ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Most common adverse events (occurring in at least 10% of subjects in the PREVYMIS group and at frequency at least 2% greater than placebo) are nausea, diarrhea, vomiting, peripheral edema, cough, headache, fatigue, and abdominal pain. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp Dohme Corp., subsidiary of Merck Co., Inc., at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. Adult CMV-seropositive Recipients [R+] of an Allogeneic HSCTThe safety of PREVYMIS was evaluated in one Phase 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 EventsThe rate of adverse events occurring in at least 10% of subjects in the PREVYMIS group and at 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 Frequency at least 2% Greater than PlaceboAdverse EventsPREVYMIS(N=373)Placebo(N=192)nausea27%23%diarrhea26%24%vomiting19%14%peripheral edema14%9%cough14%10%headache14%9%fatigue13%11%abdominal pain12%9%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.. Laboratory AbnormalitiesSelected laboratory abnormalities reported during treatment or within weeks of stopping treatment are presented in the table below.Table 2: Trial P001 Selected Laboratory AbnormalitiesPREVYMISN=373PlaceboN=192Absolute neutrophil count (cells/uL) 50019%19% 500 < 7504%7% 750 < 10008%9%Hemoglobin (g/dL) 6.52%1% 6.5 < 8.014%15% 8.0 < 9.541%43%Platelets (cells/uL) 2500027%21% 25000 < 5000017%18% 50000 < 10000020%30%Serum creatinine (mg/dL) 2.52%3% 1.5 2.517%20%The median time to engraftment (defined as absolute neutrophil count >= 500/mm3 on consecutive days after transplantation) was 19 days in the PREVYMIS group and 18 days in the placebo group.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. PREVYMIS is an antiviral drug against CMV [see Microbiology (12.4)].. 12.2 Pharmacodynamics. Cardiac ElectrophysiologyIn thorough QT trial in healthy subjects, letermovir at the therapeutic IV dose or at dose of times the approved IV dose did not prolong QTc to any clinically relevant extent.. 12.3 Pharmacokinetics. The pharmacokinetic properties of letermovir are displayed in Table 4.Table 4: Absorption, Distribution, Metabolism, Elimination (ADME), and Pharmacokinetic Properties of PREVYMISValues were obtained in studies of healthy subjects unless otherwise indicated. Pharmacokinetics in HSCT RecipientsTreatment RegimenSteady-state median (90% prediction interval) AUC (nghr/mL) of PREVYMIS 480 mg oral once daily, no cyclosporine34,400 (16,900, 73,700) 480 mg IV once daily, no cyclosporine100,000 (65,300, 148,000) 240 mg oral once daily, with cyclosporine60,800 (28,700, 122,000) 240 mg IV once daily, with cyclosporine70,300 (46,200, 106,000)Pharmacokinetics in Healthy SubjectsTreatment RegimenSteady-state geometric mean AUC and Cmax of PREVYMIS 480 mg oral once dailyCmax: 13,000 ng/mLAUC: 71,500 nghr/mLDose proportionalityGreater than proportional following single and multiple oral or IV doses of PREVYMIS 240 mg and 480 mgAccumulation ratioBased on geometric mean data. Cmax: 1.03AUC: 1.22Time to steady-state 9-10 daysAbsorptionBioavailabilityHealthy subjects administered PREVYMIS without cyclosporine: 94% at an oral dose range of 240 mg to 480 mgHSCT recipients administered PREVYMIS without cyclosporine: 35% with 480 mg oral once dailyHSCT recipients administered PREVYMIS with cyclosporine: 85% with 240 mg oral once dailyMedian Tmax (hr)1.5 to 3.0 hrEffect of food (relative to fasting) Values refer to geometric mean ratio [fed/fasted] percentage and 90% confidence interval back transformed from linear mixed-effects model performed on natural log-transformed values. The meal administered was standard high fat and high calorie meal (33 grams protein, 65 grams carbohydrates, 58 grams fat; 920 total calories). AUC: 99.63% [84.27% 117.80%]Cmax: 129.82% [104.35% -161.50%]DistributionMean steady-state volume of distribution45.5 following IV administration in HSCT recipients% In vitro bound to human plasma proteins99% across the concentration range of 0.2 to 50 mg/LIn vitro blood-to plasma ratio0.56 across the concentration range of 0.1 to 10 mg/LMetabolismIn vitro metabolismUGT1A1/1A3 (minor)Drug-related component in plasma97% unchanged parentNo major metabolites detected in plasmaEliminationRoute of elimination Hepatic uptake (OATP1B1/3)Mean terminal t1/2 (hr)12 hrs after dosing of PREVYMIS 480 mg IV once daily% of dose excreted in fecesSingle oral administration of radiolabeled letermovir in mass balance study. 93%% of dose excreted in urine <2%% of unchanged drug excreted in feces 70%. Specific Populations. Pediatric PopulationThe pharmacokinetics of letermovir in patients less than 18 years of age have not been evaluated.. Age, Gender, Race, and WeightAge (18 to 78 years), gender, race (White vs. non-White), and body weight (up to 100 kg) did not have clinically significant effect on the pharmacokinetics of letermovir.. Renal ImpairmentLetermovir 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.. Hepatic ImpairmentLetermovir AUC was approximately 1.6- and 3.8-fold higher in subjects with moderate (Child-Pugh Class [CP-B], score of 7-9) and severe (Child-Pugh Class [CP-C], score of 10-15) hepatic impairment, respectively, compared to healthy subjects.. Drug Interaction StudiesDrug 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 and Table 6).In vitro results indicate that letermovir is substrate of drug metabolizing enzymes CYP3A, CYP2D6, UGT1A1, and UGT1A3, and transporters OATP1B1/3 and P-gp. Oxidative metabolism is considered to be 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 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 reversible inhibitor of CYP2C8 in vitro. When co-administered with PREVYMIS, plasma concentrations of CYP2C8 substrates are predicted to be increased [see Table 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 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 (MRP2), OAT3, and hepatic uptake transporter OATP1B1/3 in vitro. Co-administration of PREVYMIS with substrates of OATP1B1/3 transporters (e.g. atorvastatin, known substrate of CYP3A, OATP1B1/3, and potentially BCRP) may result in clinically relevant increase in plasma concentrations of OATP1B1/3 substrates [see Table in Drug Interactions (7.3)]. There were no clinically relevant changes in plasma concentrations of digoxin, 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 DrugCo-administered DrugRegimen of Co-administered DrugLetermovir RegimenGeometric Mean Ratio [90% CI] of Letermovir PK with/without Co-administered Drug (No Effect=1.00)AUCCmaxC24hrC12hr for tacrolimus Abbreviations: PO= oralAntifungalsfluconazole400 mg single dose PO480 mg single dose PO1.11(1.01, 1.23)1.06(0.93, 1.21)1.28(1.15, 1.43)itraconazole200 mg once daily PO480 mg once daily PO1.33(1.17, 1.51)1.21(1.05, 1.39)1.90(1.58, 2.28)Antimycobacterialsrifampin600 mg single dose PO480 mg single dose PO2.03(1.84, 2.26)1.59(1.46, 1.74)2.01(1.59, 2.54)600 mg single dose IV480 mg single dose PO1.58(1.38, 1.81)1.37(1.16, 1.61)0.78(0.65, 0.93)600 mg once daily PO480 mg once daily PO0.81(0.67, 0.98)1.01(0.79, 1.28)0.14(0.11, 0.19)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 PO0.15(0.13, 0.17)0.27(0.22, 0.31)0.09(0.06, 0.12)Immunosuppressantscyclosporine200 mg single dose PO240 mg once daily PO2.11(1.97, 2.26)1.48(1.33, 1.65)2.06(1.81, 2.35)mycophenolate mofetil1 single dose PO480 mg once daily PO1.18(1.04, 1.32)1.11(0.92, 1.34)1.39(1.12, 1.74)tacrolimus5 mg single dose PO80 mg twice daily PO1.02(0.97, 1.07)0.92(0.84, 1.00)1.02(0.93, 1.12)Table 6: Drug Interactions: Changes in Pharmacokinetics for Co-administered Drug in the Presence of LetermovirCo-administered DrugRegimen of Co-administered DrugLetermovir RegimenGeometric Mean Ratio [90% CI] of Co-administered Drug PK with/without Letermovir(No Effect=1.00)AUCCmaxC24hrC12hr reported for voriconazole. Abbreviations: PO=oralCYP3A Substratesmidazolam1 mg single dose IV240 mg once daily PO1.47(1.37, 1.58)1.05(0.94, 1.17)2.74(2.16, 3.49)2 mg single dose PO240 mg once daily PO2.25(2.04, 2.48)1.72(1.55, 1.92)Not availableP-gp Substratesdigoxin0.5 mg single dose PO240 mg twice daily PO0.88(0.80, 0.96)0.75(0.63, 0.89)0.90(0.84, 0.96)Immunosuppressantscyclosporine50 mg single dose PO240 mg once daily PO1.66(1.51, 1.82)1.08(0.97, 1.19)2.19(1.80, 2.66)mycophenolate mofetil1 single dose PO480 mg once daily PO1.08(0.97, 1.20)0.96(0.82, 1.12)1.04(0.86, 1.27)tacrolimus5 mg single dose PO480 mg once daily PO2.42(2.04, 2.88)1.57(1.32, 1.86)2.53(2.12, 3.03)sirolimus2 mg single dose PO480 mg once daily PO3.40(3.01, 3.85)2.76(2.48, 3.06)3.15(2.80, 3.55)Antifungals and Antiviralsacyclovir400 mg single dose PO480 mg once daily PO1.02(0.87, 1.2)0.82(0.71, 0.93)1.13(0.94, 1.36)fluconazole400 mg single dose PO480 mg single dose PO1.03 (0.99, 1.08)0.95(0.92, 0.99)1.04(1.00, 1.08)itraconazole200 mg once daily PO480 mg once daily PO0.76(0.71, 0.81)0.84(0.76, 0.92)0.67(0.61, 0.73)posaconazole300 mg single dose PO480 mg once daily PO0.98(0.82, 1.17)1.11(0.95, 1.29)1.10(0.94, 1.30)voriconazole200 mg twice daily PO480 mg once daily PO0.56(0.51, 0.62)0.61(0.53, 0.71)0.49(0.42, 0.57)HMG-CoA Reductase Inhibitorsatorvastatin20 mg single dose PO480 mg once daily PO3.29(2.84, 3.82)2.17(1.76, 2.67)3.62(2.87, 4.55)Oral Contraceptivesethinyl estradiol (EE) /levonorgestrel (LNG)0.03 mg EE single dose PO480 mg once daily PO1.42(1.32, 1.52)0.89(0.83, 0.96)1.57(1.45, 1.70)0.15 mg LNG single dose PO1.36(1.30, 1.43)0.95(0.86, 1.04)1.38(1.32, 1.46). 12.4 Microbiology. Mechanism of ActionLetermovir 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.. Antiviral ActivityThe median EC50 value of letermovir against collection of clinical CMV isolates in cell-culture model of infection was 2.1 nM (range 0.7 nM to 6.1 nM, = 74). There was no significant difference in EC50 value by CMV gB genotype (gB1=29; gB2=27; gB3=11; and gB4=3).. Combination Antiviral ActivityNo antagonism of the antiviral activity was seen when letermovir was combined with CMV DNA polymerase inhibitors (cidofovir, foscarnet, or ganciclovir).. Viral Resistance. In Cell CultureCMV 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 StudiesIn Phase 2b trial evaluating letermovir or placebo in 131 HSCT recipients, DNA sequence analysis of 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 letermovir resistance substitution, pUL56 V236M.In Phase 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 subjects; however, no subjects had substitutions at the same positions. Cross ResistanceCross 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Adult CMV-seropositive Recipients [R+] of an Allogeneic Hematopoietic Stem Cell Transplant. To evaluate PREVYMIS prophylaxis as preventive strategy for CMV infection or disease in transplant recipients at high risk for CMV reactivation, the efficacy of PREVYMIS was assessed in multicenter, double-blind, placebo-controlled Phase Trial (P001, NCT02137772) in adult CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT). Subjects were randomized (2:1) to receive either PREVYMIS at dose of 480 mg once daily adjusted to 240 mg when co-administered with cyclosporine, or placebo. Randomization was stratified by investigational site and risk level for CMV reactivation at the time of study entry. Study drug was initiated after HSCT (at any time from Day to Day 28 post-transplant) and continued through Week 14 post-transplant. Study drug was administered either orally or intravenously; the dose of PREVYMIS was the same regardless of the route of administration. Subjects received CMV DNA monitoring weekly until post-transplant Week 14 and then bi-weekly until post-transplant Week 24, with initiation of standard-of-care CMV pre-emptive therapy if CMV viremia was considered clinically significant. Subjects had continued follow-up through Week 48 post-transplant.Among the 565 treated subjects, 70 subjects were found to have CMV viremia prior to study drug initiation and were therefore excluded from the efficacy analyses. The efficacy population consisted of 325 subjects who received PREVYMIS (including 91 subjects who received at least one IV dose) and 170 who received placebo (including 41 subjects who received at least one IV dose). The IV formulation of PREVYMIS was used at investigators discretion in subjects who were unable to take oral therapy (e.g., unable to tolerate oral intake). The median time to starting study drug was days after transplantation. Thirty-four percent (34%) of subjects were engrafted at baseline. The median age was 55 years (range: 18 to 76 years); 57% were male; 84% were White; 9% were Asian; 2% were Black or African American; and 7% were Hispanic or Latino.At baseline, 30% of all subjects had one or more of the following factors associated with increased risk for CMV reactivation (high risk stratum): Human Leukocyte Antigen (HLA)-related donor with at least one mismatch at one of the following three HLA-gene loci: HLA-A, -B or -DR; haploidentical donor; unrelated donor with at least one mismatch at one of the following four HLA-gene loci: HLA-A, -B, -C and -DRB1; use of umbilical cord blood as stem cell source; use of ex vivo T-cell-depleted grafts; Grade or greater Graft-Versus-Host Disease (GVHD) requiring systemic corticosteroids. The remaining 70% of subjects did not meet any of these high risk stratum criteria and were therefore included in the low risk stratum. Additionally, 48% of subjects received myeloablative regimen, 51% were receiving cyclosporine, and 43% were receiving tacrolimus. The most common primary reasons for transplant were acute myeloid leukemia (38%), myelodysplastic syndrome (16%), and lymphoma (12%).. Clinically Significant CMV InfectionThe 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(R) AmpliPrep/COBAS TaqMan(R) 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 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 24ParameterLetermovir(N=325)Placebo(N=170)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 missing outcome through Week 24 post-transplant visit window.Proportion of subjects who failed prophylaxis38%61%Reasons for failuresThe categories of failure are mutually exclusive and based on the hierarchy of categories in the order listed. Clinically significant CMV infection by Week 24Through Week 14, 8% of subjects in the PREVYMIS group and 39% of subjects in the placebo group experienced clinically significant CMV infection. 18%42% Initiation of PET based on documented CMV viremia16%40% CMV end-organ disease2%2% Discontinued from study before Week 24Reasons for discontinuation included adverse event, death, lost to follow-up, physician decision, and withdrawal by subject. 17%16% Missing outcome in Week 24 visit window3%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)p-value <0.0001. 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.. Figure 1. MortalityThe 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.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. PREVYMIS is contraindicated in patients receiving pimozide or ergot alkaloids: Pimozide: Concomitant administration of PREVYMIS in patients receiving pimozide may result in increased concentrations of pimozide due to inhibition of cytochrome P450 3A (CYP3A) by letermovir, which may lead to QT prolongation and torsades de pointes [see Warnings and Precautions (5.1) and Drug Interactions (7.2, 7.3)].Ergot alkaloids: Concomitant administration of PREVYMIS in patients receiving ergot alkaloids may result in increased concentrations of ergot alkaloids (ergotamine and dihydroergotamine) due to inhibition of CYP3A by letermovir, which may lead to ergotism [see Warnings and Precautions (5.1) and Drug Interactions (7.2, 7.3)]. PREVYMIS is contraindicated with pitavastatin and simvastatin when co-administered with cyclosporine. Concomitant administration of PREVYMIS in combination with cyclosporine may result in significantly increased pitavastatin or simvastatin concentrations, which may lead to myopathy or rhabdomyolysis [see Warnings and Precautions (5.1) and Drug Interactions (7.2, 7.3)].. PREVYMIS is contraindicated in patients receiving pimozide or ergot alkaloids: Pimozide: Concomitant administration of PREVYMIS in patients receiving pimozide may result in increased concentrations of pimozide due to inhibition of cytochrome P450 3A (CYP3A) by letermovir, which may lead to QT prolongation and torsades de pointes [see Warnings and Precautions (5.1) and Drug Interactions (7.2, 7.3)].Ergot alkaloids: Concomitant administration of PREVYMIS in patients receiving ergot alkaloids may result in increased concentrations of ergot alkaloids (ergotamine and dihydroergotamine) due to inhibition of CYP3A by letermovir, which may lead to ergotism [see Warnings and Precautions (5.1) and Drug Interactions (7.2, 7.3)]. Pimozide: Concomitant administration of PREVYMIS in patients receiving pimozide may result in increased concentrations of pimozide due to inhibition of cytochrome P450 3A (CYP3A) by letermovir, which may lead to QT prolongation and torsades de pointes [see Warnings and Precautions (5.1) and Drug Interactions (7.2, 7.3)].. Ergot alkaloids: Concomitant administration of PREVYMIS in patients receiving ergot alkaloids may result in increased concentrations of ergot alkaloids (ergotamine and dihydroergotamine) due to inhibition of CYP3A by letermovir, which may lead to ergotism [see Warnings and Precautions (5.1) and Drug Interactions (7.2, 7.3)].. PREVYMIS is contraindicated with pitavastatin and simvastatin when co-administered with cyclosporine. Concomitant administration of PREVYMIS in combination with cyclosporine may result in significantly increased pitavastatin or simvastatin concentrations, which may lead to myopathy or rhabdomyolysis [see Warnings and Precautions (5.1) and Drug Interactions (7.2, 7.3)].. PREVYMIS is contraindicated with:Pimozide. (4)Ergot Alkaloids. (4)Pitavastatin and simvastatin when co-administered with cyclosporine. (4). Pimozide. (4). Ergot Alkaloids. (4). Pitavastatin and simvastatin when co-administered with cyclosporine. (4).

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. 480 mg administered once daily orally or as an intravenous (IV) infusion over hour through 100 days post-transplant. (2.1, 2.2)PREVYMIS injection must be administered through sterile 0.2 micron or 0.22 micron polyethersulfone (PES) in-line filter. (2.1, 2.7)Dosage Adjustment: If PREVYMIS is co-administered with cyclosporine, the dosage of PREVYMIS should be decreased to 240 mg once daily. (2.4)Do not use PREVYMIS injection with IV bags and infusion set materials containing the plasticizer diethylhexyl phthalate (DEHP). (2.7, 2.9). 480 mg administered once daily orally or as an intravenous (IV) infusion over hour through 100 days post-transplant. (2.1, 2.2). PREVYMIS injection must be administered through sterile 0.2 micron or 0.22 micron polyethersulfone (PES) in-line filter. (2.1, 2.7). Dosage Adjustment: If PREVYMIS is co-administered with cyclosporine, the dosage of PREVYMIS should be decreased to 240 mg once daily. (2.4). Do not use PREVYMIS injection with IV bags and infusion set materials containing the plasticizer diethylhexyl phthalate (DEHP). (2.7, 2.9). 2.1Important Dosing and Administration Information. PREVYMIS TabletsAdminister with or without food.Swallow tablets whole.PREVYMIS InjectionPREVYMIS injection must be administered through sterile 0.2 micron or 0.22 micron polyethersulfone (PES) in-line filter.Administer by intravenous infusion via peripheral catheter or central venous line at constant rate over hour.Do not administer as an intravenous bolus injection.. Administer with or without food.. Swallow tablets whole.. PREVYMIS injection must be administered through sterile 0.2 micron or 0.22 micron polyethersulfone (PES) in-line filter.. Administer by intravenous infusion via peripheral catheter or central venous line at constant rate over hour.. Do not administer as an intravenous bolus injection.. 2.2Recommended Dosage for Adult Patients. The recommended dosage of PREVYMIS is 480 mg administered orally or intravenously once daily. Initiate PREVYMIS between Day and Day 28 post-transplantation (before or after engraftment), and continue through Day 100 post-transplantation. Dosage of PREVYMIS should be adjusted when co-administered with cyclosporine [see Dosage and Administration (2.4)].PREVYMIS injection, which contains hydroxypropyl betadex, should be used only in patients unable to take oral therapy. Patients should be switched to oral PREVYMIS as soon as they are able to take oral medications. PREVYMIS tablet and injection may be used interchangeably at the discretion of the physician, and no dosage adjustment is necessary when switching formulations.. 2.3 Patient Monitoring. Following the completion of PREVYMIS prophylaxis, monitoring for CMV reactivation is recommended.. 2.4Dosage Adjustment When Co-administered with Cyclosporine. If oral or intravenous PREVYMIS is co-administered with cyclosporine, the dosage of PREVYMIS should be decreased to 240 mg once daily [see Drug Interactions (7.1, 7.2, 7.3) and Clinical Pharmacology (12.3)].If cyclosporine is initiated after starting PREVYMIS, the next dose of PREVYMIS should be decreased to 240 mg once daily.If cyclosporine is discontinued after starting PREVYMIS, the next dose of PREVYMIS should be increased to 480 mg once daily.If cyclosporine dosing is interrupted due to high cyclosporine levels, no dose adjustment of PREVYMIS is needed.. If cyclosporine is initiated after starting PREVYMIS, the next dose of PREVYMIS should be decreased to 240 mg once daily.. If cyclosporine is discontinued after starting PREVYMIS, the next dose of PREVYMIS should be increased to 480 mg once daily.. If cyclosporine dosing is interrupted due to high cyclosporine levels, no dose adjustment of PREVYMIS is needed.. 2.5Use in Patients with Renal Impairment. For patients with creatinine clearance (CLcr) greater than 10 mL/min, no dosage adjustment of PREVYMIS is required based on renal impairment [see Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].There are insufficient data in patients with CLcr 10 mL/min or less or in patients on dialysis to make PREVYMIS dosing recommendations.In patients with CLcr less than 50 mL/min receiving PREVYMIS injection, accumulation of the intravenous vehicle, hydroxypropyl betadex, may occur. Closely monitor serum creatinine levels in these patients.. For patients with creatinine clearance (CLcr) greater than 10 mL/min, no dosage adjustment of PREVYMIS is required based on renal impairment [see Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].. There are insufficient data in patients with CLcr 10 mL/min or less or in patients on dialysis to make PREVYMIS dosing recommendations.. In patients with CLcr less than 50 mL/min receiving PREVYMIS injection, accumulation of the intravenous vehicle, hydroxypropyl betadex, may occur. Closely monitor serum creatinine levels in these patients.. 2.6Use in Patients with Hepatic Impairment. No dosage adjustment of PREVYMIS is required for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. PREVYMIS is not recommended for patients with severe (Child-Pugh Class C) hepatic impairment [see Use in Specific Populations (8.7)].. 2.7Preparation and Administration of Intravenous Solution. PREVYMIS injection is supplied in 30 mL single-dose vials containing either 240 mg/12 mL per vial (20 mg/mL) or 480 mg/24 mL per vial (20 mg/mL). The preparation and administration instructions are the same for either dose.PREVYMIS vials are for single use only. Discard any unused portion.. Preparation and Administration InstructionsPREVYMIS must be diluted prior to intravenous (IV) use.Inspect vial contents for discoloration and particulate matter prior to dilution. PREVYMIS injection is clear colorless solution and may contain few product-related small translucent or white particles.Do not use the vial if the solution is cloudy, discolored, or contains matter other than few small translucent or white particles.Do not use PREVYMIS injection with IV bags and infusion set materials containing the plasticizer diethylhexyl phthalate (DEHP). Use only with IV bags and infusion set materials that are DEHP-free. Materials that are phthalate-free are also DEHP-free.Do not shake PREVYMIS vial.Add one single-dose vial of PREVYMIS injection into 250 mL pre-filled IV bag containing either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP and mix bag gently. Do not shake. Only 0.9% Sodium Chloride and 5% Dextrose are chemically and physically compatible with PREVYMIS injection.Use compatible IV bags and infusion set materials. PREVYMIS injection is compatible with the following IV bags and infusion set materials. PREVYMIS injection is not recommended with any IV bags or infusion set materials not listed below (note that PREVYMIS injection is not recommended for use with polyurethane-containing IV administration set tubing). IV Bags Materials: Polyvinyl chloride (PVC), ethylene vinyl acetate (EVA) and polyolefin (polypropylene and polyethylene) Infusion Sets Materials: PVC, polyethylene (PE), polybutadiene (PBD), silicone rubber (SR), styrene-butadiene copolymer (SBC), styrene-butadiene-styrene copolymer (SBS), polystyrene (PS) Plasticizers: Tris (2-ethylhexyl) trimellitate (TOTM), benzyl butyl phthalate (BBP) Catheters: Radiopaque polyurethaneOnce diluted, the solution of PREVYMIS is clear, and ranges from colorless to yellow. Variations of color within this range do not affect the quality of the product.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.Discard if the diluted solution is cloudy, discolored, or contains matter other than few small translucent or white particles.The diluted solution is stable for up to 24 hours at room temperature or up to 48 hours under refrigeration at 2C to 8C (36F to 46F) (this time includes storage of the diluted solution in the intravenous bag through the duration of infusion).The diluted solution must be administered through sterile 0.2 micron or 0.22 micron polyethersulfone (PES) in-line filter.Do not administer through filter other than sterile 0.2 micron or 0.22 micron PES in-line filter.Administer the entire contents of the intravenous bag by intravenous infusion via peripheral catheter or central venous line at constant rate over hour [see Dosage and Administration (2.1)].. PREVYMIS must be diluted prior to intravenous (IV) use.. Inspect vial contents for discoloration and particulate matter prior to dilution. PREVYMIS injection is clear colorless solution and may contain few product-related small translucent or white particles.. Do not use the vial if the solution is cloudy, discolored, or contains matter other than few small translucent or white particles.. Do not use PREVYMIS injection with IV bags and infusion set materials containing the plasticizer diethylhexyl phthalate (DEHP). Use only with IV bags and infusion set materials that are DEHP-free. Materials that are phthalate-free are also DEHP-free.. Do not shake PREVYMIS vial.. Add one single-dose vial of PREVYMIS injection into 250 mL pre-filled IV bag containing either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP and mix bag gently. Do not shake. Only 0.9% Sodium Chloride and 5% Dextrose are chemically and physically compatible with PREVYMIS injection.. Use compatible IV bags and infusion set materials. PREVYMIS injection is compatible with the following IV bags and infusion set materials. PREVYMIS injection is not recommended with any IV bags or infusion set materials not listed below (note that PREVYMIS injection is not recommended for use with polyurethane-containing IV administration set tubing). IV Bags Materials: Polyvinyl chloride (PVC), ethylene vinyl acetate (EVA) and polyolefin (polypropylene and polyethylene) Infusion Sets Materials: PVC, polyethylene (PE), polybutadiene (PBD), silicone rubber (SR), styrene-butadiene copolymer (SBC), styrene-butadiene-styrene copolymer (SBS), polystyrene (PS) Plasticizers: Tris (2-ethylhexyl) trimellitate (TOTM), benzyl butyl phthalate (BBP) Catheters: Radiopaque polyurethane. Once diluted, the solution of PREVYMIS is clear, and ranges from colorless to yellow. Variations of color within this range do not affect the quality of the product.. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.. Discard if the diluted solution is cloudy, discolored, or contains matter other than few small translucent or white particles.. The diluted solution is stable for up to 24 hours at room temperature or up to 48 hours under refrigeration at 2C to 8C (36F to 46F) (this time includes storage of the diluted solution in the intravenous bag through the duration of infusion).. The diluted solution must be administered through sterile 0.2 micron or 0.22 micron polyethersulfone (PES) in-line filter.. Do not administer through filter other than sterile 0.2 micron or 0.22 micron PES in-line filter.. Administer the entire contents of the intravenous bag by intravenous infusion via peripheral catheter or central venous line at constant rate over hour [see Dosage and Administration (2.1)].. 2.8Compatible Drug Products Used for Intravenous Administration. Compatible Drug ProductsThe physical compatibility of PREVYMIS injection with selected injectable drug products was evaluated in two commonly available diluents. PREVYMIS should not be co-administered through the same intravenous line (or cannula) with other drug products and diluent combinations except those listed below. Refer to the respective prescribing information of the co-administered drug(s) to confirm compatibility of simultaneous co-administration.List of Compatible Drug Products when PREVYMIS and Drug Products are Prepared in 0.9% Sodium Chloride Injection, USP: Ampicillin sodium, ampicillin sodium/sulbactam sodium, anti-thymocyte globulin, caspofungin, daptomycin, fentanyl citrate, fluconazole, furosemide, human insulin, magnesium sulfate, methotrexate, micafungin.List of Compatible Drug Products when PREVYMIS and Drug Products are Prepared in 5% Dextrose Injection, USP: Amphotericin (lipid complex)Amphotericin (lipid complex) is compatible with PREVYMIS. However, Amphotericin (liposomal) is incompatible [see Dosage and Administration (2.9)]., anidulafungin, cefazolin sodium, ceftaroline, ceftriaxone sodium, doripenem, famotidine, folic acid, ganciclovir sodium, hydrocortisone sodium succinate, morphine sulfate, norepinephrine bitartrate, pantoprazole sodium, potassium chloride, potassium phosphate, tacrolimus, telavancin, tigecycline.. Ampicillin sodium, ampicillin sodium/sulbactam sodium, anti-thymocyte globulin, caspofungin, daptomycin, fentanyl citrate, fluconazole, furosemide, human insulin, magnesium sulfate, methotrexate, micafungin.. Amphotericin (lipid complex)Amphotericin (lipid complex) is compatible with PREVYMIS. However, Amphotericin (liposomal) is incompatible [see Dosage and Administration (2.9)]., anidulafungin, cefazolin sodium, ceftaroline, ceftriaxone sodium, doripenem, famotidine, folic acid, ganciclovir sodium, hydrocortisone sodium succinate, morphine sulfate, norepinephrine bitartrate, pantoprazole sodium, potassium chloride, potassium phosphate, tacrolimus, telavancin, tigecycline.. 2.9Incompatible Drug Products and Other Materials Used for Intravenous Administration. Incompatible Drug ProductsPREVYMIS injection is physically incompatible with amiodarone hydrochloride, amphotericin (liposomal), aztreonam, cefepime hydrochloride, ciprofloxacin, cyclosporine, diltiazem hydrochloride, filgrastim, gentamicin sulfate, levofloxacin, linezolid, lorazepam, midazolam HCl, mycophenolate mofetil hydrochloride, ondansetron, palonosetron.. Incompatible IV Bags and Infusion Set MaterialsPREVYMIS concentrate for solution for infusion is incompatible with diethylhexyl phthalate (DEHP) plasticizers and polyurethane-containing IV administration set tubing.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Dosage Adjustment: If PREVYMIS is co-administered with cyclosporine, the dosage of PREVYMIS should be decreased to 240 mg once daily. (2.4)Co-administration of PREVYMIS may alter the plasma concentrations of other drugs and other drugs may alter the plasma concentrations of PREVYMIS. Consult the full prescribing information prior to and during treatment for potential drug interactions. (2.4, 4, 5.1, 7.1, 7.2, 7.3, 7.4, 12.3). Dosage Adjustment: If PREVYMIS is co-administered with cyclosporine, the dosage of PREVYMIS should be decreased to 240 mg once daily. (2.4). Co-administration of PREVYMIS may alter the plasma concentrations of other drugs and other drugs may alter the plasma concentrations of PREVYMIS. Consult the full prescribing information prior to and during treatment for potential drug interactions. (2.4, 4, 5.1, 7.1, 7.2, 7.3, 7.4, 12.3). 7.1Potential for Other Drugs to Affect PREVYMIS. Letermovir is substrate of organic anion-transporting polypeptide 1B1/3 (OATP1B1/3) and P-glycoprotein (P-gp) transporters and UDP-glucuronosyltransferase 1A1/3 (UGT1A1/3) enzymes. Co-administration of PREVYMIS with drugs that are inhibitors of OATP1B1/3 transporters may result in increases in letermovir plasma concentrations (Table 3).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 decrease in letermovir plasma concentrations (see Table 3).. 7.2Potential for PREVYMIS to Affect Other Drugs. Co-administration of PREVYMIS with midazolam results in increased midazolam plasma concentrations, indicating that letermovir is moderate inhibitor of CYP3A [see Clinical Pharmacology (12.3)]. 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 (Table 3) [see Contraindications (4) and Warnings and Precautions (5.1)].Letermovir is an inhibitor of OATP1B1/3 transporters. Co-administration of PREVYMIS with drugs that are substrates of OATP1B1/3 transporters may result in clinically relevant increase in plasma concentrations of co-administered OATP1B1/3 substrates (Table 3).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.. 7.3Established and Other Potentially Significant Drug Interactions. If dose adjustments of concomitant medications are made due to treatment with PREVYMIS, doses should be readjusted after treatment with PREVYMIS is completed.Table provides listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with PREVYMIS or are predicted drug interactions that may occur with PREVYMIS [see Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].Table 3: Potentially Significant Drug Interactions: Alteration in Dose May Be Recommended Based on Results from Drug Interaction Studies or Predicted InteractionsThis table is not all inclusive. (Information in the Table Applies to Co-administration of PREVYMIS and the Concomitant Drug without Cyclosporine, Unless Otherwise Indicated)Concomitant Drug Class and/or Clearance Pathway: Drug NameEffect on Concentration =decrease, =increase Clinical CommentsAnti-arrhythmic Agentsamiodarone amiodaroneClose clinical monitoring for adverse events related to amiodarone is recommended during co-administration. Frequently monitor amiodarone concentrations when amiodarone is co-administered with PREVYMIS.Antibioticsnafcillin letermovirCo-administration of PREVYMIS and nafcillin is not recommended due to potential for loss of efficacy of PREVYMIS.Anticoagulantswarfarin warfarinWhen PREVYMIS is co-administered with warfarin, frequently monitor International Normalized Ratio (INR) Refer to the respective prescribing information..Anticonvulsantscarbamazepine letermovirCo-administration of PREVYMIS and carbamazepine is not recommended due to potential for loss of efficacy of PREVYMIS.phenobarbital letermovirCo-administration of PREVYMIS and phenobarbital is not recommended due to potential for loss of efficacy of PREVYMIS.phenytoin letermovir phenytoinCo-administration of PREVYMIS and phenytoin is not recommended due to potential for loss of efficacy of PREVYMIS.Antidiabetic AgentsExamples:glyburide, repaglinide, rosiglitazone glyburide repaglinide rosiglitazoneWhen PREVYMIS is co-administered with glyburide, repaglinide, or rosiglitazone, frequently monitor glucose concentrations.When PREVYMIS is co-administered with cyclosporine, use of repaglinide is not recommended.AntifungalsvoriconazoleThese interactions have been studied [see Clinical Pharmacology (12.3)]. voriconazoleIf concomitant administration of voriconazole is necessary, closely monitor for reduced effectiveness of voriconazole.Antimycobacterialsrifabutin letermovirCo-administration of PREVYMIS and rifabutin is not recommended due to potential for loss of efficacy of PREVYMIS.rifampin letermovirCo-administration of PREVYMIS and rifampin is not recommended due to potential for loss of efficacy of PREVYMIS.Antipsychoticspimozide pimozideCo-administration is contraindicated due to risk of QT prolongation and torsades de pointes [see Contraindications (4)].thioridazine letermovirCo-administration of PREVYMIS and thioridazine is not recommended due to potential for loss of efficacy of PREVYMIS.Endothelin Antagonistsbosentan letermovirCo-administration of PREVYMIS and bosentan is not recommended due to potential for loss of efficacy of PREVYMIS.Ergot Alkaloidsergotamine, dihydroergotamine ergotamine, dihydroergotamineCo-administration is contraindicated due to risk of ergotism [see Contraindications (4)].Herbal ProductsSt. Johns wort (Hypericum perforatum) letermovirCo-administration of PREVYMIS and St. Johns wort is not recommended due to potential for loss of efficacy of PREVYMIS.HIV Medicationsefavirenz letermovirCo-administration of PREVYMIS and efavirenz is not recommended due to potential for loss of efficacy of PREVYMIS.etravirine letermovirCo-administration of PREVYMIS and etravirine is not recommended due to potential for loss of efficacy of PREVYMIS.nevirapine letermovirCo-administration of PREVYMIS and nevirapine is not recommended due to potential for loss of efficacy of PREVYMIS.HMG-CoA Reductase Inhibitorsatorvastatin atorvastatinWhen PREVYMIS is co-administered with atorvastatin, do not exceed an atorvastatin dosage of 20 mg daily. Closely monitor patients for myopathy and rhabdomyolysis.When PREVYMIS is co-administered with cyclosporine, use of atorvastatin is not recommended.pitavastatin, simvastatin HMG-CoA reductase inhibitorsCo-administration of PREVYMIS and pitavastatin or simvastatin is not recommended.When PREVYMIS is co-administered with cyclosporine, use of either pitavastatin or simvastatin is contraindicated due to significantly increased pitavastatin or simvastatin concentrations and risk of myopathy or rhabdomyolysis [see Contraindications (4)].fluvastatin, lovastatin, pravastatin, rosuvastatin HMG-CoA reductase inhibitorsWhen PREVYMIS is co-administered with these statins, statin dosage reduction may be necessary. Closely monitor patients for myopathy and rhabdomyolysis.When PREVYMIS is co-administered with cyclosporine, use of lovastatin is not recommended.When PREVYMIS is co-administered with cyclosporine, refer to the statin prescribing information for specific statin dosing recommendations.Immunosuppressantscyclosporine cyclosporine letermovirDecrease the dosage of PREVYMIS to 240 mg once daily [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].Frequently monitor cyclosporine whole blood concentrations during treatment and after discontinuation of PREVYMIS and adjust the dose of cyclosporine accordingly.sirolimus sirolimusWhen PREVYMIS is co-administered with sirolimus, frequently monitor sirolimus whole blood concentrations during treatment and after discontinuation of PREVYMIS and adjust the dose of sirolimus accordingly.When PREVYMIS is co-administered with cyclosporine and sirolimus, refer to the sirolimus prescribing information for specific sirolimus dosing recommendations. tacrolimus tacrolimusFrequently monitor tacrolimus whole blood concentrations during treatment and after discontinuation of PREVYMIS and adjust the dose of tacrolimus accordingly.Proton Pump Inhibitorsomeprazole omeprazoleClinical monitoring and dose adjustment may be needed.pantoprazole pantoprazoleClinical monitoring and dose adjustment may be needed.Wakefulness-Promoting Agentsmodafinil letermovirCo-administration of PREVYMIS and modafinil is not recommended due to potential for loss of efficacy of PREVYMIS.CYP3A SubstratesExamples: alfentanil, fentanyl, midazolam, and quinidine CYP3A substrateWhen PREVYMIS is co-administered with CYP3A substrate, refer to the prescribing information for dosing of the CYP3A substrate with moderate CYP3A inhibitor.When PREVYMIS is co-administered with cyclosporine, the combined effect on CYP3A substrates may be similar to strong CYP3A inhibitor. Refer to the prescribing information for dosing of the CYP3A substrate with strong CYP3A inhibitor.CYP3A substrates pimozide and ergot alkaloids are contraindicated [see Contraindications (4)].. 7.4Drugs without Clinically Significant Interactions with PREVYMIS. No clinically significant interactions were observed in clinical drug-drug interaction studies of letermovir and acyclovir, digoxin, mycophenolate mofetil, fluconazole, itraconazole, posaconazole, ethinyl estradiol, and levonorgestrel.

MICROBIOLOGY SECTION.

12.4 Microbiology. Mechanism of ActionLetermovir 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.. Antiviral ActivityThe median EC50 value of letermovir against collection of clinical CMV isolates in cell-culture model of infection was 2.1 nM (range 0.7 nM to 6.1 nM, = 74). There was no significant difference in EC50 value by CMV gB genotype (gB1=29; gB2=27; gB3=11; and gB4=3).. Combination Antiviral ActivityNo antagonism of the antiviral activity was seen when letermovir was combined with CMV DNA polymerase inhibitors (cidofovir, foscarnet, or ganciclovir).. Viral Resistance. In Cell CultureCMV 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 StudiesIn Phase 2b trial evaluating letermovir or placebo in 131 HSCT recipients, DNA sequence analysis of 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 letermovir resistance substitution, pUL56 V236M.In Phase 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 subjects; however, no subjects had substitutions at the same positions. Cross ResistanceCross 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.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetic properties of letermovir are displayed in Table 4.Table 4: Absorption, Distribution, Metabolism, Elimination (ADME), and Pharmacokinetic Properties of PREVYMISValues were obtained in studies of healthy subjects unless otherwise indicated. Pharmacokinetics in HSCT RecipientsTreatment RegimenSteady-state median (90% prediction interval) AUC (nghr/mL) of PREVYMIS 480 mg oral once daily, no cyclosporine34,400 (16,900, 73,700) 480 mg IV once daily, no cyclosporine100,000 (65,300, 148,000) 240 mg oral once daily, with cyclosporine60,800 (28,700, 122,000) 240 mg IV once daily, with cyclosporine70,300 (46,200, 106,000)Pharmacokinetics in Healthy SubjectsTreatment RegimenSteady-state geometric mean AUC and Cmax of PREVYMIS 480 mg oral once dailyCmax: 13,000 ng/mLAUC: 71,500 nghr/mLDose proportionalityGreater than proportional following single and multiple oral or IV doses of PREVYMIS 240 mg and 480 mgAccumulation ratioBased on geometric mean data. Cmax: 1.03AUC: 1.22Time to steady-state 9-10 daysAbsorptionBioavailabilityHealthy subjects administered PREVYMIS without cyclosporine: 94% at an oral dose range of 240 mg to 480 mgHSCT recipients administered PREVYMIS without cyclosporine: 35% with 480 mg oral once dailyHSCT recipients administered PREVYMIS with cyclosporine: 85% with 240 mg oral once dailyMedian Tmax (hr)1.5 to 3.0 hrEffect of food (relative to fasting) Values refer to geometric mean ratio [fed/fasted] percentage and 90% confidence interval back transformed from linear mixed-effects model performed on natural log-transformed values. The meal administered was standard high fat and high calorie meal (33 grams protein, 65 grams carbohydrates, 58 grams fat; 920 total calories). AUC: 99.63% [84.27% 117.80%]Cmax: 129.82% [104.35% -161.50%]DistributionMean steady-state volume of distribution45.5 following IV administration in HSCT recipients% In vitro bound to human plasma proteins99% across the concentration range of 0.2 to 50 mg/LIn vitro blood-to plasma ratio0.56 across the concentration range of 0.1 to 10 mg/LMetabolismIn vitro metabolismUGT1A1/1A3 (minor)Drug-related component in plasma97% unchanged parentNo major metabolites detected in plasmaEliminationRoute of elimination Hepatic uptake (OATP1B1/3)Mean terminal t1/2 (hr)12 hrs after dosing of PREVYMIS 480 mg IV once daily% of dose excreted in fecesSingle oral administration of radiolabeled letermovir in mass balance study. 93%% of dose excreted in urine <2%% of unchanged drug excreted in feces 70%. Specific Populations. Pediatric PopulationThe pharmacokinetics of letermovir in patients less than 18 years of age have not been evaluated.. Age, Gender, Race, and WeightAge (18 to 78 years), gender, race (White vs. non-White), and body weight (up to 100 kg) did not have clinically significant effect on the pharmacokinetics of letermovir.. Renal ImpairmentLetermovir 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.. Hepatic ImpairmentLetermovir AUC was approximately 1.6- and 3.8-fold higher in subjects with moderate (Child-Pugh Class [CP-B], score of 7-9) and severe (Child-Pugh Class [CP-C], score of 10-15) hepatic impairment, respectively, compared to healthy subjects.. Drug Interaction StudiesDrug 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 and Table 6).In vitro results indicate that letermovir is substrate of drug metabolizing enzymes CYP3A, CYP2D6, UGT1A1, and UGT1A3, and transporters OATP1B1/3 and P-gp. Oxidative metabolism is considered to be 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 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 reversible inhibitor of CYP2C8 in vitro. When co-administered with PREVYMIS, plasma concentrations of CYP2C8 substrates are predicted to be increased [see Table 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 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 (MRP2), OAT3, and hepatic uptake transporter OATP1B1/3 in vitro. Co-administration of PREVYMIS with substrates of OATP1B1/3 transporters (e.g. atorvastatin, known substrate of CYP3A, OATP1B1/3, and potentially BCRP) may result in clinically relevant increase in plasma concentrations of OATP1B1/3 substrates [see Table in Drug Interactions (7.3)]. There were no clinically relevant changes in plasma concentrations of digoxin, 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 DrugCo-administered DrugRegimen of Co-administered DrugLetermovir RegimenGeometric Mean Ratio [90% CI] of Letermovir PK with/without Co-administered Drug (No Effect=1.00)AUCCmaxC24hrC12hr for tacrolimus Abbreviations: PO= oralAntifungalsfluconazole400 mg single dose PO480 mg single dose PO1.11(1.01, 1.23)1.06(0.93, 1.21)1.28(1.15, 1.43)itraconazole200 mg once daily PO480 mg once daily PO1.33(1.17, 1.51)1.21(1.05, 1.39)1.90(1.58, 2.28)Antimycobacterialsrifampin600 mg single dose PO480 mg single dose PO2.03(1.84, 2.26)1.59(1.46, 1.74)2.01(1.59, 2.54)600 mg single dose IV480 mg single dose PO1.58(1.38, 1.81)1.37(1.16, 1.61)0.78(0.65, 0.93)600 mg once daily PO480 mg once daily PO0.81(0.67, 0.98)1.01(0.79, 1.28)0.14(0.11, 0.19)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 PO0.15(0.13, 0.17)0.27(0.22, 0.31)0.09(0.06, 0.12)Immunosuppressantscyclosporine200 mg single dose PO240 mg once daily PO2.11(1.97, 2.26)1.48(1.33, 1.65)2.06(1.81, 2.35)mycophenolate mofetil1 single dose PO480 mg once daily PO1.18(1.04, 1.32)1.11(0.92, 1.34)1.39(1.12, 1.74)tacrolimus5 mg single dose PO80 mg twice daily PO1.02(0.97, 1.07)0.92(0.84, 1.00)1.02(0.93, 1.12)Table 6: Drug Interactions: Changes in Pharmacokinetics for Co-administered Drug in the Presence of LetermovirCo-administered DrugRegimen of Co-administered DrugLetermovir RegimenGeometric Mean Ratio [90% CI] of Co-administered Drug PK with/without Letermovir(No Effect=1.00)AUCCmaxC24hrC12hr reported for voriconazole. Abbreviations: PO=oralCYP3A Substratesmidazolam1 mg single dose IV240 mg once daily PO1.47(1.37, 1.58)1.05(0.94, 1.17)2.74(2.16, 3.49)2 mg single dose PO240 mg once daily PO2.25(2.04, 2.48)1.72(1.55, 1.92)Not availableP-gp Substratesdigoxin0.5 mg single dose PO240 mg twice daily PO0.88(0.80, 0.96)0.75(0.63, 0.89)0.90(0.84, 0.96)Immunosuppressantscyclosporine50 mg single dose PO240 mg once daily PO1.66(1.51, 1.82)1.08(0.97, 1.19)2.19(1.80, 2.66)mycophenolate mofetil1 single dose PO480 mg once daily PO1.08(0.97, 1.20)0.96(0.82, 1.12)1.04(0.86, 1.27)tacrolimus5 mg single dose PO480 mg once daily PO2.42(2.04, 2.88)1.57(1.32, 1.86)2.53(2.12, 3.03)sirolimus2 mg single dose PO480 mg once daily PO3.40(3.01, 3.85)2.76(2.48, 3.06)3.15(2.80, 3.55)Antifungals and Antiviralsacyclovir400 mg single dose PO480 mg once daily PO1.02(0.87, 1.2)0.82(0.71, 0.93)1.13(0.94, 1.36)fluconazole400 mg single dose PO480 mg single dose PO1.03 (0.99, 1.08)0.95(0.92, 0.99)1.04(1.00, 1.08)itraconazole200 mg once daily PO480 mg once daily PO0.76(0.71, 0.81)0.84(0.76, 0.92)0.67(0.61, 0.73)posaconazole300 mg single dose PO480 mg once daily PO0.98(0.82, 1.17)1.11(0.95, 1.29)1.10(0.94, 1.30)voriconazole200 mg twice daily PO480 mg once daily PO0.56(0.51, 0.62)0.61(0.53, 0.71)0.49(0.42, 0.57)HMG-CoA Reductase Inhibitorsatorvastatin20 mg single dose PO480 mg once daily PO3.29(2.84, 3.82)2.17(1.76, 2.67)3.62(2.87, 4.55)Oral Contraceptivesethinyl estradiol (EE) /levonorgestrel (LNG)0.03 mg EE single dose PO480 mg once daily PO1.42(1.32, 1.52)0.89(0.83, 0.96)1.57(1.45, 1.70)0.15 mg LNG single dose PO1.36(1.30, 1.43)0.95(0.86, 1.04)1.38(1.32, 1.46).

SPL PATIENT PACKAGE INSERT SECTION.

Patient InformationPREVYMIS(TM) (PREH-vih-miss)(letermovir) tablets(letermovir) injection, for intravenous useWhat is PREVYMISPREVYMIS is prescription medicine to help to prevent cytomegalovirus (CMV) infection and disease in adults who have received an allogeneic hematopoietic stem cell (bone marrow) transplant.It is not known if PREVYMIS is safe and effective in children under 18 years of age.Who should not take PREVYMISDo not take PREVYMIS if you take:PimozideErgot alkaloidsIf you are taking PREVYMIS with cyclosporine, do not take:Pitavastatin or simvastatinWhat should tell my doctor before taking PREVYMISTell your doctor about all your medical conditions, including if you:Have kidney or liver problems.Are pregnant or plan to become pregnant. It is not known if PREVYMIS will harm your unborn baby.Are breastfeeding or plan to breastfeed. It is not known if PREVYMIS passes into your breast milk. Talk to your doctor about the best way to feed your baby while taking PREVYMIS.Tell your doctor about all of the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. PREVYMIS may affect the way other medicines work, and other medicines may affect how PREVYMIS works and cause serious side effects.Know the medicines you take. Keep list of medicines and show it to your doctor and pharmacist when you get new medicine. Your doctor or pharmacist will tell you if it is safe to take PREVYMIS with other medicines. Do not start or stop taking another medicine without telling your doctor first.How should take PREVYMISPREVYMIS comes as tablet or can be given by your doctor through an IV line (intravenously).If you take PREVYMIS tablets:Take PREVYMIS exactly as your doctor tells you to take it. Do not stop taking PREVYMIS without talking to your doctor first.Take PREVYMIS tablet once day.Take PREVYMIS with or without food.Swallow PREVYMIS tablets whole.It is important that you do not miss or skip doses of PREVYMIS.If you miss dose, take it as soon as you remember. If you do not remember until it is time for your next dose, skip the missed dose and take your dose at the next scheduled time. Do not take doses of PREVYMIS at the same time to make up for missed dose.If you take too much PREVYMIS, call your doctor right away.If you receive PREVYMIS through an IV line (intravenously):You will receive PREVYMIS time each day given over hour.If you miss or skip your dose of PREVYMIS, call your doctor right away.What are the possible side effects of PREVYMISThe most common side effects while taking PREVYMIS include:nauseadiarrheavomitingswelling in your arms and legscoughheadachetirednessstomach (abdominal) painThese are not all the possible side effects of PREVYMIS.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store PREVYMISStore PREVYMIS tablets and PREVYMIS injection at room temperature between 68F to 77F (20C to 25C).Store PREVYMIS tablets in the original package until you are ready to take it.Store PREVYMIS injection in the original carton to protect from exposure to light.Keep PREVYMIS and all medicines out of the reach of children.General information about the safe and effective use of PREVYMISMedicines are sometimes prescribed for purposes other than those listed in the Patient Information leaflet. Do not use PREVYMIS for condition for which it was not prescribed. Do not give PREVYMIS to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about PREVYMIS that is written for healthcare professionals.What are the ingredients in PREVYMISActive ingredient: letermovirInactive ingredients:Tablets: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and povidone 25. Film coating: hypromellose 2910, iron oxide red (only for 480 mg tablets), iron oxide yellow, lactose monohydrate, titanium dioxide, triacetin. Carnauba wax is added as polishing agent.Injection: hydroxypropyl betadex, sodium chloride, sodium hydroxide, and Water for Injection, USP.. Pimozide. Ergot alkaloids. Pitavastatin or simvastatin. Have kidney or liver problems.. Are pregnant or plan to become pregnant. It is not known if PREVYMIS will harm your unborn baby.. Are breastfeeding or plan to breastfeed. It is not known if PREVYMIS passes into your breast milk. Talk to your doctor about the best way to feed your baby while taking PREVYMIS.. If you take PREVYMIS tablets:Take PREVYMIS exactly as your doctor tells you to take it. Do not stop taking PREVYMIS without talking to your doctor first.Take PREVYMIS tablet once day.Take PREVYMIS with or without food.Swallow PREVYMIS tablets whole.It is important that you do not miss or skip doses of PREVYMIS.If you miss dose, take it as soon as you remember. If you do not remember until it is time for your next dose, skip the missed dose and take your dose at the next scheduled time. Do not take doses of PREVYMIS at the same time to make up for missed dose.If you take too much PREVYMIS, call your doctor right away.. Take PREVYMIS exactly as your doctor tells you to take it. Do not stop taking PREVYMIS without talking to your doctor first.. Take PREVYMIS tablet once day.. Take PREVYMIS with or without food.. Swallow PREVYMIS tablets whole.. It is important that you do not miss or skip doses of PREVYMIS.. If you miss dose, take it as soon as you remember. If you do not remember until it is time for your next dose, skip the missed dose and take your dose at the next scheduled time. Do not take doses of PREVYMIS at the same time to make up for missed dose.. If you take too much PREVYMIS, call your doctor right away.. If you receive PREVYMIS through an IV line (intravenously):You will receive PREVYMIS time each day given over hour.If you miss or skip your dose of PREVYMIS, call your doctor right away.. You will receive PREVYMIS time each day given over hour.. If you miss or skip your dose of PREVYMIS, call your doctor right away.. nausea. diarrhea. vomiting. swelling in your arms and legs. cough. headache. tiredness. stomach (abdominal) pain. Store PREVYMIS tablets and PREVYMIS injection at room temperature between 68F to 77F (20C to 25C).. Store PREVYMIS tablets in the original package until you are ready to take it.. Store PREVYMIS injection in the original carton to protect from exposure to light.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Renal Impairment: Closely monitor serum creatinine levels in patients with CLcr less than 50 mL/min using PREVYMIS injection. (8.6)Hepatic Impairment: PREVYMIS is not recommended for patients with severe (Child-Pugh C) hepatic impairment. (8.7). Renal Impairment: Closely monitor serum creatinine levels in patients with CLcr less than 50 mL/min using PREVYMIS injection. (8.6). Hepatic Impairment: PREVYMIS is not recommended for patients with severe (Child-Pugh C) hepatic impairment. (8.7). 8.1 Pregnancy. Risk SummaryNo adequate human data are available to establish whether PREVYMIS poses 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 times higher than human exposure at the RHD). In rat pre/post-natal development study, total litter loss was observed at maternal letermovir exposures approximately 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.. Data. Animal DataLetermovir was administered orally to pregnant rats at 0, 10, 50 or 250 mg/kg/day from gestation days 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 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 to 20. Developmental toxicities, including spontaneous abortion, increased post-implantation loss, and skeletal variations, were observed at maternally toxic dose (225 mg/kg/day; approximately 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 to lactation day 22. At 180 mg/kg/day (approximately times higher than human exposure at the RHD), total litter loss due to stillbirth or possible maternal neglect was observed in 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).. 8.2 Lactation. Risk SummaryIt 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 mothers clinical need for PREVYMIS and any potential adverse effects on the breastfed child from PREVYMIS or from the underlying maternal condition.. DataIn 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.. 8.3 Females and Males of Reproductive Potential. InfertilityThere 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)].. 8.4 Pediatric Use. Safety and efficacy of PREVYMIS in patients below 18 years of age have not been established.. 8.5 Geriatric Use. Of the 373 subjects treated with PREVYMIS in Trial P001, 56 (15%) subjects were 65 years of age or older. Safety and efficacy were similar across older and younger subjects. No dosage adjustment of PREVYMIS is required based on age [see Clinical Pharmacology (12.3)].. 8.6Renal Impairment. For patients with CLcr greater than 10 mL/min (by Cockcroft-Gault equation), no dosage adjustment of PREVYMIS is required based on renal impairment [see Clinical Pharmacology (12.3)]. The safety of PREVYMIS in patients with end-stage renal disease (CLcr less than 10 mL/min), including patients on dialysis, is unknown.In patients with CLcr less than 50 mL/min receiving PREVYMIS injection, accumulation of the intravenous vehicle, hydroxypropyl betadex, could occur. Closely monitor serum creatinine levels in these patients.. 8.7Hepatic Impairment. No dosage adjustment of PREVYMIS is required for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. PREVYMIS is not recommended for patients with severe (Child-Pugh Class C) hepatic impairment [see Clinical Pharmacology (12.3)].