Safety Profile and Side Effects | LIVTENCITY® (maribavir)

Safety profile demonstrated in adult patients in a Phase 3 pivotal trial

Lower rate of treatment discontinuation due to AEs with LIVTENCITY vs IAT¹

Discontinuation rates:

13%

(n=31/234)²

of patients receiving LIVTENCITY

vs

32%

(n=37/116)²

of patients receiving IAT

LIVTENCITY

Dysgeusia, diarrhea, nausea, and recurrence of underlying disease (each reported at 1%)

Most common reasons for treatment discontinuation

IAT

Neutropenia

IAT

Acute kidney injury

AE=adverse event.

Adverse events (all grades) reported in >10% of adult patients in the LIVTENCITY group¹

The mean treatment durations (SD) for LIVTENCITY and IAT were 48.6 (± 13.82) and 31.2 (± 16.91) days, respectively.¹

ADVERSE EVENT	LIVTENCITY N=234 (%)	IAT* N=116 (%)
Taste disturbance^†	46	4
Nausea	21	22
Diarrhea	19	21
Vomiting	14	16
Fatigue	12	9

^*IAT (investigator-assigned treatment) included monotherapy or dual therapy with ganciclovir, valganciclovir, foscarnet, or cidofovir as dosed by the investigator.
^†Taste disturbance includes the following reported preferred terms: ageusia, dysgeusia, hypogeusia and taste disorder.

Treatment emergent adverse events (TEAE) in ≥5% of patients in either treatment group or for individual IAT, considered related to study-assigned treatment by the investigator⁴*

SOLSTICE, a Phase 3, multicenter, randomized, open-label, active-controlled trial, compared LIVTENCITY to Investigator-Assigned Treatment (IAT)
Study was not designed to evaluate safety differences between individual IAT types, therefore comparisons of safety profiles cannot be made
Safety data were analyzed descriptively in all patients who received a dose of study drug (Safety Population)³

Expand the table

Cid=cidofovir; Fos=foscarnet; Gan=ganciclovir; Val=valganciclovir.
*The cidofovir group was not considered in the application of the 5% cutoff due to low patient numbers (n=6).

Taste disturbance rarely led to treatment discontinuation and usually resolved while on or post-treatment^1,3

Taste disturbance was the most common AE reported in patients receiving LIVTENCITY	46% (n=108/234)² experienced taste disturbance	In some patients, taste disturbance resolved during treatment	37% (n=44/119)² had resolution while on treatment [Median duration 43 days; range 7 to 59 days]	Taste disturbance rarely led to treatment discontinuation	1% (n=2/234)² discontinued due to taste disturbance

Taste disturbance was the most common AE reported in patients receiving LIVTENCITY

46% (n=108/234)²

experienced taste disturbance

In some patients, taste disturbance resolved during treatment

37% (n=44/119)²

had resolution while on treatment
[Median duration 43 days; range 7 to 59 days]

Taste disturbance rarely led to treatment discontinuation

1% (n=2/234)²

discontinued due to taste disturbance

For patients with ongoing taste disturbance after drug discontinuation, resolution occured in 89%¹
In patients with resolution of symptoms after drug discontinuation, the median duration of symptoms off treatment was 6 days (range 2 to 85 days)¹

Taste disturbance included the terms: ageusia, dysgeusia, hypogeusia, and taste disorder.

LIVTENCITY IN PEDIATRIC POPULATION

Selected laboratory abnormalities¹

Reported by central laboratory with samples collected every 2 weeks*

Laboratory parameter	LIVTENCITY N=234 % (n)	IAT N=116 % (n)
Neutrophils (cells/μL) <500 ≥500 to <750 ≥750 to <1,000	2% (4) 3% (7) 4% (10)	3% (4) 6% (7) 5% (6)
Hemoglobin (g/dL) <6.5 ≥6.5 to <8.0 ≥8.0 to <9.5	1% (3) 15% (34) 32% (76)	1% (1) 20% (23) 28% (33)
Platelets (cells/μL) <25,000 ≥25,000 to <50,000 ≥50,000 to <100,000	5% (11) 12% (27) 18% (41)	5% (6) 9% (10) 17% (20)
Creatinine (mg/dL) >2.5 >1.5 to ≤2 .5	7% (16) 33% (78)	10% (12) 25% (29)

^*As specified by detailed protocol design per Data on File.

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1. Livtencity (maribavir) Prescribing Information. Lexington, MA: Takeda Pharmaceuticals U.S.A., Inc. 2. Data on file. Takeda Pharmaceuticals U.S.A., Inc. 3. Avery RK, Alain S, Alexander BD, et al. Clin Infect Dis. 2022;75(4):690-701. 4. Avery RK, Alain S, Alexander BD, et al. Clin Infect Dis. Supplement. 2022. doi.org/10.1093/cid/ciab988. 5. Shannon-Lowe CD, Emery VC. Herpesviridae. 2010;1(4):1-13. 6. Steingruber M, Marschall M. Microorganisms. 2020;8(4):515. 7. Biron KK, Harvey RJ, Chamberlain SC, et al. Antimicrob Agents Chemother 2002;46:2365-2372. 8. Wolf DG, Courcelle CT, Prichard MN, Mocarski ES. Proc Natl Acad Sci U S A. 2001;98(4):1895-1900. 9. Krosky PM, Baek MC, Coen DM. J Virol. 2003;77:905-914. 10. Bigley TM, Reitsma JM, Mirza SP, Terhune SS. J Virol. 2013;87(13):7393-7408.

IMPORTANT SAFETY INFORMATION

Risk of Reduced Antiviral Activity When Co-administered 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.

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.

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. Consider the potential for drug interactions prior to and during LIVTENCITY therapy; review concomitant medications during LIVTENCITY therapy and monitor for adverse reactions. Refer to the full prescribing information of LIVTENCITY for important drug interactions.

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.

Use with Immunosuppressant Drugs

LIVTENCITY has the potential to increase the drug concentrations of immunosuppressant drugs that are CYP3A 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 immunosuppressant dose, as needed.

Adverse Reactions

The most common adverse events (all grades,> 10%) in subjects treated with LIVTENCITY were taste disturbance, nausea, diarrhea, vomiting, and fatigue.

INDICATION

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.

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