Source: European Medicines Agency (EU) Revision Year: 2025 Publisher: Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands
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).
In a Phase 3 trial (P001), the safety and efficacy of letermovir has been established in HSCT patients with a negative CMV DNA test result prior to initiation of prophylaxis. CMV DNA was monitored on a weekly basis until post-transplant Week 14, and subsequently every two weeks until Week 24. In cases of clinically significant CMV DNAemia or disease, letermovir prophylaxis was stopped and standard-of-care pre-emptive therapy (PET) or treatment was initiated. In patients in whom letermovir prophylaxis was initiated and the baseline CMV DNA test was subsequently found to be positive, prophylaxis could be continued if PET criteria had not been met (see section 5.1).
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:
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).
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 m onitoring 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 Tab le 1).
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).
This medicinal product contains 23 mg (or 1 mmol) sodium per 240 mg vial, equivalent to 1.15% of the WHO recommended maximum daily intake of 2 g sodium for an adult. This should be taken into consideration by patients on a controlled sodium diet.
This medicinal product contains 46 mg (or 2 mmol) sodium per 480 mg vial, equivalent to 2.30% of the WHO recommended maximum daily intake of 2 g sodium for an adult. This should be taken into consideration by patients on a controlled sodium diet.
This medicinal product contains 1800 mg hydroxypropylbetadex (cyclodextrin) per 12 mL vial (240 mg dose).
This medicinal product contains 3600 mg hydroxypropylbetadex (cyclodextrin) per 24 mL vial (480 mg dose).
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).
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).
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).
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).
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.
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 e xpected 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.
Letermovir is a moderate i nhibitor 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.
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 intravenous 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.
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 intravenous 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.
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.
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.
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 rosuv astatin and sulfasalazine.
An example of a medicinal product transported by OATP2B1 is celiprolol.
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.
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 immunosuppre ssant.
Table 1 provides a listing of established or potentially clinically significant medic inal 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 intravenous, 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. |
| 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 intravenous)/ letermovir (480 mg single dose PO) | ↔ letermovir AUC 1.58 (1.38, 1.81) Cmax 1.37 (1.16, 1.61) C24 0.78 (0.65, 0.93) (OATP1B1/3 and/or P-gp inhibition) | |
| (600 mg once daily PO)/ letermovir (480 mg once daily PO) | ↓ letermovir AUC 0.81 (0.67, 0.98) Cmax 1.01 (0.79, 1.28) C24 0.14 (0.11, 0.19) (Sum of OATP1B1/3 and/or P-gp inhibition and P-gp/UGT induction) | |
| (600 mg once daily PO (24 hours after rifampicin))§/ letermovir (480 mg once daily PO) | ↓ letermovir AUC 0.15 (0.13, 0.17) Cmax 0.27 (0.22, 0.31) C24 0.09 (0.06, 0.12) (P-gp/UGT induction) | |
| Antipsychotics | ||
| thioridazine | Interaction not studied. Expected: ↓ letermovir (P-gp/UGT induction) | Thioridazine may decrease plasma concentrations of letermovir. Co-administration of 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. |
| 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. |
| 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 dose of PREVYMIS should be decreased to 2 40 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. |
| 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) | |
| Oral contraceptives | ||
| ethinylestradiol (EE) (0.03 mg)/ levonorgestrel (LNG)‡ (0.15 mg) single dose/ letermovir (480 mg daily) | ↔ EE AUC 1.42 (1.32, 1.52) Cmax 0.89 (0.83, 0.96) ↔ LNG AUC 1.36 (1.30, 1.43) Cmax 0.95 (0.86, 1.04) | No dose adjustment required. |
| Other systemically acting oral contraceptive steroids | Risk of ↓ contraceptive steroids | Letermovir may reduce plasma concentrations of other oral contraceptive steroids thereby affecting their efficacy. For adequate contraceptive effect to be ensured with an oral contraceptive, products containing EE and LNG should be chosen. |
| Antidiabetic medicinal products | ||
| repaglinide | Interaction not studied. Expected: ↑ or ↓ repaglinide (CYP2C8 induction, CYP2C8 and OATP1B inhibition) | Letermovir may increase or decrease the plasma concentrations of repaglinide. (The net effect is not known). Concomitant use is not recommended. When 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. |
| 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 immunosuppress ant. |
| 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. |
| Sedatives | ||
| midazolam (1 mg single dose intravenous)/ letermovir (240 mg once daily PO) midazolam (2 mg single dose PO) / letermovir (240 mg once daily PO) | ↑ midazolam intravenous: AUC 1.47 (1.37, 1.58) Cmax 1.05 (0.94, 1.17) PO: AUC 2.25 (2.04, 2. 48) Cmax 1.72 (1.55, 1.92) (CYP3A inhibition) | Close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised during co-administration of 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#. |
| 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.
Interaction studies have only been performed in adults.
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.
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.
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.
PREVYMIS may have minor influence on the ability to drive or use machines. Fatigue and vertigo have been reported in some patients during treatm ent with PREVYMIS, which may influence a patient’s ability to drive and use machines (see section 4.8).
The safety assessment of PREVYMIS was based on three Phase 3 clinical trials.
In P001, 565 HSCT recipients 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%).
In P040, 218 HSCT recipients received PREVYMIS or placebo from Week 14 (~100 days) through Week 28 (~200 days) post-HSCT and were followed for safety through Week 48 post-HSCT (see section 5.1). The adverse reactions reported were consistent with the safety profile of PREVYMIS as characterised in study P001.
In P002, 292 kidney transplant recipients received PREVYMIS through Week 28 (~200 days) post-transplant (see section 5.1).
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).
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 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.
PREVYMIS concentrate for solution for infusion is physically incompatible with amiodarone hydrochloride, amphotericin B (liposomal), aztreonam, cefepime hydrochloride, ciprofloxacin, cyclosporine, diltiazem hydrochloride, filgrastim, gentamicin sulphate, levofloxacin, linezolid, lorazepam, midazolam HCl, mycophenolate mofetil hydrochloride, ondansetron, palonosetron.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
PREVYMIS concentrate for solution for infusion is incompatible with diethylhexyl phthalate (DEHP) plasticizers and polyurethane-containing intravenous administration set tubing.
This medicinal product must not be used with other intravenous bags and infusion set materials except those mentioned in section 6.6.
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