MAVIRET is indicated for the treatment of adult patients with chronic hepatitis C virus (HCV) genotype 1, 2, 3, 4, 5 or 6 infection without cirrhosis or with compensated cirrhosis (Child-Pugh A).  MAVIRET is also indicated for the treatment of adult patients with HCV genotype 1 infection, who previously have been treated with a regimen containing an HCV NS5A inhibitor or an NS3/4A protease inhibitor (PI), but not both [see sections 4.2, 4.4 and 5.1].

Testing Prior to the Initiation of Therapy

Test all patients for evidence of current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating HCV treatment with MAVIRET [see section 4.4].

Posology

MAVIRET is a fixed-dose combination product containing glecaprevir 100 mg and pibrentasvir 40 mg in each tablet.

The recommended oral dosage of MAVIRET is three tablets (total daily dose: glecaprevir 300 mg and pibrentasvir 120 mg) taken once daily with food [see section (5.2)].

Tables 1 and 2 provide the recommended MAVIRET treatment duration based on the patient population in HCV mono-infected and HCV/HIV-1 co-infected patients with compensated liver disease (with or without cirrhosis) and with or without renal impairment including patients receiving dialysis.

Table 1: Recommended duration for Treatment-Naïve Patients

Table 2. Recommended Duration for Treatment-Experienced Patients

1. In clinical trials, subjects were treated with prior regimens containing ledipasvir and sofosbuvir or daclatasvir with pegylated interferon and ribavirin.

2. In clinical trials, subjects were treated with prior regimens containing simeprevir and sofosbuvir, or simeprevir, boceprevir, or telaprevir with pegylated interferon and ribavirin.

3. PRS=Prior treatment experience with regimens containing interferon, pegylated interferon, ribavirin, and/or sofosbuvir, but no prior treatment experience with an HCV NS3/4A PI or NS5A inhibitor.

Missed dose

If a dose is missed and it is:

• Less than 18 hours from the usual time that MAVIRET should have been taken – advise the patient to take the dose as soon as possible and then to take the next dose at the usual time.

• More than 18 hours from the usual time that MAVIRET should have been taken – advise the patient not to take the missed dose and to take the next dose at the usual time.

Elderly

In clinical trials of MAVIRET, 328 subjects were age 65 years and over (14% of the total number of subjects in the Phase 2 and 3 clinical trials) and 47 subjects were age 75 and over (2%). No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects. No dosage adjustment of MAVIRET is warranted in geriatric patients [see sections 5.1 and 5.2].

Renal impairment

No dosage adjustment of MAVIRET is required in patients with mild, moderate or severe renal impairment, including those on dialysis [see sections 5.1 and 5.2].

Hepatic impairment

MAVIRET is not recommended in patients with moderate hepatic impairment (Child-Pugh B) and is contraindicated in patients with severe hepatic impairment (Child-Pugh C) [see sections 4.3, 4.4 and 5.2].

No dosage 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). Safety and efficacy have not been established in HCV-infected patients with moderate hepatic impairment. MAVIRET is contraindicated in patients with severe hepatic impairment (Child-Pugh C) due to higher exposures of glecaprevir and pibrentasvir [see sections 4.2, 4.3 and 5.1].

Paediatric population

Safety and effectiveness of MAVIRET in children less than 18 years of age have not been established.

Method of administration

For oral use.

Patients should be instructed to take MAVIRET recommended dosage (three tablets) once daily with food as directed.

Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV

Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct-acting antivirals, and who were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure and death. Cases have been reported in patients who are HBsAg positive and also in patients with serologic evidence of resolved HBV infection (i.e., HBsAg negative and anti-HBc positive). HBV reactivation has also been reported in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV direct-acting antivirals may be increased in these patients.

HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level. In patients with resolved HBV infection reappearance of HBsAg can occur. Reactivation of HBV replication may be accompanied by hepatitis, i.e., increase in aminotransferase levels and, in severe cases, increases in bilirubin levels, liver failure, and death can occur.

Test all patients for evidence of current or prior HBV infection by measuring HBsAg and anti-HBc before initiating HCV treatment with MAVIRET. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with MAVIRET and during post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.

Risk of Reduced Therapeutic Effect Due to Concomitant Use of MAVIRET with Carbamazepine, Efavirenz Containing Regimens, or St. John’s Wort

Carbamazepine, efavirenz, and St. John’s Wort may significantly decrease plasma concentrations of glecaprevir and pibrentasvir, leading to reduced therapeutic effect of MAVIRET. The use of these agents with MAVIRET is not recommended.

Hepatic impairment

MAVIRET is not recommended in patients with moderate hepatic impairment (Child-Pugh B) and is contraindicated in patients with severe hepatic impairment (Child-Pugh C) [see sections 4.2, 4.3 and 5.2].

Mechanisms for the Potential Effect of MAVIRET on Other Drugs

Glecaprevir and pibrentasvir are inhibitors of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide (OATP) 1B1/3. Coadministration with MAVIRET may increase plasma concentration of drugs that are substrates of P-gp, BCRP, OATP1B1 or OATP1B3. Glecaprevir and pibrentasvir are weak inhibitors of cytochrome P450 (CYP) 3A, CYP1A2, and uridine glucuronosyltransferase (UGT) 1A1.

Mechanisms for the Potential Effect of Other Drugs on MAVIRET

Glecaprevir and pibrentasvir are substrates of P-gp and/or BCRP. Glecaprevir is a substrate of OATP1B1/3. Coadministration of MAVIRET with drugs that inhibit hepatic P-gp, BCRP, or OATP1B1/3 may increase the plasma concentrations of glecaprevir and/or pibrentasvir.

Coadministration of MAVIRET with drugs that induce P-gp/CYP3A may decrease glecaprevir and pibrentasvir plasma concentrations.

Carbamazepine, efavirenz, and St. John’s wort may significantly decrease plasma concentrations of glecaprevir and pibrentasvir, leading to reduced therapeutic effect of MAVIRET. The use of these agents with MAVIRET is not recommended [see section 5.2].

Established and Other Potential Drug Interactions

Table 3 provides the effect of MAVIRET on concentrations of coadministered drugs and the effect of coadministered drugs on glecaprevir and pibrentasvir [see sections 4.3 and 5.2].

Table 3. Potentially Significant Drug Interactions Identified in Drug Interaction Studies

Drugs with No Observed Clinically Significant Interactions with MAVIRET

No dose adjustment is required when MAVIRET is coadministered with the following medications: abacavir, amlodipine, buprenorphine, caffeine, dextromethorphan, dolutegravir, elvitegravir/cobicistat, emtricitabine, felodipine, lamivudine, lamotrigine, losartan, methadone, midazolam, naloxone, norethindrone or other progestin-only contraceptives, omeprazole,  raltegravir, rilpivirine, sofosbuvir, tacrolimus, tenofovir alafenamide, tenofovir disoproxil fumarate, tolbutamide, and valsartan.

Drug Interaction Studies – pharmacokinetic interactions

Drug interaction studies were performed with glecaprevir/pibrentasvir and other drugs that are likely to be coadministered and with drugs commonly used as probes for pharmacokinetic interactions. Tables 4 and 5 summarize the pharmacokinetic effects when glecaprevir/pibrentasvir was coadministered with other drugs which showed potentially clinically relevant changes. Significant interactions are not expected when MAVIRET is coadministered with substrates of CYP3A, CYP1A2, CYP2C9, CYP2C19, CYP2D6, UGT1A1, or UGT1A4.

Table 4. Drug Interactions: Changes in Pharmacokinetic Parameters of Glecaprevir (GLE) or Pibrentasvir (PIB)in the Presence of Coadministered Drug

Table 5. Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Combination of Glecaprevir/Pibrentasvir (GLE/PIB)

Fertility

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

Pregnancy

Risk Summary

No adequate human data are available to establish whether or not MAVIRET poses a risk to pregnancy outcomes. In animal reproduction studies, no adverse developmental effects were observed when the components of 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 at the recommended dose of MAVIRET [see Data]. No definitive conclusions regarding potential developmental effects of glecaprevir could be made in rabbits, since the highest achieved glecaprevir exposure in this species was only 7% (0.07 times) of the human exposure at the recommended dose. There were no effects with either compound in rodent pre/post-natal developmental studies in which maternal systemic exposures (AUC) to glecaprevir and pibrentasvir were approximately 47 and 74 times, respectively, the exposure in humans at the recommended dose [see Data].

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Glecaprevir

Glecaprevir was administered orally to pregnant rats (up to 120 mg/kg/day) and rabbits (up to 60 mg/kg/day) during the period of organogenesis (gestation days (GD) 6 to 18, and GD 7 to 19, respectively). No adverse embryo-fetal effects were observed in rats at dose levels up to 120 mg/kg/day (53 times the exposures in humans at the recommended human dose (RHD)). In rabbits, the highest glecaprevir exposure achieved was 7% (0.07 times) of the exposure in humans at RHD. As such, data in rabbits during organogenesis are not available for glecaprevir systemic exposures at or above the exposures in humans at the RHD.

In the pre/post-natal developmental study in rats, glecaprevir was administered orally (up to 120 mg/kg/day) from GD 6 to lactation day 20. No effects were observed at maternal exposures 47 times the exposures in humans at the RHD.

Pibrentasvir

Pibrentasvir was administered orally to pregnant mice and rabbits (up to 100 mg/kg/day) during the period of organogenesis (GD 6 to 15, and GD 7 to 19, respectively). No adverse embryo-fetal effects were observed at any studied dose level in either species. The systemic exposures at the highest doses were 51 times (mice) and 1.5 times (rabbits) the exposures in humans at the RHD. In the pre/post-natal developmental study in mice, pibrentasvir was administered orally (up to 100 mg/kg/day) from GD 6 to lactation day 20. No effects were observed at maternal exposures approximately 74 times the exposures in humans at the RHD.

Breast-feeding

Risk Summary

It is not known whether the components of MAVIRET are excreted in human breast milk, affect human milk production, or have effects on the breastfed infant. When administered to lactating rodents, the components of MAVIRET were present in milk, without effect on growth and development observed in the nursing pups [see Data].

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for MAVIRET and any potential adverse effects on the breastfed child from MAVIRET or from the underlying maternal condition.

Data

No significant effects of glecaprevir or pibrentasvir on growth and post-natal development were observed in nursing pups at the highest doses tested (120 mg/kg/day for glecaprevir and 100 mg/kg/day for pibrentasvir). Maternal systemic exposure (AUC) to glecaprevir and pibrentasvir was approximately 47 or 74 times the exposure in humans at the RHD. Systemic exposure in nursing pups on post-natal day 14 was approximately 0.6 to 2.2 % of the maternal exposure for glecaprevir and approximately one quarter to one third of the maternal exposure for pibrentasvir.

Glecaprevir or pibrentasvir was administered (single dose; 5 mg/kg oral) to lactating rats, 8 to 12 days post parturition. Glecaprevir in milk was 13 times lower than in plasma and pibrentasvir in milk was 1.5 times higher than in plasma. Parent drug (glecaprevir or pibrentasvir) represented the majority (>96%) of the total drug-related material in milk.

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

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of MAVIRET cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Overall Adverse Reactions in HCV-Infected Adults Without Cirrhosis or With Compensated Cirrhosis (Child-Pugh A)

The adverse reactions data for MAVIRET in subjects without cirrhosis or with compensated cirrhosis (Child-Pugh A) were derived from Phase 2 and 3 trials which evaluated approximately 2,300 subjects infected with genotype 1, 2, 3, 4, 5, or 6 HCV who received MAVIRET for 8, 12 or 16 weeks [see section 5.1].

The overall proportion of subjects who permanently discontinued treatment due to adverse reactions was 0.1% for subjects who received MAVIRET for 8, 12 or 16 weeks.

The most common adverse reactions, all grades, observed in greater than or equal to 5% of subjects receiving 8, 12, or 16 weeks of treatment with MAVIRET were headache (13%), fatigue (11%), and nausea (8%). In subjects receiving MAVIRET who experienced adverse reactions, 80% had an adverse reaction of mild severity (Grade 1). One subject experienced a serious adverse reaction.

Adverse reactions (type and severity) were similar for subjects receiving MAVIRET for 8, 12 or 16 weeks. The type and severity of adverse reactions in subjects with compensated cirrhosis (Child-Pugh A) were comparable to those seen in subjects without cirrhosis.

Adverse Reactions in HCV-Infected Adults treated with MAVIRET in Controlled Trials

ENDURANCE-2

Among 302 treatment-naïve or PRS treatment-experienced, HCV-infected adults enrolled in ENDURANCE-2, adverse reactions (all intensity) occurring in at least 5% of subjects treated with MAVIRET for 12 weeks are presented in Table 6. In subjects treated with MAVIRET for 12 weeks, 32% reported an adverse reaction, of which 98% had adverse reactions of mild or moderate severity. No subjects treated with MAVIRET or placebo in ENDURANCE-2 permanently discontinued treatment due to an adverse drug reaction.

Table 6. Adverse Reactions Reported in ≥5% of Treatment-Naïve and PRS-Experienced Adults Without Cirrhosis Receiving MAVIRET for 12 Weeks in ENDURANCE-2

ENDURANCE-3

Among 505 treatment-naïve, HCV genotype 3 infected adults without cirrhosis enrolled in ENDURANCE-3, adverse reactions (all intensity) occurring in at least 5% of subjects treated with MAVIRET for 8 or 12 weeks are presented in Table 7. In subjects treated with MAVIRET, 45% reported an adverse reaction, of which 99% had adverse reactions of mild or moderate severity. The proportion of subjects who permanently discontinued treatment due to adverse reactions was 0%, < 1% and 1% for the MAVIRET 8 week arm, MAVIRET 12 week arm and DCV + SOF arm, respectively.

Table 7.  Adverse Reactions Reported in ≥5% of Treatment-Naïve Adults Without Cirrhosis Receiving MAVIRET for 8 Weeks or 12 Weeks in ENDURANCE-3

¹ DCV=daclatasvir

² SOF=sofosbuvir

* The 8 week arm was a non-randomized treatment arm.

Adverse Reactions in HCV-Infected Adults With Severe Renal Impairment Including Subjects on Dialysis.

The safety of MAVIRET in subjects with chronic kidney disease (Stage 4 or Stage 5 including subjects on dialysis) with genotypes 1, 2, 3, 4, 5 or 6 chronic HCV infection without cirrhosis or with compensated cirrhosis (Child-Pugh A) was assessed in 104 subjects (EXPEDITION-4) who received MAVIRET for 12 weeks. The most common adverse reactions observed in greater than or equal to 5% of subjects receiving 12 weeks of treatment with MAVIRET were pruritus (17%), fatigue (12%), nausea (9%), asthenia (7%), and headache (6%). In subjects treated with MAVIRET who reported an adverse reaction, 90% had adverse reactions of mild or moderate severity (Grade 1 or 2). The proportion of subjects who permanently discontinued treatment due to adverse reactions was 2%.

Laboratory Abnormalities

Serum bilirubin elevations

Elevations of total bilirubin at least 2 times the upper limit of normal occurred in 3.5% of subjects treated with MAVIRET versus 0% in placebo; these elevations were observed in 1.2% of subjects across the Phase 2 and 3 trials. MAVIRET inhibits OATP1B1/3 and is a weak inhibitor of UGT1A1 and may have the potential to impact bilirubin transport and metabolism, including direct and indirect bilirubin. No subjects experienced jaundice and total bilirubin levels decreased after completing MAVIRET. 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

− The National Pharmacovigilance and Drug Safety Centre (NPC)

·         Fax: +966-11-205-7662

·         Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.

·         Toll free phone: 8002490000

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

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

In case of overdose, the patient should be monitored for any signs and symptoms of toxicities. Appropriate symptomatic treatment should be instituted immediately. Glecaprevir and pibrentasvir are not significantly removed by hemodialysis.

Pharmacotherapeutic group:

Direct-acting antiviral, ATC code: not yet assigned

 Mechanism of action

MAVIRET is a fixed-dose combination tablet containing glecaprevir and pibrentasvir for oral administration. Glecaprevir is a HCV NS3/4A PI, and pibrentasvir is a HCV NS5A inhibitor.

Glecaprevir/Pibrentasvir Film-Coated Immediate Release Tablets Each tablet contains 100 mg of glecaprevir and 40 mg of pibrentasvir. Glecaprevir and pibrentasvir are presented as a co-formulated, fixed-dose combination, immediate release bilayer tablet.

Glecaprevir drug substance:

The chemical name of glecaprevir is (3aR,7S,10S,12R,21E,24aR)-7-tert-butyl-N-{(1R,2R)-2-(difluoromethyl)-1-[(1-methylcyclopropane-1-sulfonyl)carbamoyl]cyclopropyl}-20,20-difluoro-5,8-dioxo-2,3,3a,5,6,7,8,11,12,20,23,24a-dodecahydro-1H,10H-9,12-methanocyclopenta[18,19][1,10,17,3,6]trioxadiazacyclononadecino[11,12-b]quinoxaline-10-carboxamide hydrate.

The molecular formula is C₃₈H₄₆F₄N₆O₉S (anhydrate) and the molecular weight for the drug substance is 838.87 g/mol (anhydrate). The strength of glecaprevir is based on anhydrous glecaprevir. Glecaprevir is a white to off-white crystalline powder with a solubility of less than 0.1 to 0.3 mg/mL across a pH range of 2–7 at 37°C and is practically insoluble in water, but is sparingly soluble in ethanol. Glecaprevir has the following molecular structure:

Pibrentasvir drug substance:

The chemical name of pibrentasvir is Methyl {(2S,3R)-1-[(2S)-2-{5-[(2R,5R)-1-{3,5-difluoro-4-[4-(4-fluorophenyl)piperidin-1-yl]phenyl}-5-(6-fluoro-2-{(2S)-1-[N-(methoxycarbonyl)-Omethyl-L-threonyl]pyrrolidin-2-yl}-1H-benzimidazol-5-yl)pyrrolidin-2-yl]-6-fluoro-1Hbenzimidazol-2-yl}pyrrolidin-1-yl]-3-methoxy-1-oxobutan-2-yl}carbamate.

The molecular formula is C₅₇H₆₅F₅N₁₀O₈ and the molecular weight for the drug substance is 1113.18 g/mol. Pibrentasvir is a white to off-white to light yellow crystalline powder with a solubility of less than 0.1 mg/mL across a pH range of 1–7 at 37°C and is practically insoluble in water, but is freely soluble in ethanol. Pibrentasvir has the following molecular structure:

Cardiac Electrophysiology

The effect of doses up to glecaprevir 600 mg (2 times the recommended dosage) with doses up to pibrentasvir 240 mg (2 times the recommended dosage) on QTc interval was evaluated in an active-controlled (moxifloxacin 400 mg) thorough QT study. At 20-fold of glecaprevir and 5- fold of pibrentasvir therapeutic concentrations, the glecaprevir and pibrentasvir combination does not prolong the QTc interval to any clinically relevant extent.

Microbiology

Mechanism of Action

Glecaprevir

Glecaprevir is an inhibitor of the HCV NS3/4A protease, which is necessary for the proteolytic cleavage of the HCV encoded polyprotein (into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins) and is essential for viral replication. In a biochemical assay, glecaprevir inhibited the proteolytic activity of recombinant NS3/4A enzymes from clinical isolates of HCV genotypes 1a, 1b, 2a, 2b, 3a, 4a, 5a, and 6a with IC50 values ranging from 3.5 to 11.3 nM.

Pibrentasvir

Pibrentasvir is an inhibitor of HCV NS5A, which is essential for viral RNA replication and virion assembly. The mechanism of action of pibrentasvir has been characterized based on cell culture antiviral activity and drug resistance mapping studies.

Antiviral Activity

In HCV replicon assays, glecaprevir had median EC50 values of 0.08-4.6 nM against laboratory and clinical isolates from subtypes 1a, 1b, 2a, 2b, 3a, 4a, 4d, 5a, and 6a. Pibrentasvir had median EC50 values of 0.5-4.3 pM against laboratory and clinical isolates from subtypes 1a, 1b, 2a, 2b,

3a, 4a, 4b, 4d, 5a, 6a, 6e and 6p.

Combination Antiviral Activity

Evaluation of combination of glecaprevir and pibrentasvir showed no antagonism in antiviral activity in HCV genotype 1 replicon cell culture assays.

Resistance

In Cell Culture

Selection of HCV genotype 1a, 1b, 2a, 3a, 4a or 6a replicons for reduced susceptibility to glecaprevir resulted in the emergence of amino acid substitutions most commonly at NS3 positions A156 or D/Q168. Individual substitutions at NS3 amino acid position A156 introduced into HCV replicons by site-directed mutagenesis generally caused the greatest reductions (>100-fold) in susceptibility to glecaprevir. Individual substitutions at NS3 position D/Q168 had varying effects on glecaprevir susceptibility depending on HCV genotype/subtype and specific amino acid change, with the greatest reductions (>30-fold) observed in genotypes 1a (D168F/Y), 3a (Q168R) and 6a (D168A/G/H/V/Y). Combinations of NS3 Y56H plus D/Q168 substitutions resulted in greater reductions in glecaprevir susceptibility. An NS3 Q80R substitution in genotype 3a caused a 21-fold reduction in glecaprevir susceptibility, while Q80 substitutions in genotypes 1a and 1b (including genotype 1a Q80K) did not reduce glecaprevir susceptibility. Individual amino acid substitutions associated with resistance to other HCV protease inhibitors at positions 36, 43, 54, 55, 56, 155, 166, or 170 in NS3 generally did not reduce susceptibility to glecaprevir.

Selection of HCV genotype 1a, 2a or 3a replicons for reduced susceptibility to pibrentasvir resulted in the emergence of amino acid substitutions at known NS5A inhibitor resistanceassociated positions, including Q30D/deletion, Y93D/H/N or H58D +Y93H in genotype 1a replicons, F28S + M31I or P29S + K30G in genotype 2a replicons, and Y93H in genotype 3a replicons. The majority of individual amino acid substitutions associated with resistance to other HCV NS5A inhibitors at positions 24, 28, 30, 31, 58, 92, or 93 in NS5A did not reduce susceptibility to pibrentasvir. Individual NS5A amino acid substitutions that reduced susceptibility to pibrentasvir include M28G or Q30D in a genotype 1a replicon (244- and 94-fold, respectively), and P32-deletion in a genotype 1b replicon (1,036-fold). Some combinations of two or more NS5A inhibitor resistance-associated amino acid substitutions may result in greater reductions in pibrentasvir susceptibility.

In Clinical Studies

Studies in Treatment-Naïve and Peginterferon, Ribavirin and/or Sofosbuvir Treatment- Experienced Subjects with or without Cirrhosis

In pooled analyses of NS3/4A PI- and NS5A inhibitor-naïve subjects who received MAVIRET for 8, 12, or 16 weeks in Phase 2 and 3 clinical studies, treatment-emergent resistance analyses were conducted for 22 subjects who experienced virologic failure (2 with genotype 1, 2 with genotype 2, 18 with genotype 3 infection). No subjects with HCV genotype 4, 5 or 6 infection experienced virologic failure.

Among the two genotype 1-infected subjects who experienced virologic failure, both subjects had a subtype 1a infection. One subject had treatment-emergent substitutions A156V in NS3, and Q30R, L31M and H58D in NS5A (Q30R and L31M were also detected at a low frequency at baseline). One subject had treatment-emergent Q30R and H58D (while Y93N was present at baseline and post-treatment) in NS5A.

Among the two genotype 2-infected subjects who experienced virologic failure, both subjects had a subtype 2a infection, and no treatment-emergent substitutions were observed in NS3 or NS5A.

Among the 18 genotype 3-infected subjects who experienced 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-treatment in 5 subjects. Treatmentemergent NS5A substitutions M28G, A30G/K, L31F, P58T, or Y93H were observed in 16 subjects, and 13 subjects had A30K (n=9) or Y93H (n=5) at baseline and post-treatment.

Studies in Subjects with or without Cirrhosis Who Were Treatment-Experienced to NS3/4A Protease and/or NS5A Inhibitors

Treatment-emergent resistance analyses were conducted for 11 HCV genotype 1 infected subjects (10 genotype 1a, 1 genotype 1b) with prior NS3/4A PI or NS5A inhibitor treatment experience who experienced virologic failure with MAVIRET with or without ribavirin in the MAGELLAN-1 study. Treatment-emergent NS3 substitutions V36A/M, Y56H, R155K/T, A156G/T/V, or D168A/T were observed in 73% (8/11) of subjects. Nine of 10 subjects (90%, not including one subject missing NS5A data at failure) had treatment-emergent NS5A substitutions M28A/G (or L28M for genotype 1b), P29Q/R, Q30K/R, H58D or Y93H/N. All 11 subjects also had NS5A inhibitor resistance-associated substitutions detected at baseline, and 7/11 had NS3 PI resistance-associated substitutions detected at baseline (see Cross-Resistance for the effect of baseline resistance-associated substitutions on treatment response for NS3/4A PI or NS5A inhibitor treatment-experienced patients).

Effect of Baseline HCV Amino Acid Polymorphisms on Treatment Response (NS3/4A PI- and NS5A Inhibitor-Naïve Subjects)

A pooled analysis of NS3/4A PI- and NS5A inhibitor-naïve subjects who received MAVIRET in the Phase 2 and Phase 3 clinical studies was conducted to identify the HCV subtypes represented and explore the association between baseline amino acid polymorphisms and treatment outcome . Baseline polymorphisms relative to a subtype-specific reference sequence at resistance-associated amino acid positions 155, 156, and 168 in NS3, and 24, 28, 30, 31, 58, 92, and 93 in NS5A were evaluated at a 15% detection threshold by next-generation sequencing. Among subjects who received MAVIRET for 8-, 12-, or 16 weeks, baseline polymorphisms in NS3 were detected in 1% (9/845), 1% (3/398), 2% (10/613), 1% (2/164), 42% (13/31), and 3%

(1/34) of subjects with HCV genotype 1, 2, 3, 4, 5, and 6 infection, respectively. No baseline polymorphisms were detected at NS3 amino acid position 156 across all genotypes. Baseline polymorphisms in NS5A were detected in 27% (225/841), 80% (331/415), 22% (136/615), 50% (80/161), 13% (4/31), and 54% (20/37) of subjects with HCV genotype 1, 2, 3, 4, 5, and 6 infection, respectively.

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

Genotype 3: Among treatment-naïve, genotype 3-infected subjects without cirrhosis who received MAVIRET for 8 weeks, an NS5A A30K polymorphism was detected in 10% (18/181) of subjects, of whom 78% (14/18) achieved SVR12. Insufficient data are available to characterize the impact of the A30K polymorphism in genotype 3-infected subjects with cirrhosis (n=1, SVR12) or prior treatment experience (n=1, relapse) who received the recommended MAVIRET regimens. All genotype 3-infected subjects (100%, 16/16) with Y93H in NS5A at baseline who received the recommended MAVIRET regimens achieved SVR12.

Cross-resistance

Based on resistance patterns observed in cell culture replicon studies and HCV-infected subjects, cross-resistance is possible between glecaprevir and other HCV NS3/4A PIs, and between pibrentasvir and other HCV NS5A inhibitors. Cross-resistance is not expected between MAVIRET and sofosbuvir, pegylated interferon or ribavirin.

In the MAGELLAN-1 study, HCV genotype 1-infected subjects who had failed prior treatment with NS3/4A protease and/or NS5A inhibitors were treated with MAVIRET for 12 or 16 weeks. Baseline sequences were analyzed by next generation sequencing at a 15% detection threshold.

Among 23 NS3/4A PI-experienced/NS5A inhibitor-naïve subjects who received MAVIRET for 12 weeks in MAGELLAN-1 (excluding 2 non-virologic failure subjects), 2 subjects each had baseline NS3 R155K or D168E/V substitutions; all 23 subjects achieved SVR12.

Among NS5A inhibitor-experienced/PI-naïve subjects who received MAVIRET for 16 weeks, baseline NS5A resistance-associated substitutions [R30Q (n=1), Y93H/N (n=5), M28A+Q30R (n=1), Q30H+Y93H (n=1), Q30R+L31M (n=2), L31M+H58P (n=1)], were detected in 73% (11/15) of subjects with available data, of whom 91% (10/11) achieved SVR12. The non-SVR12 subject experienced on-treatment virologic failure and had a genotype 1a infection with baseline NS5A Q30R and L31M substitutions.

Persistence of Resistance-Associated Substitutions

Data on the persistence of glecaprevir and pibrentasvir resistance-associated substitutions are not available. NS5A resistance-associated substitutions observed in patients treated with other NS5A inhibitors have been found to persist for longer than 1 year. In patients treated with other NS3/4A PI, viral populations with NS3 resistance-associated substitutions have been found to decline in some patients through post-treatment weeks 24 and 48. The long-term clinical impact of the emergence or persistence of virus containing glecaprevir or pibrentasvir resistanceassociated substitutions is unknown.

Description of Clinical Trials

Table 8 summarizes the clinical trials conducted to support the effectiveness of MAVIRET in subjects with HCV genotype 1, 2, 3, 4, 5 or 6 infection and compensated liver disease (including Child-Pugh A cirrhosis) according to treatment history and cirrhosis status.

Table 8. Clinical Trials Conducted with MAVIRET in Adults With HCV Genotype 1, 2, 3, 4, 5 or 6 Infection and Compensated Liver Disease

TN=treatment naïve; PI=protease inhibitor; CKD=chronic kidney disease PRS-TE= defined as prior treatment experience with regimens containing interferon, pegylated interferon, ribavirin, and/or sofosbuvir, but no prior treatment experience with an HCV NS3/4A PI or NS5A inhibitor.

* Treatment durations for some trial arms shown in this table do not reflect recommended dosing for the respective genotypes, prior treatment history, and/or cirrhosis status. For recommended dosing in adults [see section 4.2].

Serum HCV RNA values were measured during the clinical trials using the Roche COBAS AmpliPrep/COBAS Taqman HCV test (version 2.0) with a lower limit of quantification (LLOQ) of 15 IU/mL (except for SURVEYOR-1 and SURVEYOR-2 which used the Roche COBAS TaqMan real-time reverse transcriptase-PCR (RT-PCR) assay v. 2.0 with an LLOQ of 25 IU/mL). The primary endpoint across all clinical trials was sustained virologic response (SVR12), defined as HCV RNA less than LLOQ at 12 weeks after the end of treatment. Relapse was defined as HCV RNA ≥ LLOQ after end-of-treatment response among subjects who completed treatment. Subjects with missing HCV RNA data, such as those who discontinued due to an adverse event, subject withdrawal or were lost to follow-up, were counted as SVR12 failures.

Demographics and Baseline Characteristics of Clinical Trials in Treatment-Naïve or Treatment-Experienced Adults to PegInterferon, Ribavirin and/or Sofosbuvir (PRS) Without Cirrhosis or With Compensated Cirrhosis (Child-Pugh A)

Of the 2,152 treated subjects without cirrhosis or with compensated cirrhosis who were treatment-naïve or treatment-experienced to a combination of interferon, peginterferon, ribavirin and/or sofosbuvir (PRS), excluding EXPEDITION-4 and MAGELLAN-1, the median age was 54 years (range: 19 to 88); 73% were treatment-naïve, 27% were PRS treatment-experienced;

39% were HCV genotype 1; 21% were HCV genotype 2; 29% were HCV genotype 3; 7% were HCV genotype 4; 4% were HCV genotype 5-6; 13% were ≥65 years; 54% were male; 5% were Black; 12% had cirrhosis; 20% had a body mass index of at least 30 kg per m2; and median baseline HCV RNA level was 6.2 log10 IU/mL.

Treatment-Naïve or PRS Treatment-Experienced Adults With HCV Genotype 1, 2, 4, 5, or 6 Infection Without Cirrhosis

The efficacy of MAVIRET in subjects who were treatment-naïve or treatment-experienced to combinations of peginterferon, ribavirin and/or sofosbuvir (PRS) with genotype 1, 2, 4, 5 or 6 chronic HCV infection without cirrhosis was studied in four trials using 8- or 12-week durations: ENDURANCE-1, ENDURANCE-4, SURVEYOR-1 (Part 2), and SURVEYOR-2 (Part 2 and Part 4).

ENDURANCE-1 was a randomized (1:1), open-label, multi-national trial comparing the efficacy of 8 weeks of treatment with MAVIRET versus 12 weeks of treatment in subjects without cirrhosis with genotype 1 infection with or without HIV-1 co-infection (n=33 co-infected). Table 9 presents SVR12 in MAVIRET-treated genotype 1 infected subjects for the 8 week treatment arm. Due to numerically similar efficacy, MAVIRET is recommended for 8 weeks for treatment-naïve and PRS treatment-experienced genotype 1 subjects without cirrhosis, rather than 12 weeks [see section 4.2].

Table 9: ENDURANCE-1: Efficacy in Treatment-Naïve and PRS Treatment-Experienced With HCV Genotype 1 Infection and Without Cirrhosis

The SVR12 data from the open-label trials SURVEYOR-2 (Parts 2 and 4), ENDURANCE-4 and SURVEYOR-1 (Part 2) are pooled by genotype, where appropriate, in Table 10 for ease of display.

Table 10: SURVEYOR-2 (Part 2 and Part 4), ENDURANCE-4 and SURVEYOR-1 (Part 2): Efficacy in Treatment-Naïve and PRS Treatment-Experienced Adults With HCV Genotypes 2, 4, 5 or 6 Infection Without Cirrhosis

Treatment-Naïve or PRS Treatment-Experienced Adults with HCV Genotype 1, 2, 4, 5, or 6 Infection With Compensated Cirrhosis

The efficacy of MAVIRET in subjects who were treatment-naïve or treatment-experienced to combinations of peginterferon, ribavirin and/or sofosbuvir (PRS) with genotype 1, 2, 4, 5 or 6 chronic hepatitis C virus infection with compensated cirrhosis (Child-Pugh A) was studied in the single-arm, open-label EXPEDITION-1 trial, which included 146 subjects treated with

MAVIRET for 12 weeks.

Table 11. EXPEDITION-1: Efficacy in Treatment-Naïve and PRS Treatment-Experienced Adults With HCV Genotype 1, 2, 4, 5 or 6 Infection With Compensated Cirrhosis

The efficacy of MAVIRET in subjects without cirrhosis or with compensated cirrhosis who were treatment-naïve or treatment-experienced to combinations of peginterferon, ribavirin and/or sofosbuvir (PRS) with genotype 3 chronic HCV infection was studied in ENDURANCE-3 and in SURVEYOR-2 Part 3.Treatment-Naïve or PRS Treatment-Experienced Adults With HCV Genotype 3 Infection Without Cirrhosis or With Compensated Cirrhosis

ENDURANCE-3 was a partially-randomized, open-label, active-controlled trial in treatment-naïve subjects. Subjects were randomized (2:1) to either MAVIRET for 12 weeks or to the combination of sofosbuvir and daclatasvir for 12 weeks; subsequently the trial included a third non-randomized arm with MAVIRET for 8 weeks. The SVR12 data are summarized in Table 12. Due to numerically similar efficacy MAVIRET is recommended for 8 weeks for treatment-naïve genotype 3 subjects without cirrhosis, rather than 12 weeks [see section 4.2].

Table 12. ENDURANCE-3: Efficacy in Treatment-Naïve, HCV Genotype 3-Infected Subjects Without Cirrhosis

SURVEYOR-2 Part 3 was an open-label trial randomizing PRS treatment-experienced subjects with genotype 3 infection without cirrhosis to 12- or 16-weeks of treatment. In addition, the trial evaluated the efficacy of MAVIRET in genotype 3 infected subjects with compensated cirrhosis in two dedicated treatment arms using 12-week (treatment-naïve only) and 16-week (PRS treatment-experienced only) durations. Among PRS treatment-experienced subjects treated with MAVIRET for 16 weeks, 49% (34/69) had failed a previous regimen containing sofosbuvir.

Treatment-Naïve and PRS Treatment-Experienced Adults With CKD Stage 4 and 5 and Chronic HCV Infection Without Cirrhosis or With Compensated Cirrhosis

EXPEDITION-4 was an open-label, single-arm, multicenter trial to evaluate safety and efficacy in subjects with severe renal impairment (CKD Stages 4 and 5) with compensated liver disease (with and without Child-Pugh A cirrhosis). There were 104 subjects enrolled, 82% were on hemodialysis, and 53%, 15%, 11%, 19%, 1% and 1% were infected with HCV genotypes 1, 2, 3, 4, 5 and 6; respectively. Overall, 19% of subjects had compensated cirrhosis and 81% of subjects were non-cirrhotic; 58% and 42% of subjects were treatment-naïve and PRS treatment-experienced, respectively. The overall SVR12 rate was 98% and no subjects experienced virologic failure. The presence of renal impairment did not affect efficacy; no dose-adjustments were required during the trial.

Adults Who are NS5A Inhibitor or NS3/4A-Protease Inhibitor (PI)-Experienced, Without Cirrhosis or With Compensated Cirrhosis

MAGELLAN-1 was a randomized, multipart, open-label trial in 141 genotype 1- or 4-infected subjects who failed a previous regimen containing an NS5A inhibitor and/or NS3/4A PI. Part 1 (n=50) was a randomized trial exploring 12 weeks of glecaprevir 200 mg and pibrentasvir 80 mg, glecaprevir 300 mg and pibrentasvir 120 mg, with and without ribavirin (only data from glecaprevir 300 mg plus pibrentasvir 120 mg without ribavirin are included in these analyses). Part 2 (n=91) randomized genotype 1- or 4-infected subjects without cirrhosis or with compensated cirrhosis to 12- or 16-weeks of treatment with MAVIRET.

Of the 42 genotype 1-infected subjects treated in Parts 1 and 2, who were either NS5A inhibitor-experienced only (and treated for 16 weeks), or NS3/4A PI-experienced only (and treated for 12 weeks), the median age was 58 years (range: 34 to 70); 40% of the subjects were NS5A-treatment experienced only and 60% were PI experienced only; 24% had cirrhosis; 19% were ≥65 years, 69% were male; 26% were Black; 43% had a body mass index ≥ 30 kg/m2; 67% had baseline HCV RNA levels of at least 1,000,000 IU per mL; 79% had subtype 1a infection, 17% had subtype 1b infection and 5% had non-1a/1b infection.

Due to higher rates of virologic failure and treatment-emergent drug resistance, the data do not support labeling for treatment of HCV genotype 1 infected patients who are both NS3/4A PI and NS5A inhibitor-experienced.

Table 14. MAGELLAN-1: Efficacy in HCV Genotype 1-Infected Adults Who Are NS3/4A PI-Experienced or NS5A Inhibitor-Experienced, Without Cirrhosis or With Compensated Cirrhosis

The pharmacokinetic properties of the components of MAVIRET in healthy subjects are provided in Table 15. The steady-state pharmacokinetic parameters of glecaprevir and pibrentasvir in HCV-infected subjects without cirrhosis are provided in Table 16.

Table 15: Pharmacokinetic properties of the components of MAVIRET in healthy subjects

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

^b.                 Mean systemic exposures with moderate to high fat meals.

^c.                  Single dose administration of radiolabeled glecaprevir or pibrentasvir in mass balance studies.

Table 16. Steady-State Pharmacokinetic Parameters of Glecaprevir and Pibrentasvir Following Administration of MAVIRET in Non-Cirrhotic HCV-Infected Subjects

Pharmacokinetics in special populations

Age/Gender/Race/Body Weight

No clinically significant differences in the pharmacokinetics of glecaprevir or pibrentasvir were observed based on age [18-88 years], sex, race/ethnicity or body weight.

Subjects with Renal Impairment

Glecaprevir and pibrentasvir AUC were increased ≤ 56% in non-HCV infected subjects with mild, moderate, severe, or end-stage renal impairment (GFR estimated using Modification of Diet in Renal Disease) not on dialysis compared to subjects with normal renal function. Glecaprevir and pibrentasvir AUC were similar with and without dialysis (≤ 18% difference) in dialysis-dependent non-HCV infected subjects. In HCV-infected subjects, 86% higher glecaprevir and 54% higher pibrentasvir AUC were observed for subjects with end stage renal disease, with or without dialysis, compared to subjects with normal renal function.

Overall, the changes in exposures of MAVIRET in HCV-infected subjects with renal impairment with or without dialysis were not clinically significant.

Subjects with Hepatic Impairment

Following administration of MAVIRET in HCV infected subjects with compensated cirrhosis (Child-Pugh A), exposure of glecaprevir was approximately 2-fold and pibrentasvir exposure was similar to non-cirrhotic HCV infected subjects.

At the clinical dose, compared to non-HCV infected subjects with normal hepatic function, glecaprevir AUC 100% higher in Child-Pugh B subjects, and increased to 11-fold in Child-Pugh C subjects. Pibrentasvir AUC was 26% higher in Child-Pugh B subjects, and 114% higher in Child-Pugh C subjects.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis and Mutagenesis

Glecaprevir and pibrentasvir were not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo rodent micronucleus assays.

Carcinogenicity studies with glecaprevir and pibrentasvir have not been conducted.

Impairment of Fertility

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

Glecaprevir and pibrentasvir were not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo rodent micronucleus assays. Carcinogenicity studies with glecaprevir and pibrentasvir have not been conducted.

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

In animal reproduction studies, no adverse developmental effects were observed when the components of 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) higher than the human exposures at the recommended dose of Maviret. Maternal toxicity (anorexia, lower body weight, and lower body weight gain) with some embryofoetal toxicity (increase in post-implantation loss and number of resorptions and a decrease in mean fetal body weight), precluded the ability to evaluate glecaprevir in the rabbit at clinical exposures.  There were no developmental effects with either compound in rodent peri/postnatal developmental studies in which maternal systemic exposures (AUC) to glecaprevir and pibrentasvir were approximately 47 and 74 times higher, respectively, than the exposure in humans at the recommended dose. Unchanged glecaprevir was the main component observed in the milk of lactating rats without effect on nursing pups. Pibrentasvir was the only component observed in the milk of lactating rats without effect on nursing pups.

Tablet core

Copovidone (Type K 28)

Vitamin E (tocopherol) polyethylene glycol succinate

Silica, colloidal anhydrous

Propylene glycol monocaprylate (Type II)

Croscarmellose sodium

Sodium stearyl fumarate

Film coating

Hypromellose 2910 (E464)

Lactose monohydrate

Titanium dioxide

Macrogol 3350

Iron oxide red (E172)  

 The tablets do not contain gluten.

Not applicable.

Do not store above 30°C

MAVIRET is dispensed in a 4-week (monthly) carton. Each weekly carton contains seven daily dose wallets. Each monthly carton contains four weekly cartons. Each child resistant daily dose wallet contains three 100 mg/40 mg glecaprevir/pibrentasvir tablets. MAVIRET tablets are pink-coloured, film-coated, oblong biconvex shaped, debossed with “NXT” on one side.

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