Maribavir

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) and Clinical Studies (14) ] . LIVTENCITY is a 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 )

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 )

None. None. ( 4 )

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 certain immunosuppressant drugs 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 post-treatment period usually occurred within 4-8 weeks after treatment discontinuation. Some maribavir pUL97 resistance-associated substitutions confer cross-resistance to ganciclovir and valganciclovir. 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 4 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. Thus, coadministration of LIVTENCITY with these drugs is not recommended, except with a dose adjustment when coadministered with selected anticonvulsants (carbamazepine and phenytoin). With moderate CYP3A4 inducers rifabutin (antimycobacterial) and phenobarbital (anticonvulsant), a dose adjustment is recommended [see Dosage and Administration (2.2 , 2.3) and Drug Interactions (7.3) ] . For other moderate CYP3A4 inducers, the appropriate maribavir dose adjustment has not been determined. Use with Immunosuppressant Drugs LIVTENCITY has the potential to increase the drug concentrations of certain immunosuppressant drugs 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) ] .

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 a 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 3 multicenter, 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 a 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 2. Table 2: Adverse Events (All Grades) Reported in >10% of Subjects in the LIVTENCITY Group in Trial 303 ADVERSE EVENT LIVTENCITY N=234 (%) IAT IAT (Investigator-Assigned Treatment) included monotherapy or dual therapy with ganciclovir, valganciclovir, foscarnet, or cidofovir as dosed by the investigator. N=116 (%) Taste disturbance taste disturbance includes the following reported preferred terms: ageusia, dysgeusia, hypogeusia and taste disorder. 46 4 Nausea 21 22 Diarrhea 19 21 Vomiting 14 16 Fatigue 12 9 Similar 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 vs 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 7 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 6 days (range 2 to 85 days). 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. Table 3: Selected Laboratory Abnormalities Reported in Trial 303 Laboratory Parameter LIVTENCITY N=234 n (%) IAT N=116 n (%) Neutrophils (cells/µL) <500 4 (2) 4 (3) ≥500 to <750 7 (3) 7 (6) ≥750 to <1,000 10 (4) 6 (5) Hemoglobin (g/dL) <6.5 3 (1) 1 (1) ≥6.5 to <8.0 34 (15) 23 (20) ≥8.0 to <9.5 76 (32) 33 (28) Platelets (cells/µL) <25,000 11 (5) 6 (5) ≥25,000 to <50,000 27 (12) 10 (9) ≥50,000 to <100,000 41 (18) 20 (17) Creatinine (mg/dL) >2.5 16 (7) 12 (10) >1.5 to ≤2.5 78 (33) 29 (25)

Refer to the full prescribing information for important drug interactions with LIVTENCITY. ( 5.1 , 5.3 , 7 ) Coadministration with strong CYP3A4 inducers is not recommended, except with a dose adjustment when coadministered with selected anticonvulsants (carbamazepine and phenytoin). When coadministered with the moderate CYP3A4 inducers rifabutin (antimycobacterial) or phenobarbital (anticonvulsant), a dose adjustment is recommended. ( 2.2 , 2.3 , 7.3 )

7.1 Reduced 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 a substrate of CYP3A4. Coadministration of LIVTENCITY with strong inducers of CYP3A4 is not recommended, except with a dose adjustment when coadministered with selected anticonvulsants (carbamazepine and phenytoin). With the moderate CYP3A4 inducers, rifabutin (antimycobacterial) and phenobarbital (anticonvulsant), a dose adjustment is recommended [see Dosage and Administration (2.2 , 2.3) and Drug Interactions (7.3) ] . For other moderate CYP3A4 inducers, the appropriate maribavir dose adjustment has not been determined.

7.3 Potential for LIVTENCITY to Affect Other Drugs Maribavir is an inhibitor of P-gp and breast cancer resistance protein (BCRP). Coadministration of LIVTENCITY with drugs that are substrates of P-gp and/or BCRP where minimal concentration changes may lead to serious adverse events may result in a clinically relevant increase in plasma concentrations of these substrates (see Table 4 ) . Table 4 provides a 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 4: Established and Other Potentially Significant Drug Interactions This table is not all inclusive. Concomitant Drug Class: Drug Name Effect on Concentration Clinical Comments ↓=decrease, ↑=increase. Antiarrhythmics Digoxin The interaction between LIVTENCITY and the concomitant drug was evaluated in a clinical study [see Clinical Pharmacology (12.3) ] . ↑ Digoxin Use caution when LIVTENCITY and digoxin are coadministered. Monitor serum digoxin concentrations. The dose of digoxin may need to be reduced when coadministered with LIVTENCITY. Refer to the respective prescribing information. Anticonvulsants Carbamazepine ↓ Maribavir A dose adjustment of LIVTENCITY to 800 mg twice daily is recommended when coadministered with carbamazepine. Phenobarbital ↓ Maribavir A dose adjustment of LIVTENCITY to 1,200 mg twice daily is recommended when coadministration with phenobarbital. Phenytoin ↓ Maribavir A dose adjustment of LIVTENCITY to 1,200 mg twice daily is recommended when coadministration with phenytoin. Antimycobacterials Rifabutin ↓ Maribavir A dose adjustment of LIVTENCITY to 800 mg twice daily is recommended when coadministered with rifabutin. Rifampin ↓ Maribavir Coadministration of LIVTENCITY and rifampin is not recommended due to potential for a decrease in efficacy of LIVTENCITY. Herbal Products St. John's wort ↓ Maribavir Coadministration of LIVTENCITY and St. John's wort is not recommended due to potential for a decrease in efficacy of LIVTENCITY. HMG-CoA Reductase Inhibitors Rosuvastatin ↑ Rosuvastatin The patient should be closely monitored for rosuvastatin-related events, especially the occurrence of myopathy and rhabdomyolysis. Immunosuppressants Cyclosporine ↑ Cyclosporine Frequently monitor cyclosporine levels throughout treatment with LIVTENCITY, especially following initiation and after discontinuation of LIVTENCITY and adjust dose, as needed. Everolimus ↑ Everolimus Frequently monitor everolimus levels throughout treatment with LIVTENCITY, especially following initiation and after discontinuation of LIVTENCITY and adjust dose, as needed. Sirolimus ↑ Sirolimus Frequently monitor sirolimus levels throughout treatment with LIVTENCITY, especially following initiation and after discontinuation of LIVTENCITY and adjust dose, as needed. Tacrolimus ↑ Tacrolimus Frequently 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, warfarin, voriconazole, dextromethorphan, or midazolam [see Clinical Pharmacology (12.3) ] .

8.1 Pregnancy 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 Animal Data In a 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. A 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 8 to 20, at exposures approximately half the human exposure at the RHD. In the pre-and post-natal developmental toxicity study, maribavir was administered to pregnant rats at oral doses of 50, 150, or 400 mg/kg/day from GD 7 to post-natal day (PND) 21. A 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 4 were observed at any dose in the offspring born to the second generation.

8.2 Lactation 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.

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 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 (2.1) , 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.

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).

8.6 Impaired 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.

8.7 Impaired 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.

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