Table 3.
Letermovir characteristics and clinical guide
| Characteristic | Key information | Practical recommendations by authors |
|---|---|---|
| Chemical name | (4S)-2-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetic acid | — |
| Chemical structure |  | — |
| Other names | BAY-73-6327, AIC-090027, AIC-246, MK-8228, Prevymis | — |
| Mechanism of action | Inhibition of human CMV terminase complex (UL51, UL56, UL89) by binding to UL56, UL51, or both39-41,67 | — |
| Antiviral activity | Active against human CMV; median EC50 2.1 nM (range, 0.7-6.1 nM) against all CMV gB genotypes44,68 | Patients should receive antiviral prophylaxis against HSV and VZV with acyclovir, valacyclovir, or famciclovir as clinically indicated31 |
| No activity against other herpesviruses | ||
| No antagonism when combined with CMV DNA polymerase inhibitor ganciclovir, foscarnet, or cidofovir69 | ||
| Letermovir resistance | UL56 V236M clinically resistant mutant has been identified in patients in phase 235,70 and phase 3 trials31,49 ; UL56 C325W breakthrough mutant was also identified in phase 3 trial in patient who began treatment with letermovir with detectable plasma CMV DNA (not part of primary efficacy population)43,44 | Letermovir resistance testing is available in research71,72 and reference73 laboratories. |
| UL56 V236M and other letermovir-associated UL5671,72,74,75 and UL5167 mutations have been identified in vitro | ||
| Approved indication | Prophylaxis of CMV infection and disease in adult CMV-seropositive recipients of allogeneic HCT44-46 | Phase 3 trial comparing valganciclovir vs letermovir for CMV prophylaxis in CMV donor–seropositive, CMV-seronegative kidney transplant recipients is ongoing76 |
| Letermovir has been used for secondary CMV prophylaxis in solid organ transplant recipients with ganciclovir-resistant infections77 | ||
| Formulations | Tablets: 240 and 480 mg | In HCT clinical trial, 26% of patients received IV letermovir for median of 12 d,31 usually in setting of mucositis or other gastrointestinal issues that precluded oral administration; given higher bioavailability of IV letermovir, consider starting treatment with IV formulation in similar situations |
| IV: 240 mg per 12 mL and 480 mg per 24 mL in single-dose vials (20 mg/mL) dissolved in hydroxypropyl-β-cyclodextrin, at ratio of 1800 mg per 240 mg of letermovir31,78 | Although IV administration of letermovir is advisable for patients who cannot take oral tablets, and letermovir package insert does not recommend it because of lack of data,44 we have been successful in administering crushed letermovir tablets via gastrostomy tube in the outpatient setting | |
| Dosage | 480 mg per d | Letermovir exposure in patients receiving 240 mg per d of letermovir and concomitant cyclosporine was ∼50% higher than in patients who received 480 mg per d of letermovir without concomitant cyclosporine use31 |
| 240 mg per d when coadministered with cyclosporine31,48 | ||
| Bioavailability | 35% of 480 mg per d dose without cyclosporine use31 | Letermovir can be taken with or without food |
| 85% of 240 mg per d dose with cyclosporine use31 | No plasma letermovir concentration measurements available in reference laboratories to date | |
| No appreciable food effect; t1/2 11 to 18 h79 | ||
| Metabolism | Hepatic uptake via OATP1B1/3, 93% excreted in feces, 70% unchanged; highly protein bound in plasma (99%)44 | These metabolism pathways should be taken into consideration when administering concomitant medications not mentioned below |
| Substrate of metabolizing enzymes CYP3A, CYP2D6, UGT1A1, UGT1A3; transporters OATP1B1/3 and P-gp.44 | ||
| Drug interactions | Drug-drug interactions are likely more intense if using concomitant cyclosporine | Empirical dose adjustment of tacrolimus or sirolimus used for GVHD prophylaxis usually depends on drug levels when letermovir is started, as well as desired target trough levels; in our experience, in patients with low levels at beginning of coadministration (≤4 ng/mL), tacrolimus and sirolimus levels can be monitored without empirical adjustments; for patients with levels >8 ng/mL, empirical reductions of 50% and monitoring of drug levels are advisable |
| Via CYP3A inhibition (weak to moderate) | ||
| Increased levels of amiodarone, antidiabetic agents (glyburide, repaglinide, rosiglitazone), fentanyl, midazolam (2.0× AUC), quinidine, sirolimus (3.0× AUC), tacrolimus (1.8× AUC)48,80 | Consider reducing dose of statins if coadministered; we favor use of pravastatin or rosuvastatin given their lack of significant CYP metabolism81 | |
| Via induction of CYP2C9/19 (weak to moderate) | ||
| Decreased levels of voriconazole (0.56× AUC),79 warfarin, phenytoin, proton pump inhibitors (omeprazole, pantoprazole) | ||
| Via OATP1B1/3 | ||
| Increased levels of statins: atorvastatin (3.0× AUC), fluvastatin, lovastatin, pravastatin, rosuvastatin82,83 | ||
| Increased levels of cyclosporine (1.7× AUC)48,80 | ||
| No significant interactions in studies with acyclovir, digoxin, mycophenolate, posaconazole,79 ethinyl estradiol, levonorgestel44 | ||
| Contraindications | Pimozide and ergotamine, because of letermovir inhibition of CYP3A and increased levels of pimozide (increased QTc) and ergot alkaloids (ergotism)44 | These are uncommonly used drugs in HCT patients |
| Pitavastatin and simvastatin if given concurrently with cyclosporine, because of increased statin levels via OATP1B1/344 | ||
| Common adverse events | Nausea, vomiting, diarrhea, peripheral edema, cough, headache, fatigue, and abdominal pain (>10% and >2% over placebo events)31,35,44 | Consider letermovir as potential cause of persistent nausea or vomiting |
| Adverse events of note | Atrial fibrillation or flutter occurred in 4.6% of letermovir-treated patients vs 1% in those who received placebo31 ; letermovir does not prolong QTc interval31,44 | We would not start letermovir soon after conditioning regimens that involve use of CYP-metabolized drugs (eg, busulfan, cyclophosphamide); we would also withhold it during or right after posttransplantation cyclophosphamide administration to minimize risk of hepatotoxicity resulting from drug-drug and drug-metabolite interactions |
| Alanine aminotransferase levels >5× ULN were 3.5% in letermovir-treated patients vs 1.6% in those receiving placebo31 | ||
| Renal dysfunction | Increased letermovir exposure in patients with GFR <60 mL/min (< twofold)84 ; increased exposure does not require dose adjustments44 | Some caution is advised if GFR <50 mL/min and using IV formulation because of potential hydroxypropyl-β-cyclodextrin accumulation and consequent osmotic toxicity44,78 |
| No dosing recommendations for GFR <10 mL/min31,44 | The phase 3 trial enrolled patients with GFR >10 mL/min, yet no increased nephrotoxicity was observed31 | |
| No recommendation for severe renal impairment based on lack of data in this subpopulation; consider risks and benefits of letermovir prophylaxis for patients in this situation | ||
| Liver dysfunction | Patients with cirrhosis and moderate liver dysfunction (Child-Pugh class B) have < twofold higher letermovir exposures; patients with severe liver dysfunction (Child-Pugh class C) have ∼fourfold increased letermovir exposures47 | No letermovir dose adjustments are necessary for patients with cirrhosis and mild to moderate liver dysfunction (Child-Pugh class A or B), but letermovir is not recommended for cirrhotic patients with severe impairment (Child-Pugh class C)44 |
| Characteristic | Key information | Practical recommendations by authors |
|---|---|---|
| Chemical name | (4S)-2-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetic acid | — |
| Chemical structure | | — |
| Other names | BAY-73-6327, AIC-090027, AIC-246, MK-8228, Prevymis | — |
| Mechanism of action | Inhibition of human CMV terminase complex (UL51, UL56, UL89) by binding to UL56, UL51, or both39-41,67 | — |
| Antiviral activity | Active against human CMV; median EC50 2.1 nM (range, 0.7-6.1 nM) against all CMV gB genotypes44,68 | Patients should receive antiviral prophylaxis against HSV and VZV with acyclovir, valacyclovir, or famciclovir as clinically indicated31 |
| No activity against other herpesviruses | ||
| No antagonism when combined with CMV DNA polymerase inhibitor ganciclovir, foscarnet, or cidofovir69 | ||
| Letermovir resistance | UL56 V236M clinically resistant mutant has been identified in patients in phase 235,70 and phase 3 trials31,49 ; UL56 C325W breakthrough mutant was also identified in phase 3 trial in patient who began treatment with letermovir with detectable plasma CMV DNA (not part of primary efficacy population)43,44 | Letermovir resistance testing is available in research71,72 and reference73 laboratories. |
| UL56 V236M and other letermovir-associated UL5671,72,74,75 and UL5167 mutations have been identified in vitro | ||
| Approved indication | Prophylaxis of CMV infection and disease in adult CMV-seropositive recipients of allogeneic HCT44-46 | Phase 3 trial comparing valganciclovir vs letermovir for CMV prophylaxis in CMV donor–seropositive, CMV-seronegative kidney transplant recipients is ongoing76 |
| Letermovir has been used for secondary CMV prophylaxis in solid organ transplant recipients with ganciclovir-resistant infections77 | ||
| Formulations | Tablets: 240 and 480 mg | In HCT clinical trial, 26% of patients received IV letermovir for median of 12 d,31 usually in setting of mucositis or other gastrointestinal issues that precluded oral administration; given higher bioavailability of IV letermovir, consider starting treatment with IV formulation in similar situations |
| IV: 240 mg per 12 mL and 480 mg per 24 mL in single-dose vials (20 mg/mL) dissolved in hydroxypropyl-β-cyclodextrin, at ratio of 1800 mg per 240 mg of letermovir31,78 | Although IV administration of letermovir is advisable for patients who cannot take oral tablets, and letermovir package insert does not recommend it because of lack of data,44 we have been successful in administering crushed letermovir tablets via gastrostomy tube in the outpatient setting | |
| Dosage | 480 mg per d | Letermovir exposure in patients receiving 240 mg per d of letermovir and concomitant cyclosporine was ∼50% higher than in patients who received 480 mg per d of letermovir without concomitant cyclosporine use31 |
| 240 mg per d when coadministered with cyclosporine31,48 | ||
| Bioavailability | 35% of 480 mg per d dose without cyclosporine use31 | Letermovir can be taken with or without food |
| 85% of 240 mg per d dose with cyclosporine use31 | No plasma letermovir concentration measurements available in reference laboratories to date | |
| No appreciable food effect; t1/2 11 to 18 h79 | ||
| Metabolism | Hepatic uptake via OATP1B1/3, 93% excreted in feces, 70% unchanged; highly protein bound in plasma (99%)44 | These metabolism pathways should be taken into consideration when administering concomitant medications not mentioned below |
| Substrate of metabolizing enzymes CYP3A, CYP2D6, UGT1A1, UGT1A3; transporters OATP1B1/3 and P-gp.44 | ||
| Drug interactions | Drug-drug interactions are likely more intense if using concomitant cyclosporine | Empirical dose adjustment of tacrolimus or sirolimus used for GVHD prophylaxis usually depends on drug levels when letermovir is started, as well as desired target trough levels; in our experience, in patients with low levels at beginning of coadministration (≤4 ng/mL), tacrolimus and sirolimus levels can be monitored without empirical adjustments; for patients with levels >8 ng/mL, empirical reductions of 50% and monitoring of drug levels are advisable |
| Via CYP3A inhibition (weak to moderate) | ||
| Increased levels of amiodarone, antidiabetic agents (glyburide, repaglinide, rosiglitazone), fentanyl, midazolam (2.0× AUC), quinidine, sirolimus (3.0× AUC), tacrolimus (1.8× AUC)48,80 | Consider reducing dose of statins if coadministered; we favor use of pravastatin or rosuvastatin given their lack of significant CYP metabolism81 | |
| Via induction of CYP2C9/19 (weak to moderate) | ||
| Decreased levels of voriconazole (0.56× AUC),79 warfarin, phenytoin, proton pump inhibitors (omeprazole, pantoprazole) | ||
| Via OATP1B1/3 | ||
| Increased levels of statins: atorvastatin (3.0× AUC), fluvastatin, lovastatin, pravastatin, rosuvastatin82,83 | ||
| Increased levels of cyclosporine (1.7× AUC)48,80 | ||
| No significant interactions in studies with acyclovir, digoxin, mycophenolate, posaconazole,79 ethinyl estradiol, levonorgestel44 | ||
| Contraindications | Pimozide and ergotamine, because of letermovir inhibition of CYP3A and increased levels of pimozide (increased QTc) and ergot alkaloids (ergotism)44 | These are uncommonly used drugs in HCT patients |
| Pitavastatin and simvastatin if given concurrently with cyclosporine, because of increased statin levels via OATP1B1/344 | ||
| Common adverse events | Nausea, vomiting, diarrhea, peripheral edema, cough, headache, fatigue, and abdominal pain (>10% and >2% over placebo events)31,35,44 | Consider letermovir as potential cause of persistent nausea or vomiting |
| Adverse events of note | Atrial fibrillation or flutter occurred in 4.6% of letermovir-treated patients vs 1% in those who received placebo31 ; letermovir does not prolong QTc interval31,44 | We would not start letermovir soon after conditioning regimens that involve use of CYP-metabolized drugs (eg, busulfan, cyclophosphamide); we would also withhold it during or right after posttransplantation cyclophosphamide administration to minimize risk of hepatotoxicity resulting from drug-drug and drug-metabolite interactions |
| Alanine aminotransferase levels >5× ULN were 3.5% in letermovir-treated patients vs 1.6% in those receiving placebo31 | ||
| Renal dysfunction | Increased letermovir exposure in patients with GFR <60 mL/min (< twofold)84 ; increased exposure does not require dose adjustments44 | Some caution is advised if GFR <50 mL/min and using IV formulation because of potential hydroxypropyl-β-cyclodextrin accumulation and consequent osmotic toxicity44,78 |
| No dosing recommendations for GFR <10 mL/min31,44 | The phase 3 trial enrolled patients with GFR >10 mL/min, yet no increased nephrotoxicity was observed31 | |
| No recommendation for severe renal impairment based on lack of data in this subpopulation; consider risks and benefits of letermovir prophylaxis for patients in this situation | ||
| Liver dysfunction | Patients with cirrhosis and moderate liver dysfunction (Child-Pugh class B) have < twofold higher letermovir exposures; patients with severe liver dysfunction (Child-Pugh class C) have ∼fourfold increased letermovir exposures47 | No letermovir dose adjustments are necessary for patients with cirrhosis and mild to moderate liver dysfunction (Child-Pugh class A or B), but letermovir is not recommended for cirrhotic patients with severe impairment (Child-Pugh class C)44 |
AUC, area under the curve; GFR, glomerular filtration rate.