PREVYMIS 240mg perfusive solution concentrate medication leaflet

PREVYMIS 240 mg concentrate for solution for infusion

PREVYMIS 480 mg concentrate for solution for infusion

PREVYMIS 240 mg concentrate for solution for infusion

Each vial contains 240 mg (12 mL per vial) of letermovir.

Each mL contains 20 mg of letermovir.

PREVYMIS 480 mg concentrate for solution for infusion

Each vial contains 480 mg (24 mL per vial) of letermovir.

Each mL contains 20 mg of letermovir.

This medicinal product contains 23 mg (1 mmol) sodium per 240 mg vial.

This medicinal product contains 46 mg (2 mmol) sodium per 480 mg vial.

This medicinal product contains 1 800 mg hydroxypropylbetadex (cyclodextrin) per 240 mg vial.

This medicinal product contains 3 600 mg hydroxypropylbetadex (cyclodextrin) per 480 mg vial.

For additional information, see section 4.2.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate)

Clear, colourless liquidpH between 7 and 8

PREVYMIS is indicated for prophylaxis of cytomegalovirus (CMV) reactivation and disease in adultand paediatric patients weighing at least 5 kg who are CMV-seropositive recipients [R+] of anallogeneic haematopoietic stem cell transplant (HSCT).

PREVYMIS is indicated for prophylaxis of CMV disease in CMV-seronegative adult and paediatricpatients weighing at least 40 kg who have received a kidney transplant from a CMV-seropositivedonor [D+/R-].

Consideration should be given to official guidance on the appropriate use of antiviral agents.

Letermovir should be initiated by a physician experienced in the management of patients who havehad an allogeneic haematopoietic stem cell transplant or kidney transplant.

Letermovir is also available for oral administration (240 mg and 480 mg film-coated tablets, and20 mg and 120 mg granules in sachet).

Letermovir tablets, granules in sachet, and concentrate for solution for infusion may be usedinterchangeably at the discretion of the physician. Dose adjustment may be necessary for paediatricpatients weighing less than 30 kg when switching between oral and intravenous formulations. Refer tothe prescribing information for the letermovir film-coated tablets or letermovir granules in sachet fordosing information.

HSCT

Letermovir should be started after HSCT. Letermovir may be started on the day of transplant and nolater than 28 days post-HSCT. Letermovir may be started before or after engraftment. Prophylaxiswith letermovir should continue through 100 days post-HSCT.

Prolonged letermovir prophylaxis beyond 100 days post-HSCT may be of benefit in some patients athigh risk for late CMV reactivation (see section 5.1). The safety and efficacy of letermovir use formore than 200 days has not been studied in clinical trials.

Adult and paediatric patients weighing at least 30 kg who are HSCT recipients

The recommended dose of letermovir is 480 mg once daily.

Dose adjustment in adult and paediatric patients weighing at least 30 kg who are HSCT recipients

If letermovir is co-administered with cyclosporine, the dose of letermovir should be decreased to240 mg once daily (see sections 4.5 and 5.2).

* If cyclosporine is initiated after starting letermovir, the next dose of letermovir should bedecreased to 240 mg once daily.

* If cyclosporine is discontinued after starting letermovir, the next dose of letermovir should beincreased to 480 mg once daily.

* If cyclosporine dosing is temporarily interrupted due to high cyclosporine levels, no doseadjustment of letermovir is needed.

Paediatric patients weighing less than 30 kg who are HSCT recipients

The recommended doses of letermovir for paediatric patients weighing less than 30 kg are shown in

Table 1 (see also section 5.2). Letermovir should be administered once daily.

Dose adjustment in paediatric patients weighing less than 30 kg who are HSCT recipients

If intravenous letermovir is co-administered with cyclosporine, the dose of letermovir does not requireadjustment as shown in Table 1 (see also sections 4.5 and 5.2).

Table 1: Recommended dose of letermovir concentrate for solution for infusion without or withcyclosporine in paediatric patients weighing less than 30 kg

Body weight Daily intravenous dose without or with cyclosporine15 kg to less than 30 kg 120 mg7.5 kg to less than 15 kg 60 mg5 kg to less than 7.5 kg 40 mg

Kidney transplant

Letermovir should be started on the day of transplant and no later than 7 days post-kidney transplantand continued through 200 days post-transplant.

Adult and paediatric patients weighing at least 40 kg who are kidney transplant recipients

The recommended dose of letermovir is 480 mg once daily.

Dose adjustment in adult and paediatric patients weighing at least 40 kg who are kidney transplantrecipients

If letermovir is co-administered with cyclosporine, the dose of letermovir should be decreased to240 mg once daily (see sections 4.5 and 5.2).

* If cyclosporine is initiated after starting letermovir, the next dose of letermovir should bedecreased to 240 mg once daily.

* If cyclosporine is discontinued after starting letermovir, the next dose of letermovir should beincreased to 480 mg once daily.

* If cyclosporine dosing is temporarily interrupted due to high cyclosporine levels, no doseadjustment of letermovir is needed.

If a dose is missed, it should be given to the patient as soon as possible. If it is time for the next dose,skip the missed dose and go back to the regular schedule. Do not double the next dose or give morethan the prescribed dose.

No dose adjustment of letermovir is required based on age (see sections 5.1 and 5.2).

No dose adjustment of letermovir is required based on mild (Child-Pugh Class A) to moderate (Child-

Pugh Class B) hepatic impairment. Letermovir is not recommended for patients with severe (Child-

Pugh Class C) hepatic impairment (see section 5.2).

Combined hepatic and renal impairment

Letermovir is not recommended in patients with moderate hepatic impairment combined withmoderate or severe renal impairment (see section 5.2).

No dose adjustment of letermovir is recommended for patients with mild, moderate, or severe renalimpairment. No dose recommendation can be made for patients with end stage renal disease (ESRD)with or without dialysis. Efficacy and safety has not been demonstrated for patients with ESRD.

PREVYMIS concentrate for solution for infusion contains hydroxypropylbetadex (see sections 4.4 and5.3). In patients with moderate or severe renal impairment (creatinine clearance less than 50 mL/min),or in young children (less than 2 years of age) receiving PREVYMIS, accumulation ofhydroxypropylbetadex could occur. Serum creatinine levels should be closely monitored in thesepatients.

If possible, intravenous administration should not exceed 4 weeks.

The safety and efficacy of letermovir in HSCT patients weighing less than 5 kg or in kidney transplantpatients weighing less than 40 kg have not been established. No data are available. Norecommendation on posology for kidney transplant patients weighing less than 40 kg could besupported by pharmacokinetic/pharmacodynamic extrapolation.

For intravenous use only.

Letermovir concentrate for solution for infusion requires dilution (see section 6.6) prior toadministration.

Letermovir diluted solution must be administered through a sterile 0.2 micron or 0.22 micronpolyethersulfone (PES) in-line filter. Do not administer the diluted solution through a filter other thana sterile 0.2 micron or 0.22 micron PES in-line filter.

Letermovir should be administered as an intravenous infusion only.

After dilution, letermovir should be administered by intravenous infusion via peripheral or centralvenous catheter using a total time of approximately 60 minutes. The entire contents of the intravenousbag should be administered.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Concomitant administration with pimozide (see sections 4.4 and 4.5).

Concomitant administration with ergot alkaloids (see sections 4.4 and 4.5).

Concomitant administration with St. John’s wort (Hypericum perforatum) (see section 4.5).

When letermovir is combined with cyclosporine:

* Concomitant use of dabigatran, atorvastatin, simvastatin, rosuvastatin or pitavastatin iscontraindicated (see section 4.5).

Monitoring of CMV DNA in HSCT recipients

In a Phase 3 trial (P001), the safety and efficacy of letermovir has been established in HSCT patientswith a negative CMV DNA test result prior to initiation of prophylaxis. CMV DNA was monitored ona weekly basis until post-transplant Week 14, and subsequently every two weeks until Week 24. Incases of clinically significant CMV DNAemia or disease, letermovir prophylaxis was stopped andstandard-of-care pre-emptive therapy (PET) or treatment was initiated. In patients in whom letermovirprophylaxis was initiated and the baseline CMV DNA test was subsequently found to be positive,prophylaxis could be continued if PET criteria had not been met (see section 5.1).

Risk of adverse reactions or reduced therapeutic effect due to medicinal product interactions

The concomitant use of letermovir and certain medicinal products may result in known or potentiallysignificant medicinal product interactions, some of which may lead to:

* possible clinically significant adverse reactions from greater exposure of concomitant medicinalproducts or letermovir.

* significant decrease of concomitant medicinal product plasma concentrations which may lead toreduced therapeutic effect of the concomitant medicinal product.

See Table 2 for steps to prevent or manage these known or potentially significant medicinal productinteractions, including dosing recommendations (see sections 4.3 and 4.5).

Letermovir should be used with caution with medicinal products that are CYP3A substrates withnarrow therapeutic ranges (e.g., alfentanil, fentanyl, and quinidine) as co-administration may result inincreases in the plasma concentrations of CYP3A substrates. Close monitoring and/or dose adjustmentof co-administered CYP3A substrates is recommended (see section 4.5).

Increased monitoring of cyclosporine, tacrolimus, sirolimus is generally recommended the first 2weeks after initiating and ending letermovir (see section 4.5) as well as after changing route ofadministration of letermovir.

Letermovir is a moderate inducer of enzymes and transporters. Induction may give rise to reducedplasma concentrations of some metabolised and transported medicinal products (see section 4.5).

Therapeutic drug monitoring (TDM) is therefore recommended for voriconazole. Concomitant use ofdabigatran should be avoided due to risk of reduced dabigatran efficacy.

Letermovir may increase the plasma concentrations of medicinal products transported by OATP1B1/3such as many of the statins (see section 4.5 and Table 2).

Administration through a sterile 0.2 or 0.22 micron PES in-line filter

PREVYMIS concentrate for solution for infusion may contain a few product-related small translucentor white particles. Administration of PREVYMIS diluted solution always requires the use of a sterile0.2 micron or 0.22 micron PES in-line filter, regardless of whether these product-related particles arevisible in the vial or diluted solution (see sections 4.2 and 6.6).

This medicinal product contains 23 mg (or 1 mmol) sodium per 240 mg vial, equivalent to 1.15% ofthe WHO recommended maximum daily intake of 2 g sodium for an adult. This should be taken intoconsideration by patients on a controlled sodium diet.

This medicinal product contains 46 mg (or 2 mmol) sodium per 480 mg vial, equivalent to 2.30% ofthe WHO recommended maximum daily intake of 2 g sodium for an adult. This should be taken intoconsideration by patients on a controlled sodium diet.

Cyclodextrin

This medicinal product contains 300 mg hydroxypropylbetadex (cyclodextrin) per 40 mg dose.

This medicinal product contains 450 mg hydroxypropylbetadex (cyclodextrin) per 60 mg dose.

This medicinal product contains 900 mg hydroxypropylbetadex (cyclodextrin) per 120 mg dose.

This medicinal product contains 1 800 mg hydroxypropylbetadex (cyclodextrin) per 240 mg dose.

This medicinal product contains 3 600 mg hydroxypropylbetadex (cyclodextrin) per 480 mg dose.

General information about differences in exposure between different letermovir treatment regimens

- The estimated letermovir plasma exposure is different depending on the dose regimen used (see tablein section 5.2). Therefore, the clinical consequences of drug interactions for letermovir will bedependent on which letermovir regimen is used and whether or not letermovir is combined withcyclosporine.

- The combination of cyclosporine and letermovir may lead to more marked or additional effects onconcomitant medicinal products as compared to letermovir alone (see Table 2).

Effect of other medicinal products on letermovir

The elimination pathways of letermovir in vivo are biliary excretion and glucuronidation. The relativeimportance of these pathways is unknown. Both elimination pathways involve active uptake into thehepatocyte through the hepatic uptake transporters OATP1B1/3. After uptake, glucuronidation ofletermovir is mediated by UGT1A1 and 3. Letermovir also appears to be subject to P-gp and BCRPmediated efflux in the liver and intestine (see section 5.2).

Inducers of drug metabolising enzymes or transporters

Co-administration of letermovir (with or without cyclosporine) with strong and moderate inducers oftransporters (e.g., P-gp) and/or enzymes (e.g., UGTs) is not recommended, as it may lead tosubtherapeutic letermovir exposure (see Table 2).

- Examples of strong inducers include rifampicin, phenytoin, carbamazepine, rifabutin andphenobarbital.

- Examples of moderate inducers include thioridazine, modafinil, ritonavir, lopinavir, efavirenz andetravirine.

Rifampicin co-administration resulted in an initial increase in letermovir plasma concentrations (due to

OATP1B1/3 and/or P-gp inhibition) that is not clinically relevant, followed by clinically relevantdecreases in letermovir plasma concentrations (due to induction of P-gp/UGT) with continuedrifampicin co-administration (see Table 2).

Additional effects of other products on letermovir relevant when combined with cyclosporine

Inhibitors of OATP1B1 or 3

Co-administration of letermovir with medicinal products that are inhibitors of OATP1B1/3transporters may result in increased letermovir plasma concentrations. If letermovir is co-administeredwith cyclosporine (a potent OATP1B1/3 inhibitor), the recommended dose of letermovir is 240 mgonce daily in adult and paediatric patients weighing at least 30 kg (see Table 2 and sections 4.2 and5.2). If intravenous letermovir is co-administered with cyclosporine in paediatric patients weighingless than 30 kg, dose adjustment is not required (see Table 2 and sections 4.2 and 5.2). Caution isadvised if other OATP1B1/3 inhibitors are added to letermovir combined with cyclosporine.

- Examples of OATP1B1 inhibitors include gemfibrozil, erythromycin, clarithromycin, and severalprotease inhibitors (atazanavir, simeprevir).

Inhibitors of P-gp/BCRP

In vitro results indicate that letermovir is a substrate of P-gp/BCRP. Changes in letermovir plasmaconcentrations due to inhibition of P-gp/BCRP by itraconazole were not clinically relevant.

Effect of letermovir on other medicinal products

Medicinal products mainly eliminated through metabolism or influenced by active transport

Letermovir is a general inducer in vivo of enzymes and transporters. Unless a particular enzyme ortransporter is also inhibited (see below) induction can be expected. Therefore, letermovir maypotentially lead to decreased plasma exposure and possibly reduced efficacy of co-administeredmedicinal products that are mainly eliminated through metabolism or by active transport.

The size of the induction effect is dependent on letermovir route of administration and whethercyclosporine is concomitantly used. The full induction effect can be expected after 10-14 days ofletermovir treatment. The time needed to reach steady state of a specific affected medicinal productwill also influence the time needed to reach full effect on the plasma concentrations.

In vitro, letermovir is an inhibitor of CYP3A, CYP2C8, CYP2B6, BCRP, UGT1A1, OATP2B1, and

OAT3 at in vivo relevant concentrations. In vivo studies are available investigating the net effect on

CYP3A4, P-gp, OATP1B1/3 additionally on CYP2C19. The net effect in vivo on the other listedenzymes and transporters is not known. Detailed information is presented below.

It is unknown whether letermovir may affect the exposure of piperacillin/tazobactam, amphotericine Band micafungin. The potential interaction between letermovir and these medicinal products have notbeen investigated. There is a theoretical risk of reduced exposure due to induction but the size of theeffect and thus clinical relevance is presently unknown.

Medicinal products metabolised by CYP3A

Letermovir is a moderate inhibitor of CYP3A in vivo. Co-administration of letermovir with oralmidazolam (a CYP3A substrate) results in 2-3-fold increased midazolam plasma concentrations. Co-administration of letermovir may result in clinically relevant increases in the plasma concentrations ofco-administered CYP3A substrates (see sections pct. 4.3, pct. 4.4, and 5.2).

- Examples of such medicinal products include certain immunosuppressants (e.g., cyclosporine,tacrolimus, sirolimus), HMG-CoA reductase inhibitors, and amiodarone (see Table 2). Pimozide andergot alkaloids are contraindicated (see section 4.3).

The size of the CYP3A inhibitory effect is dependent on letermovir route of administration andwhether cyclosporine is concomitantly used.

Due to time dependent inhibition and simultaneous induction the net enzyme inhibitory effect may notbe reached until after 10-14 days. The time needed to reach steady state of a specific affectedmedicinal product will also influence the time needed to reach full effect on the plasma concentrations.

When ending treatment, it takes 10-14 days for the inhibitory effect to disappear. If monitoring isapplied, this is recommended the first 2 weeks after initiating and ending letermovir (see section 4.4)as well as after changing route of letermovir administration.

Medicinal products transported by OATP1B1/3

Letermovir is an inhibitor of OATP1B1/3 transporters. Administration of letermovir may result in aclinically relevant increase in plasma concentrations of co-administered medicinal products that are

OATP1B1/3 substrates.

- Examples of such medicinal products include HMG-CoA reductase inhibitors, fexofenadine,repaglinide and glyburide (see Table 2). Comparing letermovir regimen administered withoutcyclosporine, the effect is more marked after intravenous than oral letermovir.

The magnitude of the OATP1B1/3 inhibition on co-administered medicinal products is likely greaterwhen letermovir is co-administered with cyclosporine (a potent OATP1B1/3 inhibitor). This needs tobe considered when the letermovir regimen is changed during treatment with an OATP1B1/3substrate.

Medicinal products metabolised by CYP2C9 and/or CYP2C19

Co-administration of letermovir with voriconazole (a CYP2C19 substrate) results in significantlydecreased voriconazole plasma concentrations, indicating that letermovir is an inducer of CYP2C19.

CYP2C9 is likely also induced. Letermovir has the potential to decrease the exposure of CYP2C9and/or CYP2C19 substrates potentially resulting in subtherapeutic levels.

- Examples of such medicinal products include warfarin, voriconazole, diazepam, lansoprazole,omeprazole, esomeprazole, pantoprazole, tilidine, tolbutamide (see Table 2).

The effect is expected to be less pronounced for oral letermovir without cyclosporine, than intravenousletermovir with or without cyclosporine, or oral letermovir with cyclosporine. This needs to beconsidered when the letermovir regimen is changed during treatment with a CYP2C9 or CYP2C19substrate. See also general information on induction above regarding time courses of the interaction.

Medicinal products metabolised by CYP2C8

Letermovir inhibits CYP2C8 in vitro but may also induce CYP2C8 based on its induction potential.

The net effect in vivo is unknown.

- An example of a medicinal product which is mainly eliminated by CYP2C8 is repaglinide (see

Table 2). Concomitant use of repaglinide and letermovir with or without cyclosporine is notrecommended.

Medicinal products transported by P-gp in the intestine

Letermovir is an inducer of intestinal P-gp. Administration of letermovir may result in a clinicallyrelevant decrease in plasma concentrations of co-administered medicinal products that aresignificantly transported by P-gp in the intestine such as dabigatran and sofosbuvir.

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

Letermovir is a general inducer in vivo but has also been observed to inhibit CYP2B6, UGT1A1,

BCRP, and OATP2B1 in vitro. The net effect in vivo is unknown. Therefore, the plasmaconcentrations of medicinal products that are substrates of these enzymes or transporters may increaseor decrease when co-administered with letermovir. Additional monitoring may be recommended; referto the prescribing information for such medicinal products.

- Examples of medicinal products that are metabolised by CYP2B6 include bupropion.

- Examples of medicinal products metabolised by UGT1A1 are 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 the renal transporter OAT3

In vitro data indicate that letermovir is an inhibitor of OAT3; therefore, letermovir may be an OAT3inhibitor in vivo. Plasma concentrations of medicinal products transported by OAT3 may be increased.

- Examples of medicinal products transported by OAT3 includes ciprofloxacin, tenofovir, imipenem,and cilastin.

General information

If dose adjustments of concomitant medicinal products are made due to treatment with letermovir,doses should be readjusted after treatment with letermovir is completed. A dose adjustment may alsobe needed when changing route of administration or immunosuppressant.

Table 2 provides a listing of established or potentially clinically significant medicinal productinteractions. The medicinal product interactions described are based on adult studies conducted withletermovir or are predicted medicinal product interactions that may occur with letermovir (see sections4.3, pct. 4.4, 5.1, and 5.2).

Table 2: Interactions and dose recommendations with other medicinal products. Note that thetable is not extensive but provides examples of clinically relevant interactions. See also thegeneral text on DDIs above.

Unless otherwise specified, interaction studies have been performed in adults with oralletermovir without cyclosporine. Please note that the interaction potential and clinicalconsequences may be different depending on whether letermovir is administered orally orintravenously, and whether cyclosporine is concomitantly used. When changing the route ofadministration, or if changing immunosuppressant, the recommendation concerning co-administration should be revisited.

Concomitant Effect on concentration† Recommendations concerning co-medicinal product mean ratio (90% confidence administration with letermovirinterval) for AUC, Cmax(likely mechanism of action)

Antibioticsnafcillin Interaction not studied. Nafcillin may decrease plasma

Expected: concentrations of letermovir.↓ letermovir Co-administration of letermovir andnafcillin is not recommended.(P-gp/UGT induction)

Concomitant Effect on concentration† Recommendations concerning co-medicinal product mean ratio (90% confidence administration with letermovirinterval) for AUC, Cmax(likely mechanism of action)

Antifungalsfluconazole ↔ fluconazole No dose adjustment required.(400 mg single AUC 1.03 (0.99, 1.08)dose)/letermovir Cmax 0.95 (0.92, 0.99)(480 mg single dose) ↔ letermovir

AUC 1.11 (1.01, 1.23)

Cmax 1.06 (0.93, 1.21)

Interaction at steady state notstudied.

Expected:↔ fluconazole↔ letermoviritraconazole ↔ itraconazole No dose adjustment required.(200 mg once daily AUC 0.76 (0.71, 0.81)

PO)/letermovir Cmax 0.84 (0.76, 0.92)(480 mg once daily

PO) ↔ letermovir

AUC 1.33 (1.17, 1.51)

Cmax 1.21 (1.05, 1.39)posaconazole‡ ↔ posaconazole No dose adjustment required.(300 mg single AUC 0.98 (0.82, 1.17)dose)/ letermovir Cmax 1.11 (0.95, 1.29)(480 mg daily)voriconazole‡ ↓ voriconazole If concomitant administration is necessary,(200 mg twice AUC 0.56 (0.51, 0.62) TDM for voriconazole is recommendeddaily)/ letermovir Cmax 0.61 (0.53, 0.71) the first 2 weeks after initiating or ending(480 mg daily) letermovir, as well as after changing route(CYP2C9/19 induction) of administration of letermovir orimmunosuppressant.

Antimycobacterialsrifabutin Interaction not studied. Rifabutin may decrease plasma

Expected: concentrations of letermovir.↓ letermovir Co-administration of letermovir andrifabutin is not recommended.(P-gp/UGT induction)rifampicin(600 mg single dose ↔ letermovir

PO)/ letermovir AUC 2.03 (1.84, 2.26)(480 mg single dose Cmax 1.59 (1.46, 1.74)

PO) C24 2.01 (1.59, 2.54)

Multiple dose rifampicin decreases plasma(OATP1B1/3 and/or P-gp concentrations of letermovir.inhibition) Co-administration of letermovir and(600 mg single dose ↔ letermovir rifampicin is not recommended.intravenous)/ AUC 1.58 (1.38, 1.81)letermovir (480 mg Cmax 1.37 (1.16, 1.61)single dose PO) C24 0.78 (0.65, 0.93)(OATP1B1/3 and/or P-gpinhibition)

Concomitant Effect on concentration† Recommendations concerning co-medicinal product mean ratio (90% confidence administration with letermovirinterval) for AUC, Cmax(likely mechanism of action)(600 mg once daily ↓ letermovir

PO)/ letermovir AUC 0.81 (0.67, 0.98)(480 mg once daily Cmax 1.01 (0.79, 1.28)

PO) C24 0.14 (0.11, 0.19)(Sum of OATP1B1/3 and/or

P-gp inhibition and P-gp/UGTinduction)(600 mg once daily ↓ letermovir

PO (24 hours after AUC 0.15 (0.13, 0.17)rifampicin))§/ Cmax 0.27 (0.22, 0.31)letermovir (480 mg C24 0.09(0.06, 0.12)once daily PO)(P-gp/UGT induction)

Antipsychoticsthioridazine Interaction not studied. Thioridazine may decrease plasma

Expected: concentrations of letermovir.↓ letermovir Co-administration of letermovir andthioridazine is not recommended.(P-gp/UGT induction)

Endothelin antagonistsbosentan Interaction not studied. Bosentan may decrease plasma

Expected: concentrations of letermovir.↓ letermovir Co-administration of letermovir andbosentan is not recommended.(P-gp/UGT induction)

Antiviralsacyclovir‡ ↔ acyclovir No dose adjustment required.(400 mg single AUC 1.02 (0.87, 1.2)dose)/ letermovir Cmax 0.82 (0.71, 0.93)(480 mg daily)valacyclovir Interaction not studied. No dose adjustment required.

Expected:↔ valacyclovir

Herbal products

St. John’s wort Interaction not studied. St. John’s wort may decrease plasma(Hypericum Expected: concentrations of letermovir.perforatum) ↓ letermovir Co-administration of letermovir and St.

John’s wort is contraindicated.(P-gp/UGT induction)

HIV medicinal productsefavirenz Interaction not studied. Efavirenz may decrease plasma

Expected: concentrations of letermovir.↓ letermovir Co-administration of letermovir and(P-gp/UGT induction) efavirenz is not recommended.

↑ or ↓ efavirenz(CYP2B6 inhibition orinduction)

Concomitant Effect on concentration† Recommendations concerning co-medicinal product mean ratio (90% confidence administration with letermovirinterval) for AUC, Cmax(likely mechanism of action)etravirine, Interaction not studied. These antivirals may decrease plasmanevirapine, ritonavir, Expected: concentrations of letermovir.lopinavir ↓ letermovir Co-administration of letermovir with theseantivirals is not recommended.(P-gp/UGT induction)

HMG-CoA reductase inhibitorsatorvastatin‡ ↑ atorvastatin Statin-associated adverse events such as(20 mg single dose)/ AUC 3.29 (2.84, 3.82) myopathy should be closely monitored.letermovir (480 mg Cmax 2.17 (1.76, 2.67) The dose of atorvastatin should not exceeddaily) 20 mg daily when co-administered with(CYP3A, OATP1B1/3 letermovir#.inhibition)

Although not studied, when letermovir isco-administered with cyclosporine, themagnitude of the increase in atorvastatinplasma concentrations is expected to begreater than with letermovir alone.

When letermovir is co-administered withcyclosporine, atorvastatin iscontraindicated.

simvastatin, Interaction not studied. Letermovir may substantially increasepitavastatin, Expected: plasma concentrations of these statins.rosuvastatin ↑ HMG-CoA reductase Concomitant use is not recommended withinhibitors letermovir alone.

(CYP3A, OATP1B1/3 When letermovir is co-administered withinhibition) cyclosporine, use of these statins iscontraindicated.fluvastatin, Interaction not studied. Letermovir may increase statin plasmapravastatin Expected: concentrations.

↑ HMG-CoA reductaseinhibitors When letermovir is co-administered withthese statins, a statin dose reduction may(OATP1B1/3 and/or BCRP be necessary#. Statin-associated adverseinhibition) events such as myopathy should be closelymonitored.

When letermovir is co-administered withcyclosporine, pravastatin is notrecommended while for fluvastatin, a dosereduction may be necessary#. Statin-associated adverse events such asmyopathy should be closely monitored.

Concomitant Effect on concentration† Recommendations concerning co-medicinal product mean ratio (90% confidence administration with letermovirinterval) for AUC, Cmax(likely mechanism of action)

Immunosuppressantscyclosporine ↑ cyclosporine If letermovir is co-administered with(50 mg single dose)/ AUC 1.66 (1.51, 1.82) cyclosporine, the dose of letermovirletermovir (240 mg Cmax 1.08 (0.97, 1.19) should be decreased to 240 mg once dailydaily) (CYP3A inhibition) in adults (see sections 4.2 and 5.1) andpaediatric patients weighing at least 30 kgcyclosporine ↑ letermovir (see section 4.2). If intravenous letermovir(200 mg single AUC 2.11 (1.97, 2.26) is co-administered with cyclosporine indose)/ letermovir Cmax 1.48 (1.33, 1.65) paediatric patients weighing less than(240 mg daily) 30 kg, dose adjustment is not required (see(OATP1B1/3 inhibition) section 4.2).

Frequent monitoring of cyclosporinewhole blood concentrations should beperformed during treatment, whenchanging letermovir administration route,and at discontinuation of letermovir andthe dose of cyclosporine adjustedaccordingly#.

mycophenolate ↔mycophenolic acid No dose adjustment required.mofetil AUC 1.08 (0.97, 1.20)(1 g single dose)/ Cmax 0.96 (0.82, 1.12)letermovir (480 mgdaily) ↔ letermovir

AUC 1.18 (1.04, 1.32)

Cmax 1.11 (0.92, 1.34)sirolimus‡ ↑ sirolimus Frequent monitoring of sirolimus whole(2 mg single dose)/ AUC 3.40 (3.01, 3.85) blood concentrations should be performedletermovir (480 mg Cmax 2.76 (2.48, 3.06) during treatment, when changingdaily) letermovir administration route, and at(CYP3A inhibition) discontinuation of letermovir and the doseof sirolimus adjusted accordingly#.

Interaction not studied. Frequent monitoring of sirolimus

Expected: concentrations is recommended at↔ letermovir initiation or discontinuation ofcyclosporine co-administration withletermovir.

When letermovir is co-administered withcyclosporine, also refer to the sirolimusprescribing information for specific dosingrecommendations for use of sirolimus withcyclosporine.

When letermovir is co-administered withcyclosporine, the magnitude of theincrease in concentrations of sirolimusmay be greater than with letermovir alone.

tacrolimus ↑ tacrolimus Frequent monitoring of tacrolimus whole(5 mg single dose)/ AUC 2.42 (2.04, 2.88) blood concentrations should be performedletermovir (480 mg Cmax 1.57 (1.32, 1.86) during treatment, when changingdaily) (CYP3A inhibition) letermovir administration route, and at

Concomitant Effect on concentration† Recommendations concerning co-medicinal product mean ratio (90% confidence administration with letermovirinterval) for AUC, Cmax(likely mechanism of action)tacrolimus discontinuation of letermovir and the dose(5 mg single dose)/ ↔ letermovir of tacrolimus adjusted accordingly#.

letermovir (80 mg AUC 1.02 (0.97, 1.07)twice daily) Cmax 0.92 (0.84, 1.00)

Oral contraceptivesethinylestradiol (EE) ↔ EE No dose adjustment required.(0.03 mg)/ AUC 1.42 (1.32, 1.52)levonorgestrel Cmax 0.89 (0.83, 0.96)(LNG)‡(0.15 mg) single ↔ LNGdose/ letermovir AUC 1.36 (1.30, 1.43)(480 mg daily) Cmax 0.95 (0.86, 1.04)

Other systemically Risk of ↓ contraceptive Letermovir may reduce plasmaacting oral steroids concentrations of other oral contraceptivecontraceptive steroids thereby affecting their efficacy.steroids For adequate contraceptive effect to beensured with an oral contraceptive,products containing EE and LNG shouldbe chosen.

Antidiabetic medicinal productsrepaglinide Interaction not studied. Letermovir may increase or decrease the

Expected: plasma concentrations of repaglinide. (The↑ or ↓ repaglinide net effect is not known).

(CYP2C8 induction, CYP2C8 Concomitant use is not recommended.and OATP1B inhibition)

When letermovir is co-administered withcyclosporine, the plasma concentrations ofrepaglinide is expected to increase due tothe additional OATP1B inhibition bycyclosporine. Concomitant use is notrecommended#.

glyburide Interaction not studied. Letermovir may increase the plasma

Expected: concentrations of glyburide.↑ glyburide

Frequent monitoring of glucose(OATP1B1/3 inhibition concentrations is recommended the first

CYP3A inhibition, CYP2C9 2 weeks after initiating or endinginduction) letermovir, as well as after changing routeof administration of letermovir.

When letermovir is co-administered withcyclosporine, refer also to the glyburideprescribing information for specific dosingrecommendations.

Concomitant Effect on concentration† Recommendations concerning co-medicinal product mean ratio (90% confidence administration with letermovirinterval) for AUC, Cmax(likely mechanism of action)

Antiepileptic medicinal products (see also general text)carbamazepine, Interaction not studied. Carbamazepine or phenobarbital mayphenobarbital Expected: decrease plasma concentrations of↓ letermovir letermovir.

Co-administration of letermovir and(P-gp/UGT induction) carbamazepine or phenobarbital is notrecommended.

phenytoin Interaction not studied. Phenytoin may decrease plasma

Expected: concentrations of letermovir.↓ letermovir

Letermovir may decrease the plasma(P-gp/UGT induction) concentrations of phenytoin.

↓ phenytoin Co-administration of letermovir andphenytoin is not recommended.

(CYP2C9/19 induction)

Oral anticoagulantswarfarin Interaction not studied. Letermovir may decrease the plasma

Expected: concentrations of warfarin.↓ warfarin

Frequent monitoring of International(CYP2C9 induction) Normalised Ratio (INR) should beperformed when warfarin is co-administered with letermovir treatment#.

Monitoring is recommended the first2 weeks after initiating or endingletermovir, as well as after changing routeof administration of letermovir orimmunosuppressant.

dabigatran Interaction not studied. Letermovir may decrease the plasma

Expected: concentrations of dabigatran and may↓ dabigatran decrease efficacy of dabigatran.

Concomitant use of dabigatran should be(intestinal P-gp induction) avoided due to the risk of reduceddabigatran efficacy.

When letermovir is co-administered withcyclosporine, dabigatran iscontraindicated.

Sedativesmidazolam ↑ midazolam Close clinical monitoring for respiratory(1 mg single dose Intravenous: depression and/or prolonged sedationintravenous)/ AUC 1.47 (1.37, 1.58) should be exercised during co-letermovir (240 mg Cmax 1.05 (0.94, 1.17) administration of letermovir withonce daily PO) midazolam. Dose adjustment of

PO: midazolam should be considered#. Themidazolam (2 mg AUC 2.25 (2.04, 2.48) increase in midazolam plasmasingle dose PO)/Cmax 1.72 (1.55, 1.92) concentration may be greater when oralletermovir (240 mg midazolam is administered with letermovironce daily PO) (CYP3A inhibition) at the clinical dose than with the dosestudied.

Concomitant Effect on concentration† Recommendations concerning co-medicinal product mean ratio (90% confidence administration with letermovirinterval) for AUC, Cmax(likely mechanism of action)

Opioid agonists

Examples: alfentanil, Interaction not studied. Frequent monitoring for adverse reactionsfentanyl Expected: related to these medicinal products is↑ CYP3A metabolised opioids recommended during co-administration.

Dose adjustment of CYP3A metabolised(CYP3A inhibition) opioids may be needed# (see section 4.4).

Monitoring is also recommended ifchanging route of administration. Whenletermovir is co-administered withcyclosporine, the magnitude of theincrease in plasma concentrations of

CYP3A metabolised opioids may begreater. Close clinical monitoring forrespiratory depression and/or prolongedsedation should be exercised during co-administration of letermovir incombination with cyclosporine andalfentanil or fentanyl. Refer to therespective prescribing information (seesection 4.4).

Anti-arrhythmic medicinal productsamiodarone Interaction not studied. Letermovir may increase the plasma

Expected: concentrations of amiodarone.↑ amiodarone

Frequent monitoring for adverse reactions(primarily CYP3A inhibition related to amiodarone is recommendedand CYP2C8 inhibition or during co-administration. Monitoring ofinduction) amiodarone concentrations should beperformed regularly when amiodarone isco-administered with letermovir#.

quinidine Interaction not studied. Letermovir may increase the plasma

Expected: concentrations of quinidine.↑ quinidine

Close clinical monitoring should be(CYP3A inhibition) exercised during administration ofletermovir with quinidine. Refer to therespective prescribing information#.

Cardiovascular medicinal productsdigoxin‡ ↔ digoxin No dose adjustment required.(0.5 mg single dose)/ AUC 0.88 (0.80, 0.96)letermovir (240 mg Cmax 0.75 (0.63, 0.89)twice daily)(P-gp induction)

Concomitant Effect on concentration† Recommendations concerning co-medicinal product mean ratio (90% confidence administration with letermovirinterval) for AUC, Cmax(likely mechanism of action)

Proton pump inhibitorsomeprazole Interaction not studied. Letermovir may decrease the plasma

Expected: concentrations of CYP2C19 substrates.

↓omeprazole

Clinical monitoring and dose adjustment(induction of CYP2C19) may be needed.

Interaction not studied.

Expected:↔ letermovirpantoprazole Interaction not studied. Letermovir may decrease the plasma

Expected: concentrations of CYP2C19 substrates.↓ pantoprazole

Clinical monitoring and dose adjustment(likely due to induction of may be needed.

CYP2C19)

Interaction not studied.

Expected:↔ letermovir

Wakefulness-promoting agentsmodafinil Interaction not studied. Modafinil may decrease plasma

Expected: concentrations of letermovir.↓ letermovir Co-administration of letermovir andmodafinil is not recommended.(P-gp/UGT induction)

* This table is not all inclusive.† ↓ =decrease, ↑ =increase↔ =no clinically relevant change‡ One-way interaction study assessing the effect of letermovir on the concomitant medicinalproduct.§ These data are the effect of rifampicin on letermovir 24 hours after final rifampicin dose.# Refer to the respective prescribing information.

Interaction studies have only been performed in adults.

There are no data from the use of letermovir in pregnant women. Studies in animals have shownreproductive toxicity (see section 5.3).

Letermovir is not recommended during pregnancy and in women of childbearing potential not usingcontraception.

It is unknown whether letermovir is excreted in human milk. Availablepharmacodynamic/toxicological data in animals have shown excretion of letermovir in milk (seesection 5.3). A risk to the newborns/infants cannot be excluded. A decision must be made whether todiscontinue breast-feeding or to discontinue/abstain from letermovir therapy taking into account thebenefit of breast-feeding for the child and the benefit of therapy for the woman.

There were no effects on female fertility in rats. Irreversible testicular toxicity and impairment offertility was observed in male rats, but not in male mice or male monkeys (see section 5.3).

Letermovir may have minor influence on the ability to drive or use machines. Fatigue and vertigo havebeen reported in some patients during treatment with letermovir, which may influence a patient’sability to drive and use machines (see section 4.8).

The safety assessment of letermovir was based on three Phase 3 clinical trials.

HSCT

In P001, 565 adult HSCT recipients received letermovir or placebo through Week 14 post-transplantand were followed for safety through Week 24 post-transplant (see section 5.1). The most commonlyreported adverse reactions occurring in at least 1% of subjects in the letermovir group and at afrequency greater than placebo were: nausea (7.2%), diarrhoea (2.4%), and vomiting (1.9%). The mostfrequently reported adverse reactions that led to discontinuation of letermovir were: nausea (1.6%),vomiting (0.8%), and abdominal pain (0.5%).

In P040, 218 adult HSCT recipients received letermovir or placebo from Week 14 (~100 days)through Week 28 (~200 days) post-HSCT and were followed for safety through Week 48 post-HSCT(see section 5.1). The adverse reactions reported were consistent with the safety profile of letermoviras characterised in study P001.

Kidney transplant

In P002, 292 adult kidney transplant recipients received letermovir through Week 28 (~200 days) post-transplant (see section 5.1).

The following adverse reactions were identified in adult patients taking letermovir in clinical trials.

The adverse reactions are listed below by body system organ class and frequency. Frequencies aredefined 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 3: Adverse reactions identified with letermovir

Frequency Adverse reactions

Uncommon hypersensitivity

Uncommon decreased appetite

Uncommon dysgeusia, headache

Ear and labyrinth disorders

Uncommon vertigo

Common nausea, diarrhoea, vomiting

Uncommon abdominal pain

Uncommon alanine aminotransferase increased, aspartateaminotransferase increased

Uncommon muscle spasms

Uncommon blood creatinine increased

Uncommon fatigue, oedema peripheral

The safety assessment of letermovir in paediatric patients from birth up to 18 years old was based on a

Phase 2b clinical trial (P030). In P030, 63 HSCT recipients were treated with letermovir through

Week 14 post-HSCT. Their age distribution was as follows, i.e., 28 adolescents, 14 children aged 7 toless than 12 years, 13 aged 2 to less than 7 years, and 8 less than 2 years old (5 of them less than1 year old). The adverse reactions were consistent with those observed in clinical studies of letermovirin adults.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no experience with human overdose with letermovir. During Phase 1 clinical trials, 86 healthyadult subjects received doses ranging from 720 mg/day to 1 440 mg/day of letermovir for up to 14days. The adverse reaction profile was similar to that of the clinical dose of 480 mg/day. There is nospecific antidote for overdose with letermovir. In case of overdose, it is recommended that the patientbe monitored for adverse reactions and appropriate symptomatic treatment instituted.

It is unknown whether dialysis will result in meaningful removal of letermovir from systemiccirculation.

Pharmacotherapeutic group: Antivirals for systemic use, direct acting antivirals, ATC code: J05AX18

Letermovir inhibits the CMV DNA terminase complex which is required for cleavage and packagingof viral progeny DNA. Letermovir affects the formation of proper unit length genomes and interfereswith virion maturation.

The median EC50 value of letermovir against a collection of clinical CMV isolates in a cell culturemodel of infection was 2.1 nM (range=0.7 nM to 6.1 nM, n=74).

Viral resistance

The CMV genes UL51, UL56, and UL89 encode subunits of CMV DNA terminase. CMV mutantswith reduced susceptibility to letermovir have been confirmed in cell culture. EC50 values forrecombinant CMV mutants expressing the substitutions map to 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- to < 10-fold higher thanthose for wild-type reference virus; these substitutions are not likely to be clinically relevant. EC50values 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- to 9 300-fold higher than those for the wild-type reference virus;some of these substitutions have been observed in patients who have experienced prophylaxis failurein clinical trials (see below).

In clinical trials

In a Phase 2b trial evaluating letermovir doses of 60, 120, or 240 mg/day or placebo for up to 84 daysin 131 adult HSCT recipients, DNA sequence analysis of a select region of UL56 (amino acids 231 to369) was performed on samples obtained from 12 letermovir-treated subjects who experiencedprophylaxis failure and for whom samples were available for analysis. One subject (who received60 mg/day) had a letermovir resistant genotypic variant (GV) (V236M).

In a Phase 3 trial (P001), DNA sequence analysis of the entire coding regions of UL56 and UL89 wasperformed on samples obtained from 40 letermovir-treated adult subjects in the FAS population whoexperienced prophylaxis failure and for whom samples were available for analysis. Two subjects hadletermovir resistant GVs detected, both with substitutions mapping to pUL56. One subject had thesubstitution V236M and the other subject had the substitution E237G. One additional subject, who haddetectable CMV DNA at baseline (and was therefore not in the FAS population), had pUL56substitutions, C325W and R369T, detected after discontinuing letermovir.

In a Phase 3 trial (P040), DNA sequence analysis of the entire coding regions of UL51, UL56 and

UL89 was performed on samples obtained from 32 adult subjects (regardless of treatment group) whoexperienced prophylaxis failure or who discontinued early with CMV viremia. There were noletermovir resistance-associated substitutions detected above the validated assay limit of 5%.

In a Phase 3 trial (P002), DNA sequence analysis of the entire coding regions of UL51, UL56 and

UL89 was performed on samples obtained from 52 letermovir-treated adult subjects who experienced

CMV disease or who discontinued early with CMV viremia. There were no letermovir resistance-associated substitutions detected above the validated assay limit of 5%.

In a Phase 2b trial (P030), DNA sequence analysis of the entire coding regions of UL51, UL56 and

UL89 was performed on samples obtained from 10 letermovir-treated paediatric subjects at a visit forevaluation of CMV infection. A total of 2 letermovir resistance-associated substitutions both mappingto pUL56 were detected in 2 subjects. One subject had the substitution R369S and the other subjecthad the substitution C325W.

Cross-resistance is not likely with medicinal products with a different mechanism of action.

Letermovir is fully active against viral populations with substitutions conferring resistance to CMV

DNA polymerase inhibitors (ganciclovir, cidofovir, and foscarnet). A panel of recombinant CMVstrains with substitutions conferring resistance to letermovir was fully susceptible to cidofovir,foscarnet and ganciclovir with the exception of a recombinant strain with the pUL56 E237Gsubstitution which confers a 2.1-fold reduction in ganciclovir susceptibility relative to wild-type.

The effect of letermovir on doses up to 960 mg given intravenously on the QTc interval was evaluatedin a randomised, single-dose, placebo- and active-controlled (moxifloxacin 400 mg oral) 4-periodcrossover thorough QT trial in 38 healthy adult subjects. Letermovir does not prolong QTc to anyclinically relevant extent following the 960 mg intravenous dose with plasma concentrationsapproximately 2-fold higher than the 480 mg intravenous dose.

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

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

To evaluate letermovir prophylaxis as a preventive strategy for CMV infection or disease, the efficacyof letermovir was assessed in a multicentre, double-blind, placebo-controlled Phase 3 trial (P001) inadult CMV-seropositive recipients [R+] of an allogeneic HSCT. Subjects were randomised (2:1) toreceive either letermovir at a dose of 480 mg once daily adjusted to 240 mg when co-administeredwith cyclosporine, or placebo. Randomisation was stratified by investigational site and risk (high vs.low) for CMV reactivation at the time of study entry. Letermovir was initiated after HSCT (Day 0-28post-HSCT) and continued through Week 14 post-HSCT. Letermovir was administered either orally orintravenously; the dose of letermovir was the same regardless of the route of administration. Subjectswere monitored through Week 24 post-HSCT for the primary efficacy endpoint with continuedfollow-up through Week 48 post-HSCT.

Subjects received CMV DNA monitoring weekly until post-HSCT week 14 and then every two weeksuntil post-HSCT week 24, with initiation of standard-of-care CMV pre-emptive therapy if CMV

DNAemia was considered clinically significant. Subjects had continued follow-up through Week 48post-HSCT.

Among the 565 treated subjects, 373 subjects received letermovir (including 99 subjects who receivedat least one intravenous dose) and 192 received placebo (including 48 subjects who received at leastone intravenous dose). The median time to starting letermovir was 9 days after transplantation. Thirty-seven percent (37%) of subjects were engrafted at baseline. The median age was 54 years (range: 18 to78 years); 56 (15.0%) subjects were 65 years of age or older: 58% were male; 82% were White; 10%were Asian; 2% were Black or African; and 7% were Hispanic or Latino. At baseline, 50% of subjectsreceived a myeloablative regimen, 52% were receiving cyclosporine, and 42% were receivingtacrolimus. The most common primary reasons for transplant were acute myeloid leukaemia (38%),myeloblastic syndrome (15%), and lymphoma (13%). Twelve percent (12%) of subjects were positivefor CMV DNA at baseline.

At baseline, 31% of subjects were at high risk for reactivation as defined by one or more of thefollowing criteria: Human Leucocyte Antigen (HLA)-related (sibling) donor with at least onemismatch at one of the following three HLA-gene loci: HLA-A, -B or -DR, haploidentical donor;unrelated donor with at least one mismatch at one of the following four HLA-gene loci: HLA-A, -B, -

C and -DRB1; use of umbilical cord blood as stem cell source; use of ex vivo T-cell-depleted grafts;

Grade 2 or greater Graft-Versus-Host Disease (GVHD), requiring systemic corticosteroids.

Primary efficacy endpoint

The primary efficacy endpoint of clinically significant CMV infection in P001 was defined by theincidence of CMV DNAemia warranting anti-CMV pre-emptive therapy (PET) or the occurrence of

CMV end-organ disease. The Non-Completer=Failure (NC=F) approach was used, where subjectswho discontinued from the study prior to Week 24 post-HSCT or had a missing outcome at Week 24post-HSCT were counted as failures.

Letermovir demonstrated superior efficacy over placebo in the analysis of the primary endpoint, asshown in Table 4. The estimated treatment difference of -23.5% was statistically significant (one-sidedp-value < 0.0001).

Table 4: P001: Efficacy results in HSCT recipients (NC=F Approach, FAS Population)

Letermovir Placebo(N=325) (N=170)

Parameter n (%) n (%)

Primary efficacy endpoint 122 (37.5) 1 0 3 ( 6 0 . 6 )(Proportion of subjects who failed prophylaxis by

Week 24)

Reasons for Failures†

Clinically significant CMV infection 57 (17.5) 7 1 ( 4 1 . 8 )

CMV DNAemia warranting anti-CMV PET 52 (16.0) 6 8 ( 4 0 . 0 )

CMV end-organ disease 5 ( 1 . 5 ) 3 ( 1 . 8 )

Discontinued from study 56 (17.2) 2 7 ( 1 5 . 9 )

Missing outcome 9 (2.8) 5 (2.9)

Stratum-adjusted treatment difference (Letermovir-

Placebo)§

Difference (95% CI) - 2 3 .5 (-32.5, -14.6)p-value < 0.0001† The categories of failure are mutually exclusive and based on the hierarchy of categories in theorder listed.§ 95% CIs and p-value for the treatment differences in percent response were calculated usingstratum-adjusted Mantel-Haenszel method with the difference weighted by the harmonic mean ofsample size per arm for each stratum (high or low risk). A 1-sided p-value ≤0.0249 was used fordeclaring statistical significance.

FAS=Full analysis set; FAS includes randomised subjects who received at least one dose of studymedicine, and excludes subjects with detectable CMV DNA at baseline. Approach to handlingmissing values: Non-Completer=Failure (NC=F) approach. With NC=F approach, failure was definedas all subjects with clinically significant CMV infection or who prematurely discontinued from thestudy or had a missing outcome through Week 24 post-HSCT visit window.

N=number of subjects in each treatment group.n (%)=Number (percent) of subjects in each sub-category.

Note: The proportion of subjects with detectable CMV viral DNA on Day 1 that developed clinicallysignificant CMV infection in the letermovir group was 64.6% (31/48) compared to 90.9% (20/22) inthe placebo group through Week 24 post-HSCT. The estimated difference (95% CI for the 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 among letermovir-treated subjectsincluded high risk for CMV reactivation at baseline, GVHD, use of corticosteroids, and CMV negativedonor serostatus.

Figure 1: P001: Kaplan-Meier plot of time to initiation of anti-CMV PET or onset of CMV end-organ disease through Week 24 post-transplant in HSCT recipients (FAS population)

Letermovir vs Placebo50 Stratified log-rank test, two-sided p-value <0.000144.3%41.3% Placebo18.9%

Letermovir10 6.8%

Week 0 Week 14 Week 24

Weeks Post-Transplant

Number of Subjects at Risk

Letermovir 325 270 212

Placebo 170 85 70

There were no differences in the incidence of or time to engraftment between the letermovir andplacebo groups.

Efficacy consistently favoured letermovir across subgroups including low and high risk for CMVreactivation, conditioning regimens, and concomitant immunosuppressive regimens (see Figure 2).

Cumulative proportion of subjectswith CMV DNAemia or disease (%)

Figure 2: P001: Forest plot of the proportion of subjects initiating anti-CMV PET or with CMVend-organ disease through Week 24 post-HSCT by selected subgroups (NC=F approach, FASpopulation)

Overall (N=325, 170)

Risk stratum

High Risk (n=102, 45)

Low Risk (n=223, 125)

Stem Cell Source

Peripheral blood (n=241, 117)

Bone marrow (n=72, 43)

Donor mismatch

Matched related (n=108, 58)

Mismatched related (n=52, 18)

Matched unrelated (n=122, 70)

Mismatched unrelated (n=43, 24)

Haploidentical donor

Yes (n=49, 17)

No (n=276, 153)

Conditioning Regimen

Myeloablative (n=154, 85)

Reduced intensity conditioning (n=86, 48)

Non-myeloablative (n=85, 37)

Immunosuppressive Regimen

Cyclosporin A (n=162, 90)

Tacrolimus (n=145, 69)

- 70 -60 -50 -40 -30 -20 -10 0 10 20

Favors Letermovir Favors Placebo

Letermovir - Placebo Difference (%) and 95% C.I.

NC=F, Non-Completer=Failure. With NC=F approach, subjects who discontinued from the study prior to Week 24 post-transplant or had amissing outcome at Week 24 post-transplant were counted as failures.

P040: Prophylaxis from Week 14 (~100 days) through Week 28 (~200 days) post-HSCT

The efficacy of extending letermovir prophylaxis from Week 14 (~100 days) through Week 28(~200 days) post-HSCT in patients at risk for late CMV infection and disease was assessed in amulticentre, double-blind, placebo-controlled Phase 3 trial (P040) in adult CMV-seropositiverecipients [R+] of an allogeneic HSCT. Eligible subjects who completed letermovir prophylaxisthrough ~100 days post-HSCT were randomised (2:1) to receive letermovir or placebo from Week 14through Week 28 post-HSCT. Subjects were monitored through Week 28 post-HSCT for the primaryefficacy endpoint with continued off-treatment follow-up through Week 48 post-HSCT.

Among the 218 treated subjects, 144 subjects received letermovir and 74 received placebo. Themedian age was 55 years (range: 20 to 74 years); 62% were male; 79% were white; 11% were Asian;2% were Black; and 10% were Hispanic or Latino. The most common reasons for transplant wereacute myeloid leukaemia (42%), acute lymphocytic leukaemia (15%), and myelodysplastic syndrome(11%).

At study entry, all subjects had risk factors for late CMV infection and disease, with 64% having twoor more risk factors. The risk factors included: HLA-related (sibling) donor with at least one mismatchat one of the following three HLA-gene loci: HLA-A, -B or -DR; haploidentical donor; unrelateddonor with at least one mismatch at one of the following four HLA-gene loci: HLA-A, -B, -Cand -DRB1; use of umbilical cord blood as stem cell source; use of ex vivo T-cell-depleted grafts;receipt of anti-thymocyte globulin; receipt of alemtuzumab; use of systemic prednisone (or equivalent)at a dose of ≥ 1 mg/kg of body weight per day.

Primary efficacy endpoint

The primary efficacy endpoint of P040 was the incidence of clinically significant CMV infectionthrough Week 28 post-HSCT. Clinically significant CMV infection was defined as the occurrence ofeither CMV end-organ disease, or initiation of anti-CMV PET based on documented CMV viremiaand the clinical condition of the subject. The Observed Failure (OF) approach was used, wheresubjects who developed clinically significant CMV infection or discontinued prematurely from thestudy with viremia were counted as failures.

Letermovir demonstrated superior efficacy over placebo in the analysis of the primary endpoint, asshown in Table 5. The estimated treatment difference of -16.1% was statistically significant (one-sidedp-value=0.0005). Efficacy consistently favored letermovir across subgroups based on subjectcharacteristics (age, gender, race) and risk factors for late CMV infection and disease.

Table 5: P040: Efficacy results in HSCT recipients at risk for late CMV infection and disease(OF approach, FAS population)

Letermovir Placebo(~200 days (~100 days

Parameter letermovir) letermovir)(N=144) (N=74)n (%) n (%)

Failures* 4 (2.8) 14 (18.9)

Clinically significant CMV infection through 2 (1.4) 13 (17.6)

Week 28†

Initiation of PET based on documented 1 (0.7) 11 (14.9)

CMV viremia

CMV end-organ disease 1 (0.7) 2 (2.7)

Discontinued from study with CMV viremia 2 (1.4) 1 (1.4)before Week 28

Stratum-adjusted treatment difference(letermovir (~200 days letermovir)-Placebo(~100 days letermovir))‡

Difference (95% CI) -16.1 (-25.8, -6.5)p-value 0.0005

* The categories of failure are mutually exclusive and based on the hierarchy of categories in theorder listed.

† Clinically significant CMV infection was defined as CMV end-organ disease (proven or probable)or initiation of PET based on documented CMV viremia and the clinical condition of the subject.

‡ 95% CIs and p-value for the treatment differences in percent response were calculated usingstratum-adjusted Mantel-Haenszel method with the difference weighted by the harmonic mean ofsample size per arm for each stratum (haploidentical donor yes or no). A one-sided p-value ≤0.0249was used for declaring statistical significance.

Approach to handling missing values: Observed Failure (OF) approach. With the OF approach,failure was defined as all subjects who developed clinically significant CMV infection ordiscontinued prematurely from the study with CMV viremia from Week 14 (~100 days) through

Week 28 (~200 days) post-HSCT.

N=Number of subjects in each treatment group.n (%)=Number (percent) of subjects in each sub-category.

P002: Adult CMV-seronegative recipients of a kidney transplant from a CMV-seropositive donor[D+/R-]

To evaluate letermovir prophylaxis as a preventive strategy for CMV disease in kidney transplantrecipients, the efficacy of letermovir was assessed in a multicentre, double-blind, active comparator-controlled non-inferiority Phase 3 trial (P002) in adult kidney transplant recipients at high risk[D+/R-]. Subjects were randomised (1:1) to receive either letermovir or valganciclovir. Letermovirwas given concomitantly with acyclovir. Valganciclovir was given concomitantly with a placebo toacyclovir. Randomisation was stratified by the use or non-use of highly cytolytic, anti-lymphocyteimmunotherapy during induction. Letermovir or valganciclovir were initiated between Day 0 and Day7 post-kidney transplant and continued through Week 28 (~200 days) post-transplant. Subjects weremonitored through Week 52 post-transplant.

Among the 589 treated subjects, 292 subjects received letermovir and 297 received valganciclovir. Themedian age was 51 years (range: 18 to 82 years); 72% were male; 84% were White; 2% were Asian;9% were Black; 17% were Hispanic or Latino; and 60% received a kidney from a deceased donor. Themost common primary reasons for transplant were congenital cystic 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

CMV syndrome, confirmed by an independent adjudication committee) through Week 52 post-transplant. The OF approach was used, where subjects who discontinued prematurely from the studyfor any reason or were missing data at the timepoint were not considered failures.

Letermovir demonstrated non-inferiority to valganciclovir in the analysis of the primary endpoint, asshown in Table 6.

Table 6: P002: Efficacy results in kidney transplant recipients (OF approach, FAS population)

Letermovir Valganciclovir

Parameter (N=289) (N=297)n (%) n (%)

CMV disease* through Week 52 30 (10.4) 35 (11.8)

Stratum-adjusted treatment difference(Letermovir-Valganciclovir)†

Difference (95% CI) -1.4 (-6.5, 3.8)‡

* CMV disease cases confirmed by an independent adjudication committee.† The 95% CIs for the treatment differences in percent response were calculated using stratum-adjusted Mantel-Haenszel method with the difference weighted by the harmonic mean of sample sizeper arm for each stratum (use/non-use of highly cytolytic, anti-lymphocyte immunotherapy duringinduction).‡ Based on a non-inferiority margin of 10%, letermovir is non-inferior to valganciclovir.

Approach to handling missing values: Observed Failure (OF) approach. With OF approach,participants who discontinue prematurely from the study for any reason are not considered failures.

Note: Subjects randomised to the letermovir group were given acyclovir for herpes simplex virus(HSV) and varicella zoster virus (VZV) prophylaxis. Subjects randomised to the valganciclovir groupwere given a placebo to acyclovir.

N=number of subjects in each treatment group.n (%)=Number (percent) of subjects in each sub-category.

Efficacy was comparable across all subgroups, including sex, age, race, region, and the use/non-use ofhighly cytolytic, anti-lymphocyte immunotherapy during induction.

P030: Paediatric recipients of an allogeneic hematopoietic stem cell transplant

To evaluate letermovir prophylaxis as a preventive strategy for CMV infection or disease in paediatrictransplant recipients, the efficacy of letermovir was assessed in a multicentre, open-label, single-arm

Phase 2b trial (P030) in paediatric recipients of an allogeneic HSCT. Study drug was initiated after

HSCT (Day 0-28 post-HSCT) and continued through Week 14 post-HSCT. Study drug wasadministered either orally or intravenously; the dose of letermovir was based on age, body weight andformulation.

Among the 63 treated subjects, 8 were 0 to less than 2 years of age, 27 were 2 to less than 12 years ofage and 28 were 12 to less than 18 years of age. At baseline, 87% of subjects received a myeloablativeregimen, 67% were receiving cyclosporine, and 27% were receiving tacrolimus. The most commonprimary reasons for transplant were acute myeloid leukaemia (18%) and aplastic anaemia (10%) in theoverall population, and combined immunodeficiency (37.5%) and familial haemophagocyticlymphohistiocytosis (25.0%) in children less than 2 years of age.

Secondary efficacy endpoint

The efficacy endpoints of P030 were secondary and included the incidence of clinically significant

CMV infection through Week 14 post-HSCT and through Week 24 post-HSCT. Clinically significant

CMV infection was defined as the occurrence of either CMV end-organ disease, or initiation of anti-

CMV PET based on documented CMV viremia and the clinical condition of the subject. The incidenceof clinically significant CMV infection was 7.1% and 10.7% through Week 14 post-HSCT and

Week 24 post-HSCT, respectively.

In healthy adult subjects, the pharmacokinetics of letermovir have been characterised following oraland intravenous administration. Letermovir exposure increased in a greater than dose-proportionalmanner with both oral or intravenous administration. The mechanism is likelysaturation/autoinhibition of OATP1B1/3. The pharmacokinetics of letermovir have also beencharacterised following oral and intravenous administration in adult HSCT recipients (see Table 7) andpaediatric HSCT recipients (see Table 9 and Table 10) and following oral administration in adultkidney transplant recipients (see Table 8).

Healthy adult subjects

The geometric mean steady-state AUC and Cmax values were 71 500 ng*hr/mL and 13 000 ng/mL,respectively, with 480 mg once daily oral letermovir.

Letermovir reached steady-state in 9 to 10 days with an accumulation ratio of 1.2 for AUC and 1.0 for

Cmax.

Adult HSCT recipients

Letermovir AUC was estimated using population pharmacokinetic analyses using P001 Phase 3 data(see Table 7). Differences in exposure across treatment regimens are not clinically relevant; efficacywas consistent across the range of exposures observed in P001.

Table 7: Letermovir AUC (ng*hr/mL) values in adult HSCT Recipients

Treatment Regimen Median (90% Prediction Interval)*480 mg Oral, no cyclosporine 34 400 (16 900, 73 700)480 mg intravenous, no cyclosporine 100 000 (65 300, 148 000)240 mg Oral, with cyclosporine 60 800 (28 700, 122 000)240 mg intravenous, with cyclosporine 70 300 (46 200, 106 000)

* Population post-hoc predictions from the population PK analysis using Phase 3 data

Adult kidney transplant recipients

Letermovir AUC was estimated using population pharmacokinetic analysis using P002 Phase 3 data(see Table 8). Efficacy was consistent across the range of exposures observed in P002.

Table 8: Letermovir AUC (ng*hr/mL) values in adult kidney transplant recipients

Treatment Regimen Median (90% Prediction Interval)*480 mg Oral, no cyclosporine 62 200 (28 900, 145 000)240 mg Oral, with cyclosporine 57 700 (26 900, 135 000)

* Medians and 90% prediction intervals are based on simulations using the Phase 3 population PKmodel with inter-individual variability.

Note: PK of letermovir was not studied following intravenous administration in kidney transplantrecipients; however, the projected AUC following intravenous administration is similar to the modelpredicted AUC following intravenous administration in HSCT recipients (see Table 7).

In healthy adult subjects, letermovir was absorbed rapidly with a median time to maximum plasmaconcentration (Tmax) of 1.5 to 3.0 hours and declined in a biphasic manner. In adult HSCT recipients,bioavailability of letermovir was estimated to be approximately 35% with 480 mg once daily oralletermovir administered without cyclosporine. The inter-individual variability for bioavailability wasestimated to be approximately 37%. In adult kidney transplant recipients, bioavailability of letermovirwas estimated to be approximately 60% with 480 mg once daily oral letermovir administered withoutcyclosporine.

Effect of cyclosporine

In adult HSCT recipients, co-administration of cyclosporine increased plasma concentrations ofletermovir due to inhibition of OATP1B. Bioavailability of letermovir was estimated to beapproximately 85% with 240 mg once daily oral letermovir co-administered with cyclosporine inpatients.

If letermovir is co-administered with cyclosporine, the recommended dose of letermovir is 240 mgonce daily in adult and paediatric patients weighing at least 30 kg (see section 4.2). If intravenousletermovir is co-administered with cyclosporine in paediatric patients weighing less than 30 kg, doseadjustment is not required (see section 4.2).

In healthy adult subjects, oral administration of 480 mg single dose of letermovir tablet with a standardhigh fat and high calorie meal did not have any effect on the overall exposure (AUC) and resulted inapproximately 30% increase in peak levels (Cmax) of letermovir. Letermovir tablets may beadministered orally with or without food as has been done in the clinical trials (see section 4.2).

In healthy adult subjects, oral administration of 240 mg single dose of letermovir granules with softfoods (pudding or applesauce) resulted in an approximately 13% and 20% increase in overall exposure(AUC) and resulted in approximately 25% and 33% increase in peak levels (Cmax) of letermovir.

Letermovir granules may be administered with soft foods, as has been done in the paediatric trial (seesection 4.2).

Based on population pharmacokinetic analyses, the mean steady-state volume of distribution isestimated to be 45.5 L following intravenous administration in adult HSCT recipients.

Letermovir is extensively bound (98.2%) to human plasma proteins, independent of the concentrationrange (3 to 100 mg/L) evaluated, in vitro. Some saturation was observed at lower concentrations.

Blood to plasma partitioning of letermovir is 0.56 and independent of the concentration range (0.1 to10 mg/L) evaluated in vitro.

In preclinical distribution studies, letermovir is distributed to organs and tissues with the highestconcentrations observed in the gastrointestinal tract, bile duct and liver and low concentrations in thebrain.

The majority of letermovir-related components in plasma is unchanged parent (96.6%). No majormetabolites are detected in plasma. Letermovir is partly eliminated by glucuronidation mediated by

UGT1A1/1A3.

The mean apparent terminal half-life for letermovir is approximately 12 hours with 480 mgintravenous letermovir in healthy adult subjects. The major elimination pathways of letermovir isbiliary excretion as well as direct glucuronidation. The process involves the hepatic uptaketransporters OATP1B1 and 3 followed by UGT1A1/3 catalysed glucuronidation.

Based on population pharmacokinetic analyses, letermovir steady-state apparent CL is estimated to be4.84 L/hr following intravenous administration of 480 mg in adult HSCT recipients. The inter-individual variability for CL is estimated to be 24.6%.

Excretion

After oral administration of radio-labeled letermovir, 93.3% of radioactivity was recovered in faeces.

The majority of letermovir was biliary excreted as unchanged parent with a minor amount (6% ofdose) as an acyl-glucuronide metabolite in faeces. The acyl-glucuronide is unstable in faeces. Urinaryexcretion of letermovir was negligible (< 2% of dose).

Letermovir unbound AUC was approximately 81%- and 4-fold higher in adult subjects with moderate(Child-Pugh Class B [CP-B], score of 7-9) and severe (Child-Pugh Class C [CP-C], score of 10-15)hepatic impairment, respectively, compared to healthy adult subjects. The changes in letermovirexposure in adult subjects with moderate hepatic impairment are not clinically relevant.

Marked increases in letermovir unbound exposure are anticipated in patients with moderate hepaticimpairment combined with moderate or severe renal impairment (see section 4.2).

Clinical study in a renally impaired population

Letermovir unbound AUC was approximately 115- and 81% higher in adult subjects with moderate(eGFR of 31.0 to 56.8 mL/min/1.73m2) and severe (eGFR of 11.9 to 28.1 mL/min/1.73m2) renalimpairment, respectively, compared to healthy adult subjects. The changes in letermovir exposure dueto moderate or severe renal impairment are not considered to be clinically relevant. Subjects with

ESRD have not been studied.

Post-kidney transplant (P002)

Based on population pharmacokinetic analysis, letermovir AUC was approximately 12%, 27% and35% higher in adult subjects with mild (CrCl greater than or equal to 60 to less than 90 mL/min),moderate (CrCl greater than or equal to 30 to less than 60 mL/min) and severe (CrCl greater than orequal to 15 to less than 30 mL/min) renal impairment, respectively, compared to adult subjects with

CrCl greater than or equal to 90 mL/min. These changes are not considered to be clinically relevant.

Weight

Based on population pharmacokinetic analyses in healthy adult subjects, letermovir AUC is estimatedto be 18.7% lower in subjects weighing 80-100 kg compared to subjects weighing 67 kg. Based onpopulation pharmacokinetic analysis in adult kidney transplant recipients (P002), letermovir AUC isestimated to be 26% lower in subjects weighing greater than 80 kg compared to subjects weighing lessthan or equal to 80 kg. These differences are not clinically relevant.

Based on population pharmacokinetic analyses in healthy adult subjects, letermovir AUC is estimatedto be 33.2% higher in Asians compared to Whites. This change is not clinically relevant.

Based on population pharmacokinetic analyses, there is no difference in letermovir pharmacokineticsin adult females compared to males.

Based on population pharmacokinetic analyses, there is no effect of age on letermovirpharmacokinetics. No dose adjustment is required based on age.

Letermovir AUC in paediatric HSCT recipients was estimated via population pharmacokineticanalysis using observed PK data from study P030 (see Table 9 and Table 10). Exposures for paediatric

HSCT recipients across body weight bands are within the range of exposures achieved in the adult

HSCT reference exposures (see Table 7).

Table 9: Letermovir AUC (ng*hr/mL) values following oral administration in paediatric HSCTrecipients

Median Oral dose, Median

Oral dose,

Body weight no cyclosporine (90% prediction with (90% predictioninterval)* cyclosporine interval)*39 100 49 10030 kg and above 480 mg 240 mg(18 700-81 300) (23 200-104 000)15 kg to less than 38 900 51 000240 mg 120 mg30 kg (20 200-74 300) (26 600-98 200)7.5 kg to less than 32 000 41 600120 mg 60 mg15 kg (16 700-59 300) (22 300-81 100)5 kg to less than 30 600 39 00080 mg 40 mg7.5 kg (16 200-55 000) (20 600-72 000)

* Medians and 90% prediction intervals are based on simulations using the paediatric HSCTpopulation PK model with inter-individual variability.

Table 10: Letermovir AUC (ng*hr/mL) values following intravenous administration inpaediatric HSCT recipients

Intravenous Median Intravenous Median

Body weight dose, no (90% prediction dose, with (90% predictioncyclosporine interval)* cyclosporine interval)*111 000 59 80030 kg and above 480 mg 240 mg(55 700-218 000) (28 400-120 000)15 kg to less than 57 200 61 100120 mg 120 mg30 kg (29 700-113 000) (29 900-121 000)7.5 kg to less than 46 000 49 20060 mg 60 mg15 kg (24 300-83 900) (25 800-93 800)5 kg to less than 43 400 45 90040 mg 40 mg7.5 kg (24 300-81 000) (24 900-82 200)

* Medians and 90% prediction intervals are based on simulations using the paediatric HSCTpopulation PK model with inter-individual variability.

Irreversible testicular toxicity was noted only in rats at systemic exposures (AUC) ≥ 3-fold theexposures in humans at the recommended human dose (RHD). This toxicity was characterised byseminiferous tubular degeneration, and oligospermia and cell debris in the epididymides, withdecreased testicular and epididymides weights. There was no testicular toxicity in rats at exposures(AUC) similar to the exposures in humans at the RHD. Testicular toxicity was not observed in miceand monkeys at the highest doses tested at exposures up to 4-fold and 2-fold, respectively, theexposures in humans at the RHD. The relevance to humans is unknown.

It is known that hydroxypropylbetadex can cause kidney vacuolation in rats when given intravenouslyat doses greater than 50 mg/kg/day. Vacuolation was noted in the kidneys of rats administeredintravenous letermovir formulated with 1 500 mg/kg/day of the cyclodextrin excipienthydroxypropylbetadex.

Parenteral administration of hydroxypropylbetadex at ≥ 2 000 mg/kg has been associated with hearingloss resulting from damage to the inner ear in multiple animal species. By comparison, the maximumdose of hydroxypropylbetadex (120 mg/kg) in intravenous PREVYMIS at the maximumrecommended human dose (MRHD) (120 mg/kg) has not been associated with hearing loss in anyanimal studies. The active ingredient, letermovir, is not known to be associated with ototoxicity.

A 6-month oral carcinogenicity study in RasH2 transgenic (Tg.RasH2) mice showed no evidence ofhuman-relevant tumorigenesis up to the highest doses tested, 150 mg/kg/day and 300 mg/kg/day inmales and females, respectively.

Letermovir was not genotoxic in a battery of in vitro or in vivo assays, including microbialmutagenesis assays, chromosomal aberration in Chinese Hamster Ovary cells, and in an in vivo mousemicronucleus study.

Reproduction

In the fertility and early embryonic development studies in the rat, there were no effects of letermoviron female fertility. In male rats, reduced sperm concentration, reduced sperm motility, and decreasedfertility were observed at systemic exposures ≥ 3-fold the AUC in humans at the RHD (see Generaltoxicity).

In monkeys administered letermovir, there was no evidence of testicular toxicity based onhistopathologic evaluation, measurement of testicular size, blood hormone analysis (folliclestimulating hormone, inhibin B and testosterone) and sperm evaluation (sperm count, motility andmorphology) at systemic exposures approximately 2-fold the AUC in humans at the RHD.

In rats, maternal toxicity (including decrease in body weight gain) was noted at 250 mg/kg/day(approximately 11-fold the AUC at the RHD); in the offspring, decreased foetal weight with delayedossification, slightly oedematous foetuses, and increased incidence of shortened umbilical cords and ofvariations and malformations in the vertebrae, ribs, and pelvis were observed. No maternal ordevelopmental effects were noted at the dose of 50 mg/kg/day (approximately 2.5-fold the AUC at the

RHD).

In rabbits, maternal toxicity (including mortality and abortions) was noted at 225 mg/kg/day(approximately 2-fold the AUC at the RHD); in the offspring, an increased incidence of malformationsand variations in the vertebrae and ribs were observed.

In the pre- and post-natal developmental study, letermovir was administered orally to pregnant rats.

There was no developmental toxicity observed up to the highest exposure tested (2-fold the AUC atthe RHD).

Hydroxypropylbetadex (cyclodextrin)

Sodium chloride

Sodium hydroxide (E524)

Water for injections

Incompatible medicinal products

PREVYMIS concentrate for solution for infusion is physically incompatible with amiodaronehydrochloride, amphotericin B (liposomal), aztreonam, cefepime hydrochloride, ciprofloxacin,cyclosporine, diltiazem hydrochloride, filgrastim, gentamicin sulphate, levofloxacin, linezolid,lorazepam, midazolam HCl, mycophenolate mofetil hydrochloride, ondansetron, palonosetron.

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

Incompatible intravenous bags and infusion set materials

PREVYMIS concentrate for solution for infusion is incompatible with diethylhexyl phthalate (DEHP)plasticizers and polyurethane-containing intravenous administration set tubing.

This medicinal product must not be used with other intravenous bags and infusion set materials exceptthose mentioned in section 6.6.

Unopened vial: 3 years

After opening: Use immediately

Storage of diluted solution

Chemical and physical in-use stability has been demonstrated for 48 hours at 25 °C and for 48 hours at2 to 8 °C. From a microbiological point of view, the product should be used immediately. If not usedimmediately, in-use storage times and conditions prior to use are the responsibility of the user andwould normally not be longer than 24 hours at 2 to 8 °C, unless dilution has taken place in controlledand validated aseptic conditions.

This medicinal product does not require any special temperature storage conditions.

Store in original carton to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

Type I (30 mL) clear glass vial with a 20 mm fluorocoated chlorobutyl stopper with aluminium flip-off cap containing 12 mL (medium green cap) or 24 mL (dark blue cap) of solution.

Pack size: 1 vial.

PREVYMIS vials are for single use only.

PREVYMIS concentrate for solution for infusion must be diluted prior to intravenous use.

Inspect vial contents for discolouration and particulate matter prior to dilution. PREVYMISconcentrate for solution for infusion is a clear, colourless solution and may contain a few product-related small translucent or white particles. Do not use the vial if the solution is cloudy, discoloured orcontains matter other than a few small translucent or white particles.

Do not use PREVYMIS concentrate for solution for infusion with intravenous bags and infusion setmaterials containing polyurethane or the plasticizer diethylhexyl phthalate (DEHP). Materials that arephthalate-free are also DEHP-free.

Do not shake PREVYMIS vial.

For the 480 mg or 240 mg dose, add one single-dose vial (either 12 mL (240 mg dose) or 24 mL(480 mg dose)) of PREVYMIS concentrate for solution for infusion to a 250 mL pre-filled intravenousbag containing either sodium chloride 9 mg/mL (0.9%) solution for injection or 5% dextrose, and mixthe diluted solution by gentle inversion. Do not shake. If a vial is added to a 250 mL intravenousdiluent bag, the final concentration ranges of letermovir would be 0.9 mg/mL (for 240 mg dose) and1.8 mg/mL (for 480 mg dose).

For the 120 mg or 60 mg dose, prepare PREVYMIS concentrate for solution for infusion according to

Table 11 below in sodium chloride 9 mg/mL (0.9%) solution for injection or 5% dextrose, and mix thediluted solution by gentle inversion. Do not shake.

For the 40 mg dose, prepare PREVYMIS concentrate for solution for infusion according to Table 12below in either sodium chloride 9 mg/mL (0.9%) solution for injection or 5% dextrose, and mix thediluted solution by gentle inversion. Do not shake.

Table 11: Preparation of PREVYMIS intravenous solution for doses of 120 mg or 60 mg

Volume of 20 mg/mL PREVYMIS Final

Final infusion

Intravenous dose concentrate for solution for volume concentrationinfusion of letermovir120 mg 6 mL of 20 mg/mL 75 mL 1.6 mg/mL60 mg 3 mL of 20 mg/mL 50 mL 1.2 mg/mL

Table 12: Preparation of PREVYMIS intravenous solution for a dose of 40 mg

Final

Intravenous dose Volume of 2 mg/mL PREVYMIS Final infusion concentrationdilution (1:10)* volumeof letermovir40 mg 20 mL of 2 mg/mL 20 mL 2 mg/mL

* To prepare 2 mg/mL PREVYMIS dilution, add 5 mL of 20 mg/mL PREVYMIS concentrate forsolution for infusion from the vial to 45 mL of diluent (sodium chloride 9 mg/mL (0.9%) solutionfor injection or 5% dextrose) and mix gently.

Once diluted, the solution of PREVYMIS is clear, and ranges from colourless to yellow. Variations ofcolour within this range do not affect the quality of the product. The diluted solution should beinspected visually for particulate matter and discolouration prior to administration. Discard if thediluted solution is cloudy, discoloured or contains matter other than a few small translucent or whiteparticles.

See section 4.2.

PREVYMIS diluted solution must be administered through a sterile 0.2 micron or 0.22 micronpolyethersulfone (PES) in-line filter.

Compatible intravenous solutions and other medicinal products

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

PREVYMIS should not be co-administered through the same intravenous line (or cannula) with othermedicinal products and diluent combinations except those listed below.

List of compatible medicinal products when PREVYMIS and medicinal products* are preparedin 0.9% sodium chloride

* Ampicillin sodium * Fluconazole

* Ampicillin sodium/Sulbactam sodium * Human insulin

* Anti-thymocyte globulin * Magnesium sulfate

* Caspofungin * Methotrexate

* Daptomycin * Micafungin

* Fentanyl citrate

* Refer to the prescribing information to confirm compatibility of simultaneous co-administration.

List of compatible medicinal products when PREVYMIS and medicinal products* are preparedin 5% dextrose

* 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 prescribing information to confirm compatibility of simultaneous co-administration.† Amphotericin B (lipid complex) is compatible with PREVYMIS. However, Amphotericin B(liposomal) is incompatible (see section 6.2).

Compatible intravenous bags and infusion set materials

PREVYMIS is compatible with the following intravenous bags and infusion set materials. Anyintravenous bags or infusion set materials not listed below should not be used.

Intravenous bag materials

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

Infusion set materials

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

Plasticizers

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

Catheters

Radiopaque polyurethane

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Merck Sharp & Dohme B.V.

Waarderweg 392031 BN Haarlem

The Netherlands

EU/1/17/1245/003

EU/1/17/1245/004

Date of first authorisation: 8 January 2018

Date of latest renewal: 24 August 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu .