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Letermovir

Class: Antivirals, Miscellaneous
Chemical Name: 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid
Molecular Formula: C29H28F4N4O4
CAS Number: 917389-32-3
Brands: Prevymis

Medically reviewed on Nov 20, 2017

Introduction

Letermovir is an antiviral agent.

Uses for Letermovir

Letermovir has the following uses:

Letermovir is a CMV DNA terminase complex inhibitor indicated for prophylaxis of cytomegalovirus (CMV) infection and disease in adult CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT). 1

Letermovir Dosage and Administration

General

Letermovir is available in the following dosage form(s) and strength(s):

  • Tablets: 240 mg; 480 mg.1

  • Injection: 240 mg/12 mL (20 mg/mL) or 480 mg/24 mL (20 mg/mL) in a single-dose vial.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

  • 480 mg administered once daily orally or as an intravenous (IV) infusion over 1 hour through 100 days post-transplant. 1

  • Must be diluted prior to IV administration.1

  • Dosage Adjustment: If letermovir is co-administered with cyclosporine, the dosage of letermovir should be decreased to 240 mg once daily.1

Cautions for Letermovir

Contraindications

Letermovir is contraindicated with: 1

  • Pimozide.1

  • Ergot Alkaloids.1

  • Pitavastatin and simvastatin when co-administered with cyclosporine.1

Warnings/Precautions

Risk of Adverse Reactions or Reduced Therapeutic Effect Due to Drug Interactions

The concomitant use of letermovir and certain drugs may result in potentially significant drug interactions, some of which may lead to adverse reactions (letermovir or concomitant drugs) or reduced therapeutic effect of letermovir or the concomitant drug.1

Consult manufacturer's labeling for recommendations to prevent or manage these significant drug interactions, including dosing recommendations.1 Consider the potential for drug interactions prior to and during letermovir therapy; review concomitant medications during letermovir therapy, and monitor for adverse reactions associated with letermovir and concomitant medications.1

Specific Populations

Pregnancy

Risk Summary: No adequate human data are available to establish whether letermovir poses a risk to pregnancy outcomes. In animal reproduction studies, embryo-fetal developmental toxicity (including fetal malformations) was observed in rats during the period of organogenesis at letermovir exposures (AUC) 11 times higher than human exposure at the recommended human dose (RHD). In rabbits, no embryo-fetal developmental toxicity was noted at exposures that were not maternally toxic (up to letermovir exposures 2 times higher than human exposure at the RHD). In a rat pre/post-natal development study, total litter loss was observed at maternal letermovir exposures approximately 2 times higher than human exposure at the RHD.1

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.1

Animal Data: Letermovir was administered orally to pregnant rats at 0, 10, 50 or 250 mg/kg/day from gestation days 6 to 17. Developmental toxicities, including skeletal malformations and umbilical cord shortening, were observed at 250 mg/kg/day (approximately 11 times higher than human exposure at the RHD). In addition, decreased fetal body weight and skeletal variations (due to maternal toxicity) were observed at this dose. No embryo-fetal toxicities were observed at 50 mg/kg/day (approximately 3 times higher than human exposure at the RHD).1

Letermovir was administered orally to pregnant rabbits at 0, 25, 75 or 225 mg/kg/day from gestation days 6 to 20. Developmental toxicities, including spontaneous abortion, increased post-implantation loss, and skeletal variations, were observed at a maternally toxic dose (225 mg/kg/day; approximately 2 times higher than human exposure at the RHD). No embryo-fetal toxicities were observed at 75 mg/kg/day (less than human exposure at the RHD).1

In the pre/post-natal development study, letermovir was administered orally to pregnant rats at 0, 10, 45 or 180 mg/kg/day from gestation day 6 to lactation day 22. At 180 mg/kg/day (approximately 2 times higher than human exposure at the RHD), total litter loss due to stillbirth or possible maternal neglect was observed in 5 of 23 pregnant females by post-partum/lactation day 4. In surviving offspring, slight developmental delays in vaginal opening and pinna unfolding were accompanied by reduced body weight gain at this dose. No toxicities were observed at 45 mg/kg/day (similar to human exposure at the RHD).1

Lactation

Risk Summary: It is not known whether letermovir is present in human breast milk, affects human milk production, or has effects on the breastfed child.1

When administered to lactating rats, letermovir was present in the milk of lactating rats as well as the blood of nursing pups.1

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for letermovir and any potential adverse effects on the breastfed child from letermovir or from the underlying maternal condition.1

Data: In a lactation study, letermovir was excreted in milk when administered intravenously (at 10 mg/kg) to lactating rats on post-partum/lactation day 10. Letermovir was also detected in the blood of nursing pups on post-partum/lactation day 21 in the pre/post-natal developmental study.1

Females and Males of Reproductive Potential

There are no data on the effect of letermovir on human fertility. Decreased fertility due to testicular toxicity was observed in male rats.1

Pediatric Use

Safety and efficacy of letermovir in patients below 18 years of age have not been established.1

Geriatric Use

Of the 373 subjects treated with letermovir in Trial P001, 56 (15%) subjects were 65 years of age or older. Safety and efficacy were similar across older and younger subjects. No dosage adjustment of letermovir is required based on age.1

Renal Impairment

For patients with Clcr greater than 10 mL/min (by Cockcroft-Gault equation), no dosage adjustment of letermovir is required based on renal impairment. The safety of letermovir in patients with end-stage renal disease (Clcr less than 10 mL/min), including patients on dialysis, is unknown.1

In patients with Clcr less than 50 mL/min receiving letermovir injection, accumulation of the intravenous vehicle, hydroxypropyl betadex, could occur. Closely monitor serum creatinine levels in these patients.1

Hepatic Impairment

No dosage adjustment of letermovir is required for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. Letermovir is not recommended for patients with severe (Child-Pugh Class C) hepatic impairment.1

Common Adverse Effects

Most common adverse events (occurring in at least 10% of subjects in the letermovir group and at a frequency at least 2% greater than placebo) are nausea, diarrhea, vomiting, peripheral edema, cough, headache, fatigue, and abdominal pain.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • Dosage Adjustment: If letermovir is co-administered with cyclosporine, the dosage of letermovir should be decreased to 240 mg once daily.1

  • Co-administration of letermovir may alter the plasma concentrations of other drugs and other drugs may alter the plasma concentrations of letermovir. Consult the full prescribing information prior to and during treatment for potential drug interactions.1

Actions and Spectrum

Mechanism Of Action

Letermovir is an antiviral drug against CMV.1

Letermovir inhibits the CMV DNA terminase complex (pUL51, pUL56, and pUL89) which is required for viral DNA processing and packaging. Biochemical characterization and electron microscopy demonstrated that letermovir affects the production of proper unit length genomes and interferes with virion maturation. Genotypic characterization of virus resistant to letermovir confirmed that letermovir targets the terminase complex.1

Microbiology

Antiviral Activity: The median EC50 value of letermovir against a collection of clinical CMV isolates in a cell-culture model of infection was 2.1 nM (range = 0.7 nM to 6.1 nM, n = 74). There was no significant difference in EC50 value by CMV gB genotype (gB1=29; gB2=27; gB3=11; and gB4=3).1

Combination Antiviral Activity: No antagonism of the antiviral activity was seen when letermovir was combined with CMV DNA polymerase inhibitors (cidofovir, foscarnet, or ganciclovir).1

Viral Resistance in Cell Culture: CMV mutants with reduced susceptibility to letermovir have been selected in cell culture and the resistance mutations map to UL56. Resistance-associated substitutions occur between amino acid positions pUL56 231 and 369 (V231A/L, V236L/M, E237D, L241P, T244K/R, L257I, F261C/L/S, Y321C, C325F/R/Y, M329T, R369G/M/S). EC50 values for virus expressing these substitutions are 13- to 5870-fold higher than those for the wild-type reference virus.1

Viral Resistance in Clinical Studies: In a Phase 2b trial evaluating letermovir or placebo in 131 HSCT recipients, DNA sequence analysis of a select region of UL56 (amino acids 231 to 369) was performed on samples obtained from 12 letermovir-treated subjects who experienced prophylaxis failure and for whom on-treatment samples were available for analysis. One subject had a letermovir resistance substitution, pUL56 V236M.1

In a Phase 3 trial (P001), DNA sequence analysis of the entire coding regions of UL56 and UL89 was performed on samples obtained from 28 letermovir-treated subjects who had received at least one dose of study drug and experienced prophylaxis failure and for whom samples were available for analysis. Two subjects were identified as having a letermovir-resistance substitution, pUL56 V236M or C325W. These substitutions were identified from on-treatment samples. A virus from a third subject who experienced prophylaxis failure had a pUL56 E237G substitution at low frequency (<5%), and while pUL56 E237D was associated with resistance in cell culture, the clinical significance of this substitution at this frequency is unknown.1

Cross Resistance: Cross resistance is not likely with drugs outside of this class. Letermovir is fully active against viral populations with substitutions conferring resistance to CMV DNA polymerase inhibitors (cidofovir, foscarnet, and ganciclovir). These DNA polymerase inhibitors are fully active against viral populations with substitutions conferring resistance to letermovir.1

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Patient Information).1

Drug Interactions

Inform patients that letermovir may interact with some drugs; therefore, advise patients to report the use of any prescription, non-prescription medication, or herbal products to their healthcare provider.1

Administration

Inform patients that it is important not to miss or skip doses and to take letermovir for the duration that is recommended by the healthcare provider. Instruct patients that if they miss a dose of letermovir, they should take it as soon as they remember. If they do not remember until it is time for the next dose, instruct them to skip the missed dose and go back to the regular schedule. Instruct patients not to double their next dose or take more than the prescribed dose.1

Storage

Advise patients to store letermovir tablets in the original package until use.1

Additional Information

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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.

Letermovir

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablet, Film Coated

240 mg

Prevymis

Merck Sharp & Dohme Corp.

480 mg

Prevymis

Merck Sharp & Dohme Corp.

Parenteral

Injection, for IV infusion

20 mg/1 mL

Prevymis

Merck Sharp & Dohme Corp.

AHFS Drug Information. © Copyright 2018, Selected Revisions November 20, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Merck Sharp & Dohme Corp.. PREVYMIS (LETERMOVIR) tablets and injection prescribing information. 2017 Nov. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1b49df80-be4f-47e0-a0b7-123f3e69395b

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