Zepatier

Elbasvir, grazoprevir.

Each film-coated tablet contains 50 mg elbasvir and 100 mg grazoprevir.
Excipients with known effect: Each film-coated tablet contains 87.02 mg of lactose (as monohydrate) and 69.85 mg of sodium.
Excipients/Inactive Ingredients: Tablet core: Sodium laurilsulfate, Vitamin E polyethylene glycol succinate, Copovidone, Hypromellose, Microcrystalline cellulose, Mannitol (E421), Lactose monohydrate, Croscarmellose sodium, Sodium chloride, Colloidal anhydrous silica, Magnesium stearate.
Film-coating: Lactose monohydrate, Hypromellose, Titanium dioxide, Triacetin, Iron oxide yellow (E172), Iron oxide red (E172), Iron oxide black (E172), Carnauba wax.

Pharmacotherapeutic group: Antivirals for systemic use, Direct-acting antiviral, Antivirals for treatment of HCV infections. ATC code: J05AP54.
Pharmacology: Pharmacodynamics: 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.
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 NS3/4A protease enzymes from HCV genotypes 1a, 1b, 3 and 4a with IC₅₀ values ranging from 4 to 690 pM.
Antiviral activity: The EC₅₀ values of elbasvir and grazoprevir against full-length or chimeric replicons encoding NS5A or NS3 sequences from reference sequences and clinical isolates are presented in Table 1. (See Table 1.)

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Resistance: In cell culture: HCV replicons with reduced susceptibility to elbasvir and grazoprevir have been selected in cell culture for genotypes 1a, 1b and 4.
For elbasvir, in HCV genotype 1a replicons, single NS5A substitutions Q30D/E/H/R, L31M/V and Y93C/H/N reduced elbasvir antiviral activity by 6- to 2,000-fold. In genotype 1b replicons, single NS5A substitutions L31F and Y93H reduced elbasvir antiviral activity by 17-fold. In genotype 4 replicons, single NS5A substitutions L30S, M31V, and Y93H reduced elbasvir antiviral activity by 3- to 23-fold. In general, in HCV genotype 1a, 1b or 4 combinations of elbasvir resistance-associated substitutions further reduced elbasvir antiviral activity.
For grazoprevir, in HCV genotype 1a replicons, single NS3 substitutions D168A/E/G/S/V reduced grazoprevir antiviral activity by 2- to 81-fold. In genotype 1b replicons, single NS3 substitutions F43S, A156S/T/V, and D168A/G/V reduced grazoprevir antiviral activity by 3- to 375-fold. In genotype 4 replicons, single NS3 substitutions D168A/V reduced grazoprevir antiviral activity by 110- to 320-fold. In general, in HCV genotype 1a, 1b or 4 replicons, combinations of grazoprevir resistance-associated substitutions further reduced grazoprevir antiviral activity.
In clinical studies: In a pooled analysis of subjects treated with regimens containing elbasvir/grazoprevir or elbasvir + grazoprevir with or without ribavirin in Phase 2 and 3 clinical studies, resistance analyses were conducted for 50 subjects who experienced virologic failure and had sequence data available (6 with on-treatment virologic failure, 44 with post-treatment relapse).
Treatment-emergent substitutions observed in the viral populations of these subjects based on genotypes are shown in Table 2. Treatment-emergent substitutions were detected in both HCV drug targets in 23/37 (62%) genotype 1a, 1/8 (13%) genotype 1b and 2/5 (40%) genotype 4 subjects. (See Table 2.)

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Cross-resistance: Elbasvir is active in vitro against genotype 1a NS5A substitutions, M28V and Q30L, genotype 1b substitutions, L28M/V, R30Q, L31V, Y93C, and genotype 4 substitution, M31V, which confer resistance to other NS5A inhibitors. In general, other NS5A substitutions conferring resistance to NS5A inhibitors may also confer resistance to elbasvir. NS5A substitutions conferring resistance to elbasvir may reduce the antiviral activity of other NS5A inhibitors.
Grazoprevir is active in vitro against the following genotype 1a NS3 substitutions which confer resistance to other NS3/4A protease inhibitors: V36A/L/M, Q41R, F43L, T54A/S, V55A/I, Y56F, Q80K/R, V107I, S122A/G/R/T, I132V, R155K, A156S, D168N/S, I170T/V. Grazoprevir is active in vitro against the following genotype 1b NS3 substitutions conferring resistance to other NS3/4A protease inhibitors: V36A/I/L/M, Q41L/R, F43S, T54A/C/G/S, V55A/I, Y56F, Q80L/R, V107I, S122A/G/R, R155E/K/N/Q/S, A156G/S, D168E/N/S, V170A/I/T. Some NS3 substitutions at A156 and at D168 confer reduced antiviral activity to grazoprevir as well as to other NS3/4A protease inhibitors.
The substitutions associated with resistance to NS5B inhibitors do not affect the activity of elbasvir or grazoprevir.
Persistence of resistance-associated substitutions: The persistence of elbasvir and grazoprevir treatment-emergent amino acid substitutions in NS5A, and NS3, respectively, was assessed in genotype 1-infected subjects in Phase 2 and 3 studies whose virus had treatment-emergent resistance-associated substitution in the drug target, and with available data through at least 24 weeks post-treatment using population (or Sanger) sequencing.
Viral populations with treatment-emergent NS5A resistance-associated substitutions were generally more persistent than NS3 resistance-associated substitutions. Among genotype 1a-infected subjects, NS5A resistance-associated substitutions persisted at detectable levels at follow-up week 12 in 95% (35/37) of subjects and in 100% (9/9) of subjects with follow-up week 24 data. Among genotype 1b-infected subjects, NS5A resistance-associated substitutions persisted at detectable levels in 100% (7/7) of subjects at follow-up week 12 and in 100% (3/3) of subjects with follow-up week 24 data.
Among genotype 1a-infected subjects, NS3 resistance-associated substitutions persisted at detectable levels at follow-up week 24 in 31% (4/13) of subjects. Among genotype 1b-infected subjects, NS3 resistance-associated substitutions persisted at detectable levels at follow-up week 24 in 50% (1/2) of subjects.
Due to the limited number of genotype 4-infected subjects with treatment-emergent NS5A and NS3 resistance-associated substitutions, trends in persistence of treatment-emergent substitutions in this genotype could not be established.
The long-term clinical impact of the emergence or persistence of virus containing ZEPATIER resistance-associated substitutions is unknown.
Effect of baseline HCV polymorphisms on treatment response: In pooled analyses of subjects who achieved SVR12 or met criteria for virologic failure, the prevalence and impact of NS5A polymorphisms (including M28T/A, Q30E/H/R/G/K/D, L31M/V/F, H58D, and Y93C/H/N) and NS3 polymorphisms (substitutions at positions 36, 54, 55, 56, 80, 107, 122, 132, 155, 156, 158, 168, 170, and 175) that confer greater than 5-fold reduction of elbasvir and grazoprevir antiviral activity respectively in vitro were evaluated. The observed treatment response differences by treatment regimen in specific patient populations in the presence or absence of baseline NS5A or NS3 polymorphisms are summarised in Table 3. (See Table 3.)

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Clinical efficacy and safety: The safety and efficacy of elbasvir/grazoprevir (co-administered as a fixed-dose combination; EBR/GZR) or elbasvir + grazoprevir (co-administered as single agents; EBR + GZR) were evaluated in 8 clinical studies in approximately 2,000 subjects (see Table 4).

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Sustained virologic response (SVR) was the primary endpoint in all studies and was defined as HCV RNA less than the lower limit of quantification (LLOQ: 15 HCV RNA IU/mL except in C-WORTHY and C-SCAPE [25 HCV RNA IU/mL]) at 12 weeks after the cessation of treatment (SVR12).
Among genotype 1b/1 other-infected subjects, the median age was 55 years (range: 22 to 82); 61% were male; 60% were White; 20% were Black or African American; 6% were Hispanic or Latino; 82% were treatment-naïve subjects; 18% were treatment-experienced subjects; mean body mass index was 26 kg/m²; 64% had baseline HCV RNA levels greater than 800,000 IU/mL; 22% had cirrhosis; 71% had non-C/C IL28B alleles (CT or TT); 18% had HCV/HIV-1 co-infection.
Treatment outcomes in genotype 1b-infected subjects treated with elbasvir/grazoprevir for 12 weeks are presented in Table 5. (See Table 5.)

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Among genotype 1a-infected subjects, the median age was 54 years (range: 19 to 76); 71% were male; 71% were White; 22% were Black or African American; 9% were Hispanic or Latino; 74% were treatment-naïve subjects; 26% were treatment-experienced subjects; mean body mass index was 27 kg/m²; 75% had baseline HCV RNA levels greater than 800,000 IU/mL; 23% had cirrhosis; 72% had non-C/C IL28B alleles (CT or TT); 30% had HCV/HIV-1 co-infection.
Treatment outcomes in genotype 1a-infected subjects treated with elbasvir/grazoprevir for 12 weeks or elbasvir/grazoprevir with ribavirin for 16 weeks are presented in Table 6. (See Table 6.)

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Among genotype 4-infected subjects, the median age was 51 years (range: 28 to 75); 66% were male; 88% were White; 8% were Black or African American; 11% were Hispanic or Latino; 77% were treatment-naïve subjects; 23% were treatment-experienced subjects; mean body mass index was 25 kg/m²; 56% had baseline HCV RNA levels greater than 800,000 IU/mL; 22% had cirrhosis; 73% had non-C/C IL28B alleles (CT or TT); 40% had HCV/HIV-1 co-infection.
Treatment outcomes in genotype 4-infected subjects treated with elbasvir/grazoprevir for 12 weeks or elbasvir/grazoprevir with ribavirin for 16 weeks are presented in Table 7. (See Table 7.)

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Clinical study in subjects with advanced chronic kidney disease with genotype 1 CHC infection: In the C-SURFER study, overall SVR was achieved in 94% (115/122) of subjects receiving EBR + GZR for 12 weeks.
Paediatric population: The European Medicines Agency has deferred the obligation to submit the results of studies with ZEPATIER in one or more subsets of the paediatric populations in the treatment of chronic hepatitis C (see Dosage & Administration for information on paediatric use).
Pharmacokinetics: Absorption: Following administration of elbasvir/grazoprevir to HCV-infected subjects, elbasvir peak plasma concentrations occur at a median T_max of 3 hours (range of 3 to 6 hours); grazoprevir peak plasma concentrations occur at a median T_max of 2 hours (range of 30 minutes to 3 hours). For elbasvir, the absolute bioavailability is estimated to be 32%. For grazoprevir, the absolute bioavailability after a 200 mg single dose ranged from 15 - 27% and after multiple 200 mg doses ranged from 20 - 40%.
Relative to fasting conditions, the administration of a single dose of elbasvir/grazoprevir with a high-fat (900 kcal, 500 kcal from fat) meal to healthy subjects resulted in decreases in elbasvir AUC_0-inf and C_max of approximately 11% and 15%, respectively, and increases in grazoprevir AUC_0-inf and C_max of approximately 1.5-fold and 2.8-fold, respectively. These differences in elbasvir and grazoprevir exposure are not clinically relevant; therefore, elbasvir/grazoprevir may be taken without regard to food.
Elbasvir pharmacokinetics are similar in healthy subjects and HCV-infected subjects. Grazoprevir oral exposures are approximately 2-fold greater in HCV-infected subjects as compared to healthy subjects.
Based on the population pharmacokinetic modeling in non-cirrhotic, HCV-infected subjects, the geometric mean steady-state elbasvir AUC_0-24 and C_max at 50 mg were 2,180 nM·hr and 137 nM, respectively, and the geometric mean steady-state grazoprevir AUC_0-24 and C_max at 100 mg were 1,860 nM·hr and 220 nM, respectively. Following once daily administration of elbasvir/grazoprevir to HCV-infected subjects, elbasvir and grazoprevir reached steady state within approximately 6 days.
Distribution: Elbasvir and grazoprevir are extensively bound (>99.9% and 98.8%, respectively) to human plasma proteins. Both elbasvir and grazoprevir bind to human serum albumin and α1-acid glycoprotein. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment.
Elimination: The geometric mean apparent terminal half-life (% geometric mean coefficient of variation) is approximately 24 (24%) hours at 50 mg elbasvir and approximately 31 (34%) hours at 100 mg grazoprevir 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 faeces with almost all (>90%) of the radiolabeled dose recovered in faeces compared to <1% in urine.
Linearity/non-linearity: Elbasvir pharmacokinetics were approximately dose-proportional over the range of 5-100 mg once daily. Grazoprevir pharmacokinetics increased in a greater than dose-proportional manner over the range of 10-800 mg once daily in HCV-infected subjects.
Pharmacokinetics in special populations: Renal impairment: In non-HCV-infected subjects with severe renal impairment (eGFR <30 mL/min/1.73 m²) who were not on dialysis, elbasvir and grazoprevir AUC values were increased by 86% and 65%, respectively, compared to non-HCV-infected subjects with normal renal function (eGFR >80 mL/min/1.73 m²). In non-HCV-infected subjects with dialysis-dependent, severe renal impairment, elbasvir and grazoprevir AUC values were unchanged compared to subjects with normal renal function. Concentrations of elbasvir were not quantifiable in the dialysate samples. Less than 0.5% of grazoprevir was recovered in dialysate over a 4-hour dialysis session.
In population pharmacokinetic analysis in HCV-infected patients, elbasvir and grazoprevir AUCs were 25% and 10% higher, respectively, in dialysis-dependent patients and 46% and 40% higher, respectively, in non-dialysis-dependent patients with severe renal impairment compared to elbasvir and grazoprevir AUC in patients without severe renal impairment.
Hepatic impairment: In non-HCV-infected subjects with mild hepatic impairment (Child-Pugh A [CP-A], score of 5-6), elbasvir AUC_0-inf was decreased by 40% and grazoprevir steady-state AUC_0-24 was increased 70% compared to matched healthy subjects.
In non-HCV-infected subjects with moderate hepatic impairment (Child-Pugh B [CP-B], score of 7-9), and severe hepatic impairment (Child-Pugh C [CP-C], score of 10-15) elbasvir AUC decreased by 28% and 12%, respectively, while the grazoprevir steady-state AUC_0-24 was increased 5-fold and 12-fold respectively, compared to matched healthy subjects (see Dosage & Administration and Contraindications).
Population PK analyses of HCV-infected patients in Phase 2 and 3 studies demonstrated that grazoprevir steady-state AUC_0-24 increased by approximately 65% in HCV-infected patients with compensated cirrhosis (all with CP-A) compared to HCV-infected non-cirrhotic patients, while elbasvir steady-state AUC was similar (see Dosage & Administration).
Paediatric population: The pharmacokinetics of elbasvir/grazoprevir in paediatric patients less than 18 years of age have not been established (see Dosage & Administration).
Elderly: In population pharmacokinetic analyses, elbasvir and grazoprevir AUCs are estimated to be 16% and 45% higher, respectively, in subjects ≥65 years of age compared to subjects less than 65 years of age. These changes are not clinically relevant; therefore, no dose adjustment of elbasvir/grazoprevir is recommended based on age (see Dosage & Administration and Precautions).
Gender: In population pharmacokinetic analyses, elbasvir and grazoprevir AUCs are estimated to be 50% and 30% higher, respectively, in females compared to males. These changes are not clinically relevant; therefore, no dose adjustment of elbasvir/grazoprevir is recommended based on sex (see Precautions).
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. Therefore, no dose adjustment of elbasvir/grazoprevir is recommended based on weight/BMI (see Precautions).
Race/Ethnicity: In population pharmacokinetic analyses, elbasvir and grazoprevir AUCs are estimated to be 15% and 50% higher, respectively, for Asians compared to Whites. Population pharmacokinetics estimates of exposure of elbasvir and grazoprevir were comparable between Whites and Black/African Americans. These changes are not clinically relevant; therefore, no dose adjustment of elbasvir/grazoprevir is recommended based on race/ethnicity (see Precautions).
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and toxicity to reproduction and development with grazoprevir or elbasvir. Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. Carcinogenicity studies for grazoprevir and elbasvir have not been conducted.
Embryofetal and postnatal development: Elbasvir: Elbasvir was given to rats and rabbits without eliciting adverse effects on embryofetal or postnatal development at up to the highest doses tested (approximately 9- and 17-fold above human exposure in rats and rabbits, respectively). Elbasvir has been shown to cross the placenta in rats and rabbits. Elbasvir was excreted into the milk of lactating rats with concentrations 4-fold that of the maternal plasma concentrations.
Grazoprevir: Grazoprevir was given to rats and rabbits without eliciting adverse effects on embryofetal or postnatal development at up to highest doses tested (approximately 79- and 39-fold above human exposure in rats and rabbits, respectively). Grazoprevir has been shown to cross the placenta in rats and rabbits. Grazoprevir was excreted into the milk of lactating rats with concentrations <1-fold of the maternal plasma concentrations.

ZEPATIER is indicated for the treatment of chronic hepatitis C (CHC) in adults (see Dosage & Administration, Precautions and Pharmacology: Pharmacodynamics under Actions).
For hepatitis C virus (HCV) genotype-specific activity, see Precautions and Pharmacology: Pharmacodynamics under Actions.

ZEPATIER treatment should be initiated and monitored by a physician experienced in the management of patients with CHC.
Posology: The recommended dose is one tablet once daily.
Recommended regimens and treatment durations are provided in Table 8 as follows (see Precautions and Pharmacology: Pharmacodynamics under Actions): See Table 8.

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For specific dosage instructions for ribavirin, including dose modification, refer to the ribavirin Summary of Product Characteristics.
Patients should be instructed that if vomiting occurs within 4 hours of dosing, an additional tablet can be taken up to 8 hours before the next dose. If vomiting occurs more than 4 hours after dosing, no further dose is needed.
In case a dose of ZEPATIER is missed and it is within 16 hours of the time ZEPATIER is usually taken, the patient should be instructed to take ZEPATIER as soon as possible and then take the next dose of ZEPATIER at the usual time. If more than 16 hours have passed since ZEPATIER is usually taken, then the patient should be instructed that the missed dose should NOT be taken and to take the next dose per the usual dosing schedule. Patients should be instructed not to take a double dose.
Elderly: No dose adjustment of ZEPATIER is required for elderly patients (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Renal impairment and end stage renal disease (ESRD): No dose adjustment of ZEPATIER is required in patients with mild, moderate, or severe renal impairment (including patients receiving haemodialysis or peritoneal dialysis) (see Pharmacology: Pharmacokinetics under Actions).
Hepatic impairment: No dose adjustment of ZEPATIER is required 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) or those with any history of prior hepatic decompensation (see Contraindications, Precautions and Pharmacology: Pharmacokinetics under Actions).
The safety and efficacy of ZEPATIER have not been established in liver transplant recipients.
Paediatric population: The safety and efficacy of ZEPATIER in children and adolescents aged less than 18 years have not been established. No data are available.
Method of administration: For oral use.
The film-coated tablets should be swallowed whole and may be taken with or without food (see Pharmacology: Pharmacokinetics under Actions).

Human experience of overdose with ZEPATIER is limited. The highest dose of elbasvir was 200 mg once daily for 10 days, and a single dose of 800 mg. The highest dose of grazoprevir was 1,000 mg once daily for 10 days, and a single dose of 1,600 mg. In these healthy volunteer studies, adverse reactions were similar in frequency and severity to those reported in the placebo groups.
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.
Haemodialysis does not remove elbasvir or grazoprevir. Elbasvir and grazoprevir are not expected to be removed by peritoneal dialysis.

Hypersensitivity to the active substances or to any of the excipients listed in Description.
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 (see Dosage & Administration, Precautions and Pharmacology: Pharmacokinetics under Actions).
Co-administration with inhibitors of organic anion transporting polypeptide 1B (OATP1B), such as rifampicin, atazanavir, darunavir, lopinavir, saquinavir, tipranavir, cobicistat or ciclosporin. See Precautions and Interactions.
Co-administration with inducers of cytochrome P450 3A (CYP3A) or P-glycoprotein (P-gp), such as efavirenz, phenytoin, carbamazepine, bosentan, etravirine, modafinil or St. John's wort (Hypericum perforatum). See Precautions and Interactions.

ALT elevations: The rate of late ALT elevations during treatment is directly related to the plasma exposure to grazoprevir. During clinical studies 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) (see Adverse Reactions). Higher rates of late ALT elevations occurred in females (2% [11/652]), Asians (2% [4/165]), and subjects aged ≥65 years (2% [3/187]) (see Adverse Reactions and Pharmacology: Pharmacokinetics under Actions). These late ALT elevations generally occurred at or after treatment week 8.
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 discoloured faeces.
Discontinuation of ZEPATIER should be considered if ALT levels are confirmed to be greater than 10 times the ULN.
ZEPATIER should be discontinued if ALT elevation is accompanied by signs or symptoms of liver inflammation or increasing conjugated bilirubin, alkaline phosphatase, or international normalised ratio (INR).
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.
Hepatic laboratory testing should be performed in all patients. 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.
ZEPATIER is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B or C) or those with any history of prior hepatic decompensation (see Contraindications, Adverse Reactions and Pharmacology: Pharmacokinetics under Actions).
Genotype-specific activity: The efficacy of ZEPATIER has not been demonstrated in HCV genotypes 2, 3, 5 and 6. ZEPATIER is not recommended in patients infected with these genotypes.
Retreatment: The efficacy of ZEPATIER in patients previously exposed to ZEPATIER, or to medicinal products of the same classes as those of ZEPATIER (NS5A inhibitors or NS3/4A inhibitors other than telaprevir, simeprevir, boceprevir), has not been demonstrated (see Pharmacology: Pharmacodynamics under Actions).
Interactions with medicinal products: Co-administration of ZEPATIER and OATP1B inhibitors is contraindicated because it may significantly increase grazoprevir plasma concentrations.
Co-administration of ZEPATIER and CYP3A or P-gp inducers is contraindicated because it may significantly decrease elbasvir and grazoprevir plasma concentrations and may lead to a reduced therapeutic effect of ZEPATIER (see Contraindications, Interactions and Pharmacology: Pharmacokinetics under Actions).
The concomitant use of ZEPATIER and strong CYP3A inhibitors increases elbasvir and grazoprevir concentrations, and co-administration is not recommended (see Interactions).
HCV/HBV (hepatitis B virus) co-infection: Cases of hepatitis B virus (HBV) reactivation, some of them fatal, have been reported during or after treatment with direct-acting antiviral agents. HBV screening should be performed in all patients before initiation of treatment. HBV/HCV co-infected patients are at risk of HBV reactivation, and should therefore be monitored and managed according to current clinical guidelines.
Use in diabetic patients: Diabetics may experience improved glucose control potentially resulting in symptomatic hypoglycaemia, after initiating HCV direct-acting antiviral (DAA) treatment. Glucose levels of diabetic patients initiating DAA therapy should be closely monitored, particularly within the first 3 months, and their diabetic medication modified when necessary. The physician in charge of the diabetic care of the patient should be informed when DAA therapy is initiated.
Excipients: ZEPATIER contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.
ZEPATIER contains 69.85 mg sodium per tablet, equivalent to 3.5% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Effects on ability to drive and use machines: ZEPATIER (administered alone or in combination with ribavirin) is not likely to have an effect on the ability to drive and use machines. Patients should be informed that fatigue has been reported during treatment with ZEPATIER (see Adverse Reactions).
Use in Children: ZEPATIER is not recommended for use in children and adolescents under 18 years of age because the safety and efficacy have not been established in this population.

If ZEPATIER is co-administered with ribavirin, the information for ribavirin with regard to contraception, pregnancy testing, pregnancy, breast-feeding, and fertility also applies to this combination regimen (refer to the Summary of Product Characteristics for the co-administered medicinal product for additional information).
Women of childbearing potential / contraception in males and females: When ZEPATIER is used in combination with ribavirin, women of childbearing potential or their male partners must use an effective form of contraception during treatment and for a period of time after the treatment has concluded.
Pregnancy: There are no adequate and well-controlled studies with ZEPATIER in pregnant women. Animal studies do not indicate harmful effects with respect to reproductive toxicity. Because reproduction animal studies are not always predictive of human response, ZEPATIER should be used only if the potential benefit justifies the potential risk to the fetus.
Breast-feeding: It is unknown whether elbasvir or grazoprevir and their metabolites are excreted in human milk. Available pharmacokinetic data in animals has shown excretion of elbasvir and grazoprevir in milk. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from ZEPATIER therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility: No human data on the effect of elbasvir and grazoprevir on fertility are available. Animal studies do not indicate harmful effects of elbasvir or grazoprevir on fertility at elbasvir and grazoprevir exposures higher than the exposure in humans at the recommended clinical dose (see Pharmacology: Toxicology: Preclinical safety data under Actions).

Summary of the safety profile: The safety of ZEPATIER was assessed based on 3 placebo-controlled studies and 7 uncontrolled Phase 2 and 3 clinical studies in approximately 2,000 subjects with chronic hepatitis C infection with compensated liver disease (with or without cirrhosis).
In clinical studies, the most commonly reported adverse reactions (greater than 10%) were fatigue and headache. Less than 1% of subjects treated with ZEPATIER with or without ribavirin had serious adverse reactions (abdominal pain, transient ischaemic attack and anaemia). Less than 1% of subjects treated with ZEPATIER with or without ribavirin permanently discontinued treatment due to adverse reactions. The frequency of serious adverse reactions and discontinuations due to adverse reactions in subjects with compensated cirrhosis were comparable to those seen in subjects without cirrhosis.
When elbasvir/grazoprevir was studied with ribavirin, the most frequent adverse reactions to elbasvir/grazoprevir + ribavirin combination therapy were consistent with the known safety profile of ribavirin.
Tabulated summary of adverse reactions: The following adverse reactions were identified in patients taking ZEPATIER without ribavirin for 12 weeks. The adverse reactions are listed as follows by body system organ class and frequency. Frequencies are defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) or very rare (<1/10,000). (See Table 9.)

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Description of selected adverse reactions: Laboratory abnormalities: Changes in selected laboratory parameters are described in Table 10. (See Table 10.)

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Serum Late ALT elevations: During clinical studies with ZEPATIER with or without ribavirin, regardless of treatment duration, <1% (13/1,690) 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 ZEPATIER or after completion of therapy (see Precautions). The frequency of late ALT elevations was higher in subjects with higher grazoprevir plasma concentration (see Precautions, Interactions and Pharmacology: Pharmacokinetics under Actions). The incidence of late ALT elevations was not affected by treatment duration. Cirrhosis was not a risk factor for late ALT elevations. Less than 1% of subjects treated with ZEPATIER with or without ribavirin experienced ALT elevations >2.5 - 5 times the ULN during treatment; there were no treatment discontinuations due to these ALT elevations.
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.
Hepatobiliary Disorders: Hepatic decompensation, hepatic failure (see Precautions).
Paediatric population: No data are available.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.

Potential for other medicinal products to affect ZEPATIER: Grazoprevir is a substrate of OATP1B drug transporters. Co-administration of ZEPATIER with medicinal products that inhibit OATP1B transporters is contraindicated because it may result in a significant increase in the plasma concentration of grazoprevir (see Contraindications and Precautions).
Elbasvir and grazoprevir are substrates of CYP3A and P-gp. Co-administration of inducers of CYP3A or P-gp with ZEPATIER is contraindicated because it may decrease elbasvir and grazoprevir plasma concentrations, which may lead to reduced therapeutic effect of ZEPATIER (see Contraindications and Precautions).
Co-administration of ZEPATIER with strong CYP3A inhibitors increases elbasvir and grazoprevir plasma concentrations, and co-administration is not recommended (see Table 11 and Precautions). Co-administration of ZEPATIER with P-gp inhibitors is expected to have a minimal effect on the plasma concentrations of ZEPATIER.
The potential for grazoprevir to be a breast cancer resistance protein (BCRP) substrate cannot be excluded.
Potential for ZEPATIER to affect other medicinal products: Elbasvir and grazoprevir are inhibitors of the drug transporter BCRP at the intestinal level in humans and may increase plasma concentrations of co-administered BCRP substrates. Elbasvir is not a CYP3A inhibitor in vitro and grazoprevir is a weak CYP3A inhibitor in humans. Co-administration with grazoprevir did not result in clinically relevant increases in exposures of CYP3A substrates. Therefore, no dose adjustment is required for CYP3A substrates when co-administered with ZEPATIER.
Elbasvir has minimal intestinal P-gp inhibition in humans, and does not result in clinically relevant increases in concentrations of digoxin (a P-gp substrate), with an 11% increase in plasma AUC. Grazoprevir is not a P-gp inhibitor based on in vitro data. Elbasvir and grazoprevir are not OATP1B inhibitors in humans. Based on in vitro data, clinically significant interactions with ZEPATIER as an inhibitor of other CYP enzymes, UGT1A1, esterases (CES1, CES2, and CatA), OAT1, OAT3, and OCT2 are not expected. Based on in vitro data, a potential for GZR to inhibit BSEP cannot be excluded. Multiple-dose administration of elbasvir or grazoprevir is unlikely to induce the metabolism of medicinal products metabolised by CYP isoforms based on in vitro data.
Patients treated with vitamin K antagonists: As liver function may change during treatment with ZEPATIER, a close monitoring of International Normalised Ratio (INR) values is recommended.
Impact of DAA therapy on drugs metabolized by the liver: 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 (see Precautions and as follows).
Grazoprevir's weak inhibition of CYP3A may increase levels of CYP3A substrates. In addition, the plasma concentrations of drugs that are CYP3A substrates may be decreased by improvement in liver function during DAA therapy, related to clearance of HCV. Therefore, close monitoring and potential dose adjustment of CYP3A substrates with a narrow therapeutic index (e.g., calcineurin inhibitors) may be required during therapy, as drug levels may change (see Table 11).
Interactions between ZEPATIER and other medicinal products: Table 11 provides a listing of assessed or potential medicinal product interactions. An up "↑" or down "↓" arrow represents a change in exposure that requires monitoring or a dose adjustment of that medication, or the co-administration is not recommended or contraindicated. No clinically relevant change in exposure is represented by a horizontal arrow "↔".
The medicinal product interactions described are based on results from studies conducted with either ZEPATIER or elbasvir (EBR) and grazoprevir (GZR) as individual agents, or are predicted medicinal product interactions that may occur with elbasvir or grazoprevir. The table is not all-inclusive. (See Tables 11a, 11b, 11c, 11d, 11e and 11f.)

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Paediatric population: Interaction studies have only been performed in adults.

Special precautions for disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Store below 30°C.
Store in the original package until use to protect from moisture.

Antivirals

J05AP54 - elbasvir and grazoprevir ; Belongs to the class of antivirals for treatment of HCV infections. Used in the treatment of hepatitis C viral infections.

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