Sign Out
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 4).
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 Pharmacology: Pharmacokinetics under Actions).
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 4).
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 4).
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 4 as follows, Dosage & Administration, and Pharmacology: Pharmacokinetics under Actions). 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 as follows) 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 as follows.
It is unknown whether letermovir may affect the exposure of piperacillin/tazobactam, amphotericin 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 Contraindications, Precautions, and Pharmacology: Pharmacokinetics under Actions).
Examples of such medicinal products include certain immunosuppressants (e.g., cyclosporine, tacrolimus, sirolimus), HMG-CoA reductase inhibitors, and amiodarone (see Table 4). Pimozide and ergot alkaloids are contraindicated (see Contraindications).
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 Precautions) 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 4). 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 4).
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 regarding time courses of the interaction as previously mentioned.
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 4). 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 4 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 Contraindications, Precautions, and Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions). (See Tables 4a, 4b, 4c and 4d.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
Click on icon to see table/diagram/imagePaediatric population: Interaction studies have only been performed in adults.
