LETERMOVIR Drug Interactions: What You Need to Know

INTERACTIONS Dosage Adjustment: If PREVYMIS is co-administered with cyclosporine, the dosage of PREVYMIS should be decreased to 240 mg once daily in adult and pediatric patients 12 years of age and older. ( 2.4 ) If PREVYMIS is co-administered with cyclosporine in pediatric patients less than 12 years of age, dose adjustment may be required. ( 2.6 ) Co-administration of PREVYMIS may alter the plasma concentrations of other drugs and other drugs may alter the plasma concentrations of PREVYMIS. Consult the full prescribing information prior to and during treatment for potential drug interactions. ( 2.4 , 2.6 , 4 , 5.1 , 7.1 , 7.2 , 7.3 , 7.4 , 12.3 )

7.1 Potential for Other Drugs to Affect PREVYMIS Letermovir is a substrate of organic anion-transporting polypeptide 1B1/3 (OATP1B1/3) and P-glycoprotein (P-gp) transporters and UDP-glucuronosyltransferase 1A1/3 (UGT1A1/3) enzymes. Co-administration of PREVYMIS with drugs that are inhibitors of OATP1B1/3 transporters may result in increases in letermovir plasma concentrations (Table 11). Co-administration of PREVYMIS with inducers of transporters (e.g., P-gp) and/or enzymes (e.g., UGTs) is not recommended due to the potential for a decrease in letermovir plasma concentrations (see Table 11 ) .

7.2 Potential for PREVYMIS to Affect Other Drugs Co-administration of PREVYMIS with midazolam results in increased midazolam plasma concentrations, indicating that letermovir is a moderate inhibitor of CYP3A <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . Co-administration of PREVYMIS with drugs that are CYP3A substrates may result in clinically relevant increases in the plasma concentrations of co-administered CYP3A substrates (Table 11) <span class="opacity-50 text-xs">[see Contraindications (4) and Warnings and Precautions (5.1) ]</span> . Letermovir is an inhibitor of OATP1B1/3 transporters. Co-administration of PREVYMIS with drugs that are substrates of OATP1B1/3 transporters may result in a clinically relevant increase in plasma concentrations of co-administered OATP1B1/3 substrates (Table 11). The magnitude of CYP3A- and OATP1B1/3-mediated drug interactions on co-administered drugs may be different when PREVYMIS is co-administered with cyclosporine. See the prescribing information for cyclosporine for information on drug interactions with cyclosporine.

7.3 Established and Other Potentially Significant Drug Interactions If dose adjustments of concomitant medications are made due to treatment with PREVYMIS, doses should be readjusted after treatment with PREVYMIS is completed.

Table

11 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on adult studies conducted with PREVYMIS or are predicted drug interactions that may occur with PREVYMIS [see Contraindications (4) , Warnings and Precautions (5.1) , and Clinical Pharmacology (12.3) ] .

Table

11: Potentially Significant Drug Interactions: Alteration in Dose May Be Recommended Based on Results from Adult Drug Interaction Studies or Predicted Interactions This table is not all inclusive. (Information in the Table Applies to Co-administration of PREVYMIS and the Concomitant Drug without Cyclosporine, Unless Otherwise Indicated)

Concomitant Drug

Class and/or Clearance Pathway: Drug Name Effect on Concentration ↓ =decrease, ↑ =increase Clinical Comments Anti-arrhythmic Agents amiodarone ↑ amiodarone Close clinical monitoring for adverse events related to amiodarone is recommended during co-administration. Frequently monitor amiodarone concentrations when amiodarone is co-administered with PREVYMIS. Antibiotics nafcillin ↓ letermovir Co-administration of PREVYMIS and nafcillin is not recommended due to potential for loss of efficacy of PREVYMIS. Anticoagulants warfarin ↓ warfarin When PREVYMIS is co-administered with warfarin, frequently monitor International Normalized Ratio (INR) Refer to the respective prescribing information. . Anticonvulsants carbamazepine ↓ letermovir Co-administration of PREVYMIS and carbamazepine is not recommended due to potential for loss of efficacy of PREVYMIS. phenobarbital ↓ letermovir Co-administration of PREVYMIS and phenobarbital is not recommended due to potential for loss of efficacy of PREVYMIS. phenytoin ↓ letermovir ↓ phenytoin Co-administration of PREVYMIS and phenytoin is not recommended due to potential for loss of efficacy of PREVYMIS.

Antidiabetic Agents

Examples: glyburide, repaglinide, rosiglitazone ↑ glyburide ↑ repaglinide ↑ rosiglitazone When PREVYMIS is co-administered with glyburide, repaglinide, or rosiglitazone, frequently monitor glucose concentrations . When PREVYMIS is co-administered with cyclosporine, use of repaglinide is not recommended. Antifungals voriconazole These interactions have been studied [see Clinical Pharmacology (12.3) ] . ↓ voriconazole If concomitant administration of voriconazole is necessary, closely monitor for reduced effectiveness of voriconazole . Antimycobacterials rifabutin ↓ letermovir Co-administration of PREVYMIS and rifabutin is not recommended due to potential for loss of efficacy of PREVYMIS. rifampin ↓ letermovir Co-administration of PREVYMIS and rifampin is not recommended due to potential for loss of efficacy of PREVYMIS. Antipsychotics pimozide ↑ pimozide Co-administration is contraindicated due to risk of QT prolongation and torsades de pointes [see Contraindications (4) ] . thioridazine ↓ letermovir Co-administration of PREVYMIS and thioridazine is not recommended due to potential for loss of efficacy of PREVYMIS.

Endothelin

Antagonists bosentan ↓ letermovir Co-administration of PREVYMIS and bosentan is not recommended due to potential for loss of efficacy of PREVYMIS.

Ergot

Alkaloids ergotamine, dihydroergotamine ↑ ergotamine, dihydroergotamine Co-administration is contraindicated due to risk of ergotism [see Contraindications (4) ] .

Herbal

Products St. John's wort ( Hypericum perforatum ) ↓ letermovir Co-administration of PREVYMIS and St. John's wort is not recommended due to potential for loss of efficacy of PREVYMIS.

Hiv

Medications efavirenz ↓ letermovir Co-administration of PREVYMIS and efavirenz is not recommended due to potential for loss of efficacy of PREVYMIS. etravirine ↓ letermovir Co-administration of PREVYMIS and etravirine is not recommended due to potential for loss of efficacy of PREVYMIS. nevirapine ↓ letermovir Co-administration of PREVYMIS and nevirapine is not recommended due to potential for loss of efficacy of PREVYMIS. HMG-CoA Reductase Inhibitors atorvastatin ↑ atorvastatin When PREVYMIS is co-administered with atorvastatin, do not exceed an atorvastatin dosage of 20 mg daily . Closely monitor patients for myopathy and rhabdomyolysis. When PREVYMIS is co-administered with cyclosporine, use of atorvastatin is not recommended. pitavastatin, simvastatin ↑ HMG-CoA reductase inhibitors Co-administration of PREVYMIS and pitavastatin or simvastatin is not recommended. When PREVYMIS is co-administered with cyclosporine, use of either pitavastatin or simvastatin is contraindicated due to significantly increased pitavastatin or simvastatin concentrations and risk of myopathy or rhabdomyolysis [see Contraindications (4) ] . fluvastatin, lovastatin, pravastatin, rosuvastatin ↑ HMG-CoA reductase inhibitors When PREVYMIS is co-administered with these statins, a statin dosage reduction may be necessary . Closely monitor patients for myopathy and rhabdomyolysis. When PREVYMIS is co-administered with cyclosporine, use of lovastatin is not recommended. When PREVYMIS is co-administered with cyclosporine, refer to the statin prescribing information for specific statin dosing recommendations. Immunosuppressants cyclosporine ↑ cyclosporine ↑ letermovir Decrease the dosage of PREVYMIS to 240 mg once daily in adult and pediatric patients 12 years of age and older [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ] . Dose adjustment may be required in pediatric patients less than 12 years of age [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3) ] . Frequently monitor cyclosporine whole blood concentrations during treatment and after discontinuation of PREVYMIS and adjust the dose of cyclosporine accordingly . sirolimus ↑ sirolimus When PREVYMIS is co-administered with sirolimus, frequently monitor sirolimus whole blood concentrations during treatment and after discontinuation of PREVYMIS and adjust the dose of sirolimus accordingly . When PREVYMIS is co-administered with cyclosporine and sirolimus, refer to the sirolimus prescribing information for specific sirolimus dosing recommendations . tacrolimus ↑ tacrolimus Frequently monitor tacrolimus whole blood concentrations during treatment and after discontinuation of PREVYMIS and adjust the dose of tacrolimus accordingly .

Proton Pump

Inhibitors omeprazole ↓ omeprazole Clinical monitoring and dose adjustment may be needed. pantoprazole ↓ pantoprazole Clinical monitoring and dose adjustment may be needed. Wakefulness-Promoting Agents modafinil ↓ letermovir Co-administration of PREVYMIS and modafinil is not recommended due to potential for loss of efficacy of PREVYMIS. CYP3A Substrates Examples: alfentanil, fentanyl, midazolam, and quinidine ↑ CYP3A substrate When PREVYMIS is co-administered with a CYP3A substrate, refer to the prescribing information for dosing of the CYP3A substrate with a moderate CYP3A inhibitor . When PREVYMIS is co-administered with cyclosporine, the combined effect on CYP3A substrates may be similar to a strong CYP3A inhibitor. Refer to the prescribing information for dosing of the CYP3A substrate with a strong CYP3A inhibitor . CYP3A substrates pimozide and ergot alkaloids are contraindicated [see Contraindications (4) ] .

7.4 Drugs without Clinically Significant Interactions with PREVYMIS No clinically significant interactions were observed in adult clinical drug-drug interaction studies of letermovir and acyclovir, digoxin, mycophenolate mofetil, fluconazole, itraconazole, posaconazole, ethinyl estradiol, and levonorgestrel.

PREVYMIS is contraindicated in patients receiving pimozide or ergot alkaloids: Pimozide: Concomitant administration of PREVYMIS in patients receiving pimozide may result in increased concentrations of pimozide due to inhibition of cytochrome P450 3A (CYP3A) by letermovir, which may lead to QT prolongation and torsades de pointes [see Warnings and Precautions (5.1) and Drug Interactions (7.2 , 7.3) ] . Ergot alkaloids: Concomitant administration of PREVYMIS in patients receiving ergot alkaloids may result in increased concentrations of ergot alkaloids (ergotamine and dihydroergotamine) due to inhibition of CYP3A by letermovir, which may lead to ergotism [see Warnings and Precautions (5.1) and Drug Interactions (7.2 , 7.3) ] . PREVYMIS is contraindicated with pitavastatin and simvastatin when co-administered with cyclosporine. Concomitant administration of PREVYMIS in combination with cyclosporine may result in significantly increased pitavastatin or simvastatin concentrations, which may lead to myopathy or rhabdomyolysis [see Warnings and Precautions (5.1) and Drug Interactions (7.2 , 7.3) ] . PREVYMIS is contraindicated with: Pimozide. ( 4 )

Ergot

Alkaloids. ( 4 ) Pitavastatin and simvastatin when co-administered with cyclosporine. ( 4 )

AND PRECAUTIONS Risk of Adverse Reactions or Reduced Therapeutic Effect Due to Drug Interactions: The concomitant use of PREVYMIS with certain drugs may result in potentially significant drug interactions, some of which may lead to adverse reactions (PREVYMIS or concomitant drugs) or reduced therapeutic effect of PREVYMIS or the concomitant drug. Consult the full prescribing information for contraindications and dosage recommendations for concomitant drugs. ( 4 , 5.1 , 7.1 , 7.2 , 7.3 )

Risks

Associated with Hydroxypropyl Betadex Excipient in Intravenous Formulation: Intravenous formulation of PREVYMIS contains the excipient hydroxypropyl betadex. PREVYMIS injection should be used only in patients unable to take oral therapy. If possible, intravenous administration should not exceed 4 weeks. In patients with renal impairment, accumulation of hydroxypropyl betadex may occur. Animal studies have shown the potential for hydroxypropyl betadex to cause ototoxicity. ( 5.2 , 8.6 , 13.2 )

5.1 Risk of Adverse Reactions or Reduced Therapeutic Effect Due to Drug Interactions The concomitant use of PREVYMIS and certain drugs may result in potentially significant drug interactions, some of which may lead to adverse reactions (PREVYMIS or concomitant drugs) or reduced therapeutic effect of PREVYMIS or the concomitant drug <span class="opacity-50 text-xs">[see Contraindications (4) and Drug Interactions (7.1 , 7.2 , 7.3) ]</span> .

See Table

11 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 PREVYMIS therapy; review concomitant medications during PREVYMIS therapy; and monitor for adverse reactions associated with PREVYMIS and concomitant medications.

5.2 Risks Associated with Hydroxypropyl Betadex Excipient in Intravenous Formulation Intravenous formulation of PREVYMIS contains the excipient hydroxypropyl betadex. PREVYMIS injection should be used only in patients unable to take oral therapy and patients should be switched to oral PREVYMIS as soon as they are able to take oral medications. If possible, intravenous administration should not exceed 4 weeks <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) ]</span>. In patients with renal impairment, accumulation of hydroxypropyl betadex may occur. In adult patients with CLcr less than 50 mL/min and in pediatric patients with a similar degree of renal impairment (based on age-appropriate assessment of renal function) receiving PREVYMIS injection, closely monitor serum creatinine levels <span class="opacity-50 text-xs">[see Dosage and Administration (2.7) and Use in Specific Populations (8.6) ]</span> . Animal studies have shown the potential for hydroxypropyl betadex to cause ototoxicity <span class="opacity-50 text-xs">[see Nonclinical Toxicology (13.2) ]</span>. The active ingredient, letermovir, is not known to be associated with ototoxicity.