Maribavir

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 cilastin).

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.

Maribavir inhibited P-gp transporter in vitro at clinically relevant concentrations. In a clinical study, co-administration of maribavir increased plasma concentrations of digoxin. 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.

Medicinal product:

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

Effect on geometric mean ratio (90% CI) (likely mechanism of action):

↔ digoxin
AUC 1.21 (1.10, 1.32)
C_max 1.25 (1.13, 1.38)

(P-gp inhibition)

Recommendation concerning co-administration with maribavir:

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.

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. Coadministration 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.

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.

Administration of maribavir 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 maribavir is administered to patients with severe hepatic impairment.

Maribavir 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 maribavir, especially following initiation and after discontinuation of maribavir, and doses should be adjusted, as needed.

Co-administration of maribavir increased plasma concentrations of tacrolimus. 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.

There are no data of maribavir use in pregnant women. Studies in animals have shown reproductive toxicity. Maribavir 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.

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 maribavir.

Fertility

Fertility studies were not conducted in humans with maribavir. 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.

Maribavir 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. The mean exposures (SD) for maribavir 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 maribavir 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 concentration 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).

Adverse reactions identified with maribavir:

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 maribavir. These events rarely led to discontinuation of maribavir (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 maribavir. Maribavir 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).