Wirkstoffe & Arzneimittelsicherheit

Wechselwirkungen · Prevymis

PREVYMIS 240 mg film-coated tablets PREVYMIS 480 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 8

HOS-139790 · Präparat HOS-098408

Medicinal products metabolised by CYP2C9 and/or CYP2C19 Co-administration of letermovir with voriconazole (a CYP2C19 substrate) results in significantly decreased voriconazole plasma concentrations, indicating that letermovir is an inducer of CYP2C19. CYP2C9 is likely also induced. Letermovir has the potential to decrease the exposure of CYP2C9 and/or CYP2C19 substrates potentially resulting in subtherapeutic levels. -Examples of such medicinal products include warfarin, voriconazole, diazepam, lansoprazole, omeprazole, esomeprazole, pantoprazole, tilidine, tolbutamide (see Table 1). The effect is expected to be less pronounced for oral letermovir without 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.

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): lansoprazole (HOS-085166) esomeprazole (HOS-087944) pantoprazole (HOS-085167) diazepam (HOS-085904) voriconazole (HOS-084524) tilidine (HOS-139791) cyclosporine (HOS-084512) warfarin (HOS-085950) tolbutamide (HOS-086568) omeprazole (HOS-085912)

Wechselwirkungen · Prevymis

PREVYMIS 240 mg film-coated tablets PREVYMIS 480 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 8

HOS-139792 · Präparat HOS-098408

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.

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): cyclosporine (HOS-084512) repaglinide (HOS-086935)

Wechselwirkungen · Prevymis

PREVYMIS 240 mg film-coated tablets PREVYMIS 480 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 8

HOS-139793 · Präparat HOS-098408

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

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): sofosbuvir (HOS-108928) dabigatran (HOS-112096)

Wechselwirkungen · Prevymis

PREVYMIS 240 mg film-coated tablets PREVYMIS 480 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 8

HOS-139794 · Präparat HOS-098408

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.

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): bupropion (HOS-086329) sulfasalazine (HOS-089673) celiprolol (HOS-139796) dolutegravir (HOS-089992) rosuvastatin (HOS-086307) raltegravir (HOS-086187)

Wechselwirkungen · Prevymis

PREVYMIS 240 mg film-coated tablets PREVYMIS 480 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 8

HOS-139797 · Präparat HOS-098408

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.

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): tenofovir (HOS-088083) ciprofloxacin (HOS-085177) imipenem (HOS-139798)

Wechselwirkungen · Prevymis

PREVYMIS 240 mg film-coated tablets PREVYMIS 480 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 8–9

HOS-139799 · Präparat HOS-098408

8 General information

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

Wechselwirkungen · Prevymis

PREVYMIS 240 mg film-coated tablets PREVYMIS 480 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 9

HOS-139800 · Präparat HOS-098408

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

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

Wechselwirkungen · Prevymis

PREVYMIS 240 mg film-coated tablets PREVYMIS 480 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 9

HOS-139801 · Präparat HOS-098408

Table 1 provides a listing of established or potentially clinically significant medicinal product interactions. The medicinal product interactions described are based on adult studies conducted with letermovir or are predicted medicinal product interactions that may occur with letermovir (see sections 4.3, 4.4, 5.1, and 5.2).

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

Wechselwirkungen · Prevymis

PREVYMIS 240 mg film-coated tablets PREVYMIS 480 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 9

HOS-139802 · Präparat HOS-098408

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.

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

Wechselwirkungen · Prevymis

PREVYMIS 240 mg film-coated tablets PREVYMIS 480 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 9

HOS-139803 · Präparat HOS-098408

Unless otherwise specified, interaction studies have been performed in adults 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 intravenously, and whether cyclosporine is concomitantly used. When changing the route of administration, or if changing immunosuppressant, the recommendation concerning co- administration should be revisited.

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): cyclosporine (HOS-084512)

Wechselwirkungen · Prevymis

PREVYMIS 240 mg film-coated tablets PREVYMIS 480 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 9

HOS-139804 · Präparat HOS-098408

Concomitant Effect on concentration† Recommendations concerning co- medicinal product mean ratio (90% confidence administration with letermovir interval) for AUC, Cmax (likely mechanism of action) Antibiotics nafcillin Interaction not studied. Nafcillin may decrease plasma Expected: concentrations of letermovir. ↓ letermovir Co-administration of letermovir and nafcillin is not recommended. (P-gp/UGT induction) Antifungals fluconazole ↔ fluconazole No dose adjustment required. (400 mg single AUC 1.03 (0.99, 1.08) dose)/letermovir Cmax 0.95 (0.92, 0.99) (480 mg single dose) ↔ letermovir AUC 1.11 (1.01, 1.23) Cmax 1.06 (0.93, 1.21)

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): nafcillin (HOS-125452) fluconazole (HOS-087945)

Wechselwirkungen · Prevymis

PREVYMIS 240 mg film-coated tablets PREVYMIS 480 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 9

HOS-139805 · Präparat HOS-098408

Interaction at steady state not studied. Expected: ↔ fluconazole ↔ letermovir itraconazole ↔ itraconazole No dose adjustment required. (200 mg once daily AUC 0.76 (0.71, 0.81) PO)/letermovir Cmax 0.84 (0.76, 0.92) (480 mg once daily PO) ↔ letermovir AUC 1.33 (1.17, 1.51) Cmax 1.21 (1.05, 1.39) posaconazole‡ ↔ posaconazole No dose adjustment required. (300 mg single AUC 0.98 (0.82, 1.17) dose)/ letermovir Cmax 1.11 (0.95, 1.29) (480 mg daily)

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): itraconazole (HOS-084516) fluconazole (HOS-087945) posaconazole (HOS-085622)

Wechselwirkungen · Prevymis

PREVYMIS 240 mg film-coated tablets PREVYMIS 480 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 9–10

HOS-139806 · Präparat HOS-098408

9 Concomitant Effect on concentration† Recommendations concerning co- medicinal product mean ratio (90% confidence administration with letermovir interval) for AUC, Cmax (likely mechanism of action) voriconazole‡ ↓ voriconazole If concomitant administration is necessary, (200 mg twice AUC 0.56 (0.51, 0.62) TDM for voriconazole is recommended daily)/ letermovir Cmax 0.61 (0.53, 0.71) the first 2 weeks after initiating or ending (480 mg daily) letermovir, as well as after changing route (CYP2C9/19 induction) of administration of letermovir or immunosuppressant. Antimycobacterials rifabutin Interaction not studied. Rifabutin may decrease plasma Expected: concentrations of letermovir. ↓ letermovir Co-administration of letermovir and rifabutin is not recommended. (P-gp/UGT induction) rifampicin (600 mg single dose ↔letermovir PO)/ letermovir AUC 2.03 (1.84, 2.26) (480 mg single dose Cmax 1.59 (1.46, 1.74) PO) C24 2.01 (1.59, 2.54)

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): rifabutin (HOS-086262) voriconazole (HOS-084524)

Wechselwirkungen · Prevymis

PREVYMIS 240 mg film-coated tablets PREVYMIS 480 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 10

HOS-139807 · Präparat HOS-098408

(OATP1B1/3 and/or P-gp inhibition) (600 mg single dose ↔ letermovir intravenous)/ AUC 1.58 (1.38, 1.81) letermovir (480 mg Cmax 1.37 (1.16, 1.61) single dose PO) C24 0.78 (0.65, 0.93) Multiple dose rifampicin decreases plasma (OATP1B1/3 and/or P-gp concentrations of letermovir. inhibition) Co-administration of letermovir and (600 mg once daily ↓ letermovir rifampicin is not recommended. PO)/ letermovir AUC 0.81 (0.67, 0.98) (480 mg once daily Cmax 1.01 (0.79, 1.28) PO) C24 0.14 (0.11, 0.19)

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

Wechselwirkungen · Prevymis

PREVYMIS 240 mg film-coated tablets PREVYMIS 480 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 10

HOS-139808 · Präparat HOS-098408

(Sum of OATP1B1/3 and/or P-gp inhibition and P-gp/UGT induction) (600 mg once daily ↓ letermovir PO (24 hours after AUC 0.15 (0.13, 0.17) rifampicin))§/ Cmax 0.27 (0.22, 0.31) letermovir (480 mg C24 0.09 (0.06, 0.12) once daily PO) (P-gp/UGT induction) Antipsychotics thioridazine Interaction not studied. Thioridazine may decrease plasma Expected: concentrations of letermovir. ↓ letermovir Co-administration of letermovir and thioridazine is not recommended. (P-gp/UGT induction) Endothelin antagonists bosentan Interaction not studied. Bosentan may decrease plasma Expected: concentrations of letermovir. ↓ letermovir Co-administration of letermovir and bosentan is not recommended. (P-gp/UGT induction)

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): thioridazine (HOS-086281) bosentan (HOS-086291)

Wechselwirkungen · Prevymis

PREVYMIS 240 mg film-coated tablets PREVYMIS 480 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 10–11

HOS-139809 · Präparat HOS-098408

10 Concomitant Effect on concentration† Recommendations concerning co- medicinal product mean ratio (90% confidence administration with letermovir interval) for AUC, Cmax (likely mechanism of action) Antivirals acyclovir‡ ↔ acyclovir No dose adjustment required. (400 mg single AUC 1.02 (0.87, 1.2) dose)/ letermovir Cmax 0.82 (0.71, 0.93) (480 mg daily) valacyclovir Interaction not studied. No dose adjustment required. Expected: ↔ valacyclovir Herbal products St. John’s wort Interaction not studied. St. John’s wort may decrease plasma (Hypericum Expected: concentrations of letermovir. perforatum) ↓ letermovir Co-administration of letermovir and St. John’s wort is contraindicated. (P-gp/UGT induction) HIV medicinal products efavirenz Interaction not studied. Efavirenz may decrease plasma Expected: concentrations of letermovir. ↓ letermovir Co-administration of letermovir and (P-gp/UGT induction) efavirenz is not recommended.

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): valacyclovir (HOS-139811) efavirenz (HOS-087947) acyclovir (HOS-088527)

Wechselwirkungen · Prevymis

PREVYMIS 240 mg film-coated tablets PREVYMIS 480 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 11

HOS-139812 · Präparat HOS-098408

↑ or ↓ efavirenz (CYP2B6 inhibition or induction) etravirine, Interaction not studied. These antivirals may decrease plasma nevirapine, ritonavir, Expected: concentrations of letermovir. lopinavir ↓ letermovir Co-administration of letermovir with these antivirals is not recommended. (P-gp/UGT induction) HMG-CoA reductase inhibitors atorvastatin‡ ↑ atorvastatin Statin-associated adverse events such as (20 mg single dose)/ AUC 3.29 (2.84, 3.82) myopathy should be closely monitored. letermovir (480 mg Cmax 2.17 (1.76, 2.67) The dose of atorvastatin should not exceed daily) 20 mg daily when co-administered with (CYP3A, OATP1B1/3 letermovir #. inhibition) Although not studied, when letermovir is co-administered with cyclosporine, the magnitude of the increase in atorvastatin plasma concentrations is expected to be greater than with letermovir alone. When letermovir is co-administered with cyclosporine, atorvastatin is contraindicated. simvastatin, Interaction not studied. Letermovir may substantially increase pitavastatin, Expected: plasma concentrations of these statins. rosuvastatin ↑ HMG-CoA reductase Concomitant use is not recommended with inhibitors letermovir alone.

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): lopinavir (HOS-086269) atorvastatin (HOS-086304) simvastatin (HOS-086158) rosuvastatin (HOS-086307) etravirine (HOS-088088) efavirenz (HOS-087947) nevirapine (HOS-088064) ritonavir (HOS-084521) cyclosporine (HOS-084512) pitavastatin (HOS-125743)

Wechselwirkungen · Prevymis

PREVYMIS 240 mg film-coated tablets PREVYMIS 480 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 11

HOS-139813 · Präparat HOS-098408

(CYP3A, OATP1B1/3 When letermovir is co-administered with inhibition) cyclosporine, use of these statins is contraindicated.

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): cyclosporine (HOS-084512)

Wechselwirkungen · Prevymis

PREVYMIS 240 mg film-coated tablets PREVYMIS 480 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 11–12

HOS-139814 · Präparat HOS-098408

11 Concomitant Effect on concentration† Recommendations concerning co- medicinal product mean ratio (90% confidence administration with letermovir interval) for AUC, Cmax (likely mechanism of action) fluvastatin, Interaction not studied. Letermovir may increase statin plasma pravastatin Expected: concentrations. ↑ HMG-CoA reductase inhibitors When letermovir is co-administered with these statins, a statin dose reduction may (OATP1B1/3 and/or BCRP be necessary#. Statin-associated adverse inhibition) events such as myopathy should be closely monitored.

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): fluvastatin (HOS-086305) pravastatin (HOS-086306)

Wechselwirkungen · Prevymis

PREVYMIS 240 mg film-coated tablets PREVYMIS 480 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 12

HOS-139815 · Präparat HOS-098408

When letermovir 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 ↑ cyclosporine If letermovir is co-administered with (50 mg single dose)/ AUC 1.66 (1.51, 1.82) cyclosporine, the dose of letermovir letermovir (240 mg Cmax 1.08 (0.97, 1.19) should be decreased to 240 mg once daily daily) (CYP3A inhibition) in adults (see sections 4.2 and 5.1) and paediatric patients weighing at least 30 kg cyclosporine ↑ letermovir (see section 4.2). If oral letermovir is co- (200 mg single AUC 2.11 (1.97, 2.26) administered with cyclosporine in dose)/ letermovir Cmax 1.48 (1.33, 1.65) paediatric patients weighing less than (240 mg daily) 30 kg, the dose should be decreased (see (OATP1B1/3 inhibition) section 4.2).

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): fluvastatin (HOS-086305) cyclosporine (HOS-084512) pravastatin (HOS-086306)