FDA Approves PREVYMIS (Letermovir) for Prophylaxis of Cytomegalovirus (CMV) Infection and Disease in Adult CMV-seropositive Recipients [R+] of an Allogeneic Hematopoietic Stem Cell Transplant (HSCT)

On November 8, 2017, the US Food & Drug Administration (FDA) approved PREVYMIS (letermovir) for prophylaxis of cytomegalovirus (CMV) infection and disease in adult CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT). The approved recommended dosage of PREVYMIS is 480 mg administered once daily orally or as an intravenous (IV) infusion over 1 hour. Initiate PREVYMIS between Day 0 and Day 28 post-transplantation (before or after engraftment), and continue through Day 100 post-transplantation. PREVYMIS injection, which contains hydroxypropyl betadex, should be used only in patients unable to take oral therapy. Patients should be switched to oral PREVYMIS as soon as they are able to take oral medications. PREVYMIS tablet and injection may be used interchangeably at the discretion of the physician, and no dosage adjustment is necessary when switching formulations. 

Mechanism of Action (MOA) and Pharmacokinetics (PK) 
• MOA: PREVYMIS is an antiviral CMV DNA terminase complex (pUL51, pUL56, and pUL89) inhibitor.
• General PK: Letermovir concentrations increased more than proportionally with dose following single and multiple dosing in healthy subjects. Steady-state median (90% prediction interval) AUC of PREVYMIS in HSCT recipients at the approved recommended oral dosage was 34,400 ng/mL (16,900 ng/mL, 73,700 ng/mL) and at the approved recommended IV dosage was 100,000 ng/mL (65,300 ng/mL, 148,000 ng/mL). 
• Absorption: The bioavailability was 35% in HSCT recipients following oral administration of the approved recommended dosage. The median Tmax was 45 minutes to 2.25 hours.
• Distribution: The mean steady-state volume of distribution was 45.5 L following IV administration in HSCT recipients. Protein binding was approximately 99%, and the blood-to plasma ratio was 0.56 in vitro. 
• Elimination: The median terminal half-life (t1/2) was 12 hours following IV administration at the approved recommended dosage. The major route of elimination is thought to be OATP1B1/3-mediated hepatic uptake.
• Metabolism: Metabolism is a minor route of elimination. 
• Excretion: Following single oral administration of radiolabeled letermovir, 93% was excreted in feces and < 2% was excreted in urine. Approximately 70% of the drug excreted in feces was unchanged.  

Drug Interactions
Co-administration of PREVYMIS with cyclosporine increases letermovir concentrations approximately 2-fold. Decrease PREVYMIS dosage to 240 mg once daily when co-administered with cyclosporine. If cyclosporine is discontinued after starting PREVYMIS, the next dose of PREVYMIS should be increased to 480 mg once daily. If cyclosporine dosing is interrupted due to high cyclosporine levels, no dose adjustment of PREVYMIS is needed. 

Co-administration of PREVYMIS may result in a clinically significant alteration in the plasma concentrations of other drugs (e.g., certain anti-arrhythmic agents, anticoagulants, anticonvulsants, antidiabetic agents, antifungals, antipsychotics, HMG-COA reductase inhibitors, immunosuppressants, proton pump inhibitors, and CYP3A substrates) and other drugs may alter the plasma concentrations of PREVYMIS (e.g., cyclosporine and rifampin). Additional drug interaction information is available in the full prescribing information linked below.

Use in Specific Populations
No clinically significant differences in letermovir PK were observed based on age (18 to 78 years), gender, race (White vs. non-White), or body weight (up to 100 kg). The PK of letermovir in patients < 18 years of age is unknown.

Renal Impairment 
No dosage adjustment is required in patients with CLcr > 10 mL/min. Insufficient data are available to make dosing recommendations for patients with CLcr < 10 mL/min or for patients on dialysis. 

In patients with CLcr < 50 mL/min receiving PREVYMIS injection, accumulation of the intravenous vehicle, hydroxypropyl betadex, may occur. Closely monitor serum creatinine levels in these patients. Decreased elimination of hydroxypropyl betadex has been reported in the literature in patients with severe renal impairment.

Hepatic Impairment
Approximately 4-fold higher letermovir concentrations were observed in patients with severe (Child-Pugh Class C) hepatic impairment administered PREVYMIS. PREVYMIS is not recommended for patients with severe hepatic impairment. No dosage adjustment is required for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment.

Efficacy and Safety
Efficacy and safety of PREVYMIS was assessed in a multicenter, double-blind, placebo-controlled trial of adult CMV-seropositive recipients [R+] of an allogeneic HSCT. The primary efficacy endpoint was the incidence of clinically significant CMV infection through Week 24 post-transplant (prophylaxis failure). Additional information regarding the clinical trial can be found in the full prescribing information linked below. 

The most common adverse events (occurring in at least 10% of subjects in the PREVYMIS group and at a frequency at least 2% greater than placebo) are nausea, diarrhea, vomiting, peripheral edema, cough, headache, fatigue, and abdominal pain.
________________________________________
Full prescribing information is available at https://go.usa.gov/xnWeZ.

Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval. 

A non-comprehensive list of examples of clinical substrates, inhibitors and inducers for metabolic and transporter system related interactions may be found at https://go.usa.gov/xXY9C.