Zepatier

/ MSD

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 ZEPATIER.
NS5A Resistance Testing in Hepatitis C Virus (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 ZEPATIER to determine dosage regimen and duration. In subjects receiving ZEPATIER 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 ZEPATIER.
Recommended Dosage in Adults
ZEPATIER 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 ZEPATIER is one tablet taken orally once daily with or without food. The film-coated tablets should be swallowed whole.
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.
Table 1 at the attached doctor’s leaflet 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.
Renal Impairment: No dosage adjustment of ZEPATIER is recommended in patients with any degree of renal impairment including patients on hemodialysis. Administer ZEPATIER 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 ZEPATIER is recommended in patients with mild hepatic impairment (Child-Pugh A). ZEPATIER is contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh B or C).

ZEPATIER™ is indicated for the treatment of chronic hepatitis C (CHC) genotypes 1 or 4 infection in adults.

ZEPATIER is contraindicated in patients with known hypersensitivity to elbasvir, grazoprevir, or any of its components.
ZEPATIER 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.
ZEPATIER 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 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.
Please refer to Table 2 at the attached doctor’s leaflet for drugs that are contraindicated with ZEPATIER.

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 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.
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. Higher rates of late ALT elevations occurred in the following subpopulations: female sex (2% [10/608]), Asian race (2% [4/164]), and age 65 years or older (2% [3/177]).
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).
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. 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 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.
See Tables 2 and 6 at the attached doctor’s leaflet for steps to prevent or manage these known or potentially significant drug interactions, including dosing recommendations.

Fatigue, headache, nausea, insomnia, and diarrhea.
See prescribing information for full details.

Potential for Drug Interactions: Grazoprevir is a substrate of OATP1B1/3 transporters. Co-administration of ZEPATIER 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 ZEPATIER may decrease elbasvir and grazoprevir plasma concentrations, leading to reduced therapeutic effect of ZEPATIER. Co-administration of ZEPATIER with strong CYP3A inducers or efavirenz is contraindicated. Co-administration of ZEPATIER with moderate CYP3A inducers is not recommended. Co-administration of ZEPATIER with strong CYP3A inhibitors may increase elbasvir and grazoprevir concentrations. Co-administration of ZEPATIER with certain strong CYP3A inhibitors is not recommended.
Fluctuations in INR values may occur in patients receiving warfarin concomitantly with HCV treatment, including treatment with ZEPATIER. Frequent monitoring of INR values is recommended during treatment and post-treatment follow-up.
Established and other Potentially Significant Drug Interactions: If dose adjustments of concomitant medications are made due to treatment with ZEPATIER, doses should be readjusted after administration of ZEPATIER is completed.
Table 6 at the attached doctor’s leaflet provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with either ZEPATIER, the components of ZEPATIER (elbasvir [EBR] and grazoprevir [GZR]) as individual agents, or are predicted drug interactions that may occur with ZEPATIER.
Drugs without Clinically Significant Interactions with ZEPATIER: The interaction between the components of ZEPATIER (elbasvir or grazoprevir) or ZEPATIER and the following drugs were evaluated in clinical studies, and no dose adjustments are needed when ZEPATIER 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 ZEPATIER is co-administered with abacavir, emtricitabine, entecavir, and lamivudine.

Pregnancy: No adequate human data are available to establish whether or not ZEPATIER poses a risk to pregnancy outcomes.
Lactation: It is not known whether ZEPATIER 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 ZEPATIER (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 ZEPATIER and any potential adverse effects on the breastfed child from ZEPATIER or from the underlying maternal condition.
If ZEPATIER is administered with ribavirin, the information for ribavirin with regard to nursing mothers also applies to this combination.
See prescribing information for full details.

Human experience of overdose with ZEPATIER is limited. No specific antidote is available for overdose with ZEPATIER. 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.

Storage: Store up to 30°C.