4.1. Therapeutic indications

LIVTENCITY is indicated for the treatment of cytomegalovirus (CMV) infection and/or disease that are 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 cell transplant (HSCT) or solid organ transplant (SOT).

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

4.2. Posology and method of administration

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

Posology

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

Co-administration with CYP3A inducers

Co-administration of LIVTENCITY with the strong cytochrome P450 3A (CYP3A) inducers rifampicin, rifabutin or St. John's wort is not recommended due to potential for a decrease in efficacy of 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 dose should be increased to 1 200 mg twice daily (see sections 4.4, 4.5 and 5.2).

Missed dose

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

Special populations

Elderly patients

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

Renal impairment

No dose adjustment of LIVTENCITY is required for patients with mild, moderate or severe renal impairment. 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 for patients on dialysis due to the high plasma protein binding of maribavir (see section 5.2).

Hepatic impairment

No dose adjustment of LIVTENCITY is required for patients with mild (Child-Pugh Class A) or moderate hepatic impairment (Child-Pugh Class B). Administration of LIVTENCITY in patients with severe hepatic impairment (Child-Pugh Class C) has not been studied. It is not known whether exposure to maribavir will significantly increase in patients with severe hepatic impairment. Therefore, caution is advised when LIVTENCITY is administered to patients with severe hepatic impairment (see section 5.2).

Paediatric population

The safety and efficacy of LIVTENCITY in patients below 18 years of age have not been established. No data are available.

Method of administration

Oral use.

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

4.3. Contraindications

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).

4.4. Special warnings and precautions for use

Virologic failure during treatment and relapse post-treatment

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

CMV disease with CNS involvement

LIVTENCITY was not studied in patients with CMV CNS infection. Based on nonclinical data, CNS penetration 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 are cytochrome P450 (CYP)3A/P-gp substrates with narrow therapeutic margins (including tacrolimus, cyclosporine, sirolimus and everolimus). The plasma levels of these immunosuppressants must be frequently monitored throughout treatment with LIVTENCITY, especially following initiation and after discontinuation of LIVTENCITY, and doses should be adjusted, as needed (see sections 4.5, 4.8 and 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 or potentially significant medicinal product interactions, some of which may lead to:

• possible clinically significant adverse reactions from greater exposure of concomitant medicinal products.

• reduced therapeutic effect of LIVTENCITY.

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

Sodium content

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

4.5. Interaction with other medicinal products and other forms of interaction

Effect of other medicinal products on maribavir

Maribavir is primarily metabolised by CYP3A, and medicinal products that induce or inhibit CYP3A are 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 in increased plasma concentrations of maribavir (see section 5.2). However, no dose adjustment is needed 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 significantly decrease 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, rifabutin or 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 to 1 200 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 section 4.3). LIVTENCITY may antagonise the antiviral effect of ganciclovir and valganciclovir by inhibiting human CMV UL97 serine/threonine kinase, which is required for activation/phosphorylation of ganciclovir 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 clinical interaction results (Table 1 and section 5.2).

Maribavir acted as an inducer of CYP1A2 enzyme in vitro. There are no clinical data available to exclude an interaction risk via CYP1A2 induction in vivo. Therefore, the concomitant administration of maribavir and medicinal products that are sensitive substrates of CYP1A2 with a narrow therapeutic window (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 the immunosuppressants tacrolimus, cyclosporine, everolimus or sirolimus are co-administered with maribavir, immunosuppressant levels should be frequently monitored throughout treatment with maribavir, 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 may need 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 to increase their exposure and lead to undesirable effects.

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

In vitro, maribavir inhibits MATE1. There are no clinical data available whether the co-administration of maribavir with sensitive MATE1 substrates (e.g., metformin) could potentially lead to clinically relevant 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 of established or potentially clinically significant medicinal product interactions. The medicinal product interactions described are based on studies conducted with maribavir or are predicted medicinal product 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 therapeutic area

Effect on geometric mean ratio (90 % CI)

(likely mechanism of action)

Recommendation concerning co-administration with maribavir

Acid-reducing agents

antacid (aluminium and magnesium hydroxide oral suspension)

(20 mL single dose, maribavir 100 mg single dose)

↔ maribavir

AUC 0.89 (0.83, 0.96)

Cmax 0.84 (0.75, 0.94)

No dose adjustment is required.

famotidine

Interaction not studied.

Expected:

↔ maribavir

No dose adjustment is required.

pantoprazole

Interaction not studied.

Expected:

↔ maribavir

No dose adjustment is required.

omeprazole

↔ maribavir

↑ plasma omeprazole/5-hydroxyomeprazole concentration ratio

1.71 (1.51, 1.92) at 2h post-dose

(CYP2C19 inhibition)

No dose adjustment is required.

Antiarrhythmics

digoxin

(0.5 mg single dose, 400 mg twice daily maribavir)

↔ digoxin

AUC 1.21 (1.10, 1.32)

Cmax 1.25 (1.13, 1.38)

(P-gp inhibition)

Use caution when maribavir and digoxin are co-administered. Monitor serum digoxin concentrations. The dose of sensitive P-gp substrates such as digoxin may need to be reduced when co-administered with maribavir.

Antibiotics

clarithromycin

Interaction not studied.

Expected:

↑ maribavir

(CYP3A inhibition)

No dose adjustment is required.

Anticonvulsants

carbamazepine

phenobarbital

phenytoin

Interaction not studied.

Expected:

↓ maribavir

(CYP3A induction)

A dose adjustment of maribavir to 1 200 mg twice daily is recommended when co-administration with these anticonvulsants.

Antifungals

ketoconazole

(400 mg single dose, maribavir 400 mg single dose)

↑ maribavir

AUC 1.53 (1.44, 1.63)

Cmax 1.10 (1.01, 1.19)

(CYP3A and P-gp inhibition)

No dose adjustment is required.

voriconazole

(200 mg twice daily, maribavir 400 mg twice daily)

Expected:

↑ maribavir

(CYP3A inhibition)

↔ voriconazole

AUC 0.93 (0.83, 1.05)

Cmax 1.00 (0.87, 1.15)

(CYP2C19 inhibition)

No dose adjustment is required.

Antihypertensives

diltiazem

Interaction not studied.

Expected:

↑ maribavir

(CYP3A inhibition)

No dose adjustment is required.

Antimycobacterials

rifabutin

Interaction not studied.

Expected:

↓ maribavir

(CYP3A induction)

Co-administration of maribavir and rifabutin is not recommended due to potential for a decrease in efficacy of maribavir.

rifampicin

(600 mg once daily, maribavir 400 mg twice daily)

↓ maribavir

AUC 0.40 (0.36, 0.44)

Cmax 0.61 (0.52, 0.72)

Ctrough 0.18 (0.14, 0.25)

(CYP3A and CYP1A2 induction)

Co-administration of maribavir and rifampin is not recommended due to potential for a decrease in efficacy of maribavir.

Antitussives

dextromethorphan

(30 mg single dose, maribavir 400 mg twice daily)

↔ dextrorphan

AUC 0.97 (0.94, 1.00)

Cmax 0.94 (0.88, 1.01)

(CYP2D6 inhibition)

No dose adjustment is required.

CNS stimulants

Herbal products

St. John's wort (Hypericum perforatum)

Interaction not studied.

Expected:

↓ maribavir

(CYP3A induction)

Co-administration of maribavir and St. John's wort is not recommended due to potential for a decrease in efficacy of maribavir.

HIV antiviral agents

Non-nucleoside reverse transcriptase inhibitors

Efavirenz

Etravirine

Nevirapine

Interaction not studied.

Expected:

↓ maribavir

(CYP3A induction)

A dose adjustment of maribavir to 1 200 mg twice daily is recommended when co-administration with these a non-nucleoside reverse transcriptase inhibitors.

Nucleoside reverse transcriptase inhibitors

Tenofovir disoproxil

Tenofovir alafenamide

Abacavir

Lamivudine

Emtricitabine

Interaction not studied.

Expected:

↔ maribavir

↔ nucleoside reverse transcriptase inhibitors

No dose adjustment is required.

Protease inhibitors

ritonavir- boosted protease inhibitors (atazanavir, darunavir, lopinavir)

Interaction not studied.

Expected:

↑ maribavir

(CYP3A inhibition)

No dose adjustment is required.

Integrase strand transfer inhibitors

dolutegravir

Interaction not studied.

Expected:

↔ maribavir

↔ dolutegravir

No dose adjustment is required.

HMG-CoA reductase inhibitors

atorvastatin

fluvastatin

simvastatin

Interaction not studied.

Expected:

↑ HMG-CoA reductase inhibitors

(BCRP inhibition)

No dose adjustment is required.

rosuvastatina

Interaction not studied.

Expected:

↑ rosuvastatin

(BCRP inhibition)

The patient should be closely monitored for rosuvastatin-related events, especially the occurrence of myopathy and rhabdomyolysis.

Immunosuppressants

cyclosporinea

everolimusa

sirolimusa

Interaction not studied.

Expected:

↑ cyclosporine, everolimus, sirolimus

(CYP3A/P-gp inhibition)

Frequently monitor cyclosporine, everolimus and sirolimus levels, especially following initiation and after discontinuation of maribavir and adjust dose, as needed.

tacrolimusa

↑ tacrolimus

AUC 1.51 (1.39, 1.65)

Cmax 1.38 (1.20, 1.57)

Ctrough 1.57 (1.41, 1.74)

(CYP3A/P-gp inhibition)

Frequently monitor tacrolimus levels, especially following initiation and after discontinuation of maribavir and adjust dose, as needed.

Oral anticoagulants

warfarin

(10 mg single dose, maribavir 400 mg twice daily)

↔ S-warfarin

AUC 1.01 (0.95, 1.07)

(CYP2C9 inhibition)

No dose adjustment is required.

Oral contraceptives

systemically acting oral contraceptive steroids

Interaction not studied.

Expected:

↔ oral contraceptive steroids

(CYP3A inhibition)

No dose adjustment is required.

Sedatives

midazolam

(0.075 mg/kg single dose, maribavir 400 mg twice daily for 7 days)

↔ midazolam

AUC 0.89 (0.79, 1.00)

Cmax 0.82 (0.70, 0.96)

No dose adjustment is required.

↑ = 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.

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy and lactation

Pregnancy

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

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

Breast-feeding

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

Fertility

Fertility studies were not conducted in humans with LIVTENCITY. No effects on fertility or reproductive performance were noted in rats in a combined fertility and embryofoetal development study, 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 rats and monkeys (see section 5.3).

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

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 in at 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 adverse reactions were diarrhoea (2%) and nausea, weight decreased, fatigue, immunosuppressant drug level increased, and vomiting (all occurring at < 1%).

Tabulated list of adverse reactions

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 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 administration site conditions

Very common

Fatigue

Common

Decreased appetite

Investigations

Common

Immunosuppressant drug level increased*, Weight decreased

Description of selected adverse reactions*

Taste disturbance

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

Increases in plasma levels of immunosuppressants

Immunosuppressant drug level increase (comprised of the preferred terms immunosuppressant drug level 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 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.

4.9. Overdose

In Study 303, an accidental overdose of a single extra dose occurred in 1 LIVTENCITY-treated subject 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 exposed to 1 200 mg twice daily for a mean of approximately 90 days. In Study 203, 40 subjects were exposed to doses of 800 mg twice daily and 39 subjects were exposed to 1 200 mg twice daily for a maximum of 177 days. There were no appreciable differences in the safety profile in either study compared to the 400 mg twice daily group in Study 303 in which subjects received maribavir for a maximum of 60 days.

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