PREVYMIS 240 mg concentrate for solution for infusion

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

PREVYMIS is indicated for prophylaxis of CMV disease in CMV-seronegative adult and paediatric patients weighing at least 40 kg who have received a kidney transplant from a CMV-seropositive donor [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 have had an allogeneic haematopoietic stem cell transplant or kidney transplant.

Posology

Letermovir is also available for oral administration (240 mg film-coated tablets, and 20 mg and 120 mg granules in sachet).

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

HSCT

Letermovir should be started after HSCT. Letermovir may be started on the day of transplant and no later than 28 days post-HSCT. Letermovir may be started before or after engraftment. Prophylaxis with letermovir should continue through 100 days post-HSCT.

Prolonged letermovir prophylaxis beyond 100 days post-HSCT may be of benefit in some patients at high risk for late CMV reactivation (see section 5.1). The safety and efficacy of letermovir use for more 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 ciclosporin, the dose of letermovir should be decreased to 240 mg once daily (see sections 4.5 and 5.2).

• If ciclosporin is initiated after starting letermovir, the next dose of letermovir should be decreased to 240 mg once daily.

• If ciclosporin is discontinued after starting letermovir, the next dose of letermovir should be increased to 480 mg once daily.

• If ciclosporin dosing is temporarily interrupted due to high ciclosporin levels, no dose adjustment 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 ciclosporin, the dose of letermovir does not require adjustment 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 with ciclosporin in paediatric patients weighing less than 30 kg

Kidney transplant

Letermovir should be started on the day of transplant and no later than 7 days post-kidney transplant and 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 transplant recipients

If letermovir is co-administered with ciclosporin, the dose of letermovir should be decreased to 240 mg once daily (see sections 4.5 and 5.2).

• If ciclosporin is initiated after starting letermovir, the next dose of letermovir should be decreased to 240 mg once daily.

• If ciclosporin is discontinued after starting letermovir, the next dose of letermovir should be increased to 480 mg once daily.

• If ciclosporin dosing is temporarily interrupted due to high ciclosporin levels, no dose adjustment of letermovir is needed.

Missed dose

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 more than the prescribed dose.

Special populations

Elderly

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

Hepatic impairment

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 with moderate or severe renal impairment (see section 5.2).

Renal impairment

No dose adjustment of letermovir is recommended for patients with mild, moderate, or severe renal impairment. 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 and 5.3). 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 of hydroxypropylbetadex could occur. Serum creatinine levels should be closely monitored in these patients.

Paediatric population

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 transplant patients weighing less than 40 kg have not been established. No data are available. No recommendation on posology for kidney transplant patients weighing less than 40 kg could be supported by pharmacokinetic/pharmacodynamic extrapolation.

Method of administration

For intravenous use only.

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

Letermovir diluted solution must be administered through a sterile 0.2 micron or 0.22 micron polyethersulfone (PES) in-line filter. Do not administer the diluted solution through a filter other than a 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 central venous catheter using a total time of approximately 60 minutes. The entire contents of the intravenous bag 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 ciclosporin:

• Concomitant use of dabigatran, atorvastatin, simvastatin, rosuvastatin or pitavastatin is contraindicated (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 patients with a negative CMV DNA test result prior to initiation of prophylaxis. CMV DNA was monitored on a weekly basis until post‑transplant Week 14, and subsequently every two weeks until Week 24. In cases of clinically significant CMV DNAemia or disease, letermovir prophylaxis was stopped and standard-of-care pre‑emptive therapy (PET) or treatment was initiated. In patients in whom letermovir prophylaxis 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 potentially significant medicinal product interactions, some of which may lead to:

• possible clinically significant adverse reactions from greater exposure of concomitant medicinal products or letermovir.

• significant decrease of concomitant medicinal product plasma concentrations which may lead to reduced therapeutic effect of the concomitant medicinal product.

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

Drug interactions

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

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

Letermovir is a moderate inducer of enzymes and transporters. Induction may give rise to reduced plasma concentrations of some metabolised and transported medicinal products (see section 4.5). Therapeutic drug monitoring (TDM) is therefore recommended for voriconazole.

Concomitant use of dabigatran should be avoided due to risk of reduced dabigatran efficacy.

Letermovir may increase the plasma concentrations of medicinal products transported by OATP1B1/3 such 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 translucent or white particles. Administration of PREVYMIS diluted solution always requires the use of a sterile 0.2 micron or 0.22 micron PES in-line filter, regardless of whether these product-related particles are visible in the vial or diluted solution (see sections 4.2 and 6.6).

Excipients

Sodium

This medicinal product contains 23 mg (or 1 mmol) sodium per 240 mg vial, equivalent to 1.15% of the WHO recommended maximum daily intake of 2 g sodium for an adult. This should be taken into consideration 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 table in section 5.2). Therefore, the clinical consequences of drug interactions for letermovir will be dependent on which letermovir regimen is used and whether or not letermovir is combined with ciclosporin.

-The combination of ciclosporin and letermovir may lead to more marked or additional effects on concomitant 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 relative importance of these pathways is unknown. Both elimination pathways involve active uptake into the hepatocyte through the hepatic uptake transporters OATP1B1/3. After uptake, glucuronidation of letermovir is mediated by UGT1A1 and 3. Letermovir also appears to be subject to P-gp and BCRP mediated efflux in the liver and intestine (see section 5.2).

Inducers of drug metabolising enzymes or transporters

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

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

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

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 relevant decreases in letermovir plasma concentrations (due to induction of P-gp/UGT) with continued rifampicin co-administration (see Table 2).

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

Inhibitors of OATP1B1 or 3

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

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

Inhibitors of P-gp/BCRP

In vitro results indicate that letermovir is a substrate of P-gp/BCRP. Changes in letermovir plasma concentrations 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 or transporter is also inhibited (see below) induction can be expected. Therefore, letermovir may potentially lead to decreased plasma exposure and possibly reduced efficacy of co-administered medicinal 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 whether ciclosporin is concomitantly used. The full induction effect can be expected after 10-14 days of letermovir treatment. The time needed to reach steady state of a specific affected medicinal product will 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 listed enzymes and transporters is not known. Detailed information is presented below.

It is unknown whether letermovir may affect the exposure of piperacillin/tazobactam, amphotericine B and micafungin. The potential interaction between letermovir and these medicinal products have not been investigated. There is a theoretical risk of reduced exposure due to induction but the size of the effect 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 oral midazolam (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 of co-administered CYP3A substrates (see sections 4.3, 4.4, and 5.2).

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

The size of the CYP3A inhibitory effect is dependent on letermovir route of administration and whether ciclosporin is concomitantly used.

Due to time dependent inhibition and simultaneous induction the net enzyme inhibitory effect may not be reached until after 10-14 days. The time needed to reach steady state of a specific affected medicinal 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 is applied, 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 a clinically 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 without ciclosporin, the effect is more marked after intravenous than oral letermovir.

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

Medicinal products metabolised by CYP2C9 and/or CYP2C19

Co-administration of letermovir with voriconazole (a CYP2C19 substrate) results in significantly decreased 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 CYP2C9 and/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 ciclosporin, than intravenous letermovir with or without ciclosporin, or oral letermovir with ciclosporin. This needs to be considered when the letermovir regimen is changed during treatment with a CYP2C9 or CYP2C19 substrate. 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 ciclosporin is not recommended.

Medicinal products transported by P-gp in the intestine

Letermovir is an inducer of intestinal P-gp. Administration of letermovir may result in a clinically relevant decrease in plasma concentrations of co-administered medicinal products that are significantly 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 plasma concentrations of medicinal products that are substrates of these enzymes or transporters may increase or decrease when co-administered with letermovir. Additional monitoring may be recommended; refer to 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 OAT3 inhibitor 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 also be needed when changing route of administration or immunosuppressant.

Table 2 provides a listing of established or potentially clinically significant medicinal product interactions. The medicinal product interactions described are based on adult studies conducted with letermovir or are predicted medicinal product interactions that may occur with letermovir (see sections 4.3, 4.4, 5.1, and 5.2).

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

Paediatric population

Interaction studies have only been performed in adults.

Pregnancy

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

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

Breast-feeding

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

Fertility

There were no effects on female fertility in rats. Irreversible testicular toxicity and impairment of fertility 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 have been reported in some patients during treatment with letermovir, which may influence a patient's ability to drive and use machines (see section 4.8).

Summary of the safety profile

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-transplant and were followed for safety through Week 24 post-transplant (see section 5.1). The most commonly reported adverse reactions occurring in at least 1% of subjects in the letermovir group and at a frequency greater than placebo were: nausea (7.2%), diarrhoea (2.4%), and vomiting (1.9%). The most frequently 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 letermovir as 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).

Tabulated summary of adverse reactions

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 are 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 3: Adverse reactions identified with letermovir

Paediatric population

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 to less than 12 years, 13 aged 2 to less than 7 years, and 8 less than 2 years old (5 of them less than 1 year old). The adverse reactions were consistent with those observed in clinical studies of letermovir in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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

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

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

Mechanism of action

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

Antiviral activity

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

Viral resistance

In cell culture

The CMV genes UL51, UL56 and UL89 encode subunits of CMV DNA terminase. CMV mutants with reduced susceptibility to letermovir have been confirmed in cell culture. EC₅₀ values for recombinant 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 than those for wild-type reference virus; these substitutions are not likely to be clinically relevant. 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- 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 failure in 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 days in 131 adult HSCT recipients, DNA sequence analysis of a select region of UL56 (amino acids 231 to 369) was performed on samples obtained from 12 letermovir-treated subjects who experienced prophylaxis failure and for whom samples were available for analysis. One subject (who received 60 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 was performed on samples obtained from 40 letermovir-treated adult subjects in the FAS population who experienced prophylaxis failure and for whom samples were available for analysis. Two subjects had letermovir resistant GVs detected, both with substitutions mapping to pUL56. One subject had the substitution V236M and the other subject had the substitution E237G. One additional subject, who had detectable CMV DNA at baseline (and was therefore not in the FAS population), had pUL56 substitutions, 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) who experienced prophylaxis failure 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 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 for evaluation of CMV infection. A total of 2 letermovir resistance-associated substitutions both mapping to pUL56 were detected in 2 subjects. One subject had the substitution R369S and the other subject had the substitution C325W.

Cross-resistance

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 CMV strains with substitutions conferring resistance to letermovir was fully susceptible to cidofovir, foscarnet and ganciclovir with the exception of a recombinant strain with the pUL56 E237G substitution which confers a 2.1-fold reduction in ganciclovir susceptibility relative to wild-type.

Cardiac electrophysiology

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

Clinical efficacy and safety

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 efficacy of letermovir was assessed in a multicentre, double-blind, placebo-controlled Phase 3 trial (P001) in adult CMV-seropositive recipients [R+] of an allogeneic HSCT. Subjects were randomised (2:1) to receive either letermovir at a dose of 480 mg once daily adjusted to 240 mg when co-administered with ciclosporin, 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 0-28 post-HSCT) and continued through Week 14 post-HSCT. Letermovir was administered either orally or intravenously; the dose of letermovir was the same regardless of the route of administration. Subjects were monitored through Week 24 post-HSCT for the primary efficacy endpoint with continued follow-up through Week 48 post-HSCT.

Subjects received CMV DNA monitoring weekly until post-HSCT week 14 and then every two weeks until 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 48 post-HSCT.

Among the 565 treated subjects, 373 subjects received letermovir (including 99 subjects who received at least one intravenous dose) and 192 received placebo (including 48 subjects who received at least one 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 to 78 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 subjects received a myeloablative regimen, 52% were receiving ciclosporin, and 42% were receiving tacrolimus. The most common primary reasons for transplant were acute myeloid leukaemia (38%), myeloblastic syndrome (15%), and lymphoma (13%). Twelve percent (12%) of subjects were positive for CMV DNA at baseline.

At baseline, 31% of subjects were at high risk for reactivation as defined by one or more of the following criteria: Human Leucocyte Antigen (HLA)-related (sibling) donor with at least one mismatch at one of the following three HLA-gene loci: HLA-A, -B or –DR, haploidentical donor; unrelated donor with at least one mismatch at one of the following four HLA-gene loci: HLA-A, -B, -C and -DRB1; use of umbilical cord blood as stem cell source; use of ex vivo T-cell-depleted grafts; Grade 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 the incidence 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 subjects who discontinued from the study prior to Week 24 post-HSCT or had a missing outcome at Week 24 post-HSCT were counted as failures.

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

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

Factors associated with CMV DNAemia after Week 14 post-HSCT among letermovir-treated subjects included high risk for CMV reactivation at baseline, GVHD, use of corticosteroids, and CMV negative donor 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)

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

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

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

NC=F, Non-Completer=Failure. With NC=F approach, subjects who discontinued from the study prior to Week 24 post-transplant or had a missing 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 a multicentre, double-blind, placebo-controlled Phase 3 trial (P040) in adult CMV-seropositive recipients [R+] of an allogeneic HSCT. Eligible subjects who completed letermovir prophylaxis through ~100 days post-HSCT were randomised (2:1) to receive letermovir or placebo from Week 14 through Week 28 post-HSCT. Subjects were monitored through Week 28 post-HSCT for the primary efficacy 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. The median 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 were acute 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 two or more risk factors. The risk factors included: HLA-related (sibling) donor with at least one mismatch at one of the following three HLA-gene loci: HLA-A, -B or -DR; haploidentical donor; unrelated donor with at least one mismatch at one of the following four HLA-gene loci: HLA-A, -B, -C and ‑DRB1; use of umbilical cord blood as stem cell source; use of ex vivo T-cell-depleted grafts; 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 infection through Week 28 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 Observed Failure (OF) approach was used, where subjects who developed clinically significant CMV infection or discontinued prematurely from the study with viremia were counted as failures.

Letermovir demonstrated superior efficacy over placebo in the analysis of the primary endpoint, as shown in Table 5. The estimated treatment difference of -16.1% was statistically significant (one-sided p-value=0.0005). Efficacy consistently favored letermovir across subgroups based on subject characteristics (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)

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 transplant recipients, 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. Letermovir was given concomitantly with acyclovir. Valganciclovir was given concomitantly with a placebo to acyclovir. Randomisation was stratified by the use or non-use of highly cytolytic, anti-lymphocyte immunotherapy during induction. Letermovir or valganciclovir were initiated between Day 0 and Day 7 post-kidney transplant and continued through Week 28 (~200 days) post-transplant. Subjects were monitored through Week 52 post-transplant.

Among the 589 treated subjects, 292 subjects received letermovir and 297 received valganciclovir. The median 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. The most 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 study for 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, as shown in Table 6.

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

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

Paediatric population

P030: Paediatric recipients of an allogeneic hematopoietic stem cell transplant

To evaluate letermovir prophylaxis as a preventive strategy for CMV infection or disease in paediatric transplant 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 was administered either orally or intravenously; the dose of letermovir was based on age, body weight and formulation.

Among the 63 treated subjects, 8 were 0 to less than 2 years of age, 27 were 2 to less than 12 years of age and 28 were 12 to less than 18 years of age. At baseline, 87% of subjects received a myeloablative regimen, 67% were receiving ciclosporin, and 27% were receiving tacrolimus. The most common primary reasons for transplant were acute myeloid leukaemia (18%) and aplastic anaemia (10%) in the overall population, and combined immunodeficiency (37.5%) and familial haemophagocytic lymphohistiocytosis (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 incidence of 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 oral and intravenous administration. Letermovir exposure increased in a greater than dose-proportional manner with both oral or intravenous administration. The mechanism is likely saturation/autoinhibition of OATP1B1/3. The pharmacokinetics of letermovir have also been characterised following oral and intravenous administration in adult HSCT recipients (see Table 7) and paediatric HSCT recipients (see Table 9 and Table 10) and following oral administration in adult kidney transplant recipients (see Table 8).

Healthy adult subjects

The geometric mean steady-state AUC and C_max 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 C_max.

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; efficacy was consistent across the range of exposures observed in P001.

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

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

Absorption

In healthy adult subjects, letermovir was absorbed rapidly with a median time to maximum plasma concentration (T_max) 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 oral letermovir administered without ciclosporin. The inter-individual variability for bioavailability was estimated to be approximately 37%. In adult kidney transplant recipients, bioavailability of letermovir was estimated to be approximately 60% with 480 mg once daily oral letermovir administered without ciclosporin.

Effect of ciclosporin

In adult HSCT recipients, co-administration of ciclosporin increased plasma concentrations of letermovir due to inhibition of OATP1B. Bioavailability of letermovir was estimated to be approximately 85% with 240 mg once daily oral letermovir co-administered with ciclosporin in patients.

If letermovir is co-administered with ciclosporin, the recommended dose of letermovir is 240 mg once daily in adult and paediatric patients weighing at least 30 kg (see section 4.2). If intravenous letermovir is co-administered with ciclosporin in paediatric patients weighing less than 30 kg, dose adjustment is not required (see section 4.2).

Effect of food

In healthy adult subjects, oral administration of 480 mg single dose of letermovir tablet with a standard high fat and high calorie meal did not have any effect on the overall exposure (AUC) and resulted in approximately 30% increase in peak levels (C_max) of letermovir. Letermovir tablets may be administered 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 soft foods (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 (C_max) of letermovir. Letermovir granules may be administered with soft foods, as has been done in the paediatric trial (see section 4.2).

Distribution

Based on population pharmacokinetic analyses, the mean steady-state volume of distribution is estimated 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 concentration range (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 to 10 mg/L) evaluated in vitro.

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

Biotransformation

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

Elimination

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

Based on population pharmacokinetic analyses, letermovir steady-state apparent CL is estimated to be 4.84 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% of dose) as an acyl-glucuronide metabolite in faeces. The acyl-glucuronide is unstable in faeces. Urinary excretion of letermovir was negligible (< 2% of dose).

Pharmacokinetics in special populations

Hepatic impairment

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 letermovir exposure in adult subjects with moderate hepatic impairment are not clinically relevant.

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

Renal impairment

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) renal impairment, respectively, compared to healthy adult subjects. The changes in letermovir exposure due to 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% and 35% 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 or equal 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 estimated to be 18.7% lower in subjects weighing 80-100 kg compared to subjects weighing 67 kg. Based on population pharmacokinetic analysis in adult kidney transplant recipients (P002), letermovir AUC is estimated to be 26% lower in subjects weighing greater than 80 kg compared to subjects weighing less than or equal to 80 kg. These differences are not clinically relevant.

Race

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

Gender

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

Elderly

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

Paediatric population

Letermovir AUC in paediatric HSCT recipients was estimated via population pharmacokinetic analysis 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 HSCT recipients

Table 10: Letermovir AUC (ng•hr/mL) values following intravenous administration in paediatric HSCT recipients

General toxicity

Irreversible testicular toxicity was noted only in rats at systemic exposures (AUC) ≥ 3-fold the exposures in humans at the recommended human dose (RHD). This toxicity was characterised by seminiferous tubular degeneration, and oligospermia and cell debris in the epididymides, with decreased 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 mice and monkeys at the highest doses tested at exposures up to 4-fold and 2-fold, respectively, the exposures in humans at the RHD. The relevance to humans is unknown.

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

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

Carcinogenesis

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

Mutagenesis

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

Reproduction

Fertility

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

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

Development

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 delayed ossification, slightly oedematous foetuses, and increased incidence of shortened umbilical cords and of variations and malformations in the vertebrae, ribs, and pelvis were observed. No maternal or developmental 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 malformations and 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 at the RHD).

Hydroxypropylbetadex (cyclodextrin)

Sodium chloride

Sodium hydroxide (E524)

Water for injections

Incompatible medicinal products

PREVYMIS concentrate for solution for infusion is physically incompatible with amiodarone hydrochloride, amphotericin B (liposomal), aztreonam, cefepime hydrochloride, ciprofloxacin, ciclosporin, 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 in section 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 except those 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 at 2 to 8 °C. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8 °C, unless dilution has taken place in controlled and 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) of solution.

Pack size: 1 vial.

PREVYMIS vials are for single use only.

Preparation

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

Inspect vial contents for discolouration and particulate matter prior to dilution. PREVYMIS concentrate 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 or contains matter other than a few small translucent or white particles.

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

Do not shake PREVYMIS vial.

For the 480 mg or 240 mg dose, add one single-dose vial (12 mL (240 mg dose)) or two single-dose vials (2 x 12 mL (480 mg dose)) of PREVYMIS concentrate for solution for infusion to a 250 mL pre-filled intravenous bag containing either sodium chloride 9 mg/mL (0.9%) solution for injection or 5% dextrose, and mix the diluted solution by gentle inversion. Do not shake. If one vial is added to a 250 mL intravenous diluent bag, the final concentration of letermovir would be 0.9 mg/mL (for 240 mg dose). If two vials are added to a 250 mL intravenous diluent bag, the final concentration of letermovir would be 1.8 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 the diluted solution by gentle inversion. Do not shake.

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

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

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

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

Administration

See section 4.2.

PREVYMIS diluted solution must be administered through a sterile 0.2 micron or 0.22 micron polyethersulfone (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 other medicinal products and diluent combinations except those listed below.

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

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

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

* 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. Any intravenous 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 and polyethylene)

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 local requirements.