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FDA Approves Letermovir for Prophylaxis of Cytomegalovirus Infection and Disease in Allogeneic Stem Cell Transplant Patients

Today, the U.S. Food and Drug Administration (FDA) approved letermovir (Prevymis) once-daily tablets for oral use and injection for intravenous infusion. Letermovir is indicated for prophylaxis of cytomegalovirus (CMV) infection and disease in adult CMV-seropositive recipients of an allogeneic hematopoietic stem cell transplant (HSCT).

CMV is a common and potentially serious viral infection in allogeneic HSCT recipients. CMV-seropositive patients who undergo an HSCT are at high risk for CMV reactivation. Any level of CMV infection is associated with increased mortality in HSCT patients.

Trial Results

In the phase III clinical trial that supported approval, significantly fewer patients in the letermovir group (38%, n = 122 of 325) compared to the placebo group (61%, n = 103 of 170) developed clinically significant CMV infection, discontinued treatment, or had missing data through week 24 post-HSCT (treatment difference = -23.5, 95% confidence interval = -32.5 to -14.6; P < .0001), the primary efficacy endpoint. All-cause mortality in patients receiving letermovir was lower compared to placebo—12% vs 17%, respectively, at week 24 post-transplant. In this study, the incidence of bone marrow suppression in the letermovir group was comparable to the placebo group. The median time to engraftment was 19 days in the letermovir group and 18 days in the placebo group.

The cardiac adverse event rate (regardless of investigator-assessed causality) was higher in patients receiving letermovir than placebo (13% vs 6%). The most common cardiac adverse events were tachycardia (reported in 4% of letermovir patients and 2% of placebo patients) and atrial fibrillation (reported in 3% of letermovir patients and 1% of placebo patients). These adverse events were reported as mild or moderate in severity. The rate of adverse events occurring in at least 10% of letermovir-treated HSCT recipients and at a frequency at least 2% greater than placebo were nausea (27% vs 23%), diarrhea (26% vs 24%), vomiting (19% vs 14%), peripheral edema (14% vs 9%), cough (14% vs 10%), headache (14% vs 9%), fatigue (13% vs 11%), and abdominal pain (12% vs 9%). The most frequently reported adverse event that led to study drug discontinuation was nausea (occurring in 2% of letermovir patients and 1% of placebo patients). Hypersensitivity reaction, with associated moderate dyspnea, occurred in one patient following the first infusion of intravenous letermovir after switching from oral letermovir, leading to treatment discontinuation.

More Information

Letermovir is contraindicated in patients receiving pimozide or ergot alkaloids. Increased pimozide concentrations may lead to QT prolongation and torsades de pointes. Increased ergot alkaloids concentrations may lead to ergotism. Letermovir is contraindicated with pitavastatin and simvastatin when co-administered with cyclosporine. Significantly increased pitavastatin or simvastatin concentrations may lead to myopathy or rhabdomyolysis.

“Our findings demonstrate that letermovir is a significant and welcomed advance in the prevention of clinically significant CMV infection and lowers mortality in this highly vulnerable patient population,” said Francisco M. Marty, MD, Associate Professor of Medicine at Harvard Medical School and Attending Physician in Transplant and Oncology Infectious Diseases at Dana-Farber Cancer Institute and Brigham and Women’s Hospital.

The recommended dosage of letermovir is 480 mg administered once daily, initiated as early as day 0 and up to day 28 post-transplantation (before or after engraftment), and continued through day 100 post-transplantation. If letermovir is coadministered with cyclosporine, the dosage of oral or intravenous letermovir should be decreased to 240 mg once daily.

Letermovir is available as 240 mg and 480 mg tablets, which may be administered with or without food. Letermovir is also available as 240 mg and 480 mg injection for intravenous infusion via a peripheral catheter or central venous line at a constant rate over 1 hour.

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