Livtencity

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

400 mg (two 200 mg tablets) orally twice daily with or without food. (

Tablet: 200 mg, blue, oval shaped convex tablet debossed with "SHP" on one side and "620" on the other side.

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)

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.

• LIVTENCITY may antagonize the antiviral activity of ganciclovir and valganciclovir. Coadministration is not recommended. (
  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)]

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  ,
  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)]

  .
  )
• 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 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)]

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  12.4 Microbiology

  Mechanism of Action

  The antiviral activity of maribavir is mediated by competitive inhibition of the protein kinase activity of human CMV enzyme pUL97, which results in inhibition of the phosphorylation of proteins. Maribavir inhibited wild-type pUL97 protein kinase in a biochemical assay with an IC₅₀value of 0.003 µM. Maribavir and its 5'-mono- and 5'-triphosphate derivatives at 100 µM had no significant effect on the incorporation of deoxynucleoside triphosphates by human CMV DNA polymerase. At a concentration of 100 µM, neither maribavir nor its 5′-triphosphate derivative inhibited CMV DNA polymerase delta, however the 5′-monophosphate derivative inhibited incorporation by polymerase delta of all 4 natural dNTPs by approximately 55%.

  Antiviral Activity

  Maribavir inhibited human CMV replication in virus yield reduction, DNA hybridization, and plaque reduction assays in human lung fibroblast cell line (MRC-5), human embryonic kidney (HEK), and human foreskin fibroblast (MRHF) cells. The EC₅₀values ranged from 0.03 to 2.2 µM depending on the cell line and assay endpoint. The cell culture antiviral activity of maribavir has also been evaluated against CMV clinical isolates. The median EC₅₀values were 0.1 µM (n=10, range 0.03-0.13 µM) and 0.28 µM (n=10, range 0.12-0.56 µM) using DNA hybridization and plaque reduction assays, respectively. No significant difference in EC₅₀values across the four human CMV glycoprotein B genotypes (N=2, 1, 4, and 1 for gB1, gB2, gB3, and gB4, respectively) was seen.

  Combination Antiviral Activity

  When maribavir was tested in combination with other antiviral compounds, antagonism of the antiviral activity was seen in combination with ganciclovir. No antagonism was observed with cidofovir, foscarnet, letermovir and rapamycin at the drugs EC₅₀values. The pUL97 kinase activity inhibited by maribavir is necessary to activate valganciclovir/ganciclovir.

  Treatment Effect in CMV Glycoprotein B (gB) Subtypes

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

  [see Clinical Studies (14)]

  .

  Viral Resistance

  In Cell Culture

  Selection 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 Studies

  In Phase 2 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 a 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 3 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-Resistance

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

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

  Substitutions pUL97 F342Y and C480F are maribavir treatment-emergent resistance-associated substitutions that confer >1.5-fold reduced susceptibility to vGCV/GCV, a fold reduction that is associated with phenotypic resistance to vGCV/GCV. The clinical significance of this cross-resistance to vGCV/GCV for these substitutions has not been determined. Maribavir resistant virus remained susceptible to cidofovir and foscarnet. Additionally, there are no reports of any pUL27 maribavir resistance-associated substitutions being evaluated for vGCV/GCV, cidofovir, or foscarnet cross-resistance. Given the lack of resistance-associated substitutions for these drugs mapping to pUL27, cross-resistance is not expected for pUL27 maribavir substitutions.
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  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 a 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 1 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 a 2:1 allocation ratio to receive either LIVTENCITY 400 mg twice daily or IAT as dosed by the investigator for up to 8 weeks. After completion of the treatment period, subjects entered a 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 6 subjects, the combination of foscarnet and valganciclovir in 4 subjects and the combination of foscarnet and ganciclovir in 3 subjects. Baseline disease characteristics are summarized in Table 9 below.

  Table 9: Summary of Baseline Disease Characteristics in Trial 303

  Characteristic	LIVTENCITY 400 mg Twice Daily N=235 n (%)	IAT N=117 n (%)
  	CMV=cytomegalovirus, DNA=deoxyribonucleic acid, HSCT=hematopoietic stem cell transplant, IAT=investigator assigned anti-CMV treatment, N=number of patients, SOT=solid organ transplant.
  Transplant type
  HSCT	93 (40)	48 (41)
  SOT	142 (60)	69 (59)
  Kidney	74 (52)	32 (46)
  Lung	40 (28)	22 (32)
  Heart	14 (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
  No	214 (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 disease	12 (57)	1 (13)

  Primary Efficacy Endpoint

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

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

  Table 10: Primary Efficacy Endpoint Analysis at Week 8 (Randomized Set) in Trial 303

  	LIVTENCITY 400 mg Twice Daily N=235 n (%)	IAT N=117 n (%)
  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 8 (2 consecutive samples separated by at least 5 days with DNA levels < LLOQ [i.e:, <137 IU/mL]).
  Responders	131 (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	<0.001

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

  Table 11: Analysis of Failures for Primary Efficacy Endpoint

  Outcome at Week 8	LIVTENCITY N=235 n (%)	IAT N=117 n (%)
  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 8 (2 consecutive samples separated by at least 5 days with DNA levels < LLOQ [i.e:, <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)
  •  CMV DNA never < LLOQ	48 (20)	35 (30)
  •  CMV DNA breakthrough	32 (14)	7 (6)
  Due to drug/study discontinuation:	21 (9)	44 (38)
  •  Adverse events	8 (3)	26 (22)
  •  Deaths	10 (4)	3 (3)
  •  Withdrawal of consent	1 (<1)	9 (8)
  •  Other reasonsOther reasons=other reasons not including adverse events, deaths and lack of efficacy, withdrawal of consent, and non-compliance.	2 (1)	6 (5)
  Due to other reasons but remained on studyIncludes subjects who completed study assigned treatment and were non-responders.	3 (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 12)

  .

  Table 12: Responders by Subgroup in Trial 303

  	LIVTENCITY 400 mg Twice Daily N=235		IAT N=117
  	n/N	%	n/N	%
  Transplant type
  SOT	79/142	56	18/69	26
  HSCT	52/93	56	10/48	21
  Baseline CMV DNA viral load
  Low (<9,100 IU/mL)	95/153	62	21/85	25
  Intermediate (≥9,100 to <91,000 IU/mL)	32/68	47	5/25	20
  ≥9,100 to <50,000 IU/mL	29/59	49	4/20	20
  ≥50,000 to <91,000 IU/mL	3/9	33	1/5	20
  High (≥91,000 IU/mL)	4/14	29	2/7	29
  Genotypic resistance to other anti-CMV agents
  Yes	76/121	63	14/69	20
  No	42/96	44	11/34	32
  CMV syndrome/disease at baseline
  Yes	10/21	48	1/8	13
  No	121/214	57	27/109	25
  Age Group
  18 to 44 years	28/55	51	8/32	25
  45 to 64 years	71/126	56	19/69	28
  ≥65 years	32/54	59	1/16	6

  Secondary Endpoints

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

  Table 13: 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 mg Twice Daily N=235 n (%)	IAT N=117 n (%)
  Responders	44 (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.	9 (2,17)
  p-value: adjusted	0.013

  Virologic 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 4 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, a 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. A similar percentage of subjects in each treatment group died during the trial (LIVTENCITY 11% [27/235]; IAT 11% [13/117]).
  )
• 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 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)]

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  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 4for 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 Drugs

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

  [see Drug Interactions (7.3)and Clinical Pharmacology (12.3)]

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  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)]

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  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 for selected anticonvulsants

  [see Dosage and Administration (2.2)and Drug Interactions (7.3)]

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  7.3 Potential for LIVTENCITY to Affect Other Drugs

  Maribavir is a weak inhibitor of CYP3A4, and an inhibitor of P-gp and breast cancer resistance protein (BCRP). Coadministration of LIVTENCITY with drugs that are sensitive substrates of CYP3A, P-gp and BCRP 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 InteractionsThis table is not all inclusive.

  Concomitant Drug Class: Drug Name	Effect on Concentration	Clinical Comments
  ↓=decrease, ↑=increase.
  Antiarrhythmics
  DigoxinThe 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	Coadministration of LIVTENCITY and rifabutin is not recommended due to potential for a decrease in efficacy of LIVTENCITY.
  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.
  )
• 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 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 4for 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 Drugs

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

  [see Drug Interactions (7.3)and Clinical Pharmacology (12.3)]

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  )