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:

Medically reviewed by Drugs.com on Aug 29, 2022. Written by ASHP.

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 (Cl_cr 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 (Cl_cr 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

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 (Cl_cr 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.

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