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warnings and cautions
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 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) ] .
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 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)
adverse reactions table
<table width="75%"><caption>Table 2: Adverse Events (All Grades) Reported in >10% of Subjects in the LIVTENCITY Group in Trial 303</caption><col width="32%" align="left" valign="top"/><col width="36%" align="center" valign="top"/><col width="32%" align="center" valign="top"/><thead><tr><th valign="middle" align="center" styleCode="Lrule Rrule">ADVERSE EVENT</th><th styleCode="Rrule">LIVTENCITY N=234 (%)</th><th styleCode="Rrule">IAT<footnote>IAT (Investigator-Assigned Treatment) included monotherapy or dual therapy with ganciclovir, valganciclovir, foscarnet, or cidofovir as dosed by the investigator.</footnote> N=116 (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Taste disturbance<footnote>taste disturbance includes the following reported preferred terms: ageusia, dysgeusia, hypogeusia and taste disorder.</footnote></td><td styleCode="Rrule">46</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">21</td><td styleCode="Rrule">22</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea</td><td styleCode="Rrule">19</td><td styleCode="Rrule">21</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vomiting</td><td styleCode="Rrule">14</td><td styleCode="Rrule">16</td></tr><tr><td styleCode="Lrule Rrule">Fatigue</td><td styleCode="Rrule">12</td><td styleCode="Rrule">9</td></tr></tbody></table>