PLGB 16189/0127/OD1

Cytomegalovirus (CMV) infection in patients with impaired cell-mediated immunity

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.

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 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

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

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).

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

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 Very common Taste disturbance* Nervous system disorders Common Headache Very Common Diarrhoea, Nausea, Vomiting Gastrointestinal disorders Common Abdominal pain upper Very common Fatigue General disorders and administration site conditions 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.

In Study 303, an accidental 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 , 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.

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 local requirements.

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