Previmis

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PREVYMIS

Composition:

Active substance: letermovir;

1 vial contains 240 mg (12 mL/vial) of letermovir;

1 mL contains 20 mg of letermovir;

Excipients: hydroxypropylbetadex, sodium chloride, sodium hydroxide, water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear, colorless liquid; may contain fine translucent or white particles derived from the medicinal product; pH from 7 to 8.

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 required for cleavage and packaging of viral progeny DNA. Letermovir affects the formation of genomes of appropriate 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), and 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 those for the wild-type reference virus; some of these substitutions were observed in patients with prophylactic 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 to 369) was performed on samples from 12 patients receiving letermovir who experienced prophylactic failure and for whom samples were available. One patient (receiving 60 mg/day) had a letermovir-resistant genotype variant (V236M).

In a phase 3 trial (P001), DNA sequencing analysis of all coding regions of UL56 and UL89 was performed on samples obtained from 40 patients treated with letermovir in the full analysis set (FAS) population who experienced prophylactic failure and for whom samples were available. Two patients were found to have 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 (and 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 prophylactic 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 a recombinant strain with the pUL56 E237G substitution, which showed a 2.1-fold reduced susceptibility to ganciclovir compared to wild-type.

Cardiac electrophysiology

The effect of intravenous letermovir 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 QT study 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 achieved with the 480 mg intravenous dose.

Clinical efficacy and safety

CMV-seropositive adult recipients [R+] of allogeneic hematopoietic stem cell transplantation (HSCT)

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

To evaluate letermovir prophylaxis as a preventive 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 recipients [R+] of allogeneic HSCT. Patients were randomized (2:1) to receive either letermovir 480 mg once daily, adjusted to 240 mg when co-administered 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) 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 up to Week 48 post-HSCT.

Patients were monitored weekly for CMV DNA until Week 14 post-HSCT, and then every two weeks until Week 24 post-HSCT, initiating standard CMV preemptive therapy if CMV DNAemia was considered clinically significant. Patients continued to be monitored 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 to 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 for reactivation, as defined by one or more of the following criteria: HLA-related donor (sibling) with at least one mismatch at one of three HLA loci: HLA-A, -B, or -DR; haploidentical donor; 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 the incidence of clinically significant CMV infection (CMVI), defined as 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 lacked data at Week 24 post-HSCT were counted as treatment failure.

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 prophylaxis failure†
Clinically significant CMV infection	57 (17.5)	71 (41.8)
CMV DNAemia requiring preemptive 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, stratified (letermovir – placebo) §
Difference (95% CI)	-23.5 (-32.5, -14.6)
p-value	< 0.0001
† Prophylaxis failure categories 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, accounting for stratification, with the difference weighted by the harmonic mean of the sample size for 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-completion = failure (NC = F). Under the NC = F approach, outcomes were classified as failure for participants with clinically significant CMV infection, those who discontinued study early, or those with missing Week 24 post-transplant visit data. N – number of participants in each treatment group. n (%) – number (percentage) of participants in each subcategory. Note: The proportion of patients with detectable CMV DNA on Day 1 who developed clinically significant CMV infection by Week 24 post-HSCT was 64.6% (31/48) in the letermovir group compared to 90.9% (20/22) in the placebo group. The calculated 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, graft-versus-host disease (GVHD), use of corticosteroids, and CMV-seronegative donor serostatus.

Fig. 1. P001: Kaplan–Meier plot 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 (%)	Letermovir vs placebo Stratified log-rank test, two-sided p-value < 0.0001 Placebo 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 timing of engraftment between the Previmys and placebo groups.

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

Figure 2. P001: Proportion of participants initiating preemptive therapy for CMV or who had CMV end-organ disease through Week 24 after allogeneic HSCT, by selected subgroups (NC=F approach, FAS population).

NC=F = non-completer = inefficacy. With the NC=F approach, participants who discontinued the study prior to Week 24 after transplantation or who lacked results at Week 24 after transplantation were counted as treatment failures.

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

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

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 loci: HLA-A, -B, or -DR; haploidentical donor; HLA-mismatched unrelated donor with at least one mismatch at one of four HLA 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; or use of systemic prednisone (or equivalent) at a dose of ≥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 allogeneic HSCT. Clinically significant CMV infection was defined as the occurrence of CMV end-organ disease or initiation of anti-CMV pre-emptive therapy based on documented CMV viremia and the patient's clinical condition. An observed failure (OF) approach was used, whereby patients who developed clinically significant CMV infection or prematurely discontinued the study with viremia were considered treatment failures.

Letermovir demonstrated superior efficacy compared to placebo in the primary efficacy endpoint analysis, 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 allogeneic HSCT 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 (%)
Lack of efficacy*	4 (2.8)	14 (18.9)
Clinically significant CMV infection by Week 28†	2 (1.4)	13 (17.6)
Initiation of preemptive therapy (PET) 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 exposure) – placebo (~100 days exposure))‡
Difference (95% CI)	-16.1 (-25.8, -6.5) 0.0005
p-value
* Lack of efficacy 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 PET 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 harmonic mean of the sample size in each group for each stratum. One-sided p-value ≤ 0.0249 was used to declare statistical significance. Missing data handling approach: Observed failure (OF) approach. Under the OF approach, lack of efficacy was assigned to outcomes in 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: Adult CMV-seronegative 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, 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 letermovir or valganciclovir. Letermovir was administered concomitantly with acyclovir. Valganciclovir was administered concomitantly with placebo to acyclovir. Randomization was stratified by use or non-use of high-cytopolytic antilymphocyte immunotherapy during induction. Letermovir or valganciclovir was initiated between day 0 and day 7 post-kidney transplantation and continued until week 28 (~200 days) post-transplantation. Patient follow-up continued until week 52 post-transplantation.

Of the 589 patients who received treatment, 292 received letermovir and 297 received valganciclovir. The mean 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 renal cystic disease (17%), hypertension (16%), and diabetes/diabetic nephropathy (14%).

Primary efficacy endpoint

The primary efficacy endpoint in P002 was the incidence of CMV disease (target organ CMV disease or CMV syndrome, confirmed by an independent expert committee) through week 52 post-transplantation. An observed failure (OF) approach was used, in which outcomes in patients who prematurely discontinued from the study for any reason or who had missing data at a given timepoint were not considered treatment failures.

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 (OF approach, FAS population)

Parameter	Letermovir (N = 289) n (%)	Valganciclovir (N = 297) n (%)
CMV disease* at 52 weeks	30 (10.4)	35 (11.8)
Treatment difference adjusted for stratification (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 adjusting for stratification, with the difference calculated as the sample-size weighted average across strata (use/non-use of high-cytolytic, anti-lymphocyte immunotherapy during induction). ‡ Given the 10% non-inferiority margin, letermovir is non-inferior compared to valganciclovir. Missing data approach: Observed failure approach (OF). Under the OF approach, outcomes in participants who discontinued the study early for any reason are not counted 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 by sex, age, race, region, and use/non-use of high-cytolytic antilymphocyte 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 saturation/auto-inhibition of OATP1B1/3. The pharmacokinetics of letermovir 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 peak concentrations (Cmax) at steady state were 71,500 ng × h/mL and 13,000 ng/mL, respectively, following oral administration of 480 mg of letermovir once daily.

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

HSCT recipients

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

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 based on data from Phase 3 P002 (see Table 5). Efficacy was consistent across the 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 with 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 after intravenous administration in allogeneic HSCT recipients (Table 4).

Absorption

Letermovir is rapidly absorbed with a mean time to reach maximum plasma concentration (Tmax) of 1.5–3.0 hours and declines in a biphasic manner. In allogeneic hematopoietic stem cell transplant (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 in patients was approximately 85% when 240 mg letermovir was administered orally 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, oral administration of a single 480 mg 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 to HSCT recipients. Letermovir is highly bound (98.2%) to human plasma proteins across 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. This 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 to 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, with a minor amount (6% of dose) excreted 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.

A pronounced increase in unbound letermovir exposure is expected in patients with moderate hepatic impairment combined with moderate or severe renal impairment (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 – 31.0 to 56.8 mL/min/1.73 m²) and severe (estimated glomerular filtration rate – 11.9 to 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 was 18.7% lower in individuals with body weight of 80–100 kg compared to those with 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 was 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 was 33.2% higher in Mongoloid race compared to Caucasian race. This difference is not clinically significant.

Gender

Based on population pharmacokinetic analyses, no differences in the pharmacokinetics of letermovir were observed between women and men.

Elderly patients

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

Clinical characteristics.

Indications.

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

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

Official guidelines for 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 warnings and precautions for use" and "Interaction with other medicinal products and other forms of interaction").
• Concomitant use with ergot alkaloids (see sections "Special warnings and 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 drugs 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 use of 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. Following 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-metabolising enzymes or transporters

Concomitant use of Prevymis (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 lead to subtherapeutic exposure of 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 of rifampicin resulted in 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 concomitant use 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 Prevymis with medicinal products that are inhibitors of OATP1B1/3 transporters may lead to increased plasma concentrations of letermovir. When Prevymis is administered concomitantly with cyclosporine (a potent inhibitor of OATP1B1/3), the recommended dose of Prevymis 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 results 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 primarily eliminated via metabolism or active transport

Letermovir is a broad 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.

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 influence 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 to assess the pure effect on CYP3A4, P-glycoprotein, OATP1B1/3, and additionally on CYP2C19. The pure 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 and micafungin. Potential interaction between letermovir and these medicinal products has not been studied. There is a theoretical risk of reduced exposure due to induction, but the extent of the effect and thus clinical significance remains unknown.

Medicinal products metabolised by CYP3A

Letermovir is a moderate inhibitor of CYP3A in vivo. Concomitant use of Prevymis with oral midazolam (a CYP3A substrate) results in a 2- to 3-fold increase in midazolam plasma concentration. Concomitant use of Prevymis may lead to clinically significant increases in plasma concentrations of co-administered CYP3A substrates (see sections "Contraindications", "Special warnings and 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 route of letermovir administration 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 influence the time required to achieve the full effect on plasma concentrations. After treatment discontinuation, 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 warnings and precautions for use"), as well as after changes in letermovir administration regimen.

Medicinal products transported by OATP1B1/3

Letermovir is an inhibitor of OATP1B1/3 transporters. Administration of Prevymis may lead to clinically significant increases in plasma concentrations 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 letermovir administration regimens, the effect is more pronounced after intravenous administration than after oral administration when letermovir is used without cyclosporine.

The extent of inhibition of OATP1B1/3 is likely greater when Prevymis 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 metabolised by CYP2C9 and/or CYP2C19

Concomitant use of Prevymis with voriconazole (a CYP2C19 substrate) results in a significant decrease in voriconazole plasma concentration, indicating that letermovir is an inducer of CYP2C19. Induction of CYP2C9 is also possible. 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 metabolised by CYP2C8

Letermovir inhibits CYP2C8 in vitro, but may also induce CYP2C8 based on its inductive potential. The net effect in vivo 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 Prevymis may lead to clinically significant decreases in plasma concentrations of concomitant medicinal products that are primarily transported by P-glycoprotein in the intestine, such as dabigatran and sofosbuvir.

Medicinal products metabolised by CYP2B6, UGT1A1 or transported by BCRP or OATP2B1

Letermovir is a broad inducer in vivo, but inhibition of CYP2B6, UGT1A1, BCRP and OATP2B1 has also been observed in vitro. The net effect in vivo 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 metabolised by CYP2B6 is bupropion.

Examples of medicinal products metabolised 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 adjustment of concomitant medicinal products is performed due to treatment with Prevymis, their doses should be readjusted after completion of Prevymis 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 Prevymis or are predicted drug interactions that may occur with use of Prevymis (see sections "Contraindications", "Special warnings and precautions for use", "Pharmacological properties. Pharmacodynamics" and "Pharmacological properties. Pharmacokinetics").

Table 6

Interaction and dosing recommendations when used with other medicinal products. Table 6 is not exhaustive 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 coefficient (90% confidence interval) for AUC, Cmax (likely mechanism of action)	Recommendations for Concomitant Use with Prezmyr
Antibiotics
Naftcilin	Interaction not studied. Expected: ↓ letermovir (P-glycoprotein/UGT induction)	Naftcilin may reduce plasma concentrations of letermovir. Concomitant use of Prezmyr 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, and 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 Prezmyr 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) (inhibition of OATP1B1/3 and/or P-glycoprotein)
(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) (inhibition of OATP1B1/3 and/or P-glycoprotein)
(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 inhibition of OATP1B1/3 and/or P-glycoprotein and induction of P-glycoprotein/UGT)	Repeated doses of rifampicin reduce plasma concentrations of letermovir. Concomitant use of Prezmyr 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 Prezmyr 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 Prezmyr 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 Prezmyr 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 Prezmyr 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 Prezmyr 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 related to statin use, such as myopathy, should be closely monitored. The dose of atorvastatin should not exceed 20 mg daily when used concomitantly with Prezmyr#. Although not studied, increased plasma concentrations of atorvastatin are expected to be greater when Prezmyr is used concomitantly with cyclosporine than with Prezmyr alone. Atorvastatin is contraindicated when Prezmyr 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 with Prezmyr alone is not recommended. Use of these statins is contraindicated when Prezmyr is used concomitantly with cyclosporine.
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 Prezmyr#. Adverse reactions related to statins, such as myopathy, should be closely monitored. When Prezmyr is used concomitantly with cyclosporine, pravastatin is not recommended, while fluvastatin may require dose reduction#. Adverse reactions related to 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 Prezmyr is used concomitantly with cyclosporine, the dose of Prezmyr should be reduced to 240 mg once daily (see sections "Dosage and Administration" and "Pharmacological Properties. Pharmacodynamics"). Frequent monitoring of cyclosporine blood concentrations should be performed during treatment, upon changes in administration, and after discontinuation of Prezmyr, with appropriate adjustment of cyclosporine dose#.
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 blood concentrations is recommended during treatment, upon changes in administration, and after discontinuation of Prezmyr, with appropriate dose adjustment of sirolimus#. Frequent monitoring of sirolimus concentrations is recommended at initiation or discontinuation of concomitant cyclosporine with Prezmyr. When Prezmyr is used concomitantly with cyclosporine, refer to the sirolimus product information for specific recommendations on using sirolimus with cyclosporine. Increased sirolimus concentrations may be greater when Prezmyr is used concomitantly with cyclosporine than with Prezmyr 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 blood concentrations should be performed during treatment, upon changes in administration, and after discontinuation of Prezmyr, 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 oral steroid contraceptives	Risk of ↓ steroid contraceptives	Letermovir may reduce plasma concentrations of other systemic oral steroid contraceptives, thereby affecting their efficacy. To ensure adequate contraceptive effect, 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 Prezmyr 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#.
Glibenclamide	Interaction not studied. Expected: ↑ glibenclamide (OATP1B1/3 inhibition, CYP3A inhibition, CYP2C9 induction)	Letermovir may increase plasma concentrations of glibenclamide. Frequent glucose monitoring is recommended during the first 2 weeks after initiation or discontinuation of letermovir, and after changes in letermovir administration. When Prezmyr is used concomitantly with cyclosporine, refer to the glibenclamide 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 Prezmyr 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 Prezmyr 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 international normalized ratio (INR) is recommended when warfarin is used concomitantly with Prezmyr#. Monitoring is recommended during the first 2 weeks after initiation or discontinuation of letermovir, and 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 Prezmyr 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 recommended when Prezmyr is used concomitantly with midazolam. Dose adjustment of midazolam may be required#. Plasma concentrations of midazolam may be higher with oral midazolam administered with therapeutic doses of letermovir than with the studied dose.
Opioid Agonists
Examples: alfentanil, fentanyl	Interaction not studied. Expected: ↑ CYP3A-metabolized opioids (CYP3A inhibition)	Close monitoring for adverse reactions related to 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. Increased plasma concentrations of CYP3A-metabolized opioids may be more pronounced when Prezmyr is used concomitantly with cyclosporine. Close clinical monitoring for respiratory depression and/or prolonged sedation is recommended when Prezmyr 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 related to amiodarone use is recommended during concomitant use. Amiodarone concentrations should be monitored regularly when amiodarone is used concomitantly with Prezmyr#.
Quinidine	Interaction not studied. Expected: ↑ quinidine (CYP3A inhibition)	Letermovir may increase plasma concentrations of quinidine. Close clinical monitoring is recommended when Prezmyr 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 via CYP2C19 induction) Interaction not studied. Expected: ↔ letermovir	Letermovir may reduce plasma concentrations of CYP2C19 substrates. Clinical monitoring and dose adjustment may be required.
Stimulants
Modafinil	Interaction not studied. Expected: ↓ letermovir (P-glycoprotein/UGT induction)	Modafinil may reduce plasma concentrations of letermovir. Concomitant use of Prezmyr and modafinil is not recommended.
* This table does not include all data. † ↓ – decrease, ↑ – increase, ↔ – no clinically significant changes. ‡ Single-direction interaction study assessing the effect of letermovir on the concomitant medicinal product. § 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 leaflet.

Children

Interaction studies have been conducted only in adults.

Special precautions for use.

Monitoring of CMV DNA in HCT recipients

In the phase 3 study (P001), the safety and efficacy of letermovir were established in HCT 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 pre-emptive 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 administration 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, which may lead to reduced therapeutic effect of the concomitant medicinal product.

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 cautiously with medicinal products that are CYP3A substrates with a narrow therapeutic range (e.g., alfentanil, fentanyl, and quinidine), as concomitant administration 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 changes in the route of administration of letermovir.

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"). Therefore, therapeutic drug monitoring is 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).

Administration through a sterile integrated polyethersulfone (PES) filter with a pore size of 0.2 µm or 0.22 µm

Prevymis, concentrate for solution for infusion, may contain a small number of fine, translucent or white particles of the drug. Administration of diluted Prevymis solution always requires the use of a sterile integrated PES filter with a pore size of 0.2 µm or 0.22 µm, regardless of whether these drug particles are visible in the concentrate or in the diluted solution (see sections "Dosage and administration" and "Dosage and administration. Special precautions for disposal and other handling").

Excipients

Sodium

This medicinal product contains 23 mg (or 1 mmol) of sodium per vial (240 mg letermovir), equivalent to 1.15% of the maximum daily intake recommended by the WHO (2 g sodium for adults). This should be taken into account for patients on a sodium-controlled diet.

Cyclodextrin

This medicinal product contains 1800 mg of hydroxypropylbetadex (cyclodextrin) per 12 ml vial of product (240 mg dose).

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 reproductive potential who are not using contraception.

Breastfeeding

It is unknown whether letermovir is excreted in human 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 effect on fertility was observed in female rats. Irreversible testicular toxicity and impaired fertility were observed in male rats, but not in male mice or monkeys.

Ability to affect 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 Previmis should be prescribed by a physician experienced in managing patients who have received allogeneic hematopoietic stem cell transplantation or kidney transplantation.

Method of Administration

Previmis is also available in an oral formulation (film-coated tablets, 240 mg).

Previmis film-coated tablets and Previmis concentrate for infusion solution may be used interchangeably at the physician’s discretion; dosage adjustment is not required.

The recommended dose of Previmis is 480 mg once daily.

HSCT

Administration of Previmis should begin after HSCT. Previmis may be initiated on the day of transplantation or no later than 28 days after HSCT. Administration of Previmis may begin before or after engraftment. Prophylaxis with Previmis should continue for 100 days after HSCT. Extended prophylaxis with Previmis beyond 100 days after HSCT may be beneficial for some patients at high risk of late cytomegalovirus (CMV) reactivation (see section “Pharmacological Properties. Pharmacodynamics”). The safety and efficacy of Previmis use beyond 200 days have not been studied in clinical trials.

Kidney Transplantation

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

Dose Adjustment

If Previmis is administered concomitantly with cyclosporine, the dose of Previmis 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 administration is initiated after starting Previmis, the next dose of Previmis should be reduced to 240 mg once daily.
• If cyclosporine administration is discontinued after starting Previmis, the next dose of Previmis should be increased to 480 mg once daily.
• If cyclosporine administration is temporarily interrupted due to high cyclosporine levels, no dose adjustment of Previmis is required.

Missed Dose

If a dose of Previmis is missed, it should be administered as soon as possible. If it is time for the next scheduled dose, the missed dose should not be administered, and the regular dosing schedule should be resumed. The next dose should not be doubled or exceed the prescribed amount.

Special Patient Populations

Elderly Patients

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

Hepatic Impairment

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

Concomitant Hepatic and Renal Impairment

Previmis 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 Previmis 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 demonstrated in patients with ESRD.

Previmis concentrate for infusion solution contains hydroxypropylbetadex. The predicted clinical exposure to hydroxypropylbetadex following intravenous administration of letermovir is expected to be approximately 3,600 mg/day at a letermovir dose of 480 mg. No cases of kidney injury due to hydroxypropylbetadex were observed in clinical studies of intravenous letermovir administration in humans with treatment durations up to 47 days. Accumulation of hydroxypropylbetadex may occur in patients with moderate or severe renal impairment (creatinine clearance <50 mL/min) receiving Previmis. Serum creatinine levels should be closely monitored in these patients.

Method of Administration

For intravenous use only.

Previmis concentrate for infusion solution must be diluted before administration (see information below).

The diluted Previmis solution should be administered through an infusion system equipped with an in-line sterile polyethersulfone (PES) filter with a pore size of 0.2 or 0.22 microns. The diluted solution must not be administered through any filter other than a sterile in-line PES filter with a pore size of 0.2 or 0.22 microns.

Previmis should be administered only as an intravenous infusion. Previmis must not be administered as an intravenous bolus or by rapid intravenous injection.

After dilution, Previmis should be administered as an intravenous infusion via a peripheral or central venous catheter over approximately 60 minutes. The entire contents of the infusion bag should be administered.

Special Precautions for Disposal and Other Handling

Previmis vials are intended for single use only.

Preparation

Previmis concentrate for infusion solution must be diluted before intravenous administration. Before dilution, inspect the vial contents for color change and presence of mechanical particulates. Previmis concentrate for infusion solution is a clear, colorless solution that may contain a few drug-related fine semi-transparent or white particles. Do not use the vial if the solution is cloudy, has changed color, or contains mechanical particulates other than a few fine semi-transparent or white particles. When administering Previmis intravenously, infusion bags and sets containing polyurethane or the plasticizer diethylhexyl phthalate (DEHP) must not be used. Materials free of phthalates are also free of DEHP.

Do not shake the Previmis vial.

Add the contents of one vial (12 mL, 240 mg dose) or two vials (2 × 12 mL, 480 mg dose) of Previmis concentrate for infusion solution to a pre-filled 250 mL intravenous bag containing 0.9% sodium chloride solution or 5% dextrose solution for intravenous infusion, and mix the diluted solution by gently inverting the bag. Do not shake.

After dilution, the Previmis solution becomes a clear solution ranging from colorless to yellow. Color variations within this range do not affect the quality of the drug. Before administration, visually inspect the diluted solution for the presence of solid particles and color change. Discard the drug if the diluted solution is cloudy, has changed color, or contains other mechanical particulates, except for a few fine semi-transparent or white particles. If the contents of one vial are added to a 250 mL intravenous bag, the final letermovir concentration will be 0.9 mg/mL (for the 240 mg dose). If the contents of two vials are added to a 250 mL intravenous bag, the final letermovir concentration will be 1.8 mg/mL (for the 480 mg dose).

The diluted Previmis solution should be administered through a sterile in-line PES filter with a pore size of 0.2 or 0.22 microns.

Compatible Intravenous Solutions and Other Medicinal Products

Previmis concentrate for infusion solution is compatible with 0.9% sodium chloride solution and 5% dextrose solution.

Previmis must not be administered simultaneously through the same intravenous line (or cannula) with other medicinal products or in combination with solvents other than those listed below.

List of Compatible Medicinal Products when Previmis and Medicinal Products* are Prepared in 0.9% Sodium Chloride Solution

• Ampicillin sodium
• Fluconazole
• Ampicillin sodium / sulbactam sodium
• Human insulin
• Antithymocyte globulin
• Magnesium sulfate
• Caspofungin
• Methotrexate
• Daptomycin
• Micafungin
• Fentanyl citrate

* Refer to the medical instructions for each medicinal product to confirm compatibility for concomitant administration.

List of Compatible Medicinal Products when Previmis and Medicinal Products* are Prepared in 5% Dextrose Solution

• Amphotericin B (lipid complex)†
• Hydrocortisone sodium succinate
• Anidulafungin
• Morphine sulfate
• Cefazolin sodium
• Norepinephrine bitartrate
• Ceftaroline
• Pantoprazole sodium
• Ceftriaxone sodium
• Potassium chloride
• Doripenem
• Potassium phosphate
• Famotidine
• Tacrolimus
• Folic acid
• Telavancin
• Ganciclovir sodium
• Tigecycline

* Refer to the medical instructions for each medicinal product to confirm compatibility for concomitant administration.

†Amphotericin B (lipid complex) is compatible with Previmis. However, Amphotericin B (liposomal) is incompatible (see section “Incompatibility. Incompatible Medicinal Products”).

Compatible Intravenous Bags and Infusion Sets Materials

Previmis is compatible with the materials listed below used in the manufacture of intravenous bags and infusion sets. Do not use any bags or infusion sets made from materials not listed below.

Materials for Intravenous Bags

Polyvinyl chloride (PVC), ethylene vinyl acetate (EVA), and polyolefin (polypropylene and polyethylene).

Materials for Infusion Sets

PVC, polyethylene (PE), polybutadiene (PBD), silicone rubber (SR), styrene-butadiene copolymer (SBC), styrene-butadiene-styrene copolymer (SBSC), polystyrene (PS).

Plasticizers

Tris(2-ethylhexyl) trimellitate, butyl benzyl phthalate (BBP).

Catheters

Radiopaque polyurethane.

Any unused medicinal product or waste should be disposed of in accordance with local requirements.

Children.

The safety and efficacy of Previmis 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 Previmis overdose in humans. In a Phase 1 clinical trial, 86 healthy volunteers received Previmis at doses ranging from 720 mg/day to 1,440 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 Previmis 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 Previmis from systemic circulation.

Adverse reactions.

Short description of the safety profile

The safety assessment of Prevymis use 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 post-transplant and were monitored for safety up to Week 24 post-transplant (see section "Pharmacological properties. Pharmacodynamics").

The most commonly 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 commonly 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) post-HSCT and were monitored for safety up to Week 48 post-HSCT (see section "Pharmacological properties. Pharmacodynamics"). The reported adverse reactions were consistent with the safety profile of Prevymis as characterized in study P001.

Kidney transplantation

In study P002, 292 kidney transplant recipients received Prevymis up to Week 28 (~200 days) post-transplant (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 listed 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	elevation of ALT levels, elevation of AST levels
Musculoskeletal and connective tissue disorders
uncommon	muscle spasms
Renal and urinary disorders
uncommon	increased blood creatinine levels
General disorders and administration site conditions
uncommon	fatigue, peripheral edema

Reporting of suspected adverse reactions

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

Shelf life.

Unopened vial: 30 months.

After opening the vial, the product should be used immediately.

Storage of the diluted solution

Chemical and physical stability has been demonstrated for 48 hours at 25 °C and for 48 hours at a temperature of 2 to 8 °C.

From a microbiological standpoint, the product should be used immediately. If not used immediately, the responsibility for the storage conditions and duration prior to use lies with the user, and under normal circumstances, storage should not exceed 24 hours at a temperature of 2 to 8 °C, unless dilution occurs under controlled and validated aseptic conditions.

Storage conditions.

Store at a temperature not exceeding 25 °C. Keep in the original packaging to protect from light. Keep out of reach of children.

Storage conditions for the diluted medicinal product solution are described in the section "Shelf life".

Incompatibilities.

Incompatible medicinal products

Prevymis, concentrate for solution for infusion, is physically incompatible with amiodarone hydrochloride, amphotericin B (liposomal), aztreonam, cefepime hydrochloride, ciprofloxacin, cyclosporine, diltiazem hydrochloride, filgrastim, gentamicin sulfate, levofloxacin, linezolid, lorazepam, midazolam hydrochloride, mycophenolate mofetil hydrochloride, ondansetron, and palonosetron.

This medicinal product must not be mixed with other medicinal products except those specified in the section "Dosage and administration. Special precautions for disposal and other handling".

Incompatible materials of intravenous infusion bags and sets

Prevymis, concentrate for solution for infusion, is incompatible with diethylhexylphthalate (DEHP) plasticizers and polyurethane-containing intravenous administration tubing.

This medicinal product must not be used with other intravenous infusion bags and sets except those specified in the section "Dosage and administration. Special precautions for disposal and other handling".

Packaging.

Concentrate for solution in a glass vial (type I). 1 vial contains 240 mg (12 mL/vial) of letermovir. 1 mL contains 20 mg of letermovir. 1 vial in a cardboard box.

Prescription category.

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 address and location of the site of activity.

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.