LETERMOVIR
Clinical safety rating: caution
Comprehensive clinical and safety monograph for LETERMOVIR (LETERMOVIR).
Letermovir is an antiviral agent that inhibits the human cytomegalovirus (CMV) terminase complex, specifically the pUL56 subunit, thereby preventing viral DNA processing and packaging.
| Metabolism | Primarily metabolized by UGT1A1/1A3, with minor contribution from CYP3A4. Also undergoes O-glucuronidation. |
| Excretion | Letermovir is primarily eliminated via biliary/fecal excretion (approximately 93% of the dose recovered in feces, with <2% as unchanged drug) and renal excretion accounts for <7% (mostly as metabolites, <1% unchanged). |
| Half-life | The terminal elimination half-life is approximately 12 hours (range 10–18 hours) in healthy subjects, allowing once-daily dosing. |
| Protein binding | >98% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | The volume of distribution is approximately 45.5 L (not routinely normalized to body weight; ~0.6 L/kg in adults), indicating extensive tissue distribution. |
| Bioavailability | Oral bioavailability is approximately 94–98% (with food), and 92% under fasting conditions; thus, oral and IV exposures are nearly equivalent. |
| Onset of Action | Oral: Onset of plasma concentration occurs within 1–2 hours after oral administration; clinical antiviral effect begins after reaching steady state (by day 3–5). Intravenous: Immediate presence in plasma with steady state achieved more rapidly. |
| Duration of Action | The antiviral effect persists over the 24-hour dosing interval due to the half-life; recommended duration is up to 100 days post-transplant. |
480 mg orally once daily (two 240 mg tablets).
| Dosage form | TABLET |
| Renal impairment | If CrCl 10-29 mL/min not on hemodialysis: 240 mg orally once daily. If on hemodialysis: 240 mg orally once daily, administered after hemodialysis. If CrCl ≥30 mL/min: 480 mg once daily. Not recommended if CrCl <10 mL/min not on hemodialysis. |
| Liver impairment | No adjustment required for mild to moderate hepatic impairment (Child-Pugh A or B). Not studied in severe hepatic impairment (Child-Pugh C). |
| Pediatric use | Approved for kidney transplant recipients aged ≥12 years weighing ≥40 kg: 480 mg orally once daily. For weight <40 kg or age <12 years: not established. |
| Geriatric use | No specific dose adjustment recommended based on age alone; base dosing on renal function. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for LETERMOVIR (LETERMOVIR).
| Breastfeeding | Excretion into human milk unknown; animal studies show presence in rat milk. Caution advised. No M/P ratio available. |
| Teratogenic Risk | Animal studies show no adverse developmental effects at exposures up to 2 times the human AUC. No adequate human studies in pregnant women. Risk cannot be ruled out; use only if benefit outweighs risk. No trimester-specific risks identified; consider potential for fetal CMV transmission if used for maternal CMV. |
| Fetal Monitoring |
■ FDA Black Box Warning
None.
| Serious Effects |
["Hypersensitivity to letermovir or any of its excipients.","Concomitant use with pimozide or ergot alkaloids due to risk of toxicity from increased concentrations of these drugs."]
| Precautions | ["Risk of reduced efficacy if co-administered with CYP3A4 inducers (e.g., rifampin, carbamazepine) leading to decreased letermovir concentrations.","Potential for drug interactions with CYP3A4 substrates (e.g., midazolam, tacrolimus, sirolimus) requiring dose adjustment of the affected drug.","Not recommended for use in patients with severe hepatic impairment (Child-Pugh class C)."] |
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| Monitor CBC (particularly neutropenia) and liver function tests monthly during pregnancy. Assess for CMV reactivation via viral load if indicated. |
| Fertility Effects | No human fertility data. Animal studies show no impairment of mating or fertility at exposures ≤2 times human AUC. |