Letermovir

J05A - Direct acting antivirals ATC J05AX18 Small molecule approved 2017 Oral Parenteral First-in-class Orphan

JFDA label: Prevymis

Mechanism of Action

Inhibitor of DNA terminase — DNA terminase inhibitor

Target	Action	Gene / class
DNA terminase efficacy	INHIBITOR

Indications

Approved

Cytomegalovirus (prophylaxis)

Antimicrobial Spectrum

Expected / intrinsic spectrum (EUCAST breakpoints & labels) — not local resistance. Source: openfda-label.

Viruses

Organism	Activity	MIC
Cmv	Active	—
Cytomegalovirus	Active	—

Contraindications

Source: Lexicomp

Additional contraindications (not in US labeling): Hypersensitivity to letermovir or any component of the formulation Absolute
Concomitant administration with pimozide or ergot alkaloids Absolute
concomitant administration with pitavastatin and simvastatin when coadministered with cyclosporine Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (2)

Very Common Peripheral edema

Common Tachycardia

Nervous system disorders (3)

Very Common fatigue · Headache

Common Atrial fibrillation

Blood and lymphatic system disorders (2)

Very Common Decreased platelet count

Common Decreased hemoglobin

Gastrointestinal disorders (4)

Very Common abdominal pain · diarrhea · Nausea · vomiting

Respiratory, thoracic and mediastinal disorders (1)

Very Common Cough

Dosing

Source: Lexicomp

Cytomegalovirus (CMV) prophylaxis, hematopoietic stem cell transplant (HSCT) patients: IV, Oral: 480 mg once daily beginning between day 0 and day 28 postallogeneic HSCT for CMV-seropositive recipients; continue through day 100 posttransplantation. Dose adjustment for concomitant therapy with cyclosporine: Reduce letermovir to 240 mg once daily; if cyclosporine is discontinued (not held for supratherapeutic cyclosporine concentrations), increase letermovir to 480 mg once daily.

Refer to adult dosing.

Warnings & Precautions

Source: Lexicomp

Hepatic impairment

Use is not recommended in patients with severe impairment (Child-Pugh class C).

Renal impairment

Use with caution and closely monitor serum creatinine in patients with CrCl Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Dosage form specific issues:

Injection

Contains hydroxypropyl betadex; use injection only in patients unable to take oral therapy. Other warnings/precautions:

Appropriate use

Not active against other herpes viruses besides cytomegalovirus (CMV) (Marschall 2012). Additional prophylaxis targeting herpes simplex virus (HSV) in HSV-positive hematopoietic stem cell transplant recipients receiving letermovir may be necessary (Tomblyn 2009).

Resistance

Patients may have resistance to letermovir due to mutations in UL56. Cross resistance does not occur in populations with substitutions conferring resistance to CMV DNA polymerase inhibitors such as ganciclovir, cidofovir, and foscarnet.

Pregnancy & Lactation

Pregnancy

Adverse events were observed in some animal reproduction studies.

Lactation

It is not known if letermovir is present in breast milk. According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.

Monitoring

Clinical pearl	Monitor for cytomegalovirus (CMV) reactivation; serum creatinine (especially in patients with CrCl

Chemistry & Properties

Formula	C29H28F4N4O4
Molecular weight	572.56 g/mol
IUPAC name	2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid
CAS	917389-32-3
PubChem CID	45138674
InChIKey	`FWYSMLBETOMXAG-QHCPKHFHSA-N`
logP	5.71 (XLogP 4.6)
Polar surface area	77.84 Å²
H-bond acceptors / donors	7 / 1
Drug-likeness (QED)	0.38
Lipinski violations	2

SMILES

COc1cccc(N2CCN(C3=Nc4c(F)cccc4[C@H](CC(=O)O)N3c3cc(C(F)(F)F)ccc3OC)CC2)c1

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Substrate	—
CYP3A4	Substrate	—

Transporters

BCRP (Inhibitor)BCRP (Inhibitor)BSEP (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)OAT3 (Inhibitor)OATP (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)OATP2B1 (Inhibitor)P-gp (Inhibitor)BCRP (Substrate)BSEP (Substrate)MDR1 (Substrate)OATP (Substrate)OATP1B (Substrate)OATP1B1 (Substrate)OATP1B3 (Substrate)OATP2B1 (Substrate)OCT1 (Substrate)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Acalabrutinib	major
Bosutinib	major
Brigatinib	major
Cilostazol	major
Cisapride	major
Cobimetinib	major
Cyclosporine	major
Deflazacort	major
Eliglustat	major
Entrectinib	major
Everolimus	major
Hydrocodone	major
Ivacaftor	major
Ivosidenib	major
Naloxegol	major
Neratinib	major
Olaparib	major
Simvastatin	major
Siponimod	major
Sirolimus	major
Sonidegib	major
Tacrolimus	major
Venetoclax	major
Abemaciclib	moderate
Acetohexamide	moderate
Albendazole	moderate
Alpelisib	moderate
Apalutamide	moderate
Apixaban	moderate
Aprepitant	moderate
Astemizole	moderate
Axitinib	moderate
Betamethasone	moderate
Betrixaban	moderate
Budesonide	moderate
Budesonide (nasal)	moderate
Cabazitaxel	moderate
Cabozantinib	moderate
Celecoxib	moderate
Ceritinib	moderate

Showing 40 of 100+.

Registered Products (2)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Prevymis	Vial 240 mg VIL/12 ml	1 vial	Adatco Drug Store	—
Prevymis	Tablet 240 mg	28 tab	Adatco Drug Store	—