- PREVYMIS 240 mg/12 mL (20 mg/mL) injection: clear solution in a single-dose vial.
- PREVYMIS 480 mg/24 mL (20 mg/mL) injection: clear solution in a single-dose vial.
Adult CMV-seropositive Recipients [R+] of an Allogeneic HSCT
The safety of PREVYMIS was evaluated in one Phase 3 randomized, double-blind, placebo-controlled trial (P001) in which 565 subjects were randomized and treated with PREVYMIS (N=373) or placebo (N=192) through Week 14 post-transplant. Adverse events were those reported while subjects were on study medication or within two weeks of study medication completion/discontinuation. The mean time for reporting adverse events and laboratory abnormalities was approximately 22% longer in the PREVYMIS arm compared to the placebo arm.
Cardiac Adverse Events:
The cardiac adverse event rate (regardless of investigator-assessed causality) was higher in subjects receiving PREVYMIS (13%) compared to subjects receiving placebo (6%). The most common cardiac adverse events were tachycardia (reported in 4% of PREVYMIS subjects and in 2% of placebo subjects) and atrial fibrillation (reported in 3% of PREVYMIS subjects and in 1% of 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.
Common Adverse Events
The rate of adverse events occurring in at least 10% of subjects in the PREVYMIS group and at a frequency at least 2% greater than placebo are outlined in Table 1.
Table 1: Trial P001 All Grade Adverse Events Reported in ≥ 10% of PREVYMIS-Treated HSCT Recipients at a Frequency at least 2% Greater than Placebo
Overall, similar proportions of subjects in each group discontinued study medication due to an adverse event (13% of PREVYMIS subjects vs. 12% of placebo subjects). 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.
Selected laboratory abnormalities reported during treatment or within 2 weeks of stopping treatment are presented in the table below.
Table 2: Trial P001 Selected Laboratory Abnormalities
|Absolute neutrophil count (cells/μL)|
| < 500||19%||19%|
| 500 – < 750||4%||7%|
| 750 – < 1000||8%||9%|
| < 6.5||2%||1%|
| 6.5 – < 8.0||14%||15%|
| 8.0 – < 9.5||41%||43%|
| < 25000||27%||21%|
| 25000 – < 50000||17%||18%|
| 50000 – < 100000||20%||30%|
|Serum creatinine (mg/dL)|
| > 2.5||2%||3%|
| > 1.5 – 2.5||17%||20%|
The median time to engraftment (defined as absolute neutrophil count ≥ 500/mm3 on 3 consecutive days after transplantation) was 19 days in the PREVYMIS group and 18 days in the placebo group.
No adequate human data are available to establish whether PREVYMIS poses a risk to pregnancy outcomes. In animal reproduction studies, embryo-fetal developmental toxicity (including fetal malformations) was observed in rats during the period of organogenesis at letermovir exposures (AUC) 11 times higher than human exposure at the recommended human dose (RHD). In rabbits, no embryo-fetal developmental toxicity was noted at exposures that were not maternally toxic (up to letermovir exposures 2 times higher than human exposure at the RHD). In a rat pre/post-natal development study, total litter loss was observed at maternal letermovir exposures approximately 2 times higher than human exposure at the RHD (see Data).
The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Letermovir was administered orally to pregnant rats at 0, 10, 50 or 250 mg/kg/day from gestation days 6 to 17. Developmental toxicities, including skeletal malformations and umbilical cord shortening, were observed at 250 mg/kg/day (approximately 11 times higher than human exposure at the RHD). In addition, decreased fetal body weight and skeletal variations (due to maternal toxicity) were observed at this dose. No embryo-fetal toxicities were observed at 50 mg/kg/day (approximately 3 times higher than human exposure at the RHD).
Letermovir was administered orally to pregnant rabbits at 0, 25, 75 or 225 mg/kg/day from gestation days 6 to 20. Developmental toxicities, including spontaneous abortion, increased post-implantation loss, and skeletal variations, were observed at a maternally toxic dose (225 mg/kg/day; approximately 2 times higher than human exposure at the RHD). No embryo-fetal toxicities were observed at 75 mg/kg/day (less than human exposure at the RHD).
In the pre/post-natal development study, letermovir was administered orally to pregnant rats at 0, 10, 45 or 180 mg/kg/day from gestation day 6 to lactation day 22. At 180 mg/kg/day (approximately 2 times higher than human exposure at the RHD), total litter loss due to stillbirth or possible maternal neglect was observed in 5 of 23 pregnant females by post-partum/lactation day 4. In surviving offspring, slight developmental delays in vaginal opening and pinna unfolding were accompanied by reduced body weight gain at this dose. No toxicities were observed at 45 mg/kg/day (similar to human exposure at the RHD).
It is not known whether letermovir is present in human breast milk, affects human milk production, or has effects on the breastfed child.
When administered to lactating rats, letermovir was present in the milk of lactating rats as well as the blood of nursing pups (see Data).
The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for PREVYMIS and any potential adverse effects on the breastfed child from PREVYMIS or from the underlying maternal condition.
In a lactation study, letermovir was excreted in milk when administered intravenously (at 10 mg/kg) to lactating rats on post-partum/lactation day 10. Letermovir was also detected in the blood of nursing pups on post-partum/lactation day 21 in the pre/post-natal developmental study.
There are no data on the effect of letermovir on human fertility. Decreased fertility due to testicular toxicity was observed in male rats [see Nonclinical Toxicology (13.1, 13.2)].
In a thorough QT trial in healthy subjects, letermovir at the therapeutic IV dose or at a dose of 2 times the approved IV dose did not prolong QTc to any clinically relevant extent.
The pharmacokinetics of letermovir in patients less than 18 years of age have not been evaluated.
Age, Gender, Race, and Weight
Age (18 to 78 years), gender, race (White vs. non-White), and body weight (up to 100 kg) did not have a clinically significant effect on the pharmacokinetics of letermovir.
Letermovir AUC was approximately 1.9- and 1.4-fold higher in subjects with moderate (eGFR greater than or equal to 30 to 59 mL/min/1.73m2) and severe (eGFR less than 30 mL/min/1.73m2) renal impairment, respectively, compared to healthy subjects.
Hydroxypropyl betadex present in the intravenous letermovir formulation is mainly eliminated by glomerular filtration. Decreased elimination of hydroxypropyl betadex has been reported in the literature in patients with severe renal impairment.
Letermovir AUC was approximately 1.6- and 3.8-fold higher in subjects with moderate (Child-Pugh Class B [CP-B], score of 7-9) and severe (Child-Pugh Class C [CP-C], score of 10-15) hepatic impairment, respectively, compared to healthy subjects.
Drug Interaction Studies
Drug interaction studies were performed in healthy subjects with PREVYMIS and drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interactions (see Table 5 and Table 6).
In vitro results indicate that letermovir is a substrate of drug metabolizing enzymes CYP3A, CYP2D6, UGT1A1, and UGT1A3, and transporters OATP1B1/3 and P-gp. Oxidative metabolism is considered to be a minor elimination pathway based on in vivo human data. Inhibitors of OATP1B1/3 may result in increases in letermovir plasma concentrations. Changes in letermovir plasma concentrations due to inhibition of P-gp/BCRP by itraconazole were not clinically relevant. Changes in letermovir plasma concentrations due to inhibition of UGTs are not anticipated to be clinically relevant.
Based on in vitro studies, the metabolism of letermovir is not mediated by CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2E1, CYP4A11, UGT1A4, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B4, UGT2B7, UGT2B15, or UGT2B17. The transport of letermovir is not mediated by OATP2B1, OCT1, OAT1, BCRP, or MRP2 in vitro.
Letermovir is a time-dependent inhibitor and inducer of CYP3A in vitro. Co-administration of PREVYMIS with midazolam resulted in increased exposure of midazolam, indicating that the net effect of letermovir on CYP3A is moderate inhibition (see Table 6). Based on these results, co-administration of PREVYMIS with CYP3A substrates may increase the plasma concentrations of the CYP3A substrates [see Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7.2, 7.3), and Table 3]. Letermovir is a reversible inhibitor of CYP2C8 in vitro. When co-administered with PREVYMIS, plasma concentrations of CYP2C8 substrates are predicted to be increased [see Table 3 in Drug Interactions (7.3)]. Co-administration of PREVYMIS reduced the exposure of voriconazole, most likely due to the induction of voriconazole elimination pathways, CYP2C9 and CYP2C19. Co-administration of PREVYMIS with CYP2C9 and CYP2C19 substrates may decrease the plasma concentrations of the CYP2C9 and CYP2C19 substrates [see Table 3 in Drug Interactions (7.3)]. Letermovir is an inducer of CYP2B6 in vitro; the clinical relevance is unknown.
Letermovir inhibited efflux transporters P-gp, breast cancer resistance protein (BCRP), bile salt export pump (BSEP), multidrug resistance-associated protein 2 (MRP2), OAT3, and hepatic uptake transporter OATP1B1/3 in vitro. Co-administration of PREVYMIS with substrates of OATP1B1/3 transporters (e.g. atorvastatin, a known substrate of CYP3A, OATP1B1/3, and potentially BCRP) may result in a clinically relevant increase in plasma concentrations of OATP1B1/3 substrates [see Table 3 in Drug Interactions (7.3)]. There were no clinically relevant changes in plasma concentrations of digoxin, a P-gp substrate, or acyclovir, an OAT3 substrate, following co-administration with PREVYMIS in clinical studies (see Table 6). The effect of letermovir on BCRP, BSEP, and MRP2 substrates was not evaluated in clinical studies; the clinical relevance is unknown.
Based on in vitro results letermovir is not an inhibitor of CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, UGT1A4, UGT1A6, UGT1A9, or UGT2B7 and is not an inducer of CYP1A2. Letermovir is not an inhibitor of OATP2B1, OCT1, OCT2, or OAT1 in vitro.
Table 5: Drug Interactions: Changes in Pharmacokinetics of Letermovir in the Presence of Co-administered Drug
|Co-administered Drug||Regimen of Co-administered Drug||Letermovir Regimen||Geometric Mean Ratio [90% CI] of Letermovir PK with/without Co-administered Drug|
C12hr for tacrolimus
|Abbreviations: PO= oral|
|fluconazole||400 mg single dose PO||480 mg single dose PO||1.11|
|itraconazole||200 mg once daily PO||480 mg once daily PO||1.33|
|rifampin||600 mg single dose PO||480 mg single dose PO||2.03|
|600 mg single dose IV||480 mg single dose PO||1.58|
|600 mg once daily PO||480 mg once daily PO||0.81|
|600 mg once daily PO (24 hours after rifampin)|
These data are the effect of rifampin on letermovir 24 hours after final rifampin dose.
|480 mg once daily PO||0.15|
|cyclosporine||200 mg single dose PO||240 mg once daily PO||2.11|
|mycophenolate mofetil||1 g single dose PO||480 mg once daily PO||1.18|
|tacrolimus||5 mg single dose PO||80 mg twice daily PO||1.02|
Table 6: Drug Interactions: Changes in Pharmacokinetics for Co-administered Drug in the Presence of Letermovir
|Co-administered Drug||Regimen of Co-administered Drug||Letermovir Regimen||Geometric Mean Ratio [90% CI] of Co-administered Drug PK with/without Letermovir|
C12hr reported for voriconazole.
|midazolam||1 mg single dose IV||240 mg once daily PO||1.47|
|2 mg single dose PO||240 mg once daily PO||2.25|
|digoxin||0.5 mg single dose PO||240 mg twice daily PO||0.88|
|cyclosporine||50 mg single dose PO||240 mg once daily PO||1.66|
|mycophenolate mofetil||1 g single dose PO||480 mg once daily PO||1.08|
|tacrolimus||5 mg single dose PO||480 mg once daily PO||2.42|
|sirolimus||2 mg single dose PO||480 mg once daily PO||3.40|
|Antifungals and Antivirals|
|acyclovir||400 mg single dose PO||480 mg once daily PO||1.02|
|fluconazole||400 mg single dose PO||480 mg single dose PO||1.03|
|itraconazole||200 mg once daily PO||480 mg once daily PO||0.76|
|posaconazole||300 mg single dose PO||480 mg once daily PO||0.98|
|voriconazole||200 mg twice daily PO||480 mg once daily PO||0.56|
|HMG-CoA Reductase Inhibitors|
|atorvastatin||20 mg single dose PO||480 mg once daily PO||3.29|
|ethinyl estradiol (EE) /levonorgestrel (LNG)||0.03 mg EE single dose PO||480 mg once daily PO||1.42|
|0.15 mg LNG single dose PO||1.36|
Mechanism of Action
Letermovir inhibits the CMV DNA terminase complex (pUL51, pUL56, and pUL89) which is required for viral DNA processing and packaging. Biochemical characterization and electron microscopy demonstrated that letermovir affects the production of proper unit length genomes and interferes with virion maturation. Genotypic characterization of virus resistant to letermovir confirmed that letermovir targets the terminase complex.
The median EC50 value of letermovir against a collection of clinical CMV isolates in a cell-culture model of infection was 2.1 nM (range = 0.7 nM to 6.1 nM, n = 74). There was no significant difference in EC50 value by CMV gB genotype (gB1=29; gB2=27; gB3=11; and gB4=3).
Combination Antiviral Activity
No antagonism of the antiviral activity was seen when letermovir was combined with CMV DNA polymerase inhibitors (cidofovir, foscarnet, or ganciclovir).
In Cell Culture
CMV mutants with reduced susceptibility to letermovir have been selected in cell culture and the resistance mutations map to UL51, UL56, and UL89. Resistance-associated substitutions were found in pUL51 (P91S), pUL56 (C25F, S229F, V231A/L, N232Y, V236A/L/M, E237D, L241P, T244K/R, L254F, L257F/I, K258E, F261C/L/S, Y321C, C325F/R/W/Y, L328V, M329T, A365S, N368D, R369G/M/S), and pUL89 (N320H, D344E). EC50 values for recombinant CMV mutants expressing these substitutions are 1.6- to 9,300-fold higher than those for the wild-type reference virus.
In Clinical Studies
In a Phase 2b trial evaluating letermovir or placebo in 131 HSCT recipients, DNA sequence analysis of a select region of UL56 (amino acids 231 to 369) was performed on samples obtained from 12 letermovir-treated subjects who experienced prophylaxis failure and for whom on-treatment samples were available for analysis. One subject had a letermovir resistance substitution, pUL56 V236M.
In a Phase 3 trial (P001), DNA sequence analysis of the entire coding regions of UL56 and UL89 was performed on samples obtained from 50 letermovir-treated subjects who had received at least one dose of study drug and experienced prophylaxis failure and for whom samples were available for analysis. The pUL56 substitutions V236M, E237G, C325W, and R369T were detected in 3 subjects; however, no 2 subjects had substitutions at the same positions.
Cross resistance is not likely with drugs outside of this class. Letermovir is fully active against viral populations with substitutions conferring resistance to CMV DNA polymerase inhibitors (cidofovir, foscarnet, and ganciclovir). These DNA polymerase inhibitors are expected to be fully active against viral populations with substitutions conferring resistance to letermovir.
Carcinogenesis and Mutagenesis
Letermovir was not genotoxic in in vitro or in vivo assays, including microbial mutagenesis assays, chromosomal aberration in Chinese hamster ovary cells, and in an in vivo mouse micronucleus study.
Carcinogenicity studies with letermovir have not been conducted.
Impairment of Fertility
In a fertility and early embryonic development study in rats, no effects of letermovir on female fertility were observed at letermovir exposures (AUC) approximately 5 times higher than human exposure at the RHD.
In male rat fertility studies, decreased fertility associated with irreversible testicular toxicity was observed at ≥180 mg/kg/day (greater than or equal to 3 times the human exposure at the RHD). No fertility or testicular effects were observed at dose levels resulting in letermovir exposures (AUC) similar to human exposure at the RHD [see Nonclinical Toxicology (13.2)].
Clinically Significant CMV Infection
The primary efficacy endpoint of Trial P001 was the incidence of clinically significant CMV infection through Week 24 post-transplant (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 (PET) based on documented CMV viremia (using the Roche COBAS® AmpliPrep/COBAS TaqMan® assay, LLoQ is 137 IU/mL, which is approximately 150 copies/mL) and the clinical condition of the subject. The protocol-specified guidance for CMV DNA thresholds for the initiation of PET during the treatment period was ≥ 150 copies/mL or > 300 copies/mL for subjects in the high and low risk strata, respectively. From Week 14 through Week 24, the threshold was >300 copies/mL for both high and low risk strata subjects. The Non-Completer=Failure (NC=F) approach was used, where subjects who discontinued from the trial prior to Week 24 post-transplant or had a missing outcome at Week 24 post-transplant were counted as failures.
Efficacy results from Trial P001 are shown in Table 7.
Table 7: Trial P001 Efficacy Results in HSCT Recipients (NC=F Approach, FAS Population) Through Week 24
|Note: FAS=Full analysis set; FAS includes randomized subjects who received at least one dose of study medication, and excludes subjects with detectable CMV DNA at baseline. Approach to handling missing values: Non-Completer=Failure (NC=F) approach. With NC=F approach, failure was defined as all subjects who developed clinically significant CMV infection or prematurely discontinued from the study or had a missing outcome through Week 24 post-transplant visit window.|
|Proportion of subjects who failed prophylaxis||38%||61%|
|Reasons for failures|
The categories of failure are mutually exclusive and based on the hierarchy of categories in the order listed.
| Clinically significant CMV infection by Week 24|
Through Week 14, 8% of subjects in the PREVYMIS group and 39% of subjects in the placebo group experienced clinically significant CMV infection.
| Initiation of PET based on documented CMV viremia||16%||40%|
| CMV end-organ disease||2%||2%|
| Discontinued from study before Week 24|
Reasons for discontinuation included adverse event, death, lost to follow-up, physician decision, and withdrawal by subject.
| Missing outcome in Week 24 visit window||3%||3%|
|Stratum-adjusted treatment difference (Letermovir-Placebo)|
95% CI and p-value for the treatment differences in percent response were calculated using stratum-adjusted Mantel-Haenszel method with the difference weighted by the harmonic mean of sample size per arm for each stratum (high or low risk).
| Difference (95% CI)||-23.5 (-32.5, -14.6)|
Efficacy results were consistent across high and low risk strata for CMV reactivation. The time to clinically significant CMV infection is shown in Figure 1.
|Figure 1: P001: Kaplan-Meier Plot of Time to Onset of Clinically Significant CMV Infection Through Week 24 Post-Transplant in HSCT Recipients (FAS Population)|
Post-hoc analysis demonstrated that among PREVYMIS-treated subjects, inclusion in the high risk stratum for CMV reactivation at baseline, occurrence of GVHD, and steroid use at any time after randomization may be associated with the development of clinically significant CMV infection between Week 14 and Week 24 post-transplant.
The Kaplan-Meier event rate for all-cause mortality in the letermovir vs. placebo groups was 12% vs. 17% at Week 24 post-transplant, and 24% vs. 28% at Week 48 post-transplant.
Each PREVYMIS 240 mg tablet is a yellow oval tablet; each tablet is debossed with "591" on one side and Merck logo on the other side. Each PREVYMIS 480 mg tablet is a pink oval, bi-convex tablet debossed with "595" on one side and Merck logo on the other side.
The 240 mg tablets are packaged into a carton (NDC 0006-3075-02) containing four (4) Child Resistant (CR) Dosepaks®, each containing a 7-count blister card for a total of 28 tablets, or into a carton (NDC 0006-3075-04) containing two (2) unit-dose 7-count blister cards for a total of 14 tablets.
The 480 mg tablets are packaged into a carton (NDC 0006-3076-02) containing four (4) Child Resistant (CR) Dosepaks®, each containing a 7-count blister card for a total of 28 tablets, or into a carton (NDC 0006-3076-04) containing two (2) unit-dose 7-count blister cards for a total of 14 tablets.
PREVYMIS is supplied as a sterile, clear solution for intravenous use of 240 mg (12 mL per vial) or 480 mg (24 mL per vial) that may contain a few product-related small translucent or white particles. The final solutions for infusion are obtained by dilution with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP.
The single dose vials are supplied in cartons that contain a 240 mg single-dose vial (NDC 0006-5003-01) or a 480 mg single-dose vial (NDC 0006-5004-01).
Inform patients that PREVYMIS may interact with some drugs; therefore, advise patients to report the use of any prescription, non-prescription medication, or herbal products to their healthcare provider [see Dosage and Administration (2.4), Contraindications (4), Warnings and Precautions (5.1), and Drug Interactions (7)].
Inform patients that it is important not to miss or skip doses and to take PREVYMIS for the duration that is recommended by the healthcare provider. Instruct patients that if they miss a dose of PREVYMIS, they should take it as soon as they remember. If they do not remember until it is time for the next dose, instruct them to skip the missed dose and go back to the regular schedule. Instruct patients not to double their next dose or take more than the prescribed dose.
Advise patients to store PREVYMIS tablets in the original package until use [see How Supplied/Storage and Handling (16)].
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MERCK & CO., INC., Whitehouse Station, NJ 08889, USA
For patent information: www.merck.com/product/patent/home.html
The trademarks depicted herein are owned by their respective companies.
Copyright © 2017-2021 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
All rights reserved.
Distributed by: Merck Sharp & Dohme Corp., a subsidiary of
MERCK & CO.,INC., Whitehouse Station, NJ 08889, USA
For patent information: www.merck.com/product/patent/home.html
The trademarks depicted herein are owned by their respective companies.
Copyright © 2017-2019 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
All rights reserved.
For more information go to www.PREVYMIS.com or call 1-800-444-2080.
This Patient Information has been approved by the U.S. Food and Drug Administration.
Issued: March 2019