ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

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

1. NAME OF THE MEDICINAL PRODUCT

Maviret 100 mg/40 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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

Excipient with known effect

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

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet (tablet).

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

4. CLINICAL PARTICULARS 4.1 Therapeutic indications

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

4.2 Posology and method of administration

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

Posology

The recommended dose of Maviret is 300 mg/120 mg (three 100 mg/40 mg tablets), taken orally, once daily with food (see section 5.2).

The recommended Maviret 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.

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

Recommended treatment duration

Genotype

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Table 2: Recommended Maviret 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.

Missed dose

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

Elderly

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

Renal impairment

No dose adjustment of Maviret 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 Maviret is required in patients with mild hepatic impairment (Child-Pugh A). Maviret is not recommended in patients with moderate hepatic impairment (Child Pugh-B) and is contraindicated in patients with severe hepatic impairment (Child-Pugh C) (see sections 4.3, 4.4, and 5.2).

Liver transplant patients

Maviret may be used for a minimum of 12 weeks in liver transplant recipients (see section 4.4). 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 Maviret in children and adolescents aged less than 18 years have not yet been established. No data are available.

Method of administration

For oral use.

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

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4.3 Contraindications

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).

4.4 Special warnings and precautions for use

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.

Liver transplant patients

The safety and efficacy of Maviret in patients who are post-liver transplant have not yet been assessed. Treatment with Maviret in this population in accordance with the recommended posology (see section 4.2) should be guided by an assessment of the potential benefits and risks for the individual patient.

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).

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 the MAGELLAN-1 study (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. Maviret 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.

Lactose

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

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4.5 Interaction with other medicinal products and other forms of interaction Potential for Maviret 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 Maviret 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 3 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) 1A1in vivo. Clinically significant increases in exposure were not observed for sensitive substrates of CYP3A (midazolam, felodipine) or UGT1A1 (raltegravir) when administered with Maviret.

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

Significant inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, UGT1A6, UGT1A9, UGT1A4, UGT2B7, OCT1, OCT2, OAT1, OAT3, MATE1 or MATE2K are not expected.

Patients treated with vitamin K antagonists

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

Potential for other medicinal products to affect Maviret 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 Maviret or loss of virologic response. Co-administration of such medicinal products with Maviret is contraindicated (see section 4.3).

Co-administration of Maviret 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 Maviret 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 3 provides the least-squares mean Ratio (90% Confidence Interval) effect on concentration of Maviret and some common concomitant medicinal products. The direction of the arrow indicates the

direction of the change in exposures (Cmax, AUC, and Cmin) 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.

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Table 3: Interactions between Maviret and other medicinal products

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HMG-COA REDUCTASE INHIBITORS

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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 received ciclosporin dose of 100 mg or less per day had glecaprevir concentrations 4-fold higher than those not receiving ciclosporin.

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

4.6 Fertility, pregnancy and lactation

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, Maviret use is not recommended in pregnancy.

Breast-feeding

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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 Maviret 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).

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

The safety assessment of Maviret in subjects treated for 8, 12 or 16 weeks with compensated liver disease (with or without cirrhosis) was based on Phase 2 and 3 studies which evaluated approximately 2,300 subjects. The most commonly reported adverse reactions (incidence ≥ 10%) were headache and fatigue. Less than 0.1% of subjects treated with Maviret had serious adverse reactions (transient ischaemic attack). The proportion of subjects treated with Maviret who permanently discontinued treatment due to adverse reactions was 0.1%. The type and severity of adverse reactions in subjects with cirrhosis were overall comparable to those seen in subjects without cirrhosis.

Tabulated summary of adverse reactions

The following adverse reactions were identified in patients treated with Maviret. The adverse reactions are listed below by body system organ class and frequency. Frequencies are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare

(≥ 1/10,000 to < 1/1,000) or very rare (< 1/10,000). Table 4: Adverse reactions identified with Maviret

Description of selected adverse reactions

Adverse reactions in subjects 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) and genotypes 1, 2, 3, 4, 5 or 6 chronic HCV infection with compensated liver disease (with or without cirrhosis) was assessed in 104 subjects (EXPEDITION-4). The most common adverse reactions in subjects with severe renal impairment were pruritus (17%) and fatigue (12%).

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Safety in HCV/HIV-1 Co-infected Subjects

The overall safety profile in HCV/HIV-1 co -infected subjects (ENDURANCE-1 and EXPEDITION-2) was comparable to that observed in HCV mono-infected subjects.

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 national reporting system listed in Appendix V.

4.9 Overdose

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.

5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Direct-acting antiviral, ATC code: J05AP57 glecaprevir and pibrentasvir Mechanism of action

Maviret is a fixed-dose combination of two pan-genotypic, direct-acting antiviral agents, glecaprevir (NS3/4A protease inhibitor) and pibrentasvir (NS5A inhibitor), targeting multiple steps in the 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 characterized 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 5.

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

NA = not available

Thein 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 6.

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