Letermovir: Difference between revisions

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*PREVYMIS is an antiviral drug against CMV.
|PD=(Description)
|structure=
|PK=(Description)
[[image:letermovirstructure.png|none|thumb|400px|This image is provided by the National Library of Medicine.]]
|nonClinToxic=(Description)
|PD=
|clinicalStudies======Condition 1=====
=====Cardiac Electrophysiology=====
 
*In a thorough QT trial in healthy subjects, letermovir at the therapeutic IV dose or at a dose of 2 times the approved IV dose did not prolong QTc to any clinically relevant extent.
(Description)
|PK=
 
*The pharmacokinetic properties of letermovir are displayed in Table 4.
=====Condition 2=====
[[image:letermovirpd1.png|none|thumb|400px|This image is provided by the National Library of Medicine.]]
 
=====Specific Populations=====
(Description)
''Pediatric Population''
 
*The pharmacokinetics of letermovir in patients less than 18 years of age have not been evaluated.
=====Condition 3=====
''Age, Gender, Race, and Weight''
 
*Age (18 to 78 years), gender, race (White vs. non-White), and body weight (up to 100 kg) did not have a clinically significant effect on the pharmacokinetics of letermovir.
(Description)
''Renal Impairment''
*Letermovir AUC was approximately 1.9- and 1.4-fold higher in subjects with moderate (eGFR greater than or equal to 30 to 59 mL/min/1.73m<sup>2</sup>) and severe (eGFR less than 30 mL/min/1.73m2) renal impairment, respectively, compared to healthy subjects.
*Hydroxypropyl betadex present in the intravenous letermovir formulation is mainly eliminated by glomerular filtration. Decreased elimination of hydroxypropyl betadex has been reported in the literature in patients with severe renal impairment.
''Hepatic Impairment''
*Letermovir AUC was approximately 1.6- and 3.8-fold higher in subjects with moderate (Child-Pugh Class B [CP-B], score of 7-9) and severe (Child-Pugh Class C [CP-C], score of 10-15) hepatic impairment, respectively, compared to healthy subjects.
=====Drug Interaction Studies=====
*Drug interaction studies were performed in healthy subjects with PREVYMIS and drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interactions.
*In vitro results indicate that letermovir is a substrate of drug metabolizing enzymes CYP3A, CYP2D6, UGT1A1, and UGT1A3, and transporters OATP1B1/3 and P-gp. Oxidative metabolism is considered to be a minor elimination pathway based on in vivo human data. Inhibitors of OATP1B1/3 may result in increases in letermovir plasma concentrations. Changes in letermovir plasma concentrations due to inhibition of P-gp or UGTs are not anticipated to be clinically relevant.
*Based on in vitro studies, the metabolism of letermovir is not mediated by CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2E1, CYP4A11, UGT1A4, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B4, UGT2B7, UGT2B15, or UGT2B17. The transport of letermovir is not mediated by OATP2B1, OCT1, OAT1, BCRP, or MRP2 in vitro.
*Letermovir is a time-dependent inhibitor and inducer of CYP3A in vitro. Co-administration of PREVYMIS with midazolam resulted in increased exposure of midazolam, indicating that the net effect of letermovir on CYP3A is moderate inhibition. Based on these results, co-administration of PREVYMIS with CYP3A substrates may increase the plasma concentrations of the CYP3A substrates. Letermovir is a reversible inhibitor of CYP2C8 in vitro. When co-administered with PREVYMIS, plasma concentrations of CYP2C8 substrates are predicted to be increased. Co-administration of PREVYMIS reduced the exposure of voriconazole, most likely due to the induction of voriconazole elimination pathways, CYP2C9 and CYP2C19. Co-administration of PREVYMIS with CYP2C9 and CYP2C19 substrates may decrease the plasma concentrations of the CYP2C9 and CYP2C19 substrates. Letermovir is an inducer of CYP2B6 in vitro; the clinical relevance is unknown.
*Letermovir inhibited efflux transporters P-gp, breast cancer resistance protein (BCRP), bile salt export pump (BSEP), multidrug resistance-associated protein 2 (MRP2), OAT3, and hepatic uptake transporter OATP1B1/3 in vitro. Co-administration of PREVYMIS with substrates of OATP1B1/3 transporters (e.g. atorvastatin, a known substrate of CYP3A, OATP1B1/3, and potentially BCRP) may result in a clinically relevant increase in plasma concentrations of OATP1B1/3 substrates. There were no clinically relevant changes in plasma concentrations of digoxin, a P-gp substrate, or acyclovir, an OAT3 substrate, following co-administration with PREVYMIS in clinical studies. The effect of letermovir on BCRP, BSEP, and MRP2 substrates was not evaluated in clinical studies; the clinical relevance is unknown.
*Based on in vitro results letermovir is not an inhibitor of CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, UGT1A4, UGT1A6, UGT1A9, or UGT2B7 and is not an inducer of CYP1A2. Letermovir is not an inhibitor of MRP2, OATP2B1, BSEP, OCT1, OCT2, or OAT1 in vitro.
[[image:letermovirpd2.png|none|thumb|400px|This image is provided by the National Library of Medicine.]]
[[image:letermovirpd3.png|none|thumb|400px|This image is provided by the National Library of Medicine.]]
=====Microbiology=====
=====Mechanism of Action=====
*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.
=====Antiviral Activity=====
*The median EC<sub>50</sub> 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 EC<sub>50</sub> value by CMV gB genotype (gB1=29; gB2=27; gB3=11; and gB4=3).
=====Combination Antiviral Activity=====
*No antagonism of the antiviral activity was seen when letermovir was combined with CMV DNA polymerase inhibitors (cidofovir, foscarnet, or ganciclovir).
=====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). EC<sub>50</sub> values for virus expressing these substitutions are 13- to 5,870-fold higher than those for the wild-type reference virus.
''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.
*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.
=====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.
|nonClinToxic=
=====Carcinogenesis, Mutagenesis, Impairment of Fertility=====
=====Carcinogenesis and Mutagenesis=====
*Letermovir was not genotoxic in in vitro or in vivo assays, including microbial mutagenesis assays, chromosomal aberration in Chinese hamster ovary cells, and in an in vivo mouse micronucleus study.
*Carcinogenicity studies with letermovir have not been conducted.
=====Impairment of Fertility=====
*In a fertility and early embryonic development study in rats, no effects of letermovir on female fertility were observed at letermovir exposures (AUC) approximately 5 times higher than human exposure at the RHD.
*In male rat fertility studies, decreased fertility associated with irreversible testicular toxicity was observed at ≥180 mg/kg/day (greater than or equal to 3 times the human exposure at the RHD). No fertility or testicular effects were observed at dose levels resulting in letermovir exposures (AUC) similar to human exposure at the RHD.
=====Animal Toxicology and/or Pharmacology=====
*Testicular toxicity in rats observed at ≥180 mg/kg/day (greater than or equal to 3 times the human exposure at the RHD) was characterized by decreased testis weight, bilateral seminiferous tubular degeneration, decreased sperm count and motility, and resultant decreased male fertility. Male reproductive system toxicities were not observed in either a monkey testicular toxicity study up to 240 mg/kg/day (approximately 2 times higher than human exposure at the RHD), or a general toxicology study in mice up to 250 mg/kg/day (approximately 3 times higher than human exposure at the RHD).
|clinicalStudies=
=====Adult CMV-seropositive Recipients [R+] of an Allogeneic Hematopoietic Stem Cell Transplant=====
*To evaluate PREVYMIS prophylaxis as a preventive strategy for CMV infection or disease in transplant recipients at high risk for CMV reactivation, the efficacy of PREVYMIS was assessed in a multicenter, double-blind, placebo-controlled Phase 3 Trial (P001, NCT02137772) in adult CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT). Subjects were randomized (2:1) to receive either PREVYMIS at a dose of 480 mg once daily adjusted to 240 mg when co-administered with cyclosporine, or placebo. Randomization was stratified by investigational site and risk level for CMV reactivation at the time of study entry. Study drug was initiated after HSCT (at any time from Day 0 to Day 28 post-transplant) and continued through Week 14 post-transplant. Study drug was administered either orally or intravenously; the dose of PREVYMIS was the same regardless of the route of administration. Subjects received CMV DNA monitoring weekly until post-transplant Week 14 and then bi-weekly until post-transplant Week 24, with initiation of standard-of-care CMV pre-emptive therapy if CMV viremia was considered clinically significant. Subjects had continued follow-up through Week 48 post-transplant.
*Among the 565 treated subjects, 70 subjects were found to have CMV viremia prior to study drug initiation and were therefore excluded from the efficacy analyses. The efficacy population consisted of 325 subjects who received PREVYMIS (including 91 subjects who received at least one IV dose) and 170 who received placebo (including 41 subjects who received at least one IV dose). The IV formulation of PREVYMIS was used at investigators' discretion in subjects who were unable to take oral therapy (e.g., unable to tolerate oral intake). The median time to starting study drug was 8 days after transplantation. Thirty-four percent (34%) of subjects were engrafted at baseline. The median age was 55 years (range: 18 to 76 years); 57% were male; 84% were White; 9% were Asian; 2% were Black or African American; and 7% were Hispanic or Latino.
*At baseline, 30% of all subjects had one or more of the following factors associated with increased risk for CMV reactivation (high risk stratum): Human Leukocyte Antigen (HLA)-related donor with at least one mismatch at one of the following three HLA-gene loci: HLA-A, -B or –DR; haploidentical donor; unrelated donor with at least one mismatch at one of the following four HLA-gene loci: HLA-A, -B, -C and -DRB1; use of umbilical cord blood as stem cell source; use of ex vivo T-cell-depleted grafts; Grade 2 or greater Graft-Versus-Host Disease (GVHD) requiring systemic corticosteroids. The remaining 70% of subjects did not meet any of these high risk stratum criteria and were therefore included in the low risk stratum. Additionally, 48% of subjects received a myeloablative regimen, 51% were receiving cyclosporine, and 43% were receiving tacrolimus. The most common primary reasons for transplant were acute myeloid leukemia (38%), myelodysplastic syndrome (16%), and lymphoma (12%).
''Clinically Significant CMV Infection''
*The primary efficacy endpoint of Trial P001 was the incidence of clinically significant CMV infection through Week 24 post-transplant (prophylaxis failure). Clinically significant CMV infection was defined as the occurrence of either CMV end-organ disease, or initiation of anti-CMV pre-emptive therapy (PET) based on documented CMV viremia (using the Roche COBAS® AmpliPrep/COBAS TaqMan® assay, LLoQ is 137 IU/mL, which is approximately 150 copies/mL) and the clinical condition of the subject. The protocol-specified guidance for CMV DNA thresholds for the initiation of PET during the treatment period was ≥ 150 copies/mL or > 300 copies/mL for subjects in the high and low risk strata, respectively. From Week 14 through Week 24, the threshold was >300 copies/mL for both high and low risk strata subjects. The Non-Completer=Failure (NC=F) approach was used, where subjects who discontinued from the trial prior to Week 24 post-transplant or had a missing outcome at Week 24 post-transplant were counted as failures.
*Efficacy results from Trial P001 are shown in Table 7.
[[image:letermovirclinicaltrial1.png|none|thumb|400px|This image is provided by the National Library of Medicine.]]
*Efficacy results were consistent across high and low risk strata for CMV reactivation. The time to clinically significant CMV infection is shown in Figure 1.
[[image:letermovirclinicaltrial2.png|none|thumb|400px|This image is provided by the National Library of Medicine.]]
*Post-hoc analysis demonstrated that among PREVYMIS-treated subjects, inclusion in the high risk stratum for CMV reactivation at baseline, occurrence of GVHD, and steroid use at any time after randomization may be associated with the development of clinically significant CMV infection between Week 14 and Week 24 post-transplant.
''Mortality''
*The Kaplan-Meier event rate for all-cause mortality in the letermovir vs. placebo groups was 12% vs. 17% at Week 24 post-transplant, and 24% vs. 28% at Week 48 post-transplant.
|howSupplied=
|howSupplied=
=====Tablets=====
=====Tablets=====

Revision as of 14:10, 18 July 2018

Letermovir
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sonya Gelfand

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Overview

Letermovir is a Acetylcholine release inhibitor, Adrenergic receptor agonist that is FDA approved for the (type of indication of drug) of a list of indications, separated by commas.. Common adverse reactions include a list of adverse reactions, separated by commas..

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Condition 1
  • Dosing Information
  • (Dosage)
Condition 2
  • Dosing Information
  • (Dosage)

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

Condition 1
  • Developed by: (Organisation)
  • Class of Recommendation: (Class) (Link)
  • Strength of Evidence: (Category A/B/C) (Link)
  • Dosing Information/Recommendation
  • (Dosage)
Condition 2
  • Developed by: (Organisation)
  • Class of Recommendation: (Class) (Link)
  • Strength of Evidence: (Category A/B/C) (Link)
  • Dosing Information/Recommendation
  • (Dosage)

Non–Guideline-Supported Use

Condition 1
  • Dosing Information
  • (Dosage)
Condition 2
  • Dosing Information
  • (Dosage)
Condition 3
  • Dosing Information
  • (Dosage)

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Condition 1
  • Dosing Information
  • (Dosage)
Condition 2
  • Dosing Information
  • (Dosage)

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

Condition 1
  • Developed by: (Organisation)
  • Class of Recommendation: (Class) (Link)
  • Strength of Evidence: (Category A/B/C) (Link)
  • Dosing Information/Recommendation
  • (Dosage)
Condition 2
  • Developed by: (Organisation)
  • Class of Recommendation: (Class) (Link)
  • Strength of Evidence: (Category A/B/C) (Link)
  • Dosing Information/Recommendation
  • (Dosage)

Non–Guideline-Supported Use

Condition 1
  • Dosing Information
  • (Dosage)
Condition 2
  • Dosing Information
  • (Dosage)
Condition 3
  • Dosing Information
  • (Dosage)

Contraindications

CONTRAINDICATIONS

Warnings

Conidition 1

(Description)

Conidition 2

(Description)

Conidition 3

(Description)

Adverse Reactions

Clinical Trials Experience

Central Nervous System
(list/description of adverse reactions)
Cardiovascular
(list/description of adverse reactions)
Respiratory
(list/description of adverse reactions)
Gastrointestinal
(list/description of adverse reactions)
Hypersensitive Reactions
(list/description of adverse reactions)
Miscellaneous
(list/description of adverse reactions)
Condition 2
Central Nervous System
(list/description of adverse reactions)
Cardiovascular
(list/description of adverse reactions)
Respiratory
(list/description of adverse reactions)
Gastrointestinal
(list/description of adverse reactions)
Hypersensitive Reactions
(list/description of adverse reactions)
Miscellaneous
(list/description of adverse reactions)

Postmarketing Experience

(Description)

Drug Interactions

  • Drug 1
  • Drug 2
  • Drug 3
  • Drug 4
  • Drug 5
Drug 1

(Description)

Drug 2

(Description)

Drug 3

(Description)

Drug 4

(Description)

Drug 5

(Description)

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): (Description)
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Letermovir in women who are pregnant.

Labor and Delivery

(Description)

Nursing Mothers

(Description)g

Pediatric Use

(Description)

Geriatic Use

(Description)

Gender

(Description)

Race

(Description)

Renal Impairment

(Description)

Hepatic Impairment

(Description)

Females of Reproductive Potential and Males

(Description)

Immunocompromised Patients

(Description)

Others

(Description)

Administration and Monitoring

Administration

(Oral/Intravenous/etc)

Monitoring

Condition 1

(Description regarding monitoring, from Warnings section)

Condition 2

(Description regarding monitoring, from Warnings section)

Condition 3

(Description regarding monitoring, from Warnings section)

IV Compatibility

There is limited information regarding the compatibility of Letermovir and IV administrations.

Overdosage

Acute Overdose

Signs and Symptoms

(Description)

Management

(Description)

Chronic Overdose

Signs and Symptoms

(Description)

Management

(Description)

Pharmacology

Letermovir
Systematic (IUPAC) name
?
Identifiers
CAS number ?
ATC code ?
PubChem ?
Chemical data
Formula ?
Mol. mass ?
Pharmacokinetic data
Bioavailability ?
Metabolism ?
Half life ?
Excretion ?
Therapeutic considerations
Pregnancy cat.

?

Legal status
Routes ?

Mechanism of Action

  • PREVYMIS is an antiviral drug against CMV.

Structure

This image is provided by the National Library of Medicine.

Pharmacodynamics

Cardiac Electrophysiology
  • In a thorough QT trial in healthy subjects, letermovir at the therapeutic IV dose or at a dose of 2 times the approved IV dose did not prolong QTc to any clinically relevant extent.

Pharmacokinetics

  • The pharmacokinetic properties of letermovir are displayed in Table 4.
This image is provided by the National Library of Medicine.
Specific Populations

Pediatric Population

  • The pharmacokinetics of letermovir in patients less than 18 years of age have not been evaluated.

Age, Gender, Race, and Weight

  • Age (18 to 78 years), gender, race (White vs. non-White), and body weight (up to 100 kg) did not have a clinically significant effect on the pharmacokinetics of letermovir.

Renal Impairment

  • Letermovir AUC was approximately 1.9- and 1.4-fold higher in subjects with moderate (eGFR greater than or equal to 30 to 59 mL/min/1.73m2) and severe (eGFR less than 30 mL/min/1.73m2) renal impairment, respectively, compared to healthy subjects.
  • Hydroxypropyl betadex present in the intravenous letermovir formulation is mainly eliminated by glomerular filtration. Decreased elimination of hydroxypropyl betadex has been reported in the literature in patients with severe renal impairment.

Hepatic Impairment

  • Letermovir AUC was approximately 1.6- and 3.8-fold higher in subjects with moderate (Child-Pugh Class B [CP-B], score of 7-9) and severe (Child-Pugh Class C [CP-C], score of 10-15) hepatic impairment, respectively, compared to healthy subjects.
Drug Interaction Studies
  • Drug interaction studies were performed in healthy subjects with PREVYMIS and drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interactions.
  • In vitro results indicate that letermovir is a substrate of drug metabolizing enzymes CYP3A, CYP2D6, UGT1A1, and UGT1A3, and transporters OATP1B1/3 and P-gp. Oxidative metabolism is considered to be a minor elimination pathway based on in vivo human data. Inhibitors of OATP1B1/3 may result in increases in letermovir plasma concentrations. Changes in letermovir plasma concentrations due to inhibition of P-gp or UGTs are not anticipated to be clinically relevant.
  • Based on in vitro studies, the metabolism of letermovir is not mediated by CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2E1, CYP4A11, UGT1A4, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B4, UGT2B7, UGT2B15, or UGT2B17. The transport of letermovir is not mediated by OATP2B1, OCT1, OAT1, BCRP, or MRP2 in vitro.
  • Letermovir is a time-dependent inhibitor and inducer of CYP3A in vitro. Co-administration of PREVYMIS with midazolam resulted in increased exposure of midazolam, indicating that the net effect of letermovir on CYP3A is moderate inhibition. Based on these results, co-administration of PREVYMIS with CYP3A substrates may increase the plasma concentrations of the CYP3A substrates. Letermovir is a reversible inhibitor of CYP2C8 in vitro. When co-administered with PREVYMIS, plasma concentrations of CYP2C8 substrates are predicted to be increased. Co-administration of PREVYMIS reduced the exposure of voriconazole, most likely due to the induction of voriconazole elimination pathways, CYP2C9 and CYP2C19. Co-administration of PREVYMIS with CYP2C9 and CYP2C19 substrates may decrease the plasma concentrations of the CYP2C9 and CYP2C19 substrates. Letermovir is an inducer of CYP2B6 in vitro; the clinical relevance is unknown.
  • Letermovir inhibited efflux transporters P-gp, breast cancer resistance protein (BCRP), bile salt export pump (BSEP), multidrug resistance-associated protein 2 (MRP2), OAT3, and hepatic uptake transporter OATP1B1/3 in vitro. Co-administration of PREVYMIS with substrates of OATP1B1/3 transporters (e.g. atorvastatin, a known substrate of CYP3A, OATP1B1/3, and potentially BCRP) may result in a clinically relevant increase in plasma concentrations of OATP1B1/3 substrates. There were no clinically relevant changes in plasma concentrations of digoxin, a P-gp substrate, or acyclovir, an OAT3 substrate, following co-administration with PREVYMIS in clinical studies. The effect of letermovir on BCRP, BSEP, and MRP2 substrates was not evaluated in clinical studies; the clinical relevance is unknown.
  • Based on in vitro results letermovir is not an inhibitor of CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, UGT1A4, UGT1A6, UGT1A9, or UGT2B7 and is not an inducer of CYP1A2. Letermovir is not an inhibitor of MRP2, OATP2B1, BSEP, OCT1, OCT2, or OAT1 in vitro.
This image is provided by the National Library of Medicine.
This image is provided by the National Library of Medicine.
Microbiology
Mechanism of Action
  • 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.
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).
Combination Antiviral Activity
  • No antagonism of the antiviral activity was seen when letermovir was combined with CMV DNA polymerase inhibitors (cidofovir, foscarnet, or ganciclovir).
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 5,870-fold higher than those for the wild-type reference virus.

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.
  • 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.
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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis and Mutagenesis
  • Letermovir was not genotoxic in in vitro or in vivo assays, including microbial mutagenesis assays, chromosomal aberration in Chinese hamster ovary cells, and in an in vivo mouse micronucleus study.
  • Carcinogenicity studies with letermovir have not been conducted.
Impairment of Fertility
  • In a fertility and early embryonic development study in rats, no effects of letermovir on female fertility were observed at letermovir exposures (AUC) approximately 5 times higher than human exposure at the RHD.
  • In male rat fertility studies, decreased fertility associated with irreversible testicular toxicity was observed at ≥180 mg/kg/day (greater than or equal to 3 times the human exposure at the RHD). No fertility or testicular effects were observed at dose levels resulting in letermovir exposures (AUC) similar to human exposure at the RHD.
Animal Toxicology and/or Pharmacology
  • Testicular toxicity in rats observed at ≥180 mg/kg/day (greater than or equal to 3 times the human exposure at the RHD) was characterized by decreased testis weight, bilateral seminiferous tubular degeneration, decreased sperm count and motility, and resultant decreased male fertility. Male reproductive system toxicities were not observed in either a monkey testicular toxicity study up to 240 mg/kg/day (approximately 2 times higher than human exposure at the RHD), or a general toxicology study in mice up to 250 mg/kg/day (approximately 3 times higher than human exposure at the RHD).

Clinical Studies

Adult CMV-seropositive Recipients [R+] of an Allogeneic Hematopoietic Stem Cell Transplant
  • To evaluate PREVYMIS prophylaxis as a preventive strategy for CMV infection or disease in transplant recipients at high risk for CMV reactivation, the efficacy of PREVYMIS was assessed in a multicenter, double-blind, placebo-controlled Phase 3 Trial (P001, NCT02137772) in adult CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT). Subjects were randomized (2:1) to receive either PREVYMIS at a dose of 480 mg once daily adjusted to 240 mg when co-administered with cyclosporine, or placebo. Randomization was stratified by investigational site and risk level for CMV reactivation at the time of study entry. Study drug was initiated after HSCT (at any time from Day 0 to Day 28 post-transplant) and continued through Week 14 post-transplant. Study drug was administered either orally or intravenously; the dose of PREVYMIS was the same regardless of the route of administration. Subjects received CMV DNA monitoring weekly until post-transplant Week 14 and then bi-weekly until post-transplant Week 24, with initiation of standard-of-care CMV pre-emptive therapy if CMV viremia was considered clinically significant. Subjects had continued follow-up through Week 48 post-transplant.
  • Among the 565 treated subjects, 70 subjects were found to have CMV viremia prior to study drug initiation and were therefore excluded from the efficacy analyses. The efficacy population consisted of 325 subjects who received PREVYMIS (including 91 subjects who received at least one IV dose) and 170 who received placebo (including 41 subjects who received at least one IV dose). The IV formulation of PREVYMIS was used at investigators' discretion in subjects who were unable to take oral therapy (e.g., unable to tolerate oral intake). The median time to starting study drug was 8 days after transplantation. Thirty-four percent (34%) of subjects were engrafted at baseline. The median age was 55 years (range: 18 to 76 years); 57% were male; 84% were White; 9% were Asian; 2% were Black or African American; and 7% were Hispanic or Latino.
  • At baseline, 30% of all subjects had one or more of the following factors associated with increased risk for CMV reactivation (high risk stratum): Human Leukocyte Antigen (HLA)-related donor with at least one mismatch at one of the following three HLA-gene loci: HLA-A, -B or –DR; haploidentical donor; unrelated donor with at least one mismatch at one of the following four HLA-gene loci: HLA-A, -B, -C and -DRB1; use of umbilical cord blood as stem cell source; use of ex vivo T-cell-depleted grafts; Grade 2 or greater Graft-Versus-Host Disease (GVHD) requiring systemic corticosteroids. The remaining 70% of subjects did not meet any of these high risk stratum criteria and were therefore included in the low risk stratum. Additionally, 48% of subjects received a myeloablative regimen, 51% were receiving cyclosporine, and 43% were receiving tacrolimus. The most common primary reasons for transplant were acute myeloid leukemia (38%), myelodysplastic syndrome (16%), and lymphoma (12%).

Clinically Significant CMV Infection

  • The primary efficacy endpoint of Trial P001 was the incidence of clinically significant CMV infection through Week 24 post-transplant (prophylaxis failure). Clinically significant CMV infection was defined as the occurrence of either CMV end-organ disease, or initiation of anti-CMV pre-emptive therapy (PET) based on documented CMV viremia (using the Roche COBAS® AmpliPrep/COBAS TaqMan® assay, LLoQ is 137 IU/mL, which is approximately 150 copies/mL) and the clinical condition of the subject. The protocol-specified guidance for CMV DNA thresholds for the initiation of PET during the treatment period was ≥ 150 copies/mL or > 300 copies/mL for subjects in the high and low risk strata, respectively. From Week 14 through Week 24, the threshold was >300 copies/mL for both high and low risk strata subjects. The Non-Completer=Failure (NC=F) approach was used, where subjects who discontinued from the trial prior to Week 24 post-transplant or had a missing outcome at Week 24 post-transplant were counted as failures.
  • Efficacy results from Trial P001 are shown in Table 7.
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  • Efficacy results were consistent across high and low risk strata for CMV reactivation. The time to clinically significant CMV infection is shown in Figure 1.
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  • Post-hoc analysis demonstrated that among PREVYMIS-treated subjects, inclusion in the high risk stratum for CMV reactivation at baseline, occurrence of GVHD, and steroid use at any time after randomization may be associated with the development of clinically significant CMV infection between Week 14 and Week 24 post-transplant.

Mortality

  • The Kaplan-Meier event rate for all-cause mortality in the letermovir vs. placebo groups was 12% vs. 17% at Week 24 post-transplant, and 24% vs. 28% at Week 48 post-transplant.

How Supplied

Tablets
  • Each PREVYMIS 240 mg tablet is a yellow oval tablet; each tablet is debossed with "591" on one side and Merck logo on the other side. Each PREVYMIS 480 mg tablet is a pink oval, bi-convex tablet debossed with "595" on one side and Merck logo on the other side.
  • The 240 mg tablets are packaged into a carton (NDC 0006-3075-02) containing four (4) Child Resistant (CR) Dosepaks®, each containing a 7-count blister card for a total of 28 tablets, or into a carton (NDC 0006-3075-04) containing two (2) unit-dose 7-count blister cards for a total of 14 tablets.
  • The 480 mg tablets are packaged into a carton (NDC 0006-3076-02) containing four (4) Child Resistant (CR) Dosepaks®, each containing a 7-count blister card for a total of 28 tablets, or into a carton (NDC 0006-3076-04) containing two (2) unit-dose 7-count blister cards for a total of 14 tablets.
Injection
  • PREVYMIS is supplied as a sterile, clear solution for intravenous use of 240 mg (12 mL per vial) or 480 mg (24 mL per vial). The final solutions for infusion are obtained by dilution with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP.
  • The single dose vials are supplied in cartons that contain a 240 mg single-dose vial (NDC 0006-5003-01) or a 480 mg single-dose vial (NDC 0006-5004-01).

Storage

Tablets
  • Store PREVYMIS tablets in the original package until use.
  • Store PREVYMIS tablets at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
Injection
  • Store PREVYMIS injection vials at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
  • Store in the original carton to protect from exposure to light.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

  • Advise the patient to read the FDA-approved patient labeling (Patient Information).
Drug Interactions
  • Inform patients that PREVYMIS 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.
Administration
  • Inform patients that it is important not to miss or skip doses and to take PREVYMIS for the duration that is recommended by the healthcare provider. Instruct patients that if they miss a dose of PREVYMIS, 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.
Storage
  • Advise patients to store PREVYMIS tablets in the original package until use.

Precautions with Alcohol

Alcohol-Letermovir interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

Brand Names

  • Prevymis

Look-Alike Drug Names

There is limited information regarding Letermovir Look-Alike Drug Names in the drug label.

Drug Shortage Status

Drug Shortage

Price

References

The contents of this FDA label are provided by the National Library of Medicine.