4.1. Therapeutic indications

ZEPATIER is indicated for the treatment of chronic hepatitis C (CHC) in adult and paediatric patients 12 years of age and older who weigh at least 30 kg (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):

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 adult 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

No dosage adjustment of ZEPATIER is required in paediatric patients 12 years of age and older who weigh 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.

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).

Interactions with medicinal products

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

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

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

HCV/HBV (hepatitis B virus) co-infection

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

Use in diabetic patients

Diabetics may experience improved glucose control potentially resulting in symptomatic hypoglycaemia, after initiating HCV direct acting antiviral (DAA) treatment. Glucose levels of diabetic patients initiating DAA therapy should be closely monitored, particularly within the first 3 months, and their diabetic medication modified when necessary. The physician in charge of the diabetic care of the patient should be informed when DAA therapy is initiated.

Paediatric population

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

Excipients

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

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

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). Co-administration of ZEPATIER with P-gp inhibitors is expected to have a minimal effect on the plasma concentrations of ZEPATIER.

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

Potential for ZEPATIER to affect other medicinal products

Elbasvir and grazoprevir are inhibitors of the drug transporter BCRP at the intestinal level in humans and may increase plasma concentrations of co-administered BCRP substrates. Elbasvir is not a CYP3A inhibitor in vitro and grazoprevir is a weak CYP3A inhibitor in humans. Co-administration with grazoprevir did not result in clinically relevant increases in exposures of CYP3A substrates. Therefore, no dose adjustment is required for CYP3A substrates when co-administered with ZEPATIER.

Elbasvir has minimal intestinal P-gp inhibition in humans, and does not result in clinically relevant increases in concentrations of digoxin (a P-gp substrate), with an 11% increase in plasma AUC. Grazoprevir is not a P-gp inhibitor based on in vitro data. Elbasvir and grazoprevir are not OATP1B inhibitors in humans. Based on in vitro data, clinically significant interactions with ZEPATIER as an inhibitor of other CYP enzymes, UGT1A1, esterases (CES1, CES2, and CatA), OAT1, OAT3, and OCT2 are not expected. Based on in vitro data, a potential for GZR to inhibit BSEP cannot be excluded. Multiple-dose administration of elbasvir or grazoprevir is unlikely to induce the metabolism of medicinal products metabolised by CYP isoforms based on in vitro data.

Patients treated with vitamin K antagonists

As liver function may change during treatment with ZEPATIER, a close monitoring of International Normalised Ratio (INR) values is recommended.

Impact of DAA therapy on drugs metabolized by the liver

Grazoprevir's weak inhibition of CYP3A may increase levels of CYP3A substrates. In addition, the plasma concentrations of drugs that are CYP3A substrates may be decreased by improvement in liver function during DAA therapy, related to clearance of HCV. Therefore, close monitoring and potential dose adjustment of CYP3A substrates with a narrow therapeutic index (e.g., calcineurin inhibitors) may be required during therapy, as drug levels may change (see Table 2).

Interactions between ZEPATIER and other medicinal products

Table 2 provides a listing of assessed or potential medicinal product interactions. An up “↑” or down “↓” arrow represents a change in exposure that requires monitoring or a dose adjustment of that medication, or the co-administration is not recommended or contraindicated. No clinically relevant change in exposure is represented by a horizontal arrow “↔”.

The medicinal product interactions described are based on results from studies conducted with either ZEPATIER or elbasvir (EBR) and grazoprevir (GZR) as individual agents, or are predicted medicinal product interactions that may occur with elbasvir or grazoprevir. The table is not all-inclusive.

Table 2: Interactions and dose recommendations with other medicinal products

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.

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.

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)

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)

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.

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.

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)

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)

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.

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.

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.

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)

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 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).

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.

Paediatric population

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

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.