Glecaprevir/Pibrentasvir 50 mg/20 mg coated granules in sachet

Glecaprevir/Pibrentasvir coated granules is indicated for the treatment of chronic hepatitis C virus (HCV) infection in children 3 years and older (see sections 4.2, 4.4. and 5.1).

Glecaprevir/Pibrentasvir treatment should be initiated and monitored by a physician experienced in the management of patients with HCV infection.

Posology

Children aged 3 years to less than 12 years and weighing 12 kg to less than 45 kg

The recommended Glecaprevir/Pibrentasvir treatment durations for HCV genotype 1, 2, 3, 4, 5, or 6 infected patients with compensated liver disease (with or without cirrhosis) are provided in Table 1 and Table 2. The number of sachets and dose based on body weight for children are shown in Table 3. The sachets should be taken together, with food once daily.

Table 1: Recommended Glecaprevir/Pibrentasvir treatment duration for patients without prior HCV therapy

Table 2: Recommended Glecaprevir/Pibrentasvir treatment duration for patients who failed prior therapy with peg-IFN + ribavirin +/- sofosbuvir, or sofosbuvir + ribavirin

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

Table 3: Recommended dose for children 3 to less than 12 years of age

The adult dose of Glecaprevir/Pibrentasvir tablets should be used in children weighing 45 kg or greater. Refer to the Summary of Product Characteristics for Glecaprevir/Pibrentasvir film-coated tablets for dosing instructions.

Missed dose

In case a dose of Glecaprevir/Pibrentasvir is missed, the prescribed dose can be taken within 18 hours after the time it was supposed to be taken. If more than 18 hours have passed since Glecaprevir/Pibrentasvir is usually taken, the missed dose should not be taken and the patient should take the next dose per the usual dosing schedule. Patients should be instructed not to take a double dose.

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

Renal impairment

No dose adjustment of Glecaprevir/Pibrentasvir is required in patients with any degree of renal impairment including patients on dialysis (see sections 5.1 and 5.2).

Hepatic impairment

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

Liver or kidney transplant patients

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

Patients with HIV-1 co-infection

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

Paediatric population

The safety and efficacy of Glecaprevir/Pibrentasvir in children aged less than 3 years or weighing under 12 kg have not been established. No data are available. Children weighing 45 kg or more should use the tablet formulation. Because the formulations have different pharmacokinetic profiles, the tablets and the coated granules are not interchangeable. A full course of treatment with the same formulation is therefore required (see section 5.2).

Method of administration

Oral use

• Patients should be instructed to take the recommended dose of Glecaprevir/Pibrentasvir with food once daily.

• The granules for the total daily dose (the whole content of the required number of sachets, pink and yellow granules) should be sprinkled on a small amount of soft food with a low water content that will stick to a spoon and can be swallowed without chewing (e.g., peanut butter, chocolate hazelnut spread, soft/cream cheese, thick jam, or Greek yogurt).

• Liquids or foods that would drip or slide off the spoon should not be used as the medicine may dissolve quickly and become less effective.

• The mixture of food and granules should be swallowed immediately; the granules should not be crushed or chewed.

• Glecaprevir/Pibrentasvir granules should not be administered via enteral feeding tubes.

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, 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).

Hepatitis B virus reactivation

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

Hepatic impairment

Glecaprevir/Pibrentasvir 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).

Patients who failed a prior regimen containing an NS5A- and/or an NS3/4A-inhibitor

Genotype 1-infected (and a very limited number of genotype 4-infected) patients with prior failure on regimens 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 those exposed to both classes. A resistance algorithm predictive of the risk for failure by baseline resistance has not been established. Accumulating double class resistance was a general finding for patients who failed re-treatment with glecaprevir/pibrentasvir in MAGELLAN-1. No re-treatment data is available for patients infected with genotypes 2, 3, 5 or 6. Glecaprevir/Pibrentasvir is not recommended for the re-treatment of patients with prior exposure to NS3/4A- and/or NS5A inhibitors.

Drug-drug interactions

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

Use in diabetic patients

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

Lactose

Glecaprevir/Pibrentasvir granules contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Propylene glycol

This medicinal product contains 4 mg propylene glycol in each sachet.

Sodium

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

Potential for Glecaprevir/Pibrentasvir to affect other medicinal products

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 Glecaprevir/Pibrentasvir may increase plasma concentrations of medicinal products that are substrates of P-gp (e.g. dabigatran etexilate, digoxin), BCRP (e.g. rosuvastatin), or OATP1B1/3 (e.g. atorvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin). See Table 4 for specific recommendations on interactions with sensitive substrates of P-gp, BCRP, and OATP1B1/3. For other P-gp, BCRP, or OATP1B1/3 substrates, dose adjustment may be needed.

Glecaprevir and pibrentasvir are weak inhibitors of cytochrome P450 (CYP) 3A and uridine glucuronosyltransferase (UGT) 1A1 in vivo. Clinically significant increases in exposure were not observed for sensitive substrates of CYP3A (midazolam, felodipine) or UGT1A1 (raltegravir) when administered with Glecaprevir/Pibrentasvir.

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.

Patients treated with vitamin K antagonists

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

Potential for other medicinal products to affect Glecaprevir/Pibrentasvir

Use with strong P-gp/CYP3A inducers

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 significantly decrease glecaprevir or pibrentasvir plasma concentrations and may lead to reduced therapeutic effect of Glecaprevir/Pibrentasvir or loss of virologic response. Co-administration of such medicinal products with Glecaprevir/Pibrentasvir is contraindicated (see section 4.3).

Co-administration of Glecaprevir/Pibrentasvir with medicinal products that are moderate inducers P-gp/CYP3A may decrease 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 is also a substrate of the hepatic uptake transporters OATP1B1/3. Co-administration of Glecaprevir/Pibrentasvir with medicinal products that inhibit P-gp and BCRP (e.g. ciclosporin, cobicistat, dronedarone, itraconazole, ketoconazole, ritonavir) may slow elimination of glecaprevir and pibrentasvir and thereby increase plasma exposure of the antivirals. Medicinal products that inhibit OATP1B1/3 (e.g. elvitegravir, ciclosporin, darunavir, lopinavir) increase systemic concentrations of glecaprevir.

Established and other potential medicinal product interactions

Table 4 provides the least-squares mean Ratio (90% Confidence Interval) effect on concentration of Glecaprevir/Pibrentasvir and some common concomitant medicinal products. The direction of the arrow indicates the direction of the change in exposures (C_max, AUC, and C_min) in glecaprevir, pibrentasvir, and the co-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. All interaction studies were performed in adults.

Table 4: Interactions between Glecaprevir/Pibrentasvir and other medicinal products

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 had increased glecaprevir exposures to 2.4-fold of those not receiving ciclosporin.

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

Pregnancy

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

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

Breast-feeding

It is unknown whether glecaprevir or pibrentasvir are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of glecaprevir and pibrentasvir in milk (for details see section 5.3). A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Glecaprevir/Pibrentasvir therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

No human data on the effect of 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).

Glecaprevir/Pibrentasvir has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

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

Tabulated list of adverse reactions

The following adverse reactions were identified in registrational Phase 2 and 3 studies in HCV-infected adults with or without cirrhosis treated with Glecaprevir/Pibrentasvir for 8, 12 or 16 weeks, or during post-marketing experience. The adverse reactions are listed below by body system organ class and frequency. Frequencies are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000) or not known (cannot be estimated from the available data).

Table 5: Adverse reactions identified with Glecaprevir/Pibrentasvir

Description of selected adverse reactions

Adverse reactions in subjects with severe renal impairment including subjects on dialysis

The safety of Glecaprevir/Pibrentasvir in subjects with chronic kidney disease (including subjects on dialysis) and genotypes 1, 2, 3, 4, 5 or 6 chronic HCV infection with compensated liver disease (with or without cirrhosis) was assessed in adults in EXPEDITION-4 (n=104) and EXPEDITION-5 (n=101). The most common adverse reactions in subjects with severe renal impairment were pruritus (17%) and fatigue (12%) in EXPEDITION-4 and pruritus (14.9%) in EXPEDITION-5.

Adverse reactions in subjects with liver or kidney transplant

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

Safety in HCV/HIV-1 co-infected subjects

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.

Paediatric population

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

The safety of Glecaprevir/Pibrentasvir in HCV GT1-6 infected children aged 3 to less than 12 years is based on data from a Phase 2/3 open-label study in 80 subjects aged 3 to < 12 years treated with weight-based Glecaprevir/Pibrentasvir coated granules for 8, 12, or 16 weeks (DORA Part 2). The pattern of adverse reactions observed was comparable with that observed in clinical studies of Glecaprevir/Pibrentasvir film-coated tablets in adolescents and adults. Diarrhoea, nausea and vomiting occurred at a slightly higher frequency in paediatric subjects compared to adolescents (adverse reactions: 3.8% vs. 0%, 3.8% vs. 0%, and 7.5% vs. 2.1% respectively).

Serum bilirubin elevations

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

Reporting of suspected adverse reactions

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

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

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

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

Mechanism of action

Glecaprevir/Pibrentasvir 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 HCV viral lifecycle.

Glecaprevir

Glecaprevir is a pan-genotypic 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.

Pibrentasvir

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

Antiviral activity

The EC₅₀ values of glecaprevir and pibrentasvir against full-length or chimeric replicons encoding NS3 or NS5A from laboratory strains are presented in Table 6.

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

NA = not available

The in vitro activity of glecaprevir was also studied in a biochemical assay, with similarly low IC₅₀ values across genotypes.

EC₅₀ values of glecaprevir and pibrentasvir against chimeric replicons encoding NS3 or NS5A from clinical isolates are presented in Table 7.

Table 7. Activity of glecaprevir and pibrentasvir against transient replicons containing NS3 or NS5A from HCV genotypes 1-6 clinical isolates

NA = not available

Resistance

In cell culture

Amino acid substitutions in NS3 or NS5A selected in cell culture or important for the inhibitor class were 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 NS3 had no impact in genotype 2, while some substitutions at position 168 reduced glecaprevir susceptibility by up to 55-fold (genotypes 1, 3, 4), or reduced susceptibility by > 100-fold (genotype 6). 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 except for 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 in genotypes 1a and 3a (including A30K+Y93H in genotype 3a) showed reductions in susceptibility to pibrentasvir. 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 pibrentasvir in genotype 3a replicon.

In clinical studies

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

Twenty-two of the approximately 2 300 adult subjects treated with Glecaprevir/Pibrentasvir for 8, 12, or 16 weeks in registrational Phase 2 and 3 clinical studies experienced virologic failure (2 with genotype 1, 2 with genotype 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 NS3 or NS5A (the M31 polymorphism in NS5A was present at baseline and post-treatment in both subjects).

Among the 18 genotype 3-infected subjects treated with Glecaprevir/Pibrentasvir for 8, 12, or 16 weeks 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. Treatment-emergent 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 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 Glecaprevir/Pibrentasvir in the MAGELLAN-1 study for 12 or 16 weeks experienced virologic 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 7 subjects. Five of the 10 had combinations of V36M, Y56H, R155K/T, or D168A/E in NS3 at baseline and post-treatment. All of the genotype 1-infected virologic failure subjects had one or more NS5A substitutions 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 Y93H observed in 7 of the subjects at the time of failure.

Thirteen of the 177 subjects with chronic HCV GT1 infection (all virologic failures had GT1a infection) who were treatment-experienced with NS5A inhibitor + SOF treated with Glecaprevir/Pibrentasvir in study B16-439 for 12 weeks (9 out of 13) or 16 weeks (4 out of 13) experienced virologic failure. Among the 13 virologic failures, treatment-emergent NS3 substitutions were observed in 4 subjects at the time of failure: A156V (n = 2) or R155W + A156G (n = 2); 3 of these 4 subjects also had Q80K at baseline and at the time of failure. Twelve of 13 virologic failures had one or more NS5A polymorphisms detected 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 treatment failure.

Effect of baseline HCV amino acid polymorphisms on treatment response

A pooled analysis of treatment-naï ve and pegylated interferon, ribavirin and/or sofosbuvir treatment-experienced adult subjects receiving Glecaprevir/Pibrentasvir in the Phase 2 and Phase 3 clinical studies was conducted to explore the association between baseline polymorphisms and treatment outcome and to describe substitutions seen upon virologic failure. Baseline polymorphisms relative to a subtype-specific reference sequence at 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. Baseline polymorphisms 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 on treatment outcome.

Genotype 3: For subjects who received the recommended regimen (n=313), baseline polymorphisms in 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 overall prevalence of A30K and Y93H at baseline was 7.0% and 4.8%, respectively. The ability to assess the impact of baseline polymorphisms in NS5A was limited among treatment-naï ve subjects with cirrhosis and treatment-experienced subjects due to low prevalence of A30K (3.0%, 4/132) or Y93H (3.8%, 5/132).

Cross-resistance

In vitro data indicate that the majority of the resistance-associated substitutions in NS5A at amino acid positions 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 NS5A substitutions at these positions showed reductions in susceptibility to pibrentasvir. Glecaprevir was fully active against resistance-associated substitutions in NS5A, while pibrentasvir was fully active against resistance-associated substitutions in NS3. Both glecaprevir and pibrentasvir were fully active against substitutions associated with resistance to NS5B nucleotide and non-nucleotide inhibitors.

Clinical efficacy and safety

Table 8 summarizes clinical studies conducted with Glecaprevir/Pibrentasvir in subjects with HCV genotype 1, 2, 3, 4, 5 or 6 infection.

Table 8: Clinical studies conducted with Glecaprevir/Pibrentasvir in subjects with HCV genotype 1, 2, 3, 4, 5 or 6 Infection

TN=treatment-naï ve, PRS-TE=treatment-experienced (includes previous treatment that included pegIFN (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 3 subjects coinfected with HIV-1.

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

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

d. GT3 with cirrhosis from SURVEYOR-2 Part 2 - Glecaprevir/Pibrentasvir for 12 weeks (n=24) or 16 weeks (n=4); GT3 with cirrhosis from SURVEYOR-2 Part 3 - Glecaprevir/Pibrentasvir for 12 weeks (n=40) or 16 weeks (n=47).

e. GT1, 4 from MAGELLAN-1 Part 1 - Glecaprevir/Pibrentasvir for 12 weeks (n=22); GT1, 4 from MAGELLAN-1 Part 2 - Glecaprevir/Pibrentasvir for 12 weeks (n=44) or 16 weeks (n=47).

f. VOYAGE-1 and VOYAGE-2 were Asian regional studies.

g. Glecaprevir/Pibrentasvir 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) 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). Sustained virologic response (SVR12), defined as HCV RNA less than LLOQ at 12 weeks after the cessation of treatment, was the primary endpoint in all the studies to determine the HCV cure rate.

Clinical studies in treatment-naï ve or treatment-experienced subjects with or without cirrhosis

Of the 2 409 adult subjects with compensated liver disease (with or without cirrhosis) treated who were treatment-naï ve or treatment-experienced to combinations of peginterferon, ribavirin and/or sofosbuvir, the median age was 53 years (range: 19 to 88); 73.3% were treatment-naï ve, 26.7% were treatment-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 median baseline HCV RNA level was 6.2 log₁₀ IU/mL.

Table 9: SVR12 in adult subjects treatment-naï ve and treatment-experienced^a to peginterferon, ribavirin and/or sofosbuvir with genotype 1, 2, 4, 5 and 6 infection who received the recommended duration (pooled data from ENDURANCE-1b, SURVEYOR-1, -2, and EXPEDITION-1, 2^b, -4 and 8)

VF=virologic failure

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

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

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

Clinical study in subjects with genotype 5 or 6 infection

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 Glecaprevir/Pibrentasvir for 8 weeks, and subjects with compensated cirrhosis received Glecaprevir/Pibrentasvir for 12 weeks. Of the 84 subjects treated, the median age was 59 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-infected subjects and 98.4% (60/61) for GT6-infected subjects. One TN GT5-infected subject without cirrhosis experienced relapse, and one TN GT6-infected subject with compensated cirrhosis experienced on-treatment virologic failure.

Subjects with genotype 1, 2, 4, 5, or 6 infection with cirrhosis who received 8 weeks of Glecaprevir/Pibrentasvir

The safety and efficacy of Glecaprevir/Pibrentasvir given for 8 weeks in GT 1, 2, 4, 5 or 6 treatment-naï ve adult subjects 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 genotype 1, 10% had HCV genotype 2, 4.6% had HCV genotype 4, 0.4% had HCV genotype 5; 3.2% had HCV genotype 6; 60% were male; 9.6% were Black.

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

Subjects with genotype 3 infection

The efficacy of Glecaprevir/Pibrentasvir in subjects who were treatment-naï ve or treatment-experienced to combinations of peginterferon, ribavirin and/or sofosbuvir with genotype 3 chronic hepatitis C infection was demonstrated in the ENDURANCE-3 (treatment-naï ve adults without cirrhosis), EXPEDITION-8 (treatment-naï ve adults with cirrhosis), and SURVEYOR-2 Part 3 (adults with and without cirrhosis and/or treatment-experienced) clinical studies.

ENDURANCE-3 was a partially-randomised, open-label, active-controlled study in treatment-naï ve genotype 3-infected subjects. Subjects were randomised (2:1) to either Glecaprevir/Pibrentasvir for 12 weeks or the combination of sofosbuvir and daclatasvir for 12 weeks; subsequently the study included a third arm (which was non-randomised) with Glecaprevir/Pibrentasvir for 8 weeks. EXPEDITION-8 was a single-arm, open-label study in treatment-naï ve subjects with compensated cirrhosis and genotype 1, 2, 3, 4, 5 or 6 infection who received Glecaprevir/Pibrentasvir for 8 weeks. SURVEYOR-2 Part 3 was an open-label study that evaluated the efficacy of Glecaprevir/Pibrentasvir in treatment-experienced genotype 3-infected subjects without cirrhosis and with compensated cirrhosis for 16-weeks. Among treatment-experienced subjects, 46% (42/91) failed a previous regimen containing sofosbuvir.

Table 10: SVR12 in treatment-naï ve, genotype 3-infected adult subjects without cirrhosis (ENDURANCE-3)

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

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

In a pooled analysis of treatment-naï ve adult patients without cirrhosis (including Phase 2 and 3 data) where SVR12 was assessed according to the presence of baseline A30K, a numerically lower SVR12 rate 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 11: SVR12 in genotype 3-infected subjects with or without cirrhosis (SURVEYOR-2 Part 3 and EXPEDITION-8)

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

Subjects with genotype 3b infection

GT3b is a subtype reported in a relatively small number of HCV infected patients in China and a few countries 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 adult subjects without cirrhosis (VOYAGE-1) or with compensated cirrhosis (VOYAGE-2) that were treatment-naï ve (TN) or treatment-experienced to combinations of interferon, peg interferon, ribavirin and/or sofosbuvir (TE-PRS). All subjects without cirrhosis or with compensated cirrhosis received 8 or 12 weeks of Glecaprevir/Pibrentasvir, respectively, except GT3 TE-PRS subjects who received 16 weeks of Glecaprevir/Pibrentasvir. 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 subjects without 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 compensated cirrhosis, the overall SVR12 rate for GT3b infected subjects was 87.5% (7/8) [85.7% (6/7) for TN subjects 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-naï ve or treatment-experienced adult subjects with or without cirrhosis

In subjects who are treatment-naï ve (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 virologic failure 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 compensated cirrhosis, respectively) was 98.2% (165/168) from ENDURANCE-1 and EXPEDITION-2. One subject experienced on-treatment virologic failure (0.6%, 1/168) and no subjects relapsed (0%, 0/166).

Clinical study in liver or kidney transplant recipients

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 Glecaprevir/Pibrentasvir for 12 weeks. The study included subjects who were HCV treatment-naï ve or treatment-experienced to combinations of (peg) interferon, ribavirin, and/or sofosbuvir, with the exception of GT3-infected subjects who were all treatment-naï ve.

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 HCV genotype 6; 75% were male; 8% were Black; 66% were HCV treatment-naï ve; none had cirrhosis and 80% had a baseline fibrosis state of F0 or F1; 80% of subjects were post-liver transplant and 20% were post-kidney transplant. Immunosuppressants allowed for co-administration were ciclosporin ≤ 100 mg/day, tacrolimus, sirolimus, everolimus, azathioprine, mycophenolic acid, prednisone, and prednisolone.

The overall SVR12 rate in post-transplant subjects was 98.0% (98/100). There was one relapse and no on-treatment virologic failure.

Clinical study in renally impaired subjects

EXPEDITION-5 was an open-label study in 101 HCV GT1-6 infected adult subjects without cirrhosis or with compensated cirrhosis and chronic kidney disease (CKD) stage 3b, 4, or 5. Subjects were either treatment-naï ve or treatment-experienced to combinations of (peg) interferon, ribavirin, and/or sofosbuvir and received Glecaprevir/Pibrentasvir 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-naï ve; 13% had cirrhosis and 65% had a baseline fibrosis state of F0 or F1; 7% were CKD stage 3b; 17% were CKD Stage 4, and 76% were CKD Stage 5 (all receiving dialysis); 84 subjects received 8 weeks of treatment, 13 subjects received 12 weeks of treatment, and 4 subjects received 16 weeks of treatment.

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

Durability of sustained virologic response

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 Glecaprevir/Pibrentasvir maintained SVR up to their last follow-up visit (median duration of follow-up: 35.5 months): 100%, 99.6%, and 95.8% of subjects who had received 8, 12, and 16 weeks of Glecaprevir/Pibrentasvir therapy, respectively. Among the 2 subjects who did not maintain SVR, 1 experienced a late relapse 390 days after Glecaprevir/Pibrentasvir therapy, and the other subject experienced re-infection with a different HCV genotype.

Elderly

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

Paediatric population

The efficacy, safety and pharmacokinetics of Glecaprevir/Pibrentasvir in children 3 years to less than 18 years old was demonstrated in an open-label study which was comprised of two parts, DORA Part 1 and Part 2.

DORA Part 1 evaluated the safety and efficacy of Glecaprevir/Pibrentasvir 300 mg/120 mg (three 100 mg/40 mg film-coated tablets) for 8 or 16 weeks in 47 adolescents aged 12 years to less than 18 years. The median age was 14 years (range: 12 to 17); 79% had HCV genotype 1, 6% had HCV genotype 2, 9% had HCV genotype 3, 6% had HCV genotype 4; 55% were female; 11% were Black; 77% were HCV treatment-naï ve; 23% were treatment-experienced to interferon; 4% had HIV-coinfection; none had cirrhosis; the mean weight was 59 kg (range: 32 to 109).

In DORA Part 1, the overall SVR12 rate was 100% (47/47). No subject experienced virologic failure.

DORA Part 2 evaluated the safety and efficacy of weight-based dosing of Glecaprevir/Pibrentasvir granules for 8, 12 or 16 weeks in 80 children aged 3 years to less than 12 years. 18 subjects received the initial lower dose, and 62 subjects received the final recommended dose. The median age was 7 years (range: 3 to 11); 73% had HCV genotype 1, 3% had genotype 2, 23% had HCV genotype 3, 3% had HCV genotype 4; 55% were female; 6% were Black; 97.5% were HCV TN; 2.5% were treatment-experienced to interferon; 1% had HIV-coinfection; none had cirrhosis; the mean weight was 26 kg (range: 13 to 44).

In DORA Part 2, the overall SVR12 rate for the subjects who received the final recommended dose was 98.4% (61/62). No subject taking the final recommended dose experienced virologic failure. One 9 year old child with HCV GT3b infection, who had received the initial lower dose, experienced virologic failure. The child had K30R and V31M at baseline and treatment-emergent Y93H at relapse in NS5A; baseline or treatment-emergent substitutions were not detected in NS3.

The pharmacokinetic properties of the components of Glecaprevir/Pibrentasvir are provided in Table 12.

Table 12: Pharmacokinetic properties of the components of Glecaprevir/Pibrentasvir in healthy subjects

a. Median T_max 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 glecaprevir metabolites were observed in plasma.

In patients with chronic hepatitis C infection without cirrhosis, following 3 days of monotherapy with either 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 of the pharmacokinetic parameters using population pharmacokinetic models has inherent uncertainty due to dose non-linearity and cross interaction between glecaprevir and pibrentasvir. Based on population pharmacokinetic models for Glecaprevir/Pibrentasvir in chronic hepatitis C patients, steady-state AUC₂₄ values 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 to healthy subjects (N=230), population estimates of AUC_{24, ss} were similar (10% difference) for glecaprevir and 34% lower for pibrentasvir in HCV-infected patients without cirrhosis.

Linearity/non-linearity

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

Pibrentasvir AUC increased in a greater than dose-proportional manner at doses up to 120 mg, (over 10-fold exposure increase at 120 mg QD compared to 30 mg QD), but exhibited linear pharmacokinetics at doses ≥ 120 mg. The non-linear exposure increase < 120 mg may be related to saturation of efflux transporters.

Pibrentasvir bioavailability when co-administered with glecaprevir is 3-fold of pibrentasvir alone. Glecaprevir is affected to a lower extent by co-administration with pibrentasvir.

Pharmacokinetics in special populations

Race/ethnicity

No dose adjustment of Glecaprevir/Pibrentasvir is required based on race or ethnicity.

Gender

No dose adjustment of Glecaprevir/Pibrentasvir is required based on gender.

Elderly

No dose adjustment of Glecaprevir/Pibrentasvir 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 a clinically relevant effect on the exposure to glecaprevir or pibrentasvir.

Paediatric population

At the recommended doses according to the patient's body weight, exposures of glecaprevir and pibrentasvir in children aged 3 to < 12 years fell within the efficacious exposure range in adults from Phase 2/3 studies. Glecaprevir/Pibrentasvir is available as a tablet for children 12 years to less than 18 years or weighing more than 45 kg. The granules were not studied in children greater than 12 years old. Tablets and the granules are not interchangeable. The pharmacokinetics of glecaprevir and pibrentasvir have not been established in children < 3 years of age or under 12 kg in weight.

Renal impairment

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 normal renal function. Glecaprevir and pibrentasvir AUC were similar with and without dialysis (≤ 18% difference) in dialysis-dependent non-HCV infected subjects. In population pharmacokinetic analysis of 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. Larger increases may be expected when unbound concentration is considered.

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

Hepatic impairment

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 increased to 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 be expected when unbound concentration is considered.

Population pharmacokinetic analysis demonstrated that following administration of Glecaprevir/Pibrentasvir in HCV-infected subjects with compensated cirrhosis, exposure of glecaprevir was approximately 2-fold and pibrentasvir exposure was similar to non-cirrhotic HCV-infected subjects. The mechanism for the differences between glecaprevir exposure in chronic Hepatitis C patients with or without cirrhosis is unknown.

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 Glecaprevir/Pibrentasvir 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 Glecaprevir/Pibrentasvir. 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 foetal 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, respectively, 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.

Granule core

Copovidone

Tocofersolan

Propylene glycol monocaprylate

Colloidal silicon dioxide

Croscarmellose sodium (in the glecaprevir granules only)

Sodium stearyl fumarate

Granule coating

Hypromellose (E464)

Lactose monohydrate

Titanium dioxide

Macrogol

Iron oxide red (E172)

Iron oxide yellow (E172)

Not applicable.

3 years

This medicinal product does not require any special storage conditions.

Glecaprevir/Pibrentasvir coated granules are supplied in polyethylene terephthalate (PET) /aluminium/polyethylene film sachets in cartons. Each carton contains 28 sachets.

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