4.1. Therapeutic indications

PREVYMIS is indicated for prophylaxis of cytomegalovirus (CMV) reactivation and disease in adult and paediatric patients weighing at least 15 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.

4.2. Posology and method of administration

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 as granules in sachet (20 mg and 120 mg) and as concentrate for solution for infusion (240 mg).

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 concentrate for solution for infusion 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 that can be administered as two 240 mg tablets.

For patients who cannot swallow tablets, refer to the prescribing information for the letermovir granules in sachet for dosing information.

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 at least 15 kg to less than 30 kg who are HSCT recipients

The recommended dose of letermovir is 240 mg once daily that can be administered as one 240 mg tablet (see also section 5.2).

For paediatric patients who cannot swallow tablets, refer to the prescribing information for letermovir granules in sachet for dosing information.

Dose adjustment in paediatric patients weighing at least 15 kg to less than 30 kg who are HSCT recipients

If oral letermovir is co-administered with ciclosporin, the dose of letermovir should be decreased to 120 mg once daily (see also sections 4.5 and 5.2). For patients requiring a 120 mg dose, refer to the prescribing information for the letermovir granules in sachet for dosing information.

• If ciclosporin is initiated after starting letermovir, the next dose of letermovir should be decreased to 120 mg once daily.

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

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

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 that can be administered as two 240 mg tablets.

For patients who cannot swallow tablets, refer to the prescribing information for the letermovir granules in sachet for dosing information.

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

Patients should be instructed that if they miss a dose of letermovir, they should take it as soon as they remember. If they do not remember until it is time for the next dose, they should skip the missed dose and go back to the regular schedule. Patients should not double their next dose or take 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.

Paediatric population

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 oral use.

The tablet should be swallowed whole and may be taken with or without food. The tablet should not be divided, crushed, or chewed because these methods have not been studied.

4.3. Contraindications

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).

4.4. Special warnings and precautions for use

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 1 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 1).

Excipients

PREVYMIS contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

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 1).

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 1).

-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 1).

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 1 and sections 4.2 and 5.2). If oral letermovir is co-administered with ciclosporin in paediatric patients weighing less than 30 kg, the dose should be decreased (see 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 1). 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 1). 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 1).

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 1). 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 1 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 1: 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.

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

Concomitant medicinal product

Effect on concentration† mean ratio (90% confidence interval) for AUC, Cmax (likely mechanism of action)

Recommendations concerning co-administration with letermovir

Antibiotics

nafcillin

Interaction not studied.

Expected:

↓ letermovir

(P-gp/UGT induction)

Nafcillin may decrease plasma concentrations of letermovir.

Co-administration of letermovir and nafcillin is not recommended.

Antifungals

fluconazole

(400 mg single dose)/letermovir (480 mg single dose)

↔ fluconazole

AUC 1.03 (0.99, 1.08)

Cmax 0.95 (0.92, 0.99)

↔ letermovir

AUC 1.11 (1.01, 1.23)

Cmax 1.06 (0.93, 1.21)

Interaction at steady state not studied.

Expected:

↔ fluconazole

↔ letermovir

No dose adjustment required.

itraconazole

(200 mg once daily PO)/letermovir (480 mg once daily PO)

↔ itraconazole

AUC 0.76 (0.71, 0.81)

Cmax 0.84 (0.76, 0.92)

↔ letermovirAUC 1.33 (1.17, 1.51)

Cmax 1.21 (1.05, 1.39)

No dose adjustment required.

posaconazole‡

(300 mg single dose)/ letermovir (480 mg daily)

↔ posaconazole

AUC 0.98 (0.82, 1.17)

Cmax 1.11 (0.95, 1.29)

No dose adjustment required.

voriconazole‡

(200 mg twice daily)/ letermovir (480 mg daily)

↓ voriconazole

AUC 0.56 (0.51, 0.62)

Cmax 0.61 (0.53, 0.71)

(CYP2C9/19 induction)

If concomitant administration is necessary, TDM for voriconazole is recommended the first 2 weeks after initiating or ending letermovir, as well as after changing route of administration of letermovir or immunosuppressant.

Antimycobacterials

rifabutin

Interaction not studied.

Expected:

↓ letermovir

(P-gp/UGT induction)

Rifabutin may decrease plasma concentrations of letermovir.

Co-administration of letermovir and rifabutin is not recommended.

rifampicin

Multiple dose rifampicin decreases plasma concentrations of letermovir.

Co-administration of letermovir and rifampicin is not recommended.

(600 mg single dose PO)/ letermovir (480 mg single dose PO)

↔letermovir

AUC 2.03 (1.84, 2.26)

Cmax 1.59 (1.46, 1.74)

C24 2.01 (1.59, 2.54)

(OATP1B1/3 and/or P-gp inhibition)

(600 mg single dose intravenous)/ letermovir (480 mg single dose PO)

↔ letermovir

AUC 1.58 (1.38, 1.81)

Cmax 1.37 (1.16, 1.61)

C24 0.78 (0.65, 0.93)

(OATP1B1/3 and/or P-gp inhibition)

(600 mg once daily PO)/ letermovir (480 mg once daily PO)

↓ letermovir

AUC 0.81 (0.67, 0.98)

Cmax 1.01 (0.79, 1.28)

C24 0.14 (0.11, 0.19)

(Sum of OATP1B1/3 and/or P-gp inhibition and P-gp/UGT induction)

(600 mg once daily PO (24 hours after rifampicin))§/ letermovir (480 mg once daily PO)

↓ letermovir

AUC 0.15 (0.13, 0.17)

Cmax 0.27 (0.22, 0.31)

C24 0.09 (0.06, 0.12)

(P-gp/UGT induction)

Antipsychotics

thioridazine

Interaction not studied.

Expected:

↓ letermovir

(P-gp/UGT induction)

Thioridazine may decrease plasma concentrations of letermovir.

Co-administration of letermovir and thioridazine is not recommended.

Endothelin antagonists

bosentan

Interaction not studied.

Expected:

↓ letermovir

(P-gp/UGT induction)

Bosentan may decrease plasma concentrations of letermovir.

Co-administration of letermovir and bosentan is not recommended.

Antivirals

acyclovir‡

(400 mg single dose)/ letermovir (480 mg daily)

↔ acyclovir

AUC 1.02 (0.87, 1.2)

Cmax 0.82 (0.71, 0.93)

No dose adjustment required.

valacyclovir

Interaction not studied.

Expected:

↔ valacyclovir

No dose adjustment required.

Herbal products

St. John's wort (Hypericum perforatum)

Interaction not studied.

Expected:

↓ letermovir

(P-gp/UGT induction)

St. John's wort may decrease plasma concentrations of letermovir.

Co-administration of letermovir and St. John's wort is contraindicated.

HIV medicinal products

efavirenz

Interaction not studied.

Expected:

↓ letermovir

(P-gp/UGT induction)

↑ or ↓ efavirenz

(CYP2B6 inhibition or induction)

Efavirenz may decrease plasma concentrations of letermovir.

Co-administration of letermovir and efavirenz is not recommended.

etravirine, nevirapine, ritonavir, lopinavir

Interaction not studied.

Expected:

↓ letermovir

(P-gp/UGT induction)

These antivirals may decrease plasma concentrations of letermovir.

Co-administration of letermovir with these antivirals is not recommended.

HMG-CoA reductase inhibitors

atorvastatin‡

(20 mg single dose)/ letermovir (480 mg daily)

↑ atorvastatin

AUC 3.29 (2.84, 3.82)

Cmax 2.17 (1.76, 2.67)

(CYP3A, OATP1B1/3 inhibition)

Statin-associated adverse events such as myopathy should be closely monitored. The dose of atorvastatin should not exceed 20 mg daily when co-administered with letermovir#.

Although not studied, when letermovir is co-administered with ciclosporin, the magnitude of the increase in atorvastatin plasma concentrations is expected to be greater than with letermovir alone.

When letermovir is co-administered with ciclosporin, atorvastatin is contraindicated.

simvastatin, pitavastatin, rosuvastatin

Interaction not studied.

Expected:

↑ HMG-CoA reductase inhibitors

(CYP3A, OATP1B1/3 inhibition)

Letermovir may substantially increase plasma concentrations of these statins. Concomitant use is not recommended with letermovir alone.

When letermovir is co-administered with ciclosporin, use of these statins is contraindicated.

fluvastatin, pravastatin

Interaction not studied.

Expected:

↑ HMG-CoA reductase inhibitors

(OATP1B1/3 and/or BCRP inhibition)

Letermovir may increase statin plasma concentrations.

When letermovir is co-administered with these statins, a statin dose reduction may be necessary#. Statin-associated adverse events such as myopathy should be closely monitored.

When letermovir is co-administered with ciclosporin, pravastatin is not recommended while for fluvastatin, a dose reduction may be necessary#. Statin-associated adverse events such as myopathy should be closely monitored.

Immunosuppressants

ciclosporin

(50 mg single dose)/ letermovir (240 mg daily)

↑ ciclosporin

AUC 1.66 (1.51, 1.82)

Cmax 1.08 (0.97, 1.19)

(CYP3A inhibition)

If letermovir is co-administered with ciclosporin, the dose of letermovir should be decreased to 240 mg once daily in adults (see sections 4.2 and 5.1) and paediatric patients weighing at least 30 kg (see section 4.2). If oral letermovir is co-administered with ciclosporin in paediatric patients weighing less than 30 kg, the dose should be decreased (see section 4.2).

Frequent monitoring of ciclosporin whole blood concentrations should be performed during treatment, when changing letermovir administration route, and at discontinuation of letermovir and the dose of ciclosporin adjusted accordingly#.

ciclosporin

(200 mg single dose)/ letermovir (240 mg daily)

↑ letermovir

AUC 2.11 (1.97, 2.26)

Cmax 1.48 (1.33, 1.65)

(OATP1B1/3 inhibition)

mycophenolate mofetil

(1 g single dose)/ letermovir (480 mg daily)

↔mycophenolic acid

AUC 1.08 (0.97, 1.20)

Cmax 0.96 (0.82, 1.12)

↔ letermovir

AUC 1.18 (1.04, 1.32)

Cmax 1.11 (0.92, 1.34)

No dose adjustment required.

sirolimus‡

(2 mg single dose)/ letermovir (480 mg daily)

↑ sirolimus

AUC 3.40 (3.01, 3.85)

Cmax 2.76 (2.48, 3.06)

(CYP3A inhibition)

Interaction not studied.

Expected:

↔ letermovir

Frequent monitoring of sirolimus whole blood concentrations should be performed during treatment, when changing letermovir administration route, and at discontinuation of letermovir and the dose of sirolimus adjusted accordingly#.

Frequent monitoring of sirolimus concentrations is recommended at initiation or discontinuation of ciclosporin co-administration with letermovir.

When letermovir is co-administered with ciclosporin, also refer to the sirolimus prescribing information for specific dosing recommendations for use of sirolimus with ciclosporin.

When letermovir is co-administered with ciclosporin, the magnitude of the increase in concentrations of sirolimus may be greater than with letermovir alone.

tacrolimus

(5 mg single dose)/ letermovir (480 mg daily)

↑ tacrolimus

AUC 2.42 (2.04, 2.88)

Cmax 1.57 (1.32, 1.86)

(CYP3A inhibition)

Frequent monitoring of tacrolimus whole blood concentrations should be performed during treatment, when changing letermovir administration route, and at discontinuation of letermovir and the dose of tacrolimus adjusted accordingly#.

tacrolimus

(5 mg single dose)/ letermovir (80 mg twice daily)

↔ letermovir

AUC 1.02 (0.97, 1.07)

Cmax 0.92 (0.84, 1.00)

Oral contraceptives

ethinylestradiol (EE) (0.03 mg)/ levonorgestrel (LNG)‡

(0.15 mg) single dose/ letermovir (480 mg daily)

↔ EE

AUC 1.42 (1.32, 1.52)

Cmax 0.89 (0.83, 0.96)

↔ LNG

AUC 1.36 (1.30, 1.43)

Cmax 0.95 (0.86, 1.04)

No dose adjustment required.

Other systemically acting oral contraceptive steroids

Risk of ↓ contraceptive steroids

Letermovir may reduce plasma concentrations of other oral contraceptive steroids thereby affecting their efficacy.

For adequate contraceptive effect to be ensured with an oral contraceptive, products containing EE and LNG should be chosen.

Antidiabetic medicinal products

repaglinide

Interaction not studied.

Expected:

↑ or ↓ repaglinide

(CYP2C8 induction, CYP2C8 and OATP1B inhibition)

Letermovir may increase or decrease the plasma concentrations of repaglinide. (The net effect is not known).

Concomitant use is not recommended.

When letermovir is co-administered with ciclosporin, the plasma concentrations of repaglinide is expected to increase due to the additional OATP1B inhibition by ciclosporin. Concomitant use is not recommended#.

glyburide

Interaction not studied.

Expected:

↑ glyburide

(OATP1B1/3 inhibition CYP3A inhibition, CYP2C9 induction)

Letermovir may increase the plasma concentrations of glyburide.

Frequent monitoring of glucose concentrations is recommended the first 2 weeks after initiating or ending letermovir, as well as after changing route of administration of letermovir.

When letermovir is co-administered with ciclosporin, refer also to the glyburide prescribing information for specific dosing recommendations.

Antiepileptic medicinal products (see also general text)

carbamazepine, phenobarbital

Interaction not studied.

Expected:

↓ letermovir

(P-gp/UGT induction)

Carbamazepine or phenobarbital may decrease plasma concentrations of letermovir.

Co-administration of letermovir and carbamazepine or phenobarbital is not recommended.

phenytoin

Interaction not studied.

Expected:

↓ letermovir

(P-gp/UGT induction)

↓ phenytoin

(CYP2C9/19 induction)

Phenytoin may decrease plasma concentrations of letermovir.

Letermovir may decrease the plasma concentrations of phenytoin.

Co-administration of letermovir and phenytoin is not recommended.

Oral anticoagulants

warfarin

Interaction not studied.

Expected:

↓ warfarin

(CYP2C9 induction)

Letermovir may decrease the plasma concentrations of warfarin.

Frequent monitoring of International Normalised Ratio (INR) should be performed when warfarin is co-administered with letermovir treatment#. Monitoring is recommended the first 2 weeks after initiating or ending letermovir, as well as after changing route of administration of letermovir or immunosuppressant.

dabigatran

Interaction not studied.

Expected:

↓ dabigatran

(intestinal P-gp induction)

Letermovir may decrease the plasma concentrations of dabigatran and may decrease efficacy of dabigatran. Concomitant use of dabigatran should be avoided due to the risk of reduced dabigatran efficacy.

When letermovir is co-administered with ciclosporin, dabigatran is contraindicated.

Sedatives

midazolam

(1 mg single dose intravenous)/ letermovir (240 mg once daily PO)

midazolam (2 mg single dose PO) / letermovir (240 mg once daily PO)

↑ midazolam

Intravenous:

AUC 1.47 (1.37, 1.58)

Cmax 1.05 (0.94, 1.17)

PO:

AUC 2.25 (2.04, 2.48)

Cmax 1.72 (1.55, 1.92)

(CYP3A inhibition)

Close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised during co-administration of letermovir with midazolam. Dose adjustment of midazolam should be considered#. The increase in midazolam plasma concentration may be greater when oral midazolam is administered with letermovir at the clinical dose than with the dose studied.

Opioid agonists

Examples: alfentanil, fentanyl

Interaction not studied.

Expected:

↑ CYP3A metabolised opioids

(CYP3A inhibition)

Frequent monitoring for adverse reactions related to these medicinal products is recommended during co-administration. Dose adjustment of CYP3A metabolised opioids may be needed# (see section 4.4).

Monitoring is also recommended if changing route of administration. When letermovir is co-administered with ciclosporin, the magnitude of the increase in plasma concentrations of CYP3A metabolised opioids may be greater. Close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised during co-administration of letermovir in combination with ciclosporin and alfentanil or fentanyl. Refer to the respective prescribing information (see section 4.4).

Anti-arrhythmic medicinal products

amiodarone

Interaction not studied.

Expected:

↑ amiodarone

(primarily CYP3A inhibition and CYP2C8 inhibition or induction)

Letermovir may increase the plasma concentrations of amiodarone.

Frequent monitoring for adverse reactions related to amiodarone is recommended during co-administration. Monitoring of amiodarone concentrations should be performed regularly when amiodarone is co-administered with letermovir#.

quinidine

Interaction not studied.

Expected:

↑ quinidine

(CYP3A inhibition)

Letermovir may increase the plasma concentrations of quinidine.

Close clinical monitoring should be exercised during administration of letermovir with quinidine. Refer to the respective prescribing information#.

Cardiovascular medicinal products

digoxin‡

(0.5 mg single dose)/ letermovir (240 mg twice daily)

↔ digoxin

AUC 0.88 (0.80, 0.96)

Cmax 0.75 (0.63, 0.89)

(P-gp induction)

No dose adjustment required.

Proton pump inhibitors

omeprazole

Interaction not studied.

Expected:

↓omeprazole

(induction of CYP2C19)

Interaction not studied.

Expected:

↔ letermovir

Letermovir may decrease the plasma concentrations of CYP2C19 substrates.

Clinical monitoring and dose adjustment may be needed.

pantoprazole

Interaction not studied.

Expected:

↓ pantoprazole

(likely due to induction of CYP2C19)

Interaction not studied.

Expected:

↔ letermovir

Letermovir may decrease the plasma concentrations of CYP2C19 substrates.

Clinical monitoring and dose adjustment may be needed.

Wakefulness-promoting agents

modafinil

Interaction not studied.

Expected:

↓ letermovir

(P-gp/UGT induction)

Modafinil may decrease plasma concentrations of letermovir.

Co-administration of letermovir and modafinil is not recommended.

* This table is not all inclusive.

† ↓ =decrease, ↑ =increase

↔ =no clinically relevant change

‡ One-way interaction study assessing the effect of letermovir on the concomitant medicinal product.

§ These data are the effect of rifampicin on letermovir 24 hours after final rifampicin dose.

# Refer to the respective prescribing information.

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy and lactation

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).

4.7. Effects on ability to drive and use machines

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).

4.8. Undesirable effects

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 2: Adverse reactions identified with letermovir

Frequency

Adverse reactions

Immune system disorders

Uncommon

hypersensitivity

Metabolism and nutrition disorders

Uncommon

decreased appetite

Nervous system disorders

Uncommon

dysgeusia, headache

Ear and labyrinth disorders

Uncommon

vertigo

Gastrointestinal disorders

Common

nausea, diarrhoea, vomiting

Uncommon

abdominal pain

Hepatobiliary disorders

Uncommon

alanine aminotransferase increased, aspartate aminotransferase increased

Musculoskeletal and connective tissue disorders

Uncommon

muscle spasms

Renal and urinary disorders

Uncommon

blood creatinine increased

General disorders and administration site conditions

Uncommon

fatigue, oedema peripheral

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.

4.9. Overdose

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.