Prevymis

/ MSD

Letermovir should be initiated by a physician experienced in the management of patients who have had an allogeneic haematopoietic stem cell transplant.
Letermovir should be started after HSCT. Letermovir may be started on the day of transplant and no later than 28 days post-HSCT. Letermovir may be started before or after engraftment.
Prophylaxis with letermovir should continue through 100 days post-HSCT.
Prolonged letermovir prophylaxis beyond 100 days post-HSCT may be of benefit in some patients at high risk for late CMV reactivation. The safety and efficacy of letermovir use for more than 200 days has not been studied in clinical trials.
Adult and paediatric patients weighing at least 30 kg who are HSCT recipients: The recommended dose of letermovir is 480 mg once daily that can be administered either as one 480 mg tablet or as two 240 mg tablets.
Dose adjustment in adult and paediatric patients weighing at least 30 kg who are HSCT recipients: If letermovir is co-administered with cyclosporine, the dose of letermovir should be decreased to 240 mg once daily.
* If cyclosporine is initiated after starting letermovir, the next dose of letermovir should be decreased to 240 mg once daily.
* If cyclosporine is discontinued after starting letermovir, the next dose of letermovir should be increased to 480 mg once daily.
* If cyclosporine dosing is temporarily interrupted due to high cyclosporine levels, no dose adjustment of letermovir is needed.
Paediatric patients weighing at least 15 kg to less than 30 kg who are HSCT recipients: The recommended dose of letermovir is 240 mg once daily that can be administered as one 240 mg tablet.
Dose adjustment in paediatric patients weighing at least 15 kg to less than 30 kg who are HSCT recipients:
If oral letermovir is co-administered with cyclosporine, the dose of letermovir should be decreased to 120 mg once daily. For patients requiring a 120 mg dose, refer to the
prescribing information for the letermovir granules for dosing information.
* If cyclosporine is initiated after starting letermovir, the next dose of letermovir should be decreased to 120 mg once daily.
* If cyclosporine is discontinued after starting letermovir, the next dose of letermovir should be increased to 240 mg once daily.
* If cyclosporine dosing is temporarily interrupted due to high cyclosporine levels, no dose adjustment of letermovir is needed.
See prescribing information for full details.

Prophylaxis of cytomegalovirus (CMV) reactivation and disease in adult
and paediatric patients weighing at least 15 kg who are 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.

* Hypersensitivity to the active substance or to any of the excipients.
* Concomitant administration with pimozide.
* Concomitant administration with ergot alkaloids.
* Concomitant administration with St. John’s wort (Hypericum perforatum).
* When letermovir is combined with cyclosporine:concomitant use of dabigatran, atorvastatin, simvastatin, rosuvastatin or pitavastatin is contraindicated.

Monitoring of CMV DNA in HSCT recipients: 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.
Risk of adverse reactions or reduced therapeutic effect due to medicinal product interactions: The concomitant use of letermovir 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.
Drug interactions: Letermovir 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.
Increased monitoring of cyclosporine, tacrolimus, sirolimus is generally recommended the first 2 weeks after initiating and ending 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. 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.

Common: Nausea, diarrhoea, vomiting.
See prescribing information for full details.

General information about differences in exposure between different letermovir treatment regimens:
-The estimated letermovir plasma exposure is different depending on the dose regimen used. Therefore, the clinical consequences of drug interactions for letermovir will be dependent on 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.
Effect of other medicinal products on letermovir:
The elimination pathways of letermovir in vivo are biliary excretion and glucuronidation. 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.
Inducers of drug metabolising enzymes or transporters:
Co-administration of letermovir (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.
-Examples of strong inducers include rifampicin, phenytoin, carbamazepine, 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.
Additional effects of other products on letermovir relevant when combined with cyclosporine:
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. If oral letermovir is co-administered with cyclosporine in paediatric patients weighing less than 30 kg, the dose should be decreased. 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 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 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.
It is unknown whether letermovir may affect the exposure of piperacillin/tazobactam, amphotericine B and micafungin. 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 letermovir with oral midazolam (a CYP3A substrate) results in 2-3-fold increased midazolam plasma concentrations. Coadministration of letermovir may result in clinically relevant increases in the plasma concentrations of co-administered CYP3A substrates.
-Examples of such medicinal products include certain immunosuppressants (e.g., cyclosporine, tacrolimus, sirolimus), HMG-CoA reductase inhibitors, and amiodarone. Pimozide and ergot alkaloids are contraindicated.
The size of the CYP3A inhibitory effect is dependent on 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 affect 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.
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.
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 cyclosporine is discontinued during letermovir treatment with an OATP1B1/3 substrate.
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.
The effect is expected to be less pronounced for oral letermovir without cyclosporine, than oral letermovir with cyclosporine. This needs to be considered when cyclosporine is discontinued during letermovir treatment with a CYP2C9 or CYP2C19 substrate.
Medicinal products metabolised by CYP2C8: Letermovir inhibits CYP2C8 in vitro but may also induce CYP2C8 based on its induction potential.
-An example of a medicinal product which is mainly eliminated by CYP2C8 is repaglinide. 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 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.
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. 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: 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 letermovir, doses should be readjusted after treatment with letermovir is completed. A dose adjustment may also be needed when changing immunosuppressant.
See prescribing information for full details.

Pregnancy: There are no data from the use of letermovir in pregnant women. Studies in animals have shown reproductive toxicity.
Letermovir is not recommended during pregnancy and in women of childbearing potential not using contraception.
Lactation: It is unknown whether letermovir is excreted in human milk. Available
pharmacodynamic/toxicological data in animals have shown excretion of letermovir in milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from letermovir therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

There is no experience with human overdose with letermovir.
There is no specific antidote for overdose with letermovir. 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 letermovir from systemic circulation.

It is recommended to store the product at room temperature. Store in the original package in order to protect from moisture.