PREVYMIS Film-coated tablet Ref.[8782] Active ingredients: Letermovir

Monitoring of CMV DNA

The safety and efficacy of letermovir has been established in 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 bi-weekly 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).

Risk of adverse reactions or reduced therapeutic effect due to medicinal product interactions

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:

• 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.

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).

Drug interactions

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 monitoring 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 Table 1).

Excipients

PREVYMIS contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

General information about differences in exposure between different letermovir treatment regimens

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).

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 section 5.2).

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 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).

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 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).

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 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 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 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.

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 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.

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 1). 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 1). 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 above regarding time courses of the interaction.

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.

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 1 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 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 IV, and whether cyclosporine is concomitantly used. When changing the route of administration, or if changing immunosuppressant, the recommendation concerning co-administration should be revisited.

Paediatric population

Interaction studies have only been performed in adults.

Pregnancy

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.

Breast-feeding

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.

Fertility

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 treatment with PREVYMIS, which may influence a patient’s ability to drive and use machines (see section 4.8).

Summary of the safety profile

The safety assessment of PREVYMIS was based on a Phase 3 clinical trial (P001) in HSCT recipients who 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%).

Tabulated summary of adverse reactions

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:

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 of suspected adverse reactions

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.

Not applicable.