CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None. (4).

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The safety of LIVTENCITY was evaluated in one Phase multi-center, randomized, open-label, active-control trial in which 352 adult transplant recipients were randomized, and treated with LIVTENCITY (N=234) or Investigator-Assigned Treatment (IAT) consisting of monotherapy or dual therapy with ganciclovir, valganciclovir, foscarnet, or cidofovir as dosed by the investigator (N=116) for up to 8-weeks following diagnosis of CMV infection/disease refractory to treatment (with or without genotypic resistance) with ganciclovir, valganciclovir, foscarnet or cidofovir. The mean treatment durations (SD) for LIVTENCITY and IAT were 48.6 (+- 13.82) and 31.2 (+- 16.91) days, respectively. The most common adverse events occurring in more than 10% of subjects receiving LIVTENCITY are outlined in Table 1.Table 1: Adverse Events (All Grades) Reported in >10% of Subjects in the LIVTENCITY Group in Trial 303ADVERSE EVENTLIVTENCITY = 234 (%)IATIAT (Investigator-Assigned Treatment) included monotherapy or dual therapy with ganciclovir, valganciclovir, foscarnet, or cidofovir as dosed by the investigator N=116 (%)Taste disturbancetaste disturbance includes the following reported preferred terms: ageusia, dysgeusia, hypogeusia and taste disorder 464Nausea2122Diarrhea1921Vomiting1416Fatigue129Similar proportions of subjects experienced serious adverse events (38% in the LIVTENCITY group and 37% in the IAT group). The most common serious adverse event in both treatment groups occurred in the Infections and Infestations System Organ Class (SOC) (23% in the LIVTENCITY group and 15% in the IAT group) with CMV infection and disease being the most common in both groups.A higher proportion of subjects in the IAT group discontinued study medication due to an adverse event compared to the LIVTENCITY group (32% in the IAT group versus 13% in the LIVTENCITY group). The most commonly reported causes that led to study drug discontinuation were neutropenia (9%) and acute kidney injury (5%) in the IAT group and dysgeusia, diarrhea, nausea, and recurrence of underlying disease (each reported at 1%) in the LIVTENCITY group.Taste disturbance occurred in 46% of subjects treated with LIVTENCITY. These events rarely led to discontinuation of LIVTENCITY (1%) and, for 37% of the subjects, these events resolved while on therapy (median duration 43 days; range to 59 days). For the subjects with ongoing taste disturbance after drug discontinuation, resolution occurred in 89%. In subjects with resolution of symptoms after drug discontinuation, the median duration of symptoms off treatment was days (range to 85 days).. Laboratory AbnormalitiesSelected laboratory abnormalities reported in subjects with refractory (with or without genotypic resistance) CMV infections in Trial 303 are presented in Table 2.Table 2: Selected Laboratory Abnormalities Reported in Trial 303Laboratory ParameterLIVTENCITY N=234 (%)IAT N=116 (%)Neutrophils (cells /uL) <5004 (2)4 (3) >=500 to <7507 (3)7 (6) >=750 to <1,00010 (4)6 (5)Hemoglobin (g/dL) <6.53 (1)1 (1) >=6.5 to <8.034 (15)23 (20) >=8.0 to <9.576 (32)33 (28)Platelets (cells /uL) <25,00011 (5)6 (5) >=25,000 to <50,00027 (12)10 (9) >=50,000 to <100,00041 (18)20 (17)Creatinine (mg/dL) >2.516 (7)12 (10) >1.5 to <=2.578 (33)29 (25).

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The most common adverse events (all grades, >10%) in subjects treated with LIVTENCITY were taste disturbance, nausea, diarrhea, vomiting, and fatigue. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals America, Inc. at 1-877-TAKEDA-7 (1-877-825-3327) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The safety of LIVTENCITY was evaluated in one Phase multi-center, randomized, open-label, active-control trial in which 352 adult transplant recipients were randomized, and treated with LIVTENCITY (N=234) or Investigator-Assigned Treatment (IAT) consisting of monotherapy or dual therapy with ganciclovir, valganciclovir, foscarnet, or cidofovir as dosed by the investigator (N=116) for up to 8-weeks following diagnosis of CMV infection/disease refractory to treatment (with or without genotypic resistance) with ganciclovir, valganciclovir, foscarnet or cidofovir. The mean treatment durations (SD) for LIVTENCITY and IAT were 48.6 (+- 13.82) and 31.2 (+- 16.91) days, respectively. The most common adverse events occurring in more than 10% of subjects receiving LIVTENCITY are outlined in Table 1.Table 1: Adverse Events (All Grades) Reported in >10% of Subjects in the LIVTENCITY Group in Trial 303ADVERSE EVENTLIVTENCITY = 234 (%)IATIAT (Investigator-Assigned Treatment) included monotherapy or dual therapy with ganciclovir, valganciclovir, foscarnet, or cidofovir as dosed by the investigator N=116 (%)Taste disturbancetaste disturbance includes the following reported preferred terms: ageusia, dysgeusia, hypogeusia and taste disorder 464Nausea2122Diarrhea1921Vomiting1416Fatigue129Similar proportions of subjects experienced serious adverse events (38% in the LIVTENCITY group and 37% in the IAT group). The most common serious adverse event in both treatment groups occurred in the Infections and Infestations System Organ Class (SOC) (23% in the LIVTENCITY group and 15% in the IAT group) with CMV infection and disease being the most common in both groups.A higher proportion of subjects in the IAT group discontinued study medication due to an adverse event compared to the LIVTENCITY group (32% in the IAT group versus 13% in the LIVTENCITY group). The most commonly reported causes that led to study drug discontinuation were neutropenia (9%) and acute kidney injury (5%) in the IAT group and dysgeusia, diarrhea, nausea, and recurrence of underlying disease (each reported at 1%) in the LIVTENCITY group.Taste disturbance occurred in 46% of subjects treated with LIVTENCITY. These events rarely led to discontinuation of LIVTENCITY (1%) and, for 37% of the subjects, these events resolved while on therapy (median duration 43 days; range to 59 days). For the subjects with ongoing taste disturbance after drug discontinuation, resolution occurred in 89%. In subjects with resolution of symptoms after drug discontinuation, the median duration of symptoms off treatment was days (range to 85 days).. Laboratory AbnormalitiesSelected laboratory abnormalities reported in subjects with refractory (with or without genotypic resistance) CMV infections in Trial 303 are presented in Table 2.Table 2: Selected Laboratory Abnormalities Reported in Trial 303Laboratory ParameterLIVTENCITY N=234 (%)IAT N=116 (%)Neutrophils (cells /uL) <5004 (2)4 (3) >=500 to <7507 (3)7 (6) >=750 to <1,00010 (4)6 (5)Hemoglobin (g/dL) <6.53 (1)1 (1) >=6.5 to <8.034 (15)23 (20) >=8.0 to <9.576 (32)33 (28)Platelets (cells /uL) <25,00011 (5)6 (5) >=25,000 to <50,00027 (12)10 (9) >=50,000 to <100,00041 (18)20 (17)Creatinine (mg/dL) >2.516 (7)12 (10) >1.5 to <=2.578 (33)29 (25).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Two-year carcinogenicity studies were conducted in mice and rats administered oral doses up to 150 and 100 mg/kg/day, respectively. Maribavir was not carcinogenic in rats at any dose tested, corresponding to maribavir exposures less than human exposure at the RHD. At 150 mg/kg/day in male mice only, an increased incidence of hemangioma, hemangiosarcoma, and combined hemangioma/hemangiosarcoma was observed across multiple tissues, at exposures less than the human exposure at the RHD. There were no carcinogenic findings in male mice at <=75 mg/kg/day and female mice at any dose.. MutagenicityMaribavir was negative in 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 FertilityAlthough 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 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)].

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. LIVTENCITY is an antiviral drug against human CMV [see Microbiology (12.4)].. 12.2 Pharmacodynamics. Exposure-responseIn 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 Trial 303 that evaluated 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 ElectrophysiologyAt 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.. 12.3 Pharmacokinetics. LIVTENCITY pharmacological activity is due to the parent drug. Following oral administration, plasma maribavir exposure (Cmax and AUC) increased approximately dose-proportionally following single dose of 50 to 1600 mg (0.125 to four times the recommended dose) and multiple doses up to 2400 mg per day (three times the recommended daily dose). Maribavir PK is time-independent. With twice-daily dosing, steady state is reached within days, with mean accumulation ratios of Cmax and AUC ranging from 1.37 to 1.47.The pharmacokinetic properties of maribavir following administration of LIVTENCITY are displayed in Table 4. The multiple-dose pharmacokinetic parameters are provided in Table 5.Table 4: Pharmacokinetic Properties of MaribavirAbsorptionWhen taken orally with moderate fat meal versus fasted, the AUC0- and Cmax (geometric mean ratio [90% CI] of maribavir are 0.864 [0.804, 0.929] and 0.722 [0.656, 0.793], respectively. Tmax (h), median1.0 to 3.0DistributionMean apparent steady-state volume of distribution (Vss, L)27.3% bound to human plasma proteins 98.0 across the concentration range of 0.05-200 ug/mLBlood-to plasma ratio1.37Elimination Major route of eliminationHepatic metabolismHalf-life (t1/2) in transplant patients (h), mean4.32Oral clearance (CL/F) in transplant patients (L/h), mean2.85Metabolism Metabolic pathwaysIn vitro studies have shown that maribavir is biotransformed into major circulating inactive metabolite: VP 44469 (N-dealkylated metabolite), with metabolic ratio of 0.15 0.20 CYP3A4 (major) and CYP1A2 (minor)Excretion% of dose excreted as total 14C (unchanged drug) in urineDosing in mass balance study: single-dose administration of [14C] maribavir oral solution 400 mg containing 200 nCi of total radioactivity. 61 (<2)% of dose excreted as total 14C (unchanged drug) in feces 14 (5.7)Table 5. Multiple-Dose Pharmacokinetic Parameters of MaribavirGeometric Mean (%CV)Pharmacokinetic parameter values based on post-hoc estimates from maribavir population pharmacokinetic model in transplant patients with CMV receiving 400 mg of LIVTENCITY twice daily with or without food. AUC0-tau tau is maribavir dosing interval: 12 hours (ugh/mL)Cmax (ug/mL)Ctau (ug/mL)CV Coefficient of Variation; Cmax Maximum concentration; AUC0-tau Area under the time concentration curve over dosing interval; Ctau Concentration at the end of dosing interval.128 (50.7%)17.2 (39.3%)4.90 (89.7%). Specific PopulationsThere 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), mild to severe renal impairment (measured creatinine clearance ranging from 12 to 70 mL/min), or mild to moderate hepatic impairment (Child-Pugh Class or B).. Pediatric PatientsThe pharmacokinetics of maribavir in patients less than 18 years of age have not been evaluated.Using modeling and simulation, the recommended dosing regimen is expected to result in comparable steady-state plasma exposures of maribavir in patients 12 years of age and older and weighing at least 35 kg as observed in adults [see Use in Specific Populations (8.4)]. Drug InteractionsBased 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 co-administered 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 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 co-administered for pharmacokinetic interactions. The effects of co-administration of other drugs on the pharmacokinetics of maribavir are summarized in Table 6, and the effects of maribavir on the pharmacokinetics of co-administered drugs are summarized in Table 7.Dosing recommendations as result of established and other potentially significant drug-drug interactions with LIVTENCITY are provided in Table [see Drug Interactions (7.3)].Table 6: Changes in Pharmacokinetics of LIVTENCITY in the Presence of Co-administered DrugsCo-administered Drug and RegimenLIVTENCITY RegimenNGeometric Mean Ratio (90% CI) of LIVTENCITY PK with/without Co-administered Drug [No Effect=1.00]AUCCmax Ctau tau is maribavir dosing interval: 12 hours AnticonvulsantsCarbamazepineBased on physiologically based pharmacokinetic modeling results from 10 trials of 20 subjects each. The maribavir dosing regimen and geometric mean ratios (5th percentile, 95th percentile) correspond to dose-adjusted maribavir with inducer vs 400 mg twice daily without inducer. 400 mg once daily800 mg twice daily 400 mg twice daily2001.40 (1.09, 1.67)1.53 (1.22, 1.79)1.05 (0.71, 1.40)Phenobarbital 100 mg once daily1,200 mg twice daily 400 mg twice daily2001.80 (1.18, 2.35)2.17 (1.69, 2.57)0.94 (0.22, 1.97)Phenytoin 300 mg once daily1,200 mg twice daily 400 mg twice daily2001.70 (1.06, 2.46)2.05 (1.49, 2.63)0.89 (0.26, 2.04)AntimycobacterialsRifampin600 mg once daily400 mg twice daily140.40 (0.36, 0.44)0.61 (0.52, 0.72)0.18 (0.14, 0.25)AntifungalsKetoconazole400 mg single dose400 mg single dose191.53 (1.44, 1.63)1.10 (1.01, 1.19)-AntacidsAluminum hydroxide and magnesium hydroxide antacid20 mLContaining 800 mg aluminum hydroxide and 800 mg magnesium hydroxide single dose100 mg single dose150.89 (0.83, 0.96)0.84 (0.75, 0.94)-Table 7: Drug Interactions: Changes in Pharmacokinetics for Co-administered Drug in the Presence of 400 mg Twice Daily LIVTENCITYCo-administered Drug and RegimenNGeometric Mean Ratio (90% CI) of Co-administered Drug PK with/without LIVTENCITY [No Effect=1.00]AUCCmax Ctau ImmunosuppressantsTacrolimusstable dose, twice daily (total daily dose: 0.5-16 mg)201.51 (1.39, 1.65)1.38 (1.20, 1.57)1.57 (1.41, 1.74)P-gp substrateDigoxin0.5 mg single dose181.21 (1.10, 1.32)1.25 (1.13, 1.38)-. 12.4 Microbiology. Mechanism of ActionThe 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 biochemical assay with an IC50 value of 0.003 uM. Maribavir and its 5-mono- and 5-triphosphate derivatives at 100 uM had no significant effect on the incorporation of deoxynucleoside triphosphates by human CMV DNA polymerase. At concentration of 100 uM, neither maribavir nor its 5-triphosphate derivative inhibited CMV DNA polymerase delta, however the 5-monophosphate derivative inhibited incorporation by polymerase delta of all natural dNTPs by approximately 55%.. Antiviral ActivityMaribavir 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 uM 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 uM (n=10, range 0.03-0.13 uM) and 0.28 uM (n=10, range 0.12-0.56 uM) using DNA hybridization and plaque reduction assays, respectively. No significant difference in EC50 values across the four human CMV glycoprotein genotypes (N 2, 1, 4, and for gB1, gB2, gB3, and gB4, respectively) was seen.. Combination Antiviral ActivityWhen 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.. Viral Resistance. In Cell CultureSelection of maribavir resistant virus in cell culture and genotypic plus phenotypic characterization of these has identified amino acid substitutions that confer reduced susceptibility to maribavir. Substitutions identified in pUL97 include L337M, V353A, L397R, T409M, and H411L/N/Y. These substitutions confer reductions in susceptibility that range from 3.5-fold to >200-fold. Substitutions were also identified in pUL27:R233S, W362R, W153R, L193F, A269T, V353E, L426F, E22stop, W362stop, 218delC, and 301-311del. These substitutions confer reductions in susceptibility that range from 1.7- to 4.8-fold.. In Clinical StudiesIn Phase Study 202 evaluating maribavir in 120 hematopoietic stem cell transplant (HSCT) or solid organ transplant (SOT) recipients with phenotypic resistance to valganciclovir/ganciclovir, DNA sequence analysis of select region of pUL97 (amino acids 270 to 482) and pUL27 (amino acids 108 to 424) was performed on 34 paired virologic failure samples. There were 25 patients with treatment-emergent maribavir resistance-associated substitution(s) in pUL97 F342Y (4.5-fold reduction in susceptibility), T409M (78-fold reduction), H411L/Y (69- and 12-fold reduction) and/or C480F (224-fold reduction).In Phase Study 303 evaluating maribavir in patients with phenotypic resistance to valganciclovir/ganciclovir, DNA sequence analysis of the entire coding regions of pUL97 and pUL27 was performed on 134 paired sequences from maribavir-treated patients. The treatment-emergent pUL97 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 58 subjects (47 subjects were on-treatment failures and 11 subjects were relapsers). One subject with the pUL27 L193F substitution (2.6-fold reduced susceptibility to maribavir) at baseline did not meet the primary endpoint.. Cross ResistanceCross-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, 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Treatment of Adults with Post-transplant CMV Infection/Disease That Is Refractory (with or without Genotypic Resistance) to Ganciclovir, Valganciclovir, Cidofovir, or Foscarnet LIVTENCITY was evaluated in Phase 3, multicenter, randomized, open-label, active-controlled superiority trial (NCT02931539, Trial 303) to assess the efficacy and safety of LIVTENCITY compared to Investigator-Assigned Treatment (IAT) (ganciclovir, valganciclovir, foscarnet, or cidofovir) in 352 HSCT or SOT recipients with CMV infections that were refractory to treatment with ganciclovir, valganciclovir, foscarnet, or cidofovir, including CMV infections with or without confirmed resistance to or more of the IATs. Subjects with CMV disease involving the central nervous system, including the retina, were excluded from the study.Subjects were stratified by transplant type (HSCT or SOT) and screening CMV DNA levels and then randomized in 2:1 allocation ratio to receive either LIVTENCITY 400 mg twice daily or IAT as dosed by the investigator for up to weeks. After completion of the treatment period, subjects entered 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. The most common treatment used in the IAT arm was foscarnet which was administered in 47 (41%) subjects followed by ganciclovir or valganciclovir, each administered in 28 (24%) subjects. Cidofovir was administered in subjects, the combination of foscarnet and valganciclovir in subjects and the combination of foscarnet and ganciclovir in subjects. Baseline disease characteristics are summarized in Table below.Table 8: Summary of Baseline Disease Characteristics in Trial 303CharacteristicLIVTENCITY 400 mg Twice DailyIATN=235 (%)N=117 (%)CMV=cytomegalovirus, DNA=deoxyribonucleic acid, HSCT=hematopoietic stem cell transplant, IAT=investigator assigned anti-CMV treatment, N=number of patients, SOT=solid organ transplantTransplant type HSCT93 (40)48 (41) SOT142 (60)69 (59) Kidney74 (52)32 (46) Lung40 (28)22 (32) Heart14 (10)9 (13) Other (multiple, liver, pancreas, intestine)14 (10)6 (9)CMV DNA levels Low (<9,100 IU/mL)153 (65)85 (73) Intermediate (>=9,100 to <91,000 IU/mL)68 (29)25 (21) High (>=91,000 IU/mL)14 (6)7 (6)Confirmed symptomatic CMV infection at baseline No214 (91)109 (93) Yesone of the subjects had both CMV syndrome and disease but was counted for CMV disease only 21 (9)8 (7) CMV syndrome (SOT only)9 (43)7 (88) Tissue Invasive disease12 (57) (13). Primary Efficacy EndpointThe primary efficacy endpoint was confirmed CMV DNA level LLOQ (i.e. <137 IU/mL) as assessed by COBAS(R) AmpliPrep/COBAS(R) TaqMan(R) 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 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 9.Table 9: Primary Efficacy Endpoint Analysis at Week (Randomized Set) in Trial 303LIVTENCITY 400 mgIATTwice DailyN=235 (%)N=117 (%)CI=confidence interval; CMV=cytomegalovirus; IAT=investigator-assigned anti-CMV treatment; N=number of patients.Primary Endpoint: Confirmed CMV DNA Level LLOQ at Week 8Confirmed CMV DNA level LLOQ at the end of Week (2 consecutive samples separated by at least days with DNA levels LLOQ [ie, <137 IU/mL]). Responders131 (56)28 (24)Adjusted difference in proportion of responders (95% CI)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 DNA concentration. Only those with both stratification factors were included in the computation. 33 (23, 43)p-value: adjusted <0.001The reasons for failure to meet the primary endpoint are summarized in Table 10.Table 10: Analysis of Failures for Primary Efficacy EndpointOutcome at Week 8LIVTENCITY N=235 (%)IAT N=117 (%)CMV=Cytomegalovirus, IAT=Investigator-assigned anti-CMV Treatment, MBV=maribavir.Percentages are based on the number of subjects in the Randomized Set.Responders (Confirmed DNA Level LLOQ)Confirmed CMV DNA level LLOQ at the end of Week (2 consecutive samples separated by at least days with DNA levels LLOQ [ie, <137 IU/mL]). 131 (56)28 (24)Non-responders:104 (44)89 (76) Due to virologic failureCMV DNA breakthrough=achieved confirmed CMV DNA level LLOQ and subsequently became detectable.: 80 (34)42 (36) oCMV DNA never LLOQ oCMV DNA breakthrough48 (20) 32 (14)35 (30) (6) Due to drug/study discontinuation: 21 (9)44 (38) oAdverse events oDeaths oWithdrawal of consent oOther reasonsOther reasons= other reasons not including adverse events, deaths and lack of efficacy, withdrawal of consent, and non-compliance.8 (3) 10 (4) (<1) (1)26 (22) (3) (8) (5) Due to other reasons but remained on studyIncludes subjects who completed study assigned treatment and were non-responders. (1)3 (3)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 11).Table 11: Responders by Subgroup in Trial 303LIVTENCITY 400 mg Twice DailyIATN=235N=117n/N%n/N%Transplant type SOT79/1425618/6926 HSCT52/935610/4821Baseline CMV DNA viral load Low (<9,100 IU/mL)95/1536221/8525 Intermediate (>=9,100 to <91,000 IU/mL)32/68475/2520 >=9,100 to <50,000 IU/mL29/59494/2020 >=50,000 to <91,000 IU/mL3/9331/520 High (>=91,000 IU/mL)4/14292/729Genotypic resistance to other anti-CMV agents Yes76/1216314/6920 No42/964411/3432CMV syndrome/disease at baseline Yes10/21481/813 No121/2145727/10925Age Group 18 to 44 years28/55518/3225 45 to 64 years71/1265619/6928 >=65 years32/54591/166. oCMV DNA never LLOQ. oCMV DNA breakthrough. oAdverse events. oDeaths. oWithdrawal of consent. oOther reasonsOther reasons= other reasons not including adverse events, deaths and lack of efficacy, withdrawal of consent, and non-compliance.. Secondary EndpointsTable 12 shows results of the secondary endpoint, achievement of CMV DNA level LLOQ and symptom controla at Week with maintenance through Week 16.Table 12. Achievement of CMV DNA Level LLOQ and CMV Infection Symptom Control at Week 8, With Maintenance Through Week 16CMV infection 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 were asymptomatic at baseline LIVTENCITY 400 mgIAT Twice Daily N=235 (%)N=117 (%)Responders44 (19)12 (10)Adjusted difference in proportion of responders (95% CI)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 DNA concentration. Only those with both stratification factors were included in the computation. (2,17)p-value: adjusted 0.013Virologic relapse during follow-up period: After the end of treatment phase, 65/131 (50%) of subjects in the LIVTENCITY group and 11/28 (39%) subjects in the IAT group who achieved CMV DNA level LLOQ experienced virologic relapse during the follow-up period. Most of the relapses 58/65 (89%) in LIVTENCITY group and 11/11 (100% in IAT group)] occurred within weeks after study drug discontinuation; and the median time to relapse after CMV DNA level LLOQ was 15 days (range 7, 71) in the LIVTENCITY group and 15 days (range 7, 29) in the IAT group [see Warnings and Precautions (5.2) and Microbiology (12.4)].New onset symptomatic CMV infection: For the entire study period, similar percentage of subjects in each treatment group developed new onset symptomatic CMV infection (LIVTENCITY 6% [14/235]; IAT 6% [7/113]).. Overall mortality: All-cause mortality was assessed for the entire study period. similar percentage of subjects in each treatment group died during the trial (LIVTENCITY 11% [27/235]; IAT 11% [13/117]).

DESCRIPTION SECTION.

11 DESCRIPTION. LIVTENCITY tablets contain maribavir, benzimidazole riboside CMV pUL97 protein kinase inhibitor. The chemical name of maribavir is 5,6-Dichloro-N-(1-methylethyl)-1--L-ribofuranosyl-1H-benzimidazol-2-amine and the structural formula is:The molecular formula for maribavir is C15H19Cl2N3O4 and its molecular weight is 376.23.Each 200 mg tablet for oral administration contains 200 mg maribavir and the following inactive ingredients: FD&C Blue 1, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, sodium starch glycolate, titanium dioxide, and talc.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. 400 mg (two 200 mg tablets) orally twice daily with or without food. (2.1, 2.2, 8.4). 2.1 Recommended Dosage The recommended dosage in adults and pediatric patients (12 years of age and older and weighing at least 35 kg) is 400 mg (two 200 mg tablets) taken orally twice daily with or without food [see Use in Specific Populations (8.4), Clinical Pharmacology (12.3), Clinical Studies (14)].. 2.2 Dosage Adjustment When Co-administered with Anticonvulsants. If LIVTENCITY is co-administered with carbamazepine, increase the dosage of LIVTENCITY to 800 mg twice daily [see Drug Interactions (7.3)]. If LIVTENCITY is co-administered with phenytoin or phenobarbital, increase the dosage of LIVTENCITY to 1,200 mg twice daily [see Drug Interactions (7.3)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Tablet: 200 mg, blue, oval shaped convex tablet debossed with SHP on one side and 620 on the other side.. Tablets: 200 mg of maribavir. (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Refer to the full prescribing information for important drug interactions with LIVTENCITY. (5.1, 5.3, 7)Coadministration with strong CYP3A4 inducers: not recommended. Refer to full prescribing information for dosage modification when coadministered with certain anticonvulsants. (2.2, 7.3). Refer to the full prescribing information for important drug interactions with LIVTENCITY. (5.1, 5.3, 7). Coadministration with strong CYP3A4 inducers: not recommended. Refer to full prescribing information for dosage modification when coadministered with certain anticonvulsants. (2.2, 7.3). 7.1Reduced Antiviral Activity When Coadministered with Ganciclovir or Valganciclovir. LIVTENCITY is not recommended to be coadministered with valganciclovir/ganciclovir (vGCV/GCV). LIVTENCITY may antagonize the antiviral activity of ganciclovir and valganciclovir by inhibiting human CMV pUL97 kinase, which is required for activation/phosphorylation of ganciclovir and valganciclovir [see Warnings and Precautions (5.1) and Microbiology (12.4)].. 7.2 Potential for Other Drugs to Affect LIVTENCITY. Maribavir is substrate of CYP3A4. Coadministration of LIVTENCITY with strong inducers of CYP3A4 is not recommended, except for selected anticonvulsants [see Dosage and Administration (2.2) and Drug Interactions (7.3)].. 7.3 Potential for LIVTENCITY to Affect Other Drugs. Maribavir is weak inhibitor of CYP3A4, and an inhibitor of P-gp and breast cancer resistance protein (BCRP). Co-administration of LIVTENCITY with drugs that are sensitive substrates of CYP3A, P-gp and BCRP may result in clinically relevant increase in plasma concentrations of these substrates (see Table 3). Table provides list of established or potentially clinically significant drug interactions, based on either clinical drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or decrease in efficacy [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].Table 3: Established and Other Potentially Significant Drug InteractionsThis table is not all inclusive. Concomitant Drug Class: Drug NameEffect on ConcentrationClinical Comments=decrease, increaseAntiarrhythmics DigoxinThe interaction between LIVTENCITY and the concomitant drug was evaluated in clinical study [see Clinical Pharmacology (12.3)]. DigoxinUse caution when LIVTENCITY and digoxin are coadministered. Monitor serum digoxin concentrations. The dose of digoxin may need to be reduced when coadministered with LIVTENCITYRefer to the respective prescribing information..Anticonvulsants Carbamazepine MaribavirA dose adjustment of LIVTENCITY to 800 mg twice daily is recommended when co-administered with carbamazepine. Phenobarbital MaribavirA dose adjustment of LIVTENCITY to 1,200 mg twice daily is recommended when co-administration with phenobarbital. Phenytoin MaribavirA dose adjustment of LIVTENCITY to 1,200 mg twice daily is recommended when co-administration with phenytoin.Antimycobacterials Rifabutin MaribavirCo-administration of LIVTENCITY and rifabutin is not recommended due to potential for decrease in efficacy of LIVTENCITY. Rifampin MaribavirCo-administration of LIVTENCITY and rifampin is not recommended due to potential for decrease in efficacy of LIVTENCITY.Herbal Products St. Johns wort MaribavirCo-administration of LIVTENCITY and St. Johns wort is not recommended due to potential for decrease in efficacy of LIVTENCITY. HMG-CoA Reductase Inhibitors Rosuvastatin RosuvastatinThe patient should be closely monitored for rosuvastatin-related events, especially the occurrence of myopathy and rhabdomyolysis Immunosuppressants Cyclosporine CyclosporineFrequently monitor cyclosporine levels throughout treatment with LIVTENCITY, especially following initiation and after discontinuation of LIVTENCITY and adjust dose, as needed. Everolimus EverolimusFrequently monitor everolimus levels throughout treatment with LIVTENCITY, especially following initiation and after discontinuation of LIVTENCITY and adjust dose, as needed. Sirolimus SirolimusFrequently monitor sirolimus levels throughout treatment with LIVTENCITY, especially following initiation and after discontinuation of LIVTENCITY and adjust dose, as needed. Tacrolimus TacrolimusFrequently monitor tacrolimus levels throughout treatment with LIVTENCITY, especially following initiation and after discontinuation of LIVTENCITY and adjust dose, as needed.. 7.4 Drugs without Clinically Significant Interactions with LIVTENCITY. No clinically significant interactions were observed in clinical drug-drug interaction studies of LIVTENCITY and ketoconazole, antacid, caffeine, S-warfarin, voriconazole, dextromethorphan, or midazolam [see Clinical Pharmacology (12.3)].

GERIATRIC USE SECTION.

8.5 Geriatric Use. No dosage adjustment is required for patients over 65 years of age based on the results from population pharmacokinetics analysis [see Clinical Pharmacology (12.3)] and efficacy and safety data from the clinical studies. In the clinical Study 303, 54 patients aged 65 years and over were treated with LIVTENCITY. Safety, effectiveness, and pharmacokinetics were consistent between elderly patients (>=65 years) and younger patients (<65 years).

HEPATIC IMPAIRMENT SUBSECTION.

8.7Impaired Hepatic Function. No dose adjustment of LIVTENCITY is needed for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment [see Clinical Pharmacology (12.3)]. Administration of LIVTENCITY in patients with severe hepatic impairment has not been studied.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Tablet: 200 mg, blue, oval shaped convex tablet debossed with SHP on one side and 620 on the other side. They are supplied as follows:Bottles of 28 tablets with child-resistant caps (NDC 64764-800-28)Bottles of 56 tablets with child-resistant caps (NDC 64764-800-56). Storage and HandlingStore at 20C to 25C (68F to 77F), brief exposure to 15C to 30C (59F to 86F) permitted [see USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. LIVTENCITY is indicated for the treatment of adults and pediatric patients (12 years of age and older and weighing at least 35 kg) with post-transplant cytomegalovirus (CMV) infection/disease that is refractory to treatment (with or without genotypic resistance) with ganciclovir, valganciclovir, cidofovir or foscarnet [see Use in Specific Populations (8.4), Clinical Studies (14)].. LIVTENCITY is cytomegalovirus (CMV) pUL97 kinase inhibitor indicated for the treatment of adults and pediatric patients (12 years of age and older and weighing at least 35 kg) with post-transplant CMV infection/disease that is refractory to treatment (with or without genotypic resistance) with ganciclovir, valganciclovir, cidofovir or foscarnet. (1, 8.4 ).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).Inform patients that LIVTENCITY may interact with other drugs. Advise patients to report to their healthcare provider the use of any other medication [see Warnings and Precautions (5.1 and 5.3), Drug Interactions (7)].

LACTATION SECTION.

8.2 Lactation. Risk SummaryIt 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 mothers clinical need for LIVTENCITY and any potential adverse effects to the breast-fed child.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. LIVTENCITY is an antiviral drug against human CMV [see Microbiology (12.4)].

MICROBIOLOGY SECTION.

12.4 Microbiology. Mechanism of ActionThe 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 biochemical assay with an IC50 value of 0.003 uM. Maribavir and its 5-mono- and 5-triphosphate derivatives at 100 uM had no significant effect on the incorporation of deoxynucleoside triphosphates by human CMV DNA polymerase. At concentration of 100 uM, neither maribavir nor its 5-triphosphate derivative inhibited CMV DNA polymerase delta, however the 5-monophosphate derivative inhibited incorporation by polymerase delta of all natural dNTPs by approximately 55%.. Antiviral ActivityMaribavir 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 uM 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 uM (n=10, range 0.03-0.13 uM) and 0.28 uM (n=10, range 0.12-0.56 uM) using DNA hybridization and plaque reduction assays, respectively. No significant difference in EC50 values across the four human CMV glycoprotein genotypes (N 2, 1, 4, and for gB1, gB2, gB3, and gB4, respectively) was seen.. Combination Antiviral ActivityWhen 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.. Viral Resistance. In Cell CultureSelection of maribavir resistant virus in cell culture and genotypic plus phenotypic characterization of these has identified amino acid substitutions that confer reduced susceptibility to maribavir. Substitutions identified in pUL97 include L337M, V353A, L397R, T409M, and H411L/N/Y. These substitutions confer reductions in susceptibility that range from 3.5-fold to >200-fold. Substitutions were also identified in pUL27:R233S, W362R, W153R, L193F, A269T, V353E, L426F, E22stop, W362stop, 218delC, and 301-311del. These substitutions confer reductions in susceptibility that range from 1.7- to 4.8-fold.. In Clinical StudiesIn Phase Study 202 evaluating maribavir in 120 hematopoietic stem cell transplant (HSCT) or solid organ transplant (SOT) recipients with phenotypic resistance to valganciclovir/ganciclovir, DNA sequence analysis of select region of pUL97 (amino acids 270 to 482) and pUL27 (amino acids 108 to 424) was performed on 34 paired virologic failure samples. There were 25 patients with treatment-emergent maribavir resistance-associated substitution(s) in pUL97 F342Y (4.5-fold reduction in susceptibility), T409M (78-fold reduction), H411L/Y (69- and 12-fold reduction) and/or C480F (224-fold reduction).In Phase Study 303 evaluating maribavir in patients with phenotypic resistance to valganciclovir/ganciclovir, DNA sequence analysis of the entire coding regions of pUL97 and pUL27 was performed on 134 paired sequences from maribavir-treated patients. The treatment-emergent pUL97 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 58 subjects (47 subjects were on-treatment failures and 11 subjects were relapsers). One subject with the pUL27 L193F substitution (2.6-fold reduced susceptibility to maribavir) at baseline did not meet the primary endpoint.. Cross ResistanceCross-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, 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Two-year carcinogenicity studies were conducted in mice and rats administered oral doses up to 150 and 100 mg/kg/day, respectively. Maribavir was not carcinogenic in rats at any dose tested, corresponding to maribavir exposures less than human exposure at the RHD. At 150 mg/kg/day in male mice only, an increased incidence of hemangioma, hemangiosarcoma, and combined hemangioma/hemangiosarcoma was observed across multiple tissues, at exposures less than the human exposure at the RHD. There were no carcinogenic findings in male mice at <=75 mg/kg/day and female mice at any dose.. MutagenicityMaribavir was negative in 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 FertilityAlthough 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 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)].

OVERDOSAGE SECTION.

10 OVERDOSAGE. There is no known specific antidote for LIVTENCITY. 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 LIVTENCITY, dialysis is unlikely to reduce plasma concentrations of LIVTENCITY significantly.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 200 mg Bottle Carton. NDC 64764-800-28LIVTENCITY (maribavir) tablets 200 mgRx Only 28 TabletsFor Oral UseTakeda. PRINCIPAL DISPLAY PANEL 200 mg Bottle Carton.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The recommended dosing regimen in pediatric patients 12 years of age and older and weighing at least 35 kg is the same as that in adults. Use of LIVTENCITY in this age group is based on the following:Evidence from controlled studies of LIVTENCITY in adultsPopulation pharmacokinetic (PK) modeling and simulation demonstrating that age and body weight had no clinically meaningful effect on plasma exposures of LIVTENCITYLIVTENCITY exposure is expected to be similar between adults and children 12 years of age and older and weighing at least 35 kgThe course of the disease is similar between adults and pediatric patients to allow extrapolation of data in adults to pediatric patients [see Dosage and Administration (2.2), Clinical Pharmacology (12.3) and Clinical Studies (14)] The safety and effectiveness of LIVTENCITY have not been established in children younger than 12 years of age.. Evidence from controlled studies of LIVTENCITY in adults. Population pharmacokinetic (PK) modeling and simulation demonstrating that age and body weight had no clinically meaningful effect on plasma exposures of LIVTENCITY. LIVTENCITY exposure is expected to be similar between adults and children 12 years of age and older and weighing at least 35 kg. The course of the disease is similar between adults and pediatric patients to allow extrapolation of data in adults to pediatric patients [see Dosage and Administration (2.2), Clinical Pharmacology (12.3) and Clinical Studies (14)].

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Exposure-responseIn 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 Trial 303 that evaluated 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 ElectrophysiologyAt 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.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. LIVTENCITY pharmacological activity is due to the parent drug. Following oral administration, plasma maribavir exposure (Cmax and AUC) increased approximately dose-proportionally following single dose of 50 to 1600 mg (0.125 to four times the recommended dose) and multiple doses up to 2400 mg per day (three times the recommended daily dose). Maribavir PK is time-independent. With twice-daily dosing, steady state is reached within days, with mean accumulation ratios of Cmax and AUC ranging from 1.37 to 1.47.The pharmacokinetic properties of maribavir following administration of LIVTENCITY are displayed in Table 4. The multiple-dose pharmacokinetic parameters are provided in Table 5.Table 4: Pharmacokinetic Properties of MaribavirAbsorptionWhen taken orally with moderate fat meal versus fasted, the AUC0- and Cmax (geometric mean ratio [90% CI] of maribavir are 0.864 [0.804, 0.929] and 0.722 [0.656, 0.793], respectively. Tmax (h), median1.0 to 3.0DistributionMean apparent steady-state volume of distribution (Vss, L)27.3% bound to human plasma proteins 98.0 across the concentration range of 0.05-200 ug/mLBlood-to plasma ratio1.37Elimination Major route of eliminationHepatic metabolismHalf-life (t1/2) in transplant patients (h), mean4.32Oral clearance (CL/F) in transplant patients (L/h), mean2.85Metabolism Metabolic pathwaysIn vitro studies have shown that maribavir is biotransformed into major circulating inactive metabolite: VP 44469 (N-dealkylated metabolite), with metabolic ratio of 0.15 0.20 CYP3A4 (major) and CYP1A2 (minor)Excretion% of dose excreted as total 14C (unchanged drug) in urineDosing in mass balance study: single-dose administration of [14C] maribavir oral solution 400 mg containing 200 nCi of total radioactivity. 61 (<2)% of dose excreted as total 14C (unchanged drug) in feces 14 (5.7)Table 5. Multiple-Dose Pharmacokinetic Parameters of MaribavirGeometric Mean (%CV)Pharmacokinetic parameter values based on post-hoc estimates from maribavir population pharmacokinetic model in transplant patients with CMV receiving 400 mg of LIVTENCITY twice daily with or without food. AUC0-tau tau is maribavir dosing interval: 12 hours (ugh/mL)Cmax (ug/mL)Ctau (ug/mL)CV Coefficient of Variation; Cmax Maximum concentration; AUC0-tau Area under the time concentration curve over dosing interval; Ctau Concentration at the end of dosing interval.128 (50.7%)17.2 (39.3%)4.90 (89.7%). Specific PopulationsThere 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), mild to severe renal impairment (measured creatinine clearance ranging from 12 to 70 mL/min), or mild to moderate hepatic impairment (Child-Pugh Class or B).. Pediatric PatientsThe pharmacokinetics of maribavir in patients less than 18 years of age have not been evaluated.Using modeling and simulation, the recommended dosing regimen is expected to result in comparable steady-state plasma exposures of maribavir in patients 12 years of age and older and weighing at least 35 kg as observed in adults [see Use in Specific Populations (8.4)]. Drug InteractionsBased 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 co-administered 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 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 co-administered for pharmacokinetic interactions. The effects of co-administration of other drugs on the pharmacokinetics of maribavir are summarized in Table 6, and the effects of maribavir on the pharmacokinetics of co-administered drugs are summarized in Table 7.Dosing recommendations as result of established and other potentially significant drug-drug interactions with LIVTENCITY are provided in Table [see Drug Interactions (7.3)].Table 6: Changes in Pharmacokinetics of LIVTENCITY in the Presence of Co-administered DrugsCo-administered Drug and RegimenLIVTENCITY RegimenNGeometric Mean Ratio (90% CI) of LIVTENCITY PK with/without Co-administered Drug [No Effect=1.00]AUCCmax Ctau tau is maribavir dosing interval: 12 hours AnticonvulsantsCarbamazepineBased on physiologically based pharmacokinetic modeling results from 10 trials of 20 subjects each. The maribavir dosing regimen and geometric mean ratios (5th percentile, 95th percentile) correspond to dose-adjusted maribavir with inducer vs 400 mg twice daily without inducer. 400 mg once daily800 mg twice daily 400 mg twice daily2001.40 (1.09, 1.67)1.53 (1.22, 1.79)1.05 (0.71, 1.40)Phenobarbital 100 mg once daily1,200 mg twice daily 400 mg twice daily2001.80 (1.18, 2.35)2.17 (1.69, 2.57)0.94 (0.22, 1.97)Phenytoin 300 mg once daily1,200 mg twice daily 400 mg twice daily2001.70 (1.06, 2.46)2.05 (1.49, 2.63)0.89 (0.26, 2.04)AntimycobacterialsRifampin600 mg once daily400 mg twice daily140.40 (0.36, 0.44)0.61 (0.52, 0.72)0.18 (0.14, 0.25)AntifungalsKetoconazole400 mg single dose400 mg single dose191.53 (1.44, 1.63)1.10 (1.01, 1.19)-AntacidsAluminum hydroxide and magnesium hydroxide antacid20 mLContaining 800 mg aluminum hydroxide and 800 mg magnesium hydroxide single dose100 mg single dose150.89 (0.83, 0.96)0.84 (0.75, 0.94)-Table 7: Drug Interactions: Changes in Pharmacokinetics for Co-administered Drug in the Presence of 400 mg Twice Daily LIVTENCITYCo-administered Drug and RegimenNGeometric Mean Ratio (90% CI) of Co-administered Drug PK with/without LIVTENCITY [No Effect=1.00]AUCCmax Ctau ImmunosuppressantsTacrolimusstable dose, twice daily (total daily dose: 0.5-16 mg)201.51 (1.39, 1.65)1.38 (1.20, 1.57)1.57 (1.41, 1.74)P-gp substrateDigoxin0.5 mg single dose181.21 (1.10, 1.32)1.25 (1.13, 1.38)-.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryNo adequate human data are available to establish whether LIVTENCITY poses 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. Animal DataIn combined fertility and embryofetal development study, maribavir was administered to male and female rats at oral doses of 100, 200, or 400 mg/kg/day. Females were dosed for 15 consecutive days prior to pairing, throughout pairing, and up to gestation day (GD) 17, while males were dosed 29 days prior to mating and throughout mating. decrease in the number of viable fetuses and increase in early resorptions and post-implantation losses were observed at >=100 mg/kg/day (at exposures approximately half the human exposure at the RHD). Intermittent reduced body weight gain was observed in pregnant animals at >=200 mg/kg/day. Maribavir had no effect on embryo-fetal growth or development at dose levels up to 400 mg/kg/day, at exposures similar to those observed in humans at the RHD.No significant toxicological effects on embryo-fetal growth or development were observed in rabbits when maribavir was administered at oral doses up to 100 mg/kg/day from GD to 20, at exposures approximately half the human exposure at the RHD.In the pre-and postnatal developmental toxicity study maribavir was administered to pregnant rats at oral doses of 50, 150, or 400 mg/kg/day from GD to postnatal day (PND) 21. delay in developmental milestones was observed, including pinna detachment at doses >=150 mg/kg/day and eye opening and preputial separation associated with reduced bodyweight gain of the offspring at 400 mg/kg/day. In addition, decreased fetal survival and litter loss was observed due to maternal toxicity and poor maternal care, respectively, at doses >=150 mg/kg/day. No effects were observed at 50 mg/kg/day (which is estimated to be less than the human exposure at the RHD). No effects on number of offspring, proportion of males, number of live pups, or survival to PND were observed at any dose in the offspring born to the second generation.

RENAL IMPAIRMENT SUBSECTION.

8.6Impaired Renal Function. No dose adjustment of LIVTENCITY is needed for patients with mild, moderate, or severe renal impairment [see Clinical Pharmacology (12.3)]. Administration of LIVTENCITY in patients with end stage renal disease (ESRD), including patients on dialysis, has not been studied.

SPL PATIENT PACKAGE INSERT SECTION.

Patient Information LIVTENCITY (liv-TEN-city) (maribavir) tabletsThis Patient Information has been approved by the U.S. Food and Drug Administration.Issued: 11/2021 What is LIVTENCITYLIVTENCITY is prescription medicine used to treat cytomegalovirus (CMV) infection and disease in adults and children 12 years of age and older weighing at least 77 pounds (35 kg) who have received transplant, when their infection or disease does not respond to treatment with the medicines ganciclovir, valganciclovir, cidofovir or foscarnet.It is not known if LIVTENCITY is safe and effective in children under 12 years of age.Before taking LIVTENCITY, tell your healthcare provider about all your medical conditions, including if you:are pregnant or plan to become pregnant. It is not known if LIVTENCITY will harm your unborn baby.are breastfeeding or plan to breastfeed. It is not known if LIVTENCITY passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with LIVTENCITY.Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. LIVTENCITY may affect the way other medicines work, and other medicines may affect how LIVTENCITY works and cause serious side effects.Especially tell your healthcare provider if you take seizure (anticonvulsant) medicine.You can ask your healthcare provider or pharmacist for list of medicines that interact with LIVTENCITY.Do not start new medicine without telling your healthcare provider. Your healthcare provider will tell you if it is safe to take LIVTENCITY with other medicines.Know the medicines you take. Keep list of your medicines and show it to your healthcare provider and pharmacist when you get new medicine. How should take LIVTENCITYTake LIVTENCITY exactly as your healthcare provider tells you to take it.Take LIVTENCITY times day.Take LIVTENCITY with or without food.If you take too much LIVTENCITY, call your healthcare provider or go to the nearest hospital emergency room right away.What are the possible side effects of LIVTENCITYThe most common side effects of LIVTENCITY include:changes in tastenauseadiarrheavomitingtirednessThese are not all the possible side effects of LIVTENCITY.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store LIVTENCITYStore LIVTENCITY at room temperature between 68F to 77F (20C to 25C).Keep LIVTENCITY and all medicines out of the reach of children.General information about the safe and effective use of LIVTENCITY.Medicines are sometimes prescribed for purposes other than those listed in the Patient Information leaflet. Do not use LIVTENCITY for condition for which it was not prescribed. Do not give LIVTENCITY to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about LIVTENCITY that is written for health professionals.What are the ingredients in LIVTENCITYActive ingredient: maribavirInactive ingredients: FD&C Blue 1, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, sodium starch glycolate, titanium dioxide, and talc.Distributed by: Takeda Pharmaceuticals America, Inc. Lexington, MA 02421 LIVTENCITY(TM) and the LIVTENCITY(TM) logo are trademarks or registered trademarks of Takeda Pharmaceuticals International AG. TAKEDA(R) and the TAKEDA Logo(R) are registered trademarks of Takeda Pharmaceutical Company Limited. (C) 2021 Takeda Pharmaceuticals U.S.A., Inc. All rights reserved. For more information, go to www.LIVTENCITY.com or call 1-877-TAKEDA-7 (1-877-825-3327). are pregnant or plan to become pregnant. It is not known if LIVTENCITY will harm your unborn baby.. are breastfeeding or plan to breastfeed. It is not known if LIVTENCITY passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with LIVTENCITY.. You can ask your healthcare provider or pharmacist for list of medicines that interact with LIVTENCITY.. Do not start new medicine without telling your healthcare provider. Your healthcare provider will tell you if it is safe to take LIVTENCITY with other medicines.. Know the medicines you take. Keep list of your medicines and show it to your healthcare provider and pharmacist when you get new medicine.. Take LIVTENCITY exactly as your healthcare provider tells you to take it.. Take LIVTENCITY times day.. Take LIVTENCITY with or without food.. If you take too much LIVTENCITY, call your healthcare provider or go to the nearest hospital emergency room right away.. changes in taste. nausea. diarrhea. vomiting. tiredness. Store LIVTENCITY at room temperature between 68F to 77F (20C to 25C).

SPL UNCLASSIFIED SECTION.

2.1 Recommended Dosage The recommended dosage in adults and pediatric patients (12 years of age and older and weighing at least 35 kg) is 400 mg (two 200 mg tablets) taken orally twice daily with or without food [see Use in Specific Populations (8.4), Clinical Pharmacology (12.3), Clinical Studies (14)].

STORAGE AND HANDLING SECTION.

Storage and HandlingStore at 20C to 25C (68F to 77F), brief exposure to 15C to 30C (59F to 86F) permitted [see USP Controlled Room Temperature].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryNo adequate human data are available to establish whether LIVTENCITY poses 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. Animal DataIn combined fertility and embryofetal development study, maribavir was administered to male and female rats at oral doses of 100, 200, or 400 mg/kg/day. Females were dosed for 15 consecutive days prior to pairing, throughout pairing, and up to gestation day (GD) 17, while males were dosed 29 days prior to mating and throughout mating. decrease in the number of viable fetuses and increase in early resorptions and post-implantation losses were observed at >=100 mg/kg/day (at exposures approximately half the human exposure at the RHD). Intermittent reduced body weight gain was observed in pregnant animals at >=200 mg/kg/day. Maribavir had no effect on embryo-fetal growth or development at dose levels up to 400 mg/kg/day, at exposures similar to those observed in humans at the RHD.No significant toxicological effects on embryo-fetal growth or development were observed in rabbits when maribavir was administered at oral doses up to 100 mg/kg/day from GD to 20, at exposures approximately half the human exposure at the RHD.In the pre-and postnatal developmental toxicity study maribavir was administered to pregnant rats at oral doses of 50, 150, or 400 mg/kg/day from GD to postnatal day (PND) 21. delay in developmental milestones was observed, including pinna detachment at doses >=150 mg/kg/day and eye opening and preputial separation associated with reduced bodyweight gain of the offspring at 400 mg/kg/day. In addition, decreased fetal survival and litter loss was observed due to maternal toxicity and poor maternal care, respectively, at doses >=150 mg/kg/day. No effects were observed at 50 mg/kg/day (which is estimated to be less than the human exposure at the RHD). No effects on number of offspring, proportion of males, number of live pups, or survival to PND were observed at any dose in the offspring born to the second generation.. 8.2 Lactation. Risk SummaryIt 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 mothers clinical need for LIVTENCITY and any potential adverse effects to the breast-fed child.. 8.4 Pediatric Use. The recommended dosing regimen in pediatric patients 12 years of age and older and weighing at least 35 kg is the same as that in adults. Use of LIVTENCITY in this age group is based on the following:Evidence from controlled studies of LIVTENCITY in adultsPopulation pharmacokinetic (PK) modeling and simulation demonstrating that age and body weight had no clinically meaningful effect on plasma exposures of LIVTENCITYLIVTENCITY exposure is expected to be similar between adults and children 12 years of age and older and weighing at least 35 kgThe course of the disease is similar between adults and pediatric patients to allow extrapolation of data in adults to pediatric patients [see Dosage and Administration (2.2), Clinical Pharmacology (12.3) and Clinical Studies (14)] The safety and effectiveness of LIVTENCITY have not been established in children younger than 12 years of age.. Evidence from controlled studies of LIVTENCITY in adults. Population pharmacokinetic (PK) modeling and simulation demonstrating that age and body weight had no clinically meaningful effect on plasma exposures of LIVTENCITY. LIVTENCITY exposure is expected to be similar between adults and children 12 years of age and older and weighing at least 35 kg. The course of the disease is similar between adults and pediatric patients to allow extrapolation of data in adults to pediatric patients [see Dosage and Administration (2.2), Clinical Pharmacology (12.3) and Clinical Studies (14)] 8.5 Geriatric Use. No dosage adjustment is required for patients over 65 years of age based on the results from population pharmacokinetics analysis [see Clinical Pharmacology (12.3)] and efficacy and safety data from the clinical studies. In the clinical Study 303, 54 patients aged 65 years and over were treated with LIVTENCITY. Safety, effectiveness, and pharmacokinetics were consistent between elderly patients (>=65 years) and younger patients (<65 years).. 8.6Impaired Renal Function. No dose adjustment of LIVTENCITY is needed for patients with mild, moderate, or severe renal impairment [see Clinical Pharmacology (12.3)]. Administration of LIVTENCITY in patients with end stage renal disease (ESRD), including patients on dialysis, has not been studied.. 8.7Impaired Hepatic Function. No dose adjustment of LIVTENCITY is needed for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment [see Clinical Pharmacology (12.3)]. Administration of LIVTENCITY in patients with severe hepatic impairment has not been studied.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. LIVTENCITY may antagonize the antiviral activity of ganciclovir and valganciclovir. Coadministration is not recommended. (5.1, 7.1)Virologic failure can occur during and after treatment with LIVTENCITY. Monitor CMV DNA levels and check for resistance if patient does not respond to treatment. Some maribavir pUL97 resistance-associated substitutions confer cross-resistance to ganciclovir and valganciclovir. (5.2, 12.4, 14.1)The concomitant use of LIVTENCITY and certain drugs may result in potentially significant drug interactions, some of which may lead to reduced therapeutic effect of LIVTENCITY or adverse reactions of concomitant drugs. (5.1, 5.3, 7.1, 7.2, 7.3)LIVTENCITY has the potential to increase the drug concentrations of immunosuppressant drugs that are CYP3A4 and/or 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 dose, as needed. (5.3). LIVTENCITY may antagonize the antiviral activity of ganciclovir and valganciclovir. Coadministration is not recommended. (5.1, 7.1). Virologic failure can occur during and after treatment with LIVTENCITY. Monitor CMV DNA levels and check for resistance if patient does not respond to treatment. Some maribavir pUL97 resistance-associated substitutions confer cross-resistance to ganciclovir and valganciclovir. (5.2, 12.4, 14.1). The concomitant use of LIVTENCITY and certain drugs may result in potentially significant drug interactions, some of which may lead to reduced therapeutic effect of LIVTENCITY or adverse reactions of concomitant drugs. (5.1, 5.3, 7.1, 7.2, 7.3). LIVTENCITY has the potential to increase the drug concentrations of immunosuppressant drugs that are CYP3A4 and/or 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 dose, as needed. (5.3). 5.1 Risk of Reduced Antiviral Activity When Coadministered with Ganciclovir and Valganciclovir. LIVTENCITY may antagonize the antiviral activity of ganciclovir and valganciclovir by inhibiting human CMV pUL97 kinase, which is required for activation/phosphorylation of ganciclovir and valganciclovir. Coadministration of LIVTENCITY with ganciclovir or valganciclovir is not recommended [see Drug Interactions (7.1) and Microbiology (12.4)].. 5.2 Virologic Failure During Treatment and Relapse Post-Treatment. Virologic failure due to resistance can occur during and after treatment with LIVTENCITY. Virologic relapse during the posttreatment period usually occurred within 4-8 weeks after treatment discontinuation. Some maribavir pUL97 resistance-associated substitutions confer cross-resistance to ganciclovir and valganciclovir. Monitor CMV DNA levels and check for maribavir resistance if the patient is not responding to treatment or relapses [see Microbiology (12.4) and Clinical Studies (14.1)].. 5.3 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions. The concomitant use of LIVTENCITY and certain drugs may result in potentially significant drug interactions, some of which may lead to reduced therapeutic effect of LIVTENCITY or adverse reactions of concomitant drugs [see Drug Interactions (7)].See Table for steps to prevent or manage these possible or known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during LIVTENCITY therapy; review concomitant medications during LIVTENCITY therapy and monitor for adverse reactions.Maribavir is primarily metabolized by CYP3A4. Drugs that are strong inducers of CYP3A4 are expected to decrease maribavir plasma concentrations and may result in reduced virologic response; therefore, coadministration of LIVTENCITY with these drugs is not recommended, except for selected anticonvulsants [see Dosage and Administration (2.2) and Drug Interactions (7.3)].. Use with Immunosuppressant DrugsLIVTENCITY 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)].

INSTRUCTIONS FOR USE SECTION.

Instructions for Use. LIVTENCITY (liv-TEN-city)(maribavir)tablets, for oral useThis Instructions for Use contains information on how to prepare and give dose of LIVTENCITY tablets by breaking apart (dispersing) or crushing in drinking water and taking by mouth, or dispersing and giving through Nasogastric (NG) or Orogastric (OG) Tube. Read this Instructions for Use before you prepare or give the first dose of LIVTENCITY, and each time you get refill. Ask your healthcare provider or pharmacist if you have any questions.Important information you need to know before preparing dose of LIVTENCITY:You can break apart (disperse) the tablets in drinking water or crush the tablets and mix with drinking water. The tablet will not be completely dispersed in the mixture.Do not mix LIVTENCITY with any liquid other than drinking water.LIVTENCITY tablets that have been dispersed in drinking water can be given through Nasogastric (NG) or Orogastric (OG) tube (French size 10 or larger).You can prepare the mixture ahead of time and store at room temperature 68F to 77F (20C to 25C) for up to hours.Preparing dose of LIVTENCITY by dispersing or crushing tablets and taking by mouth:Gather the following supplies:small, clean container to place tablets and water indrinking waterStep 1: Choose clean, flat work surface. Place all supplies on the work surface.Step 2: Wash and dry your hands well.Step 3: Get the prescribed number of LIVTENCITY tablets needed to prepare the dose.Step 4: Place the LIVTENCITY tablets into the container.Note: If you prefer, you can crush the tablets with spoon before adding water.Step 5: Add the amount of drinking water needed for your prescribed dose.Number of TabletsAmount of Drinking water230 mL460 mL690mLStep 6: Swirl the container gently to disperse the tablets in the water and swallow the mixture right away. The mixture will have bitter taste.Step 7: Rinse the container with 15 mL of drinking water and swallow the mixture.Repeat Step 7. Check that no pieces of tablet are left in the container. Repeat Step until no pieces remain.Preparing and giving dose of LIVTENCITY through Nasogastric (NG) or Orogastric (OG) Tube:Gather the following supplies:50 mL or 60 mL syringedrinking waterStep 1: Remove the cap (if capped) and plunger out of 50 mL or 60 mL syringe. Add tablets into the syringe body and place the plunger back in the syringe.Note: Only tablets can be given through the NG or OG tube at time.Step 2: Withdraw 30 mL of drinking water into the syringe.Step 3: Hold the syringe with the tip pointing upward. Pull the plunger back so there is some air space in the syringe. If there is cap, place the cap back on the syringe. Shake the syringe well for about 30 to 45 seconds or until the tablets are completely dispersed. Be careful not to spill the contents of the syringe.Step 4: Remove the cap (if capped) from the syringe again and attach the syringe to the NG or OG tube and give the mixture right away.Step 5: Withdraw 15 mL of drinking water into the same syringe and flush through the NG or OG tube.Repeat Step 5. Check that no pieces of tablet are left in the syringe. Repeat Step until no pieces remain.Note: If your prescribed dose is more than tablets, Repeat Steps through until you give the full prescribed dose.Storing LIVTENCITY:Store LIVTENCITY at room temperature 68F to 77F (20C to 25C).Keep LIVTENCITY and all medicines out of the reach of children.For more information, go to www.LIVTENCITY.com or call 1-877-TAKEDA-7 (1-877-825-3327).Distributed by: Takeda Pharmaceuticals America, Inc., Lexington, MA 02421LIVTENCITY(TM) and the LIVTENCITY(TM) Logo are trademarks or registered trademarks of Takeda Pharmaceuticals International AG. TAKEDA(R) and the TAKEDA Logo(R) are registered trademarks of Takeda Pharmaceutical Company Limited. (C)2022 Takeda Pharmaceuticals U.S.A., Inc. All rights reserved.This Instructions for Use has been approved by the U.S. Food and Drug Administration.Issued: September 2022. You can break apart (disperse) the tablets in drinking water or crush the tablets and mix with drinking water. The tablet will not be completely dispersed in the mixture.. Do not mix LIVTENCITY with any liquid other than drinking water.. LIVTENCITY tablets that have been dispersed in drinking water can be given through Nasogastric (NG) or Orogastric (OG) tube (French size 10 or larger).. You can prepare the mixture ahead of time and store at room temperature 68F to 77F (20C to 25C) for up to hours.. small, clean container to place tablets and water in. drinking water. 50 mL or 60 mL syringe. drinking water. Store LIVTENCITY at room temperature 68F to 77F (20C to 25C).

RECENT MAJOR CHANGES SECTION.

Dosage and Administration, Administration (2.3)9/2022.