MARIBAVIR Drug Interactions: What You Need to Know

INTERACTIONS 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) and Microbiology (12.4) ]</span> .

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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.2 , 2.3) and Drug Interactions (7.3) ]</span> . 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

None. None. ( 4 )

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 <span class="opacity-50 text-xs">[see Drug Interactions (7.1) and Microbiology (12.4) ]</span> .

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 <span class="opacity-50 text-xs">[see Microbiology (12.4) and Clinical Studies (14.1) ]</span> .

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 <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span> .

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) ] .