Previmis

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PREVYMIS

Composition:

Active substance: letermovir;

One film-coated tablet contains 240 mg of letermovir;

Excipients: microcrystalline cellulose; sodium croscarmellose; povidone 25; colloidal anhydrous silicon dioxide; magnesium stearate;

Tablet coating: Opadry® II Yellow (hypromellose 2910; titanium dioxide (E 171); lactose monohydrate; triacetin; iron oxide yellow (E 172)), carnauba wax.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: yellow oval-shaped tablets with the imprint "591" on one side and the corporate logo imprint on the other side.

Pharmacotherapeutic group. Antiviral agents for systemic use, direct-acting antiviral agents. ATC code J05AX18.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of Action

Letermovir inhibits the cytomegalovirus (CMV) DNA terminase complex, which is essential for cleaving and packaging viral progeny DNA. Letermovir affects the formation of genomes of proper length and prevents virion maturation.

Antiviral Activity

The mean half-maximal effective concentration (EC₅₀) of letermovir against a panel of clinical CMV isolates in a cell culture infection model was 2.1 nM (range: 0.7 nM to 6.1 nM, n = 74).

Viral Resistance

In Cell Culture

The CMV genes UL51, UL56, and UL89 encode subunits of the CMV DNA terminase. In cell culture, CMV mutants with reduced susceptibility to letermovir have been confirmed. EC₅₀ values for recombinant CMV mutants carrying substitutions in pUL51 (P91S), pUL56 (C25F, S229F, V231A, V231L, V236A, T244K, T244R, L254F, L257F, L257I, F261C, F261L, F261S, Y321C, L328V, M329T, A365S, N368D), or pUL89 (N320H, D344E) were 1.6–<10 times higher than those for the wild-type reference virus; these substitutions are unlikely to be clinically significant. EC₅₀ values for recombinant CMV mutants expressing pUL51 substitution A95V or pUL56 substitutions N232Y, V236L, V236M, E237D, E237G, L241P, K258E, C325F, C325R, C325W, C325Y, R369G, R369M, R369S, and R369T were 10–9300 times higher than for the wild-type reference virus; some of these substitutions were observed in patients with prophylaxis failure in clinical trials.

In Clinical Trials

In a phase 2b trial evaluating letermovir at doses of 60, 120, or 240 mg/day or placebo for 84 days in 131 hematopoietic stem cell transplant (HSCT) recipients, DNA sequencing analysis of a selected region of UL56 (amino acids 231–369) was performed on samples from 12 patients receiving letermovir who experienced prophylaxis failure and for whom samples were available. One patient (receiving 60 mg/day) had a letermovir-resistant genotypic variant (V236M).

In a phase 3 trial (P001), DNA sequencing analysis of all coding regions of UL56 and UL89 was performed on samples from 40 patients treated with letermovir in the full analysis set (FAS) population who experienced prophylaxis failure and for whom samples were available. Two patients had letermovir-resistant genotypic variants, both with substitutions in pUL56. One patient had the V236M substitution and the other had the E237G substitution. One additional patient with detectable CMV DNA at baseline (thus not included in the FAS population) had pUL56 substitutions (C325W and R369T) detected after discontinuation of letermovir.

In a phase 3 trial (P040), DNA sequencing analysis of all coding regions of UL51, UL56, and UL89 was performed on samples from 32 patients (regardless of treatment group) who experienced prophylaxis failure or prematurely discontinued treatment due to CMV viremia. No substitutions associated with letermovir resistance exceeding the validated analytical threshold of 5% were detected.

In a phase 3 trial (P002), DNA sequencing analysis of all coding regions of UL51, UL56, and UL89 was performed on samples from 52 patients treated with letermovir who experienced CMV disease or prematurely discontinued treatment due to CMV viremia. No substitutions associated with letermovir resistance exceeding the validated analytical threshold of 5% were detected.

Cross-Resistance

Cross-resistance is unlikely with drugs having a different mechanism of action. Letermovir is fully active against viral populations carrying substitutions conferring resistance to CMV DNA polymerase inhibitors (ganciclovir, cidofovir, and foscarnet). A panel of recombinant CMV strains carrying substitutions conferring resistance to letermovir were fully susceptible to cidofovir, foscarnet, and ganciclovir, except for the recombinant strain carrying the pUL56 E237G substitution, which showed a 2.1-fold reduction in susceptibility to ganciclovir compared to wild-type.

Cardiac Electrophysiology

The effect of intravenous letermovir at doses up to 960 mg on the QTc interval was evaluated in a randomized, single-dose, placebo- and active-controlled (moxifloxacin 400 mg orally), 4-period crossover study of QT interval effects in 38 healthy subjects. Letermovir did not prolong the QTc interval to any clinically relevant extent after intravenous administration of 960 mg. At this dose, plasma concentrations were approximately twice those observed with the 480 mg intravenous dose.

Clinical Efficacy and Safety

Adult CMV-seropositive recipients [R+] of allogeneic hematopoietic stem cell transplantation

P001: Prophylaxis up to Week 14 (~100 days) post-HSCT

To evaluate letermovir prophylaxis as a preemptive strategy against CMV infection (CMVI) or disease, the efficacy of letermovir was assessed in a multicenter, double-blind, placebo-controlled phase 3 trial (P001) in adult CMV-seropositive [R+] recipients of allogeneic HSCT. Patients were randomized (2:1) to receive either letermovir 480 mg once daily, adjusted to 240 mg when coadministered with cyclosporine, or placebo. Randomization was stratified by study center and risk (high vs. low) of CMV reactivation at study entry. Letermovir administration was initiated post-HSCT (days 0–28 post-HSCT) and continued for 14 weeks post-HSCT. Letermovir was administered orally or intravenously; the letermovir dose was the same regardless of route of administration. Patients were monitored up to Week 24 post-HSCT for the primary efficacy endpoint, with further follow-up through Week 48 post-HSCT.

Patients were monitored weekly for CMV DNA through Week 14 post-HSCT and then every 2 weeks through Week 24 post-HSCT, with initiation of standard preemptive CMV therapy if CMV DNAemia was considered clinically significant. Patients continued to be followed through Week 48 post-HSCT.

Of the 565 patients who received treatment, 373 received letermovir (including 99 patients who received at least one intravenous dose) and 192 received placebo (including 48 patients who received at least one intravenous dose). The median time to initiation of letermovir treatment was 9 days post-transplant. Engraftment at baseline was present in 37% of patients. The median age was 54 years (range: 18–78 years); 56 (15.0%) participants were aged 65 years or older; 58% were male; 82% were White; 10% were Asian; 2% were Black or African American; and 7% were Hispanic or Latino. At baseline, 50% of patients received myeloablative conditioning, 52% received cyclosporine, and 42% received tacrolimus. The most common and primary indications for transplantation were acute myeloid leukemia (38%), myelodysplastic syndrome (15%), and lymphoma (13%). Twelve percent (12%) of participants were CMV DNA-positive at baseline.

At baseline, 31% of patients were at high risk of reactivation, defined by one or more of the following criteria: a human leukocyte antigen (HLA)-matched related donor (sibling) with at least one mismatch at one of three HLA loci: HLA-A, -B, or -DR; a haploidentical donor; an unrelated donor with at least one mismatch at one of four HLA loci: HLA-A, -B, -C, and -DRB1; use of umbilical cord blood as the stem cell source; use of ex vivo T-cell-depleted grafts; or grade 2 or higher graft-versus-host disease (GVHD) requiring systemic corticosteroids.

Primary Efficacy Endpoint

The primary efficacy endpoint in trial P001 was clinically significant CMV infection (CMVI), defined as the incidence of CMV DNAemia requiring preemptive therapy (PET) against CMV or the occurrence of end-organ CMV disease. A non-completer = failure (NC=F) approach was used, whereby outcomes in patients who discontinued the study before Week 24 post-HSCT or for whom data were missing at Week 24 post-HSCT were counted as failures.

Letermovir demonstrated superior efficacy compared to placebo in the analysis of the primary efficacy endpoint, as shown in Table 1. The calculated treatment difference of -23.5% was statistically significant (one-sided p-value < 0.0001).

Table 1

P001: Efficacy Results in HSCT Recipients (NC=F approach, FAS population)

Parameter	Letermovir (N = 325) n (%)	Placebo (N = 170) n (%)
Primary efficacy endpoint (proportion of patients with prophylaxis failure at Week 24)	122 (37.5)	103 (60.6)
Reasons for failure†
Clinically significant CMV infection	57 (17.5)	71 (41.8)
CMV DNAemia requiring pre-emptive anti-CMV therapy	52 (16.0)	68 (40.0)
CMV end-organ disease	5 (1.5)	3 (1.8)
Discontinued from study	56 (17.2)	27 (15.9)
No outcome data available	9 (2.8)	5 (2.9)
Treatment difference, adjusted for stratification (letermovir – placebo) §
Difference (95% CI)	-23.5 (-32.5, -14.6)
p-value	< 0.0001
† Categories of failure are mutually exclusive and based on a hierarchy of categories in the order listed. § 95% CI and p-value for the treatment difference in percentage of response were calculated using the Mantel-Haenszel method, adjusting for stratification, with a difference weighted by the harmonic mean of sample size in each group (high or low risk). A one-sided p-value ≤ 0.0249 was used to declare statistical significance. FAS – Full Analysis Set; FAS includes randomized patients who received at least one dose of investigational product and excludes patients with detectable CMV DNA at baseline. Approach to handling outcomes: non-completers = failure (NC = F). Under the NC = F approach, outcomes were classified as failure for participants with clinically significant CMV infection who discontinued study early or had missing post-transplant Week 24 visit results. N – number of participants in each treatment group. n (%) – number (percentage) of participants in each subcategory. Note: The proportion of patients with detectable CMV viral DNA on Day 1 who developed clinically significant CMV infection by Week 24 was 64.6% (31/48) in the letermovir group compared to 90.9% (20/22) in the placebo group following allogeneic HCT. The estimated difference (95% CI for difference) was -26.1% (-45.9%, -6.3%) with a nominal one-sided p-value < 0.0048.

Factors associated with CMV DNAemia after week 14 post-HSCT in participants treated with letermovir included high baseline risk of CMV reactivation, GVHD, corticosteroid use, and CMV-seronegative donor serostatus.

Fig. 1. P001: Kaplan–Meier curve of time to initiation of anti-CMV preemptive therapy or onset of CMV end-organ disease through week 24 post-transplant in HSCT recipients (FAS population).

Cumulative proportion of patients with CMV DNAemia or disease (%)	Placebo Hazard ratio versus placebo Stratified log-rank test, two-sided p-value < 0.0001 Letermovir
	Week 0 Week 14 Week 24
	Weeks after transplantation

Number of patients at risk
	Letermovir	325	270	212
	Placebo	170	85	70

There was no difference in the frequency or time to engraftment of the graft between the groups receiving Previmis and placebo.

The efficacy of letermovir increased consistently across all subgroups, including low and high risk of CMV reactivation, conditioning regimens, and concomitant immunosuppressive regimens (see Figure 2).

Fig. 2. P001: Graph showing the proportion of participants who initiated preemptive therapy for CMV or who had CMV end-organ disease through Week 24 after allogeneic HCT, by selected subgroups (NC = F approach, FAS population).

Non-completer = failure (NC = F). With the NC = F approach, outcomes of participants who discontinued the study prior to Week 24 after transplant or who had missing outcomes at Week 24 after transplant were counted as failures.

P040: Prophylaxis from Week 14 (~100 days) to Week 28 (~200 days) after HCT

The efficacy of continuing letermovir prophylaxis from Week 14 (~100 days) to Week 28 (~200 days) after HCT in patients at risk for late CMV infection and disease was evaluated in a multicenter, double-blind, placebo-controlled, Phase 3 trial (P040) involving adult CMV-seropositive recipients [R+] of allogeneic HCT. Eligible patients who completed letermovir prophylaxis through ~100 days after HCT were randomized (2:1) to receive letermovir or placebo from Week 14 to Week 28 after HCT. Patients were followed through Week 28 after HCT to assess the primary efficacy endpoint, with further follow-up without treatment through Week 48 after HCT.

Of the 218 patients who received treatment, 144 received letermovir and 74 received placebo. The median age was 55 years (range 20 to 74 years); 62% were male; 79% were White; 11% were Asian; 2% were Black; 10% were Hispanic or Latino. The most common transplant indications were acute myeloid leukemia (42%), acute lymphoblastic leukemia (15%), and myelodysplastic syndrome (11%).

At study entry, all participants had risk factors for late CMV infection and disease, with 64% having two or more risk factors. Risk factors included: HLA-matched related donor (sibling) with at least one mismatch at one of three HLA gene loci: HLA-A, -B, or -DR; haploidentical donor; HLA-mismatched unrelated donor with at least one mismatch at one of four HLA gene loci: HLA-A, -B, -C, or -DRB1; use of umbilical cord blood as the stem cell source; use of ex vivo T-cell-depleted grafts; receipt of antithymocyte globulin; receipt of alemtuzumab; use of systemic prednisone (or equivalent) at a dose ≥1 mg/kg/day.

Primary efficacy endpoint

The primary efficacy endpoint in P040 was the incidence of clinically significant CMV infection through Week 28 after HCT. Clinically significant CMV infection was defined as the occurrence of CMV end-organ disease or initiation of anti-CMV preemptive therapy based on documented CMV viremia and the patient's clinical status. An observed failure (OF) approach was used, whereby outcomes in patients who developed clinically significant CMV infection or who prematurely discontinued the study with viremia were considered treatment failures.

Letermovir demonstrated superior efficacy compared to placebo in the analysis of the primary efficacy endpoint, as shown in Table 2. The estimated treatment difference of -16.1% was statistically significant (one-sided p-value 0.0005). The efficacy of letermovir was consistently higher across all patient subgroups based on baseline characteristics (age, sex, race) and presence of risk factors for late CMV infection and disease.

Table 2

P040: Efficacy results in HCT recipients at risk for late CMV infection and disease (OF approach, FAS population)

Parameter	Letermovir (~200 days of letermovir exposure) (N = 144) n (%)	Placebo (~100 days of letermovir exposure) (N = 74) n (%)
Failure*	4 (2.8)	14 (18.9)
Clinically significant CMV infection by Week 28†	2 (1.4)	13 (17.6)
Initiation of pre-emptive therapy based on documented CMV viremia	1 (0.7)	11 (14.9)
CMV end-organ disease	1 (0.7)	2 (2.7)
Discontinued study early due to CMV viremia prior to Week 28	2 (1.4)	1 (1.4)
Treatment difference, stratified (letermovir (~200 days of letermovir exposure) – placebo (~100 days of letermovir exposure))‡
Difference (95% CI)	-16.1 (-25.8, -6.5) 0.0005
p-value
* Failure categories are mutually exclusive and based on a hierarchy of categories in the order listed. † Clinically significant CMV infection was defined as CMV end-organ disease (confirmed or probable) or initiation of pre-emptive therapy based on documented CMV viremia and clinical status of the patient. ‡ 95% CI and p-value for the treatment difference in percentage of response were calculated using the Mantel-Haenszel method, stratified by donor type (haploidentical donor – yes or no). The treatment difference was calculated as the sample-size weighted average across strata. One-sided p-value ≤ 0.0249 was used to determine statistical significance. Missing data approach: Observed failures approach (OF). Under the OF approach, failure was assigned to all subjects who developed clinically significant CMV infection or who discontinued the study early due to CMV viremia between Week 14 (~100 days) and Week 28 (~200 days) post-HSCT. N – number of participants in each treatment group. n (%) – number (percentage) of participants in each subcategory.

P002: Cytomegalovirus (CMV)-seronegative adult kidney transplant recipients from CMV-seropositive donors [D+/R-]

To evaluate letermovir as a prophylactic strategy for CMV disease in kidney transplant recipients, the efficacy of letermovir was assessed in a multicenter, randomized, double-blind, active-controlled, phase 3 non-inferiority study (P002) in adult kidney transplant recipients at high risk [D+/R-]. Subjects were randomized (1:1) to receive either letermovir or valganciclovir. Letermovir was administered concomitantly with acyclovir. Valganciclovir was administered concomitantly with placebo to acyclovir. Randomization was stratified by the use or non-use of high-potency anti-lymphocyte immunotherapy during induction. Letermovir or valganciclovir was initiated between day 0 and day 7 post-kidney transplantation and continued until week 28 (~200 days) after transplantation. Patient follow-up continued until week 52 after transplantation.

Among the 589 treated patients, 292 received letermovir and 297 received valganciclovir. The median age was 51 years (range 18 to 82 years); 72% were male; 84% were Caucasian; 2% Asian; 9% Black; 17% Hispanic or Latino; 60% received a kidney from a deceased donor. The most common causes of transplantation were congenital polycystic kidney disease (17%), hypertension (16%), and diabetes/diabetic nephropathy (14%).

Primary efficacy endpoint

The primary efficacy endpoint of P002 was the incidence of CMV disease (CMV end-organ disease or confirmed CMV syndrome, as determined by an independent expert committee) through week 52 after transplantation. An intention-to-treat (ITT) approach was used, in which outcomes in patients who prematurely discontinued the study for any reason or who had missing data at a given time point were counted as treatment failure.

Letermovir demonstrated non-inferior efficacy compared to valganciclovir in the analysis of the primary efficacy endpoint, as shown in Table 3.

Table 3

P002: Efficacy results in kidney transplant recipients (ITT approach, FAS population)

Parameter	Letermovir (N = 289) n (%)	Valganciclovir (N = 297) n (%)
CMV disease* at 52 weeks	30 (10.4)	35 (11.8)
Stratified treatment difference (letermovir –valganciclovir)† Difference (95% CI)	-1.4 (-6.5, 3.8)‡
* Cases of CMV disease confirmed by an independent expert committee. † 95% CI for the treatment difference in percentages of response was calculated using the Mantel–Haenszel method accounting for stratification, with the difference calculated as the sample harmonic mean of each group within each stratum (use/non-use of high-cytolytic, anti-lymphocytic immunotherapy during induction). ‡ Given the non-inferiority margin of 10%, letermovir is non-inferior to valganciclovir. Missing data approach: Observed failure (OF) approach. Under the OF approach, outcomes in participants who prematurely discontinued the study for any reason are not considered as failures. Note: Participants randomized to the letermovir group received acyclovir for prophylaxis of herpes simplex virus and varicella zoster virus. Participants randomized to the valganciclovir group received placebo to acyclovir. N – number of participants in each treatment group. n (%) – number (percentage) of participants in each subcategory.

Efficacy was comparable across all patient subgroups, including subgroups defined by sex, age, race, region, and use/non-use of high-cytolytic anti-lymphocyte immunotherapy during induction.

Pharmacokinetics.

The pharmacokinetics of letermovir were characterized in healthy subjects after oral and intravenous administration. Letermovir exposure increased more than proportionally with dose following either oral or intravenous administration. The mechanism is likely due to saturation/auto-inhibition of OATP1B1/3. The pharmacokinetics of letermmovir were also characterized after oral and intravenous administration in hematopoietic stem cell transplant (HSCT) recipients (Table 4) and after oral administration in kidney transplant recipients (Table 5).

Healthy subjects

Geometric mean values of total exposure (AUC) and maximum concentrations (C_max) at steady state were 71,500 ng×h/mL and 13,000 ng/mL, respectively, following oral administration of 480 mg letermovir once daily.

Letermovir reaches steady state within 9–10 days, with an accumulation ratio of 1.2 for AUC and 1.0 for C_max.

HSCT recipients

Letermovir AUC values were estimated using population pharmacokinetic analysis based on data from the Phase 3 P001 study (see Table 4). Differences in exposure across treatment regimens are not clinically meaningful; efficacy was consistent across the entire range of exposures in the P001 study.

Table 4

Letermovir AUC values (ng×h/mL) in HSCT recipients

Treatment regimen	Mean value (90% prediction interval)*
480 mg orally, without cyclosporine	34 400 (16 900, 73 700)
480 mg intravenously, without cyclosporine	100 000 (65 300, 148 000)
240 mg orally, with cyclosporine	60 800 (28 700, 122 000)
240 mg intravenously, with cyclosporine	70 300 (46 200, 106 000)
* Population predictions based on population pharmacokinetic analysis using phase 3 data.

Kidney transplant recipients

The AUC of letermovir was evaluated using population pharmacokinetic analysis, utilizing data from phase 3 study P002 (see Table 5). Efficacy was consistent across the entire range of exposures observed in P002.

Table 5

AUC values of letermovir (ng × h/mL) in kidney transplant recipients

Treatment regimen	Mean value (90% prediction interval)*
480 mg orally, without cyclosporine	62,200 (28,900, 145,000)
240 mg orally, with cyclosporine	57,700 (26,900, 135,000)
* Mean values and 90% prediction intervals are based on simulations using a phase 3 population pharmacokinetic model incorporating inter-individual variability. Note: The pharmacokinetics of letermovir after intravenous administration in kidney transplant recipients have not been studied; however, the predicted AUC following intravenous administration is similar to the model-predicted AUC following intravenous administration in allogeneic HSCT recipients (Table 4).

Absorption

Letermovir is rapidly absorbed with a median time to reach maximum plasma concentration (Tmax) of 1.5–3.0 hours and declines in a biphasic manner. In HSCT recipients, the bioavailability of letermovir is approximately 35% following oral administration of 480 mg letermovir once daily without cyclosporine. Inter-individual variability in bioavailability was approximately 37%. In kidney transplant recipients, the bioavailability of letermovir is approximately 60% following oral administration of 480 mg once daily without cyclosporine.

Effect of cyclosporine

In HSCT recipients, concomitant administration of cyclosporine increased letermovir plasma concentrations due to inhibition of OATP1B. The bioavailability of letermovir was approximately 85% following oral administration of 240 mg letermovir once daily concomitantly with cyclosporine. If letermovir is administered concomitantly with cyclosporine, the recommended dose of letermovir is 240 mg once daily (see section “Dosage and administration”).

Effect of food

In healthy subjects, administration of a single 480 mg oral dose of letermovir with a high-fat, high-calorie meal did not affect total exposure (AUC) and resulted in an approximately 30% increase in maximum levels (Cmax) of letermovir. Letermovir may be administered orally regardless of food intake, as was done in clinical studies (see section “Dosage and administration”).

Distribution

Based on population pharmacokinetic analyses, the mean volume of distribution at steady state is 45.5 L following intravenous administration in HSCT recipients. Letermovir is highly bound (98.2%) to human plasma proteins independent of the estimated concentration range (3 to 100 mg/L) in vitro. Some saturation was observed at lower concentrations. The blood-to-plasma ratio of letermovir is 0.56 and is independent of the estimated concentration range (0.1–10 mg/L) in vitro.

In preclinical distribution studies, letermovir distributed into organs and tissues with the highest concentrations observed in the gastrointestinal tract, bile ducts, and liver, and low concentrations in the brain.

Biotransformation

The majority of letermovir-related components in plasma are the unchanged parent compound (96.6%). No major metabolites of letermovir were detected in plasma. Letermovir is partially eliminated via glucuronidation mediated by UGT1A1/1A3.

Elimination

The mean apparent terminal half-life of letermovir is approximately 12 hours in healthy volunteers following intravenous administration of 480 mg letermovir. The primary elimination pathways of letermovir are biliary excretion and direct glucuronidation. The process involves hepatic uptake transporters OATP1B1 and 3, followed by UGT1A1/3-mediated glucuronidation.

Based on population pharmacokinetic analyses, the apparent clearance of letermovir at steady state is 4.84 L/h following intravenous administration of 480 mg in HSCT recipients. Inter-individual variability in clearance is estimated at 24.6%.

Elimination

Following oral administration of radiolabeled letermovir, 93.3% of radioactivity was recovered in feces. The majority of letermovir was excreted unchanged in bile, and a minor amount (6% of dose) as the acyl glucuronide metabolite in feces. The acyl glucuronide is unstable in feces. Renal excretion of letermovir was minimal (< 2% of dose).

Pharmacokinetics in specific patient populations

Hepatic impairment

The AUC of unbound letermovir was approximately 81% and 4-fold higher in patients with moderate (Child-Pugh class B, score 7–9) and severe (Child-Pugh class C, score 10–15) hepatic impairment, respectively, compared to healthy subjects. Changes in letermovir exposure in patients with moderate hepatic impairment are not considered clinically significant.

In patients with moderate hepatic impairment combined with moderate or severe renal impairment, a pronounced increase in unbound letermovir exposure is expected (see section “Dosage and administration”).

Renal impairment

Clinical study in a population with renal impairment

The AUC of unbound letermovir was approximately 115% and 81% higher in patients with moderate (estimated glomerular filtration rate [eGFR] 31.0–56.8 mL/min/1.73 m²) and severe (eGFR 11.9–28.1 mL/min/1.73 m²) renal impairment, respectively, compared to healthy subjects. Changes in letermovir exposure due to moderate or severe renal impairment are not considered clinically significant. Data in patients with end-stage renal disease (ESRD) are not available.

Post-kidney transplantation (P002)

Based on population pharmacokinetic analysis, the AUC of letermovir was approximately 12%, 27%, and 35% higher in patients with mild (creatinine clearance ≥60 to <90 mL/min), moderate (creatinine clearance ≥30 to <60 mL/min), and severe (creatinine clearance ≥15 to <30 mL/min) renal impairment, respectively, compared to patients with creatinine clearance ≥90 mL/min. These changes are not considered clinically significant.

Body weight

Based on population pharmacokinetic analyses in healthy subjects, the AUC of letermovir is 18.7% lower in individuals with a body weight of 80–100 kg compared to those with a body weight of 67 kg. Based on population pharmacokinetic analysis in kidney transplant recipients (P002), the AUC of letermovir in patients with body weight >80 kg is 26% lower compared to patients with body weight ≤80 kg. These changes are not considered clinically significant.

Race

Based on population pharmacokinetic analyses in healthy subjects, the AUC of letermovir is 33.2% higher in Mongoloid race individuals compared to Caucasian race individuals. This difference is not clinically significant.

Gender

Based on population pharmacokinetic analyses, there is no difference in the pharmacokinetics of letermovir between women and men.

Elderly patients

Based on population pharmacokinetic analyses, patient age has no impact on the pharmacokinetics of letermovir. Dose adjustment based on patient age is not required.

Clinical characteristics.

Indications.

The medicinal product Previmist is indicated for the prevention of cytomegalovirus (CMV) infection reactivation and CMV disease in CMV-seropositive adult recipients [R+] of allogeneic hematopoietic stem cell transplantation (HSCT).

The medicinal product Previmist is indicated for the prevention of CMV disease in CMV-seronegative adult patients who have received a kidney transplant from a CMV-seropositive donor [D+/R-].

Official guidelines on the appropriate use of antiviral agents should be taken into account.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients listed in the section "Composition".
• Concomitant use with pimozide (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").
• Concomitant use with ergot alkaloids (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").
• Concomitant use with St John's wort (Hypericum perforatum) (see section "Interaction with other medicinal products and other forms of interaction").
• When letermovir is used in combination with cyclosporine:

concomitant use of dabigatran, atorvastatin, simvastatin, rosuvastatin or pitavastatin is contraindicated (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

General information on differences in exposure between different letermovir treatment regimens

The estimated plasma exposure of letermovir varies depending on the treatment regimen (see table in section "Pharmacological properties. Pharmacokinetics"). Therefore, the clinical consequences of interactions with other medicinal products for letermovir will depend on which letermovir treatment regimen is used and whether letermovir is used in combination with cyclosporine.

The combination of cyclosporine and letermovir may lead to a more pronounced or additional effect on concomitant medicinal products compared to letermovir alone (see Table 6).

Effect of other medicinal products on letermovir

The elimination pathways of letermovir in vivo are biliary excretion and glucuronidation. The relative importance of these pathways is unknown. Both elimination pathways involve active uptake into hepatocytes mediated by hepatic uptake transporters OATP1B1/3. After uptake, glucuronidation of letermovir is mediated by UGT1A1 and 3. Letermovir is also subject to efflux in the liver and intestine mediated by P-glycoprotein and breast cancer resistance protein (BCRP) (see section "Pharmacological properties. Pharmacokinetics").

Inducers of drug-metabolizing enzymes or transporters

Concomitant use of Previmist (with or without cyclosporine) with strong and moderate inducers of transporters (e.g., P-glycoprotein) and/or enzymes (e.g., UGT) is not recommended, as this may result in subtherapeutic exposure to letermovir (see Table 6).

Examples of strong inducers include: rifampicin, phenytoin, carbamazepine, St John's wort (Hypericum perforatum), rifabutin, and phenobarbital.

Examples of moderate inducers include: thioridazine, modafinil, ritonavir, lopinavir, efavirenz, and etravirine.

Concomitant use with rifampicin led to an initial increase in plasma concentration of letermovir (due to inhibition of OATP1B1/3 and/or P-glycoprotein), which is not clinically significant, followed by a clinically significant decrease in plasma concentration of letermovir (due to induction of P-glycoprotein/UGT) with continued co-administration of rifampicin (see Table 6).

Additional effect of other medicinal products on letermovir when used in combination with cyclosporine

Inhibitors of OATP1B1 or 3

Concomitant use of Previmist with medicinal products that are inhibitors of OATP1B1/3 transporters may lead to increased plasma concentration of letermovir. If Previmist is prescribed concomitantly with cyclosporine (a potent inhibitor of OATP1B1/3), the recommended dose of Previmist is 240 mg once daily (see Table 6 and sections "Dosage and administration" and "Pharmacological properties. Pharmacokinetics"). Caution is recommended when adding other inhibitors of OATP1B1/3 to treatment with letermovir in combination with cyclosporine.

Examples of OATP1B1 inhibitors include: gemfibrozil, erythromycin, clarithromycin, and several protease inhibitors (atazanavir, simeprevir).

Inhibitors of P-glycoprotein/breast cancer resistance protein (BCRP)

In vitro data indicate that letermovir is a substrate of P-glycoprotein/BCRP. Changes in plasma concentrations of letermovir due to inhibition of P-glycoprotein/BCRP by itraconazole were not clinically significant.

Effect of letermovir on other medicinal products

MEDICINAL PRODUCTS ELIMINATED PRIMARILY BY METABOLISM OR ACTIVE TRANSPORT

Letermovir is a general inducer in vivo of enzymes and transporters. If a specific enzyme or transporter is not simultaneously inhibited (see below), induction can be expected. Therefore, letermovir may potentially lead to reduced plasma exposure and possibly reduced efficacy of concomitant medicinal products that are primarily eliminated via metabolism or active transport.

The extent of the inductive effect depends on the route of administration of letermovir and whether cyclosporine is used concomitantly.

The full inductive effect can be expected within 10–14 days of letermovir treatment. The time required to reach steady state of a particular concomitant medicinal product will also affect the time required to achieve the full effect on plasma concentrations.

In vitro, letermovir is an inhibitor of CYP3A, CYP2C8, CYP2B6, BCRP, UGT1A1, OATP2B1, and OAT3 at relevant in vivo concentrations. In vivo studies have been conducted on the net effect on CYP3A4, P-glycoprotein, OATP1B1/3, and additionally on CYP2C19. The net in vivo effect on other listed enzymes and transporters is unknown. Detailed information is provided below.

It is unknown whether letermovir may affect exposure to piperacillin/tazobactam, amphotericin B, or micafungin. Potential interactions between letermovir and these medicinal products have not been studied. There is a theoretical risk of reduced exposure due to induction, but the extent of the effect and, therefore, clinical significance remains unknown.

MEDICINAL PRODUCTS METABOLIZED BY CYP3A

Letermovir is a moderate inhibitor of CYP3A in vivo. Concomitant use of Previmist with oral midazolam (a CYP3A substrate) results in a 2–3-fold increase in midazolam plasma concentration. Concomitant use of Previmist may lead to clinically significant increases in plasma concentrations of concomitantly administered CYP3A substrates (see sections "Contraindications", "Special precautions for use", and "Pharmacological properties. Pharmacokinetics").

Examples of such medicinal products include: certain immunosuppressants (e.g., cyclosporine, tacrolimus, sirolimus), HMG-CoA reductase inhibitors, and amiodarone (see Table 6). Pimozide and ergot alkaloids are contraindicated (see section "Contraindications").

The extent of the CYP3A inhibitory effect depends on the administration regimen of letermovir and whether cyclosporine is used concomitantly.

Due to time-dependent inhibition and simultaneous induction, the net inhibitory effect on the enzyme may not be achieved earlier than 10–14 days. The time required to reach steady state of a particular concomitant medicinal product will also affect the time required to achieve the full effect on plasma concentrations. After treatment, 10–14 days are required for the inhibitory effect to disappear. If monitoring is required, it is recommended during the first 2 weeks after initiation and discontinuation of letermovir (see section "Special precautions for use"), as well as after changes in the administration regimen of letermovir.

MEDICINAL PRODUCTS TRANSPORTED BY OATP1B1/3

Letermovir is an inhibitor of OATP1B1/3 transporters. Administration of Previmist may lead to clinically significant increases in plasma concentration of concomitantly administered medicinal products that are substrates of OATP1B1/3.

Examples of such medicinal products include: HMG-CoA reductase inhibitors, fexofenadine, repaglinide, and glyburide (see Table 6). Comparing the letermovir administration regimen without cyclosporine, the effect is more pronounced after intravenous administration than after oral administration.

The extent of inhibition of OATP1B1/3 by concomitant medicinal products is likely greater when Previmist is used concomitantly with cyclosporine (a potent inhibitor of OATP1B1/3). This should be considered when the letermovir administration regimen is changed during treatment with an OATP1B1/3 substrate.

MEDICINAL PRODUCTS METABOLIZED BY CYP2C9 and/or CYP2C19

Concomitant use of Previmist with voriconazole (a CYP2C19 substrate) leads to a significant decrease in voriconazole plasma concentration, indicating that letermovir is an inducer of CYP2C19. CYP2C9 may also be induced. Letermovir may reduce exposure to CYP2C9 and/or CYP2C19 substrates, potentially leading to subtherapeutic levels.

Examples of such medicinal products include: warfarin, voriconazole, diazepam, lansoprazole, omeprazole, esomeprazole, pantoprazole, tilidine, tolbutamide (see Table 6).

The effect is expected to be less pronounced with oral administration of letermovir without cyclosporine than with intravenous administration of letermovir with or without cyclosporine or oral administration of letermovir with cyclosporine. This should be considered when changing the letermovir administration regimen during treatment with a CYP2C9 or CYP2C19 substrate. See above for general information on induction regarding the time course of interaction.

MEDICINAL PRODUCTS METABOLIZED BY CYP2C8

Letermovir inhibits CYP2C8 in vitro, but may also induce CYP2C8 based on its inductive potential. The net in vivo effect is unknown.

An example of a medicinal product primarily eliminated via CYP2C8 is repaglinide (see Table 6). Concomitant use of repaglinide and letermovir with or without cyclosporine is not recommended.

MEDICINAL PRODUCTS TRANSPORTED BY INTESTINAL P-GLYCOPROTEIN

Letermovir is an inducer of intestinal P-glycoprotein. Administration of Previmist may lead to clinically significant reductions in plasma concentration of concomitant medicinal products that are primarily transported by P-glycoprotein in the intestine, such as dabigatran and sofosbuvir.

MEDICINAL PRODUCTS METABOLIZED BY CYP2B6, UGT1A1 OR TRANSPORTED BY BCRP OR OATP2B1

Letermovir is a general inducer in vivo, but inhibition of CYP2B6, UGT1A1, BCRP, and OATP2B1 has also been observed in vitro. The net in vivo effect is unknown. Therefore, plasma concentrations of medicinal products that are substrates of these enzymes or transporters may increase or decrease when used concomitantly with letermovir. Additional monitoring may be recommended; refer to the instructions for such medicinal products.

An example of a medicinal product metabolized by CYP2B6 is bupropion.

Examples of medicinal products metabolized by UGT1A1 include raltegravir and dolutegravir.

Examples of medicinal products transported by BCRP include rosuvastatin and sulfasalazine.

An example of a medicinal product transported by OATP2B1 is celiprolol.

MEDICINAL PRODUCTS TRANSPORTED BY RENAL TRANSPORTER OAT3

In vitro data indicate that letermovir is an inhibitor of OAT3; therefore, letermovir may be an inhibitor of OAT3 in vivo. Plasma concentrations of medicinal products transported by OAT3 may be increased.

Examples of medicinal products transported by OAT3 include: ciprofloxacin, tenofovir, imipenem, and cilastatin.

General information

If dose adjustments of concomitant medicinal products are made due to treatment with Previmist, their doses should be readjusted after completion of Previmist treatment. Dose adjustment may also be required when changing the route of administration or changing the immunosuppressant.

Table 6 provides a list of established or potential clinically significant drug interactions. The described drug interactions were observed in studies conducted with Previmist or are predicted interactions that may occur with the use of Previmist (see sections "Contraindications", "Special precautions for use", "Pharmacological properties. Pharmacodynamics", and "Pharmacological properties. Pharmacokinetics").

Table 6

Interactions and dosing recommendations when used with other medicinal products. Table 6 is not comprehensive but contains examples of clinically significant interactions (see also general information on drug interactions above).

Unless otherwise stated, interaction studies were conducted for oral letermovir without cyclosporine. The potential for interaction and clinical consequences may differ depending on whether letermovir is administered orally or intravenously, and whether cyclosporine is used concomitantly. When changing the route of administration or changing the immunosuppressant, the recommendation for concomitant use should be reviewed.

Concomitant Medicinal Products	Effect on Concentration † Mean Ratio (90% Confidence Interval) for AUC, Cmax (likely mechanism of action)	Recommendations for Concomitant Use with Prezcoyd
Antibiotics
Naftcilin	Interaction not studied. Expected: ↓ letermovir (P-glycoprotein/UGT induction)	Naftcilin may reduce plasma concentrations of letermovir. Concomitant use of Prezcoyd and naftcilin is not recommended.
Antifungal Agents
fluconazole (400 mg single dose) / letermovir (480 mg single dose)	↔ fluconazole AUC 1.03 (0.99, 1.08) Cmax 0.95 (0.92, 0.99) ↔ letermovir AUC 1.11 (1.01, 1.23) Cmax 1.06 (0.93, 1.21) Interaction at steady state not studied. Expected: ↔ fluconazole ↔ letermovir	No dose adjustment required.
itraconazole (200 mg once daily orally) / letermovir (480 mg once daily orally)	↔ itraconazole AUC 0.76 (0.71, 0.81) Cmax 0.84 (0.76, 0.92) ↔ letermovir AUC 1.33 (1.17, 1.51) Cmax 1.21 (1.05, 1.39)	No dose adjustment required.
posaconazole ‡ (300 mg single dose) / letermovir (480 mg daily)	↔ posaconazole AUC 0.98 (0.82, 1.17) Cmax 1.11 (0.95, 1.29)	No dose adjustment required.
voriconazole ‡ (200 mg twice daily) / letermovir (480 mg daily)	↓ voriconazole AUC 0.56 (0.51, 0.62) Cmax 0.61 (0.53, 0.71) (CYP2C9/19 induction)	If concomitant use is necessary, therapeutic drug monitoring for voriconazole is recommended during the first 2 weeks after initiation or discontinuation of letermovir, as well as after changes in letermovir administration or immunosuppressant regimen.
Antituberculosis Agents
Rifabutin	Interaction not studied. Expected: ↓ letermovir (P-glycoprotein/UGT induction)	Rifabutin may reduce plasma concentrations of letermovir. Concomitant use of Prezcoyd and rifabutin is not recommended.
Rifampicin
(600 mg single oral dose) / letermovir (480 mg single oral dose)	↔ letermovir AUC 2.03 (1.84, 2.26) Cmax 1.59 (1.46, 1.74) C24 2.01 (1.59, 2.54) (OATP1B1/3 and/or P-glycoprotein inhibition)
(600 mg single intravenous dose) / letermovir (480 mg single oral dose)	↔ letermovir AUC 1.58 (1.38, 1.81) Cmax 1.37 (1.16, 1.61) C24 0.78 (0.65, 0.93) (OATP1B1/3 and/or P-glycoprotein inhibition)
(600 mg once daily orally) / letermovir (480 mg once daily orally)	↓ letermovir AUC 0.81 (0.67, 0.98) Cmax 1.01 (0.79, 1.28) C24 0.14 (0.11, 0.19) (combined OATP1B1/3 and/or P-glycoprotein inhibition and P-glycoprotein/UGT induction)	Multiple doses of rifampicin reduce plasma concentrations of letermovir. Concomitant use of Prezcoyd and rifampicin is not recommended.
(600 mg single oral dose (24 hours after rifampicin))§ / letermovir (480 mg once daily orally)	↓ letermovir AUC 0.15 (0.13, 0.17) Cmax 0.27 (0.22, 0.31) C24 0.09 (0.06, 0.12) (P-glycoprotein/UGT induction)
Antipsychotics
Thioridazine	Interaction not studied. Expected: ↓ letermovir (P-glycoprotein/UGT induction)	Thioridazine may reduce plasma concentrations of letermovir. Concomitant use of Prezcoyd and thioridazine is not recommended.
Endothelin Receptor Antagonists
Bosentan	Interaction not studied. Expected: ↓ letermovir (P-glycoprotein/UGT induction)	Bosentan may reduce plasma concentrations of letermovir. Concomitant use of Prezcoyd and bosentan is not recommended.
Antiviral Agents
acyclovir ‡ (400 mg single dose) / letermovir (480 mg daily)	↔ acyclovir AUC 1.02 (0.87, 1.2) Cmax 0.82 (0.71, 0.93)	No dose adjustment required.
Valacyclovir	Interaction not studied. Expected: ↔ valacyclovir	No dose adjustment required.
Herbal Medicinal Products
St. John's wort (Hypericum perforatum)	Interaction not studied. Expected: ↓ letermovir (P-glycoprotein/UGT induction)	St. John's wort may reduce plasma concentrations of letermovir. Concomitant use of Prezcoyd and St. John's wort is contraindicated.
HIV Medicinal Products
efavirenz	Interaction not studied. Expected: ↓ letermovir (P-glycoprotein/UGT induction) ↑ or ↓ efavirenz (CYP2B6 inhibition or induction)	Efavirenz may reduce plasma concentrations of letermovir. Concomitant use of Prezcoyd and efavirenz is not recommended.
etravirine, nevirapine, ritonavir, lopinavir	Interaction not studied. Expected: ↓ letermovir (P-glycoprotein/UGT induction)	These antiviral agents may reduce plasma concentrations of letermovir. Concomitant use of Prezcoyd with these antiviral agents is not recommended.
HMG-CoA Reductase Inhibitors
atorvastatin ‡ (20 mg single dose) / letermovir (480 mg daily)	↑ atorvastatin AUC 3.29 (2.84, 3.82) Cmax 2.17 (1.76, 2.67) (CYP3A, OATP1B1/3 inhibition)	Adverse reactions associated with statins, such as myopathy, should be closely monitored. The dose of atorvastatin should not exceed 20 mg daily when used concomitantly with Prezcoyd#. Although not studied, concomitant use of Prezcoyd with cyclosporine is expected to result in higher plasma concentrations of atorvastatin than with Prezcoyd alone. Atorvastatin is contraindicated when Prezcoyd is used concomitantly with cyclosporine.
simvastatin, pitavastatin, rosuvastatin	Interaction not studied. Expected: ↑ HMG-CoA reductase inhibitors (CYP3A, OATP1B1/3 inhibition)	Letermovir may significantly increase plasma concentrations of these statins. Concomitant use is not recommended with Prezcoyd alone. When Prezcoyd is used concomitantly with cyclosporine, use of these statins is contraindicated.
fluvastatin, pravastatin	Interaction not studied. Expected: ↑ HMG-CoA reductase inhibitors (OATP1B1/3 and/or BCRP inhibition)	Letermovir may increase plasma concentrations of statins. Dose reduction of the statin may be required when used concomitantly with Prezcoyd#. Adverse reactions associated with statins, such as myopathy, should be closely monitored. When Prezcoyd is used concomitantly with cyclosporine, pravastatin is not recommended, while dose reduction of fluvastatin may be required#. Adverse reactions associated with statins, such as myopathy, should be closely monitored.
Immunosuppressants
cyclosporine (50 mg single dose) / letermovir (240 mg daily)	↑ cyclosporine AUC 1.66 (1.51, 1.82) Cmax 1.08 (0.97, 1.19) (CYP3A inhibition)	When Prezcoyd is coadministered with cyclosporine, the dose of Prezcoyd should be reduced to 240 mg once daily (see sections "Dosage and Administration" and "Pharmacological Properties. Pharmacodynamics"). Frequent monitoring of cyclosporine concentrations in whole blood should be performed during treatment, upon changes in administration, and upon discontinuation of Prezcoyd, with appropriate dose adjustment of cyclosporine#.
cyclosporine (200 mg single dose) / letermovir (240 mg daily)	↑ letermovir AUC 2.11 (1.97, 2.26) Cmax 1.48 (1.33, 1.65) (OATP1B1/3 inhibition)
mycophenolate mofetil (1 g single dose) / letermovir (480 mg daily)	↔ mycophenolic acid AUC 1.08 (0.97, 1.20) Cmax 0.96 (0.82, 1.12) ↔ letermovir AUC 1.18 (1.04, 1.32) Cmax 1.11 (0.92, 1.34)	No dose adjustment required.
sirolimus ‡ (2 mg single dose) / letermovir (480 mg daily)	↑ sirolimus AUC 3.40 (3.01, 3.85) Cmax 2.76 (2.48, 3.06) (CYP3A inhibition) Interaction not studied. Expected: ↔ letermovir	Frequent monitoring of sirolimus concentrations in whole blood is recommended during treatment, upon changes in administration, and upon discontinuation of Prezcoyd, with appropriate dose adjustment of sirolimus#. Frequent monitoring of sirolimus concentrations is recommended at initiation or discontinuation of concomitant cyclosporine with Prezcoyd. When Prezcoyd is used concomitantly with cyclosporine, refer to the sirolimus product information for specific recommendations on sirolimus use with cyclosporine. When Prezcoyd is used concomitantly with cyclosporine, increases in sirolimus concentrations may be greater than with Prezcoyd alone.
tacrolimus (5 mg single dose) / letermovir (480 mg daily)	↑ tacrolimus AUC 2.42 (2.04, 2.88) Cmax 1.57 (1.32, 1.86) (CYP3A inhibition)	Frequent monitoring of tacrolimus concentrations in whole blood should be performed during treatment, upon changes in administration, and upon discontinuation of Prezcoyd, with appropriate dose adjustment of tacrolimus#.
tacrolimus (5 mg single dose) / letermovir (80 mg twice daily)	↔ letermovir AUC 1.02 (0.97, 1.07) Cmax 0.92 (0.84, 1.00)
Oral Contraceptives
ethinylestradiol (0.03 mg) / levonorgestrel‡ (0.15 mg) single dose / letermovir (480 mg daily)	↔ ethinylestradiol AUC 1.42 (1.32, 1.52) Cmax 0.89 (0.83, 0.96) ↔ levonorgestrel AUC 1.36 (1.30, 1.43) Cmax 0.95 (0.86, 1.04)	No dose adjustment required.
Other systemic steroid oral contraceptives	Risk of ↓ steroid contraceptives	Letermovir may reduce plasma concentrations of other systemic steroid oral contraceptives, thereby affecting their efficacy. To ensure adequate contraceptive efficacy, oral contraceptives containing ethinylestradiol and levonorgestrel should be selected.
Antidiabetic Agents
repaglinide	Interaction not studied. Expected: ↑ or ↓ repaglinide (CYP2C8 induction, CYP2C8 and OATP1B inhibition)	Letermovir may increase or decrease plasma concentrations of repaglinide (net effect unknown). Concomitant use is not recommended. When Prezcoyd is used concomitantly with cyclosporine, plasma concentrations of repaglinide are expected to increase due to additional OATP1B inhibition by cyclosporine. Concomitant use is not recommended#.
glipizide	Interaction not studied. Expected: ↑ glipizide (OATP1B1/3 inhibition, CYP3A inhibition, CYP2C9 induction)	Letermovir may increase plasma concentrations of glipizide. Frequent monitoring of glucose concentrations is recommended during the first 2 weeks after initiation or discontinuation of letermovir, as well as after changes in letermovir administration. When Prezcoyd is used concomitantly with cyclosporine, refer to the glipizide product information for specific dosing recommendations.
Antiepileptic Agents (see also general information)
carbamazepine, phenobarbital	Interaction not studied. Expected: ↓ letermovir (P-glycoprotein/UGT induction)	Carbamazepine or phenobarbital may reduce plasma concentrations of letermovir. Concomitant use of Prezcoyd and carbamazepine or phenobarbital is not recommended.
phenytoin	Interaction not studied. Expected: ↓ letermovir (P-glycoprotein/UGT induction) ↓ phenytoin (CYP2C9/19 induction)	Phenytoin may reduce plasma concentrations of letermovir. Letermovir may reduce plasma concentrations of phenytoin. Concomitant use of Prezcoyd and phenytoin is not recommended.
Oral Anticoagulants
warfarin	Interaction not studied. Expected: ↓ warfarin (CYP2C9 induction)	Letermovir may reduce plasma concentrations of warfarin. Frequent monitoring of the international normalized ratio (INR) should be performed when warfarin is used concomitantly with Prezcoyd#. Monitoring is recommended during the first 2 weeks after initiation or discontinuation of letermovir, as well as after changes in letermovir administration or immunosuppressant regimen.
dabigatran	Interaction not studied. Expected: ↓ dabigatran (induction of intestinal P-glycoprotein)	Letermovir may reduce plasma concentrations and efficacy of dabigatran. Concomitant use should be avoided due to the risk of reduced dabigatran efficacy. Dabigatran is contraindicated when Prezcoyd is used concomitantly with cyclosporine.
Sedatives
midazolam (1 mg single intravenous dose) / letermovir (240 mg once daily orally) midazolam (2 mg single oral dose) / letermovir (240 mg once daily orally)	↑ midazolam intravenous: AUC 1.47 (1.37, 1.58) Cmax 1.05 (0.94, 1.17) oral: AUC 2.25 (2.04, 2.48) Cmax 1.72 (1.55, 1.92) (CYP3A inhibition)	Close clinical monitoring for respiratory depression and/or prolonged sedation is required when Prezcoyd is used concomitantly with midazolam. Dose adjustment of midazolam should be considered#. Plasma concentrations of midazolam may increase more with oral midazolam coadministered with letermovir at clinical doses than with the studied dose.
Opioid Agonists
Examples: alfentanil, fentanyl	Interaction not studied. Expected: ↑ CYP3A-metabolized opioids (CYP3A inhibition)	Close monitoring for adverse reactions associated with these medicinal products is recommended during concomitant use. Dose adjustment of CYP3A-metabolized opioids may be required# (see section "Special Warnings and Precautions for Use"). Monitoring is also recommended upon changes in administration. When Prezcoyd is used concomitantly with cyclosporine, plasma concentrations of CYP3A-metabolized opioids may increase more markedly. Close clinical monitoring for respiratory depression and/or prolonged sedation is required when Prezcoyd is used concomitantly with cyclosporine and alfentanil or fentanyl. Refer to the relevant information in the product information (see section "Special Warnings and Precautions for Use").
Antiarrhythmic Agents
amiodarone	Interaction not studied. Expected: ↑ amiodarone (mainly CYP3A inhibition and inhibition or induction of CYP2C8)	Letermovir may increase plasma concentrations of amiodarone. Close monitoring for adverse reactions associated with amiodarone is recommended during concomitant use. Amiodarone concentrations should be monitored regularly when amiodarone is coadministered with Prezcoyd#.
quinidine	Interaction not studied. Expected: ↑ quinidine (CYP3A inhibition)	Letermovir may increase plasma concentrations of quinidine. Close clinical monitoring is required when Prezcoyd is used with quinidine. Refer to the relevant information in the product information#.
Cardiovascular Agents
digoxin‡ (0.5 mg single dose) / letermovir (240 mg twice daily)	↔ digoxin AUC 0.88 (0.80, 0.96) Cmax 0.75 (0.63, 0.89) (P-glycoprotein induction)	No dose adjustment required.
Proton Pump Inhibitors
omeprazole	Interaction not studied. Expected: ↓ omeprazole (CYP2C19 induction) Interaction not studied. Expected: ↔ letermovir	Letermovir may reduce plasma concentrations of CYP2C19 substrates. Clinical monitoring and dose adjustment may be required.
pantoprazole	Interaction not studied. Expected: ↓ pantoprazole (likely due to CYP2C19 induction) Interaction not studied. Expected: ↔ letermovir	Letermovir may reduce plasma concentrations of CYP2C19 substrates. Clinical monitoring and dose adjustment may be required.
Wakefulness-Promoting Agents
modafinil	Interaction not studied. Expected: ↓ letermovir (P-glycoprotein/UGT induction)	Modafinil may reduce plasma concentrations of letermovir. Concomitant use of Prezcoyd and modafinil is not recommended.
* This table does not include all available data. † ↓ – decrease, ↑ – increase, ↔ – no clinically significant changes. ‡ Single-direction interaction study in which the effect of letermovir on the concomitant medicinal product is evaluated. § These data refer to the effect of rifampicin on letermovir 24 hours after the last dose of rifampicin. # Refer to the relevant information in the product information for the medicinal product.

Children

Interaction studies have been conducted only in adults.

Special precautions for use.

Monitoring of CMV DNA in HCTC recipients

In the phase 3 study (P001), the safety and efficacy of letermovir use were established in HCTC patients with a negative CMV DNA test result prior to initiation of prophylaxis. CMV DNA was monitored weekly until week 14 after transplantation, and then twice weekly until week 24. In cases of clinically significant CMV DNAemia or CMV disease, letermovir prophylaxis was discontinued and standard preemptive therapy (PET) was initiated or treatment was started. In patients who initiated letermovir prophylaxis and subsequently tested positive for CMV DNA, prophylaxis may be continued if PET criteria were not met (see section "Pharmacological properties. Pharmacodynamics").

Risk of adverse reactions or reduced therapeutic effect due to interactions with other medicinal products

Concomitant use of Prevymis and certain medicinal products may lead to known or potentially significant interactions, some of which may result in:

• clinically significant adverse reactions due to increased exposure of concomitant medicinal products or letermovir;
• significant reduction in plasma concentration of the concomitant medicinal product, potentially leading to reduced therapeutic effect.

See Table 6 for actions to prevent or manage known or potentially significant drug interactions, including dosing recommendations (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Drug interactions

Prevymis should be used with caution with medicinal products that are CYP3A substrates with a narrow therapeutic range (e.g., alfentanil, fentanyl, and quinidine), as concomitant use may increase plasma concentrations of CYP3A substrates. Careful monitoring and/or dose adjustment of concomitantly administered CYP3A substrates is recommended (see section "Interaction with other medicinal products and other forms of interaction").

Close monitoring of cyclosporine, tacrolimus, and sirolimus levels is generally recommended during the first 2 weeks after initiation and discontinuation of letermovir (see section "Interaction with other medicinal products and other forms of interaction"), as well as after any change in the route of letermovir administration.

Letermovir is a moderate inducer of enzymes and transporters. Induction may lead to decreased plasma concentrations of certain metabolized and transported medicinal products (see section "Interaction with other medicinal products and other forms of interaction"). Therapeutic drug monitoring is therefore recommended for voriconazole. Concomitant use of dabigatran should be avoided due to the risk of reduced efficacy.

Letermovir may increase plasma concentrations of medicinal products transported by OATP1B1/3, such as statins (see section "Interaction with other medicinal products and other forms of interaction" and Table 6).

Excipients

Prevymis contains lactose monohydrate. Patients with rare hereditary conditions of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product. Each 240 mg film-coated tablet contains 4 mg of lactose (as monohydrate). This should be considered when administering the medicinal product to patients with diabetes mellitus.

The medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy

There are no data on the use of letermovir in pregnant women. Animal studies have shown reproductive toxicity.

Prevymis is not recommended for use in pregnant women or women of childbearing potential who are not using contraception.

Breastfeeding

It is unknown whether letermovir is excreted in human breast milk.

Available pharmacodynamic/toxicological data in animals indicate that letermovir passes into breast milk.

A risk to newborns/infants cannot be excluded.

A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from therapy with Prevymis, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility

No effects on fertility in female rats were observed. Irreversible testicular toxicity and impaired fertility were observed in male rats, but not in male mice or monkeys.

Ability to influence reaction speed when driving or operating machinery.

Prevymis may have a minor influence on the ability to drive and use machines. Fatigue and dizziness have been reported in some patients during treatment with Prevymis, which may affect the patient's ability to drive or operate machinery (see section "Adverse reactions").

Method of Administration and Dosage

The drug Prevymis should be prescribed by a physician experienced in managing patients who have received allogeneic hematopoietic stem cell transplantation or kidney transplantation.

Method of Administration

Prevymis is also available as a concentrate for solution for infusion (240 mg).

Prevymis tablets, film-coated, and the concentrate for solution for infusion can be used interchangeably at the physician’s discretion; dose adjustment is not required.

The recommended dose of Prevymis is 480 mg once daily.

HSCT

Administration of Prevymis should be initiated after HSCT. Treatment with Prevymis may be started on the day of transplantation and no later than 28 days after HSCT. Administration of Prevymis may be initiated before or after engraftment. Prophylaxis with Prevymis should continue for 100 days after HSCT.

Prolonged prophylaxis with Prevymis beyond 100 days after HSCT may be beneficial for certain patients at high risk of late cytomegalovirus (CMV) reactivation (see section "Pharmacological Properties. Pharmacodynamics"). Safety and efficacy of Prevymis use beyond 200 days have not been studied in clinical trials.

Kidney Transplantation

Prevymis should be initiated on the day of transplantation and no later than 7 days after kidney transplantation, and continued for 200 days after transplantation.

Dose Adjustment

If Prevymis is used concomitantly with cyclosporine, the dose of Prevymis should be reduced to 240 mg once daily (see sections "Interaction with Other Medicinal Products and Other Forms of Interaction" and "Pharmacological Properties. Pharmacokinetics").

• If cyclosporine is initiated after starting treatment with Prevymis, the next dose of Prevymis should be reduced to 240 mg once daily.
• If cyclosporine is discontinued after starting treatment with Prevymis, the next dose of Prevymis should be increased to 480 mg once daily.
• If cyclosporine administration is temporarily interrupted due to high cyclosporine levels, dose adjustment of Prevymis is not required.

Missed Dose

Patients should be informed that if they miss a dose of Prevymis, they should take it as soon as possible. If the patient does not remember the missed dose until it is time for the next dose, the missed dose should not be taken; instead, the patient should return to the regular dosing schedule. The next dose should not be doubled or a higher dose than prescribed taken.

Special Patient Groups

Elderly Patients

Dose adjustment of Prevymis is not required based on patient age (see sections "Pharmacological Properties. Pharmacodynamics" and "Pharmacological Properties. Pharmacokinetics").

Hepatic Impairment

Dose adjustment of Prevymis is not required in patients with mild (Child-Pugh class A) to moderate (Child-Pugh class B) hepatic impairment. Prevymis is not recommended for patients with severe hepatic impairment (Child-Pugh class C) (see section "Pharmacological Properties. Pharmacokinetics").

Concomitant Hepatic and Renal Impairment

Prevymis is not recommended for patients with moderate hepatic impairment in combination with moderate or severe renal impairment (see section "Pharmacological Properties. Pharmacokinetics").

Renal Impairment

Dose adjustment of Prevymis is not recommended for patients with mild, moderate, or severe renal impairment. There are no dosage recommendations for patients with end-stage renal disease (ESRD), with or without dialysis. Efficacy and safety have not been established in patients with ESRD.

Method of Administration

For oral use.

The tablet should be swallowed whole and may be taken independently of food. The tablet must not be divided, crushed, or chewed.

Children

The safety and efficacy of Prevymis in patients under 18 years of age have not been established.

Data are lacking (see section "Pharmacological Properties. Pharmacodynamics").

Overdose

There is no experience with Prevymis overdose in humans. In a Phase 1 clinical trial, 86 healthy volunteers received Prevymis at doses ranging from 720 mg/day to 1440 mg/day for 14 days. The adverse reaction profile was similar to that observed with the clinical dose of 480 mg/day. There is no specific antidote for Prevymis overdose. In case of overdose, monitoring for adverse reactions and initiation of appropriate symptomatic treatment are recommended.

It is unknown whether dialysis leads to significant removal of Prevymis from systemic circulation.

Adverse reactions.

Summary of safety profile

The safety assessment of Prevymis was based on three phase 3 clinical trials.

HSCT

In study P001, involving 565 HSCT recipients who received Prevymis or placebo up to Week 14 after transplantation and were monitored for safety up to Week 24 after transplantation (see section "Pharmacological properties. Pharmacodynamics").

The most frequently reported adverse reactions occurring in at least 1% of patients in the Prevymis group and more frequently than with placebo were nausea (7.2%), diarrhea (2.4%), and vomiting (1.9%).

The most frequently reported adverse reactions leading to discontinuation of Prevymis were nausea (1.6%), vomiting (0.8%), and abdominal pain (0.5%).

In study P040, 218 HSCT recipients received Prevymis or placebo from Week 14 (~100 days) to Week 28 (~200 days) after HSCT and were monitored for safety up to Week 48 after HSCT (see section "Pharmacological properties. Pharmacodynamics"). The reported adverse reactions were consistent with the safety profile of Prevymis established in study P001.

Kidney transplantation

In study P002, 292 kidney transplant recipients received Prevymis up to Week 28 (~200 days) after transplantation (see section "Pharmacological properties. Pharmacodynamics").

Table of adverse reactions

The adverse reactions listed below were observed in patients receiving Prevymis in clinical trials. Adverse reactions are presented by system organ class and frequency. Frequency is defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), or very rare (< 1/10,000).

Table 7

Adverse reactions occurring during treatment with Prevymis

Frequency	Adverse reactions
Immune system disorders
uncommon	hypersensitivity
Metabolism and nutrition disorders
uncommon	decreased appetite
Nervous system disorders
uncommon	dysgeusia, headache
Ear and labyrinth disorders
uncommon	vertigo
Gastrointestinal disorders
common	nausea, diarrhea, vomiting
uncommon	abdominal pain
Hepatobiliary disorders
uncommon	elevated ALT levels, elevated AST levels
Musculoskeletal and connective tissue disorders
uncommon	muscle spasms
Renal and urinary disorders
uncommon	increased blood creatinine levels
General disorders
uncommon	fatigue, peripheral edema

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after the medicinal product has been registered. This allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store at a temperature not exceeding 30 °C in the original packaging to protect from moisture. Keep out of reach and sight of children.

Packaging.

4 blisters of 7 tablets each (28 tablets) in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Organon Heist bv, Belgium/

Organon Heist bv, Belgium.

Merck Sharp & Dohme B.V., the Netherlands/

Merck Sharp & Dohme B.V., the Netherlands.

Manufacturer's location and address of its business site.

Industriepark 30, 2220 Heist-op-den-Berg, Belgium/

Industriepark 30, 2220 Heist-op-den-Berg, Belgium.

Waarderweg 39, 2031 BN Haarlem, the Netherlands/

Waarderweg 39, 2031 BN Haarlem, the Netherlands.