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ZEPATIER is a brand name for Elbasvir. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: 1 INDICATIONS AND USAGE ZEPATIER ® is indicated for the treatment of chronic hepatitis C virus (HCV) genotype 1 or 4 infection in adult and pediatric patients 12 years of age and older or weighing at least 30 kg. ZEPATIER is indicated for use with ribavirin in certain patient populations [see Dosage and Administration…
Verbatim from this product's FDA label. Tap a section to expand.
2 DOSAGE AND ADMINISTRATION Testing Prior to Initiation of Therapy: Test all patients for HBV infection by measuring HBsAg and anti-HBc. 1 ) Genotype 1a: Testing for the presence of virus with NS5A resistance-associated polymorphisms is recommended.
1 ) Obtain hepatic laboratory testing. 1 ) Recommended dosage in adult and pediatric patients 12 years of age and older or weighing at least 30 kg: One tablet taken orally once daily with or without food. 2 ) Dosage Regimens and Durations for ZEPATIER in Patients with Genotype 1 or 4 HCV with or without Cirrhosis Patient Population Treatment Duration Genotype 1a: Treatment-naïve or PegIFN/RBV-experienced Peginterferon alfa + ribavirin.
without baseline NS5A polymorphisms Polymorphisms at amino acid positions 28, 30, 31, or 93.
ZEPATIER 12 weeks Genotype 1a:
Treatment-naïve or PegIFN/RBV-experienced with baseline NS5A polymorphisms ZEPATIER + ribavirin 16 weeks Genotype 1b: Treatment-naïve or PegIFN/RBV-experienced ZEPATIER 12 weeks Genotype 1a or 1b: PegIFN/RBV/PI-experienced Peginterferon alfa + ribavirin + HCV NS3/4A protease inhibitor.
ZEPATIER + ribavirin 12 weeks Genotype 4:
Treatment-naïve ZEPATIER 12 weeks Genotype 4: PegIFN/RBV-experienced ZEPATIER + ribavirin 16 weeks HCV/HIV-1 co-infection: Follow the dosage recommendations in the table above. 2 ) Renal Impairment, including hemodialysis: No dosage adjustment of ZEPATIER is recommended.
Refer to ribavirin prescribing information for ribavirin dosing and dosage modifications. 1) ] . 2) , Table 1 ] . 4) , Table 12 ] . 3) ]. 2 Recommended Dosage in Adult and Pediatric Patients 12 Years of Age and Older or Weighing at Least 30 kg ZEPATIER is a two-drug, fixed-dose combination product containing 50 mg of elbasvir and 100 mg of grazoprevir in a single tablet.
3) ] . ZEPATIER is used in combination with ribavirin in certain patient populations (see Table 1 ). When administered with ZEPATIER, 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 [see Clinical Studies (14) ].
2) ]. In subjects receiving ZEPATIER for 12 weeks, the most commonly reported adverse reactions of all intensity (greater than or equal to 5% in placebo-controlled trials) were fatigue, headache, and nausea. In subjects receiving ZEPATIER with ribavirin for 16 weeks, the most commonly reported adverse reactions of moderate or severe intensity (greater than or equal to 5%) were anemia and headache.
gov/medwatch . 1 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 ZEPATIER is administered with ribavirin, refer to the prescribing information for ribavirin for a description of ribavirin-associated adverse reactions. Clinical Trials in Adult Subjects The safety of ZEPATIER in adult subjects 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) [see Clinical Studies (14) ] .
Adverse Reactions with ZEPATIER in Treatment-Naïve Subjects C-EDGE TN was a Phase 3 randomized, double-blind, placebo-controlled trial in 421 treatment-naïve (TN) subjects with HCV infection who received ZEPATIER 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 ZEPATIER for 12 weeks are presented in Table 3 . In subjects treated with ZEPATIER 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 ZEPATIER or placebo had serious adverse reactions. The proportion of subjects treated with ZEPATIER or placebo who permanently discontinued treatment due to adverse reactions was 1% in each group.
5 WARNINGS AND PRECAUTIONS Risk of Hepatitis B Virus Reactivation: Test all patients for evidence of current or prior HBV infection before initiation of HCV treatment. Monitor HCV/HBV coinfected patients for HBV reactivation and hepatitis flare during HCV treatment and post-treatment follow-up.
Initiate appropriate patient management for HBV infection as clinically indicated. 1 ) ALT Elevations: Perform hepatic laboratory testing prior to therapy, at treatment week 8, and as clinically indicated. For patients receiving 16 weeks of therapy, perform additional hepatic laboratory testing at treatment week 12.
For ALT elevations on ZEPATIER, follow recommendations in full prescribing information. 2 ) Risk of Hepatic Decompensation/Failure in Patients with Evidence of Advanced Liver Disease: Hepatic decompensation/failure, including fatal outcomes, have been reported mostly in patients with cirrhosis and baseline moderate or severe liver impairment (Child-Pugh B or C) treated with HCV NS3/4A protease inhibitor-containing regimens.
Monitor for clinical and laboratory evidence of hepatic decompensation. Discontinue ZEPATIER in patients who develop evidence of hepatic decompensation/failure. 3 ) Risk Associated with Ribavirin Combination Treatment: If ZEPATIER is administered with ribavirin, the warnings and precautions for ribavirin also apply.
1 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. , 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.
3) ] . 9) ] . 3) ] . If ZEPATIER 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. Table 2 lists drugs that are contraindicated with ZEPATIER.
Table 2:
Drugs that are Contraindicated with ZEPATIER Drug Class Drug(s) within Class that are Contraindicated Clinical Comment This table is not a comprehensive list of all drugs that strongly induce CYP3A. This table may not include all OATP1B1/3 inhibitors that significantly increase grazoprevir plasma concentrations.
Anticonvulsants Phenytoin Carbamazepine May lead to loss of virologic response to ZEPATIER due to significant decreases in elbasvir and grazoprevir plasma concentrations caused by strong CYP3A induction. Antimycobacterials Rifampin May lead to loss of virologic response to ZEPATIER due to significant decreases in elbasvir and grazoprevir plasma concentrations caused by strong CYP3A induction.
Herbal Products St. John's Wort (Hypericum perforatum) May lead to loss of virologic response to ZEPATIER due to significant decreases in elbasvir and grazoprevir plasma concentrations caused by strong CYP3A induction. HIV Medications Efavirenz Efavirenz is included as a strong CYP3A inducer in this table, since co-administration reduced grazoprevir exposure by ≥80% [see Table 9 ] .
May lead to loss of virologic response to ZEPATIER due to significant decreases in elbasvir and grazoprevir plasma concentrations caused by CYP3A induction. HIV Medications Atazanavir Darunavir Lopinavir Saquinavir Tipranavir May increase the risk of ALT elevations due to a significant increase in grazoprevir plasma concentrations caused by OATP1B1/3 inhibition.
Immunosuppressants Cyclosporine May increase the risk of ALT elevations due to a significant increase in grazoprevir plasma concentrations caused by OATP1B1/3 inhibition. Patients with moderate or severe hepatic impairment (Child-Pugh B or C).
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Table 1 below provides the recommended ZEPATIER 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.
Table 1:
Recommended Dosage Regimens and Durations for ZEPATIER for Treatment of HCV Genotype 1 or 4 in Patients with or without Cirrhosis Patient Population Treatment Duration Genotype 1a: Treatment-naïve or PegIFN/RBV-experienced Patients who have failed treatment with peginterferon alfa (PegIFN) + ribavirin (RBV).
without baseline NS5A polymorphisms NS5A resistance-associated polymorphisms at amino acid positions 28, 30, 31, or 93. 1 Testing prior to the initiation of therapy, subsection NS5A resistance testing in HCV genotype 1a-infected patients.
ZEPATIER 12 weeks Genotype 1a:
Treatment-naïve or PegIFN/RBV-experienced with baseline NS5A polymorphisms ZEPATIER + RBV For patients with CrCl greater than 50 mL per minute, the recommended dosage of ribavirin is 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 in two divided doses with food.
For patients with CrCl less than or equal to 50 mL per minute, including patients receiving hemodialysis, refer to the ribavirin tablet prescribing information for the correct ribavirin dosage. In pediatric patients, the dosing for ribavirin is weight-based in two divided doses.
Refer to the ribavirin tablet prescribing information for the correct ribavirin dosage regimen. 16 weeks Genotype 1b: Treatment-naïve or PegIFN/RBV-experienced ZEPATIER 12 weeks Genotype 1a The optimal ZEPATIER-based treatment regimen and duration of therapy for PegIFN/RBV/PI-experienced genotype 1a-infected patients with one or more baseline NS5A resistance-associated polymorphisms at positions 28, 30, 31, and 93 has not been established.
or 1b: PegIFN/RBV/PI-experienced Patients who have failed treatment with PegIFN + RBV + HCV NS3/4A protease inhibitor (PI): boceprevir, simeprevir, or telaprevir. 3 Renal Impairment No dosage adjustment of ZEPATIER is recommended in patients with any degree of renal impairment including patients on hemodialysis.
4) ] . 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. 4 Hepatic Impairment No dosage adjustment of ZEPATIER is recommended in patients with mild hepatic impairment (Child-Pugh A).
3) ].
Table 3:
Adverse Reactions (All Intensity) Reported in ≥5% of Treatment-Naïve Subjects with HCV Treated with ZEPATIER for 12 Weeks in C-EDGE TN C-EDGE TN ZEPATIER N=316 % 12 weeks Placebo N=105 % 12 weeks Fatigue 11% 10% Headache 10% 9% C-EDGE COINFECTION was a Phase 3 open-label trial in 218 treatment-naïve HCV/HIV co-infected subjects who received ZEPATIER one tablet once daily for 12 weeks.
Adverse reactions (all intensity) reported in C-EDGE COINFECTION in at least 5% of subjects treated with ZEPATIER 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 mm 3 was observed at the end of 12 weeks of treatment. Adverse Reactions with ZEPATIER 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 ZEPATIER one tablet once daily for 12 weeks or ZEPATIER one tablet once daily with ribavirin for 16 weeks are presented in Table 4 .
No subjects treated with ZEPATIER without ribavirin for 12 weeks reported serious adverse reactions or discontinued treatment due to adverse reactions. The proportion of subjects treated with ZEPATIER with ribavirin for 16 weeks with serious adverse reactions was 1%.
The proportion of subjects treated with ZEPATIER 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.
Table 4:
Adverse Reactions (Moderate or Severe Intensity) Reported in ≥2% of PegIFN/RBV-Experienced Subjects with HCV Treated with ZEPATIER for 12 Weeks or ZEPATIER + Ribavirin for 16 Weeks in C-EDGE TE C-EDGE TE ZEPATIER N=105 % 12 weeks ZEPATIER + Ribavirin N=106 % 16 weeks Anemia 0% 8% Headache 0% 6% Fatigue 5% 4% Dyspnea 0% 4% Rash or Pruritus 0% 4% Irritability 1% 3% Abdominal pain 2% 2% Depression 1% 2% Arthralgia 0% 2% Diarrhea 2% 0% The type and severity of adverse reactions with ZEPATIER with or without ribavirin in 10 treatment-experienced subjects with HCV/HIV co-infection were comparable to those reported in subjects without HIV co-infection.
Median increase in CD4+ T-cell counts of 32 cells/mm 3 was observed at the end of 12 weeks of treatment with ZEPATIER alone. In subjects treated with ZEPATIER with ribavirin for 16 weeks, CD4+ T-cell counts decreased a median of 135 cells per mm 3 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 ZEPATIER 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.
4) ] . The adverse reactions (all intensity) occurring in at least 5% of subjects treated with ZEPATIER for 12 weeks are presented in Table 5 . In subjects treated with ZEPATIER who reported an adverse reaction, 76% had adverse reactions of mild severity.
The proportion of subjects treated with ZEPATIER 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.
Table 5:
Adverse Reactions (All Intensity) Reported in ≥5% of Treatment-Naïve or PegIFN/RBV-Experienced Subjects with Stage 4 or 5 Chronic Kidney Disease and HCV Treated with ZEPATIER for 12 Weeks in C-SURFER ZEPATIER N=122 % 12 weeks Placebo N=113 % 12 weeks Nausea 11% 8% Headache 11% 5% Fatigue 5% 8% Laboratory Abnormalities in Subjects Receiving ZEPATIER with or without Ribavirin Serum ALT Elevations During clinical trials with ZEPATIER 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. 2) ] . 3) ] . The incidence of late ALT elevations was not affected by treatment duration. Cirrhosis was not a risk factor for late ALT elevations. 5 times ULN were observed in 6% of subjects receiving ZEPATIER with ribavirin compared to less than 1% in those receiving ZEPATIER 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. 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.
5 g per dL during treatment. 5 g per dL. Clinical Trial in Pediatric Subjects Adverse Reactions in Pediatric Subjects 12 Years of Age and Older The safety of ZEPATIER was assessed in pediatric subjects 12 years of age and older based on data from 22 subjects, without cirrhosis, who were treated with ZEPATIER for 12 weeks in a Phase 2b, open-label clinical trial (MK-5172-079).
6) ] . The adverse drug reactions observed in greater than or equal to 5% of subjects receiving ZEPATIER were headache (14%) and nausea (9%). 2 Postmarketing Experience The following adverse reactions have been identified during post approval use of ZEPATIER.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 3) ]
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. , 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 ZEPATIER. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with ZEPATIER and during post-treatment follow-up.
Initiate appropriate patient management for HBV infection as clinically indicated. 2 Increased Risk of ALT Elevations During clinical trials with ZEPATIER 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. 1) ] . 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 ZEPATIER if ALT levels remain persistently greater than 10 times the 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). 3 Risk of Hepatic Decompensation/Failure in Patients with Evidence of Advanced Liver Disease 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.
Reported cases occurred in patients treated with HCV NS3/4A protease inhibitor-containing regimens with baseline cirrhosis with and without moderate or severe liver impairment (Child-Pugh B or C) as well as some patients without cirrhosis.
Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 2) ]. In patients with compensated cirrhosis (Child-Pugh A) or evidence of advanced liver disease, such as portal hypertension, more frequent hepatic laboratory testing may be warranted; and patients should be monitored for signs and symptoms of hepatic decompensation such as the presence of jaundice, ascites, hepatic encephalopathy, and variceal hemorrhage.
Discontinue ZEPATIER in patients who develop evidence of hepatic decompensation/failure. 3) ] . 4 Risks Associated with Ribavirin Combination Treatment If ZEPATIER is administered with ribavirin, the warnings and precautions for ribavirin, including the pregnancy avoidance warning, also apply to this combination regimen.
2) ] . 5 Risk of Adverse Reactions or Reduced Therapeutic Effect Due to Drug Interactions The concomitant use of ZEPATIER 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 ZEPATIER.
Significant decrease of elbasvir and grazoprevir plasma concentrations which may lead to reduced therapeutic effect of ZEPATIER and possible development of resistance. 2) ] .
( 4 ) OATP1B1/3 inhibitors that are known or expected to significantly increase grazoprevir plasma concentrations, strong CYP3A inducers, and efavirenz. ( 4 ) If ZEPATIER is administered with ribavirin, the contraindications to ribavirin also apply.
( 4 )