Wirkstoffe & Arzneimittelsicherheit

Wechselwirkungen · Prevymis

PREVYMIS 240 mg film-coated tablets PREVYMIS 480 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 7

HOS-139778 · Präparat HOS-098408

Inhibitors of OATP1B1 or 3 Co-administration of letermovir with medicinal products that are inhibitors of OATP1B1/3 transporters may result in increased letermovir plasma concentrations. If letermovir is co-administered with cyclosporine (a potent OATP1B1/3 inhibitor), the recommended dose of letermovir is 240 mg once daily in adult and paediatric patients weighing at least 30 kg (see Table 1 and sections 4.2 and 5.2). If oral letermovir is co-administered with cyclosporine in paediatric patients weighing less than 30 kg, the dose should be decreased (see sections 4.2 and 5.2). Caution is advised if other OATP1B1/3 inhibitors are added to letermovir combined with cyclosporine. -Examples of OATP1B1 inhibitors include gemfibrozil, erythromycin, clarithromycin, and several protease inhibitors (atazanavir, simeprevir).

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): atazanavir (HOS-086180) protease (HOS-085623) gemfibrozil (HOS-088403) clarithromycin (HOS-084517) erythromycin (HOS-084514) simeprevir (HOS-086302) cyclosporine (HOS-084512)

Wechselwirkungen · Prevymis

PREVYMIS 240 mg film-coated tablets PREVYMIS 480 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 7

HOS-139779 · Präparat HOS-098408

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.

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)

Wechselwirkungen · Prevymis

PREVYMIS 240 mg film-coated tablets PREVYMIS 480 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 7

HOS-139780 · Präparat HOS-098408

Effect of letermovir on other medicinal products

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 7

HOS-139781 · Präparat HOS-098408

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.

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): lead (HOS-085592)

Wechselwirkungen · Prevymis

PREVYMIS 240 mg film-coated tablets PREVYMIS 480 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 7

HOS-139782 · Präparat HOS-098408

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.

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

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HOS-139783 · Präparat HOS-098408

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.

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 7

HOS-139784 · Präparat HOS-098408

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.

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): tazobactam (HOS-131224) piperacillin (HOS-139785) micafungin (HOS-117342)

Wechselwirkungen · Prevymis

PREVYMIS 240 mg film-coated tablets PREVYMIS 480 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 7

HOS-139788 · Präparat HOS-098408

Medicinal products metabolised by CYP3A Letermovir is a moderate inhibitor of CYP3A in vivo. Co-administration of letermovir with oral midazolam (a CYP3A substrate) results in 2-3-fold increased midazolam plasma concentrations. Co- administration of letermovir may result in clinically relevant increases in the plasma concentrations of co-administered CYP3A substrates (see sections 4.3, 4.4, and 5.2). -Examples of such medicinal products include certain immunosuppressants (e.g., 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.

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): ergot alkaloids (HOS-108807) tacrolimus (HOS-085202) pimozide (HOS-085600) sirolimus (HOS-085172) amiodarone (HOS-085596) cyclosporine (HOS-084512) midazolam (HOS-086167)

Wechselwirkungen · Prevymis

PREVYMIS 240 mg film-coated tablets PREVYMIS 480 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 7–8

HOS-139789 · Präparat HOS-098408

7 Medicinal products transported by OATP1B1/3 Letermovir is an inhibitor of OATP1B1/3 transporters. Administration of letermovir may result in a clinically relevant increase in plasma concentrations of co-administered medicinal products that are OATP1B1/3 substrates. -Examples of such medicinal products include HMG-CoA reductase inhibitors, fexofenadine, repaglinide and glyburide (see Table 1). Comparing letermovir regimen administered without 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 letermovir 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.

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): fexofenadine (HOS-086255) glyburide (HOS-109273) 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-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)