letermovir
Brand: Prevymis
Prototype Drug
Drug Class: antiviral — CMV terminase inhibitor
Drug Family: antiviral
Subclass: first-in-class CMV terminase complex inhibitor
Organ Systems: infectious-disease
Mechanism of Action
Inhibits the CMV terminase complex responsible for cleaving viral DNA to unit-length genomes and packaging into capsids; novel mechanism distinct from all other anti-CMV drugs, with no cross-resistance with ganciclovir or foscarnet.
CMV terminase complex (pUL51-pUL56-pUL89)
Indications
- CMV prophylaxis in adult CMV-seropositive recipients of allogeneic hematopoietic stem cell transplant (HSCT)
Contraindications
- letermovir hypersensitivity
- concurrent use of pimozide or ergot alkaloids (drug interactions via CYP inhibition)
Adverse Effects
Common
- nausea
- diarrhea
- vomiting
- peripheral edema
- cough
Serious
- drug interactions via CYP3A4 and OATP1B1/3 inhibition
- bradycardia (with co-administration of amiodarone)
- hepatotoxicity (rare)
Pharmacokinetics (ADME)
| Absorption | oral: 35% bioavailability; IV: complete; IV and oral have equivalent AUC |
| Distribution | widely distributed; moderate protein binding |
| Metabolism | minimal CYP3A4; primarily eliminated unchanged; letermovir inhibits CYP3A4, CYP2C8, and OATP1B1/B3 transporters |
| Excretion | primarily biliary/fecal (93%); renal minimal |
| Half-life | 12 hours |
| Onset | rapid |
| Peak | 1.5 hours (oral) |
| Duration | 24 hours (once-daily) |
| Protein Binding | 99% |
| Vd | moderate |
Drug Interactions
| Drug / Agent | Mechanism | Severity |
|---|---|---|
| cyclosporine | OATP inhibition increases letermovir AUC ~2-fold; reduce letermovir dose from 480 mg to 240 mg when combined with cyclosporine | major |
| statins (substrates of OATP1B1/3) | OATP inhibition by letermovir increases statin exposure; rhabdomyolysis risk | major |
| pimozide | CYP3A4 inhibition may increase pimozide to toxic levels; contraindicated | major |
Nursing Considerations
- Administer once daily; when cyclosporine is co-administered, verify the letermovir dose is reduced from 480 mg to 240 mg daily.
- Screen all concurrent medications for drug interactions, particularly statins and CYP3A4/OATP substrates.
- Letermovir can be given IV or oral with equivalent efficacy; transition to oral when patient can tolerate medication.
- Monitor for signs of breakthrough CMV infection; letermovir does not replace CMV monitoring (weekly quantitative CMV PCR) in HSCT recipients.
Clinical Pearls
- Letermovir's unique mechanism — inhibition of CMV DNA packaging terminase — provides zero cross-resistance with ganciclovir and foscarnet, and its minimal myelosuppression profile makes it ideal for CMV prophylaxis in the already myelosuppressed HSCT population.
- The 480 mg dose is reduced to 240 mg when combined with cyclosporine because cyclosporine (an OATP inhibitor) reduces letermovir's hepatic uptake by transporters, thereby dramatically increasing letermovir systemic exposure.
Safety Profile
Pregnancy use-with-caution
Lactation avoid
Renal Adjustment Not required
Hepatic Adjustment Required
TDM Not required
Guideline Update pending
Concordance Terms
Cross-referenced clinical concepts — click any term to see all content where it appears.