PREVYMIS

(letermovir) 240 mg, 480 mg tablets; Injection 20 mg/mL

Clinical Data

Primary endpoint results


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Clinically significant CMV infection at week 24


PREVYMIS demonstrated significant efficacy vs placebo in the primary endpoint: Clinically significant CMV infectiona at week 24 (NC=F approach)b

Parameter PREVYMIS Placebo
(n=325) (n=170)
Proportion of subjects who failed prophylaxis 38% 61%

Treatment difference for PREVYMIS vs placebo (95% CI)

-23.5 (-32.5, -14.6) P<0.0001
Reasons for failuresc
Clinically significant CMV infection by week 24d 18% 42%

Initiation of PET based on documented CMV viremia

16%

40%

CMV end-organ disease

2%

2%

Discontinued from study before week 24e 17% 16%
Missing outcome in week 24 visit window 3% 3%

(a) Clinically significant CMV infection was defined as either the occurrence of CMV end-organ disease or initiation of anti-CMV PET, based on documented CMV viremia and the clinical condition of the patient. Viremia was determined using the Roche COBAS® AmpliPrep/COBAS TaqMan® assay; lower limit of quantification was 137 IU/mL, which is approximately 150 copies/mL.

(b) The Noncompleter=Failure (NC=F) approach was used in which patients who discontinued from the study prior to week 24 post-transplant or had a missing outcome at week 24 post-transplant were counted as failures.

(c) The categories of failure are mutually exclusive and based on the hierarchy of categories in the order listed.

(d) Through week 14, 8% of subjects in the PREVYMIS group and 39% of subjects in the placebo group experienced clinically significant CMV infection.

(e) Reasons for discontinuation included adverse event (AE), death, lost to follow-up, physician decision, and withdrawal by subject.

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Rate of clinically significant CMV infection

Significantly lower rate of onset of clinically significant CMVf infection for PREVYMIS vs placebo1,g

Rate of Clinically Significant CMV Infection vs Placebo

Copyright © 2017 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.1

(f) Clinically significant CMV infection was defined as either the occurrence of CMV end-organ disease or initiation of anti-CMV PET, based on documented CMV viremia and the clinical condition of the patient. Viremia was determined using the Roche COBAS® AmpliPrep/COBAS TaqMan® assay; lower limit of quantification was 137 IU/mL, which is approximately 150 copies/mL.

(g) Included patients who received at least 1 dose of study drug and excluded patients with detectable CMV DNA at baseline.

Factors associated with clinically significant CMV infection between week 14 and week 24 post-transplant among PREVYMIS patients included:

  • High-risk stratum for CMV reactivation at baseline
  • Having GVHD
  • Steroid use at any time after randomization
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High and low risk strata

Efficacy results were consistent across high and low risk strata for CMV.

Treatment difference with clinically significant CMV infection at week 24 for PREVYMIS vs placebo2

Treatment Difference With Clinically Significant CMV Infection at Week 24 for PREVYMIS vs Placebo

PREVYMIS was studied in adult R+ patients who were at high risk for CMV reactivation. At baseline, 30% of all subjects had 1 or more of the following additional risk factors and were placed in the high-risk stratum:

  • Related donor with HLA mismatch
  • Haploidentical donor
  • Unrelated donor with HLA mismatch
  • Use of umbilical cord blood
  • Use of ex vivo T-cell–depleted grafts
  • GVHD requiring systemic corticosteroids

70% of subjects had no additional risk factors.

References

1. Marty FM, Ljungman P, Chemaly RF, et al. Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell transplantation. N Engl J Med. 2017;377(25):2433–2444.

2. Data available on request from Merck Professional Services-DAP, WP1, PO Box 4, West Point, PA 19486-0004. Please specify information package AINF-1228859-0001_RD2.

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Indication

PREVYMIS is indicated for prophylaxis of cytomegalovirus (CMV) infection and disease in adult CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT).

Selected Safety Information

Contraindications

  • PREVYMIS 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.
  • PREVYMIS is contraindicated with pitavastatin and simvastatin when co-administered with cyclosporine. Significantly increased pitavastatin or simvastatin concentrations may lead to myopathy or rhabdomyolysis.

Warnings and Precautions

  • The concomitant use of PREVYMIS and certain drugs may result in potentially significant drug interactions, some of which may lead to adverse reactions (PREVYMIS or concomitant drugs) or reduced therapeutic effect of PREVYMIS or the concomitant drug. Consider the potential for drug interactions prior to and during PREVYMIS therapy; review concomitant medications during PREVYMIS therapy; and monitor for adverse reactions associated with PREVYMIS and concomitant medications.

Adverse Reactions

  • The cardiac adverse event rate (regardless of investigator-assessed causality) was higher in subjects receiving PREVYMIS than placebo (13% vs 6%). The most common cardiac adverse events were tachycardia (reported in 4% PREVYMIS subjects and 2% placebo subjects) and atrial fibrillation (reported in 3% PREVYMIS subjects and 1% placebo subjects). Among those subjects who experienced one or more cardiac adverse events, 85% of PREVYMIS and 92% of placebo subjects had events reported as mild or moderate in severity.
  • The rate of adverse events occurring in at least 10% of PREVYMIS-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 PREVYMIS subjects and 1% of placebo subjects). Hypersensitivity reaction, with associated moderate dyspnea, occurred in one subject following the first infusion of IV PREVYMIS after switching from oral PREVYMIS, leading to treatment discontinuation.

Drug Interactions

  • Co-administration of PREVYMIS with drugs that are inhibitors of organic anion-transporting polypeptide 1B1/3 (OATP1B1/3) transporters may result in increases in letermovir plasma concentrations.
  • Co-administration of PREVYMIS with midazolam results in increased midazolam plasma concentrations. Co-administration of PREVYMIS with drugs that are CYP3A substrates may result in clinically relevant increases in the plasma concentrations of co-administered CYP3A substrates.
  • Co-administration of PREVYMIS with drugs that are substrates of OATP1B1/3 transporters may result in a clinically relevant increase in plasma concentrations of co-administered OATP1B1/3 substrates.
  • The magnitude of CYP3A- and OATP1B1/3-mediated drug interactions on co-administered drugs may be different when PREVYMIS is co-administered with cyclosporine. See the prescribing information for cyclosporine for information on drug interactions with cyclosporine.
  • If dose adjustments of concomitant medications are made due to treatment with PREVYMIS, doses should be readjusted after PREVYMIS treatment is completed.
  • Drug interactions may occur based on results from studies. Drug interactions may also occur based on predicted interactions. Potentially significant drug interactions include, but are not limited to, the following (information below applies to co-administration of PREVYMIS and the concomitant drug without cyclosporine, unless otherwise indicated):

    • Anti-arrhythmic agents
      • Amiodarone: increases ↑amiodarone concentration
    • Anticoagulants
      • Warfarin: decreases ↓warfarin concentration
    • Anticonvulsants
      • Phenytoin: decreases ↓phenytoin concentration
    • Antidiabetic agents
      • Glyburide: increases ↑glyburide concentration
      • Repaglinide: increases ↑repaglinide concentration
      • Rosiglitazone: increases ↑rosiglitazone concentration
      ­
    • Antifungals
      • Voriconazole: decreases ↓voriconazole concentration
      ­
    • Antimycobacterial
      • Rifampin: decreases ↓letermovir concentration
      ­
    • Antipsychotics
      • Pimozide: increases ↑pimozide concentration; co-administration is contraindicated
      ­
    • Ergot alkaloids
      • Ergotamine: increases ↑ergotamine concentration; co-administration is contraindicated
      • Dihydroergotamine: increases ↑dihydroergotamine concentration; co-administration is contraindicated
      ­
    • HMG-CoA reductase inhibitors
      • Pitavastatin, simvastatin: increases ↑HMG-CoA reductase inhibitors concentration; co-administration is contraindicated when PREVYMIS is co-administered with cyclosporine
      • Atorvastatin: increases ↑atorvastatin concentration
      • Fluvastatin, lovastatin, pravastatin, rosuvastatin: increases ↑HMG-CoA reductase inhibitors concentration
    • Immunosuppressants
      • Cyclosporine: increases ↑both cyclosporine and letermovir concentrations
      • Sirolimus: increases ↑sirolimus concentration
      • Tacrolimus: increases ↑tacrolimus concentration
    • Proton pump inhibitors
      • Omeprazole: decreases ↓omeprazole concentration
      • Pantoprazole: decreases ↓pantoprazole concentration
    • CYP3A substrate examples
      • Alfentanil, fentanyl, midazolam and quinidine: may increase ↑CYP3A substrate concentration
      • Pimozide and ergot alkaloids are contraindicated

Use in Specific Populations

  • The safety and efficacy of PREVYMIS in patients below 18 years of age have not been established.
  • For patients with creatinine clearance (CLcr) greater than 10 mL/min (by Cockcroft-Gault equation), no dosage adjustment of PREVYMIS is required based on renal impairment. The safety of PREVYMIS in patients with end-stage renal disease (CLcr less than 10 mL/min), including patients on dialysis, is unknown.
  • No dosage adjustment of PREVYMIS is required based on mild (Child-Pugh Class A) to moderate (Child-Pugh Class B) hepatic impairment. PREVYMIS is not recommended for patients with severe (Child-Pugh Class C) hepatic impairment.

Before prescribing PREVYMIS, please read the accompanying Prescribing Information. The Patient Product Information also is available.

AINF-1253685-000008/18