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November 9, 2017

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209939Orig1s000,209940Orig1s000lbl.pdf

On November 9, 2017, the U.S. Food and Drug Administration approved letermovir (Prevymis, Merck and Co., Inc.) for the prevention of cytomegalovirus (CMV) infection and disease in adult allogeneic hematopoietic stem cell transplant (HSCT) patients.

Approval was based on a phase 3 multicenter double-blind placebo-controlled clinical trial that included 495 HSCT recipients who were CMV-positive. Significantly fewer patients in the letermovir arm developed clinically significant CMV infection by week 24 post-HSCT compared to the placebo arm (18% vs. 42%, respectively). Letermovir was administered at a dose of 480 mg once daily (240 mg when coadministered with cyclosporine). The medication was initiated between day 0 and day 28 and continued through week 14 post-HSCT.

The most common adverse reactions (occurring in at least 10% of patients) were nausea (27%), diarrhea (26%), vomiting (19%), peripheral edema (14%), cough (14%), headache (14%), fatigue (13%), and abdominal pain (12%).

The recommended letermovir dose is 480 mg orally once daily, initiated as early as day 0 and up to day 28 post-HSCT and continued through day 100 post-HSCT. Letermovir is also available as 240-mg and 480-mg injection for intravenous infusion.

View full prescribing Information for Letermovir.

A description of FDA programs is available in the Guidance for Industry: Expedited Programs for Serious Conditions—Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


Pharmacist’s Applications to Practice

Letermovir for Prophylaxis of Cytomegalovirus Infection and Disease in Adult Allogeneic Hematopoietic Cell Transplantation Recipients

Author: May Aziz, PharmD BCOP BCPS
Clinical Pharmacy Specialist, Hematology/Oncology
VCU Health
Richmond, VA

What is the potential role for letermovir in the prevention of cytomegalovirus (CMV) infection and disease in allogeneic hematopoietic stem-cell transplantation (HSCT) recipients?1,2

  • CMV infection remains a serious complication after allogeneic HSCT. The American Society for Blood and Marrow Transplantation (ASBMT) clinical practice guidelines for infection prevention recommend either prophylaxis or a preemptive treatment strategy through at least 100 days post-HSCT for the prevention of CMV disease.
    • Traditional antiviral agents with activity against CMV have limited utility as prophylaxis in the post-HSCT setting because of significant toxicities, including myelosuppression (with ganciclovir, valganciclovir, and cidofovir) and nephrotoxicity (with foscarnet and cidofovir).
    • Most transplant centers have adopted a preemptive strategy, which has been successful in reducing the incidence of CMV disease. However, a safe and effective prophylaxis strategy would still be advantageous to prevent CMV reactivation and infection, particularly in high-risk patients.
  • Letermovir, which was approved by the U.S. Food and Drug Administration (FDA) in November 2017, is the first drug indicated for prophylaxis of CMV infection and disease specifically in CMV-seropositive recipients (CMV-R+) of an allogeneic HSCT.
  • Letermovir has a novel mechanism of action compared to other available anti-CMV agents because it inhibits CMV replication by inhibiting the CMV DNA terminase complex required for DNA packaging and processing.
  • Approval was granted based on the results of a multicenter double-blind randomized placebo-controlled phase 3 trial in adult CMV-R+ allogeneic HSCT patients with undetectable CMV DNA at randomization (N = 565). Patients received either letermovir 480 mg by mouth (PO) or intravenously (IV) daily or matching placebo (i.e., a preemptive strategy) through week 14 (~100 days) post-HSCT.
    • At week 24 (the primary end point), 37.5% of letermovir patients vs. 60.6% in the placebo group developed clinically significant CMV infection or were assigned as having met the end point because of discontinuation or missing data (p < .001). At week 14 (the secondary end point), rates were 19.1% versus 50% for letermovir versus placebo (p < .001).
    • The incidence of CMV infection in the letermovir group increased significantly beginning at week 18, or 4 weeks after discontinuation of the drug.
    • At week 24, all-cause mortality was lower in letermovir patients (10.2% vs. 15.9%, p = .03), with no difference in mortality at week 48.
    • Results were consistent across both high-risk and low-risk subgroups, with a more pronounced treatment effect in the high-risk group.
  • Although clinical practice guidelines have not been updated with recommendations regarding the use of letermovir, it should be considered as an alternative to the preemptive strategy in post-allogeneic HSCT patients, particularly in those at high risk for CMV reactivation or disease, such as recipients of mismatched, haploidentical, or umbilical cord blood transplants, or patients on high-dose steroids for graft-versus-host disease (GVHD).

What role can the pharmacist play in the management of patients on letermovir?2,3

  • Pharmacists should ensure that dosing of letermovir is accurate:
    • Standard dose: 480 mg PO or IV once daily through day 100
    • Patients on cyclosporine: 240 mg PO or IV once daily through day 100
    • No dose adjustment is required in patients with creatinine clearance (CrCl) > 10 ml/min or those with mild to moderate hepatic impairment (Child-Pugh class A or B).
  • Letermovir is a moderate CYP3A4 and OATP1B1/3 inhibitor and a substrate of OATP1B1/3, so pharmacists should monitor and adjust for clinically significant drug-drug interactions, including those with cyclosporine, tacrolimus, sirolimus, and HMG-CoA reductase inhibitors.
  • Letermovir is generally well tolerated, with low rates of serious adverse events across clinical trials. Common adverse events reported with letermovir include nausea (27%), diarrhea (26%), peripheral edema (14%), headache (14%), and cardiac events (13%), including atrial fibrillation.
    • It is important to note that letermovir is not associated with myelosuppression or delays in time to engraftment.

Clinical Pearls2-4

  • Letermovir has no activity against the herpes viruses, including herpes simplex virus (HSV) and varicella zoster virus (VZV). Therefore, patients should continue to receive acyclovir, valacyclovir, or famciclovir for HSV and VZV prophylaxis while on letermovir.
  • Letermovir should be started between day 0 and day 28 post-HCT. In the phase 3 study, patients began treatment at a median of 9 days post-HCT. However, the optimal time to initiate letermovir (i.e., before or after engraftment) is unknown.
  • Many patients will continue to be at risk for CMV infection beyond day 100 because of delayed immune reconstitution, continued immunosuppression, new onset of GVHD, or receipt of corticosteroid therapy. In the phase 3 study, the frequency of CMV infection increased significantly after discontinuation of letermovir. Thus clinicians may want to consider extending letermovir prophylaxis beyond the FDA-approved duration of 100 days in high-risk patients with continued risk factors for CMV infection.
  • If patients develop CMV infection while on letermovir, it should be discontinued and patients should begin induction therapy with another anti-CMV agent. It is not known whether patients can be safely switched back to letermovir prophylaxis after resolution of the infection.
    • Further studies are needed to evaluate the potential role of letermovir in the treatment of CMV infection or disease.
  • Because of their different mechanisms, there is no known cross-resistance between letermovir and the CMV polymerase inhibitors (ganciclovir, cidofovir, foscarnet).
    • UL56 gene mutations are known to confer letermovir resistance, but these strains remain susceptible to other anti-CMV agents.
    • Likewise, letermovir is fully active against CMV strains with UL97 or UL54 mutations that confer resistance to the CMV polymerase inhibitors.
  • Patients with CrCl < 50 ml/min who receive IV letermovir should be monitored for renal toxicity related to accumulation of the vehicle hydroxypropyl beta cyclodextrin.
  • No safety, efficacy, or pharmacokinetic data in pediatric patients are currently available.
  • The reported wholesale cost for letermovir is $195/day for the oral tablets and $270/day for the IV formulation, for an estimated total treatment cost of ~$100,000 per patient. Cost-benefit analyses comparing it to preemptive treatment would help clinicians decide if it should be used for all CMV-R+ allogeneic HSCT recipients or be reserved for high-risk patients only.
  • Financial assistance is available through Merck in the form of coupon cards and copay assistance for privately insured patients, and through a patient assistance program for other eligible patients. More information is available at https://www.merckaccessprogram-prevymis.com/hcp.

References

  1. Tomblyn M, Chiller T, Einsele H, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant 2009;15:1143-1238.
  2. Marty FM, Ljungman P, Chemaly RF, et al. Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell transplantation. N Engl J Med. 2017;377:2433-2444.
  3. Prevymis (letermovir) [package insert]. Whitehouse Station, NJ: Merck and Co., Inc.; November 2017.
  4. Merck Receives FDA Approval for PREVYMIS (letermovir) for Prevention of Cytomegalovirus (CMV) Infection and Disease in Adult Allogeneic Stem Cell Transplant Patients. Retrieved from https://www.businesswire.com/news/home/20171109005397/en/Merck-Receives-FDA-Approval-PREVYMIS%E2%84%A2-letermovir-Prevention. Accessed December 29, 2017.
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