Zepatier  is indicated for the treatment of chronic hepatitis C (CHC) in adults. (see sections 4.2, 4.4 and 5.1).

For hepatitis C virus (HCV) genotype-specific activity see sections 4.4 and 5.1.

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 1 below (see sections 4.4

and 5.1):

Table 1 - Recommended Zepatier therapy for Treatment of Chronic Hepatitis C Infection in Patients with or without compensated cirrhosis (Child-Pugh A only)

^A In the clinical studies, the dose of ribavirin was weight-based (< 66 kg = 800 mg/day, 66 to 80 kg = 1,000 mg/day, 81 to 105 kg = 1,200 mg/day, > 105 kg = 1,400 mg/day) administered in two divided doses with food.

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 sections 4.4 and 5.2).

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 section 5.2).

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) (see sections 4.3 and 5.2).

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 section 5.2).

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 section 4.8). 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 sections 4.8 and 5.2). 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).

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 section 5.1).

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 sections 4.3, 4.5 and 5.2).

The concomitant use of ZEPATIER and strong CYP3A inhibitors increases elbasvir and grazoprevir concentrations, and co-administration is not recommended (see section 4.5).

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.

Paediatric population

ZEPATIER is not indicated for use in children under 12 years of age. 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.

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 sections 4.3 and 4.4).

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 sections 4.3 and 4.4).

Co-administration of ZEPATIER with strong CYP3A inhibitors increases elbasvir and grazoprevir plasma concentrations , and co-administration is not recommended (see Table 2 and section 4.4).

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

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 2).

Interactions between ZEPATIER and other medicinal products  

Table 2 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.

Table 2: Interactions and dose recommendations with other medicinal products

Paediatric population

Interaction studies have only been performed in adults.

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 section 5.3).

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 section 4.8).

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 below 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).

Table 3: Adverse reactions identified with ZEPATIER*

*Based on pooled data from patients treated with ZEPATIER for 12 weeks without ribavirin

Description of selected adverse reactions

Laboratory abnormalities

Changes in selected laboratory parameters are described in Table 4.

Table 4: Selected treatment emergent laboratory abnormalities

*Based on pooled data from patients treated with ZEPATIER for 12 weeks without ribavirin

†ULN: Upper limit of normal according to testing laboratory.

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 section 4.4). The frequency of late ALT elevations was higher in subjects with higher grazoprevir plasma concentration (see sections 4.4, 4.5 and 5.2). 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.

Paediatric population

No data are available.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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 via:

• Saudi Arabia:

The National Pharmacovigilance and Drug Safety Centre (NPC), at SFDA

o Fax: +966-11-205-7662

o Call NPC at +966-11-20382222, Exts: 2317-2356-2353-2354-2334-2340.

o Toll free phone: 8002490000

o E-mail: npc.drug@sfda.gov.sa

o Website: www.sfda.gov.sa/npc

• Other GCC States:

Please contact the relevant competent authority.

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.

Hemodialysis does not remove elbasvir or grazoprevir .Elbasvir and grazoprevir are

not expected to be removed by peritoneal dialysis.

Pharmacotherapeutic group: Antivirals for systemic use; Direct-acting antiviral, ATC code: J05AX68

Mechanism of Action

ZEPATIER combines two direct-acting antiviral agents with distinct mechanisms of action and nonoverlapping 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  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 5.

Table 5: Activities of elbasvir and grazoprevir in GT1a, GT1b and GT4 reference sequences and clinical isolates in replicon cells

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/K/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 replicons, 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 6. 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.

Table 6 - Treatment-Emergent Amino Acid Substitutions in the Pooled Analysis of Zepatier with and without Ribavirin Regimens in Phase 2 and Phase 3 Clinical Trials

 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 are susceptible to 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 1binfected 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 1-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 these genotypes 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 7.

Table 7: SVR in GT1a-, GT1b- or treatment-experienced GT4-infected subjects bearing baseline NS5A or NS3 polymorphisms

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 8).

Table 8: Studies conducted with ZEPATIER

GT = Genotype

TN = Treatment-Naïve

TE = Treatment-Experienced (failed prior treatment with interferon [IFN] or peginterferon alfa [peg-IFN] with or without ribavirin (RBV) or were intolerant to prior therapy)

*EBR = elbasvir 50 mg; GZR = grazoprevir 100 mg; EBR/GZR = co-administered as a fixed-dose combination; EBR + GZR = co-administered as separate single agents

†RBV was administered at a total daily dose of 800 mg to 1,400 mg based on weight (see section 4.2)

‡ Failed prior treatment with boceprevir, telaprevir, or simeprevir in combination with peg-IFN + RBV

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/1other-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 9.

Table 9: SVR in genotype 1b†-infected subjects¶

†Includes four subjects infected with genotype 1 subtypes other than 1a or 1b.

¶Includes subjects from C-EDGE TN, C-EDGE COINFECTION, C-EDGE TE, C-WORTHY and C-SURFER.

*Includes subjects with virologic breakthrough.

‡Other includes subjects who discontinued due to adverse event, lost to follow-up, or subject withdrawal.

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 10.

Table 10: SVR in genotype 1a-infected subjects¶

¶Includes subjects from C-EDGE TN, C-EDGE COINFECTION, C-EDGE TE, C-WORTHY and C-SURFER.

*Includes subjects with virologic breakthrough.

‡Other includes subjects who discontinued due to adverse event, lost to follow-up, or subject withdrawal.

†Includes subjects with baseline sequencing data and who either achieved SVR12 or met criteria for virologic failure.

§GT1a NS5A polymorphisms: M28T/A, Q30E/H/R/G/K/D, L31M/V/F, H58D, and Y93C/H/N.

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 11.

Table 11: SVR in genotype 4-infected subjects¶

¶Includes subjects from C-EDGE TN, C-EDGE COINFECTION, C-EDGE TE and C-SCAPE.

*Includes subjects with virologic breakthrough.

†Both relapsers had baseline HCV RNA >800,000 IU/mL

‡Both subjects who failed to achieve SVR for reasons other than virologic failure had baseline HCV RNA

<=800,000 IU/mL.

§Includes 1 subject with cirrhosis status of “unknown” in C-SCAPE.

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 section 4.2 for information on paediatric use).

Absorption

Following administration of elbasvir/grazoprevir to HCV-infected subjects, elbasvir peak plasma concentrations occur at a median Tmax of 3 hours (range of 3 to 6 hours); grazoprevir peak plasma concentrations occur at a median Tmax 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 AUC0-inf and Cmax of approximately 11% and 15%, respectively, and increases in grazoprevir AUC0-inf and Cmax 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 AUC0-24 and Cmax at 50 mg were 2,180 nM•hr and 137 nM, respectively, and the geometric mean steady-state grazoprevir AUC0-24 and Cmax 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 a1-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 and 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 feces with almost all

(>90%) of radiolabeled dose recovered in feces 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 AUC0-inf was decreased by 40% and grazoprevir steady-state AUC0-24 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 AUC0-24 was increased 5-fold and 12-fold respectively, compared to matched healthy subjects (see sections 4.2 and 4.3).

Population PK analyses of HCV-infected patients in Phase 2 and 3 studies demonstrated that grazoprevir steady-state AUC0-24 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 section 4.2).

Paediatric population

The pharmacokinetics of elbasvir/grazoprevir in paediatric patients less than 18 years of age have not been established (see section 4.2).

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 sections 4.2 and 4.4).

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 section 4.4).

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 section 4.4).

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 section 4.4).

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.

Embryo fetal and post natal development

Elbasvir

Elbasvir was given to rats and rabbits without eliciting adverse effects on embryofetal or post natal 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 post natal 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.

Tablet core

colloidal silicon dioxide, copovidone, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, sodium chloride, sodium lauryl sulfate, vitamin E polyethylene glycol succinate.

Film-coating

carnauba wax, ferrosoferric oxide, hypromellose, iron oxide red, iron oxide yellow, lactose monohydrate, titanium dioxide and triacetin

Not applicable.

·         Keep Zepatier in its original blister pack until you are ready to take it. Do not take the pills out of the original blister pack to store in another container such as a pill box. This is important because the pills are sensitive to moisture. The pack is designed to protect them.

·         Store Zepatier below 30°C. Protect from moisture

The tablets are packaged into a carton containing two (2) cardboard cards, each cardboard card containing (2) 7-count aluminium blisters sealed in a cardboard card for a total of 28 tablets.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.