PREVYMIS

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

Clinical Data for PREVYMIS™ (letermovir)

Background: CMV in HSCT

Hematopoietic stem cell transplant (HSCT) patients are at increased risk for cytomegalovirus (CMV) infection, disease, and associated mortality1–4

Positive CMV serostatus pre-HSCT is a strong predictor of CMV infection and disease.1,2

  • CMV infection has been shown to occur in ~30-65% of CMV-seropositive allogeneic HSCT patients.3,5
  • More than 30% of HSCT patients who were CMV-seropositive or had a seropositive donor had CMV infection within 1 month post-transplant.4

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Any level of CMV viremia is associated with increased risk of mortality in the first year post-HSCT4,a


CMV viral load as a time-dependent risk factor for overall mortality 1 year after HSCT (n=926)4

Day 0-60>500 vs ≤500 IU/mL>750 vs ≤750 IU/mL>1000 vs ≤1000 IU/mLDay 61-365Adjusted HR (95% CI)Any positive viremia vs negative viremia2.6 (1.4-5.0)>250 vs ≤250 IU/mL19.8 (9.6-41.1)20.4 (9.4-44.5)21.2 (9.5-47.7)18.9 (7.8-33.0)Any positive viremia vs negative viremia1.7 (1.2-2.4)>250 vs ≤250 IU/mL1.8 (1.3-2.3)>500 vs ≤500 IU/mL2.0 (1.5-2.8)>750 vs ≤750 IU/mL2.3 (1.7-3.2)>1000 vs ≤1000 IU/mL2.4 (1.7-3.3)1010010.1Risk of overall mortality

CI, confidence interval; HR, hazard ratio.

(a) Results from a large, retrospective, noninterventional cohort study of previously collected CMV viral load and clinical outcome measures (n=926).4


Early CMV reactivation is associated with increased non-relapse mortality and reduced overall survival following allogeneic HSCT5


OverallsurvivalNon-relapsemortalityAML ALL CML MDS 0.0030.0005<0.0001<0.0001valuePAML ALL CML MDS 0.00020.0004<0.0001<0.00010.51.01.52.02.5
AML, ALL, CML, and MDS disease groups experienced:Associated with CMV reactivation5Increased non-relapse mortality Reduced overall survival

Adapted from a CIBMTR analysis by Teira et al.

ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CIBMTR, Center for International Blood and Marrow Transplant Research; CML, chronic myeloid leukemia; MDS, myelodysplastic syndrome.

Study limitations

  • No data was collected on how CMV reactivation was monitored with respect to tests used and values applied for implementing preemptive therapy.5
  • Institutional practices for preemptive and prophylactic therapy vary with respect to initiation and duration of therapy, affecting the ability to assess efficacy of initial therapy and duration of CMV reactivation.5
  • The retrospective nature of the analysis limits generalization of results across transplant settings.5

Study design

  • Retrospective, multivariate analysis of 9,469 patients from the Center for International Blood and Marrow Transplant Research (CIBMTR) database who received their first allogeneic HSCT between 2003 and 20105
  • Multivariable analysis of risk factors for outcomes depending on CMV serostatus and reactivation with hematologic disease relapse, non-relapse mortality, and overall survival (AML [n=5,310], ALL [n=1,883], CML [n=1,079], and MDS [n=1,197])5

How could initiation of CMV prophylaxis make a difference for your adult R+ patients?


References

1. George B, Pati N, Gilroy N, et al. Pre-transplant cytomegalovirus (CMV) serostatus remains the most important determinant of CMV reactivation after allogeneic hematopoietic stem cell transplantation in the era of surveillance and preemptive therapy. Transpl Infect Dis. 2010;12(4):322–329.

2. Ljungman P, Hakki M, Boeckh M. Cytomegalovirus in hematopoietic stem cell transplant recipients. Hematol Oncol Clin North Am. 2011;25(1):151–169.

3. Sousa H, Boutolleau D, Ribeiro J, et al. Cytomegalovirus infection in patients who underwent allogeneic hematopoietic stem cell transplantation in Portugal: a five-year retrospective review. Biol Blood Marrow Transplant. 2014;20(12):1958–1967.

4. Green ML, Leisenring W, Xie H, et al. Cytomegalovirus viral load and mortality after haematopoietic stem cell transplantation in the era of pre-emptive therapy: a retrospective cohort study. Lancet Haematol. 2016;3(3):e119–e127.

5. Teira P, Battiwalla M, Ramanathan M, et al. Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis. Blood. 2016; 127(20)2427-2438. doi:10.1182/blood-2015-11-679639

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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

  • 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.
  • 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.
  • 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.
  • 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 inducers of transporters (e.g. P-gp) and/or enzymes (e.g. UGTs) is not recommended due to the potential for a decrease 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
    • Antibiotics
      • Nafcillin: decreases ↓letermovir concentration
    • Anticoagulants
      • Warfarin: decreases ↓warfarin concentration
    • Anticonvulsants
      • Carbamazepine: decreases ↓letermovir concentration
      • Phenobarbital: decreases ↓letermovir concentration
      • Phenytoin: decreases ↓both phenytoin and letermovir concentrations
    • Antidiabetic Agents
      • Glyburide: increases ↑glyburide concentration
      • Repaglinide: increases ↑repaglinide concentration
      • Rosiglitazone: increases ↑rosiglitazone concentration
    • Antifungals
      • Voriconazole: decreases ↓voriconazole concentration
    • Antimycobacterials
      • Rifabutin: decreases ↓letermovir concentration
      • Rifampin: decreases ↓letermovir concentration
    • Antipsychotics
      • Pimozide: increases ↑pimozide concentration; co-administration is contraindicated
      • Thioridazine: decreases ↓letermovir concentration
    • Endothelin Antagonists
      • Bosentan: decreases ↓letermovir concentration
    • Ergot Alkaloids
      • Ergotamine: increases ↑ergotamine concentration; co-administration is contraindicated
      • Dihydroergotamine: increases ↑dihydroergotamine concentration; co-administration is contraindicated
    • Herbal Products
      • St. John's wort (Hypericum perforatum): decreases ↓letermovir concentration
    • HIV Medications
      • Efavirenz: decreases ↓letermovir concentration
      • Etravirine: decreases ↓letermovir concentration
      • Nevirapine: decreases ↓letermovir concentration
    • 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
    • Wakefulness-Promoting Agents
      • Modafinil: decreases ↓letermovir concentration
    • CYP3A Substrate Examples
      • Alfentanil, fentanyl, midazolam and quinidine: may increase ↑CYP3A substrate concentration
      • Pimozide and ergot alkaloids are contraindicated
  • 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 Information also is available.

US-CYT-0119006/22