Zepatier

1

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

 



2

This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions.

1. NAME OF THE MEDICINAL PRODUCT

ZEPATIER 50 mg/100 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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

Excipients with known effect

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

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet.

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

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

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.

4.2 Posology and method of administration

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):

 



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Table 1: Recommended ZEPATIER therapy for treatment of chronic hepatitis C infection in 
patients with or without compensated cirrhosis (Child-Pugh A only)
HCV genotype Treatment and duration 

1a ZEPATIER for 12 weeks

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

1b ZEPATIER for 12 weeks

4 ZEPATIER for 12 weeks

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

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.

 



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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). 

4.3 Contraindications

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 as 
rifampicin, atazanavir, darunavir, lopinavir, saquinavir, tipranavir, cobicistat or ciclosporin (see 
sections 4.4 and 4.5).

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

4.4 Special warnings and precautions for use

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).

 



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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 recommended for use in children and adolescents under 18 years of age because the 
safety and efficacy have not been established in this population.

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.

4.5 Interaction with other medicinal products and other forms of interaction

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). 

 



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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.

 



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Table 2: Interactions and dose recommendations with other medicinal products
Medicinal 
product by 
therapeutic 
areas 

Effects on medicinal product levels. 
Mean ratio (90 % confidence interval) 
for AUC, Cmax, C12 or C24
(likely mechanism of interaction)

Recommendation concerning co-
administration with ZEPATIER

ACID REDUCING AGENTS 
H2-receptor antagonists
Famotidine 
(20 mg single 
dose)/ elbasvir (50 
mg single dose)/ 
grazoprevir (100
mg single dose) 

↔ Elbasvir
AUC 1.05 (0.92, 1.18) 
Cmax 1.11 (0.98, 1.26) 
C24 1.03 (0.91, 1.17)

↔ Grazoprevir
AUC 1.10 (0.95, 1.28) 

Cmax 0.89 (0.71, 1.11) 
C24 1.12 (0.97, 1.30)

No dose adjustment is required.

Proton pump inhibitors
Pantoprazole
(40 mg once daily)/ 
elbasvir (50 mg 
single dose)/
grazoprevir (100 
mg single dose) 

↔ Elbasvir
AUC 1.05 (0.93, 1.18) 
Cmax 1.02 (0.92, 1.14) 
C24
1.03 (0.92, 1.17)

↔ Grazoprevir
AUC 1.12 (0.96, 1.30) 
Cmax 1.10 (0.89, 1.37) 
C24 1.17 (1.02, 1.34)

No dose adjustment is required.

Antacids
Aluminium or 
magnesium 
hydroxide; calcium 
carbonate

Interaction not studied. 
Expected: 
↔ Elbasvir
↔ Grazoprevir

No dose adjustment is required.

ANTIARRHYTHMICS
Digoxin
(0.25 mg single 
dose)/  elbasvir 
(50 mg once daily)

↔ Digoxin
AUC 1.11 (1.02, 1.22)
Cmax 1.47 (1.25, 1.73) 

(P-gp inhibition)

No dose adjustment is required.

ANTICOAGULANTS
Dabigatran
etexilate

Interaction not studied. 
Expected: 
↑ Dabigatran

(P-gp inhibition)

Concentrations of dabigatran may 

increase when co-administered with 

elbasvir, with possible increased bleeding 

risk. Clinical and laboratory monitoring is 

recommended. 
Vitamin K 
antagonists

Interaction not studied. Close monitoring of INR is recommended 

with all vitamin K antagonists. This is due 

to liver function changes during treatment 

with ZEPATIER.

ANTICONVULSANTS
Carbamazepine
Phenytoin

Interaction not studied. 
Expected: 
↓ Elbasvir
↓ Grazoprevir

(CYP3A or P-gp induction)

Co-administration is contraindicated.

 



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Medicinal 
product by 
therapeutic 
areas 

Effects on medicinal product levels. 
Mean ratio (90 % confidence interval) 
for AUC, Cmax, C12 or C24
(likely mechanism of interaction)

Recommendation concerning co-
administration with ZEPATIER

ANTIFUNGALS
Ketoconazole

(400 mg PO once 
daily)/ elbasvir 
(50 mg single dose)

↔ Elbasvir
AUC 1.80 (1.41, 2.29)
Cmax 1.29 (1.00, 1.66) 
C24 1.89 (1.37, 2.60)

Co-administration is not recommended.

(400 mg PO once 
daily)/ grazoprevir 
(100 mg single 
dose)

↑ Grazoprevir
AUC 3.02 (2.42, 3.76) 
Cmax 1.13 (0.77, 1.67)

(CYP3A inhibition)

ANTIMYCOBACTERIALS
Rifampicin
(600 mg IV single 
dose)/ elbasvir 
(50 mg single dose)

↔ Elbasvir
AUC 1.22 (1.06, 1.40)
Cmax 1.41 (1.18, 1.68) 
C24 1.31 (1.12, 1.53) 

Co-administration is contraindicated.

(600 mg IV single 
dose)/ grazoprevir 
(200 mg single 
dose)

↑ Grazoprevir
AUC 10.21 (8.68, 12.00) 
Cmax 10.94 (8.92, 13.43)
C24 1.77 (1.40, 2.24) 

(OATP1B inhibition)
(600 mg PO single 
dose)/ elbasvir 
(50 mg single dose)

↔ Elbasvir
AUC 1.17 (0.98, 1.39)
Cmax 1.29 (1.06, 1.58) 
C24 1.21 (1.03, 1.43)

(600 mg PO single 
dose)/ grazoprevir 
(200 mg once 
daily)

↑ Grazoprevir
AUC 8.35 (7.38, 9.45)
Cmax 6.52 (5.16, 8.24) 
C24 1.31 (1.12, 1.53)

(OATP1B inhibition)
(600 mg PO once 
daily)/ grazoprevir 
(200 mg once 
daily) 

↔ Grazoprevir
AUC 0.93 (0.75, 1.17) 
Cmax 1.16 (0.82, 1.65) 
C24 0.10 (0.07, 0.13)

(OATP1B inhibition and CYP3A induction)

ASTHMA AGENTS
Montelukast
(10 mg single 
dose)/ grazoprevir 
(200 mg single 
dose)

↔ Montelukast
AUC 1.11 (1.01, 1.20)
Cmax 0.92 (0.81, 1.06) 
C24 1.39 (1.25, 1.56)

No dose adjustment is required.

ENDOTHELIN ANTAGONIST
Bosentan Interaction not studied. 

Expected: 
↓ Elbasvir
↓ Grazoprevir

(CYP3A or P-gp induction)

Co-administration is contraindicated.

 



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Medicinal 
product by 
therapeutic 
areas 

Effects on medicinal product levels. 
Mean ratio (90 % confidence interval) 
for AUC, Cmax, C12 or C24
(likely mechanism of interaction)

Recommendation concerning co-
administration with ZEPATIER

HCV ANTIVIRAL AGENTS
Sofosbuvir
(400 mg single 
dose sofosbuvir)/ 
elbasvir (50 mg 
once daily)/ 
grazoprevir 
(200 mg once daily

↔ Sofosbuvir
AUC 2.43 (2.12, 2.79)
Cmax 2.27 (1.72, 2.99) 

↔ GS-331007
AUC 1.13 (1.05, 1.21)
Cmax 0.87 (0.78, 0.96) 
C24 1.53 (1.43, 1.63)

No dose adjustment is required. 

HERBAL SUPPLEMENTS
St. John’s wort 
(Hypericum 
perforatum)

Interaction not studied. 
Expected: 
↓ Elbasvir
↓ Grazoprevir

(CYP3A or P-gp induction)

Co-administration is contraindicated.

HBV AND HIV ANTIVIRAL AGENTS: NUCLEOS(T)IDE REVERSE TRANSCRIPTASE 
INHIBITORS
Tenofovir disoproxil fumarate
(300 mg once 
daily)/ elbasvir 
(50 mg once daily)

↔ Elbasvir
AUC 0.93 (0.82, 1.05)
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) 

No dose adjustment is required. 

(300 mg once 
daily)/ grazoprevir 
(200 mg once 
daily)

↔ Grazoprevir
AUC 0.86 (0.55, 1.12)
Cmax 0.78 (0.51, 1.18) 
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 
daily)/elbasvir 
(50 mg once 
daily)/grazoprevir 
(100 mg once 
daily)

↔ Tenofovir 
AUC 1.27 (1.20, 1.35)
Cmax 1.14 (0.95, 1.36) 
C24 1.23 (1.09, 1.40)

 



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Medicinal 
product by 
therapeutic 
areas 

Effects on medicinal product levels. 
Mean ratio (90 % confidence interval) 
for AUC, Cmax, C12 or C24
(likely mechanism of interaction)

Recommendation concerning co-
administration with ZEPATIER

Lamivudine
Abacavir
Entecavir

Interaction not studied. 
Expected: 
↔ Elbasvir
↔ Grazoprevir
↔ Lamivudine
↔ Abacavir
↔ Entecavir

No dose adjustment is required. 

Emtricitabine
(200 mg once 
daily)

Interaction studied with 

elvitegravir/cobicistat/emtricitabine/tenofovir 

disoproxil fumarate (fixed-dose 

combination)

↔ Emtricitabine
AUC 1.07 (1.03, 1.10)
Cmax 0.96 (0.90, 1.02) 
C24 1.19 (1.13, 1.25)

No dose adjustment is required.

HIV ANTIVIRAL AGENTS: PROTEASE INHIBITORS
Atazanavir/ritonavir
(300 mg once 
daily)/ ritonavir 
(100 mg once daily/ 
elbasvir (50 mg 
once daily)

↑ Elbasvir 
AUC 4.76 (4.07, 5.56)
Cmax 4.15 (3.46, 4.97) 
C24 6.45 (5.51, 7.54)

(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)

Co-administration is contraindicated.

(300 mg once 
daily)/ ritonavir 
(100 mg once daily/ 
grazoprevir 
(200 mg once 
daily)

↑ Grazoprevir 
AUC 10.58 (7.78, 14.39) 
Cmax 6.24 (4.42, 8.81) 
C24 11.64 (7.96, 17.02)

(combination of OATP1B and CYP3A 
inhibition)

↔ Atazanavir
AUC 1.43 (1.30, 1.57) 
Cmax 1.12 (1.01, 1.24) 
C24 1.23 (1.13, 2.34)

 



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Medicinal 
product by 
therapeutic 
areas 

Effects on medicinal product levels. 
Mean ratio (90 % confidence interval) 
for AUC, Cmax, C12 or C24
(likely mechanism of interaction)

Recommendation concerning co-
administration with ZEPATIER

Darunavir/ritonavir
(600 mg twice 
daily)/ ritonavir 
(100 mg twice 
daily/ elbasvir 
(50 mg once daily)

↔ Elbasvir
AUC 1.66 (1.35, 2.05)
Cmax 1.67 (1.36, 2.05) 
C24 1.82 (1.39, 2.39)

↔ Darunavir
AUC 0.95 (0.86, 1.06)
Cmax 0.95 (0.85, 1.05) 
C12 0.94 (0.85, 1.05)

Co-administration is contraindicated.

(600 mg twice 
daily)/ ritonavir 
(100 mg twice 
daily/ grazoprevir 
(200 mg once 
daily)

↑ Grazoprevir
AUC 7.50 (5.92, 9.51)
Cmax 5.27 (4.04, 6.86)
C24 8.05 (6.33, 10.24)
  
(combination of OATP1B and CYP3A 
inhibition)

↔ 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 
daily)/ ritonavir 
(100 mg twice 
daily/ elbasvir 
(50 mg once daily)

↑ Elbasvir
AUC 3.71 (3.05, 4.53)
Cmax 2.87 (2.29, 3.58) 
C24 4.58 (3.72, 5.64)

(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)

Co-administration is contraindicated.

(400 mg twice 
daily)/ ritonavir 
(100 mg twice 
daily/ grazoprevir 
(200 mg once 
daily)

↑ Grazoprevir
AUC 12.86 (10.25, 16.13)
Cmax 7.31 (5.65, 9.45)
C24 21.70 (12.99, 36.25)

(combination of OATP1B and CYP3A 
inhibition)

↔ Lopinavir
AUC 1.03 (0.96, 1.16)
Cmax 0.97 (0.88, 1.08)
C12 0.97 (0.81, 1.15)  

Saquinavir/ritonavir
Tipranavir/ritonavir
Atazanavir

Interaction not studied.
Expected: 
↑ Grazoprevir

(combination of mechanisms including 
CYP3A inhibition)

Co-administration is contraindicated.

 



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Medicinal 
product by 
therapeutic 
areas 

Effects on medicinal product levels. 
Mean ratio (90 % confidence interval) 
for AUC, Cmax, C12 or C24
(likely mechanism of interaction)

Recommendation concerning co-
administration with ZEPATIER

HIV ANTIVIRAL AGENTS: NON-NUCLEOSIDE HIV REVERSE TRANSCRIPTASE 
INHIBITORS
Efavirenz
(600 mg once 
daily)/ elbasvir 
(50 mg once daily)

↓ Elbasvir
AUC 0.46 (0.36, 0.59)
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)

Co-administration is contraindicated.

(600 mg once 
daily)/ grazoprevir 
(200 mg once 
daily)

↓Grazoprevir
AUC 0.17 (0.13, 0.24)
Cmax 0.13 (0.09, 0.19)
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. 
Expected: 
↓ Elbasvir
↓ Grazoprevir

(CYP3A or P-gp induction)

Co-administration is contraindicated.

Rilpivirine
(25 mg once daily)/ 
elbasvir (50 mg 
once daily)/ 
grazoprevir 
(200 mg once 
daily) 

↔ Elbasvir
AUC 1.07 (1.00, 1.15)
Cmax 1.07 (0.99, 1.16) 
C24 1.04 (0.98, 1.11) 

↔ Grazoprevir
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) 

No dose adjustment is required.

 



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Medicinal 
product by 
therapeutic 
areas 

Effects on medicinal product levels. 
Mean ratio (90 % confidence interval) 
for AUC, Cmax, C12 or C24
(likely mechanism of interaction)

Recommendation concerning co-
administration with ZEPATIER

HIV ANTIVIRAL AGENTS: INTEGRASE STRAND TRANSFER INHIBITORS
Dolutegravir
(50 mg single 
dose)/ elbasvir 
(50 mg once daily)/ 
grazoprevir 
(200 mg once 
daily) 

↔ Elbasvir
AUC 0.98 (0.93, 1.04)
Cmax 0.97 (0.89, 1.05) 
C24 0.98 (0.93, 1.03) 

↔ Grazoprevir
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) 

No dose adjustment is required.

Raltegravir
(400 mg single 
dose)/ elbasvir 
(50 mg single dose)

↔ Elbasvir
AUC 0.81 (0.57, 1.17)
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) 

No dose adjustment is required.

(400 mg twice 
daily)/ grazoprevir 
(200 mg once 
daily) 

↔ Grazoprevir
AUC 0.89 (0.72, 1.09)
Cmax 0.85 (0.62, 1.16) 
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)

 



14

Medicinal 
product by 
therapeutic 
areas 

Effects on medicinal product levels. 
Mean ratio (90 % confidence interval) 
for AUC, Cmax, C12 or C24
(likely mechanism of interaction)

Recommendation concerning co-
administration with ZEPATIER

HIV ANTIVIRAL AGENTS: OTHER
Elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (fixed-dose combination)
elvitegravir 
(150 mg once 
daily)/cobicistat 
(150 mg once 
daily)/ 
emtricitabine 
(200 mg once 
daily)/ tenofovir 
disoproxil fumarate 
(300 mg once 
daily)/elbasvir 
(50 mg once daily)/ 
grazoprevir 
(100 mg once 
daily) 

↑ Elbasvir
AUC 2.18 (2.02, 2.35)
Cmax 1.91 (1.77, 2.05) 
C24 2.38 (2.19, 2.60)

(CYP3A and OATP1B inhibition)

↑ Grazoprevir
AUC 5.36 (4.48, 6.43)
Cmax 4.59 (3.70, 5.69) 
C24 2.78 (2.48, 3.11) 

(CYP3A and OATP1B inhibition)

↔ 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)

Co-administration with ZEPATIER is 
contraindicated.

HMG-CoA REDUCTASE INHIBITORS
Atorvastatin
(20 mg single 
dose)/ grazoprevir 
(200 mg once 
daily) 

↑ Atorvastatin
AUC 3.00 (2.42, 3.72)
Cmax 5.66 (3.39, 9.45) 

(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) 

The dose of atorvastatin should not 
exceed a daily dose of 20 mg when 
co-administered with ZEPATIER.

(10 mg single 
dose)/ elbasvir 
(50 mg once daily) 
/ grazoprevir 
(200 mg once 
daily) 

↑ Atorvastatin
AUC 1.94 (1.63, 2.33)
Cmax 4.34 (3.10, 6.07) 
C24 0.21 (0.17, 0.26) 

 



15

Medicinal 
product by 
therapeutic 
areas 

Effects on medicinal product levels. 
Mean ratio (90 % confidence interval) 
for AUC, Cmax, C12 or C24
(likely mechanism of interaction)

Recommendation concerning co-
administration with ZEPATIER

Rosuvastatin
(10 mg single 
dose)/ grazoprevir 
(200 mg once 
daily) 

↑ Rosuvastatin
AUC 1.59 (1.33, 1.89)
Cmax 4.25 (3.25, 5.56) 
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) 

The dose of rosuvastatin should not 
exceed a daily dose of 10 mg when 
co-administered with ZEPATIER.

(10 mg single 
dose)/ elbasvir 
(50 mg once daily)/ 
grazoprevir 
(200 mg once 
daily)

↑ Rosuvastatin
AUC 2.26 (1.89, 2.69)
Cmax 5.49 (4.29, 7.04) 
C24 0.98 (0.84, 1.13) 

(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
Lovastatin
Simvastatin

Interaction not studied. 
Expected: 
↑ Fluvastatin
(primarily due to intestinal BCRP inhibition)

↑ Lovastatin
(CYP3A inhibition) 

↑ Simvastatin
(primarily due to intestinal BCRP inhibition 
and CYP3A inhibition)

The dose of fluvastatin, lovastatin, or 
simvastatin should not exceed a daily dose 
of 20 mg when co-administered with 
ZEPATIER.

Pitavastatin
(1 mg single dose)/ 
grazoprevir 
(200 mg once 
daily) 

↔ Pitavastatin
AUC 1.11 (0.91, 1.34)
Cmax 1.27 (1.07, 1.52) 

↔ Grazoprevir
AUC 0.81 (0.70, 0.95)
Cmax 0.72 (0.57, 0.92) 
C24 0.91 (0.82, 1.01) 

No dose adjustment is required.

 



16

Medicinal 
product by 
therapeutic 
areas 

Effects on medicinal product levels. 
Mean ratio (90 % confidence interval) 
for AUC, Cmax, C12 or C24
(likely mechanism of interaction)

Recommendation concerning co-
administration with ZEPATIER

Pravastatin
(40 mg single 
dose)/ elbasvir 
(50 mg once daily)/ 
grazoprevir 
(200 mg once 
daily) 

↔ Pravastatin
AUC 1.33 (1.09, 1.64)
Cmax 1.28 (1.05, 1.55)

↔ Elbasvir
AUC 0.98 (0.93, 1.02)
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) 

No dose adjustment is required.

IMMUNOSUPPRESSANTS
Ciclosporin
(400 mg single 
dose)/ elbasvir 
(50 mg once daily)/ 
grazoprevir 
(200 mg once 
daily) 

↔ Elbasvir
AUC 1.98 (1.84, 2.13)
Cmax 1.95 (1.84, 2.07) 
C24 2.21 (1.98, 2.47) 

↑ Grazoprevir
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 CYP3A 
inhibition)

↔ Ciclosporin
AUC 0.96 (0.90, 1.02)
Cmax 0.90 (0.85, 0.97) 
C12 1.00 (0.92, 1.08) 

Co-administration is contraindicated.

Mycophenolate 
mofetil
(1,000 mg single 
dose)/ elbasvir 
(50 mg once daily)/ 
grazoprevir 
(200 mg once 
daily) 

↔ Elbasvir
AUC 1.07 (1.00, 1.14)
Cmax 1.07 (0.98, 1.16) 
C24 1.05 (0.97, 1.14) 

↔ Grazoprevir
AUC 0.74 (0.60, 0.92)
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) 

No dose adjustment is required.

 



17

Medicinal 
product by 
therapeutic 
areas 

Effects on medicinal product levels. 
Mean ratio (90 % confidence interval) 
for AUC, Cmax, C12 or C24
(likely mechanism of interaction)

Recommendation concerning co-
administration with ZEPATIER

Prednisone
(40 mg single 
dose)/ elbasvir 
(50 mg once daily)/ 
grazoprevir 
(200 mg once daily 

↔ Elbasvir
AUC 1.17 (1.11, 1.24)
Cmax 1.25 (1.16, 1.35) 
C24 1.04 (0.97, 1.12) 

↔ 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) 

No dose adjustment is required.

Tacrolimus
(2 mg single dose)/ 
elbasvir (50 mg 
once daily)/ 
grazoprevir 
(200 mg once 
daily) 

↔ Elbasvir
AUC 0.97 (0.90, 1.06)
Cmax 0.99 (0.88, 1.10) 
C24 0.92 (0.83, 1.02) 

↔ Grazoprevir
AUC 1.12 (0.97, 1.30)
Cmax 1.07 (0.83, 1.37) 
C24 0.94 (0.87, 1.02) 

↑ Tacrolimus
AUC 1.43 (1.24, 1.64)
Cmax 0.60 (0.52, 0.69) 
C12 1.70 (1.49, 1.94) 

(CYP3A inhibition)

Frequent monitoring of tacrolimus whole 
blood concentrations, changes in renal 
function, and tacrolimus-associated 
adverse events upon the initiation of co-
administration is recommended. Close 
monitoring and potential dose adjustment 
of tacrolimus may be required during 
therapy, as tacrolimus levels may decrease 
related to clearance of HCV.

KINASE INHIBITOR
Sunitinib Interaction not studied. 

Expected: 
↑ sunitinib

(possibly due to intestinal BCRP inhibition)

Co-administration of ZEPATIER with 
sunitinib may increase sunitinib 
concentrations leading to an increased risk 
of sunitinib-associated adverse events. 
Use with caution; dose adjustment of 
sunitinib may be required.

 



18

Medicinal 
product by 
therapeutic 
areas 

Effects on medicinal product levels. 
Mean ratio (90 % confidence interval) 
for AUC, Cmax, C12 or C24
(likely mechanism of interaction)

Recommendation concerning co-
administration with ZEPATIER

OPIOID-SUBSTITUTION THERAPY
Buprenorphine/naloxone
(8 mg/2 mg single 
dose)/ elbasvir 
(50 mg single dose)

↔ Elbasvir
AUC 1.22 (0.98, 1.52)
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)

No dose adjustment is required.

(8-24 mg/2-6 mg 
once daily)/ 
grazoprevir 
(200 mg once 
daily)

↔ Grazoprevir
AUC 0.80 (0.53, 1.22)
Cmax 0.76 (0.40, 1.44) 
C24 0.69 (0.54, 0.88) 

↔ Buprenorphine
AUC 0.98 (0.81, 1.19)
Cmax 0.90 (0.76, 1.07) 

Methadone
(20-120 mg once 
daily)/ elbasvir 
(50 mg once daily)

↔ R-Methadone
AUC 1.03 (0.92, 1.15)
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)

No dose adjustment is required. 

(20-150 mg once 
daily)/ grazoprevir 
(200 mg once 
daily)

↔ R-Methadone
AUC 1.09 (1.02, 1.17)
Cmax 1.03 (0.96, 1.11) 

↔ 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/ 
0.15 mg LNG 
single-dose)/ 
elbasvir (50 mg 
once daily)

↔ EE
AUC 1.01 (0.97, 1.05)
Cmax 1.10 (1.05, 1.16) 

↔ LNG
AUC 1.14 (1.04, 1.24)
Cmax 1.02 (0.95, 1.08)

No dose adjustment is required.

(0.03 mg EE/ 
0.15 mg LNG 
single-dose)/ 
grazoprevir 
(200 mg once 
daily)

↔ EE
AUC 1.10 (1.05, 1.14)
Cmax 1.05 (0.98, 1.12) 

↔ LNG
AUC 1.23 (1.15, 1.32)
Cmax 0.93 (0.84, 1.03)

 



19

Medicinal 
product by 
therapeutic 
areas 

Effects on medicinal product levels. 
Mean ratio (90 % confidence interval) 
for AUC, Cmax, C12 or C24
(likely mechanism of interaction)

Recommendation concerning co-
administration with ZEPATIER

PHOSPHATE BINDERS
Calcium acetate
(2,668 mg single
dose)/ elbasvir 
(50 mg single 
dose)/ grazoprevir 
(100 mg single 
dose) 

↔ Elbasvir
AUC 0.92 (0.75, 1.14) 
Cmax 0.86 (0.71, 1.04) 
C24 0.87 (0.70, 1.09)

↔ Grazoprevir
AUC 0.79 (0.68, 0.91)
Cmax 0.57 (0.40, 0.83) 
C24 0.77 (0.61, 0.99)

No dose adjustment is required.

Sevelamer 
carbonate
(2,400 mg single 
dose)/ elbasvir 
(50 mg single 
dose)/ grazoprevir 
(100 mg single 
dose) 

↔ Elbasvir
AUC 1.13 (0.94, 1.37) 
Cmax 1.07 (0.88, 1.29) 
C24 1.22 (1.02, 1.45)

↔ Grazoprevir
AUC 0.82 (0.68, 0.99) 
Cmax 0.53 (0.37, 0.76) 
C24 0.84 (0.71, 0.99)

SEDATIVES
Midazolam
(2 mg single dose)/ 
grazoprevir 
(200 mg once 
daily)

↔ Midazolam
AUC 1.34 (1.29, 1.39)
Cmax 1.15 (1.01, 1.31) 

No dose adjustment is required. 

STIMULANTS
Modafinil Interaction not studied. 

Expected: 
↓ Elbasvir
↓ Grazoprevir

(CYP3A or P-gp induction)

Co-administration is contraindicated.

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

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 

 



20

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). 

4.7 Effects on ability to drive and use machines

ZEPATIER (administered alone or in combination with ribavirin) is not likely to have an effect on the 
ability to drive and use machines. Patients should be informed that fatigue has been reported during 
treatment with ZEPATIER (see section 4.8).

4.8 Undesirable effects

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).

 



21

Table 3: Adverse reactions identified with ZEPATIER*

Frequency Adverse reactions
Metabolism and nutrition disorders:
Common decreased appetite
Psychiatric disorders:
Common insomnia, anxiety, depression
Nervous system disorders: 
Very common headache
Common dizziness
Gastrointestinal disorders:
Common nausea, diarrhoea, constipation, upper abdominal pain, abdominal 

pain, dry mouth, vomiting
Skin and subcutaneous tissue disorders:
Common pruritus, alopecia
Musculoskeletal and connective tissue disorders:
Common arthralgia, myalgia
General disorders and administration site conditions:
Very common fatigue
Common asthenia, irritability
*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
Laboratory Parameters ZEPATIER*

N = 834
n (%)

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.

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. 

 



22

Paediatric population

No data are available.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.

4.9 Overdose

Human experience of overdose with ZEPATIER is limited. The highest dose of elbasvir was 200 mg 
once daily for 10 days, and a single dose of 800 mg. The highest dose of grazoprevir was 1,000 mg 
once daily for 10 days, and a single dose of 1,600 mg. In these healthy volunteer studies, adverse 
reactions were similar in frequency and severity to those reported in the placebo groups.

In case of overdose, it is recommended that the patient be monitored for any signs or symptoms of 
adverse reactions and appropriate symptomatic treatment instituted. 

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

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

Mechanism of action

ZEPATIER combines two direct-acting antiviral agents with distinct mechanisms of action and non-
overlapping resistance profiles to target HCV at multiple steps in the viral lifecycle.

Elbasvir is an inhibitor of HCV NS5A, which is essential for viral RNA replication and virion 
assembly. 

Grazoprevir is an inhibitor of the HCV NS3/4A protease which is necessary for the proteolytic 
cleavage of the HCV encoded polyprotein (into mature forms of the NS3, NS4A, NS4B, NS5A, and 
NS5B proteins) and is essential for viral replication. In a biochemical assay, grazoprevir inhibited the 
proteolytic activity of the recombinant NS3/4A protease enzymes from HCV genotypes 1a, 1b, 3 and
4a with IC50 values ranging from 4 to 690 pM. 

Antiviral activity

The EC50 values of elbasvir and grazoprevir against full-length or chimeric replicons encoding NS5A 
or NS3 sequences from reference sequences and clinical isolates are presented in Table 5.

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


23

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

Resistance

In cell culture 
HCV replicons with reduced susceptibility to elbasvir and grazoprevir have been selected in cell 
culture for genotypes 1a, 1b and 4. 

For elbasvir, in HCV genotype 1a replicons, single NS5A substitutions Q30D/E/H/R, L31M/V and 
Y93C/H/N reduced elbasvir antiviral activity by 6- to 2,000-fold. In genotype 1b replicons, single 
NS5A substitutions L31F and Y93H reduced elbasvir antiviral activity by 17-fold. In genotype 4 
replicons, single NS5A substitutions L30S, M31V, and Y93H reduced elbasvir antiviral activity by 3-
to 23-fold. In general, in HCV genotype 1a, 1b or 4 combinations of elbasvir resistance-associated 
substitutions further reduced elbasvir antiviral activity.

For grazoprevir, in HCV genotype 1a replicons, single NS3 substitutions D168A/E/G/S/V reduced 
grazoprevir antiviral activity by 2- to 81-fold. In genotype 1b replicons, single NS3 substitutions 
F43S, A156S/T/V, and D168A/G/V reduced grazoprevir antiviral activity by 3- to 375-fold. In 
genotype 4 replicons, single NS3 substitutions D168A/V reduced grazoprevir antiviral activity by 110-
to 320-fold. In general, in HCV genotype 1a, 1b or 4 replicons, combinations of grazoprevir 
resistance-associated substitutions further reduced grazoprevir antiviral activity.

In clinical studies
In a pooled analysis of subjects treated with regimens containing elbasvir/grazoprevir or elbasvir + 
grazoprevir with or without ribavirin in Phase 2 and 3 clinical studies, resistance analyses were 
conducted for 50 subjects who experienced virologic failure and had sequence data available (6 with 
on-treatment virologic failure, 44 with post-treatment relapse). 

Treatment-emergent substitutions observed in the viral populations of these subjects based on 
genotypes are shown in Table 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 subjects.

 



24

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 studies

Target Emergent Amino Acid 
Substitutions

Genotype 1a
N = 37
% (n)

Genotype 1b
N = 8
% (n)

Genotype 4
N = 5
% (n)

NS5A Any of the following NS5A 
substitutions: M/L28A/G/T/S* 
Q30H/K/R/Y, L/M31F/M/I/V, 
H/P58D, Y93H/N/S 

81% (30) 88% (7) 100% (5)

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 
substitutions: V36L/M, Y56F/H,
V107I, R155I/K, A156G/M/T/V, 
V158A, D168A/C/E/G/N/V/Y, 
V170I

78% (29) 25% (2) 40% (2)

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

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. 

 



25

Grazoprevir is active in vitro against the following genotype 1a NS3 substitutions which confer 
resistance to other NS3/4A protease inhibitors: V36A/L/M, Q41R, F43L, T54A/S, V55A/I, Y56F, 
Q80K/R, V107I, S122A/G/R/T, I132V, R155K, A156S, D168N/S, I170T/V. Grazoprevir is active in 
vitro against the following genotype 1b NS3 substitutions conferring resistance to other NS3/4A
protease inhibitors: V36A/I/L/M, Q41L/R, F43S, T54A/C/G/S, V55A/I, Y56F, Q80L/R, V107I,
S122A/G/R, R155E/K/N/Q/S, A156G/S, D168E/N/S, V170A/I/T. Some NS3 substitutions at A156 
and at D168 confer reduced antiviral activity to grazoprevir as well as to other NS3/4A protease 
inhibitors. 

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

Persistence of resistance-associated substitutions 

The persistence of elbasvir and grazoprevir treatment-emergent amino acid substitutions in NS5A, and
NS3, respectively, was assessed in genotype 1-infected subjects in Phase 2 and 3 studies whose virus 
had treatment-emergent resistance-associated substitution in the drug target, and with available data 
through at least 24 weeks post-treatment using population (or Sanger) sequencing. 

Viral populations with treatment-emergent NS5A resistance-associated substitutions were generally 
more persistent than NS3 resistance associated substitutions. Among genotype 1a-infected subjects, 
NS5A resistance-associated substitutions persisted at detectable levels at follow-up week 12 in 95% 
(35/37) of subjects and in 100% (9/9) of subjects with follow-up week 24 data. Among genotype 1b-
infected subjects, NS5A resistance-associated substitutions persisted at detectable levels in 100% (7/7) 
of subjects at follow-up week 12 and in 100% (3/3) of subjects with follow-up week 24 data.

Among genotype 1a-infected subjects, NS3 resistance-associated substitutions persisted at detectable 
levels at follow-up week 24 in 31% (4/13) of subjects. Among genotype 1b-infected subjects, NS3 
resistance-associated substitutions persisted at detectable levels at follow-up week 24 in 50% (1/2) of 
subjects. 

Due to the limited number of genotype 4-infected subjects with treatment emergent NS5A and NS3 
resistance associated substitutions, trends in persistence of treatment emergent substitutions in this 
genotype could not be established.

The long-term clinical impact of the emergence or persistence of virus containing ZEPATIER 
resistance-associated substitutions is unknown.

Effect of baseline HCV polymorphisms on treatment response 

In pooled analyses of subjects who achieved SVR12 or met criteria for virologic failure, the 
prevalence and impact of NS5A polymorphisms (including M28T/A, Q30E/H/R/G/K/D, L31M/V/F, 
H58D, and Y93C/H/N) and NS3 polymorphisms (substitutions at positions 36, 54, 55, 56, 80, 107, 
122, 132, 155, 156, 158, 168, 170, and 175) that confer greater than 5-fold reduction of elbasvir and 
grazoprevir antiviral activity respectively in vitro were evaluated. The observed treatment response 
differences by treatment regimen in specific patient populations in the presence or absence of baseline 
NS5A or NS3 polymorphisms are summarised in Table 7.

 



26

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 
Population

Subjects without 
baseline NS5A

polymorphisms,*

% (n/N)

Subjects with 
baseline NS5A 

polymorphisms,*

% (n/N)

Subjects without 
baseline NS5A 

polymorphisms,*

% (n/N)

Subjects with 
baseline NS5A 

polymorphisms,*

% (n/N)

GT1a†
97%

(464/476)
53%

(16/30)
100%

(51/51)
100%
(4/4)

GT1b‡
99%

(259/260)
92%

(36/39)

Subjects without 
baseline NS3

polymorphisms,¶

% (n/N)

Subjects with 
baseline NS3 

polymorphisms,¶ 

% (n/N)
GT4 (treatment-
experienced)♯

86%
(25/29)

100%
(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 was 

7% (55/825)
‡Overall prevalence of GT1b-infected subjects with baseline NS5A polymorphisms in the pooled analyses was 

14% (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 was 

19% (7/36)

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).

 



27

Table 8: Studies conducted with ZEPATIER
Study Population Study Arms and 

Duration
(Number of 

Subjects Treated)

Additional Study Details

C-EDGE TN
(double-blind)

GT 1, 4, 6
TN with or 

without 
cirrhosis

 EBR/GZR* for 
12 weeks 
(N=316)

 Placebo for 
12 weeks 
(N=105)

Placebo-controlled study in which subjects 
were randomised in a 3:1 ratio to: EBR/GZR
for 12 weeks (immediate treatment group 
[ITG]) or placebo for 12 weeks followed by 
open-label treatment with EBR/GZR for 
12 weeks (deferred treatment group (DTG)).

C-EDGE 
COINFECTION 
(open-label)

GT 1, 4, 6
TN with or 

without 
cirrhosis

HCV/HIV-1 
co-infection

 EBR/GZR for 
12 weeks 
(N=218)

C-SURFER
(double-blind)

GT 1
TN or TE with 

or without 
cirrhosis
Chronic 
Kidney 
Disease

 EBR* + GZR*  
for 12 weeks 
(N=122) 

 Placebo for 
12 weeks 
(N=113)

Placebo-controlled study in subjects with 
CKD Stage 4 (eGFR 15-29 mL/min/1.73 m2)
or Stage 5 (eGFR < 15 mL/min/1.73 m2), 
including subjects on hemodialysis, Subjects 
were randomised in a 1:1 ratio to one of the 
following treatment groups: EBR + GZR for 
12 weeks (ITG) or placebo for 12 weeks 
followed by open-label treatment with 
EBR/GZR for 12 weeks (DTG). In addition, 
11 subjects received open-label EBR + GZR 
for 12 weeks (intensive PK arm).

C-WORTHY
(open-label)

GT 1, 3
TN with or 

without 
cirrhosis 
TE Null 

Responder 
with or without 

cirrhosis
TN HCV/HIV-
1 co-infection 

without 
cirrhosis

 EBR* + GZR*  
for 8, 12, or 
18 weeks 
(N=31, 136, 
and 63, 
respectively)

 EBR* + GZR*  
+ RBV† for 8, 
12, or 18 weeks 
(N=60, 152, 
and 65, 
respectively)

Multi-arm, multi-stage study.
Subjects with GT 1b infection without 
cirrhosis were randomised in a 1:1 ratio to 
EBR + GZR with or without RBV for 
8 weeks. 
TN subjects with GT 3 infection without 
cirrhosis were randomised to EBR + GZR 
with RBV for 12 or 18 weeks. 
TN subjects with GT 1 infection with or 
without cirrhosis (with or without HCV/HIV-
1 co-infection) or who were peg-IFN + RBV 
null responders, were randomised to EBR + 
GZR with or without RBV for 8, 12 or 
18 weeks.

C-SCAPE
(open-label)

GT 4, 6 
TN without 

cirrhosis

 EBR* + GZR*  
for 12 weeks 
(N=14) 

 EBR* + GZR*  
+ RBV† for 
12 weeks 
(N=14)

Subjects were randomised in a 1:1 ratio to the 
study arms.

 



28

Study Population Study Arms and 
Duration

(Number of 
Subjects Treated)

Additional Study Details

C-EDGE TE
(open-label)

GT 1, 4, 6
TE with or 

without 
cirrhosis, and 

with or without
HCV/HIV-1 
co-infection

 EBR/GZR for 
12 or 16 weeks 
(N=105 and 
105, 
respectively)

 EBR/GZR + 
RBV† for 12 or 
16 weeks 
(N=104 and
106, 
respectively)

Subjects were randomised in a 1:1:1:1 ratio to 
the study arms.

C-SALVAGE
(open-label)

GT 1
TE with HCV 

protease 
inhibitor 

regimen‡ with 
or without 
cirrhosis

 EBR* + GZR*  
+ RBV† for 
12 weeks 
(N=79)

Subjects who had failed prior treatment with 
boceprevir, simeprevir, or telaprevir in 
combination with peg-IFN + RBV received 
EBR + GZR with RBV for 12 weeks.

C-EDGE 
COSTAR
(double-blind)

GT 1, 4, 6
TN with or 

without 
cirrhosis 

Opiate agonist 
therapy

 EBR/GZR for 
12 weeks 
(N=201)

 Placebo for
12 weeks 
(N=100)

Placebo-controlled study in which subjects 
were randomised in a 2:1 ratio to EBR/GZR 
for 12 weeks (ITG) or placebo for 12 weeks 
followed by open-label treatment with 
EBR/GZR for 12 weeks (DTG). Subjects were 
not excluded or discontinued from the trial 
based on a positive urine drug screen.

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/1 other-infected subjects,  the median age was 55 years (range: 22 to 82); 61% 
were male; 60 % were White; 20% were Black or African American; 6% were Hispanic or Latino; 
82% were treatment-naïve subjects; 18% were treatment-experienced subjects; mean body mass index 
was 26 kg/m2; 64 % had baseline HCV RNA levels greater than 800,000 IU/mL; 22 % had cirrhosis; 
71% had non-C/C IL28B alleles (CT or TT); 18 % had HCV/HIV-1 co-infection.

Treatment outcomes in genotype 1b-infected subjects treated with elbasvir/grazoprevir for 12 weeks 
are presented in Table 9.

 



29

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 % 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.

 



30

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

Baseline Characteristics SVR

EBR with GZR EBR with GZR + RBV

12 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 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.

 



31

Table 11: SVR in genotype 4-infected subjects¶

Baseline Characteristics SVR

EBR with GZR EBR with GZR + RBV

12 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.

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).

5.2 Pharmacokinetic properties

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.

 



32

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 1-acid glycoprotein.
Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment.

Elimination

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

Metabolism

Elbasvir and grazoprevir are partially eliminated by oxidative metabolism, primarily by CYP3A. No 
circulating metabolites of either elbasvir or grazoprevir were detected in human plasma.

Excretion

The primary route of elimination of elbasvir and grazoprevir is through faeces with almost all 
(> 90 %) of the radiolabeled dose recovered in faeces compared to < 1 % in urine.

Linearity/non-linearity

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

Pharmacokinetics in special populations

Renal impairment
In non-HCV-infected subjects with severe renal impairment (eGFR < 30 mL/min/1.73 m2) who were 
not on dialysis, elbasvir and grazoprevir AUC values were increased by 86 % and 65 %, respectively, 
compared to non-HCV-infected subjects with normal renal function (eGFR > 80 mL/min/1.73 m2). In 
non-HCV-infected subjects with dialysis-dependent, severe renal impairment, elbasvir and grazoprevir 
AUC values were unchanged compared to subjects with normal renal function. Concentrations of
elbasvir were not quantifiable in the dialysate samples. Less than 0.5 % of grazoprevir was recovered 
in dialysate over a 4-hour dialysis session.

In population pharmacokinetic analysis in HCV-infected patients, elbasvir and grazoprevir AUCs were 
25 % and 10 % higher, respectively, in dialysis-dependent patients and 46 % and 40 % higher, 
respectively, in non-dialysis-dependent patients with severe renal impairment compared to elbasvir 
and grazoprevir AUC in patients without severe renal impairment.

Hepatic impairment
In non-HCV-infected subjects with mild hepatic impairment (Child-Pugh A [CP-A], score of 5-6), 
elbasvir AUC0-inf was decreased by 40% and grazoprevir steady-state AUC0-24 was increased 70 % 
compared to matched healthy subjects.

 



33

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).

5.3 Preclinical safety data

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

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.

 



34

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.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core
Sodium laurilsulfate
Vitamin E polyethylene glycol succinate
Copovidone
Hypromellose
Microcrystalline cellulose
Mannitol (E421)
Lactose monohydrate
Croscarmellose sodium
Sodium chloride
Colloidal anhydrous silica
Magnesium stearate

Film-coating
Lactose monohydrate
Hypromellose
Titanium dioxide
Triacetin
Iron oxide yellow (E172)
Iron oxide red (E172)
Iron oxide black (E172)
Carnauba wax

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

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

6.5 Nature and contents of container

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. 

6.6 Special precautions for disposal 

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

 



35

7. MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

8. MARKETING AUTHORISATION NUMBER(S) 

EU/1/16/1119/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 22 July 2016

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.

 



36

ANNEX II

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 
AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE 
SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT

 



37

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer(s) responsible for batch release

Schering-Plough Labo N.V.
Industriepark 30 - Zone A
2220 Heist-op-den-Berg
BELGIUM

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2).

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION 

 Periodic safety update reports (PSURs)

The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal.

The marketing authorisation holder (MAH) shall submit the first PSUR for this product within 6 
months following authorisation.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT

 Risk management plan (RMP)

The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing 
authorisation and any agreed subsequent updates of the RMP.

An updated RMP should be submitted:
 At the request of the European Medicines Agency;
 Whenever the risk management system is modified, especially as the result of new 
information being received that may lead to a significant change to the benefit/risk profile or as 
the result of an important (pharmacovigilance or risk minimisation) milestone being reached. 

 Obligation to conduct post-authorisation measures

The MAH shall complete, within the stated timeframe, the below measures:

Description Due Date
In order to evaluate the recurrence of 
hepatocellular carcinoma associated with Zepatier
the MAH shall conduct and submit the results of 
a prospective safety study using data deriving 
from a cohort of a well-defined group of patients, 
based on an agreed protocol. The final study 
report shall be submitted by:

Q2 2023

 



38

ANNEX III

LABELLING AND PACKAGE LEAFLET

 



39

A. LABELLING

 



40

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Outer carton

1. NAME OF THE MEDICINAL PRODUCT

ZEPATIER 50 mg/100 mg film-coated tablets
elbasvir/grazoprevir

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

3. LIST OF EXCIPIENTS

Contains lactose and sodium.
See package leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

Film-coated tablet
28 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

 



41

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/16/1119/001

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

ZEPATIER

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

 



42

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING

Inner wallet

1. NAME OF THE MEDICINAL PRODUCT

ZEPATIER 50 mg/100 mg film-coated tablets
elbasvir/grazoprevir

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

3. LIST OF EXCIPIENTS

Contains lactose and sodium.
See package leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

Film-coated tablet
14 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use.
MON
TUE
WED
THU
FRI
SAT
SUN

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

 



43

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

MSD + logo

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/16/1119/001

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

ZEPATIER

 



44

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTER GLUED WITHIN THE INNER WALLET

1. NAME OF THE MEDICINAL PRODUCT

ZEPATIER
elbasvir/grazoprevir
elbasvirum/grazoprevirum

2. NAME OF THE MARKETING AUTHORISATION HOLDER

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

MSD logo

 



45

B. PACKAGE LEAFLET

 



46

Package leaflet: Information for the user

ZEPATIER 50 mg/100 mg film-coated tablets
elbasvir/grazoprevir

This medicine is subject to additional monitoring. This will allow quick identification of new 
safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects.

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you.
 Keep this leaflet. You may need to read it again. 
 If you have any further questions, ask your doctor or pharmacist.
 This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
 If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What ZEPATIER is and what it is used for 
2. What you need to know before you take ZEPATIER
3. How to take ZEPATIER
4. Possible side effects 
5. How to store ZEPATIER
6. Contents of the pack and other information

1. What ZEPATIER is and what it is used for

What ZEPATIER is
ZEPATIER is an antiviral medicine that contains the active substances elbasvir and grazoprevir.

What ZEPATIER is used for
ZEPATIER is used to treat long-term hepatitis C infection in adults aged 18 years and older. 

How ZEPATIER works
Hepatitis C is a virus that infects the liver. The active substances in the medicine work together by 
blocking two different proteins that the hepatitis C virus needs to grow and reproduce. This allows the 
infection to be permanently removed from the body. 

ZEPATIER is sometimes taken with another medicine, ribavirin.

It is very important that you also read the leaflets for the other medicines that you will be taking with
ZEPATIER. If you have any questions about your medicines, please ask your doctor or pharmacist.

2. What you need to know before you take ZEPATIER

Do not take ZEPATIER if:
 you are allergic to elbasvir, grazoprevir or any of the other ingredients of this medicine (listed in 

section 6)
 you have certain moderate or severe liver problems
 you are taking any of the following medicines:

o rifampicin, usually given for tuberculosis
o HIV protease inhibitors such as atazanavir, darunavir, lopinavir, saquinavir, or tipranavir

 



47

o efavirenz or etravirine for HIV
o elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate or

elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide for HIV
o ciclosporin to stop organ transplant rejection or to treat serious inflammatory illnesses of 

eyes, kidney, joints or skin
o bosentan for pulmonary arterial hypertension
o carbamazepine or phenytoin, mainly used for epilepsy and seizures
o modafinil to help people who cannot stay awake
o St. John’s wort (Hypericum perforatum, a herbal medicine) for depression or other 

problems

If you are taking ZEPATIER with ribavirin, please make sure that you read the "Do not take" section 
of the ribavirin package leaflet. If you are unsure of any information in the package leaflet, please 
contact your doctor or pharmacist.

Warnings and precautions 
Talk to your doctor or pharmacist before taking ZEPATIER if you:
 have a current or previous infection with the hepatitis B virus, since your doctor may want to 

monitor you more closely
 have ever taken any medicine for hepatitis C
 have any liver problems other than hepatitis C
 have had a liver transplant
 have diabetes. You may need closer monitoring of your blood glucose levels and/or adjustment 

of your diabetes medication after starting ZEPATIER. Some diabetic patients have experienced 
low sugar levels in the blood (hypoglycaemia) after starting treatment with medicines like 
ZEPATIER.

 have any other medical conditions.

Blood tests 
Your doctor will test your blood before, during and after your treatment with ZEPATIER. This is so 
your doctor can: 
 decide if you should take ZEPATIER and for how long
 decide what other medicines you should take with ZEPATIER and for how long
 check for side effects 
 check if your treatment has worked and you are free of hepatitis C
 check how your liver is working - tell your doctor straight away if you have any of the 

following signs of liver problems: loss of appetite; feeling or being sick; feeling tired or weak; 
yellowing of your skin or eyes; colour changes in your stool. Your doctor may want to test your 
blood to check how your liver is working if you develop any of these symptoms.

Children and adolescents
ZEPATIER is not for use in children and adolescents under 18 years of age. This is because 
ZEPATIER has not been tested in this age group.

Other medicines and ZEPATIER
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. This includes herbal medicines and medicines obtained without a prescription. Keep a list 
of your medicines and show it to your doctor and pharmacist when you get a new medicine. 

There are some medicines you must not take with ZEPATIER. See list under “Do not take 
ZEPATIER if you are taking any of the following medicines.”

Tell your doctor or pharmacist if you take any of the following medicines:
 oral ketoconazole for fungal infections
 tacrolimus to prevent organ transplant rejection
 dabigatran to prevent blood clots

 



48

 rosuvastatin, atorvastatin, fluvastatin, simvastatin, or lovastatin, for lowering blood cholesterol
 sunitinib to treat certain cancers
 warfarin and other similar medicines called vitamin K antagonists used to thin the blood. Your 

doctor may need to increase the frequency of your blood tests to check how well your blood can 
clot.

Your liver function may improve with treatment of hepatitis C and therefore may affect other 

medications that are handled by the liver. Your doctor may need to closely monitor these other 

medicines you are taking and make adjustments during ZEPATIER therapy.

Your doctor may have to change your medicines or change the dose of your medicines.

If any of the above apply to you (or you are not sure), talk to your doctor or pharmacist before taking 
ZEPATIER.

Pregnancy and contraception
The effects of ZEPATIER in pregnancy are not known. If you are pregnant, think you might be 
pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. 

ZEPATIER with ribavirin
 You must not become pregnant if you are taking ZEPATIER with ribavirin. Ribavirin can be 

very damaging to an unborn baby. This means you and your partner must take special 
precautions in sexual activity if there is any chance you or your partner could become pregnant. 

 You or your partner must use an effective method of contraception during treatment with 
ZEPATIER with ribavirin and for some time afterwards. Talk to your doctor about different
contraception methods that are suitable for you. 

 If you or your partner becomes pregnant while taking ZEPATIER with ribavirin or in the 
months that follow, tell your doctor straight away. 

 It is very important that you read the information concerning pregnancy and contraception in the 
ribavirin package leaflet very carefully. It is important that both men and women read the 
information.

Breast-feeding 
Talk to your doctor before taking ZEPATIER if you are breast-feeding. It is not known whether the 
two medicines in ZEPATIER pass into human breast milk.

If you are taking ZEPATIER with ribavirin, make sure that you also read the Pregnancy and 
Breast-feeding sections of the package leaflet for this other medicine.

Driving and using machines
Do not drive or operate machines if you feel tired after taking your medicine. 

ZEPATIER contains lactose

ZEPATIER contains lactose monohydrate. If you have been told by your doctor that you have an 
intolerance to some sugars, talk to your doctor before taking this medicine. 

ZEPATIER contains sodium

This medicine contains 69.85 mg sodium (main component of cooking / table salt) in each tablet. This 
is equivalent to 3.5% of the recommended maximum daily dietary intake of sodium for an adult.

 



49

3. How to take ZEPATIER

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure. Talk to your doctor or pharmacist before taking ZEPATIER if you 
have ever taken any medicines for hepatitis C or if you have any other medical condition.

How much to take
The recommended dose is one tablet once a day with or without food. Your doctor will tell you how 
many weeks you should take ZEPATIER for.

Swallow the tablet whole with or without food. Do not chew, crush or split the tablet. Tell your doctor 
or pharmacist if you have problems swallowing tablets.

If you take more ZEPATIER than you should 
If you take more ZEPATIER than you should, talk to a doctor straight away. Take the medicine pack 
with you so that you can show the doctor what you have taken. 

If you forget to take ZEPATIER
It is important not to miss a dose of this medicine. If you do miss a dose, work out how long it is since 
you should have taken ZEPATIER: 
 If it has been less than 16 hours since you should have taken your dose, take the missed dose as 

soon as possible. Then take your next dose at your usual time. 
 If it has been more than 16 hours since you should have taken your dose, do not take the missed 

dose. Wait and take your next dose at your usual time. 
 Do not take a double dose (two doses together) to make up for a forgotten dose.

Do not stop taking ZEPATIER
Do not stop taking this medicine unless your doctor tells you to. It is very important that you complete
the full course of treatment. This will give the medicine the best chance to treat your hepatitis C
infection. 

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. The 
following side effects may happen with this medicine:

Tell your doctor or pharmacist if you notice any of the following side effects. 

Very common: may affect more than 1 in 10 people 
 feeling very tired (fatigue) 
 headache

Common: may affect up to 1 in 10 people 
 feeling sick (nausea) 
 feeling weak or lack of energy (asthenia)
 itching 
 diarrhoea
 trouble sleeping (insomnia)
 joint pain or painful, swollen joints 
 constipation
 feeling dizzy
 loss of appetite
 feeling irritable

 



50

 muscle aches 
 stomach pain
 unusual hair loss or thinning
 feeling nervous (anxiety)
 depression
 dry mouth
 being sick (vomiting)

Uncommon: may affect up to 1 in 100 people
 abnormalities in laboratory tests of liver function

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine.

5. How to store ZEPATIER

Keep this medicine out of the sight and reach of children. 

Do not use the medicine after the expiry date which is stated on the carton and blister packaging after 
‘EXP’. The expiry date refers to the last day of that month. 

This medicine does not require any special temperature storage conditions.

Store in the original package until use to protect from moisture.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help to protect the environment.

6. Contents of the pack and other information

What ZEPATIER contains

 The active substances are: elbasvir and grazoprevir. Each film-coated tablet contains 50 mg 
elbasvir and 100 mg grazoprevir.

 The other ingredients are: 
Tablet core: 
Sodium laurilsulfate, vitamin E polyethylene glycol succinate, copovidone, hypromellose, 
microcrystalline cellulose, mannitol (E421), lactose monohydrate, croscarmellose sodium, 
sodium chloride, colloidal anhydrous silica, magnesium stearate.
Film-coating: 
Lactose monohydrate, hypromellose, titanium dioxide, triacetin, iron oxide yellow (E172), iron 
oxide red (E172), iron oxide black (E172), carnauba wax.

What ZEPATIER looks like and contents of the pack
The film-coated tablets are beige, oval, debossed with “770” on one side and plain on the other. The 
tablet is 21 mm long and 10 mm wide.

The tablets are packaged into a carton containing two cardboard cards, each cardboard card containing 
two 7-count aluminium blisters. Each carton contains a total of 28 tablets. 

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


51

Marketing Authorisation Holder
Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

Manufacturer
Schering-Plough Labo NV
Industriepark 30 – Zone A
B-2220 Heist-op-den-Berg
Belgium

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

BE/LU
MSD Belgium BVBA/SPRL
Tél/Tel: +32(0)27766211
dpoc_belux@merck.com

LT
UAB Merck Sharp & Dohme
Tel.: +370 5 278 02 47
msd_lietuva@merck.com

BG
Мерк Шарп и Доум България ЕООД
Тел.: +359 2 819 3737
info-msdbg@merck.com

HU
MSD Pharma Hungary Kft.
Tel.: +361 888 53 00
hungary_msd@merck.com

CZ
Merck Sharp & Dohme s.r.o.
Tel.: +420 233 010 111
dpoc_czechslovak@merck.com

MT
Merck Sharp & Dohme Cyprus Limited
Tel: 8007 4433 (+356 99917558)
malta_info@merck.com

DK
MSD Danmark ApS
Tlf: +45 4482 4000
dkmail@merck.com

NL
Merck Sharp & Dohme B.V.
Tel: 0800 99 99 000 (+31 23 5153153)
medicalinfo.nl@merck.com

DE
MSD SHARP & DOHME GMBH
Tel: 0800 673 673 673 (+49 (0) 89 4561 2612)
e-mail@msd.de

NO
MSD (Norge) AS
Tlf: +47 32 20 73 00
msdnorge@msd.no

EE
Merck Sharp & Dohme OÜ
Tel.: +372 6144 200
msdeesti@merck.com

AT
Merck Sharp & Dohme Ges.m.b.H.
Tel: +43 (0) 1 26 044
msd-medizin@merck.com

EL
MSD Α.Φ.Β.Ε.Ε.
Τηλ: + 30 210 98 97 300
dpoc_greece@merck.com

PL
MSD Polska Sp.z o.o. 
Tel.: +48 22 549 51 00
msdpolska@merck.com

ES
Merck Sharp & Dohme de España, S.A.
Tel: +34 91 321 06 00
msd_info@merck.com

PT
Merck Sharp & Dohme, Lda
Tel: +351 21 446 5700
inform_pt@merck.com

FR
MSD France
Tél: + 33 (0) 1 80 46 40 40

RO
Merck Sharp & Dohme Romania S.R.L.
Tel: + 4021 529 29 00
msdromania@merck.com

 



52

HR
Merck Sharp & Dohme d.o.o.
Tel: + 385 1 66 11 333
croatia_info@merck.com

SI
Merck Sharp & Dohme, inovativna zdravila d.o.o.
Tel: + 386 1 5204201
msd_slovenia@merck.com

IE
Merck Sharp & Dohme Ireland (Human Health) 
Limited
Tel: +353 (0)1 2998700
medinfo_ireland@merck.com

SK
Merck Sharp & Dohme, s. r. o.
Tel.: +421 2 58282010
dpoc_czechslovak@merck.com

IS
Vistor hf.
Sími: +354 535 7000

FI
MSD Finland Oy
Puh/Tel: +358 (0) 9 804 650
info@msd.fi

IT
MSD Italia S.r.l.
Tel: +39 06 361911
medicalinformation.it@merck.com

SE
Merck Sharp & Dohme (Sweden) AB
Tel: +46 77 5700488
medicinskinfo@merck.com

CY
Merck Sharp & Dohme Cyprus Limited
Τηλ: 800 00 673 (+357 22866700)
cyprus_info@merck.com

UK
Merck Sharp & Dohme Limited
Tel: +44 (0) 1992 467272
medicalinformationuk@merck.com

LV
SIA Merck Sharp & Dohme Latvija
Tel: +371 67364 224
msd_lv@merck.com

This leaflet was last revised in {MM/YYYY}.

Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu.

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET