Renal impairment

In chronic HCV GT1 infection:

A powerful cure* for patients with renal impairment, including those on hemodialysis

* Cure = sustained virologic response, defined as HCV ribonucleic acid (RNA) less than lower limit of quantification (<LLOQ) at 12 weeks after completion of therapy (SVR12).¹ SVR12 was the primary end point in all studies.

ZEPATIER is indicated for the treatment of chronic hepatitis C virus (HCV) genotype (GT) 1 or 4 infection in adults. ZEPATIER is indicated for use with ribavirin (RBV) in certain patient populations.

Study design

Randomized, double-blind, placebo-controlled study in patients with HCV GT1 infection, with or without cirrhosis, with CKD stage 4 (eGFR 15–29 mL/min/1.73 m²) or stage 5 (eGFR <15 mL/min/1.73 m²), including patients on hemodialysis, who were TN or who failed prior therapy with IFN or pegIFN ± RBV. Patients were randomized in a 1:1 ratio to the following treatment groups: ZEPATIER for 12 weeks (immediate-treatment group, n=111) or placebo for 12 weeks followed by open-label treatment with ZEPATIER for 12 weeks (deferred-treatment group, n=113). In addition, 11 patients received open-label ZEPATIER for 12 weeks (intensive pharmacokinetic [PK] group). Among patients in the immediate-treatment and intensive PK groups, 45% were Black or African American, 6% had cirrhosis, 52% had GT1a infection, and 48% had GT1b infection. SVR12 was assessed in the pooled immediate-treatment group and the intensive PK group (n=122).

No patients experienced on-treatment virologic failure, and 1 patient experienced treatment relapse.
Consistently high cure* rates were seen in patients receiving hemodialysis (93%, 86/92) and those not receiving hemodialysis (97%, 29/30).
More than one-third of the patients receiving ZEPATIER in C-SURFER had comorbid diabetes.²

99% (115/116) of patients included in the prespecified primary analysis population achieved SVR12

This population excluded patients not receiving at least 1 dose of study treatment and those with missing data due to death or early study discontinuation for reasons unrelated to treatment response (n=6).

ZEPATIER is predominantly eliminated through the liver (not the kidneys), providing a treatment option for chronic HCV–infected patients with any degree of renal impairment.

Definitions

CKD = chronic kidney disease

eGFR = estimated glomerular filtration rate

IFN = interferon

pegIFN = peginterferon alfa

RBV = ribavirin

TN = treatment-naïve

References

1. AASLD-IDSA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed March 16, 2018.

2. Roth D, Nelson D, Bruchfeld A, et al. Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4-5 chronic kidney disease (the C-SURFER study): a combination phase 3 study. Lancet. 2015;386:1537–1545.

Selected Safety Information

WARNING: RISK OF HEPATITIS B VIRUS (HBV) REACTIVATION IN PATIENTS COINFECTED WITH HCV AND HBV

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 treatment with ZEPATIER. HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct-acting antivirals and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Monitor HCV/HBV coinfected patients for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.

HBV reactivation has been reported in HBsAg positive patients and also in patients with serologic evidence of resolved HBV infection (ie, HBsAg negative and anti-HBc positive). The risk of HBV reactivation may be increased in patients receiving some immunosuppressant or chemotherapeutic agents. 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, ie, increases in aminotransferase levels and, in severe cases, increases in bilirubin levels, liver failure, and death can occur.
Contraindications: ZEPATIER is contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh B or C or those with any history of hepatic decompensation due to the risk of hepatic decompensation). ZEPATIER is also contraindicated with inhibitors of OATP1B1/3 that are known or expected to significantly increase grazoprevir plasma concentrations (eg, atazanavir, darunavir, lopinavir, saquinavir, tipranavir, cyclosporine), strong CYP3A inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s Wort), and efavirenz.
Risk of Hepatic Decompensation/Failure: Postmarketing cases of hepatic decompensation/failure, including those with fatal outcomes, have been reported in patients treated with HCV NS3/4A protease inhibitor-containing regimens, including ZEPATIER. These cases occurred in patients with baseline cirrhosis with and without moderate or severe liver impairment (Child-Pugh B or C) as well as some patients without cirrhosis.

Hepatic lab testing should be performed in all patients and more frequent testing may be warranted in patients with compensated cirrhosis or evidence of advanced liver disease. Discontinue ZEPATIER in patients who develop evidence of hepatic decompensation/failure.
Risks Associated with RBV Combination Treatment: If ZEPATIER is administered with RBV, the contraindications, warnings and precautions, adverse reactions, and dosing for RBV also apply to this combination regimen. Refer to the RBV prescribing information.
Increased Risk of ALT Elevations: Elevations of ALT to >5 times the upper limit of normal (ULN) occurred in 1% of subjects, generally at or after treatment week 8. These late ALT elevations were typically asymptomatic and most resolved with ongoing or completion of therapy. Perform hepatic lab testing on patients prior to therapy, at treatment week 8, and as clinically indicated. For patients receiving 16 weeks of therapy, perform additional hepatic lab testing at treatment week 12.

Patients should be instructed to consult their health care professional without delay if they have onset of fatigue, weakness, lack of appetite, nausea and vomiting, jaundice, or discolored feces. Consider discontinuing ZEPATIER if ALT levels remain persistently >10 times ULN. Discontinue ZEPATIER if ALT elevation is accompanied by signs or symptoms of liver inflammation or increasing conjugated bilirubin, alkaline phosphatase, or International Normalized Ratio (INR).
Risk of Adverse Reactions Due to Drug Interactions: Coadministration of ZEPATIER is not recommended with certain strong CYP3A inhibitors (eg, oral ketoconazole or the cobicistat-containing regimens of elvitegravir/cobicistat/emtricitabine/tenofovir [disoproxil fumarate or alafenamide]). The concomitant use of ZEPATIER with these drugs may lead to greater exposure to ZEPATIER.

ZEPATIER may increase concentrations of certain drugs. Do not exceed atorvastatin 20 mg/daily or rosuvastatin 10 mg/daily when given with ZEPATIER. If ZEPATIER is given with fluvastatin, lovastatin, or simvastatin, give the lowest statin dose necessary and closely monitor for statin-associated adverse events. If ZEPATIER and tacrolimus are coadministered, frequent monitoring of tacrolimus whole blood concentrations, changes in renal function, and tacrolimus-associated adverse events is recommended.
Risk of Reduced Therapeutic Effect Due to Drug Interactions: The concomitant use of ZEPATIER and certain drugs may cause significant decrease of elbasvir and grazoprevir plasma concentrations, which may lead to reduced therapeutic effect of ZEPATIER and possible development of resistance. Coadministration of ZEPATIER is not recommended with moderate CYP3A inducers (eg, nafcillin, bosentan, etravirine, modafinil).
Established & Potentially Significant Drug Interactions: Clearance of HCV infection with direct-acting antivirals may lead to changes in hepatic function, which may impact the safe and effective use of concomitant medications. For example, altered blood glucose control has been reported in diabetic patients.

Frequent monitoring of relevant lab parameters (eg, INR in patients taking warfarin, blood glucose levels in diabetic patients) or drug concentrations of concomitant medications such as CYP450 substrates with a narrow therapeutic index is recommended to ensure safe and effective use. Dose adjustments of concomitant medications may be necessary.
Adverse Reactions: In subjects receiving ZEPATIER for 12 weeks, the most commonly reported adverse reactions of all intensity (≥5% in placebo-controlled trials) compared to placebo were fatigue, headache, and nausea. In subjects receiving ZEPATIER with RBV for 16 weeks, the most commonly reported adverse reactions of moderate or severe intensity (≥5%) were anemia and headache.

Dosage and Administration

ZEPATIER is a single tablet taken once daily.

The dosing regimens and durations for treatment with once-daily ZEPATIER for chronic HCV GT1 or GT4 infection in patients with or without cirrhosis, HIV-1 coinfection, or renal impairment are as follows:

Twelve weeks of treatment with ZEPATIER is recommended for: GT1a-infected patients who are treatment-naïve or who have failed prior treatment with peginterferon alfa plus RBV (PegIFN/RBV-experienced) without baseline NS5A resistance-associated substitutions (amino acid positions 28, 30, 31, or 93); GT1b-infected patients who are treatment-naïve or PegIFN/RBV-experienced; and GT4-infected patients who are treatment-naïve.
Twelve weeks of treatment with ZEPATIER in combination with RBV* is recommended for GT1a- or GT1b-infected patients who have failed prior treatment with PegIFN/RBV + an HCV NS3/4A protease inhibitor (PI) (boceprevir, simeprevir, or telaprevir).†
Sixteen weeks of treatment with ZEPATIER in combination with RBV* is recommended for: GT1a-infected patients who are treatment-naïve or PegIFN/RBV-experienced with baseline NS5A resistance-associated substitutions; and GT4-infected patients who are PegIFN/RBV-experienced.

*For patients with CrCl >50 mL per minute, the recommended dosage of RBV is weight-based (800 mg/day to 1,400 mg/day) administered in 2 divided doses with food. For patients with CrCl ≤50 mL per minute, including patients receiving hemodialysis, refer to the RBV tablet prescribing information for the correct RBV dosage.

†For GT1a-infected PegIFN/RBV/PI-experienced patients with one or more baseline NS5A resistance-associated substitutions, the optimal ZEPATIER-based treatment regimen and duration of therapy has not been established.

Testing patients with HCV GT1a infection for the presence of NS5A resistance-associated substitutions (RASs) at positions 28, 30, 31, or 93 is recommended prior to initiation of treatment with ZEPATIER to determine dosage regimen and duration.

Before prescribing ZEPATIER, please read the accompanying Prescribing Information, including the Boxed Warning about the risk of hepatitis B virus (HBV) reactivation in patients coinfected with HCV and HBV. The Patient Information also is available.

Indications and Usage

ZEPATIER is indicated for the treatment of chronic hepatitis C virus (HCV) genotype (GT) 1 or 4 infection in adults. ZEPATIER is indicated for use with ribavirin (RBV) in certain patient populations.

Selected Safety Information

WARNING: RISK OF HEPATITIS B VIRUS (HBV) REACTIVATION IN PATIENTS COINFECTED WITH HCV AND HBV

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 treatment with ZEPATIER. HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct-acting antivirals and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Monitor HCV/HBV coinfected patients for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.

HBV reactivation has been reported in HBsAg positive patients and also in patients with serologic evidence of resolved HBV infection (ie, HBsAg negative and anti-HBc positive). The risk of HBV reactivation may be increased in patients receiving some immunosuppressant or chemotherapeutic agents. 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, ie, increases in aminotransferase levels and, in severe cases, increases in bilirubin levels, liver failure, and death can occur.
Contraindications: ZEPATIER is contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh B or C or those with any history of hepatic decompensation due to the risk of hepatic decompensation). ZEPATIER is also contraindicated with inhibitors of OATP1B1/3 that are known or expected to significantly increase grazoprevir plasma concentrations (eg, atazanavir, darunavir, lopinavir, saquinavir, tipranavir, cyclosporine), strong CYP3A inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s Wort), and efavirenz.
Risk of Hepatic Decompensation/Failure: Postmarketing cases of hepatic decompensation/failure, including those with fatal outcomes, have been reported in patients treated with HCV NS3/4A protease inhibitor-containing regimens, including ZEPATIER. These cases occurred in patients with baseline cirrhosis with and without moderate or severe liver impairment (Child-Pugh B or C) as well as some patients without cirrhosis.

Hepatic lab testing should be performed in all patients and more frequent testing may be warranted in patients with compensated cirrhosis or evidence of advanced liver disease. Discontinue ZEPATIER in patients who develop evidence of hepatic decompensation/failure.
Risks Associated with RBV Combination Treatment: If ZEPATIER is administered with RBV, the contraindications, warnings and precautions, adverse reactions, and dosing for RBV also apply to this combination regimen. Refer to the RBV prescribing information.
Increased Risk of ALT Elevations: Elevations of ALT to >5 times the upper limit of normal (ULN) occurred in 1% of subjects, generally at or after treatment week 8. These late ALT elevations were typically asymptomatic and most resolved with ongoing or completion of therapy. Perform hepatic lab testing on patients prior to therapy, at treatment week 8, and as clinically indicated. For patients receiving 16 weeks of therapy, perform additional hepatic lab testing at treatment week 12.

Patients should be instructed to consult their health care professional without delay if they have onset of fatigue, weakness, lack of appetite, nausea and vomiting, jaundice, or discolored feces. Consider discontinuing ZEPATIER if ALT levels remain persistently >10 times ULN. Discontinue ZEPATIER if ALT elevation is accompanied by signs or symptoms of liver inflammation or increasing conjugated bilirubin, alkaline phosphatase, or International Normalized Ratio (INR).
Risk of Adverse Reactions Due to Drug Interactions: Coadministration of ZEPATIER is not recommended with certain strong CYP3A inhibitors (eg, oral ketoconazole or the cobicistat-containing regimens of elvitegravir/cobicistat/emtricitabine/tenofovir [disoproxil fumarate or alafenamide]). The concomitant use of ZEPATIER with these drugs may lead to greater exposure to ZEPATIER.

ZEPATIER may increase concentrations of certain drugs. Do not exceed atorvastatin 20 mg/daily or rosuvastatin 10 mg/daily when given with ZEPATIER. If ZEPATIER is given with fluvastatin, lovastatin, or simvastatin, give the lowest statin dose necessary and closely monitor for statin-associated adverse events. If ZEPATIER and tacrolimus are coadministered, frequent monitoring of tacrolimus whole blood concentrations, changes in renal function, and tacrolimus-associated adverse events is recommended.
Risk of Reduced Therapeutic Effect Due to Drug Interactions: The concomitant use of ZEPATIER and certain drugs may cause significant decrease of elbasvir and grazoprevir plasma concentrations, which may lead to reduced therapeutic effect of ZEPATIER and possible development of resistance. Coadministration of ZEPATIER is not recommended with moderate CYP3A inducers (eg, nafcillin, bosentan, etravirine, modafinil).
Established & Potentially Significant Drug Interactions: Clearance of HCV infection with direct-acting antivirals may lead to changes in hepatic function, which may impact the safe and effective use of concomitant medications. For example, altered blood glucose control has been reported in diabetic patients.

Frequent monitoring of relevant lab parameters (eg, INR in patients taking warfarin, blood glucose levels in diabetic patients) or drug concentrations of concomitant medications such as CYP450 substrates with a narrow therapeutic index is recommended to ensure safe and effective use. Dose adjustments of concomitant medications may be necessary.
Adverse Reactions: In subjects receiving ZEPATIER for 12 weeks, the most commonly reported adverse reactions of all intensity (≥5% in placebo-controlled trials) compared to placebo were fatigue, headache, and nausea. In subjects receiving ZEPATIER with RBV for 16 weeks, the most commonly reported adverse reactions of moderate or severe intensity (≥5%) were anemia and headache.

Dosage and Administration

ZEPATIER is a single tablet taken once daily.

Twelve weeks of treatment with ZEPATIER is recommended for: GT1a-infected patients who are treatment-naïve or who have failed prior treatment with peginterferon alfa plus RBV (PegIFN/RBV-experienced) without baseline NS5A resistance-associated substitutions (amino acid positions 28, 30, 31, or 93); GT1b-infected patients who are treatment-naïve or PegIFN/RBV-experienced; and GT4-infected patients who are treatment-naïve.
Twelve weeks of treatment with ZEPATIER in combination with RBV* is recommended for GT1a- or GT1b-infected patients who have failed prior treatment with PegIFN/RBV + an HCV NS3/4A protease inhibitor (PI) (boceprevir, simeprevir, or telaprevir).†
Sixteen weeks of treatment with ZEPATIER in combination with RBV* is recommended for: GT1a-infected patients who are treatment-naïve or PegIFN/RBV-experienced with baseline NS5A resistance-associated substitutions; and GT4-infected patients who are PegIFN/RBV-experienced.

US-ZEP-0005011/20