Maribavir (Monograph)
Brand name: Livtencity
Drug class: Antivirals, Miscellaneous
VA class: AM800
Chemical name: (2S,3S,4R,5S)-2-[5,6-dichloro-2-(propan-2-ylamino)benzimidazol-1-yl]-5-(hydroxymethyl)oxolane-3,4-diol
Molecular formula: C15H19Cl2N3O4
CAS number: 176161-24-3:
Introduction
Antiviral; a cytomegalovirus (CMV) pUL97 protein kinase inhibitor active against CMV.
Uses for Maribavir
Treatment of CMV Infection and Disease
Treatment of CMV infection and disease that is refractory to treatment (with or without genotype resistance) with ganciclovir, valganciclovir, cidofovir or foscarnet in adult and pediatric transplant recipients ≥12 years of age who weigh ≥35 kg.
Maribavir Dosage and Administration
General
Pretreatment Screening
-
Consider the potential for drug interactions prior to maribavir therapy.
Patient Monitoring
-
Monitor CMV DNA levels and check for resistance if the patient does not respond to treatment.
-
Consider the potential for drug interactions during maribavir therapy; review concomitant medications during maribavir therapy and monitor for adverse reactions.
-
Frequently monitor immunosuppressant drug levels throughout treatment with maribavir, especially following initiation and after discontinuation of maribavir.
Administration
Oral Administration
Administer orally without regard to meals.
Dosage
Pediatric Patients
CMV Infection and Disease in Transplant Recipients
Oral
Adolescents ≥12 years of age weighing ≥35 kg: 400 mg (two 200-mg tablets) twice daily.
If used concomitantly with carbamazepine, increase maribavir dosage to 800 mg twice daily. If used concomitantly with phenobarbital or phenytoin, increase maribavir dosage to 1200 mg twice daily.
Adults
CMV Infection and Disease in Transplant Recipients
Oral
400 mg (two 200-mg tablets) twice daily.
If used concomitantly with carbamazepine, increase maribavir dosage to 800 mg twice daily. If used concomitantly with phenobarbital or phenytoin, increase maribavir dosage to 1200 mg twice daily.
Special Populations
Hepatic Impairment
No dosage adjustment necessary in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. Not studied in patients with severe hepatic impairment.
Renal Impairment
No dosage adjustment necessary in patients with mild, moderate, or severe renal impairment (Clcr 12–70 mL/minute). Not studied in patients with end-stage renal disease (ESRD), including those on dialysis.
Geriatric Patients
No dosage adjustment necessary.
Cautions for Maribavir
Contraindications
-
None.
Warnings/Precautions
Reduced Antiviral Activity When Coadministered with Valganciclovir and Ganciclovir
Maribavir (which inhibits CMV pUL97 kinase) may antagonize the antiviral activity of valganciclovir and ganciclovir, which require activation by CMV pUL97 kinase. Concomitant administration of maribavir and valganciclovir/ganciclovir not recommended.
Virologic Failure During Treatment and Relapse Post-Treatment
Possible treatment failure due to resistance during and after treatment with maribavir can occur. Virologic relapse during the post-treatment period occurred within 4–8 weeks after treatment discontinuation. Maribavir pUL97 resistance-associated substitutions may confer cross-resistance to ganciclovir and valganciclovir.
Monitor CMV DNA levels and check for maribavir resistance if the patient is not responding to treatment.
Loss of Virologic Response or Risk of Adverse Reactions Due to Drug Interactions
Concomitant use of certain drugs may result in potentially significant drug interactions, which may decrease therapeutic efficacy or increase risk of adverse reactions.
Review concomitant medications and monitor for adverse reactions.
Specific Populations
Pregnancy
No adequate human data available.
In animal studies, embryofetal toxicity (increased resorptions, post-implantation loss) observed in rats receiving maribavir in dosages resulting in exposures less than the systemic exposures achieved in humans at the recommended human dose.
Lactation
Not known if distributed into human milk, affects milk production, or has any effects on breast-fed infants.
Consider benefits of breast-feeding and importance of maribavir to the woman; also consider potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.
Pediatric Use
Safety and efficacy not established in pediatric patients <12 years of age.
Safety and efficacy in pediatric transplant recipients ≥12 years of age based on data from pharmacokinetic modeling and extrapolation of data and evidence from adults.
Course of disease and exposure in pediatric patients expected to be similar to adults.
Geriatric Use
No overall differences in safety and efficacy in patients ≥65 years of age compared with younger adults.
Hepatic Impairment
Mild to moderate hepatic impairment (Child-Pugh Class A or B): pharmacokinetics not altered.
Not evaluated systematically in patients with severe hepatic impairment.
Renal Impairment
Mild to severe renal impairment (Clcr 12–70 mL/minute): pharmacokinetics not altered.
Not evaluated systematically in patients with end-stage renal disease requiring dialysis.
Common Adverse Effects
Adverse effects (≥10%): taste disturbance, nausea, diarrhea, vomiting, fatigue.
Interactions for Maribavir
Metabolized primarily by CYP3A4, and to lesser extent, by CYP1A2. In vitro, maribavir is not a substrate of CYP2B6, 2C8, 2C9, 2C19, 3A5; uridine diphosphate-glucuronosyltransferase (UGT) 1A4, 1A6, 1A10, 2B15; organic anion transporting polypeptide (OATP) 1B1, 1B3; or bile salt export pump (BSEP).
Weakly inhibits CYP3A4 and inhibits P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in vitro.
Drugs Affecting Hepatic Microsomal Enzymes
Potent inducers of CYP3A4: decreased maribavir plasma concentrations expected, which may result in reduced therapeutic efficacy. Concomitant use not recommended, except for selected anticonvulsants.
Drugs Metabolized by Hepatic Microsomal Enzymes
Substrates of CYP3A4: maribavir may increase plasma concentrations of drugs that are CYP3A4 substrates; in some cases, minimal concentration changes may lead to serious adverse events such as with some immunosuppressant drugs (e.g., tacrolimus, cyclosporine, sirolimus, everolimus). Frequently monitor immunosuppressant drug levels throughout treatment with maribavir, especially following initiation and after discontinuation of maribavir; adjust dosage of the immunosuppressant drug as needed.
Drugs Affected by Transporter Systems
Sensitive substrates of P-gp or BCRP: Potential pharmacokinetic interaction (increased exposure of P-gp or BCRP substrate) and possible increased toxicity of these substrates.
Specific Drugs
Drug |
Interaction |
Comments |
---|---|---|
Antacids (aluminum hydroxide and magnesium hydroxide) |
Clinically important pharmacokinetic interaction unlikely |
|
Antiviral agents |
Valganciclovir/ganciclovir: antagonism of antiviral activity possible since maribavir inhibits pUL97 kinase activity necessary for activation of valganciclovir and ganciclovir Cidofovir, foscarnet, letermovir: No antagonistic effects observed |
Valganciclovir/ganciclovir: concomitant use not recommended |
Carbamazepine |
Potent CYP3A inducers: Decreased maribavir peak plasma concentration and AUC and possible decreased maribavir efficacy |
Increase maribavir dosage to 800 mg twice daily |
Cyclosporine |
Increased cyclosporine plasma concentrations and possible cyclosporine toxicity |
If used concomitantly, monitor serum cyclosporine concentrations and adjust cyclosporine dosage as needed |
Dextromethorphan |
Clinically important pharmacokinetic interaction unlikely |
|
Digoxin |
Increased digoxin plasma concentrations and possible digoxin toxicity |
Caution advised; carefully monitor serum digoxin concentrations and reduce digoxin dosage as needed |
Everolimus |
Increased everolimus plasma concentrations and possible everolimus toxicity |
Monitor serum everolimus concentrations and adjust everolimus dosage as needed |
Ketoconazole |
Clinically important pharmacokinetic interaction unlikely |
|
Midazolam |
Clinically important pharmacokinetic interaction unlikely |
|
Phenobarbital |
Potent CYP3A inducers: Decreased maribavir plasma concentrations and possible decreased maribavir efficacy |
Increase maribavir dosage to 1200 mg twice daily |
Phenytoin |
Potent CYP3A inducers: Decreased maribavir plasma concentrations and possible decreased efficacy |
Increase maribavir dosage to 1200 mg twice daily |
Rifabutin |
Potent CYP3A inducers: Decreased maribavir plasma concentrations and possible decreased efficacy |
Avoid concomitant use |
Rifampin |
Potent CYP3A inducers: Decreased maribavir plasma concentrations and possible decreased efficacy |
Avoid concomitant use |
Rosuvastatin |
Increased rosuvastatin plasma concentrations and possible increased toxicity |
Carefully monitor for rosuvastatin-related toxicity (e.g., myopathy, rhabdomyolysis) |
St. John's wort |
Potent CYP3A inducers: Decreased maribavir peak plasma concentration and AUC, possibly reducing maribavir efficacy |
Avoid concomitant use |
Sirolimus |
Increased sirolimus plasma concentrations and possible sirolimus toxicity |
Monitor serum sirolimus concentrations and adjust sirolimus dosage as needed |
Tacrolimus |
Increased tacrolimus plasma concentrations and possible tacrolimus toxicity |
Monitor serum tacrolimus concentrations and adjust tacrolimus dosage as needed |
Voriconazole |
Clinically important pharmacokinetic interaction unlikely |
|
Warfarin |
Clinically important pharmacokinetic interaction unlikely |
Maribavir Pharmacokinetics
Absorption
Bioavailability
Median time to peak plasma concentrations following oral administration is 1–3 hours.
Systemic exposure and peak plasma concentrations increase in a dose-proportional manner with single doses up to 1600 mg and multiple doses up to 2400 mg daily.
Steady-state concentrations achieved within 2 days; mean accumulation ratios of peak plasma concentration and AUC are 1.37–1.47.
Food
Food does not affect systemic bioavailability.
Distribution
Extent
Not known whether distributed into human milk.
Plasma Protein Binding
98%.
Elimination
Metabolism
Metabolized primarily by CYP3A4, and to a lesser extent, by CYP1A2 to an inactive metabolite N-dealkylated metabolite (VP 44469).
Elimination Route
Eliminated in urine (61%) and feces (14%); unchanged drug accounted for <2% of dose recovered in urine and 5.7% of dose in feces.
Half-life
Mean 4.32 hours in transplant patients.
Special Populations
Mild or moderate hepatic impairment (Child-Pugh class A or B): No effect on pharmacokinetics.
Severe hepatic impairment (Child-Pugh class C): Pharmacokinetics not studied.
Mild, moderate, or severe renal impairment (Clcr 12–70 mL/minute): No effect on pharmacokinetics.
No clinically important differences in pharmacokinetics based on age (18–79 years of age), sex, race, or body weight (36–141 kg).
Pharmacokinetics not studied in patients <18 years of age.
Stability
Storage
Oral
Tablets
20–25°C (excursions permitted between 15–30°C).
Actions
-
A benzimidazole riboside CMV pUL97 protein kinase inhibitor.
-
Competitively inhibits protein kinase activity of CMV pUL97, resulting in inhibition of protein phosphorylation, and inhibition of viral DNA replication, encapsidation, and nuclear egress of viral capsids.
-
Inhibits CMV replication in virus yield reduction, DNA hybridization, and plaque reduction assays in human cell lines.
-
Active in vitro and in vivo against human CMV, including strains resistant to ganciclovir, foscarnet, cidofovir, or valganciclovir.
-
CMV isolates with reduced susceptibility to maribavir produced in vitro have been identified.
-
Cross-resistance between maribavir and ganciclovir/valganciclovir observed in cell culture and clinical studies. Maribavir resistant virus remained susceptible to cidofovir and foscarnet.
-
Remains susceptible to CMV isolates with substitutions in viral DNA polymerase pUL54 conferring resistance to DNA polymerase inhibitors (e.g., cidofovir, foscarnet, ganciclovir, valganciclovir). Cross-resistance due to pUL27 maribavir substitutions not expected.
Advice to Patients
-
Advise the patient to read the FDA-approved patient labeling (Patient Information).
-
Importance of not missing or skipping doses and importance of continuing maribavir for the duration recommended by the clinician.
-
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
-
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (e.g., anticonvulsants) and OTC drugs and dietary or herbal supplements (e.g., St. John’s wort), as well as any concomitant illnesses.
-
Advise patients of other important precautionary information. (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes |
Dosage Forms |
Strengths |
Brand Names |
Manufacturer |
---|---|---|---|---|
Oral |
Tablets, film-coated |
200 mg |
Livtencity |
Takeda |
AHFS DI Essentials™. © Copyright 2023, Selected Revisions August 29, 2022. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
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