LIVTENCITY 200mg film-coated tablets medication leaflet

LIVTENCITY 200 mg film-coated tablets.

Each tablet contains 200 mg maribavir.

For the full list of excipients, see section 6.1.

Film-coated tablet.

Blue, oval shaped convex tablet of 15.5 mm, debossed with “SHP” on one side and “620” on the otherside.

LIVTENCITY is indicated for the treatment of cytomegalovirus (CMV) infection and/or disease thatare refractory (with or without resistance) to one or more prior therapies, including ganciclovir,valganciclovir, cidofovir or foscarnet in adult patients who have undergone a haematopoietic stem celltransplant (HSCT) or solid organ transplant (SOT).

Consideration should be given to official guidance on the appropriate use of antiviral agents.

LIVTENCITY should be initiated by a physician experienced in the management of patients who haveundergone solid organ transplant or haematopoietic stem cell transplant.

The recommended dose of LIVTENCITY is 400 mg (two 200 mg tablets) twice daily resulting in adaily dose of 800 mg for 8 weeks. Treatment duration may need to be individualised based on theclinical characteristics of each patient.

Co-administration with CYP3A inducers

Co-administration of LIVTENCITY with the strong cytochrome P450 3A (CYP3A) inducersrifampicin, rifabutin or St. John’s wort is not recommended due to potential for a decrease in efficacyof maribavir.

If co-administration of LIVTENCITY with other strong or moderate CYP3A inducers (e,g.,carbamazepine, efavirenz, phenobarbital and phenytoin) cannot be avoided, the LIVTENCITY doseshould be increased to 1 200 mg twice daily (see sections 4.4, 4.5 and 5.2).

Patients should be instructed that if they miss a dose of LIVTENCITY, and the next dose is due withinthe next 3 hours, they should skip the missed dose and continue with the regular schedule. Patientsshould not double their next dose or take more than the prescribed dose.

No dose adjustment is required for patients over 65 years (see sections 5.1 and 5.2).

No dose adjustment of LIVTENCITY is required for patients with mild, moderate or severe renalimpairment. Administration of LIVTENCITY in patients with end stage renal disease (ESRD),including patients on dialysis, has not been studied. No dose adjustments is expected to be required forpatients on dialysis due to the high plasma protein binding of maribavir (see section 5.2).

No dose adjustment of LIVTENCITY is required for patients with mild (Child-Pugh Class A) ormoderate hepatic impairment (Child-Pugh Class B). Administration of LIVTENCITY in patients withsevere hepatic impairment (Child-Pugh Class C) has not been studied. It is not known whetherexposure to maribavir will significantly increase in patients with severe hepatic impairment.

Therefore, caution is advised when LIVTENCITY is administered to patients with severe hepaticimpairment (see section 5.2).

The safety and efficacy of LIVTENCITY in patients below 18 years of age have not been established.

No data are available.

Oral use.

LIVTENCITY is intended for oral use only and can be taken with or without food. The film-coatedtablet can be taken as a whole tablet, a crushed tablet, or a crushed tablet through a nasogastric ororogastric tube.

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

Co-administration with ganciclovir or valganciclovir (see section 4.5).

Virologic failure during treatment and relapse post-treatment

Virologic failure can occur during and after treatment with LIVTENCITY. Virologic relapse duringthe post-treatment period usually occurred within 4-8 weeks after treatment discontinuation. Somemaribavir pUL97 resistance-associated substitutions confer cross-resistance to ganciclovir andvalganciclovir. CMV DNA levels should be monitored and resistance mutations should beinvestigated in patients who do not respond to treatment. Treatment should be discontinued ifmaribavir resistance mutations are detected.

CMV disease with CNS involvement

LIVTENCITY was not studied in patients with CMV CNS infection. Based on nonclinical data, CNSpenetration of maribavir is expected to be low compared to plasma levels (section 5.2 and 5.3).

Therefore, LIVTENCITY is not expected to be effective in treating CMV CNS infections (e.g.meningo-encephalitis).

Use with immunosuppressants

LIVTENCITY has the potential to increase the concentrations of immunosuppressants that arecytochrome P450 (CYP)3A/P-gp substrates with narrow therapeutic margins (including tacrolimus,cyclosporine, sirolimus and everolimus). The plasma levels of these immunosuppressants must befrequently monitored throughout treatment with LIVTENCITY, especially following initiation andafter discontinuation of LIVTENCITY, and doses should be adjusted, as needed (see sections 4.5, pct. 4.8and 5.2).

Risk of adverse reactions or reduced therapeutic effect due to medicinal product interactions

The concomitant use of LIVTENCITY and certain medicinal products may result in known orpotentially significant medicinal product interactions, some of which may lead to:

- possible clinically significant adverse reactions from greater exposure of concomitantmedicinal products.

- reduced therapeutic effect of LIVTENCITY.

See Table 1 for steps to prevent or manage these known or potentially significant medicinal productinteractions, including dosing recommendations (see sections 4.3 and 4.5).

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

Effect of other medicinal products on maribavir

Maribavir is primarily metabolised by CYP3A, and medicinal products that induce or inhibit CYP3Aare expected to affect the clearance of maribavir (see section 5.2).

Co-administration of maribavir and medicinal products that are inhibitors of CYP3A may result inincreased plasma concentrations of maribavir (see section 5.2). However, no dose adjustment isneeded when maribavir is co-administered with CYP3A inhibitors.

Concomitant administration of strong or moderate CYP3A inducers, (such as rifampicin, rifabutin,carbamazepine, phenobarbital, phenytoin, efavirenz and St John’s wort), is expected to significantlydecrease maribavir plasma concentrations, which may result in decrease in efficacy. Therefore,alternative medicinal products with no CYP3A induction potential should be considered. Co-administration of maribavir with strong cytochrome P450 3A (CYP3A) inducers rifampicin, rifabutinor St. John’s wort is not recommended.

If co-administration of maribavir with other strong or moderate CYP3A inducers (e.g., carbamazepine,efavirenz, phenobarbital and phenytoin) cannot be avoided, the maribavir dose should be increased to1 200 mg twice daily (see sections 4.2 and 5.2).

Effect of maribavir on other medicinal products

Co-administration of maribavir with valganciclovir and ganciclovir is contraindicated (see section4.3). LIVTENCITY may antagonise the antiviral effect of ganciclovir and valganciclovir by inhibitinghuman CMV UL97 serine/threonine kinase, which is required for activation/phosphorylation ofganciclovir and valganciclovir (see sections 4.3 and 5.1).

At therapeutic concentrations, clinically relevant interactions are not expected when maribavir is co-administered with substrates of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2E1, 2D6, and 3A4; UGT1A1,1A4, 1A6, 1A9, 2B7; bile salt export pump (BSEP); multidrug and toxin extrusion protein(MATE)/2K; organic anion transporters (OAT)1; organic cation transporters (OCT)1 and OCT2;organic anion transporting polypeptide (OATP)1B1 and OATP1B3 based on in vitro and clinicalinteraction results (Table 1 and section 5.2).

Maribavir acted as an inducer of CYP1A2 enzyme in vitro. There are no clinical data available toexclude an interaction risk via CYP1A2 induction in vivo. Therefore, the concomitant administrationof maribavir and medicinal products that are sensitive substrates of CYP1A2 with a narrow therapeuticwindow (e.g., tizanidine and theophylline) should be avoided due to the risk for lack of efficacy of

CYP1A2 substrates.

Co-administration of maribavir increased plasma concentrations of tacrolimus (see Table 1). When theimmunosuppressants tacrolimus, cyclosporine, everolimus or sirolimus are co-administered withmaribavir, immunosuppressant levels should be frequently monitored throughout treatment withmaribavir, especially following initiation and after discontinuation of maribavir and dose adjusted,when needed (see sections 4.4 and Table 1).

Maribavir inhibited P-gp transporter in vitro at clinically relevant concentrations. In a clinical study,co-administration of maribavir increased plasma concentrations of digoxin (see Table 1 Therefore,caution should be exercised when maribavir and sensitive P-gp substrates (e.g., digoxin, dabigatran)are co-administered. Serum digoxin concentrations should be monitored, and dose of digoxin mayneed to be reduced, as needed (see Table 1).

Maribavir inhibited BCRP transporter in vitro at clinically relevant concentrations. Therefore,co-administration of maribavir with sensitive BCRP substrates such as rosuvastatin, is expected toincrease their exposure and lead to undesirable effects.

In vitro, maribavir inhibits OAT3, therefore, plasma concentrations of medicinal products transportedby OAT3 may be increased (e.g.: ciprofloxacin, imipenem, and cilastatin).

In vitro, maribavir inhibits MATE1. There are no clinical data available whether the co-administrationof maribavir with sensitive MATE1 substrates (e.g., metformin) could potentially lead to clinicallyrelevant interactions.

General information

If dose adjustments of concomitant medicinal products are made due to treatment with maribavir,doses should be readjusted after treatment with maribavir is completed. Table 1 provides a listing ofestablished or potentially clinically significant medicinal product interactions. The medicinal productinteractions described are based on studies conducted with maribavir or are predicted medicinalproduct interactions that may occur with maribavir (see sections 4.4 and 5.2).

Table 1: Interactions and dose recommendations with other medicinal products.

Medicinal product by Effect on geometric mean Recommendation concerningtherapeutic area ratio (90 % CI) co-administration with(likely mechanism of action) maribavir

A cid-reducing agentsantacid (aluminium and ↔ maribavir No dose adjustment is required.magnesium hydroxide oral AUC 0.89 (0.83, 0.96)suspension) Cmax 0.84 (0.75, 0.94)(20 mL single dose, maribavir100 mg single dose)famotidine Interaction not studied. No dose adjustment is required.

Expected:↔ maribavirpantoprazole Interaction not studied. No dose adjustment is required.

Expected:↔ maribaviromeprazole ↔ maribavir No dose adjustment is required.↑ plasma omeprazole/5-hydroxyomeprazoleconcentration ratio1.71 (1.51, 1.92) at 2h post-dose(CYP2C19 inhibition)

Antiarrhythmicsdigoxin ↔ digoxin Use caution when maribavir and(0.5 mg single dose, 400 mg AUC 1.21 (1.10, 1.32) digoxin are co-administered.twice daily maribavir) Cmax 1.25 (1.13, 1.38) Monitor serum digoxin(P-gp inhibition) concentrations. The dose ofsensitive P-gp substrates such asdigoxin may need to be reducedwhen co-administered withmaribavir.

Antibioticsclarithromycin Interaction not studied. No dose adjustment is required.

Expected:↑ maribavir(CYP3A inhibition)

Anticonvulsantscarbamazepine Interaction not studied. A dose adjustment of maribavir tophenobarbital Expected: 1 200 mg twice daily isphenytoin ↓ maribavir recommended when(CYP3A induction) co-administration with theseanticonvulsants.

Antifungalsketoconazole ↑ maribavir No dose adjustment is required.(400 mg single dose, maribavir AUC 1.53 (1.44, 1.63)400 mg single dose) Cmax 1.10 (1.01, 1.19)(CYP3A and P-gp inhibition)voriconazole Expected: No dose adjustment is required.(200 mg twice daily, maribavir ↑ maribavir400 mg twice daily) (CYP3A inhibition)↔ voriconazole

AUC 0.93 (0.83, 1.05)

Medicinal product by Effect on geometric mean Recommendation concerningtherapeutic area ratio (90 % CI) co-administration with(likely mechanism of action) maribavir

Cmax 1.00 (0.87, 1.15)(CYP2C19 inhibition)

Antihypertensivesdiltiazem Interaction not studied. No dose adjustment is required.

Expected:↑ maribavir(CYP3A inhibition)

Antimycobacterialsrifabutin Interaction not studied. Co-administration of maribavir

Expected: and rifabutin is not recommended↓ maribavir due to potential for a decrease in(CYP3A induction) efficacy of maribavir.

rifampicin ↓ maribavir Co-administration of maribavir(600 mg once daily, maribavir AUC 0.40 (0.36, 0.44) and rifampin is not recommended400 mg twice daily) Cmax 0.61 (0.52, 0.72) due to potential for a decrease in

Ctrough 0.18 (0.14, 0.25) efficacy of maribavir.(CYP3A and CYP1A2induction)

Antitussivesdextromethorphan ↔ dextrorphan No dose adjustment is required.(30 mg single dose, maribavir AUC 0.97 (0.94, 1.00)400 mg twice daily) Cmax 0.94 (0.88, 1.01)(CYP2D6 inhibition)

CNS stimulants

Herbal products

St. John's wort (Hypericum Interaction not studied. Co-administration of maribavirperforatum) Expected: and St. John's wort is not↓ maribavir recommended due to potential for(CYP3A induction) a decrease in efficacy of maribavir.

HIV antiviral agents

Non-nucleoside reverse transcriptase inhibitors

Efavirenz Interaction not studied. A dose adjustment of maribavir to

Etravirine Expected: 1 200 mg twice daily is

Nevirapine ↓ maribavir recommended when(CYP3A induction) co-administration with these anon-nucleoside reversetranscriptase inhibitors.

Nucleoside reverse transcriptase inhibitors

Tenofovir disoproxil Interaction not studied. No dose adjustment is required.

Tenofovir alafenamide Expected:

Abacavir ↔ maribavir

Lamivudine ↔ nucleoside reverse

Emtricitabine transcriptase inhibitors

Protease inhibitors

Medicinal product by Effect on geometric mean Recommendation concerningtherapeutic area ratio (90 % CI) co-administration with(likely mechanism of action) maribavirritonavir- boosted protease Interaction not studied. No dose adjustment is required.inhibitors (atazanavir, Expected:darunavir, lopinavir) ↑ maribavir(CYP3A inhibition)

Integrase strand transfer inhibitorsdolutegravir Interaction not studied. No dose adjustment is required.

Expected:↔ maribavir↔ dolutegravir

HMG-CoA reductase inhibitorsatorvastatin Interaction not studied. No dose adjustment is required.fluvastatin Expected:simvastatin ↑ HMG-CoA reductaseinhibitors(BCRP inhibition)rosuvastatina Interaction not studied. The patient should be closely

Expected: monitored for rosuvastatin-related↑ rosuvastatin events, especially the occurrence(BCRP inhibition) of myopathy and rhabdomyolysis.

Immunosuppressantscyclosporinea Interaction not studied. Frequently monitor cyclosporine,everolimusa Expected: everolimus and sirolimus levels,sirolimusa ↑ cyclosporine, everolimus, especially following initiation andsirolimus after discontinuation of maribavir(CYP3A/P-gp inhibition) and adjust dose, as needed.

tacrolimusa ↑ tacrolimus Frequently monitor tacrolimus

AUC 1.51 (1.39, 1.65) levels, especially following

Cmax 1.38 (1.20, 1.57) initiation and after discontinuation

Ctrough 1.57 (1.41, 1.74) of maribavir and adjust dose, as(CYP3A/P-gp inhibition) needed.

Oral anticoagulantswarfarin ↔ S-warfarin No dose adjustment is required.(10 mg single dose, maribavir AUC 1.01 (0.95, 1.07)400 mg twice daily) (CYP2C9 inhibition)

Oral contraceptivessystemically acting oral Interaction not studied. No dose adjustment is required.contraceptive steroids Expected:

↔ oral contraceptive steroids(CYP3A inhibition)

Sedativesmidazolam ↔ midazolam No dose adjustment is required.(0.075 mg/kg single dose,maribavir 400 mg twice daily AUC 0.89 (0.79, 1.00)for 7 days) Cmax 0.82 (0.70, 0.96)↑ = increase, ↓ = decrease, ↔ = no change

CI = Confidence Interval

*AUC0-∞ for single dose, AUC0-12 for twice daily dose daily.

Note: the table is not extensive but provides examples of clinically relevant interactions.a Refer to the respective prescribing information.

Interaction studies have only been performed in adults.

There are no data of maribavir use in pregnant women. Studies in animals have shown reproductivetoxicity (see section 5.3). LIVTENCITY is not recommended during pregnancy and in women ofchildbearing potential not using contraception.

Maribavir is not expected to affect the plasma concentrations of systemically acting oral contraceptivesteroids (see Section 4.5).

It is unknown whether maribavir or its metabolites are excreted in human milk. A risk to the sucklingchild cannot be excluded. Breast-feeding should be discontinued during treatment with LIVTENCITY.

Fertility studies were not conducted in humans with LIVTENCITY. No effects on fertility orreproductive performance were noted in rats in a combined fertility and embryofoetal developmentstudy, however, a decrease in sperm straight line velocity was observed at doses ≥ 100 mg/kg/day(which is estimated to be < 1 times the human exposure at the recommended human dose [RHD]).

There were no effects on reproductive organs in either males or females in nonclinical studies in ratsand monkeys (see section 5.3).

LIVTENCITY has no influence on the ability to drive and use machines.

Adverse events were collected during the treatment phase and follow-up phase through Study

Week 20 in the Phase 3 study (see section 5.1). The mean exposures (SD) for LIVTENCITY was 48.6(13.82) days with a maximum of 60 days. The most commonly reported adverse reactions occurring inat least 10% of subjects in the LIVTENCITY group were: taste disturbance (46%), nausea (21%),diarrhoea (19%), vomiting (14%) and fatigue (12%). The most commonly reported serious adversereactions were diarrhoea (2%) and nausea, weight decreased, fatigue, immunosuppressant drug levelincreased, and vomiting (all occurring at < 1%).

The adverse reactions are listed below by body system organ class and frequency. Frequencies aredefined 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 2: Adverse reactions identified with LIVTENCITY

System Organ Class Frequency Adverse reactions

Nervous system disorders Very common Taste disturbance*

Common Headache

Gastrointestinal disorders Very Common Diarrhoea, Nausea, Vomiting

Common Abdominal pain upper

General disorders and Very common Fatigueadministration site conditions

Common Decreased appetite

Investigations Common Immunosuppressant drug levelincreased*, Weight decreased

Description of selected adverse reactions*

Taste disturbance

Taste disturbance (comprised of the reported preferred terms ageusia, dysgeusia, hypogeusia and tastedisorder) occurred in 46% of patients treated with LIVTENCITY. These events rarely led todiscontinuation of LIVTENCITY (0.9%) and, for most patients, resolved while patients remained ontherapy (37%) or within a median of 7 days (Kaplan-Meier estimate, 95% CI: 4-8 days) after treatmentdiscontinuation.

Increases in plasma levels of immunosuppressants

Immunosuppressant drug level increase (comprised of the preferred terms immunosuppressant druglevel increased and drug level increased) occurred in 9% of patients treated with LIVTENCITY.

LIVTENCITY has the potential to increase the drug concentrations of immunosuppressants that are

CYP3A and/or P-gp substrates with narrow therapeutic ranges (including tacrolimus, cyclosporine,sirolimus and everolimus). (See sections 4.4, 4.5 and 5.2).

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

In Study 303, an accidental overdose of a single extra dose occurred in 1 LIVTENCITY-treatedsubject on Day 13 (1 200 mg total daily dose). No adverse reactions were reported.

In Study 202, 40 subjects were exposed to doses of 800 mg twice daily and 40 subjects were exposedto 1 200 mg twice daily for a mean of approximately 90 days. In Study 203, 40 subjects were exposedto doses of 800 mg twice daily and 39 subjects were exposed to 1 200 mg twice daily for a maximumof 177 days. There were no appreciable differences in the safety profile in either study compared to the400 mg twice daily group in Study 303 in which subjects received maribavir for a maximum of60 days.

There is no known specific antidote for maribavir. In case of overdose, it is recommended that thepatient be monitored for adverse reactions and appropriate symptomatic treatment instituted. Due tothe high plasma protein binding of maribavir, dialysis is unlikely to reduce plasma concentrations ofmaribavir significantly.

Pharmacotherapeutic group: Antivirals for systemic use, direct acting antivirals, ATC code: J05AX10.

Maribavir is a competitive inhibitor of the UL97 protein kinase. UL97 inhibition occurs at the viral

DNA replication phase, inhibiting UL97 serine/threonine kinase by competitively inhibiting thebinding of ATP to the kinase ATP-binding site, without affecting the concatemer maturation process,abolishing phosphotransferase inhibiting CMV DNA replication and maturation, CMV DNAencapsidation, and CMV DNA nuclear egress.

Maribavir inhibited human CMV replication in virus yield reduction, DNA hybridization, and plaquereduction assays in human lung fibroblast cell line (MRC-5), human embryonic kidney (HEK), andhuman foreskin fibroblast (MRHF) cells. The EC50 values ranged from 0.03 to 2.2 µM depending onthe cell line and assay endpoint. The cell culture antiviral activity of maribavir has also been evaluatedagainst CMV clinical isolates. The median EC50 values were 0.1 μM (n=10, range 0.03-0.13 μM) and0.28 μM (n=10, range 0.12-0.56 μM) using DNA hybridization and plaque reduction assays,respectively. No significant difference in EC50 values across the four human CMV glycoprotein Bgenotypes (N = 2, 1, 4, and 1 for gB1, gB2, gB3, and gB4, respectively) was seen.

Combination antiviral activity

When maribavir was tested in in vitro combination with other antiviral compounds, strong antagonismwas seen with ganciclovir.

No antagonism was seen in combination with cidofovir, foscarnet and letermovir.

Viral resistance

Maribavir does not affect the UL54encoded DNA polymerase that, when presenting certain mutations,confers resistance to ganciclovir/valganciclovir, foscarnet and/or cidofovir. Mutations conferringresistance to maribavir have been identified on gene UL97: L337M, F342Y, V353A, V356G, L397R,

T409M, H411L/N/Y, D456N, V466G C480F, P521L, and Y617del. These mutations confer resistancethat ranges from 3.5-fold to > 200-fold increase in EC50 values. UL27 gene variants (R233S, W362R,

W153R, L193F, A269T, V353E, L426F, E22stop, W362stop, 218delC, and 301311del) conferredonly mild maribavir resistance (< 5fold increase in EC50), while L335P conferred high maribavirresistance.

In Phase 2 Study 202 and Study 203 evaluating maribavir in 279 HSCT or SOT recipients,post-treatment pUL97 genotyping data from 23 of 29 patients who initially achieved viraemiaclearance and later experienced recurrent CMV infection while on maribavir showed 17 patients withmutations T409M or H411Y and 6 patients with mutation C480F. Among 25 patients who did notrespond to > 14 days of maribavir therapy, 9 had mutations T409M or H411Y, and 5 patients hadmutation C480F. Additional pUL27 genotyping was performed on 39 patients in Study 202 and43 patients in Study 203. The only resistance-associated amino acid substitution in pUL27 that was notdetected at baseline was G344D. Phenotypic analysis of pUL27 and pUL97 recombinants showed thatpUL97 mutations T409M, H411Y, and C480F conferred 78-fold, 15-fold, and 224-fold increases,respectively, in maribavir EC50 compared with the wild-type strain, whereas the pUL27 mutation

G344D showed no difference in maribavir EC50 as compared to the wild-type strain.

In Phase 3 Study 303 evaluating maribavir in patients with phenotypic resistance tovalganciclovir/ganciclovir, DNA sequence analysis of the entire coding regions of pUL97 and pUL27was performed on 134 paired sequences from maribavir-treated patients. The treatment-emergentpUL97 substitutions F342Y (4.5-fold), T409M (78-fold), H411L/N/Y (69-, 9-, and 12-fold,respectively), and/or C480F (224-fold) were detected in 60 subjects and were associated with non-response (47 subjects were on-treatment failures and 13 subjects were relapsers). One subject with thepUL27 L193F substitution (2.6-fold reduced susceptibility to maribavir) at baseline did not meet theprimary endpoint. In addition, the following multiple mutations were associated with non-response;

F342Y+T409M+H411N (78-fold), C480F+H411L+H411Y (224-fold), F342Y+H411Y (56-fold),

T409M+C480F (224-fold) and H411Y+C480F (224-fold).

Cross-resistance has been observed between maribavir and ganciclovir/valganciclovir (vGCV/GCV)in cell culture and in clinical studies. In the phase 3 Study 303, a total of 44 patients in the maribavirarm had a treatment emergent resistance associated substitutions (RAS) to Investigator assignedtreatment (IAT). Of these 24 had treatment-emergent C480F or the F342Y RAS, both are cross-resistant to both ganciclovir/valganciclovir and maribavir. Of these 24 patients, 1 (4%) achieved theprimary endpoint. Overall, only eight of these 44 patients achieved the primary endpoint.pUL97 vGCV/GCV resistance-associated substitutions F342S/Y, K355del, V356G, D456N, V466G,

C480R, P521L, and Y617del reduce susceptibility to maribavir > 4.5-fold. Other vGCV/GCVresistance pathways have not been evaluated for cross-resistance to maribavir. pUL54 DNApolymerase substitutions conferring resistance to vGCV/GCV, cidofovir, or foscarnet remainedsusceptible to maribavir.

Substitutions pUL97 F342Y and C480F are maribavir treatment-emergent resistance-associatedsubstitutions that confer > 1.5-fold reduced susceptibility to vGCV/GCV, a fold reduction that isassociated with phenotypic resistance to vGCV/GCV. The clinical significance of this cross-resistanceto vGCV/GCV for these substitutions has not been determined. Maribavir resistant virus remainedsusceptible to cidofovir and foscarnet. Additionally, there are no reports of any pUL27 maribavirresistance-associated substitutions being evaluated for vGCV/GCV, cidofovir, or foscarnet cross-resistance. Given the lack of resistance-associated substitutions for these drugs mapping to pUL27,cross-resistance is not expected for pUL27 maribavir substitutions.

A Phase 3, multi-centre, randomised, open-label, active-controlled superiority study (Study

SHP620-303) assessed the efficacy and safety of LIVTENCITY treatment compared to Investigatorassigned treatment (IAT) in 352 HSCT and SOT recipients with CMV infections that were refractoryto treatment with ganciclovir, valganciclovir, foscarnet, or cidofovir, including CMV infections withor without confirmed resistance to 1 or more anti-CMV agents. Refractory CMV infection was definedas documented failure to achieve > 1 log10 decrease in CMV DNA level in whole blood or plasmaafter a 14-day or longer treatment period with intravenous ganciclovir/oral valganciclovir, intravenousfoscarnet, or intravenous cidofovir. This definition was applied to the current CMV infection and themost recently administered anti-CMV agent.

Patients were stratified by transplant type (HSCT or SOT) and screening CMV DNA levels and thenrandomised in a 2:1 ratio to receive LIVTENCITY 400 mg twice daily or IAT (ganciclovir,valganciclovir, foscarnet, or cidofovir) for an 8-week treatment period and a 12 week follow-up phase.

The mean age of trial subjects was 53 years and most subjects were male (61%), white (76%) and not

Hispanic or Latino (83%), with similar distributions across the two treatment arms. Baseline diseasecharacteristics are summarised in Table 3 below.

Table 3: Summary of the baseline disease characteristics of the study population in Study 303.

Characteristica IAT LIVTENCITY400 mg Twice Daily(N=117) (N=235)

IAT treatment prior to randomization, n (%)b

Ganciclovir/ Valganciclovir 98 (84) 204 (87)

Foscarnet 18 (15) 27 (12)

Cidofovir 1 (1) 4 (2)

IAT treatment after randomization, n (%)

Foscarnet 47 (41) n/a

Ganciclovir/ Valganciclovir 56 (48) n/a

Cidofovir 6 (5) n/a

Foscarnet+ Ganciclovir/Valganciclovir 7 (6) n/a

Transplant type, n (%)

HSCT 48 (41) 93 (40)

SOTc 69 (59) 142 (60)

Kidneyd 32 (46) 74 (52)

Lungd 22 (32) 40 (28)

Heartd 9 (13) 14 (10)

Multipled 5 (7) 5 (4)

Liverd 1 (1) 6 (4)

Pancreasd 0 2 (1)

Intestined 0 1 (1)

CMV DNA levels category as reported by centrallaboratory, n (%)e

High 7 (6) 14 (6)

Intermediate 25 (21) 68 (29)

Low 85 (73) 153 (65)

Baseline symptomatic CMV infectionf

No 109 (93) 214 (91)

Yesf 8 (7) 21 (9)

CMV syndrome (SOT only), n (%)d,f,g 7 (88) 10 (48)

Tissue invasive disease, n (%)f, d, g 1 (13) 12 (57)

CMV=cytomegalovirus, DNA=deoxyribonucleic acid, HSCT=haematopoietic stem cell transplant, IAT=investigatorassigned anti-CMV treatment, max=maximum, min=minimum, N=number of patients, SOT=solid organ transplant.a Baseline was defined as the last value on or before the first dose date of study-assigned treatment, or date of randomisationfor patients who did not receive study-assigned treatment.b Percentages are based on the number of subjects in the Randomized set within each column. Most recent anti-CMV agent,used to confirm refractory eligibility criteria.c The most recent transplant.d Percentages are based on the number of patients within the category.e Viral load was defined for analysis by the baseline central specialty laboratory plasma CMV DNA qPCR results as high(≥91,000 IU/mL), intermediate (≥ 9,100 and < 91,000 IU/mL), and low (< 9,100 IU/mL).f Confirmed by Endpoint Adjudication Committee (EAC).g Patients could have CMV syndrome and tissue invasive disease.

The primary efficacy endpoint was confirmed CMV viraemia clearance (plasma CMV DNAconcentration below the lower limit of quantification (< LLOQ; i.e., < 137 IU/mL) at Week 8regardless of whether either study-assigned treatment was discontinued before the end of the stipulated8 weeks of therapy. The key secondary endpoint was CMV viraemia clearance and CMV infectionsymptom control at Week 8 with maintenance of this treatment effect through Study Week 16. CMVinfection symptom control was defined as resolution or improvement of tissue-invasive disease or

CMV syndrome for symptomatic patients at baseline, or no new symptoms for patients who wereasymptomatic at baseline.

For the primary endpoint, LIVTENCITY was superior to IAT (56% vs. 24%, respectively, p < 0.001).

For the key secondary endpoint, 19% vs. 10% achieved both CMV viraemia clearance and CMVinfection symptom control in the LIVTENCITY and IAT group, respectively (p=0.013) (See Table 4).

Table 4: Primary and key secondary efficacy endpoint analysis (randomised set) in Study 303

LIVTENCITY

IAT 400 mg twice daily(N=117) (N=235)n (%) n (%)

Primary endpoint: CMV viraemia clearance response at week 8

Overall

Responders 28 (24) 131 (56)

Adjusted difference in proportion of responders (95% CI)a 32.8 (22.8, 42.7)p-value: adjusteda < 0.001

Key secondary endpoint: Achievement of CMV viraemia clearance and CMV infection symptomcontrolb at week 8, with maintenance through week 16b

Overall

Responders 12 (10) 44 (19)

Adjusted difference in proportion of responders (95% CI)a 9.45 (2.0, 16.9)p-value: Adjusteda 0.013

CI=confidence interval; CMV=cytomegalovirus; HSCT=haematopoietic stem cell transplant; IAT=investigator-assignedanti-CMV treatment; N=number of patients; SOT=solid organ transplant.a Cochran-Mantel-Haenszel weighted average approach was used for the adjusted difference in proportion (maribavir-IAT),the corresponding 95% CI, and the p-value after adjusting for the transplant type and baseline plasma CMV DNAconcentration.b CMV infection symptom control was defined as resolution or improvement of tissue-invasive disease or CMV syndromefor symptomatic patients at baseline, or no new symptoms for patients who were asymptomatic at baseline.

The treatment effect was consistent across transplant type, age group, and the presence of CMVsyndrome/disease at baseline. However, LIVTENCITY was less effective against subjects withincreased CMV DNA levels (≥ 50 000 IU/mL) and patients with absence of genotypic resistance (seetable 5).

Table 5: Percentage of Responders by subgroup in Study 303

IAT LIVTENCITY 400 mg(N=117) Twice Daily(N=235)n/N % n/N %

Transplant type

SOT 18/69 26 79/142 56

HSCT 10/48 21 52/93 56

Baseline CMV DNA viral load

Low 21/85 25 95/153 62

Intermediate/High 7/32 22 36/82 44

Genotypic resistance to other anti-CMV agents

Yes 14/69 20 76/121 63

No 11/34 32 42/96 44

CMV syndrome/disease at baseline

Yes 1/8 13 10/21 48

No 27/109 25 121/214 57

Age Group18 to 44 years 8/32 25 28/55 5145 to 64 years 19/69 28 71/126 56≥ 65 years 1/16 6 32/54 59

CMV=cytomegalovirus, DNA=deoxyribonucleic acid, HSCT=haematopoietic stem cell transplant, SOT=solid organtransplant

Recurrence

The secondary endpoint of recurrence of CMV viraemia was reported in 57% of the maribavir treatedpatients and in 34% of the IAT treated patients. Of these, 18% in the maribavir group had recurrenceof CMV viraemia while on-treatment compared to 12% the IAT group. Recurrence of CMV viraemiaduring follow up was seen in 39% of patients in the maribavir group and in 22% of the patients in the

IAT group.

Overall mortality: All-cause mortality was assessed for the entire study period. A similar percentage ofsubjects in each treatment group died during the trial (LIVTENCITY 11% [27/235]; IAT 11%[13/117]).

The European Medicines Agency has deferred the obligation to submit the results of studies with

LIVTENCITY in one or more subsets of the paediatric population for treatment of cytomegalovirusinfection (see section 4.2).

Maribavir pharmacological activity is due to the parent medicinal product. The pharmacokinetics ofmaribavir have been characterised following oral administration in healthy subjects and transplantpatients. Maribavir exposure increased in an approximately dose proportionally manner. In healthysubjects, the geometric mean steady-state AUC0-t, Cmax and Ctrough values were 101 µg*h/mL,16.4 µg/mL and 2.89 µg/mL, respectively, following 400 mg twice daily oral maribavir doses.

In transplant recipients, maribavir steady state exposure following oral administration of 400 mg twicedaily doses are provided below, based on a population pharmacokinetics analysis. Steady-state wasreached in 2 days, with an accumulation ratio of 1.47 for AUC and 1.37 for Cmax. The intrasubjectvariability (< 22%) and intersubject variability (< 37%) in maribavir PK parameters are low tomoderate.

Table 6: Maribavir pharmacokinetic properties in transplant recipients based on a populationpharmacokinetics analysis

Parameter GM (% CV) AUC0- tau Cmax Ctroughµg*h/mL µg/mL µg/mL

Maribavir 400 mg twice daily 142 (48.5%) 20.1 (35.5%) 5.43 (85.9%)

GM: Geometric mean, % CV: Geometric coefficient of variation

Maribavir was rapidly absorbed with peak plasma concentrations occurring 1.0 to 3.0 hours post dose.

Exposure to maribavir is unaffected by crushing the tablet, administration of crushed tablet throughnasogastric (NG)/orogastric tubes or co-administration with proton pump inhibitors (PPIs), histamine

H2 receptor antagonists (H2 blockers) or antacids.

In healthy subjects, oral administration of a single 400 mg dose of maribavir with a high fat, highcaloric meal resulted in no change in the overall exposure (AUC) and a 28% decrease in Cmax ofmaribavir, which was not considered clinically relevant.

Based on population pharmacokinetic analyses, the apparent steady-state volume of distribution isestimated to be 24.9 L.

In vitro binding of maribavir to human plasma proteins was 98.0% over the concentration range of0.05-200 μg/mL. Ex vivo protein binding of maribavir (98.5%-99.0%) was consistent with in vitrodata, with no apparent difference observed among healthy subjects, subjects with hepatic (moderate)or renal (mild, moderate or severe) impairment, human immunodeficiency virus (HIV) patients, ortransplant patients.

Maribavir may cross the blood-brain barrier in humans but CNS penetration is expected to be lowcompared to plasma levels (see section 4.4 and 5.3).

In vitro data indicate that maribavir is a substrate of P-glycoprotein (P-gp), breast cancer resistanceprotein (BCRP) and organic cation transporter 1 (OCT1) transporters. Changes in maribavir plasmaconcentrations due to inhibition of P-gp/BCRP/OCT1 were not clinically relevant.

Maribavir is primarily eliminated by hepatic metabolism via CYP3A4 (primary metabolic pathwayfraction metabolised estimated to be at least 35%), with secondary contribution from CYP1A2(fraction metabolised estimated at no more than 25%). The major metabolite of maribavir is formed by

N-dealkylation of the isopropyl moiety and is considered pharmacologically inactive. The metabolicratio for this major metabolite in plasma was 0.15-0.20. Multiple UGT enzymes, namely UGT1A1,

UGT1A3, UGT2B7, and possibly UGT1A9, are involved in the glucuronidation of maribavir inhumans, however, the contribution of glucuronidation to the overall clearance of maribavir is lowbased on in vitro data.

Based on in vitro studies, metabolism of maribavir is not mediated by CYP2B6, CYP2C8, CYP2C9,

CYP2C19, CYP3A5, 1A4, UGT1A6, UGT1A10, or UGT2B15.

The elimination half-life and oral clearance of maribavir are estimated at 4.3 hours and 2.67 L/h,respectively, in transplant patients. After single dose oral administration of [14C]-maribavir,approximately 61% and 14% of the radioactivity were recovered in urine and faeces, respectively,primarily as the major and inactive metabolite. Urinary excretion of unchanged maribavir is minimal.

No clinically significant effect of mild, moderate or severe renal impairment (measured creatinineclearance ranging from 12 to 70 mL/min) was observed on maribavir total PK parameters following asingle dose of 400 mg maribavir. The difference in maribavir PK parameters between subjects withmild/moderate or severe renal impairment and subjects with normal renal function was < 9%. Asmaribavir is highly bound to plasma proteins, it is unlikely that maribavir will be significantlyremoved by haemodialysis or peritoneal dialysis.

No clinically significant effect of moderate hepatic impairment (Child-Pugh Class B, score of 7-9) wasobserved on total or unbound maribavir PK parameters following a single dose of 200 mg ofmaribavir. Compared to the healthy control subjects, AUC and Cmax were 26% and 35% higher,respectively, in subjects with moderate hepatic impairment. It is not known whether the exposure tomaribavir will increase in patients with severe hepatic impairment.

Age, gender, race, ethnicity, and weight

Age (18-79 years), gender, race (Caucasian, Black, Asian, or others), ethnicity (Hispanic/Latino ornon-Hispanic/Latino) and body weight (36 to 141 kg) did not have clinically significant effect on thepharmacokinetics of maribavir based on population PK analysis.

Transplant types

Transplant types (HSCT vs. SOT) or between SOT types (liver, lung, kidney, or heart) or presence ofgastrointestinal (GI) graft-versus host disease (GvHD) do not have a clinically significant impact on

PK of maribavir.

Regenerative anaemia and mucosal cell hyperplasia in the intestinal tract, observed with dehydrationwas noted in rats and monkeys, together with clinical observations of soft to liquid stool, andelectrolyte changes (in monkeys only). A no observed adverse effect level (NOAEL) was notestablished in monkeys and was < 100 mg/kg/day, which is approximately 0.25 the human exposure atthe recommended human dose (RHD). In rats the NOAEL was 25 mg/kg/day, at which exposureswere 0.05 and 0.1 times the human exposure at the RHD in males and females, respectively.

Maribavir did not demonstrate phototoxicity in vitro, therefore, the potential for phototoxicity inhumans is considered unlikely.

Maribavir was detected at low levels in the choroid plexus of rats and the brain and CSF of themonkey (see section 4.4 and 5.2).

No carcinogenic potential was identified in rats up to 100 mg/kg/day at which exposures in males andfemales were 0.2 and 0.36 times, respectively the human exposure at the RHD. In male mice, anequivocal elevation in the incidence of haemangioma, haemangiosarcoma, and combinedhaemangioma/ haemangiosarcoma across multiple tissues at 150 mg/kg/day is of uncertain relevancein terms of its translation to human risk given the lack of an effect in female mice or in rats after104 weeks of administration, lack of neoplastic proliferative effects in male and female mice after13 weeks administration, the negative genotoxicity package and the difference in duration ofadministration in humans. There were no carcinogenic findings at the next lower dose of75 mg/kg/day, which is approximately 0.35 and 0.25 in males and females, respectively, the humanexposure at the RHD.

Maribavir was not mutagenic in a bacterial mutation assay, nor clastogenic in the bone marrowmicronucleus assay. In mouse lymphoma assays, maribavir demonstrated mutagenic potential in theabsence of metabolic activation and the results were equivocal in the presence of metabolic activation.

Overall, the weight of evidence indicates that maribavir does not exhibit genotoxic potential.

Reproduction

In the combined fertility and embryofoetal development study in rats, there were no effects ofmaribavir on fertility. However, in male rats decreases in sperm straight line velocity, were observedat doses ≥ 100 mg/kg/day (which is estimated to be less than the human exposure at the RHD), butwithout any impact on male fertility.

Prenatal and postnatal development

In a combined fertility and embryofoetal development study in rats, maribavir was not teratogenic andhad no effect on embryofoetal growth or development at doses up to 400 mg/kg/day. A decrease in thenumber of viable foetuses due to increase in early resorptions and post-implantation losses wasobserved in females at all tested maribavir doses which were also maternally toxic. The lowest dosecorresponded to approximately half the human exposure at the RHD. In the pre and postnataldevelopmental toxicity study conducted in rats, decreased pup survival due to poor maternal care andreduced body weight gain associated with a delay in developmental milestones (pinna detachment, eyeopening and preputial separation) were observed at maribavir doses ≥ 150 mg/kg/day. Postnataldevelopment was not affected at 50 mg/kg/day. Fertility and mating performance of the F1 generation,and their ability to maintain pregnancy and to deliver live offspring, was unaffected up to400 mg/kg/day.

In rabbits, maribavir was not teratogenic at doses up to 100 mg/kg/day (approximately 0.45 times thehuman exposure at the RHD).

Microcrystalline cellulose (E460(i))

Sodium starch glycolate

Magnesium stearate (E470b)

Polyvinyl alcohol (E1203)

Macrogol (polyethylene glycol) (E1521)

Titanium dioxide (E171)

Talc (E553b)

Brilliant blue FCF aluminum lake (EU) (E133)

Not applicable.

36 months.

Do not store above 30 °C.

High-density polyethylene (HDPE) bottles with child resistant cap.

Pack-sizes of 28, 56 or 112 (2 bottles of 56) film-coated tablets.

Not all pack sizes may be marketed.

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

Takeda Pharmaceuticals International AG Ireland Branch

Block 2 Miesian Plaza50-58 Baggot Street Lower

Dublin 2

D02 HW68

Ireland

E-mail: medinfoEMEA@takeda.com

EU/1/22/1672/001

EU/1/22/1672/002

EU/1/22/1672/003

Date of first authorisation: 09 November 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.