/RBV-experienced genotype 1 patients. For treatment outcomes for elbasvir and grazoprevir in genotype 4 infection.
- Treatment-Experienced Subjects who Failed Prior PegIFN + RBV + HCV Protease Inhibitor Therapy (C-SALVAGE)
C-SALVAGE was an open-label single-arm trial in subjects with genotype 1 infection, with or without cirrhosis, who had failed prior treatment with boceprevir, simeprevir, or telaprevir in combination with PegIFN + RBV. Subjects received EBR 50 mg once daily + GZR 100 mg once daily + RBV for 12 weeks. Subjects had a median age of 55 years (range: 23 to 75); 58% of the subjects were male; 97% were White; 3% were Black or African American; 15% were Hispanic or Latino; mean body mass index was 28 kg/m2; 63% had baseline HCV RNA levels greater than 800,000 IU/mL; 43% had cirrhosis; and 97% had non-C/C IL28B alleles (CT or TT); 46% had baseline NS3 resistance-associated substitutions.
Overall SVR was achieved in 96% (76/79) of subjects receiving EBR + GZR + RBV for 12 weeks. Four percent (3/79) of subjects did not achieve SVR due to relapse. Treatment outcomes were consistent in genotype 1a and genotype 1b subjects, in subjects with different response to previous HCV therapy, and in subjects with or without cirrhosis. Treatment outcomes were generally consistent in subjects with or without NS3 resistance-associated substitutions at baseline, although limited data are available for subjects with specific NS3 resistance-associated substitutions.
- C-SALVAGE was an open-label single-arm trial in subjects with genotype 1 infection, with or without cirrhosis, who had failed prior treatment with boceprevir, simeprevir, or telaprevir in combination with PegIFN + RBV. Subjects received EBR 50 mg once daily + GZR 100 mg once daily + RBV for 12 weeks. Subjects had a median age of 55 years (range: 23 to 75); 58% of the subjects were male; 97% were White; 3% were Black or African American; 15% were Hispanic or Latino; mean body mass index was 28 kg/m2; 63% had baseline HCV RNA levels greater than 800,000 IU/mL; 43% had cirrhosis; and 97% had non-C/C IL28B alleles (CT or TT); 46% had baseline NS3 resistance-associated substitutions.
- Overall SVR was achieved in 96% (76/79) of subjects receiving EBR + GZR + RBV for 12 weeks. Four percent (3/79) of subjects did not achieve SVR due to relapse. Treatment outcomes were consistent in genotype 1a and genotype 1b subjects, in subjects with different response to previous HCV therapy, and in subjects with or without cirrhosis. Treatment outcomes were generally consistent in subjects with or without NS3 resistance-associated substitutions at baseline, although limited data are available for subjects with specific NS3 resistance-associated substitutions.
Clinical Trial in Subjects with Genotype 1 HCV and Severe Renal Impairment including Subjects on Hemodialysis (C-SURFER)
- C-SURFER was a randomized, double-blind, placebo-controlled trial in subjects with genotype 1 infection, with or without cirrhosis, with chronic kidney disease (CKD) Stage 4 (eGFR 15-29 mL/min/1.73 m2) or CKD Stage 5 (eGFR <15 mL/min/1.73 m2), including subjects on hemodialysis, who were treatment-naive or who had failed prior therapy with IFN or PegIFN  RBV therapy. Subjects were randomized in a 1:1 ratio to one of the following treatment groups: EBR 50 mg once daily + GZR 100 mg once daily for 12 weeks (immediate treatment group) or placebo for 12 weeks followed by open-label treatment with EBR + GZR for 12 weeks (deferred treatment group). In addition, 11 subjects received open-label EBR + GZR for 12 weeks (intensive pharmacokinetic  group). Subjects randomized to the immediate treatment group and intensive PK group had a median age of 58 years (range: 31 to 76); 75% of the subjects were male; 50% were White; 45% were Black or African American; 11% were Hispanic or Latino; 57% had baseline HCV RNA levels greater than 800,000 IU/mL; 6% had cirrhosis; and 72% had non-C/C IL28B alleles (CT or TT).
- Treatment outcomes in subjects treated with elbasvir and grazoprevir for 12 weeks in the pooled immediate treatment group and intensive PK group are presented in TABLE 15.
Clinical Trials with Genotype 4 HCV
- The efficacy of elbasvir and grazoprevir in subjects with genotype 4 chronic HCV infection was demonstrated in C-EDGE TN, C-EDGE COINFECTION, C-EDGE TE, and C-SCAPE. C-SCAPE was a randomized, open-label trial which included treatment-naive subjects with genotype 4 infection without cirrhosis. Subjects were randomized in a 1:1 ratio to EBR 50 mg once daily + GZR 100 mg once daily for 12 weeks or EBR 50 mg once daily + GZR 100 mg once daily + RBV for 12 weeks. In these combined studies in subjects with genotype 4 infection, 64% were treatment-naive; 66% of the subjects were male; 87% were White; 10% were Black or African American; 22% had cirrhosis; and 30% had HCV/HIV-1 co-infected.
- In C-SCAPE, C-EDGE TN, and C-EDGE COINFECTION trials combined, a total of 66 genotype 4 treatment-naive subjects received elbasvir and grazoprevir or EBR + GZR for 12 weeks. In these combined trials, SVR12 among subjects treated with elbasvir and grazoprevir or EBR + GZR for 12 weeks was 97% (64/66).
- In C-EDGE TE, a total of 37 genotype 4 treatment-experienced subjects received a 12- or 16-week elbasvir and grazoprevir with or without RBV regimen. SVR12 among randomized subjects treated with elbasvir and grazoprevir + RBV for 16 weeks was 100% (8/8).

# How Supplied
Each elbasvir and grazoprevir tablet contains 50 mg elbasvir and 100 mg grazoprevir, is beige, oval-shaped, film-coated, debossed with "770" on one side and plain on the other. The tablets are packaged into a carton (NDC 0006-3074-02) containing two (2) 14-count child-resistant dose packs for a total of 28 tablets.

## Storage
- Store elbasvir and grazoprevir in the original blister package until use to protect from moisture.
- Store elbasvir and grazoprevir at 20C to 25C (68F to 77F); excursions permitted between 15C to 30C (between 59F to 86F) .

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling.
For patients receiving elbasvir and grazoprevir with ribavirin, advise patients to read the FDA-approved patient labeling (Medication Guide) for ribavirin.
- Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV
Inform patients that HBV reactivation can occur in patients coinfected with HBV during or after treatment of HCV infection. Advise patients to tell their healthcare provider if they have a history of hepatitis B virus infection.
- Inform patients that HBV reactivation can occur in patients coinfected with HBV during or after treatment of HCV infection. Advise patients to tell their healthcare provider if they have a history of hepatitis B virus infection.
- Risk of ALT Elevations
Inform patients to watch for early warning signs of liver inflammation, such as fatigue, weakness, lack of appetite, nausea and vomiting, as well as later signs such as jaundice and discolored feces, and to consult their healthcare professional without delay if such symptoms occur.
- Inform patients to watch for early warning signs of liver inflammation, such as fatigue, weakness, lack of appetite, nausea and vomiting, as well as later signs such as jaundice and discolored feces, and to consult their healthcare professional without delay if such symptoms occur.
- Pregnancy
Advise patients taking elbasvir and grazoprevir with ribavirin to avoid pregnancy during treatment and within 6 months of stopping ribavirin and to notify their healthcare provider immediately in the event of a pregnancy.
- Advise patients taking elbasvir and grazoprevir with ribavirin to avoid pregnancy during treatment and within 6 months of stopping ribavirin and to notify their healthcare provider immediately in the event of a pregnancy.
- Drug Interactions
Inform patients that elbasvir and grazoprevir may interact with some drugs; therefore, advise patients to report the use of any prescription, non-prescription medication, or herbal products to their healthcare provider.
- Inform patients that elbasvir and grazoprevir may interact with some drugs; therefore, advise patients to report the use of any prescription, non-prescription medication, or herbal products to their healthcare provider.
- Storage
Advise patients to store elbasvir and grazoprevir in the original package until use to protect from moisture
- Advise patients to store elbasvir and grazoprevir in the original package until use to protect from moisture
- Administration
Advise patients to take elbasvir and grazoprevir every day at the regularly scheduled time with or without food. Inform patients that it is important not to miss or skip doses and to take elbasvir and grazoprevir for the duration that is recommended by the healthcare provider.
- Advise patients to take elbasvir and grazoprevir every day at the regularly scheduled time with or without food. Inform patients that it is important not to miss or skip doses and to take elbasvir and grazoprevir for the duration that is recommended by the healthcare provider.

# Precautions with Alcohol
Alcohol-Elbasvir and grazoprevir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
ZEPATIER

# Look-Alike Drug Names
There is limited information regarding Elbasvir / grazoprevir Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price