Administration of Dispersed Tablets or Crushed Tablets by Mouth

1. Place the appropriate number of tablets for the prescribed dose into a suitable container. If desired, the tablets may be crushed. Add the appropriate volume of drinking water (other liquids have not been tested) to make a suspension (see Table 1 below).

   Table 1: Number of Tablets and Volume of Drinking Water Needed to Make a Suspension for Administration of Dispersed or Crushed Tablets by Mouth

   Recommended Dosage	Number of 200 mg Tablets	Volume of Drinking Water
   400 mg	Two	30 mL
   800 mg	Four	60 mL
   1,200 mg	Six	90 mL

2. Swirl the container gently to keep the particles from settling, and administer the suspension before it settles. The mixture will have a bitter taste.
3. Rinse the container with 15 mL of drinking water and administer the rinse water.
4. Repeat Step 3. Visually confirm that no particles are left in the container. If particles remain, repeat Step 3.

Administration of Dispersed Tablets through a Nasogastric (NG) or Orogastric (OG) Tube

1. Remove the cap (if applicable) and plunger out of a 50 or 60 mL catheter-tip compatible syringe or equivalent. Add two tablets into the syringe body and place the plunger back in the syringe. Only two tablets can be administered via NG or OG tube at a time.
2. Draw 30 mL of drinking water (other liquids have not been tested) into the syringe and hold the syringe with the tip pointing upward. Pull the plunger further to a higher volume position to have some air space in the syringe. Place the cap back on the syringe (if applicable). Shake the syringe well (careful not to spill the contents) for about 30 to 45 seconds or until the tablets are completely dispersed.
3. Once the tablets are completely dispersed in the syringe, remove the cap from the syringe again (if applicable) and attach the syringe to the NG or OG tube and administer the dispersion before it settles.
4. Draw 15 mL of water using the same syringe and flush through the same NG or OG tube.
5. Repeat Step 4 and make sure no particles are left in the syringe by visual inspection. If particles remain, repeat Step 4.
6. For doses of 800 mg (four 200 mg tablets) and 1,200 mg (six 200 mg tablets) [see Dosage and Administration (2.2)], repeat Steps 1-5 until prescribed dose is reached. The same syringe, NG or OG tube can be used.

Use with Immunosuppressant Drugs

LIVTENCITY has the potential to increase the drug concentrations of immunosuppressant drugs that are CYP3A4 and/or P-glycoprotein (P-gp) substrates where minimal concentration changes may lead to serious adverse events (including tacrolimus, cyclosporine, sirolimus and everolimus). Frequently monitor immunosuppressant drug levels throughout treatment with LIVTENCITY, especially following initiation and after discontinuation of LIVTENCITY and adjust the immunosuppressant dose, as needed [see Drug Interactions (7.3) and Clinical Pharmacology (12.3)].

Laboratory Abnormalities

Selected laboratory abnormalities reported in subjects with refractory (with or without genotypic resistance) CMV infections in Trial 303 are presented in Table 3.

Risk Summary

No adequate human data are available to establish whether LIVTENCITY poses a risk to pregnancy outcomes. In animal reproduction studies, embryo-fetal survival was decreased in rats, but not in rabbits, at maribavir exposures less than those observed in humans at the recommended human dose (RHD) (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Risk Summary

It is not known whether maribavir or its metabolites are present in human or animal milk, affect milk production, or have effects on the breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for LIVTENCITY and any potential adverse effects to the breast-fed child.

Exposure-Response

In dose-ranging studies that evaluated doses of 400 mg twice daily and twice daily doses of two and three times the recommended dose, no exposure-response relationship was observed for viral load or probability of unquantifiable plasma CMV DNA.

In Phase 3 Trial 303 that evaluated a maribavir dose of 400 mg twice daily, increasing maribavir exposure was not associated with increased probability of confirmed plasma CMV DNA < LLOQ (lower limit of quantification) at Week 8.

Cardiac Electrophysiology

At three times the recommended dose (approximately twice the peak concentration observed following the recommended dose), LIVTENCITY does not prolong the QT interval to any clinically relevant extent.

Specific Populations

There were no clinically significant differences in the pharmacokinetics of maribavir based on age (18-79 years), gender, race (Caucasian, Black, Asian, or others), ethnicity (Hispanic/Latino or non-Hispanic/Latino), body weight (36 to 141 kg), transplant type, mild to severe renal impairment (measured creatinine clearance ranging from 12 to 70 mL/min), or mild to moderate hepatic impairment (Child-Pugh Class A or B).

Drug Interactions

Based on in vitro studies, the metabolism of maribavir is not mediated by CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A5, UGT1A4, UGT1A6, UGT1A10, or UGT2B15. The transport of maribavir is not mediated by organic anion transporting polypeptide (OATP)1B1, OATP1B3, or bile salt export pump (BSEP).

At clinically relevant concentrations, clinically significant interactions are not expected when LIVTENCITY is coadministered with substrates of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, CYP2D6, CYP3A4; uridine diphosphate-glucuronosyltransferase (UGT)1A1, UGT1A4, UGT1A6, UGT1A9, UGT2B7; P-gp; BSEP; multidrug and toxin extrusion protein (MATE)1/2K; organic anion transporters (OAT)1 and OAT3; organic cation transporters (OCT)1 and OCT2; OATP1B1 and OATP1B3. In a clinical drug-drug interaction cocktail study, coadministration with maribavir had no effect on substrates of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4.

Drug interaction studies were performed with LIVTENCITY and other drugs likely to be coadministered for pharmacokinetic interactions. The effects of coadministration of other drugs on the pharmacokinetics of maribavir are summarized in Table 7, and the effects of maribavir on the pharmacokinetics of coadministered drugs are summarized in Table 8.

Dosing recommendations as a result of established and other potentially significant drug-drug interactions with LIVTENCITY are provided in Table 4 [see Drug Interactions (7.3)].

Mechanism of Action

The antiviral activity of maribavir is mediated by competitive inhibition of the protein kinase activity of human CMV enzyme pUL97, which results in inhibition of the phosphorylation of proteins. Maribavir inhibited wild-type pUL97 protein kinase in a biochemical assay with an IC50 value of 0.003 µM. Maribavir and its 5'-mono- and 5'-triphosphate derivatives at 100 µM had no significant effect on the incorporation of deoxynucleoside triphosphates by human CMV DNA polymerase. At a concentration of 100 µM, neither maribavir nor its 5′-triphosphate derivative inhibited CMV DNA polymerase delta, however the 5′-monophosphate derivative inhibited incorporation by polymerase delta of all 4 natural dNTPs by approximately 55%.

Antiviral Activity

Maribavir inhibited human CMV replication in virus yield reduction, DNA hybridization, and plaque reduction assays in human lung fibroblast cell line (MRC-5), human embryonic kidney (HEK), and human foreskin fibroblast (MRHF) cells. The EC50 values ranged from 0.03 to 2.2 µM depending on the cell line and assay endpoint. The cell culture antiviral activity of maribavir has also been evaluated against CMV clinical isolates. The median EC50 values were 0.1 µM (n=10, range 0.03-0.13 µM) and 0.28 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 B genotypes (N=2, 1, 4, and 1 for gB1, gB2, gB3, and gB4, respectively) was seen.

Combination Antiviral Activity

When maribavir was tested in combination with other antiviral compounds, antagonism of the antiviral activity was seen in combination with ganciclovir. No antagonism was observed with cidofovir, foscarnet, letermovir and rapamycin at the drugs EC50 values. The pUL97 kinase activity inhibited by maribavir is necessary to activate valganciclovir/ganciclovir.

Treatment Effect in CMV Glycoprotein B (gB) Subtypes

In Trial 303, the primary endpoint response rates for LIVTENCITY across CMV gB subtypes 1, 2, 3, 4, and 5 were 65% (55/85), 39% (22/57), 54% (22/41), 67% (14/21), and 64% (7/11), respectively. The primary endpoint response rates for IAT across CMV gB subtypes 1, 2, 3, 4, and 5 were 28% (15/53), 27% (4/15), 11% (2/19), 20% (2/10), and 17% (1/6), respectively [see Clinical Studies (14)].

Viral Resistance

Cross-Resistance

Cross-resistance has been observed between maribavir and ganciclovir/valganciclovir in cell culture and in clinical studies.

pUL97 valganciclovir/ganciclovir resistance-associated substitutions F342S/Y, K355del, V356G, D456N, V466G, C480R, P521L, and Y617del reduce susceptibility to maribavir >4.5-fold. Other vGCV/GCV resistance pathways have not been evaluated for cross-resistance to maribavir. pUL54 DNA polymerase substitutions conferring resistance to vGCV/GCV, cidofovir, or foscarnet remained susceptible to maribavir.

Substitutions pUL97 F342Y and C480F are maribavir treatment-emergent resistance-associated substitutions that confer >1.5-fold reduced susceptibility to vGCV/GCV, a fold reduction that is associated with phenotypic resistance to vGCV/GCV. The clinical significance of this cross-resistance to vGCV/GCV for these substitutions has not been determined. Maribavir resistant virus remained susceptible to cidofovir and foscarnet. Additionally, there are no reports of any pUL27 maribavir resistance-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.

Mutagenicity

Maribavir was negative in a bacterial mutation assay and the in vivo rat bone marrow micronucleus assay. Maribavir was positive in the absence of metabolic activation in the mouse lymphoma assay, and the results were equivocal in the presence of metabolic activation.

Impairment of Fertility

Although decreased sperm straight line velocity was observed in males (at maribavir exposures less than those observed in humans at the RHD), there were no effects on fertility in males or females in a combined oral fertility and embryo-fetal study in rats administered maribavir at up to 400 mg/kg/day [see Use in Specific Populations (8.1)].

Primary Efficacy Endpoint

The primary efficacy endpoint was confirmed CMV DNA level < LLOQ (i.e;, <137 IU/mL) as assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test) at the end of Week 8. The key secondary endpoint was CMV DNA level < LLOQ and CMV infection symptom control at the end of Study Week 8 with maintenance of this treatment effect through Study Week 16.

For the primary endpoint, LIVTENCITY was statistically superior to IAT (56% vs 24%, respectively), as shown in Table 10.

The reasons for failure to meet the primary endpoint are summarized in Table 11.

The treatment effect of LIVTENCITY was consistent across transplant type, age group, and the presence of CMV syndrome/disease at baseline. However, LIVTENCITY was less effective against subjects with increased CMV DNA levels (≥50,000 IU/mL) and subjects with absence of genotypic resistance (see Table 12).

Secondary Endpoints

Table 13 shows results of the secondary endpoint, achievement of CMV DNA level < LLOQ and symptom controla at Week 8 with maintenance through Week 16.