For: Chronic Hepatitis C
Zepatier (elbasvir and grazoprevir) is a once-daily, single tablet, NS5A replication complex inhibitor and NS3/4A protease inhibitor combination for the treatment of chronic hepatitis C virus (HCV) genotypes 1 and 4 infections. ZEPATIER- elbasvir and grazoprevir tablet, film coated
Merck Sharp & Dohme Corp.
1 INDICATIONS AND USAGE
ZEPATIER� is indicated with or without ribavirin for the treatment of chronic hepatitis C virus (HCV) genotypes 1 or 4 infection in adults.
2 DOSAGE AND ADMINISTRATION
2.1 Testing Prior to the Initiation of Therapy
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 ZEPATIER to determine dosage regimen and duration [see Dosage and Administration (2.2)], Table 1. 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 [see Warnings and Precautions (5.1)].
2.2 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 [see Clinical Pharmacology (12.3)]. 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)].
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.
DESCRIPTION
ZEPATIER is a fixed-dose combination tablet containing elbasvir and grazoprevir for oral administration.
Elbasvir is an HCV NS5A inhibitor, and grazoprevir is an HCV NS3/4A protease inhibitor.
Each tablet contains 50 mg elbasvir and 100 mg grazoprevir. The tablets include the following inactive ingredients: colloidal silicon dioxide, copovidone, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, sodium chloride, sodium lauryl sulfate, and vitamin E polyethylene glycol succinate. The tablets are film-coated with a coating material containing the following inactive ingredients: carnauba wax, ferrosoferric oxide, hypromellose, iron oxide red, iron oxide yellow, lactose monohydrate, titanium dioxide, and triacetin.
Elbasvir:
The IUPAC name for elbasvir is Dimethyl N ,N" -([(6S)-6-phenylindolo[1,2-c ][1,3]benzoxazine-3,10-diyl]bis{1H -imidazole-5,2-diyl-(2S)-pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyl]})dicarbamate.
It has a molecular formula of C49 H55 N9 O7 and a molecular weight of 882.02
Grazoprevir:
The IUPAC name for grazoprevir is (1aR ,5S ,8S ,10R ,22aR)-N -[(1R ,2S)-1-[(Cyclopropylsulfonamido)carbonyl]-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-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b ]quinoxaline-8-carboxamide.
It has a molecular formula of C38 H50 N6 O9 S and a molecular weight of 766.90
Mechanism of Action
ZEPATIER is a fixed-dose combination of elbasvir and grazoprevir which are direct-acting antiviral agents against the hepatitis C virus
Microbiology
Mechanism of Action
ZEPATIER 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.
Antiviral Activity
In HCV replicon assays, the EC50 values of elbasvir against full-length replicons from genotypes 1a, 1b, and 4, were 4 pM, 3 pM, and 0.3 pM, respectively. The median EC50 values of elbasvir against chimeric replicons encoding NS5A sequences from clinical isolates were 5 pM for genotype 1a (range 3-9 pM; N=5), 9 pM for genotype 1b (range 5-10 pM; N=4), 0.2 pM for genotype 4a (range 0.2-0.2 pM; N=2), 3,600 pM for genotype 4b (range 17 pM-34,000 pM; N=3), 0.45 pM for genotype 4d (range 0.4-0.5 pM; N=2), 1.9 pM for genotype 4f (N=1), 36.3 pM for genotype 4g (range 0.6-72 pM; N=2), 0.6 pM for genotype 4m (range 0.4-0.7 pM; N=2), 2.2 pM for genotype 4o (N=1), and 0.5 pM for genotype 4q (N=1).
In HCV replicon assays, the EC50 values of grazoprevir against full-length replicons from genotypes 1a, 1b, and 4, were 0.4 nM, 0.5 nM, and 0.3 nM, respectively. The median EC50 values of grazoprevir against chimeric replicons encoding NS3/4A sequences from clinical isolates were 0.8 nM for genotype 1a (range 0.4-5.1 nM; N=10), 0.3 nM for genotype 1b (range 0.2-5.9 nM; N=9), 0.3 nM for genotype 4a (N=1), 0.16 nM for genotype 4b (range 0.11-0.2 nM; N=2), and 0.24 nM for genotype 4g (range 0.15-0.33 nM; N=2).
Combination Antiviral Activity
Evaluation of elbasvir in combination with grazoprevir or ribavirin showed no antagonistic effect in reducing HCV RNA levels in replicon cells. Evaluation of grazoprevir in combination with ribavirin showed no antagonistic effect in reducing HCV RNA levels in replicon cells.
