Prevymis Tab Inj

Drug Monograph

® Drug/Drug Prevymis (letermovir) film coated tablet and Class: solution for injection/ CMV Agents Prepared for: MO HealthNet Prepared by: Conduent

New Criteria Revision of Existing Criteria

Executive Summary

The purpose of this monograph is to provide a review of new therapy to determine whether the reviewed drug should be made available on an open Purpose: access basis to prescribers, require a clinical edit or require prior authorization for use.

Prevymis® is available in a film coated tablet containing either 240 mg or 480 mg of letermovir. It is also available in a single dose vial containing either 240 Dosage Forms & mg/12 ml or 480 mg/24 ml of letermovir respectively. Manufacturer:

Distributed by: Merck & Co., Inc., Whitehouse Station, NJ 08889

In a phase 3, double-blind, placebo-controlled trial that evaluated the incidence of clinically significant CMV infection, 38% of patients receiving Prevymis were considered to have failed prophylaxis compared to 61% of Summary of patients receiving placebo. The reason for failure in the Prevymis group Findings: were: 18% had clinically significant CMV infection by week 24, 16% had initiation of anti CMV pre-emptive therapy based on documented CMV viremia, 2% had CMV end-organ disease, 17% discontinued from study before week 24, and 3% were missing outcome in Week 24 visit window.

Status Prior Authorization (PA) Required Open Access Recommendation: Clinical Edit PDL

Type of PA Increased Risk of ADE Preferred Agent Criteria: Appropriate Indications No PA Required

Purpose The purpose of this monograph is to provide a review of new therapy to determine whether the reviewed drug should be considered a prior authorization drug, a clinical edit drug or an open access drug. While prescription expenditures are increasing at double-digit rates, payers are evaluating ways to control these costs by influencing prescriber behavior and guide appropriate medication usage. This review will assist in the achievement of qualitative and economic goals related to health care resource utilization. Restricting the use of certain medications can reduce costs by requiring documentation of appropriate indications for use, and where appropriate, encourage the use of less expensive agents within a drug class.

Introduction (2) Cytomegalovirus (CMV) is a common and potentially serious viral infection in allogeneic hematopoietic stem cell transplant recipients (HSCT). 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. CMV disease can lead to end-organ damage, including gastrointestinal tract disease, pneumonia or retinitis. Transplant recipients who develop CMV infection post-transplant are at increased risk for transplant failure and death.

Dosage Form(s) (1) Prevymis® is available in a film coated tablet containing either 240 mg or 480 mg of letermovir. It is also available in a single dose vial containing either 240 mg/12 ml or 480 mg/24 ml of letermovir respectively.

Manufacturer (1) Distributed by: Merck & Co., Inc., Whitehouse Station, NJ 08889

Indication(s) (1) Prevymis® is indicated for prophylaxis of cytomegalovirus (CMV) infection and disease in adult CMV-seropositive recipients of an allogeneic hematopoietic stem cell transplant.

(1) Clinical Efficacy (mechanism of action/pharmacology, comparative efficacy) Prevymis® contains letermovir, which is an inhibitor of the CMV DNA terminase complex.

Pharmacokinetics: Prevymis® Protein Binding 99% bound to plasma proteins Volume of Distribution 45.5 L Metabolism UGT1A1/1A3 (minor) Excretion Feces; 93% Urine; < 2% Half-life 12 hours

Adult CMV-seropositive Recipients of an Allogeneic Hematopoietic Stem Cell Transplant

STUDY DESIGN Multicenter, double-blind, placebo-controlled Phase 3 Trial

INCLUSION Adult CMV-seropositive recipients of an allogeneic hematopoietic stem CRITERIA cell transplant (HSCT).

EXCLUSION Patients with CMV viremia prior to study drug initiation. CRITERIA

TREATMENT Patients were randomized 2:1 to receive either Prevymis™ 480 mg on REGIMEN daily adjusted to 240 mg when co-administered with cyclosporine, or placebo. Study drug was initiated after HSCT (at any point from Day 0 to Day 28 post-transplant) and continued through Week 14 post-transplant. The IV formulation was used in patients who were unable to take oral therapy.

RESULTS The primary efficacy endpoint was the incidence of clinically significant CMF infection through week 24 post-transplant. This was considered prophylaxis failure. Clinically significant CMV infection was defined as the occurrence of either CMV end-organ disease, or initiation of anti-CMV pre- emptive therapy based on documented CMV viremia, and the clinical condition of the patient. 38% of patients in the Prevymis™ group failed prophylaxis compared to 61% of patients receiving placebo. Efficacy results were consistent across high and low risk strata for CMV reactivation.

SAFETY The Kaplan-Meier event rate for all-cause mortality in the Prevymis™ vs. placebo groups was 12% and 17% at week 24 post transplant.

Contraindications (1)  Prevymis™ is contraindicated in patients receiving pimozide or ergot alkaloids  Prevymis™ is contraindicated with pitavastatin and simvastatin when co-administered with cyclosporine

Warnings and Precautions (1)  The concomitant use of Prevymis™ and certain drugs may result in potentially significant drug interactions, some of which may lead to adverse reactions or reduced therapeutic effect of Prevymis™ or the concomitant drug. Drug interactions listed below.

Adverse Effects (1)

Most common, ≥ 10% Prevymis® Placebo (n=373) (n=192) Nausea 27% 23%

Diarrhea 26% 24%

Vomiting 19% 14%

Peripheral edema 14% 9%

Cough 14% 10%

Headache 14% 9%

Fatigue 13% 11%

Abdominal pain 12% 9%

Drug Interactions (1)  Inhibitors and substrates of OATP1B1/3  CYP3A substrates; may increase CYP3A substrate concentrations  Amiodarone; may increase amiodarone concentration  Warfarin; may decrease warfarin concentration  Phenytoin; may decrease phenytoin concentration  Antidiabetic agents; may increase glyburide, repaglinide, and rosiglitazone concentrations  Voriconazole; may decrease voriconazole concentration  Rifampin; may decrease letermovir concentration  Pimozide; may increase pimozide concentration  Ergotamine alkaloids; co administration is contraindicated  Statins; may increase statin concentrations. Use with pitavastatin and simvastatin is not recommended  Cyclosporine; may increase letermovir and cyclosporine concentrations  Sirolimus; may increase sirolimus concentrations  Tacrolimus; may increase tacrolimus concentrations

Dosage and Administration (1) The recommended dose is 480 mg administered orally or intravenously once daily. Prevymis™ should be initiated between Day 0 and Day 28 post-transplantation, and continue through Day 100 post-transplantation. If Prevymis™ is co-administered with cyclosporine, the dosage should be decreased to 240 mg once daily.

Cost

GENERIC BRAND MANUFACTURER STRENGTH DOSE COST/ NAME NAME MONTH Letermovir Prevymis Merck 240 mg tab 1 tab daily $5,850* 240 mg/12 ml 240 mg daily $8,100* vial 480 mg tab 1 tab daily $5,850* 480 mg/24 ml 480 mg daily $8,100* vial

Valganciclovir Valcyte Genentech 450 mg tab 2 tabs daily $1,042.80** * Wholesale Acquisition Cost

** Maximum Allowable Cost

Conclusion Prevymis® is indicated for prophylaxis of CMV infection and disease in adult CMV seropositive recipients of an allogeneic hematopoietic stem cell transplant. It is available as both an oral tablet and for intravenous infusion. Treatment should begin between Day 0 and Day 28 post- transplantation, and continued through Day 100 post-transplantation. In a Phase 3, double-blind, placebo-controlled trial, 23% fewer patients receiving Prevymis® failed prophylaxis compared with placebo. The concomitant use of Prevymis® and certain drugs may result in potentially significant drug interactions. This is important to evaluate prior to beginning treatment. The most common side effects were nausea, diarrhea, vomiting, peripheral edema, cough, headache, fatigue, and abdominal pain.

Recommendation MO HealthNet Division recommends Open Access status for this product.

References 1) Prevymis. Retrieved 2/21/2018 from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1b49df80-be4f-47e0-a0b7- 123f3e69395b&audience=consumer#t3 2) Merck Receives FDA Approval of Prevymis™ (letermovir) for Prevention of Cytomegalovirus Infection and Disease in Adult Allogeneic Stem Cell Transplant Patients. Retrieved 2/21/2018 from: http://www.mrknewsroom.com/news- release/prescription-medicine-news/merck-receives-fda-approval-prevymis-letermovir- prevention-c

Prepared by: Luke Boehmer PharmD Date: February 21, 2018