ZEPATIER 50mg / 100mg film-coated tablets medication leaflet

ZEPATIER 50 mg/100 mg film-coated tablets

Each film-coated tablet contains 50 mg elbasvir and 100 mg grazoprevir.

Each film-coated tablet contains 87.02 mg of lactose (as monohydrate) and 69.85 mg of sodium.

For the full list of excipients, see section 6.1.

Film-coated tablet.

Beige, oval tablet of dimensions 21 mm x 10 mm debossed with “770” on one side and plain on theother.

ZEPATIER is indicated for the treatment of chronic hepatitis C (CHC) in adult and paediatric patients12 years of age and older who weigh at least 30 kg (see sections 4.2, pct. 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 themanagement of patients with CHC.

The recommended dose is one tablet once daily.

Recommended regimens and treatment durations are provided in Table 1 below (see sections 4.4and 5.1):

Table 1: Recommended ZEPATIER therapy for treatment of chronic hepatitis C infection inpatients with or without compensated cirrhosis (Child-Pugh A only)

HCV genotype Treatment and duration1a ZEPATIER for 12 weeks

ZEPATIER for 16 weeks plus ribavirinA should be considered inpatients with baseline HCV RNA level >800,000 IU/mL and/or thepresence of specific NS5A polymorphisms causing at least a 5-foldreduction in activity of elbasvir to minimise the risk of treatment failure(see section 5.1).

1b ZEPATIER for 12 weeks4 ZEPATIER for 12 weeks

ZEPATIER for 16 weeks plus ribavirinA should be considered inpatients with baseline HCV RNA level >800,000 IU/mL to minimisethe risk of treatment failure (see section 5.1).

A In the adult clinical studies, the dose of ribavirin was weight-based (< 66 kg = 800 mg/day, 66 to80 kg = 1,000 mg/day, 81 to 105 kg = 1,200 mg/day, > 105 kg = 1,400 mg/day) administered in twodivided 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 canbe taken up to 8 hours before the next dose. If vomiting occurs more than 4 hours after dosing, nofurther dose is needed.

In case a dose of ZEPATIER is missed and it is within 16 hours of the time ZEPATIER is usuallytaken, the patient should be instructed to take ZEPATIER as soon as possible and then take the nextdose of ZEPATIER at the usual time. If more than 16 hours have passed since ZEPATIER is usuallytaken, then the patient should be instructed that the missed dose should NOT be taken and to take thenext dose per the usual dosing schedule. Patients should be instructed not to take a double dose.

No dose adjustment of ZEPATIER is required for elderly patients (see sections 4.4 and 5.2).

No dose adjustment of ZEPATIER is required in patients with mild, moderate, or severe renalimpairment (including patients receiving haemodialysis or peritoneal dialysis) (see section 5.2).

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.

No dosage adjustment of ZEPATIER is required in paediatric patients 12 years of age and older whoweigh at least 30 kg (see sections 5.1 and 5.2).

The safety and efficacy of ZEPATIER in children aged less than 12 years have not been established.

For oral use.

The film-coated tablets should be swallowed whole and may be taken with or without food (seesection 5.2).

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Patients with moderate or severe hepatic impairment (Child-Pugh B or C) (see sections 4.2 and 5.2).

Co-administration with inhibitors of organic anion transporting polypeptide 1B (OATP1B), such asrifampicin, atazanavir, darunavir, lopinavir, saquinavir, tipranavir, cobicistat or ciclosporin (seesections 4.4 and 4.5).

Co-administration with inducers of cytochrome P450 3A (CYP3A) or P-glycoprotein (P-gp), such asefavirenz, phenytoin, carbamazepine, bosentan, etravirine, modafinil or St. John’s wort (Hypericumperforatum) (see sections 4.4 and 4.5).

The rate of late ALT elevations during treatment is directly related to the plasma exposure tograzoprevir. During clinical studies with ZEPATIER with or without ribavirin, < 1 % of subjectsexperienced 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 clinicallyindicated. For patients receiving 16 weeks of therapy, additional hepatic laboratory testing should beperformed at treatment week 12.

* Patients should be instructed to consult their healthcare professional without delay if they haveonset of fatigue, weakness, lack of appetite, nausea and vomiting, jaundice or discolouredfaeces.

* Discontinuation of ZEPATIER should be considered if ALT levels are confirmed to be greaterthan 10 times the ULN.

* ZEPATIER should be discontinued if ALT elevation is accompanied by signs or symptoms ofliver inflammation or increasing conjugated bilirubin, alkaline phosphatase, or internationalnormalised ratio (INR).

The efficacy of ZEPATIER has not been demonstrated in HCV genotypes 2, 3, 5 and 6. ZEPATIER isnot recommended in patients infected with these genotypes.

The efficacy of ZEPATIER in patients previously exposed to ZEPATIER, or to medicinal products ofthe 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).

Co-administration of ZEPATIER and OATP1B inhibitors is contraindicated because it maysignificantly increase grazoprevir plasma concentrations.

Co-administration of ZEPATIER and CYP3A or P-gp inducers is contraindicated because it maysignificantly decrease elbasvir and grazoprevir plasma concentrations and may lead to a reducedtherapeutic effect of ZEPATIER (see sections pct. 4.3, 4.5 and 5.2).

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

Cases of hepatitis B virus (HBV) reactivation, some of them fatal, have been reported during or aftertreatment with direct-acting antiviral agents. HBV screening should be performed in all patients beforeinitiation of treatment. HBV/HCV co-infected patients are at risk of HBV reactivation, and shouldtherefore be monitored and managed according to current clinical guidelines.

Diabetics may experience improved glucose control potentially resulting in symptomatichypoglycaemia, after initiating HCV direct acting antiviral (DAA) treatment. Glucose levels ofdiabetic patients initiating DAA therapy should be closely monitored, particularly within the first3 months, and their diabetic medication modified when necessary. The physician in charge of thediabetic care of the patient should be informed when DAA therapy is initiated.

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

ZEPATIER contains lactose monohydrate. Patients with rare hereditary problems of galactoseintolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinalproduct.

ZEPATIER contains 69.85 mg sodium per tablet, equivalent to 3.5 % of the WHO recommendedmaximum daily intake of 2 g sodium for an adult.

Grazoprevir is a substrate of OATP1B drug transporters. Co-administration of ZEPATIER withmedicinal products that inhibit OATP1B transporters is contraindicated because it may result in asignificant 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 CYP3Aor P-gp with ZEPATIER is contraindicated because it may decrease elbasvir and grazoprevir plasmaconcentrations, 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 grazoprevirplasma 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 theplasma concentrations of ZEPATIER.

The potential for grazoprevir to be a breast cancer resistance protein (BCRP) substrate cannot beexcluded.

Elbasvir and grazoprevir are inhibitors of the drug transporter BCRP at the intestinal level in humansand 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-administrationwith 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 relevantincreases 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 OATP1Binhibitors in humans. Based on in vitro data, clinically significant interactions with ZEPATIER as aninhibitor 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 beexcluded. Multiple-dose administration of elbasvir or grazoprevir is unlikely to induce the metabolismof medicinal products metabolised by CYP isoforms based on in vitro data.

As liver function may change during treatment with ZEPATIER, a close monitoring of International

Normalised Ratio (INR) values is recommended.

Grazoprevir’s weak inhibition of CYP3A may increase levels of CYP3A substrates. In addition, theplasma concentrations of drugs that are CYP3A substrates may be decreased by improvement in liverfunction during DAA therapy, related to clearance of HCV. Therefore, close monitoring and potentialdose 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).

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 thatmedication, or the co-administration is not recommended or contraindicated. No clinically relevantchange 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 medicinalproduct interactions that may occur with elbasvir or grazoprevir. The table is not all-inclusive.

Table 2: Interactions and dose recommendations with other medicinal products

Medicinal Effects on medicinal product levels. Recommendation concerning co-product by Mean ratio (90 % confidence interval) administration with ZEPATIERtherapeutic for AUC, Cmax, C12 or C24areas (likely mechanism of interaction)

ACID REDUCING AGENTS

H2-receptor antagonists

Famotidine ↔ Elbasvir No dose adjustment is required.(20 mg single AUC 1.05 (0.92, 1.18)dose)/ elbasvir (50 Cmax 1.11 (0.98, 1.26)mg single dose)/ C24 1.03 (0.91, 1.17)grazoprevir (100mg single dose) ↔ Grazoprevir

AUC 1.10 (0.95, 1.28)

Cmax 0.89 (0.71, 1.11)

C24 1.12 (0.97, 1.30)

Pantoprazole ↔ Elbasvir No dose adjustment is required.(40 mg once daily)/ AUC 1.05 (0.93, 1.18)elbasvir (50 mg Cmax 1.02 (0.92, 1.14)single dose)/ C24grazoprevir (100 1.03 (0.92, 1.17)mg single dose)↔ Grazoprevir

AUC 1.12 (0.96, 1.30)

Cmax 1.10 (0.89, 1.37)

C24 1.17 (1.02, 1.34)

Antacids

Aluminium or Interaction not studied. No dose adjustment is required.magnesium Expected:hydroxide; calcium ↔ Elbasvircarbonate ↔ Grazoprevir

ANTIARRHYTHMICS

Digoxin ↔ Digoxin No dose adjustment is required.(0.25 mg single AUC 1.11 (1.02, 1.22)dose)/ elbasvir Cmax 1.47 (1.25, 1.73)(50 mg once daily)(P-gp inhibition)

ANTICOAGULANTS

Dabigatran Interaction not studied. Concentrations of dabigatran mayetexilate Expected: increase when co-administered with↑ Dabigatran elbasvir, with possible increased bleedingrisk. Clinical and laboratory monitoring is(P-gp inhibition)recommended.

Vitamin K Interaction not studied. Close monitoring of INR is recommendedantagonists with all vitamin K antagonists. This is dueto liver function changes during treatmentwith ZEPATIER.

ANTICONVULSANTS

Carbamazepine Interaction not studied. Co-administration is contraindicated.

Phenytoin Expected:

↓ Elbasvir↓ Grazoprevir(CYP3A or P-gp induction)

Medicinal Effects on medicinal product levels. Recommendation concerning co-product by Mean ratio (90 % confidence interval) administration with ZEPATIERtherapeutic for AUC, Cmax, C12 or C24areas (likely mechanism of interaction)

ANTIFUNGALS

Ketoconazole(400 mg PO once ↔ Elbasvir Co-administration is not recommended.daily)/ elbasvir AUC 1.80 (1.41, 2.29)(50 mg single dose) Cmax 1.29 (1.00, 1.66)

C24 1.89 (1.37, 2.60)(400 mg PO once ↑ Grazoprevirdaily)/ grazoprevir AUC 3.02 (2.42, 3.76)(100 mg single Cmax 1.13 (0.77, 1.67)dose)(CYP3A inhibition)

ANTIMYCOBACTERIALS

Rifampicin(600 mg IV single ↔ Elbasvir Co-administration is contraindicated.dose)/ elbasvir AUC 1.22 (1.06, 1.40)(50 mg single dose) Cmax 1.41 (1.18, 1.68)

C24 1.31 (1.12, 1.53)(600 mg IV single ↑ Grazoprevirdose)/ grazoprevir AUC 10.21 (8.68, 12.00)(200 mg single Cmax 10.94 (8.92, 13.43)dose) C24 1.77 (1.40, 2.24)(OATP1B inhibition)(600 mg PO single ↔ Elbasvirdose)/ elbasvir AUC 1.17 (0.98, 1.39)(50 mg single dose) Cmax 1.29 (1.06, 1.58)

C24 1.21 (1.03, 1.43)(600 mg PO single ↑ Grazoprevirdose)/ grazoprevir AUC 8.35 (7.38, 9.45)(200 mg once Cmax 6.52 (5.16, 8.24)daily) C24 1.31 (1.12, 1.53)(OATP1B inhibition)(600 mg PO once ↔ Grazoprevirdaily)/ grazoprevir AUC 0.93 (0.75, 1.17)(200 mg once Cmax 1.16 (0.82, 1.65)daily) C24 0.10 (0.07, 0.13)(OATP1B inhibition and CYP3A induction)

ASTHMA AGENTS

Montelukast ↔ Montelukast No dose adjustment is required.(10 mg single AUC 1.11 (1.01, 1.20)dose)/ grazoprevir Cmax 0.92 (0.81, 1.06)(200 mg single C24 1.39 (1.25, 1.56)dose)

ENDOTHELIN ANTAGONIST

Bosentan Interaction not studied. Co-administration is contraindicated.

Expected:↓ Elbasvir↓ Grazoprevir(CYP3A or P-gp induction)

Medicinal Effects on medicinal product levels. Recommendation concerning co-product by Mean ratio (90 % confidence interval) administration with ZEPATIERtherapeutic for AUC, Cmax, C12 or C24areas (likely mechanism of interaction)

HCV ANTIVIRAL AGENTS

Sofosbuvir ↔ Sofosbuvir No dose adjustment is required.(400 mg single AUC 2.43 (2.12, 2.79)dose sofosbuvir)/ Cmax 2.27 (1.72, 2.99)elbasvir (50 mgonce daily)/ ↔ GS-331007grazoprevir AUC 1.13 (1.05, 1.21)(200 mg once daily Cmax 0.87 (0.78, 0.96)

C24 1.53 (1.43, 1.63)

HERBAL SUPPLEMENTS

St. John’s wort Interaction not studied. Co-administration is contraindicated.(Hypericum Expected:

perforatum) ↓ Elbasvir↓ Grazoprevir(CYP3A or P-gp induction)

HBV AND HIV ANTIVIRAL AGENTS: NUCLEOS(T)IDE REVERSE TRANSCRIPTASE

INHIBITORS

Tenofovir disoproxil fumarate(300 mg once ↔ Elbasvir No dose adjustment is required.daily)/ elbasvir AUC 0.93 (0.82, 1.05)(50 mg once daily) Cmax 0.88 (0.77, 1.00)

C24 0.92 (0.18, 1.05)↔ Tenofovir

AUC 1.34 (1.23, 1.47)

Cmax 1.47 (1.32, 1.63)

C24 1.29 (1.18, 1.41)(300 mg once ↔ Grazoprevirdaily)/ grazoprevir AUC 0.86 (0.55, 1.12)(200 mg once Cmax 0.78 (0.51, 1.18)daily) C24 0.89 (0.78, 1.01)↔ Tenofovir

AUC 1.18 (1.09, 1.28)

Cmax 1.14 (1.04, 1.25)

C24 1.24 (1.10, 1.39)(300 mg once ↔ Tenofovirdaily)/elbasvir AUC 1.27 (1.20, 1.35)(50 mg once Cmax 1.14 (0.95, 1.36)daily)/grazoprevir C24 1.23 (1.09, 1.40)(100 mg oncedaily)

Medicinal Effects on medicinal product levels. Recommendation concerning co-product by Mean ratio (90 % confidence interval) administration with ZEPATIERtherapeutic for AUC, Cmax, C12 or C24areas (likely mechanism of interaction)

Lamivudine Interaction not studied. No dose adjustment is required.

Abacavir Expected:

Entecavir ↔ Elbasvir↔ Grazoprevir↔ Lamivudine↔ Abacavir↔ Entecavir

Emtricitabine Interaction studied with No dose adjustment is required.(200 mg once elvitegravir/cobicistat/emtricitabine/tenofovirdaily) disoproxil fumarate (fixed-dosecombination)↔ Emtricitabine

AUC 1.07 (1.03, 1.10)

Cmax 0.96 (0.90, 1.02)

C24 1.19 (1.13, 1.25)

HIV ANTIVIRAL AGENTS: PROTEASE INHIBITORS

Atazanavir/ritonavir(300 mg once ↑ Elbasvir Co-administration is contraindicated.daily)/ ritonavir AUC 4.76 (4.07, 5.56)(100 mg once daily/ Cmax 4.15 (3.46, 4.97)elbasvir (50 mg C24 6.45 (5.51, 7.54)once daily)(combination of mechanisms including

CYP3A inhibition)↔ Atazanavir

AUC 1.07 (0.98, 1.17)

Cmax 1.02 (0.96, 1.08)

C24 1.15 (1.02, 1.29)(300 mg once ↑ Grazoprevirdaily)/ ritonavir AUC 10.58 (7.78, 14.39)(100 mg once daily/ Cmax 6.24 (4.42, 8.81)grazoprevir C24 11.64 (7.96, 17.02)(200 mg oncedaily) (combination of OATP1B and CYP3Ainhibition)↔ Atazanavir

AUC 1.43 (1.30, 1.57)

Cmax 1.12 (1.01, 1.24)

C24 1.23 (1.13, 2.34)

Medicinal Effects on medicinal product levels. Recommendation concerning co-product by Mean ratio (90 % confidence interval) administration with ZEPATIERtherapeutic for AUC, Cmax, C12 or C24areas (likely mechanism of interaction)

Darunavir/ritonavir(600 mg twice ↔ Elbasvir Co-administration is contraindicated.daily)/ ritonavir AUC 1.66 (1.35, 2.05)(100 mg twice Cmax 1.67 (1.36, 2.05)daily/ elbasvir C24 1.82 (1.39, 2.39)(50 mg once daily)↔ Darunavir

AUC 0.95 (0.86, 1.06)

Cmax 0.95 (0.85, 1.05)

C12 0.94 (0.85, 1.05)(600 mg twice ↑ Grazoprevirdaily)/ ritonavir AUC 7.50 (5.92, 9.51)(100 mg twice Cmax 5.27 (4.04, 6.86)daily/ grazoprevir C24 8.05 (6.33, 10.24)(200 mg oncedaily) (combination of OATP1B and CYP3Ainhibition)↔ Darunavir

AUC 1.11 (0.99, 1.24)

Cmax 1.10 (0.96, 1.25)

C12 1.00 (0.85, 1.18)

Lopinavir/ritonavir(400 mg twice ↑ Elbasvir Co-administration is contraindicated.daily)/ ritonavir AUC 3.71 (3.05, 4.53)(100 mg twice Cmax 2.87 (2.29, 3.58)daily/ elbasvir C24 4.58 (3.72, 5.64)(50 mg once daily)(combination of mechanisms including

CYP3A inhibition)↔ Lopinavir

AUC 1.02 (0.93, 1.13)

Cmax 1.02 (0.92, 1.13)

C12 1.07 (0.97, 1.18)(400 mg twice ↑ Grazoprevirdaily)/ ritonavir AUC 12.86 (10.25, 16.13)(100 mg twice Cmax 7.31 (5.65, 9.45)daily/ grazoprevir C24 21.70 (12.99, 36.25)(200 mg oncedaily) (combination of OATP1B and CYP3Ainhibition)↔ Lopinavir

AUC 1.03 (0.96, 1.16)

Cmax 0.97 (0.88, 1.08)

C12 0.97 (0.81, 1.15)

Saquinavir/ritonavir Interaction not studied. Co-administration is contraindicated.

Tipranavir/ritonavir Expected:

Atazanavir ↑ Grazoprevir(combination of mechanisms including

CYP3A inhibition)

Medicinal Effects on medicinal product levels. Recommendation concerning co-product by Mean ratio (90 % confidence interval) administration with ZEPATIERtherapeutic for AUC, Cmax, C12 or C24areas (likely mechanism of interaction)

HIV ANTIVIRAL AGENTS: NON-NUCLEOSIDE HIV REVERSE TRANSCRIPTASE

INHIBITORS

Efavirenz(600 mg once ↓ Elbasvir Co-administration is contraindicated.daily)/ elbasvir AUC 0.46 (0.36, 0.59)(50 mg once daily) Cmax 0.55 (0.41, 0.73)

C24 0.41 (0.28, 0.59)(CYP3A or P-gp induction)↔ Efavirenz

AUC 0.82 (0.78, 0.86)

Cmax 0.74 (0.67, 0.82)

C24 0.91 (0.87, 0.96)(600 mg once ↓Grazoprevirdaily)/ grazoprevir AUC 0.17 (0.13, 0.24)(200 mg once Cmax 0.13 (0.09, 0.19)daily) C24 0.31 (0.25, 0.38)(CYP3A or P-gp induction)↔ Efavirenz

AUC 1.00 (0.96, 1.05)

Cmax 1.03 (0.99, 1.08)

C24 0.93 (0.88, 0.98)

Etravirine Interaction not studied. Co-administration is contraindicated.

Expected:

↓ Elbasvir↓ Grazoprevir(CYP3A or P-gp induction)

Rilpivirine ↔ Elbasvir No dose adjustment is required.(25 mg once daily)/ AUC 1.07 (1.00, 1.15)elbasvir (50 mg Cmax 1.07 (0.99, 1.16)once daily)/ C24 1.04 (0.98, 1.11)grazoprevir(200 mg once ↔ Grazoprevirdaily) AUC 0.98 (0.89, 1.07)

Cmax 0.97 (0.83, 1.14)

C24 1.00 (0.93, 1.07)↔ Rilpivirine

AUC 1.13 (1.07, 1.20)

Cmax 1.07 (0.97, 1.17)

C24 1.16 (1.09, 1.23)

Medicinal Effects on medicinal product levels. Recommendation concerning co-product by Mean ratio (90 % confidence interval) administration with ZEPATIERtherapeutic for AUC, Cmax, C12 or C24areas (likely mechanism of interaction)

HIV ANTIVIRAL AGENTS: INTEGRASE STRAND TRANSFER INHIBITORS

Dolutegravir ↔ Elbasvir No dose adjustment is required.(50 mg single AUC 0.98 (0.93, 1.04)dose)/ elbasvir Cmax 0.97 (0.89, 1.05)(50 mg once daily)/ C24 0.98 (0.93, 1.03)grazoprevir(200 mg once ↔ Grazoprevirdaily) AUC 0.81 (0.67, 0.97)

Cmax 0.64 (0.44, 0.93)

C24 0.86 (0.79, 0.93)↔ Dolutegravir

AUC 1.16 (1.00, 1.34)

Cmax 1.22 (1.05, 1.40)

C24 1.14 (0.95, 1.36)

Raltegravir(400 mg single ↔ Elbasvir No dose adjustment is required.dose)/ elbasvir AUC 0.81 (0.57, 1.17)(50 mg single dose) Cmax 0.89 (0.61, 1.29)

C24 0.80 (0.55, 1.16)↔ Raltegravir

AUC 1.02 (0.81, 1.27)

Cmax 1.09 (0.83, 1.44)

C12 0.99 (0.80, 1.22)(400 mg twice ↔ Grazoprevirdaily)/ grazoprevir AUC 0.89 (0.72, 1.09)(200 mg once Cmax 0.85 (0.62, 1.16)daily) C24 0.90 (0.82, 0.99)↔ Raltegravir

AUC 1.43 (0.89, 2.30)

Cmax 1.46 (0.78, 2.73)

C12 1.47 (1.08, 2.00)

Medicinal Effects on medicinal product levels. Recommendation concerning co-product by Mean ratio (90 % confidence interval) administration with ZEPATIERtherapeutic for AUC, Cmax, C12 or C24areas (likely mechanism of interaction)

HIV ANTIVIRAL AGENTS: OTHER

Elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (fixed-dose combination)elvitegravir ↑ Elbasvir Co-administration with ZEPATIER is(150 mg once AUC 2.18 (2.02, 2.35) contraindicated.daily)/cobicistat Cmax 1.91 (1.77, 2.05)(150 mg once C24 2.38 (2.19, 2.60)daily)/emtricitabine (CYP3A and OATP1B inhibition)(200 mg oncedaily)/ tenofovir ↑ Grazoprevirdisoproxil fumarate AUC 5.36 (4.48, 6.43)(300 mg once Cmax 4.59 (3.70, 5.69)daily)/elbasvir C24 2.78 (2.48, 3.11)(50 mg once daily)/grazoprevir (CYP3A and OATP1B inhibition)(100 mg oncedaily) ↔ Elvitegravir

AUC 1.10 (1.00, 1.21)

Cmax 1.02 (0.93, 1.11)

C24 1.31 (1.11, 1.55)↔ Cobicistat

AUC 1.49 (1.42, 1.57)

Cmax 1.39 (1.29, 1.50)↔ Emtricitabine

AUC 1.07 (1.03, 1.10)

Cmax 0.96 (0.90, 1.02)

C24 1.19 (1.13, 1.25)↔ Tenofovir

AUC 1.18 (1.13, 1.24)

Cmax 1.25 (1.14, 1.37)

C24 1.20 (1.15, 1.26)

HMG-CoA REDUCTASE INHIBITORS

Atorvastatin(20 mg single ↑ Atorvastatin The dose of atorvastatin should notdose)/ grazoprevir AUC 3.00 (2.42, 3.72) exceed a daily dose of 20 mg when(200 mg once Cmax 5.66 (3.39, 9.45) co-administered with ZEPATIER.daily)(primarily due to intestinal BCRP inhibition)↔ Grazoprevir

AUC 1.26 (0.97, 1.64)

Cmax 1.26 (0.83, 1.90)

C24 1.11 (1.00, 1.23)(10 mg single ↑ Atorvastatindose)/ elbasvir AUC 1.94 (1.63, 2.33)(50 mg once daily) Cmax 4.34 (3.10, 6.07)/ grazoprevir C24 0.21 (0.17, 0.26)(200 mg oncedaily)

Medicinal Effects on medicinal product levels. Recommendation concerning co-product by Mean ratio (90 % confidence interval) administration with ZEPATIERtherapeutic for AUC, Cmax, C12 or C24areas (likely mechanism of interaction)

Rosuvastatin(10 mg single ↑ Rosuvastatin The dose of rosuvastatin should notdose)/ grazoprevir AUC 1.59 (1.33, 1.89) exceed a daily dose of 10 mg when(200 mg once Cmax 4.25 (3.25, 5.56) co-administered with ZEPATIER.daily) C24 0.80 (0.70, 0.91)(intestinal BCRP inhibition)↔ Grazoprevir

AUC 1.16 (0.94, 1.44)

Cmax 1.13 (0.77, 1.65)

C24 0.93 (0.84, 1.03)(10 mg single ↑ Rosuvastatindose)/ elbasvir AUC 2.26 (1.89, 2.69)(50 mg once daily)/ Cmax 5.49 (4.29, 7.04)grazoprevir C24 0.98 (0.84, 1.13)(200 mg oncedaily) (intestinal BCRP inhibition)↔ Elbasvir

AUC 1.09 (0.98, 1.21)

Cmax 1.11 (0.99, 1.26)

C24 0.96 (0.86, 1.08)↔ Grazoprevir

AUC 1.01 (0.79, 1.28)

Cmax 0.97 (0.63, 1.50)

C24 0.95 (0.87, 1.04)

Fluvastatin Interaction not studied. The dose of fluvastatin, lovastatin, or

Lovastatin Expected: simvastatin should not exceed a daily dose

Simvastatin ↑ Fluvastatin of 20 mg when co-administered with(primarily due to intestinal BCRP inhibition) ZEPATIER.

↑ Lovastatin(CYP3A inhibition)↑ Simvastatin(primarily due to intestinal BCRP inhibitionand CYP3A inhibition)

Pitavastatin ↔ Pitavastatin No dose adjustment is required.(1 mg single dose)/ AUC 1.11 (0.91, 1.34)grazoprevir Cmax 1.27 (1.07, 1.52)(200 mg oncedaily) ↔ Grazoprevir

AUC 0.81 (0.70, 0.95)

Cmax 0.72 (0.57, 0.92)

C24 0.91 (0.82, 1.01)

Medicinal Effects on medicinal product levels. Recommendation concerning co-product by Mean ratio (90 % confidence interval) administration with ZEPATIERtherapeutic for AUC, Cmax, C12 or C24areas (likely mechanism of interaction)

Pravastatin ↔ Pravastatin No dose adjustment is required.(40 mg single AUC 1.33 (1.09, 1.64)dose)/ elbasvir Cmax 1.28 (1.05, 1.55)(50 mg once daily)/grazoprevir ↔ Elbasvir(200 mg once AUC 0.98 (0.93, 1.02)daily) Cmax 0.97 (0.89, 1.05)

C24 0.97 (0.92, 1.02)↔ Grazoprevir

AUC 1.24 (1.00, 1.53)

Cmax 1.42 (1.00, 2.03)

C24 1.07 (0.99, 1.16)

IMMUNOSUPPRESSANTS

Ciclosporin ↔ Elbasvir Co-administration is contraindicated.(400 mg single AUC 1.98 (1.84, 2.13)dose)/ elbasvir Cmax 1.95 (1.84, 2.07)(50 mg once daily)/ C24 2.21 (1.98, 2.47)grazoprevir(200 mg once ↑ Grazoprevirdaily) AUC 15.21 (12.83, 18.04)

Cmax 17.00 (12.94, 22.34)

C24 3.39 (2.82, 4.09)(due in part to OATP1B and CYP3Ainhibition)↔ Ciclosporin

AUC 0.96 (0.90, 1.02)

Cmax 0.90 (0.85, 0.97)

C12 1.00 (0.92, 1.08)

Mycophenolate ↔ Elbasvir No dose adjustment is required.mofetil AUC 1.07 (1.00, 1.14)(1,000 mg single Cmax 1.07 (0.98, 1.16)dose)/ elbasvir C24 1.05 (0.97, 1.14)(50 mg once daily)/grazoprevir ↔ Grazoprevir(200 mg once AUC 0.74 (0.60, 0.92)daily) Cmax 0.58 (0.42, 0.82)

C24 0.97 (0.89, 1.06)↔ Mycophenolic acid

AUC 0.95 (0.87, 1.03)

Cmax 0.85 (0.67, 1.07)

Medicinal Effects on medicinal product levels. Recommendation concerning co-product by Mean ratio (90 % confidence interval) administration with ZEPATIERtherapeutic for AUC, Cmax, C12 or C24areas (likely mechanism of interaction)

Prednisone ↔ Elbasvir No dose adjustment is required.(40 mg single AUC 1.17 (1.11, 1.24)dose)/ elbasvir Cmax 1.25 (1.16, 1.35)(50 mg once daily)/ C24 1.04 (0.97, 1.12)grazoprevir(200 mg once daily ↔ Grazoprevir

AUC 1.09 (0.95, 1.25)

Cmax 1.34 (1.10, 1.62)

C24 0.93 (0.87, 1.00)↔ Prednisone

AUC 1.08 (1.00, 1.17)

Cmax 1.05 (1.00, 1.10)↔ Prednisolone

AUC 1.08 (1.01, 1.16)

Cmax 1.04 (0.99, 1.09)

Tacrolimus ↔ Elbasvir Frequent monitoring of tacrolimus whole(2 mg single dose)/ AUC 0.97 (0.90, 1.06) blood concentrations, changes in renalelbasvir (50 mg Cmax 0.99 (0.88, 1.10) function, and tacrolimus-associatedonce daily)/ C24 0.92 (0.83, 1.02) adverse events upon the initiation of co-grazoprevir administration is recommended. Close(200 mg once ↔ Grazoprevir monitoring and potential dose adjustmentdaily) AUC 1.12 (0.97, 1.30) of tacrolimus may be required during

Cmax 1.07 (0.83, 1.37) therapy, as tacrolimus levels may decrease

C24 0.94 (0.87, 1.02) related to clearance of HCV.

↑ Tacrolimus

AUC 1.43 (1.24, 1.64)

Cmax 0.60 (0.52, 0.69)

C12 1.70 (1.49, 1.94)(CYP3A inhibition)

KINASE INHIBITOR

Sunitinib Interaction not studied. Co-administration of ZEPATIER with

Expected: sunitinib may increase sunitinib↑ sunitinib concentrations leading to an increased riskof sunitinib-associated adverse events.(possibly due to intestinal BCRP inhibition) Use with caution; dose adjustment ofsunitinib may be required.

Medicinal Effects on medicinal product levels. Recommendation concerning co-product by Mean ratio (90 % confidence interval) administration with ZEPATIERtherapeutic for AUC, Cmax, C12 or C24areas (likely mechanism of interaction)

OPIOID-SUBSTITUTION THERAPY

Buprenorphine/naloxone(8 mg/2 mg single ↔ Elbasvir No dose adjustment is required.dose)/ elbasvir AUC 1.22 (0.98, 1.52)(50 mg single dose) Cmax 1.13 (0.87, 1.46)

C24 1.22 (0.99, 1.51)↔ Buprenorphine

AUC 0.98 (0.89, 1.08)

Cmax 0.94 (0.82, 1.08)

C24 0.98 (0.88, 1.09)↔ Naloxone

AUC 0.88 (0.76, 1.02)

Cmax 0.85 (0.66, 1.09)(8-24 mg/2-6 mg ↔ Grazoprevironce daily)/ AUC 0.80 (0.53, 1.22)grazoprevir Cmax 0.76 (0.40, 1.44)(200 mg once C24 0.69 (0.54, 0.88)daily)↔ Buprenorphine

AUC 0.98 (0.81, 1.19)

Cmax 0.90 (0.76, 1.07)

Methadone(20-120 mg once ↔ R-Methadone No dose adjustment is required.daily)/ elbasvir AUC 1.03 (0.92, 1.15)(50 mg once daily) Cmax 1.07 (0.95, 1.20)

C24 1.10 (0.96, 1.26)↔ S-Methadone

AUC 1.09 (0.94, 1.26)

Cmax 1.09 (0.95, 1.25)

C24 1.20 (0.98, 1.47)(20-150 mg once ↔ R-Methadonedaily)/ grazoprevir AUC 1.09 (1.02, 1.17)(200 mg once Cmax 1.03 (0.96, 1.11)daily)↔ S-Methadone

AUC 1.23 (1.12, 1.35)

Cmax 1.15 (1.07, 1.25)

ORAL CONTRACEPTIVES

Ethinyl oestradiol (EE)/Levonorgestrel (LNG)(0.03 mg EE/ ↔ EE No dose adjustment is required.0.15 mg LNG AUC 1.01 (0.97, 1.05)single-dose)/ Cmax 1.10 (1.05, 1.16)elbasvir (50 mgonce daily) ↔ LNG

AUC 1.14 (1.04, 1.24)

Cmax 1.02 (0.95, 1.08)(0.03 mg EE/ ↔ EE0.15 mg LNG AUC 1.10 (1.05, 1.14)single-dose)/ Cmax 1.05 (0.98, 1.12)grazoprevir(200 mg once ↔ LNGdaily) AUC 1.23 (1.15, 1.32)

Cmax 0.93 (0.84, 1.03)

Medicinal Effects on medicinal product levels. Recommendation concerning co-product by Mean ratio (90 % confidence interval) administration with ZEPATIERtherapeutic for AUC, Cmax, C12 or C24areas (likely mechanism of interaction)

PHOSPHATE BINDERS

Calcium acetate ↔ Elbasvir No dose adjustment is required.(2,668 mg single AUC 0.92 (0.75, 1.14)dose)/ elbasvir Cmax 0.86 (0.71, 1.04)(50 mg single C24 0.87 (0.70, 1.09)dose)/ grazoprevir(100 mg single ↔ Grazoprevirdose) AUC 0.79 (0.68, 0.91)

Cmax 0.57 (0.40, 0.83)

C24 0.77 (0.61, 0.99)

Sevelamer ↔ Elbasvircarbonate AUC 1.13 (0.94, 1.37)(2,400 mg single Cmax 1.07 (0.88, 1.29)dose)/ elbasvir C24 1.22 (1.02, 1.45)(50 mg singledose)/ grazoprevir ↔ Grazoprevir(100 mg single AUC 0.82 (0.68, 0.99)dose) Cmax 0.53 (0.37, 0.76)

C24 0.84 (0.71, 0.99)

SEDATIVES

Midazolam ↔ Midazolam No dose adjustment is required.(2 mg single dose)/ AUC 1.34 (1.29, 1.39)grazoprevir Cmax 1.15 (1.01, 1.31)(200 mg oncedaily)

STIMULANTS

Modafinil Interaction not studied. Co-administration is contraindicated.

Expected:

↓ Elbasvir↓ Grazoprevir(CYP3A or P-gp induction)

Interaction studies have only been performed in adults.

If ZEPATIER is co-administered with ribavirin, the information for ribavirin with regard tocontraception, pregnancy testing, pregnancy, breast-feeding, and fertility also applies to thiscombination regimen (refer to the Summary of Product Characteristics for the co-administeredmedicinal 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 theirmale partners must use an effective form of contraception during treatment and for a period of timeafter the treatment has concluded.

There are no adequate and well-controlled studies with ZEPATIER in pregnant women. Animalstudies do not indicate harmful effects with respect to reproductive toxicity. Because reproductionanimal studies are not always predictive of human response, ZEPATIER should be used only if thepotential benefit justifies the potential risk to the fetus.

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. Adecision 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 oftherapy for the woman.

No human data on the effect of elbasvir and grazoprevir on fertility are available. Animal studies donot indicate harmful effects of elbasvir or grazoprevir on fertility at elbasvir and grazoprevir exposureshigher 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 theability to drive and use machines. Patients should be informed that fatigue has been reported duringtreatment with ZEPATIER (see section 4.8).

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 withcompensated liver disease (with or without cirrhosis).

In clinical studies, the most commonly reported adverse reactions (greater than 10%) were fatigue andheadache. Less than 1 % of subjects treated with ZEPATIER with or without ribavirin had seriousadverse reactions (abdominal pain, transient ischaemic attack and anaemia). Less than 1 % of subjectstreated with ZEPATIER with or without ribavirin permanently discontinued treatment due to adversereactions. The frequency of serious adverse reactions and discontinuations due to adverse reactions insubjects with compensated cirrhosis were comparable to those seen in subjects without cirrhosis.

When elbasvir/grazoprevir was studied with ribavirin, the most frequent adverse reactions toelbasvir/grazoprevir + ribavirin combination therapy were consistent with the known safety profile ofribavirin.

The following adverse reactions were identified in patients taking ZEPATIER without ribavirin for 12weeks. The adverse reactions are listed below by body system organ class and frequency. Frequenciesare 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*

Frequency Adverse reactions

Common decreased appetite

Common insomnia, anxiety, depression

Very common headache

Common dizziness

Common nausea, diarrhoea, constipation, upper abdominal pain, abdominalpain, dry mouth, vomiting

Common pruritus, alopecia

Common arthralgia, myalgia

Very common fatigue

Common asthenia, irritability

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

Changes in selected laboratory parameters are described in Table 4.

Table 4: Selected treatment emergent laboratory abnormalities

Laboratory Parameters ZEPATIER*

N = 834n (%)

ALT (IU/L)5.1-10.0 × ULN† (Grade 3) 6 (0.7%)>10.0 × ULN (Grade 4) 6 (0.7%)

Total Bilirubin (mg/dL)2.6-5.0 × ULN (Grade 3) 3 (0.4%)>5.0 × ULN (Grade 4) 0

*Based on pooled data from patients treated with ZEPATIER for 12 weeks without ribavirin†ULN: Upper limit of normal according to testing laboratory.

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 timesthe ULN, generally at or after treatment week 8 (mean onset time 10 weeks, range 6-12 weeks). Theselate ALT elevations were typically asymptomatic. Most late ALT elevations resolved with ongoingtherapy with ZEPATIER or after completion of therapy (see section 4.4). The frequency of late ALTelevations was higher in subjects with higher grazoprevir plasma concentration (see sections 4.4, 4.5and 5.2). The incidence of late ALT elevations was not affected by treatment duration. Cirrhosis wasnot a risk factor for late ALT elevations. Less than 1% of subjects treated with ZEPATIER with orwithout ribavirin experienced ALT elevations >2.5 - 5 times the ULN during treatment; there were notreatment discontinuations due to these ALT elevations.

The safety assessment of Zepatier in paediatric patients aged 12 years and older is based on data froma Phase 2b, open-label clinical study that enrolled 22 patients who were treated with Zepatier for12 weeks.The adverse reactions observed were consistent with those observed in clinical studies of

Zepatier in adults.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Human experience of overdose with ZEPATIER is limited. The highest dose of elbasvir was 200 mgonce daily for 10 days, and a single dose of 800 mg. The highest dose of grazoprevir was 1,000 mgonce daily for 10 days, and a single dose of 1,600 mg. In these healthy volunteer studies, adversereactions 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 ofadverse reactions and appropriate symptomatic treatment instituted.

Haemodialysis does not remove elbasvir or grazoprevir. Elbasvir and grazoprevir are not expected tobe removed by peritoneal dialysis.

Pharmacotherapeutic group: Antivirals for systemic use, Direct acting antivirals, Antivirals fortreatment of HCV infections, ATC code: J05AP54.

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 virionassembly.

Grazoprevir is an inhibitor of the HCV NS3/4A protease which is necessary for the proteolyticcleavage 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 theproteolytic activity of the recombinant NS3/4A protease enzymes from HCV genotypes 1a, 1b, 3 and4a with IC50 values ranging from 4 to 690 pM.

The EC50 values of elbasvir and grazoprevir against full-length or chimeric replicons encoding NS5Aor 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 andclinical isolates in replicon cells

Elbasvir Grazoprevir

Reference EC50 nM

GT1a (H77) 0.004 0.4

GT1b (con 1) 0.003 0.5

GT4 (ED43) 0.0003 0.3

Clinical Isolates Median EC50 (range) nM

GT1a 0.005 (0.003 - 0.009)a 0.8 (0.4 - 5.1)d

GT1b 0.009 (0.005 - 0.01)b 0.3 (0.2 - 5.9)e

GT4 0.0007 (0.0002 - 34)c 0.2 (0.11 - 0.33)a

Number of isolates tested: a=5, b=4, c=14, d=10, e=9

HCV replicons with reduced susceptibility to elbasvir and grazoprevir have been selected in cellculture 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 4replicons, 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-associatedsubstitutions further reduced elbasvir antiviral activity.

For grazoprevir, in HCV genotype 1a replicons, single NS3 substitutions D168A/E/G/S/V reducedgrazoprevir 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. Ingenotype 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 grazoprevirresistance-associated substitutions further reduced grazoprevir antiviral activity.

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 wereconducted for 50 subjects who experienced virologic failure and had sequence data available (6 withon-treatment virologic failure, 44 with post-treatment relapse).

Treatment-emergent substitutions observed in the viral populations of these subjects based ongenotypes are shown in Table 6. Treatment-emergent substitutions were detected in both HCV drugtargets in 23/37 (62 %) genotype 1a, 1/8 (13 %) genotype 1b and 2/5 (40 %) genotype 4 subjects.

Table 6: Treatment-emergent amino acid substitutions in the pooled analysis of ZEPATIERwith and without ribavirin regimens in Phase 2 and Phase 3 clinical studies

Target Emergent Amino Acid Genotype 1a Genotype 1b Genotype 4

Substitutions N = 37 N = 8 N = 5% (n) % (n) % (n)

NS5A Any of the following NS5A 81% (30) 88% (7) 100% (5)substitutions: M/L28A/G/T/S*

Q30H/K/R/Y, L/M31F/M/I/V,

H/P58D, Y93H/N/S

M/L28A/G/T/S 19% (7) 13% (1) 60% (3)

Q30H/K/Y 14% (5) -- --

Q30R 46% (17) -- --

L/M31M/F/I/V† 11% (4) 25% (2) 40% (2)

H/P58D‡ 5% (3) -- 20% (1)

Y93H/N/S 14% (5) 63% (5) 20% (1)

NS3 Any of the following NS3 78% (29) 25% (2) 40% (2)substitutions: V36L/M, Y56F/H,

V107I, R155I/K, A156G/M/T/V,

V158A, D168A/C/E/G/N/V/Y,

V170I

V36L/M 11% (4) -- --

Y56F/H 14% (5) 13% (1) --

V107I 3% (1) 13% (1) --

R155I/K 5% (2) -- --

A156T 27% (10) 13% (1) 20% (1)

A156G/V/M 8% (3) -- 60% (3)

V158A 5% (2) -- --

D168A 35% (13) -- 20% (1)

D168C/E/G/N/V/Y 14% (5) -- 20% (1)

V170I -- -- 20% (1)

*Reference sequences for NS5A at amino acid 28 are M (genotype 1a) and L (genotype 1b and genotype 4a and4d).†Reference sequences for NS5A at amino acid 31 are L (genotype 1a and genotype 1b) and M (genotype 4a and4d).‡Reference sequences for NS5A at amino acid 58 are H (genotype 1a) and P (genotype 1b and genotype 4a and4d).

Elbasvir is active in vitro against genotype 1a NS5A substitutions, M28V and Q30L, genotype 1bsubstitutions, L28M/V, R30Q, L31V, Y93C, and genotype 4 substitution, M31V, which conferresistance to other NS5A inhibitors. In general, other NS5A substitutions conferring resistance to

NS5A inhibitors may also confer resistance to elbasvir. NS5A substitutions conferring resistance toelbasvir may reduce the antiviral activity of other NS5A inhibitors.

Grazoprevir is active in vitro against the following genotype 1a NS3 substitutions which conferresistance 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 invitro against the following genotype 1b NS3 substitutions conferring resistance to other NS3/4Aprotease 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 A156and at D168 confer reduced antiviral activity to grazoprevir as well as to other NS3/4A proteaseinhibitors.

The substitutions associated with resistance to NS5B inhibitors do not affect the activity of elbasvir orgrazoprevir.

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 virushad treatment-emergent resistance-associated substitution in the drug target, and with available datathrough at least 24 weeks post-treatment using population (or Sanger) sequencing.

Viral populations with treatment-emergent NS5A resistance-associated substitutions were generallymore 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 detectablelevels at follow-up week 24 in 31% (4/13) of subjects. Among genotype 1b-infected subjects, NS3resistance-associated substitutions persisted at detectable levels at follow-up week 24 in 50% (1/2) ofsubjects.

Due to the limited number of genotype 4-infected subjects with treatment emergent NS5A and NS3resistance associated substitutions, trends in persistence of treatment emergent substitutions in thisgenotype could not be established.

The long-term clinical impact of the emergence or persistence of virus containing ZEPATIERresistance-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, theprevalence 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 andgrazoprevir antiviral activity respectively in vitro were evaluated. The observed treatment responsedifferences 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

SVR12 by Treatment Regimen

ZEPATIER, 12 Weeks ZEPATIER + RBV, 16 Weeks

Patient Subjects without Subjects with Subjects without Subjects with

Population baseline NS5A baseline NS5A baseline NS5A baseline NS5Apolymorphisms,* polymorphisms,* polymorphisms,* polymorphisms,*% (n/N) % (n/N) % (n/N) % (n/N)† 97% 53% 100% 100%

GT1a(464/476) (16/30) (51/51) (4/4)‡ 99% 92%

GT1b(259/260) (36/39)

Subjects without Subjects withbaseline NS3 baseline NS3polymorphisms,¶ polymorphisms,¶% (n/N) % (n/N)

GT4 (treatment- 86% 100%experienced)♯ (25/29) (7/7)

*NS5A polymorphisms (conferring > 5-fold potency loss to elbasvir) included M28T/A, Q30E/H/R/G/K/D,

L31M/V/F, H58D, and Y93C/H/N†Overall prevalence of GT1a-infected subjects with baseline NS5A polymorphisms in the pooled analyses was7% (55/825)‡Overall prevalence of GT1b-infected subjects with baseline NS5A polymorphisms in the pooled analyses was14% (74/540)¶NS3 polymorphisms considered were any amino acid substitution at positions 36, 54, 55, 56, 80, 107, 122,132, 155, 156, 158, 168, 170, and 175.♯Overall prevalence of GT4-infected subjects with baseline NS3 polymorphisms in the pooled analyses was19% (7/36)

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 evaluatedin 8 adult clinical studies and 1 paediatric clinical study in approximately 2,000 subjects (see Table 8).

Table 8: Studies conducted with ZEPATIER

Study Population Study Arms and Additional Study Details

Duration(Number of

Subjects Treated)

C-EDGE TN GT 1, 4, 6 Placebo-controlled study in which subjects

* EBR/GZR* for(double-blind) TN with or were randomised in a 3:1 ratio to: EBR/GZR12 weekswithout for 12 weeks (immediate treatment group(N=316)cirrhosis [ITG]) or placebo for 12 weeks followed byopen-label treatment with EBR/GZR for

* Placebo for 12 weeks (deferred treatment group (DTG)).12 weeks(N=105)

C-EDGE GT 1, 4, 6

COINFECTION TN with or * EBR/GZR for(open-label) without 12 weekscirrhosis (N=218)

HCV/HIV-1co-infection

C-SURFER GT 1 Placebo-controlled study in subjects with(double-blind) TN or TE with * EBR* + GZR* CKD Stage 4 (eGFR 15-29 mL/min/1.73 m2)or without for 12 weeks or Stage 5 (eGFR < 15 mL/min/1.73 m2),cirrhosis (N=122) including subjects on hemodialysis, Subjects

Chronic were randomised in a 1:1 ratio to one of the

* Placebo for following treatment groups: EBR + GZR for

Kidney 12 weeks 12 weeks (ITG) or placebo for 12 weeks

Disease (N=113) followed by open-label treatment with

EBR/GZR for 12 weeks (DTG). In addition,11 subjects received open-label EBR + GZRfor 12 weeks (intensive PK arm).

C-WORTHY GT 1, 3 Multi-arm, multi-stage study.

(open-label) TN with or * EBR* + GZR* Subjects with GT 1b infection withoutwithout for 8, 12, or cirrhosis were randomised in a 1:1 ratio tocirrhosis 18 weeks EBR + GZR with or without RBV for

TE Null (N=31, 136, 8 weeks.

and 63, TN subjects with GT 3 infection without

Responderrespectively) cirrhosis were randomised to EBR + GZRwith or without with RBV for 12 or 18 weeks.

cirrhosis

* EBR* + GZR* TN subjects with GT 1 infection with or

TN HCV/HIV- + RBV† for 8, without cirrhosis (with or without HCV/HIV-1 co-infection 12, or 18 weeks 1 co-infection) or who were peg-IFN + RBVwithout (N=60, 152, null responders, were randomised to EBR +cirrhosis GZR with or without RBV for 8, 12 orand 65, 18 weeks.respectively)

C-SCAPE GT 4, 6 Subjects were randomised in a 1:1 ratio to the(open-label) TN without * EBR* + GZR* study arms.

cirrhosis for 12 weeks(N=14)

* EBR* + GZR*+ RBV† for12 weeks(N=14)

Study Population Study Arms and Additional Study Details

Duration(Number of

Subjects Treated)

C-EDGE TE GT 1, 4, 6 Subjects were randomised in a 1:1:1:1 ratio to(open-label) TE with or * EBR/GZR for the study arms.

without 12 or 16 weekscirrhosis, and (N=105 andwith or without 105,

HCV/HIV-1 respectively)co-infection

* EBR/GZR +

RBV† for 12 or16 weeks(N=104 and106,respectively)

C-SALVAGE GT 1 Subjects who had failed prior treatment with

* EBR* + GZR*(open-label) TE with HCV boceprevir, simeprevir, or telaprevir in+ RBV† forprotease combination with peg-IFN + RBV received12 weeksinhibitor EBR + GZR with RBV for 12 weeks.

‡ (N=79)regimen withor withoutcirrhosis

C-EDGE GT 1, 4, 6 Placebo-controlled study in which subjects

COSTAR TN with or * EBR/GZR for were randomised in a 2:1 ratio to EBR/GZR(double-blind) without 12 weeks for 12 weeks (ITG) or placebo for 12 weekscirrhosis (N=201) followed by open-label treatment with

EBR/GZR for 12 weeks (DTG). Subjects were

Opiate agonist

* Placebo for not excluded or discontinued from the trialtherapy 12 weeks based on a positive urine drug screen.(N=100)

MK-5172A-079 GT 1, 4 Non-randomised, single-arm, open-label study(open-label) TN or TE * EBR/GZR for in treatment-naïve or treatment-experiencedpediatric 12 weeks pediatric subjects, including 22 subjectssubjects (N=22) 12 years to less than 18 years of age, withchronic Hepatitis C (CHC) GT 1 or 4 infectionwithout cirrhosis who received EBR/GZR for12 weeks.

GT = Genotype

TN = Treatment-Naïve

TE = Treatment-Experienced (failed prior treatment with interferon [IFN] or peginterferon alfa [peg-IFN] withor 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-WORTHYand 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 indexwas 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 weeksare presented in Table 9.

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

Baseline Characteristics SVR

EBR with GZR for 12 weeks (N = 312)

Overall SVR 96% (301/312)

Outcome for subjects without SVR

On-treatment virologic failure* 0% (0/312)

Relapse 1% (4/312)

Other‡ 2% (7/312)

SVR by cirrhosis status

Non-cirrhotic 95% (232/243)

Cirrhotic 100% (69/69)†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 % weremale; 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 was27 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 orelbasvir/grazoprevir with ribavirin for 16 weeks are presented in Table 10.

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

Baseline Characteristics SVR

EBR with GZR EBR with GZR + RBV12 Weeks 16 Weeks

N=519 N=58

Overall SVR 93% (483/519) 95% (55/58)

Outcome for subjects without SVR

On-treatment virologic failure* 1% (3/519) 0% (0/58)

Relapse 4% (23/519) 0% (0/58)

Other‡ 2% (10/519) 5% (3/58)

SVR by cirrhosis status

Non-cirrhotic 93% (379/408) 92% (33/36)

Cirrhotic 94% (104/111) 100% (22/22)

SVR by presence of baseline NS5A resistance-associated polymorphisms†, §

Absent 97% (464/476) 100% (51/51)

Present 53% (16/30) 100% (4/4)

SVR by baseline HCV RNA<=800,000 IU/mL 98% (135/138) 100% (9/9)>800,000 IU/mL 91% (348/381) 94% (46/49)¶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 virologicfailure.§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% weretreatment-naïve subjects; 23% were treatment-experienced subjects; mean body mass index was25 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 orelbasvir/grazoprevir with ribavirin for 16 weeks are presented in Table 11.

Table 11: SVR in genotype 4-infected subjects¶

Baseline Characteristics SVR

EBR with GZR EBR with GZR + RBV12 Weeks 16 Weeks

N=65 N=8

Overall SVR 94% (61/65) 100% (8/8)

Outcome for subjects without SVR

On-treatment virologic failure* 0% (0/65) 0% (0/8)

Relapse† 3% (2/65) 0% (0/8)

Other‡ 3% (2/65) 0% (0/8)

SVR by cirrhosis status

Non-cirrhotic§ 96% (51/53) 100% (4/4)

Cirrhotic 83% (10/12) 100% (4/4)

SVR by baseline HCV RNA<=800,000 IU/mL‡ 93% (27/29) 100% (3/3)>800,000 IU/mL† 94% (34/36) 100% (5/5)¶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.

In the C-SURFER study, overall SVR was achieved in 94 % (115/122) of subjects receiving EBR +

GZR for 12 weeks.

The efficacy of ZEPATIER was evaluated in an open-label clinical study in 22 paediatric subjects12 years to less than 18 years of age who received ZEPATIER for 12 weeks. HCV GT1a infectedsubjects with one or more baseline NS5A resistance-associated substitutions were excluded from studyparticipation.

In this study, treatment-naïve or treatment-experienced subjects 12 years to less than 18 years of agewith genotype 1 or 4 CHC, without cirrhosis, were treated with ZEPATIER for 12 weeks. The medianage was 13.5 years (range: 12 to 17); 50 % were female; 95 % were White; the weight range was28.1 kg to 96.5 kg; 95.5 % had genotype 1 and 4.5 % had genotype 4; 63.6 % were treatment-naïve,36.4 % were treatment-experienced; 45.5 % had baseline HCV RNA levels greater than800,000 IU/mL. The overall SVR12 rate was 100 % (22/22). The safety, pharmacokinetics andefficacy observed in this study were comparable to those observed in adults.

Following administration of elbasvir/grazoprevir to HCV-infected subjects, elbasvir peak plasmaconcentrations occur at a median Tmax of 3 hours (range of 3 to 6 hours); grazoprevir peak plasmaconcentrations occur at a median Tmax of 2 hours (range of 30 minutes to 3 hours). For elbasvir, theabsolute bioavailability is estimated to be 32%. For grazoprevir, the absolute bioavailability after a200 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 ofapproximately 1.5-fold and 2.8-fold, respectively. These differences in elbasvir and grazoprevirexposure are not clinically relevant; therefore, elbasvir/grazoprevir may be taken without regard tofood.

Elbasvir pharmacokinetics are similar in healthy subjects and HCV-infected subjects. Grazoprevir oralexposures 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, thegeometric 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 were1,860 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.

Elbasvir and grazoprevir are extensively bound (> 99.9 % and 98.8 %, respectively) to human plasmaproteins. Both elbasvir and grazoprevir bind to human serum albumin and 1-acid glycoprotein.

Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment.

The geometric mean apparent terminal half-life (% geometric mean coefficient of variation) isapproximately 24 (24 %) hours at 50 mg elbasvir and approximately 31 (34 %) hours at 100 mggrazoprevir in HCV-infected subjects.

Elbasvir and grazoprevir are partially eliminated by oxidative metabolism, primarily by CYP3A. Nocirculating 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.

Elbasvir pharmacokinetics were approximately dose-proportional over the range of 5-100 mg oncedaily. Grazoprevir pharmacokinetics increased in a greater than dose-proportional manner over therange of 10-800 mg once daily in HCV-infected subjects.

In non-HCV-infected subjects with severe renal impairment (eGFR < 30 mL/min/1.73 m2) who werenot 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). Innon-HCV-infected subjects with dialysis-dependent, severe renal impairment, elbasvir and grazoprevir

AUC values were unchanged compared to subjects with normal renal function. Concentrations ofelbasvir were not quantifiable in the dialysate samples. Less than 0.5 % of grazoprevir was recoveredin dialysate over a 4-hour dialysis session.

In population pharmacokinetic analysis in HCV-infected patients, elbasvir and grazoprevir AUCs were25 % 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 elbasvirand grazoprevir AUC in patients without severe renal 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 by28 % and 12%, respectively, while the grazoprevir steady-state AUC0-24 was increased 5-fold and12-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 thatgrazoprevir steady-state AUC0-24 increased by approximately 65 % in HCV-infected patients withcompensated cirrhosis (all with CP-A) compared to HCV-infected non-cirrhotic patients, whileelbasvir steady-state AUC was similar (see section 4.2).

The pharmacokinetics of elbasvir and grazoprevir have been evaluated in 22 paediatric subjects12 years of age and older who received a daily dose of ZEPATIER (50 mg elbasvir/100 mggrazoprevir). Elbasvir and grazoprevir exposures in paediatric subjects were comparable to thoseobserved in adults.

In paediatric subjects 12 years of age and older, the geometric mean steady-state elbasvir AUC0-24 and

Cmax at 50 mg were 2,410 nM*hr and 190 nM, respectively, and the geometric mean steady-stategrazoprevir AUC0-24 and Cmax at 100 mg were 1,450 nM*hr and 246 nM, respectively.

In population pharmacokinetic analyses, elbasvir and grazoprevir AUCs are estimated to be 16 % and45 % 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 isrecommended based on age (see sections 4.2 and 4.4).

In population pharmacokinetic analyses, elbasvir and grazoprevir AUCs are estimated to be 50 % and30 % 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).

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. Thischange is not clinically relevant for grazoprevir. Therefore, no dose adjustment ofelbasvir/grazoprevir is recommended based on weight/BMI (see section 4.4).

In population pharmacokinetic analyses, elbasvir and grazoprevir AUCs are estimated to be 15 % and50 % higher, respectively, for Asians compared to Whites. Population pharmacokinetics estimates ofexposure 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 isrecommended based on race/ethnicity (see section 4.4).

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, and toxicity to reproduction and developmentwith grazoprevir or elbasvir. Effects in non-clinical studies were observed only at exposuresconsidered sufficiently in excess of the maximum human exposure indicating little relevance toclinical use. Carcinogenicity studies for grazoprevir and elbasvir have not been conducted.

Elbasvir was given to rats and rabbits without eliciting adverse effects on embryofetal or post nataldevelopment at up to the highest doses tested (approximately 9- and 17-fold above human exposure inrats 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 maternalplasma concentrations.

Grazoprevir was given to rats and rabbits without eliciting adverse effects on embryofetal or post nataldevelopment at up to highest doses tested (approximately 79- and 39-fold above human exposure inrats 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 maternalplasma concentrations.

Sodium laurilsulfate

Vitamin E polyethylene glycol succinate

Copovidone

Hypromellose

Microcrystalline cellulose

Mannitol (E421)

Lactose monohydrate

Croscarmellose sodium

Sodium chloride

Colloidal anhydrous silica

Magnesium stearate

Lactose monohydrate

Hypromellose

Titanium dioxide

Triacetin

Iron oxide yellow (E172)

Iron oxide red (E172)

Iron oxide black (E172)

Carnauba wax

Not applicable.

3 years.

This medicinal product does not require any special temperature storage conditions. Store in theoriginal package until use to protect from moisture.

The tablets are packaged into a carton containing two (2) cardboard cards, each cardboard cardcontaining (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 localrequirements.

Merck Sharp & Dohme B.V.

Waarderweg 392031 BN Haarlem

The Netherlands

EU/1/16/1119/001

Date of first authorisation: 22 July 2016

Date of latest renewal: 06 May 2021

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.