MAVIRET 100mg / 40mg tablets medication leaflet

Maviret 100 mg/40 mg film-coated tablets

Each film-coated tablet contains 100 mg glecaprevir and 40 mg pibrentasvir.

Each film-coated tablet contains 7.48 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Pink, oblong, biconvex, film-coated tablet of dimensions 18.8 mm x 10.0 mm, debossed on one sidewith ‘NXT’.

Maviret is indicated for the treatment of chronic hepatitis C virus (HCV) infection in adults andchildren aged 3 years and older (see sections 4.2, pct. 4.4. and 5.1).

Maviret treatment should be initiated and monitored by a physician experienced in the management ofpatients with HCV infection.

Adults, adolescents aged 12 years and older, or children weighing at least 45 kg

The recommended dose of Maviret is 300 mg/120 mg (three 100 mg/40 mg tablets), taken orally, oncedaily at the same time with food (see section 5.2).

The recommended Maviret treatment durations for HCV genotype 1, 2, 3, 4, 5, or 6 infected patientswith compensated liver disease (with or without cirrhosis) are provided in Table 1 and Table 2.

Table 1: Recommended Maviret treatment duration for patients without prior HCV therapy

Recommended treatment duration

Genotype

No cirrhosis Cirrhosis

GT 1, 2, 3, 4, 5, 6 8 weeks 8 weeks

Table 2: Recommended Maviret treatment duration for patients who failed prior therapy withpeg-IFN + ribavirin +/- sofosbuvir, or sofosbuvir + ribavirin

Genotype Recommended treatment duration

No cirrhosis Cirrhosis

GT 1, 2, 4-6 8 weeks 12 weeks

GT 3 16 weeks 16 weeks

For patients who failed prior therapy with an NS3/4A- and/or an NS5A inhibitor, see section 4.4.

In case a dose of Maviret is missed, the prescribed dose can be taken within 18 hours after the time itwas supposed to be taken. If more than 18 hours have passed since Maviret is usually taken, themissed dose should not be taken and the patient should take the next dose per the usual dosingschedule. Patients should be instructed not to take a double dose.

If vomiting occurs within 3 hours of dosing, an additional dose of Maviret should be taken. Ifvomiting occurs more than 3 hours after dosing, an additional dose of Maviret is not needed.

No dose adjustment of Maviret is required in elderly patients (see sections 5.1 and 5.2).

No dose adjustment of Maviret is required in patients with any degree of renal impairment includingpatients on dialysis (see sections 5.1 and 5.2).

No dose adjustment of Maviret is required in patients with mild hepatic impairment (Child-Pugh A).

Maviret is not recommended in patients with moderate hepatic impairment (Child-Pugh B) and iscontraindicated in patients with severe hepatic impairment (Child-Pugh C) (see sections pct. 4.3, pct. 4.4, and5.2).

A 12-week treatment duration has been evaluated and is recommended in liver or kidney transplantrecipients with or without cirrhosis (see section 5.1). A 16-week treatment duration should beconsidered in genotype 3-infected patients who are treatment-experienced with peg-IFN + ribavirin +/-sofosbuvir, or sofosbuvir + ribavirin.

Follow the dosing recommendations in Tables 1 and 2. For dosing recommendations with HIVantiviral agents, refer to section 4.5.

The safety and efficacy of Maviret in children aged less than 3 years or under 12 kg have not beenestablished and no data are available.

Maviret coated granules formulation is intended for children aged 3 to less than 12 years weighing12 kg to less than 45 kg. Refer to the Summary of Product Characteristics for Maviret coated granulesin sachet for dosing instructions based on body weight. Because the formulations have differentpharmacokinetic profiles, the tablets and the coated granules are not interchangeable. A full course oftreatment with the same formulation is therefore required (see section 5.2).

For oral use.

Patients should be instructed to swallow tablets whole with food and not to chew, crush or break thetablets as it may alter the bioavailability of the agents (see section 5.2).

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

Patients with severe hepatic impairment (Child-Pugh C) (see sections 4.2, pct. 4.4, and 5.2).

Concomitant use with atazanavir containing products, atorvastatin, simvastatin, dabigatran etexilate,ethinyl oestradiol-containing products, strong P-gp and CYP3A inducers (e.g., rifampicin,carbamazepine, St. John’s wort (Hypericum perforatum), phenobarbital, phenytoin, and primidone)(see section 4.5).

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

Maviret is not recommended in patients with moderate hepatic impairment (Child-Pugh B) and iscontraindicated in patients with severe hepatic impairment (Child-Pugh C) (see sections 4.2, pct. 4.3, and5.2).

Genotype 1-infected (and a very limited number of genotype 4-infected) patients with prior failure onregimens that may confer resistance to glecaprevir/pibrentasvir were studied in studies

MAGELLAN-1 and B16-439 (section 5.1). The risk of failure was, as expected, highest for thoseexposed to both classes. A resistance algorithm predictive of the risk for failure by baseline resistancehas not been established. Accumulating double class resistance was a general finding for patients whofailed re-treatment with glecaprevir/pibrentasvir in MAGELLAN-1. No re-treatment data is availablefor patients infected with genotypes 2, 3, 5 or 6. Maviret is not recommended for the re-treatment ofpatients with prior exposure to NS3/4A- and/or NS5A inhibitors.

Co-administration is not recommended with several medicinal products as detailed in section 4.5.

Diabetics may experience improved glucose control, potentially resulting in symptomatichypoglycaemia, after initiating HCV direct acting antiviral treatment. Glucose levels of diabeticpatients initiating direct acting antiviral therapy should be closely monitored, particularly within thefirst 3 months, and their diabetic medicines modified when necessary. The physician in charge of thediabetic care of the patient should be informed when direct acting antiviral therapy is initiated.

Maviret contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactasedeficiency or glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially‘sodium-free’.

Glecaprevir and pibrentasvir are inhibitors of P-glycoprotein (P-gp), breast cancer resistance protein(BCRP), and organic anion transporting polypeptide (OATP) 1B1/3. Co-administration with Maviretmay increase plasma concentrations of medicinal products that are substrates of P-gp (e.g. dabigatranetexilate, digoxin), BCRP (e.g. rosuvastatin), or OATP1B1/3 (e.g. atorvastatin, lovastatin, pravastatin,rosuvastatin, simvastatin). See Table 3 for specific recommendations on interactions with sensitivesubstrates of P-gp, BCRP, and OATP1B1/3. For other P-gp, BCRP, or OATP1B1/3 substrates, doseadjustment may be needed.

Glecaprevir and pibrentasvir are weak inhibitors of cytochrome P450 (CYP) 3A and uridineglucuronosyltransferase (UGT) 1A1 in vivo. Clinically significant increases in exposure were notobserved for sensitive substrates of CYP3A (midazolam, felodipine) or UGT1A1 (raltegravir) whenadministered with Maviret.

Both glecaprevir and pibrentasvir inhibit the bile salt export pump (BSEP) in vitro.

Significant inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, UGT1A6, UGT1A9, UGT1A4,

UGT2B7, OCT1, OCT2, OAT1, OAT3, MATE1 or MATE2K are not expected.

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

Normalised Ratio (INR) values is recommended.

Medicinal products that are strong P-gp and CYP3A inducers (e.g., rifampicin, carbamazepine, St.

John’s wort (Hypericum perforatum), phenobarbital, phenytoin, and primidone) could significantlydecrease glecaprevir or pibrentasvir plasma concentrations and may lead to reduced therapeutic effectof Maviret or loss of virologic response. Co-administration of such medicinal products with Maviret iscontraindicated (see section 4.3).

Co-administration of Maviret with medicinal products that are moderate inducers P-gp/CYP3A maydecrease glecaprevir and pibrentasvir plasma concentrations (e.g. oxcarbazepine, eslicarbazepine,lumacaftor, crizotinib). Co-administration of moderate inducers is not recommended (see section 4.4).

Glecaprevir and pibrentasvir are substrates of the efflux transporters P-gp and/or BCRP. Glecaprevir isalso a substrate of the hepatic uptake transporters OATP1B1/3. Co-administration of Maviret withmedicinal products that inhibit P-gp and BCRP (e.g. ciclosporin, cobicistat, dronedarone, itraconazole,ketoconazole, ritonavir) may slow elimination of glecaprevir and pibrentasvir and thereby increaseplasma exposure of the antivirals. Medicinal products that inhibit OATP1B1/3 (e.g. elvitegravir,ciclosporin, darunavir, lopinavir) increase systemic concentrations of glecaprevir.

Table 3 provides the least-squares mean Ratio (90% Confidence Interval) effect on concentration of

Maviret and some common concomitant medicinal products. The direction of the arrow indicates thedirection of the change in exposures (Cmax, AUC, and Cmin) in glecaprevir, pibrentasvir, and theco-administered medicinal product (↑ = increase (more than 25%), ↓ = decrease (more than 20%), ↔= no change (equal to or less than 20% decrease or 25% increase)). This is not an exclusive list. Allinteraction studies were performed in adults.

Table 3: Interactions between Maviret and other medicinal products

Medicinalproduct by

Effect ontherapeutic Clinicalmedicinal Careas/possible max AUC Cmin commentsproduct levelsmechanism ofinteraction

ANGIOTENSIN-II RECEPTOR BLOCKERS

Losartan ↑ losartan 2.51 1.56 -- No dose50 mg single dose (2.00, 3.15) (1.28, adjustment is1.89) required.↑ losartan 2.18 ↔ --carboxylic (1.88, 2.53)acid

Valsartan ↑ valsartan 1.36 1.31 -- No dose80 mg single dose (1.17, 1.58) (1.16, adjustment is1.49) required.(Inhibition of

OATP1B1/3)

ANTIARRHYTHMICS

Digoxin ↑ digoxin 1.72 1.48 -- Caution and0.5 mg single dose (1.45, 2.04) (1.40, therapeutic1.57) concentration(Inhibition of P- monitoring ofgp) digoxin isrecommended.

ANTICOAGULANTS

Dabigatran ↑ dabigatran 2.05 2.38 -- Co-administrationetexilate (1.72, 2.44) (2.11, is contraindicated150 mg single 2.70) (see section 4.3).dose(Inhibition of P-gp)

ANTICONVULSANTS

Carbamazepine ↓ glecaprevir 0.33 0.34 -- Co-administration200 mg twice (0.27, 0.41) (0.28, may lead todaily 0.40) reduced↓ pibrentasvir 0.50 0.49 -- therapeutic effect(Induction of P- (0.42, 0.59) (0.43, of Maviret and isgp/CYP3A) 0.55) contraindicated

Phenytoin, Not studied. (see section 4.3).phenobarbital, Expected: ↓ glecaprevir and ↓ pibrentasvirprimidone

ANTIMYCOBACTERIALS

Rifampicin ↑ glecaprevir 6.52 8.55 Co-administration600 mg single (5.06, 8.41) (7.01, -- is contraindicateddose 10.4) (see section 4.3).

↔ ↔ ↔ --(Inhibition of pibrentasvir

OATP1B1/3)

Rifampicin ↓ glecaprevir 0.14 0.12 --600 mg once (0.11, 0.19) (0.09,dailya 0.15)↓ pibrentasvir 0.17 0.13 --(Induction of P- (0.14, 0.20) (0.11,gp/BCRP/CYP3A 0.15))

ETHINYL-OESTRADIOL-CONTAINING PRODUCTS

Ethinyloestradiol ↑ EE 1.31 1.28 1.38 Co-administration(EE)/Norgestimate (1.24, 1.38) (1.23, (1.25, 1.52) of Maviret with35 µg/250 µg once 1.32) ethinyloestradiol-daily ↑ ↔ 1.44 1.45 containingnorelgestromi (1.34, (1.33, 1.58) products isn 1.54) contraindicated↑ norgestrel 1.54 1.63 1.75 due to the risk of(1.34, 1.76) (1.50, (1.62, 1.89) ALT elevations1.76) (see section 4.3).

EE/Levonorgestrel ↑ EE 1.30 1.40 1.56 No dose20 µg/100 µg once (1.18, 1.44) (1.33, (1.41, 1.72) adjustment isdaily 1.48) required with↑ norgestrel 1.37 1.68 1.77 levonorgestrel,(1.23, 1.52) (1.57, (1.58, 1.98) norethidrone or1.80) norgestimate ascontraceptiveprogestagen.

HERBAL PRODUCTS

St. John’s wort Not studied. Co-administration(Hypericum Expected: ↓ glecaprevir and ↓ pibrentasvir may lead toperforatum) reducedtherapeutic effect(Induction of P- of Maviret and isgp/CYP3A) contraindicated(see section 4.3).

HIV-ANTIVIRAL AGENTS

Atazanavir + ↑ glecaprevir ≥4.06 ≥6.53 ≥14.3 Co-administrationritonavir (3.15, pct. 5.23) (5.24, (9.85, 20.7) with atazanavir is300/100 mg once 8.14) contraindicateddailyb ↑ pibrentasvir ≥1.29 ≥1.64 ≥2.29 due to the risk of(1.15, 1.45) (1.48, (1.95, 2.68) ALT elevations1.82) (see section 4.3).

Darunavir + ↑ glecaprevir 3.09 4.97 8.24 Co-administrationritonavir (2.26, 4.20) (3.62, (4.40, 15.4) with darunavir is800/100 mg once 6.84) notdaily ↔ ↔ ↔ 1.66 recommended.

pibrentasvir (1.25, 2.21)

Efavirenz/emtricit ↑ tenofovir ↔ 1.29 1.38 Co-administrationabine/tenofovir (1.23, (1.31, 1.46) with efavirenzdisoproxil 1.35) may lead tofumarate The effect of efavirenz/emtricitabine/tenofovir disoproxil reducedfumarate on glecaprevir and pibrentasvir was not directly therapeutic effect600/200/300 mg quantified within this study, but glecaprevir and of Maviret and isonce daily pibrentasvir exposures were significantly lower than nothistorical controls. recommended. Noclinicallysignificantinteractions areexpected withtenofovirdisoproxilfumarate.

Elvitegravir/cobici ↔ tenofovir ↔ ↔ ↔ No dosestat/emtricitabine/ ↑ glecaprevir 2.50 3.05 4.58 adjustment istenofovir (2.08, 3.00) (2.55, (3.15, 6.65) required.alafenamide 3.64)↑ pibrentasvir ↔ 1.57 1.89(P-gp, BCRP, and (1.39, (1.63, 2.19)

OATP inhibition 1.76)by cobicistat,

OATP inhibitionby elvitegravir)

Lopinavir/ritonavi ↑ glecaprevir 2.55 4.38 Co-administration18.6r 400/100 mg (1.84, 3.52) (3.02, is not(10.4, 33.5)twice daily 6.36) recommended.

↑ pibrentasvir 1.40 2.46 5.24(1.17, 1.67) (2.07, (4.18, 6.58)2.92)

Raltegravir ↑ raltegravir 1.34 1.47 2.64 No dose400 mg twice (0.89, 1.98) (1.15, (1.42, 4.91) adjustment isdaily 1.87) required.

(Inhibition of

UGT1A1)

HCV-ANTIVIRAL AGENTS

Sofosbuvir ↑ sofosbuvir 1.66 2.25 -- No dose400 mg single (1.23, 2.22) (1.86, adjustment isdose 2.72) required.

↑ GS-331007 ↔ ↔ 1.85(P-gp/BCRP (1.67, 2.04)inhibition) ↔ ↔ ↔ ↔glecaprevir↔ ↔ ↔ ↔pibrentasvir

HMG-COA REDUCTASE INHIBITORS

Atorvastatin ↑ atorvastatin 22.0 8.28 -- Co-administration10 mg once daily (16.4, 29.5) (6.06, with atorvastatin11.3) and simvastatin is(Inhibition of contraindicated

OATP1B1/3, P- (see section 4.3).gp, BCRP,

CYP3A)

Simvastatin ↑ simvastatin 1.99 2.32 --5 mg once daily (1.60, 2.48) (1.93,2.79)(Inhibition of ↑ simvastatin 10.7 4.48 --

OATP1B1/3, P- acid (7.88, 14.6) (3.11,gp, BCRP) 6.46)

Lovastatin ↑ lovastatin ↔ 1.70 -- Co-administration10 mg once daily (1.40, is not2.06) recommended. If(Inhibition of ↑ lovastatin 5.73 4.10 -- used, lovastatin

OATP1B1/3, P- acid (4.65, 7.07) (3.45, should not exceedgp, BCRP) 4.87) a dose of 20mg/day andpatients should bemonitored.

Pravastatin ↑ pravastatin 2.23 2.30 -- Caution is10 mg once daily (1.87, 2.65) (1.91, recommended.

2.76) Pravastatin dose(Inhibition of should not exceed

OATP1B1/3) 20 mg per day

Rosuvastatin ↑ 5.62 2.15 -- and rosuvastatin5 mg once daily rosuvastatin (4.80, 6.59) (1.88, dose should not2.46) exceed 5 mg per(Inhibition of day.

OATP1B1/3,

BCRP)

Fluvastatin, Not studied. Interactions with

Pitavastatin Expected: ↑ fluvastatin and ↑ pitavastatin fluvastatin andpitavastatin arelikely and cautionis recommendedduring thecombination. Alow dose of thestatin isrecommended atthe initiation ofthe DAAtreatment.

IMMUNOSUPPRESSANTS

Ciclosporin ↑ glecaprevirc 1.30 1.37 1.34 Maviret is not100 mg single (0.95, 1.78) (1.13, (1.12, 1.60) recommended fordose 1.66) use in patients↑ pibrentasvir ↔ ↔ 1.26 requiring stable(1.15, 1.37) ciclosporin doses

Ciclosporin ↑ glecaprevir 4.51 5.08 -- > 100 mg per day.400 mg single (3.63, 6.05) (4.11, If the combinationdose 6.29) is unavoidable,↑ pibrentasvir ↔ 1.93 -- use can be(1.78, considered if the2.09) benefit outweighsthe risk with aclose clinicalmonitoring.

Tacrolimus ↑ tacrolimus 1.50 1.45 -- The combination1 mg single dose (1.24, 1.82) (1.24, of Maviret with1.70) tacrolimus should(CYP3A4 and P- ↔ ↔ ↔ ↔ be used withgp inhibition) glecaprevir caution. Increase↔ ↔ ↔ ↔ of tacrolimuspibrentasvir exposure isexpected.

Therefore, atherapeutic drugmonitoring oftacrolimus isrecommended anda dose adjustmentof tacrolimusmade accordingly.

PROTON PUMP INHIBITORS

Omeprazole ↓ glecaprevir 0.78 0.71 -- No dose20 mg once daily (0.60, (0.58, 0.86) adjustment is1.00) required.(Increase gastric ↔ ↔ ↔ --pH value) pibrentasvir

Omeprazole ↓ glecaprevir 0.36 0.49 --40 mg once daily (0.21, (0.35, 0.68)(1 hour before 0.59)breakfast) ↔ ↔ ↔ --pibrentasvir

Omeprazole ↓ glecaprevir 0.54 0.51 --40 mg once daily (0.44, (0.45, 0.59)(evening without 0.65)food) ↔ ↔ ↔ --pibrentasvir

VITAMIN K ANTAGONISTS

Vitamin K Not studied. Close monitoringantagonists of INR isrecommendedwith all vitamin Kantagonists. Thisis due to liverfunction changesduring treatmentwith Maviret.

DAA=direct acting antiviral

a. Effect of rifampicin on glecaprevir and pibrentasvir 24 hours after final rifampicin dose.

b. Effect of atazanavir and ritonavir on the first dose of glecaprevir and pibrentasvir is reported.

c. HCV-infected transplant recipients who received a median ciclosporin dose of 100 mg per day hadincreased glecaprevir exposures to 2.4-fold of those not receiving ciclosporin.

Additional drug-drug interaction studies were performed with the following medical products andshowed no clinically significant interactions with Maviret: abacavir, amlodipine, buprenorphine,caffeine, dextromethorphan, dolutegravir, emtricitabine, felodipine, lamivudine, lamotrigine,methadone, midazolam, naloxone, norethindrone or other progestin-only contraceptives, rilpivirine,tenofovir alafenamide and tolbutamide.

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of glecapreviror pibrentasvir in pregnant women.

Studies in rats/mice with glecaprevir or pibrentasvir do not indicate direct or indirect harmful effectswith respect to reproductive toxicity. Maternal toxicity associated with embryo-foetal loss has beenobserved in the rabbit with glecaprevir which precluded evaluation of glecaprevir at clinical exposuresin this species (see section 5.3). As a precautionary measure, Maviret use is not recommended inpregnancy.

It is unknown whether glecaprevir or pibrentasvir are excreted in human milk. Availablepharmacokinetic data in animals have shown excretion of glecaprevir and pibrentasvir in milk (fordetails see section 5.3). A risk to the suckling child cannot be excluded. A decision must be madewhether to discontinue breast-feeding or to discontinue/abstain from Maviret therapy taking intoaccount the benefit of breast-feeding for the child and the benefit of therapy for the woman.

No human data on the effect of glecaprevir and/or pibrentasvir on fertility are available. Animalstudies do not indicate harmful effects of glecaprevir or pibrentasvir on fertility at exposures higherthan the exposures in humans at the recommended dose (see section 5.3).

Maviret has no or negligible influence on the ability to drive and use machines.

In pooled Phase 2 and 3 clinical studies of adult subjects receiving Maviret with genotype 1, 2, 3, 4, 5or 6 HCV infection the most commonly reported adverse reactions (incidence ≥ 10%) were headacheand fatigue. Less than 0.1% of subjects treated with Maviret had serious adverse reactions (transientischaemic attack). The proportion of subjects treated with Maviret who permanently discontinuedtreatment due to adverse reactions was 0.1%.

The following adverse reactions were identified in registrational Phase 2 and 3 studies in HCV-infected adults with or without cirrhosis treated with Maviret for 8, 12 or 16 weeks, or during post-marketing experience. The adverse reactions are listed below by body system organ class andfrequency. 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), very rare (< 1/10 000) or not known(cannot be estimated from the available data).

Table 4: Adverse reactions identified with Maviret

Frequency Adverse reactions

Uncommon angioedema

Very common headache

Common diarrhoea, nausea

Not known pruritus

Very common fatigue

Common asthenia

Common elevation in total bilirubin

The safety of Maviret in subjects with chronic kidney disease (including subjects on dialysis) andgenotypes 1, 2, 3, 4, 5 or 6 chronic HCV infection with compensated liver disease (with or withoutcirrhosis) was assessed in adults in EXPEDITION-4 (n=104) and EXPEDITION-5 (n=101). The mostcommon adverse reactions in subjects with severe renal impairment were pruritus (17%) and fatigue(12%) in EXPEDITION-4 and pruritus (14.9%) in EXPEDITION-5.

The safety of Maviret was assessed in 100 post-liver or -kidney transplant adult recipients withgenotypes 1, 2, 3, 4, or 6 chronic HCV infection without cirrhosis (MAGELLAN-2). The overallsafety profile in transplant recipients was comparable to that observed in subjects in the Phase 2 and 3studies. Adverse reactions observed in greater than or equal to 5% of subjects receiving Maviret for 12weeks were headache (17%), fatigue (16%), nausea (8%) and pruritus (7%).

The overall safety profile in HCV/HIV-1 co-infected adult subjects (ENDURANCE-1 and

EXPEDITION-2) was comparable to that observed in HCV mono-infected adult subjects.

The safety of Maviret in HCV GT1-6 infected adolescents is based on data from a Phase 2/3open-label study in 47 subjects aged 12 years to < 18 years treated with Maviret for 8 to 16 weeks(DORA Part 1). The adverse reactions observed were comparable with those observed in clinicalstudies of Maviret in adults.

Elevations in total bilirubin of at least 2x upper limit normal (ULN) were observed in 1.3% of subjectsrelated to glecaprevir-mediated inhibition of bilirubin transporters and metabolism. Bilirubinelevations were asymptomatic, transient, and typically occurred early during treatment. Bilirubinelevations were predominantly indirect and not associated with ALT elevations. Directhyperbilirubinemia was reported in 0.3% of subjects.

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

The highest documented doses administered to healthy volunteers is 1 200 mg once daily for 7 daysfor glecaprevir and 600 mg once daily for 10 days for pibrentasvir. Asymptomatic serum ALTelevations (> 5x ULN) were observed in 1 out of 70 healthy subjects following multiple doses ofglecaprevir (700 mg or 800 mg) once daily for ≥ 7 days. In case of overdose, the patient should bemonitored for any signs and symptoms of toxicities (see section 4.8). Appropriate symptomatictreatment should be instituted immediately. Glecaprevir and pibrentasvir are not significantly removedby haemodialysis.

Pharmacotherapeutic group: Antivirals for systemic use, direct acting antivirals, ATC code: J05AP57

Maviret is a fixed-dose combination of two pan-genotypic, direct acting antiviral agents, glecaprevir(NS3/4A protease inhibitor) and pibrentasvir (NS5A inhibitor), targeting multiple steps in the HCVviral lifecycle.

Glecaprevir is a pan-genotypic inhibitor of the HCV NS3/4A protease, which is necessary for theproteolytic cleavage of the HCV encoded polyprotein (into mature forms of the NS3, NS4A, NS4B,

NS5A, and NS5B proteins) and is essential for viral replication.

Pibrentasvir is a pan-genotypic inhibitor of HCV NS5A, which is essential for viral RNA replicationand virion assembly. The mechanism of action of pibrentasvir has been characterised based on cellculture antiviral activity and drug resistance mapping studies.

The EC50 values of glecaprevir and pibrentasvir against full-length or chimeric replicons encoding

NS3 or NS5A from laboratory strains are presented in Table 5.

Table 5. Activity of glecaprevir and pibrentasvir against HCV genotypes 1-6 replicon cell lines

HCV Subtype Glecaprevir EC50, nM Pibrentasvir EC50, nM1a 0.85 0.00181b 0.94 0.00432a 2.2 0.00232b 4.6 0.00193a 1.9 0.00214a 2.8 0.00195a NA 0.00146a 0.86 0.0028

NA = not available

The in vitro activity of glecaprevir was also studied in a biochemical assay, with similarly low IC50values across genotypes.

EC50 values of glecaprevir and pibrentasvir against chimeric replicons encoding NS3 or NS5A fromclinical isolates are presented in Table 6.

Table 6. Activity of glecaprevir and pibrentasvir against transient replicons containing NS3 or

NS5A from HCV genotypes 1-6 clinical isolates

Glecaprevir Pibrentasvir

HCV

Number of Median EC50, nM Number of Median EC50, nMsubtypeclinical isolates (range) clinical isolates (range)0.08 0.00091a 11 11(0.05 - 0.12) (0.0006 - 0.0017)0.29 0.00271b 9 8(0.20 - 0.68) (0.0014 - 0.0035)1.6 0.00092a 4 6(0.66 - 1.9) (0.0005 - 0.0019)2.2 0.00132b 4 11(1.4 - 3.2) (0.0011 - 0.0019)2.3 0.00073a 2 14(0.71 - 3.8) (0.0005 - 0.0017)0.41 0.00054a 6 8(0.31 - 0.55) (0.0003 - 0.0013)0.00124b NA NA 3(0.0005 - 0.0018)0.17 0.00144d 3 7(0.13 - 0.25) (0.0010 - 0.0018)5a 1 0.12 1 0.00110.00076a NA NA 3(0.0006 - 0.0010)6e NA NA 1 0.00086p NA NA 1 0.0005

NA = not available

Amino acid substitutions in NS3 or NS5A selected in cell culture or important for the inhibitor classwere phenotypically characterised in replicons.

Substitutions important for the HCV protease inhibitor class at positions 36, 43, 54, 55, 56, 155, 166,or 170 in NS3 had no impact on glecaprevir activity. Substitutions at amino acid position 168 in NS3had no impact in genotype 2, while some substitutions at position 168 reduced glecaprevirsusceptibility by up to 55-fold (genotypes 1, 3, 4), or reduced susceptibility by > 100-fold (genotype6). Some substitutions at position 156 reduced susceptibility to glecaprevir (genotypes 1 to 4) by> 100-fold. Substitutions at amino acid position 80 did not reduce susceptibility to glecaprevir exceptfor Q80R in genotype 3a, which reduced susceptibility to glecaprevir by 21-fold.

Single substitutions important for the NS5A inhibitor class at positions 24, 28, 30, 31, 58, 92, or 93 in

NS5A in genotypes 1 to 6 had no impact on the activity of pibrentasvir. Specifically in genotype 3a,

A30K or Y93H had no impact on pibrentasvir activity. Some combinations of substitutions ingenotypes 1a and 3a (including A30K+Y93H in genotype 3a) showed reductions in susceptibility topibrentasvir. In genotype 3b replicon, the presence of naturally occurring polymorphisms K30 and

M31 in NS5A reduced susceptibility to pibrentasvir by 24-fold relative to the activity of pibrentasvirin genotype 3a replicon.

Studies in treatment-naïve and peginterferon (pegIFN), ribavirin (RBV) and/or sofosbuvir treatment-experienced adult subjects with or without cirrhosis

Twenty-two of the approximately 2 300 subjects treated with Maviret for 8, 12, or 16 weeks inregistrational Phase 2 and 3 clinical studies experienced virologic failure (2 with genotype 1, 2 withgenotype 2, 18 with genotype 3 infection).

Among the 2 genotype 1-infected subjects who experienced virologic failure, one had treatment-emergent substitutions A156V in NS3 and Q30R/L31M/H58D in NS5A, and one had Q30R/H58D(while Y93N was present at baseline and post-treatment) in NS5A.

Among the 2 genotype 2-infected subjects, no treatment-emergent substitutions were observed in NS3or NS5A (the M31 polymorphism in NS5A was present at baseline and post-treatment in bothsubjects).

Among the 18 genotype 3-infected subjects treated with Maviret for 8, 12, or 16 weeks whoexperienced virologic failure, treatment-emergent NS3 substitutions Y56H/N, Q80K/R, A156G, or

Q168L/R were observed in 11 subjects. A166S or Q168R were present at baseline and post-treatmentin 5 subjects. Treatment-emergent NS5A substitutions M28G, A30G/K, L31F, P58T, or Y93H wereobserved in 16 subjects, and 13 subjects had A30K (n=9) or Y93H (n=5) at baseline andpost-treatment.

Studies in adult subjects with or without compensated cirrhosis who were treatment-experienced to

NS3/4A protease and/or NS5A inhibitors

Ten of 113 subjects treated with Maviret in the MAGELLAN-1 study for 12 or 16 weeks experiencedvirologic failure. Among the 10 genotype 1-infected subjects with virologic failure, treatment-emergent NS3 substitutions V36A/M, R155K/T, A156G/T/V, or D168A/T were observed in 7subjects. Five of the 10 had combinations of V36M, Y56H, R155K/T, or D168A/E in NS3 at baselineand post-treatment. All of the genotype 1-infected virologic failure subjects had one or more NS5Asubstitutions L/M28M/T/V, Q30E/G/H/K/L/R, L31M, P32 deletion, H58C/D, or Y93H at baseline,with additional treatment-emergent NS5A substitutions M28A/G, P29Q/R, Q30K, H58D, or Y93Hobserved in 7 of the subjects at the time of failure.

Thirteen of the 177 subjects with chronic HCV GT1 infection (all virologic failures had GT1ainfection) who were treatment-experienced with NS5A inhibitor + SOF treated with Maviret in study

B16-439 for 12 weeks (9 out of 13) or 16 weeks (4 out of 13) experienced virologic failure. Amongthe 13 virologic failures, treatment-emergent NS3 substitutions were observed in 4 subjects at the timeof failure: A156V (n = 2) or R155W + A156G (n = 2); 3 of these 4 subjects also had Q80K at baselineand at the time of failure. Twelve of 13 virologic failures had one or more NS5A polymorphismsdetected at signature amino acid positions (M28V/T, Q30E/H/N/R, L31M/V, H58D, E62D/Q, or

Y93H/N) at baseline, and 10 of 13 developed additional NS5A substitutions (M28A/S/T (n = 3),

Q30N (n = 1), L31M/V (n = 2), P32del (n = 1), H58D (n = 4), E62D (n = 1)) at time of treatmentfailure.

A pooled analysis of treatment-naïve and pegylated interferon, ribavirin and/or sofosbuvir treatment-experienced adult subjects receiving Maviret in the Phase 2 and Phase 3 clinical studies was conductedto explore the association between baseline polymorphisms and treatment outcome and to describesubstitutions seen upon virologic failure. Baseline polymorphisms relative to a subtype-specificreference sequence at amino acid positions 155, 156, and 168 in NS3, and 24, 28, 30, 31, 58, 92, and93 in NS5A were evaluated at a 15% detection threshold by next-generation sequencing. Baselinepolymorphisms in NS3 were detected in 1.1% (9/845), 0.8% (3/398), 1.6% (10/613), 1.2% (2/164),41.9% (13/31), and 2.9% (1/34) of subjects with HCV genotype 1, 2, 3, 4, 5, and 6 infection,respectively. Baseline polymorphisms in NS5A were detected in 26.8% (225/841), 79.8% (331/415),22.1% (136/615), 49.7% (80/161), 12.9% (4/31), and 54.1% (20/37) of subjects with HCV genotype 1,2, 3, 4, 5, and 6 infection, respectively.

Genotype 1, 2, 4, 5, and 6: Baseline polymorphisms in genotypes 1, 2, 4, 5 and 6 had no impact ontreatment outcome.

Genotype 3: For subjects who received the recommended regimen (n=313), baseline polymorphismsin NS5A (Y93H included) or NS3 did not have a relevant impact on treatment outcomes. All subjects(15/15) with Y93H and 77% (17/22) with A30K in NS5A at baseline achieved SVR12. The overallprevalence of A30K and Y93H at baseline was 7.0% and 4.8%, respectively. The ability to assess theimpact of baseline polymorphisms in NS5A was limited among treatment-naïve subjects with cirrhosisand treatment-experienced subjects due to low prevalence of A30K (3.0%, 4/132) or Y93H (3.8%,5/132).

In vitro data indicate that the majority of the resistance-associated substitutions in NS5A at amino acidpositions 24, 28, 30, 31, 58, 92, or 93 that confer resistance to ombitasvir, daclatasvir, ledipasvir,elbasvir, or velpatasvir remained susceptible to pibrentasvir. Some combinations of NS5Asubstitutions at these positions showed reductions in susceptibility to pibrentasvir. Glecaprevir wasfully active against resistance-associated substitutions in NS5A, while pibrentasvir was fully activeagainst resistance-associated substitutions in NS3. Both glecaprevir and pibrentasvir were fully activeagainst substitutions associated with resistance to NS5B nucleotide and non-nucleotide inhibitors.

Table 7 summarizes clinical studies conducted with Maviret in adult and adolescent subjects with

HCV genotype 1, 2, 3, 4, 5 or 6 infection.

Table 7: Clinical studies conducted with Maviret in subjects with HCV genotype 1, 2, 3, 4, 5 or 6

Infection

Genotype Clinical study Summary of study design(GT)

TN and PRS-TE subjects without cirrhosis

ENDURANCE- Maviret for 8 weeks (n=351) or 12 weeks (n=352)

GT1 1a

SURVEYOR-1 Maviret for 8 weeks (n=34)

ENDURANCE-2 Maviret (n=202) or Placebo (n=100) for 12 weeks

GT2

SURVEYOR-2b Maviret for 8 weeks (n=199) or 12 weeks (n=25)

Maviret for 8 weeks (n=157) or 12 weeks (n=233)

ENDURANCE-3

Sofosbuvir + daclatasvir for 12 weeks (n=115)

GT3

Maviret for 8 weeks (TN only, n=29) or 12 weeks (n=76) or

SURVEYOR-216 weeks (TE only, n=22)

ENDURANCE-4 Maviret for 12 weeks (n=121)

ENDURANCE- Maviret for 8 weeks (n=75)

GT4, 5, 6 5,6

SURVEYOR-1 Maviret for 12 weeks (n=32)

SURVEYOR-2c Maviret for 8 weeks (n=58)f Maviret for 8 weeks (GT1, 2, 4, 5, and 6 and GT3 TN)

GT1-6 VOYAGE-1(n=356) or 16 weeks (GT3 TE only) (n=6)

TN and PRS-TE subjects with cirrhosis

GT1, 2, 4, 5, 6 EXPEDITION-1 Maviret for 12 weeks (n=146)

GT3 d Maviret for 12 weeks (TN only, n=64) or 16 weeks (TE only,

SURVEYOR-2n=51)

ENDURANCE-

GT5, 6 Maviret for 12 weeks (n=9)5,6

GT1-6 f Maviret for 12 weeks (GT1, 2, 4, 5, and 6 and GT3 TN)

VOYAGE-2(n=157) or 16 weeks (GT3 TE only) (n=3)

GT1-6 EXPEDITION-8 Maviret for 8 weeks (n=343) (TN only)

Subjects with CKD stage 3b, 4 and 5 with or without cirrhosis

GT1-6 EXPEDITION-4 Maviret for 12 weeks (n=104)

Maviret for 8 weeks (n=84) or 12 weeks (n=13) or 16 weeks

GT1-6 EXPEDITION-5(n=4)

NS5A inhibitor and/or PI-experienced subjects with or without cirrhosis

GT1, 4 MAGELLAN-1e Maviret for 12 weeks (n=66) or 16 weeks (n=47)

GT1 Maviret for 12 weeks (n=78) or 16 weeks (n=78) or Maviret +

B16-439

RBV for 12 weeks (n=21)g

HCV/HIV-1 co-infected subjects with or without cirrhosis

GT1-6 EXPEDITION-2 Maviret for 8 weeks (n=137) or 12 weeks (n=16)

Liver or kidney transplant recipients

GT1-6 MAGELLAN-2 Maviret for 12 weeks (n=100)

Adolescent subjects (12 to < 18 years)

GT1-6 DORA (Part 1)a Maviret for 8 weeks (n=44) or 16 weeks (n=3)

TN=treatment-naïve, PRS-TE=treatment-experienced (includes previous treatment that includedpegIFN (or IFN), and/or RBV and/or sofosbuvir), PI=Protease Inhibitor, CKD=chronic kidney disease

a. ENDURANCE-1 included 33 subjects co-infected with HIV-1. DORA included 2 subjectscoinfectedwith HIV-1.

b. GT2 from SURVEYOR-2 Parts 1 and 2 - Maviret for 8 weeks (n=54) or 12 weeks (n=25); GT2from SURVEYOR-2 Part 4 - Maviret for 8 weeks (n=145).

c. GT3 without cirrhosis from SURVEYOR-2 Parts 1 and 2 - Maviret for 8 weeks (n=29) or 12 weeks(n=54); GT3 without cirrhosis from SURVEYOR-2 Part 3 - Maviret for 12 weeks (n=22) or 16 weeks(n=22).

d. GT3 with cirrhosis from SURVEYOR-2 Part 2 - Maviret for 12 weeks (n=24) or 16 weeks (n=4);

GT3 with cirrhosis from SURVEYOR-2 Part 3 - Maviret for 12 weeks (n=40) or 16 weeks (n=47).

e. GT1, 4 from MAGELLAN-1 Part 1 - Maviret for 12 weeks (n=22); GT1, 4 from MAGELLAN-1

Part 2 - Maviret for 12 weeks (n=44) or 16 weeks (n=47).

f. VOYAGE-1 and VOYAGE-2 were Asian regional studies.g. Maviret is not recommended for the re-treatment of patients with prior exposure to NS3/4A- and/or

NS5A inhibitors (see section 4.4).

Serum HCV RNA values were measured during the clinical studies using the Roche COBAS

AmpliPrep/COBAS Taqman HCV test (version 2.0) with a lower limit of quantification (LLOQ) of15 IU/mL (except for SURVEYOR-1 and SURVEYOR-2 which used the Roche COBAS TaqManreal-time reverse transcriptase-PCR (RT-PCR) assay v. 2.0 with an LLOQ of 25 IU/mL). Sustainedvirologic response (SVR12), defined as HCV RNA less than LLOQ at 12 weeks after the cessation oftreatment, was the primary endpoint in all the studies to determine the HCV cure rate.

Of the 2 409 adult subjects with compensated liver disease (with or without cirrhosis) treated whowere treatment-naïve or treatment-experienced to combinations of peginterferon, ribavirin and/orsofosbuvir, the median age was 53 years (range: 19 to 88); 73.3% were treatment-naïve, 26.7% weretreatment-experienced to a combination containing either sofosbuvir, ribavirin and/or peginterferon;40.3% were HCV genotype 1; 19.8% were HCV genotype 2; 27.8% were HCV genotype 3; 8.1%were HCV genotype 4; 3.4% were HCV genotype 5-6; 13.1% were ≥ 65 years; 56.6% were male;6.2% were Black; 12.3% had cirrhosis; 4.3% had severe renal impairment or end stage renal disease;20.0% had a body mass index of at least 30 kg per m2; 7.7% had HIV-1 coinfection and the medianbaseline HCV RNA level was 6.2 log10 IU/mL.

Table 8: SVR12 in adult subjects treatment-naïve and treatment-experienceda to peginterferon,ribavirin and/or sofosbuvir with genotype 1, 2, 4, 5 and 6 infection who received therecommended duration (pooled data from ENDURANCE-1b, SURVEYOR-1, -2, and

EXPEDITION-1, 2b, -4 and 8)

Genotype 1 Genotype 2 Genotype 4 Genotype Genotype 6

SVR12 in subjects without cirrhosis8 weeks 99.2% 98.1% 95.2% 100% 92.3%(470/474) (202/206) (59/62) (2/2) (12/13)

Outcome for subjects without SVR12

On-treatment 0.2% 0% 0% 0% 0%

VF (1/474) (0/206) (0/62) (0/2) (0/13)

Relapsec 0% 1.0% 0% 0% 0%(0/471) (2/204) (0/61) (0/2) (0/13)

Otherd 0.6% 1.0% 4.8% 0% 7.7%(3/474) (2/206) (3/62) (0/2) (1/13)

SVR12 in subjects with cirrhosis8 weeks 97.8% 100% 100% 100% 100%(226/231) (26/26) (13/13) (1/1) (9/9)12 weeks 96.8% 90.0% 100% 100%(30/31) (9/10) (8/8) --- (1/1)

Outcome for subjects without SVR12

On-treatment VF 0% 0% 0% 0% 0%(0/262) (0/36) (0/21) (0/1) (0/10)

Relapsec 0.4% 0% 0% 0% 0%(1/256) (0/35) (0/20) (0/1) (0/10)

Otherd 1.9% (5/262) 2.8% 0% 0% 0%(1/36) (0/21) (0/1) (0/10)

VF=virologic failure

a. Percent of subjects with prior treatment-experience to PRS is 26%, 14%, 24%, 0%, and 13% forgenotypes 1, 2, 4, 5, and 6, respectively. None of the GT5 subjects were TE-PRS, and 3 GT6 subjectswere TE-PRS.

b. Includes a total of 154 subjects coinfected with HIV-1 in ENDURANCE-1 and EXPEDITION-2who received the recommended duration.

c. Relapse is defined as HCV RNA ≥ LLOQ after end-of-treatment response among those whocompleted treatment.

d. Includes subjects who discontinued due to adverse event, lost to follow-up, or subject withdrawal.

Of the genotype 1-, 2-, 4-, 5-, or 6 infected subjects with end stage renal disease enrolled in

EXPEDITION-4, 97.8% (91/93) achieved SVR12 with no virologic failures.

ENDURANCE-5,6 was an open-label study in 84 HCV GT5 (N=23) or 6 infected (N=61) TN or

TE-PRS adult subjects. Subjects without cirrhosis received Maviret for 8 weeks, and subjects withcompensated cirrhosis received Maviret for 12 weeks. Of the 84 subjects treated, the median age was59 years (range 24-79); 27% had HCV genotype 5, 73% had HCV genotype 6; 54% were female, 30%were White, 68% were Asian; 90% were HCV TN; 11% had compensated cirrhosis.

The overall SVR12 rate was 97.6% (82/84). The SVR12 rate was 95.7% (22/23) for GT5-infectedsubjects and 98.4% (60/61) for GT6-infected subjects. One TN GT5-infected subject without cirrhosisexperienced relapse, and one TN GT6-infected subject with compensated cirrhosis experienced on-treatment virologic failure.

The safety and efficacy of Maviret given for 8 weeks in GT 1, 2, 4, 5 or 6 treatment-naïve adultsubjects with compensated cirrhosis was evaluated in a single-arm, open-label study(EXPEDITION-8).

Of the 280 subjects treated, the median age was 60 years (range: 34 to 88); 81.8% had HCV genotype1, 10% had HCV genotype 2, pct. 4.6% had HCV genotype 4, 0.4% had HCV genotype 5; 3.2% had HCVgenotype 6; 60% were male; 9.6% were Black.

The overall SVR12 rate was 98.2% (275/280). There were no virologic failures.

The efficacy of Maviret in subjects who were treatment-naïve or treatment-experienced tocombinations of peginterferon, ribavirin and/or sofosbuvir with genotype 3 chronic hepatitis Cinfection was demonstrated in the ENDURANCE-3 (treatment-naïve adults without cirrhosis),

EXPEDITION-8 (treatment-naïve adults with cirrhosis), and SURVEYOR-2 Part 3 (adults with andwithout cirrhosis and/or treatment-experienced) clinical studies.

ENDURANCE-3 was a partially-randomised, open-label, active-controlled study in treatment-naïvegenotype 3-infected subjects. Subjects were randomised (2:1) to either Maviret for 12 weeks or thecombination of sofosbuvir and daclatasvir for 12 weeks; subsequently the study included a third arm(which was non-randomised) with Maviret for 8 weeks. EXPEDITION-8 was a single-arm, open-labelstudy in treatment-naïve subjects with compensated cirrhosis and genotype 1, 2, 3, 4, 5 or 6 infectionwho received Maviret for 8 weeks. SURVEYOR-2 Part 3 was an open-label study that evaluated theefficacy of Maviret in treatment-experienced genotype 3-infected subjects without cirrhosis and withcompensated cirrhosis for 16-weeks. Among treatment-experienced subjects, 46% (42/91) failed aprevious regimen containing sofosbuvir.

Table 9: SVR12 in treatment-naïve, genotype 3-infected subjects without cirrhosis(ENDURANCE-3)

SVR Maviret 8 weeks Maviret 12 weeks SOF+DCV 12 weeks

N=157 N=233 N=11594.9% (149/157) 95.3% (222/233) 96.5% (111/115)

Treatment difference -1.2%;95% confidence interval (-5.6% to 3.1%)

Treatment difference -0.4%;97.5% confidence interval (-5.4% to 4.6%)

Outcome for subjects without SVR12

On-treatment VF 0.6% (1/157) 0.4% (1/233) 0% (0/115)

Relapsea 3.3% (5/150) 1.4% (3/222) 0.9% (1/114)

Otherb 1.3% (2/157) 3.0% (7/233) 2.6% (3/115)

a. Relapse is defined as HCV RNA ≥ LLOQ after end-of-treatment response among those whocompleted treatment.

b. Includes subjects who discontinued due to adverse event, lost to follow-up, or subject withdrawal.

In a pooled analysis of treatment-naïve adult patients without cirrhosis (including Phase 2 and 3 data)where SVR12 was assessed according to the presence of baseline A30K, a numerically lower SVR12rate was achieved in patients with A30K treated for 8 weeks as compared to those treated for 12 weeks[78% (14/18) vs 93% (13/14)].

Table 10: SVR12 in genotype 3-infected subjects with or without cirrhosis (SURVEYOR-2 Part3 and EXPEDITION-8)

Treatment-naïve Treatment-experienced

Treatment-naïvewith cirrhosis with or withoutwith cirrhosiscirrhosis

Maviret Maviret Maviret8 weeks 12 weeks 16 weeks(N=63) (N=40) (N=69)

SVR 95.2% (60/63) 97.5% (39/40) 95.7% (66/69)

Outcome for subjects without SVR12

On-treatment VF 0% (0/63) 0% (0/40) 1.4% (1/69)

Relapsea 1.6% (1/62) 0% (0/39) 2.9% (2/68)

Otherb 3.2% (2/63) 2.5% (1/40) 0% (0/69)

SVR by cirrhosis status

No Cirrhosis NA NA 95.5% (21/22)

Cirrhosis 95.2% (60/63) 97.5% (39/40) 95.7% (45/47)

a. Relapse is defined as HCV RNA ≥ LLOQ after end-of-treatment response among those whocompleted treatment.

b. Includes subjects who discontinued due to adverse event, lost to follow-up, or subject withdrawal.

Of the genotype 3-infected subjects with end stage renal disease enrolled in EXPEDITION-4, 100%(11/11) achieved SVR12.

GT3b is a subtype reported in a relatively small number of HCV infected patients in China and a fewcountries in South and Southeast Asia, but rarely outside of this region. Studies VOYAGE-1 and

VOYAGE-2 were conducted in China, Singapore, and South Korea in HCV genotype 1-6 adultsubjects without cirrhosis (VOYAGE-1) or with compensated cirrhosis (VOYAGE-2) that weretreatment-naïve (TN) or treatment-experienced to combinations of interferon, peg interferon, ribavirinand/or sofosbuvir (TE-PRS). All subjects without cirrhosis or with compensated cirrhosis received 8or 12 weeks of Maviret, respectively, except GT3 TE-PRS subjects who received 16 weeks of

Maviret. The overall SVR12 rates were 97.2% (352/362) and 99.4% (159/160) in VOYAGE-1 and

VOYAGE-2, respectively.

Among GT3b subjects without cirrhosis, a numerically lower SVR12 rate of 58.3% (7/12) [62.5%(5/8) for TN subjects and 50% (2/4) for TE-PRS subjects] was observed compared to GT3a subjectswithout cirrhosis (92.9% (13/14)). Three GT3b TN subjects experienced relapse and two GT3b

TE-PRS subjects experienced on-treatment virologic failure. Among subjects with compensatedcirrhosis, the overall SVR12 rate for GT3b infected subjects was 87.5% (7/8) [85.7% (6/7) for TNsubjects and 100% (1/1) for TE-PRS subjects] and 100% (6/6) for GT3a infected subjects. One GT3b

TN subject experienced relapse.

Overall SVR12 rate from the clinical studies in treatment-naïve or treatment-experienced adultsubjects with or without cirrhosis

In subjects who are treatment-naïve (TN) or treatment-experienced to combinations of interferon,peginterferon, ribavirin and/or sofosbuvir (TE-PRS) who received the recommended duration, 97.5%(1 395/1 431) achieved SVR12 overall, while 0.2% (3/1 431) experienced on-treatment virologicfailure and 0.9% (12/1 407) experienced post-treatment relapse.

In TN or TE-PRS subjects with compensated cirrhosis who received the recommended duration,97.1% (431/444) achieved SVR12 (among which 97.7% [335/343] of TN subjects achieved SVR12),while 0.2% (1/444) experienced on-treatment virologic failure and 0.9% (4/434) experienced post-treatment relapse.

In TN subjects without cirrhosis who received the recommended duration of 8 weeks, 97.5%(749/768) achieved SVR12, while 0.1% (1/768) experienced on-treatment virologic failure and 0.7%(5/755) experienced post-treatment relapse.

In TE-PRS subjects without cirrhosis who received the recommended duration, 98.2% (215/219)achieved SVR12, while 0.5% (1/219) experienced on-treatment virologic failure and 1.4% (3/218)experienced post-treatment relapse.

The presence of HIV-1 coinfection did not impact efficacy. The SVR12 rate in TN or TE-PRS

HCV/HIV-1 co-infected subjects treated for 8 or 12 weeks (without cirrhosis and with compensatedcirrhosis, respectively) was 98.2% (165/168) from ENDURANCE-1 and EXPEDITION-2. Onesubject experienced on-treatment virologic failure (0.6%, 1/168) and no subjects relapsed (0%, 0/166).

MAGELLAN-2 was a single-arm, open-label study in 100 post-liver or -kidney transplant HCV

GT1-6 infected adult subjects without cirrhosis who received Maviret for 12 weeks. The studyincluded subjects who were HCV treatment-naïve or treatment-experienced to combinations of (peg)interferon, ribavirin, and/or sofosbuvir, with the exception of GT3-infected subjects who were alltreatment-naïve.

Of the 100 subjects treated, the median age was 60 years (range: 39 to 78); 57% had HCV genotype 1,13% had HCV genotype 2, 24% had HCV genotype 3, 4% had HCV genotype 4, 2% had HCVgenotype 6; 75% were male; 8% were Black; 66% were HCV treatment-naïve; none had cirrhosis and80% had a baseline fibrosis state of F0 or F1; 80% of subjects were post-liver transplant and 20% werepost-kidney transplant. Immunosuppressants allowed for co-administration were ciclosporin≤ 100 mg/day, tacrolimus, sirolimus, everolimus, azathioprine, mycophenolic acid, prednisone, andprednisolone.

The overall SVR12 rate in post-transplant subjects was 98.0% (98/100). There was one relapse and noon-treatment virologic failure.

EXPEDITION-5 was an open-label study in 101 HCV GT1-6 infected adult subjects without cirrhosisor with compensated cirrhosis and chronic kidney disease (CKD) stage 3b, 4, or 5. Subjects wereeither treatment-naïve or treatment-experienced to combinations of (peg) interferon, ribavirin, and/orsofosbuvir and received Maviret for 8, 12, or 16 weeks per approved treatment durations.

Of the 101 subjects treated, the median age was 58 years (range 32-87); 53% had HCV genotype 1;27% had HCV genotype 2; 15% had HCV genotype 3; 4% had HCV genotype 4; 59% were male;73% were White; 80% were HCV treatment-naïve; 13% had cirrhosis and 65% had a baseline fibrosisstate of F0 or F1; 7% were CKD stage 3b; 17% were CKD Stage 4, and 76% were CKD Stage 5 (allreceiving dialysis); 84 subjects received 8 weeks of treatment, 13 subjects received 12 weeks oftreatment, and 4 subjects received 16 weeks of treatment.

The overall SVR12 rate was 97% (98/101). There were no virologic failures.

In a long-term follow-up study (M13-576), 99.5% (374/376) of adult subjects who had achieved

SVR12 in prior clinical studies of Maviret maintained SVR up to their last follow-up visit (medianduration of follow-up: 35.5 months): 100%, 99.6%, and 95.8% of subjects who had received 8, 12, and16 weeks of Maviret therapy, respectively. Among the 2 subjects who did not maintain SVR, 1experienced a late relapse 390 days after Maviret therapy, and the other subject experienced re-infection with a different HCV genotype.

Clinical studies of Maviret included 328 patients aged 65 and over (13.8% of the total number ofsubjects). The response rates observed for patients ≥ 65 years of age were similar to that of patients< 65 years of age, across treatment groups.

DORA (Part 1) was an open-label study to evaluate safety and efficacy in adolescents aged 12 years toless than 18 years who received Maviret 300 mg/120 mg (three 100 mg/40 mg film-coated tablets) for8 or 16 weeks. 47 subjects were enrolled in DORA (Part 1). The median age was 14 years (range: 12to 17); 79% had HCV genotype 1, 6% had HCV genotype 2, 9% had HCV genotype 3, 6% had HCVgenotype 4; 55% were female; 11% were Black; 77% were HCV treatment-naïve; 23% weretreatment-experienced to interferon; 4% had HIV-coinfection; none had cirrhosis; the mean weightwas 59 kg (range: 32 to 109).

The overall SVR12 rate was 100% (47/47). No subject experienced virologic failure.

Refer to the Summary of Product Characteristics for Maviret granules for clinical study data from

DORA Part 2 which evaluated the safety and efficacy of weight-based dosing of Maviret granules for8, 12 or 16 weeks in 80 children aged 3 years to less than 12 years.

The pharmacokinetic properties of the components of Maviret are provided in Table 11.

Table 11: Pharmacokinetic properties of the components of Maviret in healthy adult subjects

Glecaprevir Pibrentasvir

T amax (h) 5.0 5.0

Effect of meal (relative to fasting)b ↑ 83-163% ↑ 40-53%

Distribution% Bound to human plasma proteins 97.5 > 99.9

Blood-to-plasma ratio 0.57 0.62

Biotransformation secondary none

Major route of elimination Biliary excretion Biliary excretiont1/2 (h) at steady-state 6 - 9 23 - 29% of dose excreted in urinec 0.7 0% of dose excreted in faecesc 92.1d 96.6

Transport

Substrate of transporter P-gp, BCRP, and P-gp and not

OATP1B1/3 excluded BCRP

a. Median Tmax following single doses of glecaprevir and pibrentasvir in healthy subjects.

b. Mean systemic exposure with moderate to high fat meals.

c. Single dose administration of [14C]glecaprevir or [14C]pibrentasvir in mass balance studies.

d. Oxidative metabolites or their byproducts accounted for 26% of radioactive dose. No glecaprevirmetabolites were observed in plasma.

In patients with chronic hepatitis C infection without cirrhosis, following 3 days of monotherapy witheither glecaprevir 300 mg per day (N=6) or pibrentasvir 120 mg per day (N=8) alone, geometric mean

AUC24 values were 13 600 ng*h/mL for glecaprevir and 459 ng*h/mL for pibrentasvir. Estimation ofthe pharmacokinetic parameters using population pharmacokinetic models has inherent uncertaintydue to dose non-linearity and cross interaction between glecaprevir and pibrentasvir. Based onpopulation pharmacokinetic models for Maviret in chronic hepatitis C patients, steady-state AUC24values for glecaprevir and pibrentasvir were 4 800 and 1 430 ng*h/mL in subjects without cirrhosis(N=1 804), and 10 500 and 1 530 ng*h/mL in subjects with cirrhosis (N=280), respectively. Relative tohealthy subjects (N=230), population estimates of AUC24, ss were similar (10% difference) forglecaprevir and 34% lower for pibrentasvir in HCV-infected patients without cirrhosis.

Glecaprevir AUC increased in a greater than dose-proportional manner (1 200 mg QD had 516-foldhigher exposure than 200 mg QD) which may be related to saturation of uptake and effluxtransporters.

Pibrentasvir AUC increased in a greater than dose-proportional manner at doses up to 120 mg, (over10-fold exposure increase at 120 mg QD compared to 30 mg QD), but exhibited linearpharmacokinetics at doses ≥ 120 mg. The non-linear exposure increase < 120 mg may be related tosaturation of efflux transporters.

Pibrentasvir bioavailability when coadministered with glecaprevir is 3-fold of pibrentasvir alone.

Glecaprevir is affected to a lower extent by co-administration with pibrentasvir.

No dose adjustment of Maviret is required based on race or ethnicity.

Gender/weight

No dose adjustment of Maviret is required based on gender or body weight ≥ 45 kg.

No dose adjustment of Maviret is required in elderly patients. Population pharmacokinetic analysis in

HCV-infected subjects showed that within the age range (12 to 88 years) analysed, age did not have aclinically relevant effect on the exposure to glecaprevir or pibrentasvir.

No dose adjustment of Maviret is required in children 12 years and older or weighing at least 45 kg.

Exposures of glecaprevir and pibrentasvir in adolescents aged 12 to < 18 years were comparable tothose in adults from Phase 2/3 studies.

Maviret is available as a granule formulation for children 3 years to less than 12 years of age andweighing 12 kg to less than 45 kg and is dosed based on body weight. Children weighing 45 kg ormore should use the tablet formulation. Because the formulations have different pharmacokineticprofiles, the tablets and the coated granules are not interchangeable.

The pharmacokinetics of glecaprevir and pibrentasvir have not been established in children < 3 yearsof age or weighing under 12 kg.

Glecaprevir and pibrentasvir AUC were increased ≤ 56% in non-HCV infected subjects with mild,moderate, severe, or end stage renal impairment not on dialysis compared to subjects with normalrenal function. Glecaprevir and pibrentasvir AUC were similar with and without dialysis (≤ 18%difference) in dialysis-dependent non-HCV infected subjects. In population pharmacokinetic analysisof HCV-infected subjects, 86% higher glecaprevir and 54% higher pibrentasvir AUC were observedfor subjects with end stage renal disease, with or without dialysis, compared to subjects with normalrenal function. Larger increases may be expected when unbound concentration is considered.

Overall, the changes in exposures of Maviret in HCV-infected subjects with renal impairment with orwithout dialysis were not clinically significant.

At the clinical dose, compared to non-HCV infected subjects with normal hepatic function, glecaprevir

AUC was 33% higher in Child-Pugh A subjects, 100% higher in Child-Pugh B subjects, and increasedto 11-fold in Child-Pugh C subjects. Pibrentasvir AUC was similar in Child-Pugh A subjects, 26%higher in Child-Pugh B subjects, and 114% higher in Child-Pugh C subjects. Larger increases may beexpected when unbound concentration is considered.

Population pharmacokinetic analysis demonstrated that following administration of Maviret in HCV-infected subjects with compensated cirrhosis, exposure of glecaprevir was approximately 2-fold andpibrentasvir exposure was similar to non-cirrhotic HCV-infected subjects. The mechanism for thedifferences between glecaprevir exposure in chronic Hepatitis C patients with or without cirrhosis isunknown.

Glecaprevir and pibrentasvir were not genotoxic in a battery of in vitro or in vivo assays, includingbacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivorodent micronucleus assays. Carcinogenicity studies with glecaprevir and pibrentasvir have not beenconducted.

No effects on mating, female or male fertility, or early embryonic development were observed inrodents at up to the highest dose tested. Systemic exposures (AUC) to glecaprevir and pibrentasvirwere approximately 63 and 102 times higher, respectively, than the exposure in humans at therecommended dose.

In animal reproduction studies, no adverse developmental effects were observed when the componentsof Maviret were administered separately during organogenesis at exposures up to 53 times (rats;glecaprevir) or 51 and 1.5 times (mice and rabbits, respectively; pibrentasvir) the human exposures atthe recommended dose of Maviret. Maternal toxicity (anorexia, lower body weight, and lower bodyweight gain) with some embryofoetal toxicity (increase in post-implantation loss and number ofresorptions and a decrease in mean foetal body weight), precluded the ability to evaluate glecaprevir inthe rabbit at clinical exposures. There were no developmental effects with either compound in rodentperi/postnatal developmental studies in which maternal systemic exposures (AUC) to glecaprevir andpibrentasvir were approximately 47 and 74 times, respectively, the exposure in humans at therecommended dose. Unchanged glecaprevir was the main component observed in the milk of lactatingrats without effect on nursing pups. Pibrentasvir was the only component observed in the milk oflactating rats without effect on nursing pups.

Copovidone (Type K 28)

Vitamin E (tocopherol) polyethylene glycol succinate

Silica, colloidal anhydrous

Propylene glycol monocaprylate (Type II)

Croscarmellose sodium

Sodium stearyl fumarate

Hypromellose 2910 (E464)

Lactose monohydrate

Titanium dioxide

Macrogol 3350

Iron oxide red (E172)

Not applicable.

5 years.

This medicinal product does not require any special storage conditions.

PVC/PE/PCTFE aluminium foil blister packs.

Pack containing 84 (4 cartons of 21 tablets) film-coated tablets.

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

AbbVie Deutschland GmbH & Co. KG

Knollstrasse67061 Ludwigshafen

Germany

EU/1/17/1213/001

Date of first authorisation: 26 July 2017

Date of latest renewal: 22 March 2022

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