Letermovir

Letermovir (brand name Prevymis) is an antiviral approved to prevent cytomegalovirus (CMV) in certain transplant recipients.

• Prevymis prevents CMV infection and disease in adults and pediatric patients 6 months of age and older (weighing at least 6 kg) who are CMV-seropositive and have received an allogeneic hematopoietic stem cell transplant (HSCT) — meaning a stem cell transplant from a donor.
• Prevymis prevents CMV disease in adults and pediatric patients 12 years of age and older (weighing at least 40 kg) who have received a kidney transplant and are at high risk because the donor was CMV-positive and the recipient was CMV-negative (D+/R-).

Letermovir targets a viral enzyme complex called the CMV DNA terminase complex — a molecular machine that cytomegalovirus uses to cut and package its DNA into new virus particles. By blocking this complex, letermovir prevents the virus from producing functional copies of itself, keeping viral levels from rising and causing disease in people whose immune systems are already weakened by transplantation.

Unlike some older antivirals that work by mimicking building blocks of DNA, letermovir uses a completely different mechanism. This means it may remain active against strains of CMV that have developed resistance to other antiviral drugs.

Prevymis is taken once daily and is available as tablets, oral pellets, and an intravenous (IV) infusion. Tablets can be taken with or without food and should be swallowed whole. Oral pellets are mixed with soft food or given through a feeding tube. The IV form is infused over one hour and reserved for patients who cannot take medication by mouth — patients should switch to oral therapy as soon as possible, and IV use should ideally not exceed 4 weeks.

• Dosing is adjusted for patients who also take cyclosporine — your prescriber will manage this.
• Pediatric patients receive weight-based doses; the appropriate form and amount are determined by your child's prescriber.
• Treatment is typically started shortly after transplant and continued for up to 100 or 200 days depending on transplant type and individual risk — follow your prescriber's plan exactly.
• After completing your course, stem cell transplant recipients should be monitored for CMV reactivation.

The most common side effects reported in clinical trials of Prevymis include:

• Nausea
• Diarrhea
• Vomiting
• Peripheral edema (swelling, typically in the legs or feet)
• Cough
• Headache
• Fatigue
• Abdominal pain

More serious reactions to watch for include cardiac events such as fast or irregular heartbeat (tachycardia, atrial fibrillation), signs of a severe allergic reaction (difficulty breathing, swelling) especially after an IV dose, and muscle pain or weakness that could indicate a dangerous interaction with certain cholesterol medications. Contact your healthcare team promptly if any of these occur.

• Drug interactions are a major concern: Letermovir affects and is affected by many drugs commonly used in transplant patients — including immunosuppressants (cyclosporine, tacrolimus, sirolimus), certain statins, blood thinners, anticonvulsants, and antifungals. Some combinations are contraindicated; others require dose adjustments and close monitoring. Always give your full medication list to your transplant team.
• IV formulation risk in kidney impairment: The injectable form contains hydroxypropyl betadex, a carrier ingredient that can accumulate in patients with reduced kidney function. In these patients, kidney function (serum creatinine) should be monitored closely. Animal studies also showed a potential hearing-related risk from this ingredient, though letermovir itself is not known to cause hearing problems.
• IV use should be limited: The injection form is intended only for patients who cannot take oral therapy and should ideally not continue beyond 4 weeks. Patients should be transitioned to oral Prevymis as soon as they are able.
• Severe liver disease: Prevymis is not recommended for patients with severe hepatic (liver) impairment (Child-Pugh Class C).

Letermovir has a wide range of drug interactions — it both affects the levels of other drugs and can be affected by them. Key interactions include:

• Pimozide — contraindicated; Prevymis raises pimozide levels, risking dangerous heart rhythm problems (QT prolongation, torsades de pointes)
• Ergot alkaloids (ergotamine, dihydroergotamine) — contraindicated; raised levels can cause ergotism, a dangerous narrowing of blood vessels
• Pitavastatin and simvastatin with cyclosporine — contraindicated combination; greatly increased statin levels risk serious muscle damage (myopathy, rhabdomyolysis)
• Cyclosporine — raises letermovir levels significantly; Prevymis dose must be reduced when taken together, and cyclosporine levels need frequent monitoring
• Tacrolimus and sirolimus — Prevymis raises their levels; blood concentrations must be monitored closely and doses adjusted
• Atorvastatin and other statins — Prevymis raises statin levels; dose limits apply and muscle-related side effects should be monitored
• Warfarin — Prevymis may lower warfarin effectiveness; INR (clotting measure) should be monitored frequently
• Certain anticonvulsants, antimycobacterials, and herbal products (carbamazepine, rifampin, phenytoin, phenobarbital, St. John's Wort, and others) — these can lower letermovir levels, potentially making it less effective; combinations are generally not recommended
• Antidiabetic agents (glyburide, repaglinide, rosiglitazone) — Prevymis can raise their levels; blood glucose should be monitored more closely

This is not a complete list of interactions. Always talk with your doctor or pharmacist before starting, stopping, or changing any medication.

• Tell your prescriber about every medication, supplement, and herbal product you take — interactions are common and can be serious
• Tell your doctor if you have kidney problems, especially if you may need the IV form; close monitoring is required and end-stage kidney disease use has not been established as safe
• Tell your doctor if you have liver disease; Prevymis is not recommended for severe (Child-Pugh Class C) hepatic impairment
• If you are pregnant or planning to become pregnant: animal studies showed potential harm to the fetus; discuss the risks and benefits with your doctor
• If you are breastfeeding: it is not known whether letermovir passes into human breast milk; discuss this with your doctor
• Pediatric patients: safety and effectiveness have not been established for HSCT recipients under 6 months of age or weighing less than 6 kg, or for kidney transplant recipients under 12 years of age or weighing less than 40 kg
• Older adults (65+): no dose adjustment is needed based on age, and safety and effectiveness were similar to younger patients in clinical trials

There is no specific antidote for a Prevymis overdose. If too much is taken, medical staff will monitor for side effects and provide supportive care based on symptoms. It is not known whether dialysis would meaningfully remove letermovir from the body.

In a dedicated cardiac safety study, letermovir at standard IV doses — and even at twice the approved IV dose — did not cause any meaningful prolongation of the QTc interval (the part of the heart's electrical cycle measured to assess arrhythmia risk). This suggests letermovir itself does not carry a direct risk of drug-induced heart rhythm problems from this mechanism, though cardiac adverse events were observed at higher rates than placebo in transplant trials.

After oral dosing, letermovir is absorbed relatively quickly, with peak blood levels reached within about 1.5 to 3 hours. It is very highly bound to proteins in the blood (about 99%) and is mostly cleared unchanged — roughly 97% of the drug circulates as the original compound with no major breakdown products. The body clears letermovir primarily through the liver (via bile), with about 93% exiting in the stool. The half-life (the time it takes the body to eliminate half the drug) is approximately 12 hours after an IV dose.

How much of the oral dose actually reaches the bloodstream varies considerably depending on whether cyclosporine is also being taken and the type of transplant — this is why dose adjustments are made when cyclosporine is part of the regimen. Food does not meaningfully change the total amount of letermovir absorbed from tablets, though peak levels may be slightly higher with a high-fat meal.

Store PREVYMIS tablets in the original package until use to protect from moisture. 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) .