Chemical formula: C₂₉H₂₈F₄N₄O₄ Molecular mass: 572.561 g/mol
Letermovir interacts in the following cases:
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. Concomitant use of repaglinide and letermovir with or without cyclosporine is not recommended
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. 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 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.
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 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.
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.
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 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 as well as after changing route of letermovir administration.
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.
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.
Letermovir is not recommended in patients with moderate hepatic impairment combined with moderate or severe renal impairment.
Letermovir is not recommended for patients with severe (Child-Pugh Class C) hepatic impairment.
Effect on concentration – Mean ratio (90% confidence interval) for AUC, Cmax (likely mechanism of action):
Systemically acting oral contraceptive steroids:
Risk of ↓ contraceptive steroids
Recommendations concerning co-administration with letermovir: Letermovir may reduce plasma concentrations of other oral contraceptive steroids thereby affecting their efficacy. For adequate contraceptive effect to be ensured with an oral contraceptive, products containing EE and LNG should be chosen.
Effect on concentration – Mean ratio (90% confidence interval) for AUC, Cmax (likely mechanism of action):
Interaction not studied.
Expected:
↑ CYP3A metabolised opioids (CYP3A inhibition)
Recommendations concerning co-administration with letermovir: Frequent monitoring for adverse reactions related to these medicinal products is recommended during co-administration. Dose adjustment of CYP3A metabolised opioids may be needed#. Monitoring is also recommended if changing route of administration. When letermovir is co-administered with cyclosporine, the magnitude of the increase in plasma concentrations of CYP3A metabolised opioids may be greater. Close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised during coadministration of letermovir in combination with cyclosporine and alfentanil or fentanyl.
# Refer to the respective prescribing information.
Effect on concentration – Mean ratio (90% confidence interval) for AUC, Cmax (likely mechanism of action):
Interaction not studied.
Expected:
↑ amiodarone (primarily CYP3A inhibition and CYP2C8 inhibition or induction)
Recommendations concerning co-administration with letermovir: Letermovir may increase the plasma concentrations of amiodarone. Frequent monitoring for adverse reactions related to amiodarone is recommended during co-administration. Monitoring of amiodarone concentrations should be performed regularly when amiodarone is co-administered with letermovir#.
# Refer to the respective prescribing information.
Effect on concentration – Mean ratio (90% confidence interval) for AUC, Cmax (likely mechanism of action):
Atorvastatin‡ (20 mg single dose)/letermovir (480 mg daily):
(CYP3A, OATP1B1/3 inhibition)
‡ One-way interaction study assessing the effect of letermovir on the concomitant medicinal product.
Recommendations concerning co-administration with letermovir:
Statin-associated adverse events such as myopathy should be closely monitored. The dose of atorvastatin should not exceed 20 mg daily when co-administered with letermovir#.
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.
# Refer to the respective prescribing information.
Effect on concentration – Mean ratio (90% confidence interval) for AUC, Cmax (likely mechanism of action):
Interaction not studied.
Expected:
↓ letermovir (P-gp/UGT induction)
Recommendations concerning co-administration with letermovir: Bosentan may decrease plasma concentrations of letermovir. Co-administration of letermovir and bosentan is not recommended.
Effect on concentration – Mean ratio (90% confidence interval) for AUC, Cmax (likely mechanism of action):
Interaction not studied.
Expected:
↓ letermovir (P-gp/UGT induction)
Recommendations concerning co-administration with letermovir: Carbamazepine or phenobarbital may decrease plasma concentrations of letermovir. Co-administration of letermovir and carbamazepine or phenobarbital is not recommended.
If letermovir is co-administered with cyclosporine, the dosage of letermovir should be decreased to 240 mg once daily.
When letermovir is combined with cyclosporine: Concomitant use of dabigatran, atorvastatin, simvastatin, rosuvastatin or pitavastatin is contraindicated.
The combination of cyclosporine and letermovir may lead to more marked or additional effects on concomitant medicinal products as compared to letermovir alone.
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.
Effect on concentration – Mean ratio (90% confidence interval) for AUC, Cmax (likely mechanism of action):
Interaction not studied.
Expected:
↓ dabigatran (intestinal P-gp induction)
Recommendations concerning co-administration with letermovir: Letermovir may decrease the plasma concentrations of dabigatran and may decrease efficacy of dabigatran. Concomitant use of dabigatran should be avoided due to the risk of reduced dabigatran efficacy. When letermovir is co-administered with cyclosporine, dabigatran is contraindicated.
Effect on concentration – Mean ratio (90% confidence interval) for AUC, Cmax (likely mechanism of action):
Interaction not studied.
Expected:
↓ letermovir (P-gp/UGT induction)
↑ or ↓ efavirenz (CYP2B6 inhibition or induction)
Recommendations concerning co-administration with letermovir: Efavirenz may decrease plasma concentrations of letermovir. Co-administration of letermovir and efavirenz is not recommended.
Effect on concentration – Mean ratio (90% confidence interval) for AUC, Cmax (likely mechanism of action):
Interaction not studied.
Expected:
↓ letermovir (P-gp/UGT induction)
Recommendations concerning co-administration with letermovir: These antivirals (etravirine, nevirapine, ritonavir, lopinavir) may decrease plasma concentrations of letermovir. Co-administration of letermovir with these antivirals is not recommended.
Effect on concentration – Mean ratio (90% confidence interval) for AUC, Cmax (likely mechanism of action):
Interaction not studied.
Expected:
↑ HMG-CoA reductase inhibitors (OATP1B1/3 and/or BCRP inhibition)
Recommendations concerning co-administration with letermovir: Letermovir may increase statin plasma concentrations. When letermovir is co-administered with these statins, a statin dose reduction may be necessary#. Statin-associated adverse events such as myopathy should be closely monitored. 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.
# Refer to the respective prescribing information.
Effect on concentration – Mean ratio (90% confidence interval) for AUC, Cmax (likely mechanism of action):
Interaction not studied.
Expected:
↑ glyburide (OATP1B1/3 inhibition CYP3A inhibition, CYP2C9 induction)
Recommendations concerning co-administration with letermovir: Letermovir may increase the plasma concentrations of glyburide. Frequent monitoring of glucose concentrations is recommended the first 2 weeks after initiating or ending letermovir, as well as after changing route of administration of letermovir.
Effect on concentration – Mean ratio (90% confidence interval) for AUC, Cmax (likely mechanism of action):
Midazolam (1 mg single dose IV)/letermovir (240 mg once daily PO):
Midazolam (2 mg single dose PO)/letermovir (240 mg once daily PO):
(CYP3A inhibition)
Recommendations concerning co-administration with letermovir: Close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised during co-administration of letermovir with midazolam. Dose adjustment of midazolam should be considered#. The increase in midazolam plasma concentration may be greater when oral midazolam is administered with letermovir at the clinical dose than with the dose studied.
# Refer to the respective prescribing information.
Effect on concentration – Mean ratio (90% confidence interval) for AUC, Cmax (likely mechanism of action):
Interaction not studied.
Expected:
↓ letermovir (P-gp/UGT induction)
Recommendations concerning co-administration with letermovir: Modafinil may decrease plasma concentrations of letermovir. Co-administration of letermovir and modafinil is not recommended.
Effect on concentration – Mean ratio (90% confidence interval) for AUC, Cmax (likely mechanism of action):
Interaction not studied.
Expected:
↓ omeprazole (induction of CYP2C19)
Interaction not studied.
Expected:
↔ letermovir
Recommendations concerning co-administration with letermovir: Letermovir may decrease the plasma concentrations of CYP2C19 substrates. Clinical monitoring and dose adjustment may be needed.
Effect on concentration – Mean ratio (90% confidence interval) for AUC, Cmax (likely mechanism of action):
Interaction not studied.
Expected:
↓ pantoprazole (likely due to induction of CYP2C19)
Interaction not studied.
Expected:
↔ letermovir
Recommendations concerning co-administration with letermovir: Letermovir may decrease the plasma concentrations of CYP2C19 substrates. Clinical monitoring and dose adjustment may be needed.
Effect on concentration – Mean ratio (90% confidence interval) for AUC, Cmax (likely mechanism of action):
Interaction not studied.
Expected:
↓ letermovir (P-gp/UGT induction)
↓ phenytoin (CYP2C9/19 induction)
Recommendations concerning co-administration with letermovir: Phenytoin may decrease plasma concentrations of letermovir. Letermovir may decrease the plasma concentrations of phenytoin. Co-administration of letermovir and phenytoin is not recommended.
Effect on concentration – Mean ratio (90% confidence interval) for AUC, Cmax (likely mechanism of action):
Interaction not studied.
Expected:
↑ quinidine (CYP3A inhibition)
Recommendations concerning co-administration with letermovir: Letermovir may increase the plasma concentrations of quinidine. Close clinical monitoring should be exercised during administration of letermovir with quinidine.
Effect on concentration – Mean ratio (90% confidence interval) for AUC, Cmax (likely mechanism of action):
Interaction not studied.
Expected:
↑ or ↓ repaglinide (CYP2C8 induction, CYP2C8 and OATP1B inhibition)
Recommendations concerning co-administration with letermovir:
Letermovir may increase or decrease the plasma concentrations of repaglinide. (The net effect is not known).
Concomitant use is not recommended.
When letermovir is co-administered with cyclosporine, the plasma concentrations of repaglinide is expected to increase due to the additional OATP1B inhibition by cyclosporine. Concomitant use is not recommended#.
# Refer to the respective prescribing information.
Effect on concentration – Mean ratio (90% confidence interval) for AUC, Cmax (likely mechanism of action):
Interaction not studied.
Expected:
↓ letermovir (P-gp/UGT induction)
Recommendations concerning co-administration with letermovir: Rifabutin may decrease plasma concentrations of letermovir. Co-administration of letermovir and rifabutin is not recommended.
Effect on concentration – Mean ratio (90% confidence interval) for AUC, Cmax (likely mechanism of action):
Rifampicin (600 mg single dose PO)/letermovir (480 mg single dose PO):
(OATP1B1/3 and/or P-gp inhibition)
Rifampicin (600 mg single dose IV)/letermovir (480 mg single dose PO):
(OATP1B1/3 and/or P-gp inhibition)
Rifampicin (600 mg once daily PO)/letermovir (480 mg once daily PO):
(Sum of OATP1B1/3 and/or Pgp inhibition and P-gp/UGT induction)
Rifampicin (600 mg once daily PO (24 hours after rifampicin))§/letermovir (480 mg once daily PO):
(P-gp/UGT induction)
§ These data are the effect of rifampicin on letermovir 24 hours after final rifampicin dose.
Recommendations concerning co-administration with letermovir: Multiple dose rifampicin decreases plasma concentrations of letermovir. Co-administration of letermovir and rifampicin is not recommended.
Effect on concentration – Mean ratio (90% confidence interval) for AUC, Cmax (likely mechanism of action):
Interaction not studied.
Expected:
↑ HMG-CoA reductase inhibitors (CYP3A, OATP1B1/3 inhibition)
Recommendations concerning co-administration with letermovir: Letermovir may substantially increase plasma concentrations of these statins (simvastatin, pitavastatin, rosuvastatin). Concomitant use is not recommended with letermovir alone. When letermovir is co-administered with cyclosporine, use of these statins is contraindicated.
Effect on concentration – Mean ratio (90% confidence interval) for AUC, Cmax (likely mechanism of action):
Sirolimus‡ (2 mg single dose)/letermovir (480 mg daily):
(CYP3A inhibition)
Interaction not studied.
Expected:
‡ One-way interaction study assessing the effect of letermovir on the concomitant medicinal product.
Recommendations concerning co-administration with letermovir: Frequent monitoring of sirolimus whole blood concentrations should be performed during treatment, when changing letermovir administration route, and at discontinuation of letermovir and the dose of sirolimus adjusted accordingly#. Frequent monitoring of sirolimus concentrations is recommended at initiation or discontinuation of cyclosporine co-administration with letermovir. When letermovir is co-administered with cyclosporine, also refer to the sirolimus prescribing information for specific dosing recommendations for use of sirolimus with cyclosporine. When letermovir is co-administered with cyclosporine, the magnitude of the increase in concentrations of sirolimus may be greater than with letermovir alone.
# Refer to the respective prescribing information.
Effect on concentration – Mean ratio (90% confidence interval) for AUC, Cmax (likely mechanism of action):
Tacrolimus (5 mg single dose)/letermovir (480 mg daily):
(CYP3A inhibition)
Tacrolimus (5 mg single dose)/letermovir (80 mg twice daily):
Recommendations concerning co-administration with letermovir: Frequent monitoring of tacrolimus whole blood concentrations should be performed during treatment, when changing letermovir administration route, and at discontinuation of letermovir and the dose of tacrolimus adjusted accordingly#.
Effect on concentration – Mean ratio (90% confidence interval) for AUC, Cmax (likely mechanism of action):
Interaction not studied.
Expected:
↓ letermovir (P-gp/UGT induction)
Recommendations concerning co-administration with letermovir: Thioridazine may decrease plasma concentrations of letermovir. Co-administration of letermovir and thioridazine is not recommended.
Effect on concentration – Mean ratio (90% confidence interval) for AUC, Cmax (likely mechanism of action):
Voriconazole‡ (200 mg twice daily)/letermovir (480 mg daily):
(CYP2C9/19 induction)
Recommendations concerning co-administration with letermovir: If concomitant administration is necessary, TDM for voriconazole is recommended the first 2 weeks after initiating or ending letermovir, as well as after changing route of administration of letermovir or immunosuppressant.
Effect on concentration – Mean ratio (90% confidence interval) for AUC, Cmax (likely mechanism of action):
Interaction not studied.
Expected:
↓ warfarin (CYP2C9 induction)
Recommendations concerning co-administration with letermovir: Letermovir may decrease the plasma concentrations of warfarin. Frequent monitoring of International Normalised Ratio (INR) should be performed when warfarin is coadministered with letermovir treatment#. Monitoring is recommended the first 2 weeks after initiating or ending letermovir, as well as after changing route of administration of letermovir or immunosuppressant.
# Refer to the respective prescribing information.
No dose recommendation can be made for patients with end stage renal disease (ESRD) with or without dialysis. Efficacy and safety has not been demonstrated for patients with ESRD.
Effect on concentration – Mean ratio (90% confidence interval) for AUC, Cmax (likely mechanism of action):
Interaction not studied.
Expected:
↓ letermovir (P-gp/UGT induction)
Recommendations concerning co-administration with letermovir: Nafcillin may decrease plasma concentrations of letermovir. Co-administration of letermovir and nafcillin is not recommended.
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.
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 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.
Letermovir may have minor influence on the ability to drive or use machines. Fatigue and vertigo have been reported in some patients during treatment with letermovir, which may influence a patient’s ability to drive and use machines.
The safety assessment of letermovir was based on a Phase 3 clinical trial (P001) in HSCT recipients who received letermovir or placebo through Week 14 post-transplant and were followed for safety through Week 24 post-transplant.
The most commonly reported adverse reactions occurring in at least 1% of subjects in the letermovir 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 letermovir were nausea (1.6%), vomiting (0.8%), and abdominal pain (0.5%).
The following adverse reactions were identified in patients taking letermovir 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).
Adverse reactions identified with letermovir:
Uncommon: hypersensitivity
Uncommon: decreased appetite
Uncommon: dysgeusia, headache
Uncommon: vertigo
Common: nausea, diarrhoea, vomiting
Uncommon: abdominal pain
Uncommon: alanine aminotransferase increased, aspartate aminotransferase increased
Uncommon: muscle spasms
Uncommon: blood creatinine increased
Uncommon: fatigue, oedema peripheral
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