Prevymis

1

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

 



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This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions.

1. NAME OF THE MEDICINAL PRODUCT

PREVYMIS 240 mg film-coated tablets
PREVYMIS 480 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

PREVYMIS 240 mg film-coated tablets
Each film-coated tablet contains 240 mg of letermovir.

PREVYMIS 480 mg film-coated tablets
Each film-coated tablet contains 480 mg of letermovir.

Excipients with known effect
Each 240 mg film-coated tablet contains 4 mg of lactose (as monohydrate).
Each 480 mg film-coated tablet contains 6.4 mg of lactose (as monohydrate).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet (tablet)

PREVYMIS 240 mg film-coated tablets
Yellow oval tablet of dimensions 16.5 mm x 8.5 mm, debossed with “591” on one side and MSD logo 
on the other side.

PREVYMIS 480 mg film-coated tablets
Pink oval, bi-convex tablet of dimensions 21.2 mm x 10.3 mm, debossed with “595” on one side and
MSD logo on the other side.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

PREVYMIS is indicated for prophylaxis of cytomegalovirus (CMV) reactivation and disease in adult
CMV-seropositive recipients [R+] of an allogeneic haematopoietic stem cell transplant (HSCT).

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

4.2 Posology and method of administration

PREVYMIS should be initiated by a physician experienced in the management of patients who have 
had an allogeneic haematopoietic stem cell transplant.

Posology
PREVYMIS is also available as concentrate for solution for infusion (240 mg and 480 mg).

 



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PREVYMIS tablets and concentrate for solution for infusion may be used interchangeably at the 
discretion of the physician, and no dose adjustment is necessary.

The recommended dosage of PREVYMIS is one 480 mg tablet once daily.

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

The safety and efficacy of letermovir use for more than 100 days has not been studied in clinical 
trials. Prolonged letermovir prophylaxis beyond 100 days post-transplant may be of benefit in some
patients at high risk for late CMV reactivation (see section 5.1). Use of letermovir prophylaxis for 
greater than 100 days requires a careful assessment of the benefit-risk balance.

Dosage adjustment 
If PREVYMIS is co-administered with cyclosporine, the dosage of PREVYMIS should be decreased 
to 240 mg once daily (see sections 4.5 and 5.2).
 If cyclosporine is initiated after starting PREVYMIS, the next dose of PREVYMIS should be 

decreased to 240 mg once daily.
 If cyclosporine is discontinued after starting PREVYMIS, the next dose of PREVYMIS should be 

increased to 480 mg once daily.
 If cyclosporine dosing is temporarily interrupted due to high cyclosporine levels, no dose 

adjustment of PREVYMIS is needed.

Missed dose
Patients should be instructed that if they miss a dose of PREVYMIS, 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 one.

Special populations

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

Hepatic impairment
No dose adjustment of PREVYMIS is required based on mild (Child-Pugh Class A) to moderate 
(Child-Pugh Class B) hepatic impairment. PREVYMIS is not recommended for patients with severe 
(Child-Pugh Class C) hepatic impairment (see section 5.2).

Combined hepatic and renal impairment
PREVYMIS 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 PREVYMIS 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 PREVYMIS in patients below 18 years of age have not been established. 
No data are available (see section 5.1).

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.

 



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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 cyclosporine: 
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
The safety and efficacy of letermovir has been established in 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 bi-weekly 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 PREVYMIS 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
PREVYMIS 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 cyclosporine, 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’.

 



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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 
cyclosporine.
-The combination of cyclosporine 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 metabolizing enzymes or transporters
Co-administration of PREVYMIS (with or without cyclosporine) 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, St. John’s wort 
(Hypericum perforatum), 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 cyclosporine

Inhibitors of OATP1B1 or 3
Co-administration of PREVYMIS with medicinal products that are inhibitors of OATP1B1/3 
transporters may result in increased letermovir plasma concentrations. If PREVYMIS is co-
administered with cyclosporine (a potent OATP1B1/3 inhibitor), the recommended dose of 
PREVYMIS is 240 mg once daily (see Table 1 and sections 4.2 and 5.2). Caution is advised if other 
OATP1B1/3 inhibitors are added to letermovir combined with cyclosporine.
-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
cyclosporine is concomitantly used. The full induction effect can be expected after 10-14 days of 

 



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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 PREVYMIS with oral
midazolam (a CYP3A substrate) results in 2-3-fold increased midazolam plasma concentrations. Co-
administration of PREVYMIS 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., cyclosporine, 
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 cyclosporine 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 PREVYMIS 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 
cyclosporine, the effect is more marked after iv than oral letermovir.
The magnitude of the OATP1B1/3 inhibition on co-administered medicinal products is likely greater 
when PREVYMIS is co-administered with cyclosporine (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 PREVYMIS 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 cyclosporine, than IV 
letermovir with or without cyclosporine, or oral letermovir with cyclosporine. 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. 

 



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-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 cyclosporine is not 
recommended.

Medicinal products transported by P-gp in the intestine
Letermovir is an inducer of intestinal P-gp. Administration of PREVYMIS 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 PREVYMIS,
doses should be readjusted after treatment with PREVYMIS 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 studies conducted with 
PREVYMIS or are predicted medicinal product interactions that may occur with PREVYMIS (see 
sections 4.3, 4.4, 5.1, and 5.2). 

 



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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 with oral letermovir without 
cyclosporine. Please note that the interaction potential and clinical consequences may be 
different depending on whether letermovir is administered orally or IV, and whether 
cyclosporine 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 PREVYMIS

Antibiotics
nafcillin Interaction not studied.

Expected:
↓ letermovir

(P-gp/UGT induction)

Nafcillin may decrease plasma 
concentrations of letermovir.
Co-administration of PREVYMIS 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)

↔ letermovir
AUC 1.33 (1.17, 1.51)
Cmax 1.21 (1.05, 1.39)

No dose adjustment required.

posaconazole‡

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

↔ posaconazole
AUC 0.98 (0.82, 1.17)
Cmax 1.11 (0.95, 1.29)

No dose adjustment required.

voriconazole‡

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

↓ voriconazole
AUC 0.56 (0.51, 0.62)
Cmax 0.61 (0.53, 0.71)

(CYP2C9/19 induction)

If concomitant 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.

 



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Concomitant 
medicinal product 

Effect on concentration†

Mean ratio (90 % confidence 
interval) for AUC, Cmax

(likely mechanism of action)

Recommendations concerning co-
administration with PREVYMIS

Antimycobacterials
rifabutin Interaction not studied.

Expected:
↓ letermovir

(P-gp/UGT induction)

Rifabutin may decrease plasma 
concentrations of letermovir.
Co-administration of PREVYMIS and 
rifabutin is not recommended.

rifampicin

Multiple dose rifampicin decreases plasma 
concentrations of letermovir. 
Co-administration of PREVYMIS 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 
IV)/ 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 PREVYMIS 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 PREVYMIS 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.

 



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Concomitant 
medicinal product 

Effect on concentration†

Mean ratio (90 % confidence 
interval) for AUC, Cmax

(likely mechanism of action)

Recommendations concerning co-
administration with PREVYMIS

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 PREVYMIS 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 PREVYMIS 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 PREVYMIS 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 
PREVYMIS#.

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

When PREVYMIS is co-administered with 
cyclosporine, use of these statins is 
contraindicated.

 



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Concomitant 
medicinal product 

Effect on concentration†

Mean ratio (90 % confidence 
interval) for AUC, Cmax

(likely mechanism of action)

Recommendations concerning co-
administration with PREVYMIS

fluvastatin, 
pravastatin

Interaction not studied.
Expected:
↑ HMG-CoA reductase 
inhibitors

(OATP1B1/3 and/or BCRP 
inhibition)

Letermovir may increase statin plasma 
concentrations. 

When PREVYMIS 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 PREVYMIS is co-administered with 
cyclosporine, 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
cyclosporine
(50 mg single dose)/ 
letermovir (240 mg 
daily)

↑ cyclosporine
AUC 1.66 (1.51, 1.82)
Cmax 1.08 (0.97, 1.19) 
(CYP3A inhibition)

If PREVYMIS is co-administered with 
cyclosporine, the dosage of PREVYMIS
should be decreased to 240 mg once daily 
(see sections 4.2 and 5.1).

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

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

↑ letermovir
AUC 2.11 (1.97, 2.26)
Cmax 1.48 (1.33, 1.65)

(OATP1B1/3 inhibition)

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

↔mycophenolic acid
AUC 1.08 (0.97, 1.20)
Cmax 0.96 (0.82, 1.12)

↔ letermovir
AUC 1.18 (1.04, 1.32)
Cmax 1.11 (0.92, 1.34)

No dose adjustment required.

 



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Concomitant 
medicinal product 

Effect on concentration†

Mean ratio (90 % confidence 
interval) for AUC, Cmax

(likely mechanism of action)

Recommendations concerning co-
administration with PREVYMIS

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 
PREVYMIS administration route, and at 
discontinuation of PREVYMIS and the 
dose of sirolimus adjusted accordingly#.
Frequent monitoring of sirolimus 
concentrations is recommended at initiation 
or discontinuation of cyclosporine co-
administration with PREVYMIS. 

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

When PREVYMIS is co-administered with 
cyclosporine, the magnitude of the increase 
in concentrations of sirolimus may be 
greater than with PREVYMIS 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 
PREVYMIS administration route, and at 
discontinuation of PREVYMIS 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.

 



13

Concomitant 
medicinal product 

Effect on concentration†

Mean ratio (90 % confidence 
interval) for AUC, Cmax

(likely mechanism of action)

Recommendations concerning co-
administration with PREVYMIS

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 PREVYMIS is co-administered with 
cyclosporine, the plasma concentrations of 
repaglinide is expected to increase due to 
the additional OATP1B inhibition by 
cyclosporine. 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 PREVYMIS is co-administered with 
cyclosporine, refer also to the glyburide 
prescribing information for specific dosing 
recommendations.

 



14

Concomitant 
medicinal product 

Effect on concentration†

Mean ratio (90 % confidence 
interval) for AUC, Cmax

(likely mechanism of action)

Recommendations concerning co-
administration with PREVYMIS

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 PREVYMIS 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 PREVYMIS 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 PREVYMIS 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 PREVYMIS is co-administered with 
cyclosporine, dabigatran is contraindicated.

 



15

Concomitant 
medicinal product 

Effect on concentration†

Mean ratio (90 % confidence 
interval) for AUC, Cmax

(likely mechanism of action)

Recommendations concerning co-
administration with PREVYMIS

Sedatives
midazolam
(1 mg single dose 
IV)/ letermovir 
(240 mg once daily 
PO)

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

↑ midazolam
IV:
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 PREVYMIS 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 
PREVYMIS is co-administered with 
cyclosporine, 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 PREVYMIS in 
combination with cyclosporine 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 PREVYMIS#. 

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 
PREVYMIS with quinidine. Refer to the 
respective prescribing information#.

 



16

Concomitant 
medicinal product 

Effect on concentration†

Mean ratio (90 % confidence 
interval) for AUC, Cmax

(likely mechanism of action)

Recommendations concerning co-
administration with PREVYMIS

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

 



17

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 
PREVYMIS 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.

4.7 Effects on ability to drive and use machines

PREVYMIS may have minor influence on the ability to drive or use machines. Fatigue and vertigo 
have been reported in some patients during treatment with PREVYMIS, 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 PREVYMIS was based on a Phase 3 clinical trial (P001) in HSCT recipients 
who received PREVYMIS 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 PREVYMIS
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 PREVYMIS were nausea 
(1.6%), vomiting (0.8%), and abdominal pain (0.5%).

Tabulated summary of adverse reactions
The following adverse reactions were identified in patients taking PREVYMIS 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).

 



18

Table 2: Adverse reactions identified with PREVYMIS
Frequency Adverse reactions
Immune system disorders
Uncommon hypersensitivity
Metabolism and nutrition disorders
Uncommon decreased appetite
Nervous system disorders
Uncommon dysgeusia, headache
Ear and labyrinth disorders
Uncommon vertigo
Gastrointestinal disorders
Common nausea, 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

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 national reporting system 
listed in Appendix V.

4.9 Overdose

There is no experience with human overdose with PREVYMIS. During Phase 1 clinical trials, 86 
healthy subjects received doses ranging from 720 mg/day to 1440 mg/day of PREVYMIS 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 PREVYMIS. 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 PREVYMIS from systemic 
circulation.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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). 

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


19

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 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 studies (see 
below). 

In clinical studies
In a Phase 2b trial evaluating letermovir doses of 60, 120, or 240 mg/day or placebo for up to 84 days 
in 131 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 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.

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 IV 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 subjects. Letermovir does not prolong QTc to any clinically 
relevant extent following the 960 mg IV dose with plasma concentrations approximately 2-fold higher 
than the 480 mg IV dose.

Clinical efficacy and safety

Adult CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant
To evaluate letermovir prophylaxis as a preventive strategy for CMV infection or disease, the efficacy 
of letermovir was assessed in a multicenter, double-blind, placebo-controlled Phase 3 trial (P001) in 
adult CMV-seropositive recipients [R+] of 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 cyclosporine, or placebo. Randomisation was stratified by investigational site and risk (high vs. 
low) for CMV reactivation at the time of study entry. Letermovir was initiated after HSCT (Day 0-28 
post-transplant) and continued through Week 14 post-transplant. Letermovir was administered either 
orally or IV; the dose of letermovir was the same regardless of the route of administration. Subjects 

 



20

were monitored through Week 24 post-transplant for the primary efficacy endpoint with continued 
follow-up through Week 48 post-transplant.

Subjects received CMV DNA monitoring weekly until post-transplant week 14 and then bi-weekly
until post-transplant 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-transplant. 

Among the 565 treated subjects, 373 subjects received letermovir (including 99 subjects who received 
at least one IV dose) and 192 received placebo (including 48 subjects who received at least one IV 
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 cyclosporine, and 42% were receiving tacrolimus. The 
most common primary reasons for transplant were acute myeloid leukemia (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 Leukocyte 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-transplant or had a missing outcome at Week 
24 post-transplant were counted as failures.

Letermovir demonstrated superior efficacy over placebo in the analysis of the primary endpoint, as 
shown in Table 3. The estimated treatment difference of -23.5% was statistically significant (one-sided 
p-value <0.0001).

 



21

Table 3: P001: Efficacy results in HSCT recipients (NC=F Approach, FAS Population)

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

Parameter       n (%) n (%) 
Primary efficacy endpoint
(Proportion of subjects who failed prophylaxis by 
Week 24)                 

122 (37.5)                                        103 (60.6)                         

Reasons for Failures†                                                  
                                                                                  

Clinically significant CMV infection                     57 (17.5)                                              71 (41.8)                                    
     CMV DNAemia warranting anti-CMV PET   52 (16.0)                                                 68 (40.0)                                    
    CMV end-organ disease                                                                5 (1.5)                                         3 (1.8)                                      

Discontinued from study                                     56 (17.2)                                              27 (15.9)                                    
Missing outcome                                         9 (2.8)                                                  5 (2.9)                            
                                                                                                                                                                                    
Stratum-adjusted treatment difference (Letermovir-
Placebo)§            

                                                                                          

Difference (95% CI)                                                             -23.5 (-32.5, -14.6)                                                                
p-value                                                                         <0.0001                                                                                             
† The categories of failure are mutually exclusive and based on the hierarchy of categories in the order 
listed.
§ 95% CIs and p-value for the treatment differences in percent response were calculated using stratum-
adjusted Mantel-Haenszel method with the difference weighted by the harmonic mean of sample size 
per arm for each stratum (high or low risk). A 1-sided p-value ≤0.0249 was used for declaring 
statistical significance.
FAS=Full analysis set; FAS includes randomised subjects who received at least one dose of study 
medicine, and excludes subjects with detectable CMV DNA at baseline. Approach to handling missing 
values: Non-Completer=Failure (NC=F) approach. With NC=F approach, failure was defined as all 
subjects with clinically significant CMV infection or who prematurely discontinued from the study or 
had a missing outcome through Week 24 post-transplant visit window.
N = number of subjects in each treatment group.
n (%) = Number (percent) of subjects in each sub-category.
Note: The proportion of subjects with detectable CMV viral DNA on Day 1 that developed clinically 
significant CMV infection in the letermovir group was 64.6% (31/48) compared to 90.9% (20/22) in 
the placebo group through Week 24 post-transplant. The estimated difference (95% CI for the 
difference) was -26.1% (-45.9%, -6.3%), with a nominal one-sided p-value <0.0048.

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

 



22

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)

C
u

m
u

la
tiv

e
p

ro
p

o
rt

io
n

o
f
su

b
je

c
ts

w
ith

C
M

V
 D

N
A

e
m

ia
 o

r 
d

is
e
a
se

(%
)

0

10

20

30

40

50

60

Weeks Post-Transplant

Week 0 Week 14 Week 24

Number of Subjects at Risk

Letermovir

Placebo

325 270 212

170 85 70

Letermovir vs Placebo

Stratified log-rank test, two-sided p-value <0.0001

6.8%

18.9%

41.3%
44.3%

Letermovir

Placebo

There were no differences in the incidence of or time to engraftment between the PREVYMIS 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).

 



23

Figure 2: P001: Forest plot of the proportion of subjects initiating anti-CMV PET or with CMV 
end-organ disease through Week 24 post-transplant 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.

Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with 
PREVYMIS in one or more subsets of the paediatric population for prophylaxis of cytomegalovirus 
infection (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

The pharmacokinetics of letermovir have been characterized following oral and IV administration in 
healthy subjects and HSCT recipients. Letermovir exposure increased in a greater than dose-
proportional manner with both oral or IV administration. The mechanism is likely
saturation/autoinhibition of OATP1B1/3.

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

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

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

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

Tacrolimus (n=145, 69)

Favors Placebo

Reduced intensity conditioning (n=86, 48)

Cyclosporin A (n=162, 90)

Haploidentical donor

Non-myeloablative (n=85, 37)

Immunosuppressive Regimen

Conditioning Regimen
Myeloablative (n=154, 85)

No (n=276, 153)
Yes (n=49, 17)

Mismatched unrelated (n=43, 24)

Mismatched related (n=52, 18)
Matched unrelated (n=122, 70)

Matched related (n=108, 58)
Donor mismatch

Bone marrow (n=72, 43)
Peripheral blood (n=241, 117)

Stem Cell Source

High Risk (n=102, 45)
Low Risk  (n=223, 125)

Risk stratum

Overall  (N=325, 170)

 



24

In HSCT recipients, letermovir AUC was estimated using population pharmacokinetic analyses using 
Phase 3 data (see Table 4). Differences in exposure across treatment regimens are not clinically 
relevant; efficacy was consistent across the range of exposures observed in P001.

Table 4: Letermovir AUC (ng•hr/mL) values in HSCT Recipients
Treatment Regimen Median (90% Prediction Interval)*

480 mg Oral, no cyclosporine 34,400 (16,900, 73,700)

480 mg IV, no cyclosporine 100,000 (65,300, 148,000)

240 mg Oral, with cyclosporine 60,800 (28,700, 122,000)

240 mg IV, with cyclosporine 70,300 (46,200, 106,000)

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

Absorption
Letermovir was absorbed rapidly with a median time to maximum plasma concentration (Tmax) of 1.5
to 3.0 hours and declined in a biphasic manner. In HSCT recipients, bioavailability of letermovir was 
estimated to be approximately 35% with 480 mg once daily oral letermovir administered without 
cyclosporine. The inter-individual variability for bioavailability was estimated to be approximately 
37%. 

Effect of cyclosporine
In HSCT recipients, co-administration of cyclosporine 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 cyclosporine in patients.
If letermovir is co-administered with cyclosporine, the recommended dose of letermovir is 240 mg 
once daily (see section 4.2).

Effect of food
In healthy subjects, oral administration of 480 mg single dose of letermovir 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 (Cmax) of letermovir. Letermovir may be administered 
orally with or without food as has been done in the clinical studies (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 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. 

 



25

Elimination
The mean apparent terminal half-life for letermovir is approximately 12 hours with 480 mg IV 
letermovir in healthy 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 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 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 subjects. The changes in letermovir exposure in 
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
Letermovir unbound AUC was approximately 115- and 81% higher in 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 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.

Weight
Based on population pharmacokinetic analyses, letermovir AUC is estimated to be 18.7% lower in 
subjects weighing 80-100 kg compared to subjects weighing 67 kg. This difference is not clinically 
relevant.

Race
Based on population pharmacokinetic analyses, 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 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.

 



26

5.3 Preclinical safety data

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 characterized 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 IV 
letermovir formulated with 1500 mg/kg/day of the cyclodextrin excipient hydroxypropylbetadex. 

Carcinogenesis
Carcinogenicity studies with letermovir have not been conducted.

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).

 



27

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core
Microcrystalline cellulose (E460)
Croscarmellose sodium (E468)
Povidone (E1201)
Colloidal anhydrous silica (E551)
Magnesium stearate (E470b)

Film-coating
Lactose monohydrate
Hypromellose (E464)
Titanium dioxide (E171)
Triacetin (E1518)
Iron oxide yellow (E172)
Iron oxide red (only for 480 mg tablets) (E172)
Carnauba wax (E903)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

This medicinal product does not require any special temperature storage conditions. Store in the 
original package in order to protect from moisture.

6.5 Nature and contents of container

240 mg film-coated tablets
Polyamide/Aluminium/PVC – Aluminium blister card. Each carton contains four (4) 7-count blister 
cards for a total of 28 tablets.

480 mg film-coated tablets
Polyamide/Aluminium/PVC – Aluminium blister cards. Each carton contains four (4) 7-count blister 
cards for a total of 28 tablets.

6.6 Special precautions for disposal

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

7. MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

 



28

8. MARKETING AUTHORISATION NUMBER(S) 

EU/1/17/1245/001
EU/1/17/1245/002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 8 January 2018

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.

 

http://www.ema.europa.eu/


29

This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions.

1. NAME OF THE MEDICINAL PRODUCT

PREVYMIS 240 mg concentrate for solution for infusion
PREVYMIS 480 mg concentrate for solution for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

PREVYMIS 240 mg concentrate for solution for infusion
Each vial contains 240 mg (12 mL per vial) of letermovir.
Each mL contains 20 mg of letermovir.

PREVYMIS 480 mg concentrate for solution for infusion
Each vial contains 480 mg (24 mL per vial) of letermovir.
Each mL contains 20 mg of letermovir.

Excipient with known effect
This medicinal product contains 23 mg (1.0 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 medicinal product contains 46 mg (2.0 mmol) sodium per 480 mg vial, equivalent to 2.30% of the 
WHO recommended maximum daily intake of 2 g sodium for an adult.

Each 240 mg dose (12 mL vial) of this medicinal product contains 1800 mg hydroxypropylbetadex
(cyclodextrin).
Each 480 mg dose (24 mL vial) of this medicinal product contains 3600 mg hydroxypropylbetadex
(cyclodextrin).
For additional information, see section 4.2.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Concentrate for solution for infusion (sterile concentrate)
Clear, colourless liquid
pH between 7 and 8

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

PREVYMIS is indicated for prophylaxis of cytomegalovirus (CMV) reactivation and disease in adult 
CMV-seropositive recipients [R+] of an allogeneic haematopoietic stem cell transplant (HSCT).

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

4.2 Posology and method of administration

PREVYMIS should be initiated by a physician experienced in the management of patients who have 
had an allogeneic haematopoietic stem cell transplant.

 



30

Posology
PREVYMIS is also available for oral administration (240 mg and 480 mg film-coated tablets).

PREVYMIS tablets and concentrate for solution for infusion may be used interchangeably at the 
discretion of the physician, and no dose adjustment is necessary.

The recommended dosage of PREVYMIS is 480 mg once daily.

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

The safety and efficacy of letermovir use for more than 100 days has not been studied in clinical 
trials. Prolonged letermovir prophylaxis beyond 100 days post-transplant may be of benefit in some 
patients at high risk for late CMV reactivation (see section 5.1). Use of letermovir prophylaxis for 
greater than 100 days requires a careful assessment of the benefit-risk balance.

Dosage adjustment 
If PREVYMIS is co-administered with cyclosporine, the dosage of PREVYMIS should be decreased 
to 240 mg once daily (see sections 4.5 and 5.2).
 If cyclosporine is initiated after starting PREVYMIS, the next dose of PREVYMIS should be 

decreased to 240 mg once daily.
 If cyclosporine is discontinued after starting PREVYMIS, the next dose of PREVYMIS should be 

increased to 480 mg once daily.
 If cyclosporine dosing is temporarily interrupted due to high cyclosporine levels, no dose 

adjustment of PREVYMIS 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 PREVYMIS is required based on age (see sections 5.1 and 5.2).

Hepatic impairment
No dose adjustment of PREVYMIS is required based on mild (Child-Pugh Class A) to moderate 
(Child-Pugh Class B) hepatic impairment. PREVYMIS is not recommended for patients with severe 
(Child-Pugh Class C) hepatic impairment (see section 5.2).

Combined hepatic and renal impairment
PREVYMIS 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 PREVYMIS 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. The anticipated 
clinical exposure to hydroxypropylbetadex with intravenously administered letermovir is expected to 
be approximately 3600 mg/day for a letermovir dose of 480 mg. There were no cases of kidney injury 
caused by hydroxypropylbetadex in human studies of intravenously administered letermovir with 
treatment durations of up to 47 days. In patients with moderate or severe renal impairment (creatinine 

 



31

clearance less than 50 mL/min) receiving PREVYMIS, accumulation of hydroxypropylbetadex, could 
occur (see section 5.3). Serum creatinine levels should be closely monitored in these patients.

Paediatric population
The safety and efficacy of PREVYMIS in patients below 18 years of age have not been established. 
No data are available (see section 5.1).

Method of administration
For intravenous use only.
PREVYMIS concentrate for solution for infusion requires dilution (see section 6.6) prior to 
administration.
PREVYMIS 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.
PREVYMIS should be administered as an intravenous (IV) infusion only. PREVYMIS should not be 
administered as an intravenous push or bolus.
After dilution, PREVYMIS 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 IV bag 
should be administered.

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 cyclosporine:
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
The safety and efficacy of letermovir has been established in 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 bi-weekly 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 PREVYMIS 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
PREVYMIS 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).

 



32

Increased monitoring of cyclosporine, 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).

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
PREVYMIS 240 mg concentrate for solution for infusion contains 23 mg (or 1.0 mmol) sodium per 
dose. This should be taken into consideration by patients on a controlled sodium diet.
PREVYMIS 480 mg concentrate for solution for infusion contains 46 mg (or 2.0 mmol) sodium per 
dose. This should be taken into consideration by patients on a controlled sodium diet.

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 
cyclosporine.
-The combination of cyclosporine 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 metabolizing enzymes or transporters
Co-administration of PREVYMIS (with or without cyclosporine) 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, St. John’s wort 
(Hypericum perforatum), 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).

 



33

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

Inhibitors of OATP1B1 or 3 
Co-administration of PREVYMIS with medicinal products that are inhibitors of OATP1B1/3 
transporters may result in increased letermovir plasma concentrations. If PREVYMIS is co-
administered with cyclosporine (a potent OATP1B1/3 inhibitor), the recommended dose of 
PREVYMIS is 240 mg once daily (see Table 1 and sections 4.2 and 5.2). Caution is advised if other 
OATP1B1/3 inhibitors are added to letermovir combined with cyclosporine.
-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
cyclosporine 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 PREVYMIS with oral 
midazolam (a CYP3A substrate) results in 2-3-fold increased midazolam plasma concentrations. Co-
administration of PREVYMIS 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., cyclosporine, 
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 cyclosporine 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.

 



34

Medicinal products transported by OATP1B1/3
Letermovir is an inhibitor of OATP1B1/3 transporters. Administration of PREVYMIS 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 
cyclosporine, the effect is more marked after iv than oral letermovir. 
The magnitude of the OATP1B1/3 inhibition on co-administered medicinal products is likely greater 
when PREVYMIS is co-administered with cyclosporine (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 PREVYMIS 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 cyclosporine, than IV
letermovir with or without cyclosporine, or oral letermovir with cyclosporine. 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 cyclosporine is not recommended.

Medicinal products transported by P-gp in the intestine
Letermovir is an inducer of intestinal P-gp. Administration of PREVYMIS 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 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 PREVYMIS, 
doses should be readjusted after treatment with PREVYMIS is completed. A dose adjustment may also 
be needed when changing route of administration or immunosuppressant.

 



35

Table 1 provides a listing of established or potentially clinically significant medicinal product 
interactions. The medicinal product interactions described are based on studies conducted with 
PREVYMIS or are predicted medicinal product interactions that may occur with PREVYMIS (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 with oral letermovir without
cyclosporine. Please note that the interaction potential and clinical consequences may be 
different depending on whether letermovir is administered orally or IV, and whether
cyclosporine 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 PREVYMIS

Antibiotics
nafcillin Interaction not studied.

Expected:
↓ letermovir

(P-gp/UGT induction)

Nafcillin may decrease plasma 
concentrations of letermovir.
Co-administration of PREVYMIS 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)

↔ letermovir
AUC 1.33 (1.17, 1.51)
Cmax 1.21 (1.05, 1.39)

No dose adjustment required.

posaconazole‡

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

↔ posaconazole
AUC 0.98 (0.82, 1.17)
Cmax 1.11 (0.95, 1.29)

No dose adjustment required.

voriconazole‡

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

↓ voriconazole
AUC 0.56 (0.51, 0.62)
Cmax 0.61 (0.53, 0.71)

(CYP2C9/19 induction)

If concomitant 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.

 



36

Concomitant 
medicinal product 

Effect on concentration†

Mean ratio (90 % confidence 
interval) for AUC, Cmax

(likely mechanism of action)

Recommendations concerning co-
administration with PREVYMIS

Antimycobacterials
rifabutin Interaction not studied.

Expected:
↓ letermovir

(P-gp/UGT induction)

Rifabutin may decrease plasma 
concentrations of letermovir.
Co-administration of PREVYMIS and 
rifabutin is not recommended.

Rifampicin

Multiple dose rifampicin decreases plasma 
concentrations of letermovir. 
Co-administration of PREVYMIS 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 
IV)/ 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 PREVYMIS 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 PREVYMIS 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.

 



37

Concomitant 
medicinal product 

Effect on concentration†

Mean ratio (90 % confidence 
interval) for AUC, Cmax

(likely mechanism of action)

Recommendations concerning co-
administration with PREVYMIS

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 PREVYMIS 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 PREVYMIS 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 PREVYMIS 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 
PREVYMIS#.

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

When PREVYMIS is co-administered with 
cyclosporine, use of these statins is 
contraindicated.

 



38

Concomitant 
medicinal product 

Effect on concentration†

Mean ratio (90 % confidence 
interval) for AUC, Cmax

(likely mechanism of action)

Recommendations concerning co-
administration with PREVYMIS

fluvastatin, 
pravastatin

Interaction not studied.
Expected:
↑ HMG-CoA reductase 
inhibitors

(OATP1B1/3 and/or BCRP 
inhibition)

Letermovir may increase statin plasma 
concentrations. 

When PREVYMIS 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 PREVYMIS is co-administered with 
cyclosporine, 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
cyclosporine
(50 mg single dose)/ 
letermovir (240 mg 
daily)

↑ cyclosporine
AUC 1.66 (1.51, 1.82)
Cmax 1.08 (0.97, 1.19) 
(CYP3A inhibition)

If PREVYMIS is co-administered with 
cyclosporine, the dosage of PREVYMIS 
should be decreased to 240 mg once daily 
(see sections 4.2 and 5.1).

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

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

↑ letermovir
AUC 2.11 (1.97, 2.26)
Cmax 1.48 (1.33, 1.65)

(OATP1B1/3 inhibition)

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

↔mycophenolic acid
AUC 1.08 (0.97, 1.20)
Cmax 0.96 (0.82, 1.12)

↔ letermovir
AUC 1.18 (1.04, 1.32)
Cmax 1.11 (0.92, 1.34)

No dose adjustment required.

 



39

Concomitant 
medicinal product 

Effect on concentration†

Mean ratio (90 % confidence 
interval) for AUC, Cmax

(likely mechanism of action)

Recommendations concerning co-
administration with PREVYMIS

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 
PREVYMIS administration route, and at 
discontinuation of PREVYMIS and the 
dose of sirolimus adjusted accordingly#.
Frequent monitoring of sirolimus 
concentrations is recommended at initiation 
or discontinuation of cyclosporine co-
administration with PREVYMIS. 

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

When PREVYMIS is co-administered with 
cyclosporine, the magnitude of the increase 
in concentrations of sirolimus may be 
greater than with PREVYMIS 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 
PREVYMIS administration route, and at 
discontinuation of PREVYMIS 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.

 



40

Concomitant 
medicinal product 

Effect on concentration†

Mean ratio (90 % confidence 
interval) for AUC, Cmax

(likely mechanism of action)

Recommendations concerning co-
administration with PREVYMIS

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 PREVYMIS is co-administered with 
cyclosporine, the plasma concentrations of 
repaglinide is expected to increase due to 
the additional OATP1B inhibition by 
cyclosporine. 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 PREVYMIS is co-administered with 
cyclosporine, refer also to the glyburide 
prescribing information for specific dosing 
recommendations.

 



41

Concomitant 
medicinal product 

Effect on concentration†

Mean ratio (90 % confidence 
interval) for AUC, Cmax

(likely mechanism of action)

Recommendations concerning co-
administration with PREVYMIS

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 PREVYMIS 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 PREVYMIS 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 PREVYMIS 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 PREVYMIS is co-administered with 
cyclosporine, dabigatran is contraindicated.

 



42

Concomitant 
medicinal product 

Effect on concentration†

Mean ratio (90 % confidence 
interval) for AUC, Cmax

(likely mechanism of action)

Recommendations concerning co-
administration with PREVYMIS

Sedatives
midazolam
(1 mg single dose 
IV)/ letermovir 
(240 mg once daily 
PO)

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

↑ midazolam
IV:
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 PREVYMIS 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 
PREVYMIS is co-administered with 
cyclosporine, 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 PREVYMIS in 
combination with cyclosporine 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 PREVYMIS#. 

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 
PREVYMIS with quinidine. Refer to the 
respective prescribing information#.

 



43

Concomitant 
medicinal product 

Effect on concentration†

Mean ratio (90 % confidence 
interval) for AUC, Cmax

(likely mechanism of action)

Recommendations concerning co-
administration with PREVYMIS

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

 



44

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 
PREVYMIS 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.

4.7 Effects on ability to drive and use machines

PREVYMIS may have minor influence on the ability to drive or use machines. Fatigue and vertigo 
have been reported in some patients during treatment with PREVYMIS, 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 PREVYMIS was based on a Phase 3 clinical trial (P001) in HSCT recipients 
who received PREVYMIS 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 PREVYMIS
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 PREVYMIS were nausea 
(1.6%), vomiting (0.8%), and abdominal pain (0.5%).

Tabulated summary of adverse reactions
The following adverse reactions were identified in patients taking PREVYMIS 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).

 



45

Table 2: Adverse reactions identified with PREVYMIS
Frequency Adverse reactions
Immune system disorders
Uncommon hypersensitivity
Metabolism and nutrition disorders
Uncommon decreased appetite
Nervous system disorders
Uncommon dysgeusia, headache
Ear and labyrinth disorders
Uncommon vertigo
Gastrointestinal disorders
Common nausea, 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

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 national reporting system 
listed in Appendix V.

4.9 Overdose

There is no experience with human overdose with PREVYMIS. During Phase 1 clinical trials, 86 
healthy subjects received doses ranging from 720 mg/day to 1440 mg/day of PREVYMIS 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 PREVYMIS. 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 PREVYMIS from systemic 
circulation.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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). 

 

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46

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 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 studies (see 
below). 

In clinical studies
In a Phase 2b trial evaluating letermovir doses of 60, 120, or 240 mg/day or placebo for up to 84 days 
in 131 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 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.

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 IV 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 subjects. Letermovir does not prolong QTc to any clinically 
relevant extent following the 960 mg IV dose with plasma concentrations approximately 2-fold higher 
than the 480 mg IV dose.

Clinical efficacy and safety

Adult CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant
To evaluate letermovir prophylaxis as a preventive strategy for CMV infection or disease, the efficacy 
of letermovir was assessed in a multicenter, double-blind, placebo-controlled Phase 3 trial (P001) in 
adult CMV-seropositive recipients [R+] of 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 cyclosporine, or placebo. Randomisation was stratified by investigational site and risk (high vs. 
low) for CMV reactivation at the time of study entry. Letermovir was initiated after HSCT (Day 0-28 
post-transplant) and continued through Week 14 post-transplant. Letermovir was administered either 
orally or IV; the dose of letermovir was the same regardless of the route of administration. Subjects 

 



47

were monitored through Week 24 post-transplant for the primary efficacy endpoint with continued 
follow-up through Week 48 post-transplant. 

Subjects received CMV DNA monitoring weekly until post-transplant week 14 and then bi-weekly 
until post-transplant 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-transplant. 

Among the 565 treated subjects, 373 subjects received letermovir (including 99 subjects who received 
at least one IV dose) and 192 received placebo (including 48 subjects who received at least one IV 
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 cyclosporine, and 42% were receiving tacrolimus. The 
most common primary reasons for transplant were acute myeloid leukemia (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 Leukocyte 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-transplant or had a missing outcome at Week 
24 post-transplant were counted as failures.
Letermovir demonstrated superior efficacy over placebo in the analysis of the primary endpoint, as 
shown in Table 3. The estimated treatment difference of -23.5% was statistically significant (one-sided 
p-value <0.0001).

 



48

Table 3: P001: Efficacy results in HSCT recipients (NC=F Approach, FAS Population)

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

Parameter       n (%) n (%) 
Primary efficacy endpoint
(Proportion of subjects who failed prophylaxis by 
Week 24)                 

122 (37.5)                                        103 (60.6)                              

Reasons for Failures†                                                  
                                                                                          

Clinically significant CMV infection                      57 (17.5)                                              71 (41.8)                                    
     CMV DNAemia warranting anti-CMV PET    52 (16.0)                                                 68 (40.0)                                    
    CMV end-organ disease                                                                5 (1.5)                                          3 (1.8)                                      
Discontinued from study                                    56 (17.2)                                              27 (15.9)                                    
Missing outcome                                         9 (2.8)                                                  5 (2.9)                             
                                                                                                                                                                                            
Stratum-adjusted treatment difference (Letermovir-
Placebo)§            

                                                                                          

Difference (95% CI)                                                             -23.5 (-32.5, -14.6)                                                                                
p-value                                                                         <0.0001                                                                                             
† The categories of failure are mutually exclusive and based on the hierarchy of categories in the order 
listed.
§ 95% CIs and p-value for the treatment differences in percent response were calculated using stratum-
adjusted Mantel-Haenszel method with the difference weighted by the harmonic mean of sample size 
per arm for each stratum (high or low risk). A 1-sided p-value ≤0.0249 was used for declaring 
statistical significance.
FAS=Full analysis set; FAS includes randomised subjects who received at least one dose of study 
medicine, and excludes subjects with detectable CMV DNA at baseline. Approach to handling missing 
values: Non-Completer=Failure (NC=F) approach. With NC=F approach, failure was defined as all 
subjects with clinically significant CMV infection or who prematurely discontinued from the study or 
had a missing outcome through Week 24 post-transplant visit window.
N = number of subjects in each treatment group.
n (%) = Number (percent) of subjects in each sub-category.
Note: The proportion of subjects with detectable CMV viral DNA on Day 1 that developed clinically 
significant CMV infection in the letermovir group was 64.6% (31/48) compared to 90.9% (20/22) in 
the placebo group through Week 24 post-transplant. The estimated difference (95% CI for the 
difference) was -26.1% (-45.9%, -6.3%), with a nominal one-sided p-value <0.0048.

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

 



49

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)

C
u

m
u

la
tiv

e
p

ro
p

o
rt

io
n

o
f
su

b
je

c
ts

w
ith

C
M

V
 D

N
A

e
m

ia
 o

r 
d

is
e
a
se

(%
)

0

10

20

30

40

50

60

Weeks Post-Transplant

Week 0 Week 14 Week 24

Number of Subjects at Risk

Letermovir

Placebo

325 270 212

170 85 70

Letermovir vs Placebo

Stratified log-rank test, two-sided p-value <0.0001

6.8%

18.9%

41.3%
44.3%

Letermovir

Placebo

There were no differences in the incidence of or time to engraftment between the PREVYMIS 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).

 



50

Figure 2: P001: Forest plot of the proportion of subjects initiating anti-CMV PET or with CMV 
end-organ disease through Week 24 post-transplant 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.

Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with 
PREVYMIS in one or more subsets of the paediatric population for prophylaxis of cytomegalovirus 
infection (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

The pharmacokinetics of letermovir have been characterized following oral and IV administration in 
healthy subjects and HSCT recipients. Letermovir exposure increased in a greater than dose-
proportional manner with both oral or IV administration. The mechanism is likely 
saturation/autoinhibition of OATP1B1/3.

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

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

In HSCT recipients, letermovir AUC was estimated using population pharmacokinetic analyses using 
Phase 3 data (see Table 4). Differences in exposure across treatment regimens are not clinically 
relevant; efficacy was consistent across the range of exposures observed in P001.

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

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

Tacrolimus (n=145, 69)

Favors Placebo

Reduced intensity conditioning (n=86, 48)

Cyclosporin A (n=162, 90)

Haploidentical donor

Non-myeloablative (n=85, 37)

Immunosuppressive Regimen

Conditioning Regimen
Myeloablative (n=154, 85)

No (n=276, 153)
Yes (n=49, 17)

Mismatched unrelated (n=43, 24)

Mismatched related (n=52, 18)
Matched unrelated (n=122, 70)

Matched related (n=108, 58)
Donor mismatch

Bone marrow (n=72, 43)
Peripheral blood (n=241, 117)

Stem Cell Source

High Risk (n=102, 45)
Low Risk (n=223, 125)

Risk stratum

Overall  (N=325, 170)

 



51

Table 4: Letermovir AUC (ng•hr/mL) values in HSCT Recipients
Treatment Regimen Median (90% Prediction Interval)*

480 mg Oral, no cyclosporine 34,400 (16,900, 73,700)

480 mg IV, no cyclosporine 100,000 (65,300, 148,000)

240 mg Oral, with cyclosporine 60,800 (28,700, 122,000)

240 mg IV, with cyclosporine 70,300 (46,200, 106,000)

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

Absorption
Letermovir was absorbed rapidly with a median time to maximum plasma concentration (Tmax) of 1.5
to 3.0 hours and declined in a biphasic manner. In HSCT recipients, bioavailability of letermovir was 
estimated to be approximately 35% with 480 mg once daily oral letermovir administered without 
cyclosporine. The inter-individual variability for bioavailability was estimated to be approximately 
37%. 

Effect of cyclosporine
In HSCT recipients, co-administration of cyclosporine 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 cyclosporine in patients.
If letermovir is co-administered with cyclosporine, the recommended dose of letermovir is 240 mg 
once daily (see section 4.2).

Effect of food
In healthy subjects, oral administration of 480 mg single dose of letermovir 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 (Cmax) of letermovir. Letermovir may be administered 
orally with or without food as has been done in the clinical studies (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 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 IV 
letermovir in healthy 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.

 



52

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 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 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 subjects. The changes in letermovir exposure in 
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
Letermovir unbound AUC was approximately 115- and 81% higher in 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 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.

Weight
Based on population pharmacokinetic analyses, letermovir AUC is estimated to be 18.7% lower in 
subjects weighing 80-100 kg compared to subjects weighing 67 kg. This difference is not clinically 
relevant.

Race
Based on population pharmacokinetic analyses, 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 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.

5.3 Preclinical safety data

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 characterized 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. 

 



53

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 IV 
letermovir formulated with 1500 mg/kg/day of the cyclodextrin excipient hydroxypropylbetadex. 

Carcinogenesis
Carcinogenicity studies with letermovir have not been conducted.

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).

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Hydroxypropylbetadex (cyclodextrin)
Sodium chloride
Sodium hydroxide (E524)
Water for injections

6.2 Incompatibilities

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

 



54

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 IV 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.

6.3. Shelf life

Unopened vial: 30 months
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.

6.4 Special precautions for storage

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.

6.5 Nature and contents of container

Type I (30 mL) clear glass vial with a 20 mm fluorocoated chlorobutyl stopper with aluminium flip-off 
cap containing 12 mL(medium green cap) or 24 mL (dark blue cap) of solution.
Pack size: 1 vial.

6.6 Special precautions for disposal and other handling

PREVYMIS vials are for single use only. 

Preparation
The preparation and administration instructions are the same for either dose. 
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 IV 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.
Add one single-dose vial (either 12 mL (240 mg dose) or 24 mL (480 mg dose)) of PREVYMIS
concentrate for solution for infusion to a 250 mL pre-filled IV bag containing either 0.9% sodium
chloride or 5% dextrose, and mix the diluted solution by gentle inversion. Do not shake.
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

 



55

particles. If a vial is added to a 250 mL IV diluent bag, the final concentration ranges of letermovir 
would be 0.9 mg/mL (for 240 mg dose) and 1.8 mg/mL (for 480 mg dose).

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
• Ampicillin sodium • Fluconazole 
• Ampicillin sodium/Sulbactam sodium • Human insulin 
• Anti-thymocyte globulin • Magnesium sulfate 
• Caspofungin • Methotrexate 
• Daptomycin • Micafungin 
• Fentanyl citrate 

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

List of compatible medicinal products when PREVYMIS and medicinal products* are prepared 
in 5% dextrose
• Amphotericin B (lipid complex)† • Hydrocortisone sodium succinate
• Anidulafungin • Morphine sulfate
• Cefazolin sodium • Norepinephrine bitartrate
• Ceftaroline • Pantoprazole sodium
• Ceftriaxone sodium • Potassium chloride 
• Doripenem • Potassium phosphate 
• Famotidine • Tacrolimus 
• Folic acid • Telavancin 
• Ganciclovir sodium • Tigecycline 

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

Compatible intravenous bags and infusion set materials
PREVYMIS is compatible with the following intravenous bags and infusion set materials. 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)

 



56

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.

7. MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

8. MARKETING AUTHORISATION NUMBER(S) 

EU/1/17/1245/003
EU/1/17/1245/004

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 8 January 2018

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.

 

http://www.ema.europa.eu/


57

ANNEX II

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH 
RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 
AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 
THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT

 



58

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer(s) responsible for batch release
Schering-Plough Labo NV
Industriepark 30
2220 Heist-op-den-Berg
BELGIUM

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 

Characteristics, section 4.2).

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION 

 Periodic safety update reports (PSURs)

The requirements for submission of PSUR for this medicinal product are set out in the list of Union 

reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 

subsequent updates published on the European medicines web-portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT

 Risk management plan (RMP)

The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 

and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing 

authorisation and any agreed subsequent updates of the RMP.

An updated RMP should be submitted:

 At the request of the European Medicines Agency;

 Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk profile or 

as the result of an important (pharmacovigilance or risk minimisation) milestone being 

reached. 

 Obligation to conduct post-authorisation measures

The MAH shall complete, within the stated timeframe, the below measures:

Description Due date

In order to optimise the sterility assurance level (SAL) of the manufacturing process, the 

marketing authorisation holder should implement the measures outlined in the Post 

Approval Change Management Protocol (PACMP) agreed with the CHMP concerning 

development, validation and introduction of terminal sterilisation.

31 May 2021
(PACMP Step 2)

 



59

ANNEX III

LABELLING AND PACKAGE LEAFLET

 



60

A. LABELLING

 



61

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Outer carton for 240 mg film-coated tablets

1. NAME OF THE MEDICINAL PRODUCT

PREVYMIS 240 mg film-coated tablets
letermovir

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 240 mg of letermovir.

3. LIST OF EXCIPIENTS

Contains lactose.
See package leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

28 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use
The tablets shall be swallowed whole with some water. 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in the original package in order to protect from moisture.

 



62

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/17/1245/001

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

PREVYMIS 240 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

 



63

MINIMUM PARTICULARS TO APPEAR ON BLISTERS

Blister for 240 mg film-coated tablets

1. NAME OF THE MEDICINAL PRODUCT

PREVYMIS 240 mg tablets
letermovir

2. NAME OF THE MARKETING AUTHORISATION HOLDER

MSD

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

 



64

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Outer carton for 480 mg film-coated tablets

1. NAME OF THE MEDICINAL PRODUCT

PREVYMIS 480 mg film-coated tablets
letermovir

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 480 mg of letermovir.

3. LIST OF EXCIPIENTS

Contains lactose.
See package leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

28 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use
The tablets shall be swallowed whole with some water.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in the original package in order to protect from moisture.

 



65

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/17/1245/002

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

PREVYMIS 480 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

 



66

MINIMUM PARTICULARS TO APPEAR ON BLISTERS

Blister for 480 mg film-coated tablets

1. NAME OF THE MEDICINAL PRODUCT

PREVYMIS 480 mg tablets
letermovir

2. NAME OF THE MARKETING AUTHORISATION HOLDER

MSD

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

 



67

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Outer carton for 240 mg concentrate for solution for infusion

1. NAME OF THE MEDICINAL PRODUCT

PREVYMIS 240 mg concentrate for solution for infusion
letermovir

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each 12 mL vial contains 240 mg letermovir.
Each mL contains 20 mg of letermovir.

3. LIST OF EXCIPIENTS

Contains sodium and cyclodextrin.
See package leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

Concentrate for solution for infusion 
1 vial

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Intravenous use after dilution, must be infused through an in-line filter.
Single use only

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in the original carton in order to protect from light.

 



68

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/17/1245/003

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Justification for not including Braille accepted.

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

 



69

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

Vial label for 240 mg concentrate for solution for infusion

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

PREVYMIS 240 mg sterile concentrate 
letermovir
I.V., must be infused through an in-line filter.

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

6. OTHER

MSD 

 



70

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Outer carton for 480 mg concentrate for solution for infusion

1. NAME OF THE MEDICINAL PRODUCT

PREVYMIS 480 mg concentrate for solution for infusion
letermovir

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each 24 mL vial contains 480 mg of letermovir.
Each mL contains 20 mg of letermovir.

3. LIST OF EXCIPIENTS

Contains sodium and cyclodextrin.
See package leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

Concentrate for solution for infusion 
1 vial

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Intravenous use after dilution, must be infused through an in-line filter.
Single use only

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in the original carton in order to protect from light.

 



71

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/17/1245/004

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Justification for not including Braille accepted.

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

 



72

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

Vial label for 480 mg concentrate for solution for infusion

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

PREVYMIS 480 mg sterile concentrate
letermovir
I.V., must be infused through an in-line filter.

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

6. OTHER

MSD

 



73

B. PACKAGE LEAFLET

 



74

Package leaflet: Information for the patient

PREVYMIS 240 mg film-coated tablets
PREVYMIS 480 mg film-coated tablets

letermovir

This medicine is subject to additional monitoring. This will allow quick identification of new 
safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects.

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you.
 Keep this leaflet. You may need to read it again.
 If you have any further questions, ask your doctor, pharmacist, or nurse.
 This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
 If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What PREVYMIS is and what it is used for
2. What you need to know before you take PREVYMIS
3. How to take PREVYMIS
4. Possible side effects
5. How to store PREVYMIS
6. Contents of the pack and other information

1. What PREVYMIS is and what it is used for

PREVYMIS is an antiviral prescription medicine that contains the active substance letermovir. 

PREVYMIS is a medicine for adults who have recently had a bone marrow transplant. The medicine 
helps stop you from getting ill from CMV (‘cytomegalovirus’).

CMV is a virus that a lot of people have without knowing. Normally, CMV just stays in their body and 
it does not hurt them. However, if your immune system is weak after you get a bone marrow 
transplant, you may be at high risk of becoming ill from CMV.

2. What you need to know before you take PREVYMIS

Do not take PREVYMIS if:
 you are allergic to letermovir or any of the other ingredients of this medicine (listed in section 6).
 you take either of these medicines:

o pimozide - used for Tourette’s syndrome
o ergot alkaloids (such as ergotamine and dihydroergotamine) - used for migraine

headaches.
 you take the following herbal product:

o St. John’s wort (Hypericum perforatum)
Do not take PREVYMIS if any of the above apply to you. If you are not sure, talk to your doctor, 
pharmacist or nurse before taking PREVYMIS.

 



75

If you are taking PREVYMIS with cyclosporine, do not take the following medicines: 
o dabigatran - used for blood clots
o atorvastatin, simvastatin, rosuvastatin, pitavastatin –for high cholesterol

Warnings and precautions 
If you are also taking a medicine for high cholesterol (see list of medicines in section “Other medicines
and PREVYMIS” below) you must tell your doctor immediately if you have unexplained muscle aches
or pains especially if you feel unwell or have a fever. Your medicine or dose may then need to be 
changed. See the package leaflet for your other medicine for further information.

Additional blood tests may be needed to monitor the following medicinal products:
 Cyclosporine, tacrolimus, sirolimus
 Voriconazole

Children and adolescents
PREVYMIS is not for use in children and adolescents under 18 years old. This is because PREVYMIS
has not been tested in this age group.

Other medicines and PREVYMIS
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other 
medicines. This is because PREVYMIS may affect the way other medicines work, and other 
medicines may affect how PREVYMIS works. Your doctor or pharmacist will tell you if it is safe to 
take PREVYMIS with other medicines.

There are some medicines you must not take with PREVYMIS. See list under “Do not take
PREVYMIS if you take either of these medicines.”

Also tell your doctor if you are taking any of the following medicines. This is because your doctor may
have to change your medicines or change the dose of your medicines:
 alfentanil - for severe pain
 fentanyl - for severe pain
 quinidine - for abnormal heart rhythms
 cyclosporine, tacrolimus, sirolimus - used to prevent transplant rejection
 voriconazole - for fungal infections
 statins, such as atorvastatin, fluvastatin, rosuvastatin, simvastatin, pravastatin, pitavastatin - for

high cholesterol
 glyburide, repaglinide - for high blood sugar
 carbamazepine, phenobarbital, phenytoin - for fits or seizures
 dabigatran, warfarin - used to thin the blood or for blood clots
 midazolam – used as a sedative  
 amiodarone - used to correct irregular heartbeats
 oral contraceptive steroids-for birth control
 omeprazole, pantoprazole – for stomach ulcers and other stomach

problems
 nafcillin - for bacterial infections
 rifabutin, rifampicin - for mycobacterial infections
 thioridazine - for psychiatric disorders
 bosentan - for high blood pressure in the vessels in the lungs
 efavirenz, etravirine, nevirapine, lopinavir, ritonavir - for HIV
 modafinil - for wakefulness

You can ask your doctor or pharmacist for a list of medicines that may interact with PREVYMIS.

Pregnancy
If you are pregnant, think you may be pregnant, or are planning to have a baby, ask your doctor for 
advice before taking this medicine. PREVYMIS is not recommended in pregnancy. This is because it 

 



76

has not been studied in pregnancy and it is not known if PREVYMIS will harm your baby while you 
are pregnant.

Breast-feeding
If you are breast-feeding or are planning to breast-feed, tell your doctor before taking this medicine. 
Breast-feeding is not recommended while taking PREVYMIS. This is because it is not known if 
PREVYMIS gets in your breast milk and will be passed to your baby.

Driving and using machines
PREVYMIS may have minor influence on your ability to drive and use machines (see section 4 
Possible Side Effects below). Some patients have reported fatigue (feeling very tired) or vertigo 
(feeling like you are spinning) during treatment with PREVYMIS. If you experience any of these 
effects, do not drive or use machines until the effect wears off. 

PREVYMIS contains lactose
PREVYMIS contains lactose monohydrate. If you have been told by your doctor that you have an 
intolerance to some sugars, contact your doctor before taking this medicinal product.

PREVYMIS contains sodium
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is
to say essentially ‘sodium-free’.

3. How to take PREVYMIS

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure.

How much to take
The recommended dose of PREVYMIS is one 480 mg tablet once a day. If you also take cyclosporine, 
your doctor will decrease the dose of PREVYMIS to one 240 mg tablet once a day. 
 Take PREVYMIS at the same time every day.
 Take it with or without food.

How to take
 Swallow the tablet whole with some water. Do not break, crush, or chew the tablet. 

If you take more PREVYMIS than you should
If you take more PREVYMIS than you should, call your doctor straight away.

If you forget to take PREVYMIS
It is very important that you do not miss or skip doses of PREVYMIS.
 If you forget a dose, take it as soon as you remember. However, if it is nearly time for the next 

dose, skip the missed dose. Take your next dose at the usual time.
 Do not take two doses of PREVYMIS at the same time to make up for a missed dose.
 If you are not sure what to do, call your doctor or pharmacist.

Do not stop taking PREVYMIS
Do not stop taking PREVYMIS without talking to your doctor first. Do not run out of PREVYMIS. 
This will give the medicine the best chance to keep you from becoming ill from CMV after you get a 
bone marrow transplant.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist, or nurse.

4. Possible side effects

 



77

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Common: may affect up to 1 in 10 people
 diarrhoea
 feeling sick (nausea)
 being sick (vomiting)

Uncommon: may affect up to 1 in 100 people
 allergic reaction (hypersensitivity) – the signs may include wheezing, difficulty breathing, rashes 

or hives, itchiness, swelling
 loss of appetite
 changes in taste
 headache
 feeling like you are spinning (vertigo)
 stomach ache
 abnormalities in laboratory tests of liver function
 muscle spasms
 high blood creatinine - shown in blood tests
 feeling very tired (fatigue)
 swelling of hands or feet

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine.

5. How to store PREVYMIS

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and blister card after EXP. 
The expiry date refers to the last day of that month.

This medicinal product does not require any special temperature storage conditions. Store in the 
original package in order to protect from moisture.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to
throw away medicines you no longer use. These measures will help to protect the environment.

6. Contents of the pack and other information

What PREVYMIS contains
The active substance is letermovir. Each film-coated tablet contains 240 mg letermovir or 480 mg 
letermovir.

The other ingredients are:
Tablet core
Microcrystalline cellulose (E460), croscarmellose sodium (E468), povidone (E1201), colloidal 
anhydrous silica (E551), magnesium stearate (E470b). 
Film-coating
Lactose monohydrate, hypromellose (E464), titanium dioxide (E171), triacetin (E1518), iron oxide 
yellow (E172), iron oxide red (only for 480 mg tablets) (E172), carnauba wax (E903).

 

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78

What PREVYMIS looks like and contents of the pack
PREVYMIS 240 mg film-coated tablets
PREVYMIS 240 mg film-coated tablet is a yellow oval tablet, debossed with “591” on one side and 
MSD logo on the other side. The tablet is 16.5 mm long and 8.5 mm wide.
The 240 mg tablets are packaged into a carton containing four (4) 7-count Polyamide/Aluminium/PVC 
– Aluminium blister cards for a total of 28 tablets.

PREVYMIS 480 mg film-coated tablets
PREVYMIS 480 mg film-coated tablet is a pink oval, bi-convex tablet, debossed with “595” on one
side and MSD logo on the other side. The tablet is 21.2 mm long and 10.3 mm wide.
The 480 mg tablets are packaged into a carton containing four (4) 7-count Polyamide/Aluminium/PVC 
– Aluminium blister cards for a total of 28 tablets.

Marketing Authorisation Holder
Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

Manufacturer
Schering-Plough Labo NV
Industriepark 30 – Zone A
B-2220 Heist-op-den-Berg
Belgium

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
MSD Belgium BVBA/SPRL
Tél/Tel: +32(0)27766211
dpoc_belux@merck.com

Lietuva
UAB Merck Sharp & Dohme
Tel. + 370 5 278 02 47
msd_lietuva@merck.com

България
Мерк Шарп и Доум България ЕООД
Тел.: +359 2 819 3737
info-msdbg@merck.com

Luxembourg/Luxemburg
MSD Belgium BVBA/SPRL
Tél/Tel: +32(0)27766211
dpoc_belux@merck.com

Česká republika
Merck Sharp & Dohme s.r.o.
Tel: +420 233 010 111 
dpoc_czechslovak@merck.com

Magyarország
MSD Pharma Hungary Kft. 
Tel.: +36 1 888 5300
hungary_msd@merck.com

Danmark
MSD Danmark ApS
Tlf: + 45 4482 4000
dkmail@merck.com

Malta
Merck Sharp & Dohme Cyprus Limited
Tel: 8007 4433 (+356 99917558)
malta_info@merck.com

Deutschland
MSD Sharp & Dohme GmbH
Tel: 0800 673 673 673 (+49 (0) 89 4561 2612)
e-mail@msd.de

Nederland
Merck Sharp & Dohme B.V.
Tel: 0800 9999000 (+31 23 5153153)
medicalinfo.nl@merck.com

Eesti
Merck Sharp & Dohme OÜ
Tel.: +372 6144 200
msdeesti@merck.com

Norge
MSD (Norge) AS
Tlf: +47 32 20 73 00
msdnorge@msd.no

 



79

Ελλάδα
MSD Α.Φ.Β.Ε.Ε.
Τηλ: +30 210 98 97 300
dpoc_greece@merck.com

Österreich
Merck Sharp & Dohme Ges.m.b.H.
Tel: +43 (0) 1 26 044
msd-medizin@merck.com

España
Merck Sharp & Dohme de España, S.A.
Tel: +34 91 321 06 00
msd_info@merck.com

Polska
MSD Polska Sp. z o.o.
Tel: +48 22 549 51 00
msdpolska@merck.com

France
MSD France
Tél: + 33 (0) 1 80 46 40 40

Portugal
Merck Sharp & Dohme, Lda
Tel: +351 21 4465700
inform_pt@merck.com

Hrvatska:
Merck Sharp & Dohme d.o.o. 
Tel: + 385 1 6611 333
croatia_info@merck.com  

România
Merck Sharp & Dohme Romania S.R.L.
Tel: +40 21 529 29 00
msdromania@merck.com

Ireland
Merck Sharp & Dohme Ireland (Human Health) 
Limited
Tel: +353 (0)1 2998700
medinfo_ireland@merck.com

Slovenija
Merck Sharp & Dohme, inovativna zdravila d.o.o.
Tel: +386 1 5204 201
msd.slovenia@merck.com

Ísland
Vistor hf.
Sími: + 354 535 7000

Slovenská republika
Merck Sharp & Dohme, s. r. o.
Tel: +421 2 58282010
dpoc_czechslovak@merck.com

Italia
MSD Italia S.r.l.
Tel: +39 06 361911
medicalinformation.it@merck.com

Suomi/Finland
MSD Finland Oy
Puh/Tel: +358 (0)9 804 650
info@msd.fi

Κύπρος
Merck Sharp & Dohme Cyprus Limited
Τηλ.: 800 00 673 (+357 22866700)
cyprus_info@merck.com

Sverige
Merck Sharp & Dohme (Sweden) AB
Tel: +46 77 5700488
medicinskinfo@merck.com

Latvija
SIA Merck Sharp & Dohme Latvija
Tel: + 371 67364224
msd_lv@merck.com

United Kingdom
Merck Sharp & Dohme Limited
Tel: +44 (0) 1992 467272
medicalinformationuk@msd.com

This leaflet was last revised in {MM/YYYY}.

Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu.

 

mailto:cyprus_info@merck.com
mailto:medicalinformation.it@merck.com
mailto:msd.slovenia@merck.com
mailto:croatia_info@merck.com
mailto:msdpolska@merck.com
mailto:msd_info@merck.com


80

Package leaflet: Information for the patient

PREVYMIS 240 mg concentrate for solution for infusion
PREVYMIS 480 mg concentrate for solution for infusion

letermovir

This medicine is subject to additional monitoring. This will allow quick identification of new
safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects.

Read all of this leaflet carefully before you are given this medicine because it contains important 
information for you.
 Keep this leaflet. You may need to read it again.
 If you have any further questions, ask your doctor, pharmacist, or nurse.
 If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What PREVYMIS is and what it is used for
2. What you need to know before you are given PREVYMIS
3. How you are given PREVYMIS
4. Possible side effects
5. How to store PREVYMIS
6. Contents of the pack and other information

1. What PREVYMIS is and what it is used for

PREVYMIS is an antiviral prescription medicine that contains the active substance letermovir.

PREVYMIS is a medicine for adults who have recently had a bone marrow transplant. The medicine 
helps stop you from getting ill from CMV (‘cytomegalovirus’).

CMV is a virus that a lot of people have without knowing. Normally, CMV just stays in their body and 
it does not hurt them. However, if your immune system is weak after you get a bone marrow 
transplant, you may be at high risk of becoming ill from CMV.

2. What you need to know before you are given PREVYMIS

You should not be given PREVYMIS if:
 you are allergic to letermovir or any of the other ingredients of this medicine (listed in section 6).
 you take either of these medicines:

o pimozide - used for Tourette’s syndrome
o ergot alkaloids (such as ergotamine and dihydroergotamine) - used for migraine 

headaches.
 you take the following herbal product:

o St. John’s wort (Hypericum perforatum)
You should not be given PREVYMIS if any of the above apply to you. If you are not sure, talk to your 
doctor, pharmacist or nurse before you are given PREVYMIS.

If you are taking PREVYMIS with cyclosporine, do not take the following medicines: 
o dabigatran - used for blood clots
o atorvastatin, simvastatin, rosuvastatin, pitavastatin –for high cholesterol

 



81

Warnings and precautions 
If you are also taking a medicine for high cholesterol (see list of medicines in section “Other medicines 
and PREVYMIS” below) you must tell your doctor immediately if you have unexplained muscle aches 
or pains especially if you feel unwell or have a fever. Your medicine or dose may then need to be 
changed. See the package leaflet for your other medicine for further information.

Additional blood tests may be needed to monitor the following medicinal products:
 Cyclosporine, tacrolimus, sirolimus
 Voriconazole

Children and adolescents
PREVYMIS is not for use in children and adolescents under 18 years old. This is because PREVYMIS
has not been tested in this age group.

Other medicines and PREVYMIS
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other 
medicines. This is because PREVYMIS may affect the way other medicines work, and other 
medicines may affect how PREVYMIS works. Your doctor or pharmacist will tell you if it is safe to 
take PREVYMIS with other medicines.

There are some medicines you must not take with PREVYMIS. See list under “Do not take
PREVYMIS if you take either of these medicines.”

Also tell your doctor if you are taking any of the following medicines. This is because your doctor may 
have to change your medicines or change the dose of your medicines:
 alfentanil - for severe pain
 fentanyl - for severe pain
 quinidine - for abnormal heart rhythms
 cyclosporine, tacrolimus, sirolimus - used to prevent transplant rejection
 voriconazole - for fungal infections
 statins, such as atorvastatin, fluvastatin, rosuvastatin, simvastatin, pravastatin, pitavastatin - for 

high cholesterol
 glyburide, repaglinide - for high blood sugar
 carbamazepine, phenobarbital, phenytoin - for fits or seizures
 dabigatran, warfarin - used to thin the blood or for blood clots
 midazolam – used as a sedative  
 amiodarone - used to correct irregular heartbeats
 oral contraceptive steroids-for birth control
 omeprazole, pantoprazole – for stomach ulcers and other stomach

problems
 nafcillin - for bacterial infections
 rifabutin, rifampicin - for mycobacterial infections
 thioridazine - for psychiatric disorders
 bosentan - for high blood pressure in the vessels in the lungs
 efavirenz, etravirine, nevirapine, lopinavir, ritonavir - for HIV
 modafinil - for wakefulness

You can ask your doctor or pharmacist for a list of medicines that may interact with PREVYMIS.

Pregnancy
If you are pregnant, think you may be pregnant, or are planning to have a baby, ask your doctor for 
advice before taking this medicine. PREVYMIS is not recommended in pregnancy. This is because it 
has not been studied in pregnancy and it is not known if PREVYMIS will harm your baby while you 
are pregnant.

 



82

Breast-feeding
If you are breast-feeding or are planning to breast-feed, tell your doctor before taking this medicine. 
Breast-feeding is not recommended while taking PREVYMIS. This is because it is not known if 
PREVYMIS gets in your breast milk and will be passed to your baby.

Driving and using machines
PREVYMIS may have minor influence on your ability to drive and use machines (see section 4 
Possible Side Effects below). Some patients have reported fatigue (feeling very tired) or vertigo 
(feeling like you are spinning) during treatment with PREVYMIS. If you experience any of these 
effects, do not drive or use machines until the effect wears off. 

PREVYMIS contains sodium
PREVYMIS contains sodium. If you are on a low sodium diet, talk to your doctor before you are given 
this medicine.

Each 240 mg vial contains 23 mg sodium (main component of cooking/table salt). This is equivalent to 
1.15% of the recommended maximum daily dietary intake of sodium for an adult.

Each 480 mg vial contains 46 mg sodium (main component of cooking/table salt). This is equivalent to 
2.30% of the recommended maximum daily dietary intake of sodium for an adult.

PREVYMIS contains cyclodextrin
Each 240 mg dose (12 mL vial) of this medicine contains 1800 mg cyclodextrin.
Each 480 mg dose (24 mL vial) of this medicine contains 3600 mg cyclodextrin.

If you have a kidney disease, talk to your doctor before you receive this medicine.

3. How you are given PREVYMIS

The recommended dose of PREVYMIS is 480 mg once a day. If you also take cyclosporine, your 
doctor will decrease the dose of PREVYMIS to 240 mg once a day. 
You will get PREVYMIS as an infusion (drip) into a vein and it will take about 1 hour.
You will get PREVYMIS once a day.

If you are given more PREVYMIS than you should
If you think you have been given too much PREVYMIS, tell your doctor straight away.

If you miss your appointment to get PREVYMIS
It is very important that you do not miss or skip doses of PREVYMIS.
 If you miss your appointment to get PREVYMIS, call your doctor straight away to reschedule 

your appointment.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Common: may affect up to 1 in 10 people
 diarrhoea
 feeling sick (nausea)
 being sick (vomiting)

 



83

Uncommon: may affect up to 1 in 100 people
 allergic reaction (hypersensitivity) – the signs may include wheezing, difficulty breathing, rashes 

or hives, itchiness, swelling
 loss of appetite
 changes in taste
 headache
 feeling like you are spinning (vertigo)
 stomach ache
 abnormalities in laboratory tests of liver function 
 muscle spasms
 high blood creatinine - shown in blood tests
 feeling very tired (fatigue)
 swelling of hands or feet

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine.

5. How to store PREVYMIS

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and vial after EXP. The 
expiry date refers to the last day of that month.

This medicine does not require any special temperature storage conditions. Store in original carton to 
protect from light.

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.

Any unused portion of the infusion solution should be discarded.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help to protect the environment.

6. Contents of the pack and other information

What PREVYMIS contains
The active substance is letermovir. Each vial contains 240 mg or 480 mg letermovir. Each mL of 
concentrate contains 20 mg/mL.
The other ingredients are: hydroxypropylbetadex (cyclodextrin), sodium chloride, sodium hydroxide 
(E524), water for injections.

What PREVYMIS looks like and contents of the pack
PREVYMIS 240 mg and 480 mg concentrate for solution for infusion is a clear, colourless liquid and 
may contain a few product-related small translucent or white particles.
The 240 mg and 480 mg concentrate for solution for infusion is packaged in clear, glass vials. Each 

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


84

vial is packaged in a carton.

Marketing Authorisation Holder
Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

Manufacturer
Schering-Plough Labo NV
Industriepark 30 – Zone A
B-2220 Heist-op-den-Berg
Belgium

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
MSD Belgium BVBA/SPRL
Tél/Tel: +32(0)27766211
dpoc_belux@merck.com

Lietuva
UAB Merck Sharp & Dohme
Tel. + 370 5 278 02 47
msd_lietuva@merck.com

България
Мерк Шарп и Доум България ЕООД
Тел.: +359 2 819 3737
info-msdbg@merck.com

Luxembourg/Luxemburg
MSD Belgium BVBA/SPRL
Tél/Tel: +32(0)27766211
dpoc_belux@merck.com

Česká republika
Merck Sharp & Dohme s.r.o.
Tel: +420 233 010 111 
dpoc_czechslovak@merck.com

Magyarország
MSD Pharma Hungary Kft. 
Tel.: +36 1 888 5300
hungary_msd@merck.com

Danmark
MSD Danmark ApS
Tlf: + 45 4482 4000
dkmail@merck.com

Malta
Merck Sharp & Dohme Cyprus Limited
Tel: 8007 4433 (+356 99917558)
malta_info@merck.com

Deutschland
MSD Sharp & Dohme GmbH
Tel: 0800 673 673 673 (+49 (0) 89 4561 2612)
e-mail@msd.de

Nederland
Merck Sharp & Dohme B.V.
Tel: 0800 9999000 (+31 23 5153153)
medicalinfo.nl@merck.com

Eesti
Merck Sharp & Dohme OÜ
Tel.: +372 6144 200
msdeesti@merck.com

Norge
MSD (Norge) AS
Tlf: +47 32 20 73 00
msdnorge@msd.no

Ελλάδα
MSD Α.Φ.Β.Ε.Ε.
Τηλ: +30 210 98 97 300
dpoc_greece@merck.com

Österreich
Merck Sharp & Dohme Ges.m.b.H.
Tel: +43 (0) 1 26 044
msd-medizin@merck.com

España
Merck Sharp & Dohme de España, S.A.
Tel: +34 91 321 06 00
msd_info@merck.com

Polska
MSD Polska Sp. z o.o.
Tel: +48 22 549 51 00
msdpolska@merck.com

 

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85

France
MSD France
Tél: + 33 (0) 1 80 46 40 40

Portugal
Merck Sharp & Dohme, Lda
Tel: +351 21 4465700
inform_pt@merck.com

Hrvatska:
Merck Sharp & Dohme d.o.o. 
Tel: + 385 1 6611 333
croatia_info@merck.com  

România
Merck Sharp & Dohme Romania S.R.L.
Tel: +40 21 529 29 00
msdromania@merck.com

Ireland
Merck Sharp & Dohme Ireland (Human Health) 
Limited
Tel: +353 (0)1 2998700
medinfo_ireland@merck.com

Slovenija
Merck Sharp & Dohme, inovativna zdravila d.o.o.
Tel: +386 1 5204 201
msd.slovenia@merck.com

Ísland
Vistor hf.
Sími: + 354 535 7000

Slovenská republika
Merck Sharp & Dohme, s. r. o.
Tel: +421 2 58282010
dpoc_czechslovak@merck.com

Italia
MSD Italia S.r.l. 
Tel: +39 06 361911
medicalinformation.it@merck.com

Suomi/Finland
MSD Finland Oy
Puh/Tel: +358 (0)9 804 650
info@msd.fi

Κύπρος
Merck Sharp & Dohme Cyprus Limited
Τηλ.: 800 00 673 (+357 22866700)
cyprus_info@merck.com

Sverige
Merck Sharp & Dohme (Sweden) AB
Tel: +46 77 5700488
medicinskinfo@merck.com

Latvija
SIA Merck Sharp & Dohme Latvija
Tel: + 371 67364224
msd_lv@merck.com

United Kingdom
Merck Sharp & Dohme Limited
Tel: +44 (0) 1992 467272
medicalinformationuk@msd.com

This leaflet was last revised in {MM/YYYY}.

Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu.

The following information is intended for healthcare professionals only:

Administration instructions for PREVYMIS concentrate for solution for infusion

PREVYMIS concentrate for solution for infusion vials are for single use only. Discard any unused 
portion.

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.

 

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86

Preparation
PREVYMIS concentrate for solution for infusion must be diluted prior to intravenous (IV) use. The
preparation and administration instructions are the same for either dose.

 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 IV 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.
 Add one single-dose vial of (either 12 mL (240 mg dose) or 24 mL (480 mg dose)) of PREVYMIS

concentrate for solution for infusion to a 250 mL pre-filled IV bag containing either 0.9% sodium 
chloride or 5% dextrose, and mix the diluted solution by gentle inversion. Do not shake.

 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. If a vial is added to a 250 mL IV diluent bag, the final concentration 
ranges of letermovir would be 0.9 mg/mL (for 240 mg dose) and 1.8 mg/mL (for 480 mg dose).

Administration
 The diluted solution must be administered through a sterile 0.2 micron or 0.22 micron 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.
 Administer as an intravenous infusion only. Do not administer as an intravenous push or bolus.
 After dilution, administer PREVYMIS via intravenous infusion via peripheral or central venous 

catheter using a total time of approximately 60 minutes. Administer the entire contents of the IV 
bag.

Compatible intravenous solutions and other medicinal products
 PREVYMIS concentrate for solution for infusion is compatible with 0.9% sodium chloride and 

5% dextrose solutions.
 Compatible medicinal products are listed below.
 This medicinal product must not be mixed with other medicinal products except those listed

below.
 PREVYMIS should not be co-administered through the same intravenous line (or cannula) with 

other medicinal products and diluent combinations except those listed below.

 



87

List of compatible medicinal products when PREVYMIS and medicinal products* are prepared 
in 0.9% sodium chloride
• Ampicillin sodium • Fluconazole 
• Ampicillin sodium/Sulbactam sodium • Human insulin
• Anti-thymocyte globulin • Magnesium sulfate 
• Caspofungin • Methotrexate 
• Daptomycin • Micafungin 
• Fentanyl citrate 

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

List of compatible medicinal products when PREVYMIS and medicinal products* are prepared 
in 5% dextrose
• Amphotericin B (lipid complex)† • Hydrocortisone sodium succinate
• Anidulafungin • Morphine sulfate
• Cefazolin sodium • Norepinephrine bitartrate
• Ceftaroline • Pantoprazole sodium
• Ceftriaxone sodium • Potassium chloride 
• Doripenem • Potassium phosphate 
• Famotidine • Tacrolimus 
• Folic acid • Telavancin 
• Ganciclovir sodium • Tigecycline 
*Refer to the prescribing information to confirm compatibility of simultaneous co-administration.

†Amphotericin B (lipid complex) is compatible with PREVYMIS. However, Amphotericin B (liposomal) is 
incompatible (see section 6.2).

Compatible intravenous bags and infusion set materials

PREVYMIS is compatible with the following intravenous bags and infusion set materials. 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

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

Incompatible IV bags and infusion set materials
PREVYMIS is incompatible with diethylhexyl phthalate (DEHP) plasticizers and
polyurethane-containing IV administration set tubing.

 



88

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


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET