LETERMOVIR TAB,ORAL

Clinical Criteria Summary

Treatment of cytomegalovirus (CMV) infection
Coadministration of medications not recommended with letermovir (e.g., nafcillin, phenytoin, phenobarbital, carbamazepine, rifamycins, bosentan, St. John’s wort, efavirenz, etravirine, modafinil)

Prescribed by Infectious Diseases, Solid organ or Hematopoietic stem cell transplant, or other facility authorized providers

ONE of the following must be met:
Prevention of infection in high-risk (CMV Recipient positive, R+) allogeneic hematopoietic stem cell transplant recipient for up to 200 days
Prevention of CMV infection in high-risk (CMV donor positive / recipient negative, D+/R-) solid-organ transplant recipients when valganciclovir cannot be used due to tolerability, difficulty dosing due to changing renal function or resistance

Cytomegalovirus (CMV) prophylaxis for high-risk kidney transplant recipients
Approved for CMV prophylaxis after allogeneic hematopoietic stem-cell transplant (HSCT)
High-risk HSCT defined by donor properties, stem cell source, receipt of anti-thymocyte globulin or alemtuzumab, or graft vs. host disease requiring ongoing corticosteroids
Excluded populations: end-stage renal disease, severe hepatic insufficiency/disease, drug interactions, prior solid organ transplant, double kidney transplant, CMV disease within 6 months prior to randomization

480 mg daily (PO or IV)
Dose decreased to 240 mg if concomitant cyclosporine A is used
Available as tablets and injection for intravenous use
IV formulation contains hydroxypropyl betadex; recommend changing to oral formulation as soon as possible

Non-inferior to valganciclovir for prevention of CMV in high-risk kidney transplant recipients through week 52
Consistently reduced CMV infection and clinically significant CMV infection in HSCT patients across trials and observational studies
Primary endpoint discontinuation of study drug for any reason was lower with letermovir (38%) vs placebo (61%)
Clinically significant CMV infection rates: 18% vs 41% (letermovir vs placebo) in initial HSCT trial
Extended prophylaxis to 200 days showed similar efficacy and safety to the initial 100-day trial
Impact on all-cause mortality was less consistent; lower at week 24 but not week 48 in initial trial

GI adverse events most common (vomiting, abdominal pain)
Cardiac adverse events reported (tachycardia, atrial fibrillation), mostly mild-moderate
Hematologic parameters not different from placebo in HSCT trials
In kidney transplant vs valganciclovir: lower drug-related AEs, significant decrease in leukopenia and neutropenia, lower discontinuation due to AEs (4% vs 14%)
Real-world cohorts note improvement/resolution of cytopenias and reduced need for immunosuppression modification when switching from valganciclovir

No cross-resistance with other anti-CMV agents
Not active against HSV or VZV; additional prophylaxis for these viruses is necessary
Resistance-associated substitutions not identified in letermovir-treated subjects in Phase 3 trials, unlike 12% in the valganciclovir group
Theoretical risk that prolonged prophylaxis might delay CMV-specific cellular reconstitution; optimal strategy and duration remain unclear

Formulary status: NF/TBD
Can be used as primary prophylaxis in very-high-risk allo-HSCT patients vs pre-emptive therapy
Offers an option to continue prophylaxis in high-risk solid organ transplant patients who develop cytopenias on valganciclovir or have CMV resistant to valganciclovir, minimizing adverse events of valganciclovir
Currently not indicated for treatment of CMV disease