Prevymis

Cytomegalovirus Non-Nucleoside DNA Terminase Complex Inhibitor Antivirals

Oral Administration Oral Solid Formulations

Swallow tablets whole.
Administer with or without food.

Injectable Administration

Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. The solution should be clear and colorless and may contain a few product-related small translucent or white particles. Do not use if the solution is cloudy, discolored, or contains matter other than a few small translucent or white particles.[62611]

Intravenous Administration

Dilution
Vials are for single use only.
Do not shake the vial.
Add one single-dose vial into a 250 mL pre-filled IV bag containing either 0.9% Sodium Chloride Injection or 5% Dextrose Injection.
Mix bag gently. Do not shake.
Use compatible IV bags and infusion materials per the manufacturer's recommendations.
DO NOT use with IV bags and infusion set materials containing the plasticizer diethylhexyl phthalate (DEHP). Make sure IV bags and infusion set materials are DEHP-free. Materials that are phthalate-free are also DEHP-free.
DO NOT use with polyurethane-containing IV administration set tubing.
Storage: The diluted solution may be stored for up to 24 hours at room temperature or up to 48 hours under refrigeration (2 to 8 degrees C or 36 to 46 degrees F). Storage time includes the duration of the IV infusion.[62611]
 
Intermittent IV infusion
Must be administered through a sterile 0.2-micron or 0.22-micron polyethersulfone (PES) in-line filter; DO NOT administer through any other filter.
Administer IV infusion via a peripheral catheter or central venous line at a constant rate over 1 hour.
Do not administer as an IV bolus injection.[62611]

Severe

atrial fibrillation / Early / 3.0-3.0

Moderate

anemia / Delayed / 2.0-41.0
thrombocytopenia / Delayed / 1.0-27.0
neutropenia / Delayed / 1.0-19.0
peripheral edema / Delayed / 14.0-14.0
leukopenia / Delayed / 1.0-10.0
sinus tachycardia / Rapid / 4.0-4.0
dyspnea / Early / Incidence not known

Mild

diarrhea / Early / 26.0-32.0
nausea / Early / 27.0-27.0
vomiting / Early / 19.0-19.0
headache / Early / 14.0-14.0
cough / Delayed / 14.0-14.0
fatigue / Early / 13.0-13.0
abdominal pain / Early / 12.0-12.0

Prevymis

Rx

Cytomegalovirus (CMV) DNA terminase complex inhibitor
Used for prophylaxis of CMV infection and disease in adult CMV-seropositive recipients [R+] of an allogenic hematopoietic stem cell transplant (HSCT) and in adult kidney transplant recipients at high risk (Donor CMV seropositive/Recipient CMV seronegative [D+/R-])
Significant drug interactions are possible; dosage adjustments are required when administered with cyclosporine

For cytomegalovirus (CMV) disease prophylaxis. For prophylaxis of CMV infection and disease in CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT). Oral dosage Adults

480 mg PO once daily initiated between Day 0 and Day 28 post-transplant (before or after engraftment), and continued through Day 100 post-transplant. In patients at risk for late CMV infection and disease, may continue through Day 200 post-transplant. Monitor for CMV reactivation following completion of prophylaxis.

Adults on concurrent cyclosporine

240 mg PO once daily initiated between Day 0 and Day 28 post-transplant (before or after engraftment), and continued through Day 100 post-transplant. In patients at risk for late CMV infection and disease, may continue through Day 200 post-transplant. Monitor for CMV reactivation following completion of prophylaxis. If cyclosporine is initiated after starting letermovir, reduce letermovir to 240 mg PO with the next dose. If cyclosporine is discontinued after starting letermovir, increase the dose of letermovir to 480 mg PO. If cyclosporine dosing is interrupted due to high cyclosporine concentrations, no dosage adjustment of letermovir is needed.

Intravenous dosage Adults

480 mg IV once daily initiated between Day 0 and Day 28 post-transplant (before or after engraftment), and continued through Day 100 post-transplant. In patients at risk for late CMV infection and disease, may continue through Day 200 post-transplant. Monitor for CMV reactivation following completion of prophylaxis. Patients should be switched to oral therapy as soon as possible.

Adults on concurrent cyclosporine

240 mg IV once daily initiated between Day 0 and Day 28 post-transplant (before or after engraftment), and continued through Day 100 post-transplant. In patients at risk for late CMV infection and disease, may continue through Day 200 post-transplant. Monitor for CMV reactivation following completion of prophylaxis. If cyclosporine is initiated after starting letermovir, reduce letermovir to 240 mg IV with the next dose. If cyclosporine is discontinued after starting letermovir, increase the dose of letermovir to 480 mg IV. If cyclosporine dosing is interrupted due to high cyclosporine concentrations, no dosage adjustment of letermovir is needed. Patients should be switched to oral therapy as soon as possible.

For prophylaxis of CMV disease in kidney transplant recipients at high risk (Donor CMV seropositive/Recipient CMV seronegative [D+/R-]). Oral dosage Adults

480 mg PO once daily initiated between Day 0 and Day 7 post-transplant, and continued through Day 200 post-transplant.

Adults on concurrent cyclosporine

240 mg PO once daily initiated between Day 0 and Day 7 post-transplant, and continued through Day 200 post-transplant. If cyclosporine is initiated after starting letermovir, reduce letermovir to 240 mg PO with the next dose. If cyclosporine is discontinued after starting letermovir, increase the dose of letermovir to 480 mg PO. If cyclosporine dosing is interrupted due to high cyclosporine concentrations, no dosage adjustment of letermovir is needed.

Intravenous dosage Adults

480 mg IV once daily initiated between Day 0 and Day 7 post-transplant, and continued through Day 200 post-transplant. Patients should be switched to oral therapy as soon as possible.

Adults on concurrent cyclosporine

240 mg IV once daily initiated between Day 0 and Day 7 post-transplant, and continued through Day 200 post-transplant. If cyclosporine is initiated after starting letermovir, reduce letermovir to 240 mg IV with the next dose. If cyclosporine is discontinued after starting letermovir, increase the dose of letermovir to 480 mg IV. If cyclosporine dosing is interrupted due to high cyclosporine concentrations, no dosage adjustment of letermovir is needed. Patients should be switched to oral therapy as soon as possible.

Hepatic Impairment

No dosage adjustments are needed for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. Letermovir is not recommended for use in patients with severe (Child-Pugh Class C) hepatic impairment.[62611]

Renal Impairment

CrCl greater than 50 mL/minute: No dosage adjustment needed.
CrCl 11 to 49 mL/minute: No dosage adjustment needed; however, accumulation of the IV vehicle, hydroxypropyl betadex, may occur.
CrCl 10 mL/minute or less: There are insufficient data to make dosing recommendations. The safety for use is unknown.
 
Intermittent hemodialysis:
There are insufficient data to make dosing recommendations. The safety for use is unknown.

Abacavir; Dolutegravir; Lamivudine: (Moderate) A clinically relevant increase in the plasma concentration of dolutegravir may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Dolutegravir is partially metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor.
Abemaciclib: (Moderate) In patients receiving abemaciclib and letermovir WITHOUT concomitant cyclosporine, monitor for an increase in abemaciclib-related adverse reactions; consider reducing the dose of abemaciclib in 50-mg decrements if toxicities occur. In patients who are also receiving treatment with cyclosporine, a dose reduction of abemaciclib is required because the magnitude of this interaction may be amplified. Reduce the dose of abemaciclib to 100 mg PO twice daily in patients on either of the recommended starting doses of either 200 mg or 150 mg twice daily. In patients who have had already had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the dose of abemaciclib to 50 mg PO twice daily. If letermovir and cyclosporine are discontinued, resume the original dose of abemaciclib after 3 to 5 half-lives. Abemaciclib is a CYP3A4 substrate and letermovir is a moderate CYP3A4 inhibitor; however, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors is predicted to increase the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by approximately 1.6- to 2.4-fold. Coadministration with a strong CYP3A4 inhibitor increased the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 2.5-fold in cancer patients.
Acalabrutinib: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with letermovir. Avoid concomitant use in patients also receiving cyclosporine because the magnitude of the interaction may be increased. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; letermovir is a moderate CYP3A4 inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be like a strong CYP3A4 inhibitor.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with letermovir may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of letermovir could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If letermovir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Letermovir is a moderate inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with letermovir may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of letermovir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If letermovir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Letermovir is a moderate inhibitor of CYP3A4.
Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of letermovir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like letermovir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If letermovir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of letermovir is necessary. If letermovir is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a CYP3A4 inhibitor like letermovir can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If letermovir is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Ado-Trastuzumab emtansine: (Moderate) Caution is advised when administering ado-trastuzumab with letermovir. If the patient is also receiving cyclosporine, use of ado-trastuzumab should be avoided for 3 half-lives after discontinuation of letermovir and cyclosporine. If these drugs must be administered concurrently, closely monitor for adverse drug reactions. Administering letermovir with ado-trastuzumab may increase ado-trastuzumab concentration and risk for adverse events. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Ado-trastuzumab is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Albuterol; Budesonide: (Moderate) A clinically relevant increase in the plasma concentration of budesonide may occur when given concurrently with letermovir; monitor for adverse events. Avoid coadministration of oral budesonide and letermovir in patients who are also receiving treatment with cyclosporine, because the magnitude of this interaction may be amplified. Budesonide is a sensitive CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent use of a strong inhibitor increased the AUC of oral budesonide by 8-fold.
Alfentanil: (Moderate) Consider a reduced dose of alfentanil with frequent monitoring for respiratory depression and sedation if concurrent use of letermovir is necessary; the magnitude of this interaction may be amplified if the patient is also receiving cyclosporine. If letermovir is discontinued, consider increasing the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Alfentanil is a sensitive CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like letermovir can increase alfentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of alfentanil. If letermovir is discontinued, alfentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to alfentanil.
Alfuzosin: (Moderate) Coadministration of alfuzosin with letermovir may increase alfuzosin exposure and risk for adverse events. Concurrent use is contraindicated if the patient is also receiving cyclosporine because the magnitude of the interaction may be amplified. Alfuzosin is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with alfuzosin increased the alfuzosin AUC by 2.5-fold to 3.2-fold.
Almotriptan: (Moderate) No dosage adjustment is required in patients receiving letermovir with almotriptan who are not also receiving cyclosporine. The recommended starting dose of almotriptan is 6.25 mg (not to exceed 12.5 mg within a 24-hour period) in patients receiving letermovir with cyclosporine. Avoid almotriptan in combination with letermovir and cyclosporine in patients with renal or hepatic impairment. When cyclosporine is added to letermovir the magnitude of drug interactions may be increased. Almotriptan is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent use with another moderate CYP3A4 inhibitor increased the maximum plasma concentration and exposure of almotriptan by 24% and 20%, respectively. Neither of these changes was considered clinically significant and did not require dose adjustment. However, concurrent administration with a strong CYP3A4 inhibitor increased almotriptan exposure by approximately 60%.
Alogliptin; Pioglitazone: (Moderate) Plasma concentrations of pioglitazone could be increased when administered concurrently with letermovir. If these drugs are given together, closely monitor for pioglitazone-related adverse events. Letermovir is an inhibitor of CYP2C8; pioglitazone is a CYP2C8 substrate.
Alosetron: (Moderate) A clinically relevant increase in the plasma concentration of alosetron is not expected if coadministered with letermovir; however, in patients also receiving cyclosporine, the magnitude of the interaction may be increased. Alosetron is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor. In a drug interaction study, concurrent administration with another strong CYP3A4 inhibitor increased mean alosetron plasma concentrations (AUC) by 29%.
Alprazolam: (Major) Avoid coadministration of alprazolam and letermovir due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. Coadministration is not recommended if the patient is also receiving cyclosporine, because the magnitude of the interaction may be increased. If coadministration is necessary, consider reducing the dose of alprazolam as clinically appropriate and monitor for an increase in alprazolam-related adverse reactions. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with letermovir, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect CYP3A4 substrates is similar to a strong CYP3A4 inhibitor. Concurrent administration with other moderate to strong inhibitors increased alprazolam exposure by 1.61- to 3.98-fold.
Amiodarone: (Moderate) Closely monitor for amiodarone-related adverse events and frequently monitor amiodarone concentrations if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. A clinically relevant increase in the plasma concentration of amiodarone, a CYP3A4 substrate, may occur during concurrent administration with letermovir, a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Amlodipine: (Moderate) Amlodipine dose reductions may be required during concurrent administration with letermovir; monitor for symptoms of hypotension and edema to determine the need for dose adjustment. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Administering these drugs together may increase amlodipine concentration and risk for adverse events. Amlodipine is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent administration with a moderate CYP3A inhibitor increased amlodipine exposure by 60%; however, another moderate inhibitor did not significantly change amlodipine exposure. Strong CYP3A4 inhibitors may increase amlodipine exposure to a greater extent.
Amlodipine; Atorvastatin: (Major) Do not exceed an atorvastatin dosage of 20 mg daily and closely monitor for myopathy and rhabdomyolysis if coadministration with letermovir is necessary. Concurrent use is not recommended for patients who are also receiving cyclosporine, as the magnitude of this interaction may be amplified. A clinically relevant increase in the plasma concentration of atorvastatin may occur during concurrent administration with letermovir. Atorvastatin is a substrate of CYP3A4 and the organic anion-transporting polypeptides 1B1 and 1B3 (OATP1B1/3). Both letermovir and cyclosporine are moderate inhibitors of CYP3A4 and inhibitors of OATP1B1; letermovir is also an OATP1B3 inhibitor. Coadministration of letermovir increased the AUC and Cmax of atorvastatin by 3.29-fold and 2.17-fold, respectively. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. (Moderate) Amlodipine dose reductions may be required during concurrent administration with letermovir; monitor for symptoms of hypotension and edema to determine the need for dose adjustment. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Administering these drugs together may increase amlodipine concentration and risk for adverse events. Amlodipine is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent administration with a moderate CYP3A inhibitor increased amlodipine exposure by 60%; however, another moderate inhibitor did not significantly change amlodipine exposure. Strong CYP3A4 inhibitors may increase amlodipine exposure to a greater extent.
Amlodipine; Benazepril: (Moderate) Amlodipine dose reductions may be required during concurrent administration with letermovir; monitor for symptoms of hypotension and edema to determine the need for dose adjustment. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Administering these drugs together may increase amlodipine concentration and risk for adverse events. Amlodipine is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent administration with a moderate CYP3A inhibitor increased amlodipine exposure by 60%; however, another moderate inhibitor did not significantly change amlodipine exposure. Strong CYP3A4 inhibitors may increase amlodipine exposure to a greater extent.
Amlodipine; Celecoxib: (Moderate) Amlodipine dose reductions may be required during concurrent administration with letermovir; monitor for symptoms of hypotension and edema to determine the need for dose adjustment. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Administering these drugs together may increase amlodipine concentration and risk for adverse events. Amlodipine is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent administration with a moderate CYP3A inhibitor increased amlodipine exposure by 60%; however, another moderate inhibitor did not significantly change amlodipine exposure. Strong CYP3A4 inhibitors may increase amlodipine exposure to a greater extent.
Amlodipine; Olmesartan: (Moderate) Amlodipine dose reductions may be required during concurrent administration with letermovir; monitor for symptoms of hypotension and edema to determine the need for dose adjustment. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Administering these drugs together may increase amlodipine concentration and risk for adverse events. Amlodipine is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent administration with a moderate CYP3A inhibitor increased amlodipine exposure by 60%; however, another moderate inhibitor did not significantly change amlodipine exposure. Strong CYP3A4 inhibitors may increase amlodipine exposure to a greater extent.
Amlodipine; Valsartan: (Moderate) Amlodipine dose reductions may be required during concurrent administration with letermovir; monitor for symptoms of hypotension and edema to determine the need for dose adjustment. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Administering these drugs together may increase amlodipine concentration and risk for adverse events. Amlodipine is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent administration with a moderate CYP3A inhibitor increased amlodipine exposure by 60%; however, another moderate inhibitor did not significantly change amlodipine exposure. Strong CYP3A4 inhibitors may increase amlodipine exposure to a greater extent.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Amlodipine dose reductions may be required during concurrent administration with letermovir; monitor for symptoms of hypotension and edema to determine the need for dose adjustment. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Administering these drugs together may increase amlodipine concentration and risk for adverse events. Amlodipine is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent administration with a moderate CYP3A inhibitor increased amlodipine exposure by 60%; however, another moderate inhibitor did not significantly change amlodipine exposure. Strong CYP3A4 inhibitors may increase amlodipine exposure to a greater extent.
Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Administering clarithromycin concurrently with letermovir may result in elevated concentrations of both drugs. The impact on the serum concentration of clarithromycin may be increased in patients receiving letermovir with cyclosporine. Closely monitor for adverse events including tachycardia, atrial fibrillation, gastrointestinal events, dizziness, or confusion. Clarithromycin is an inhibitor of the organic anion-transporting polypeptides (OATP1B1/3), and a substrate of CYP3A4. Letermovir is an OATP1B1/3 substrate and a moderate CYP3A4 inhibitor. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In a drug interaction study, concurrent use with another CYP3A inhibitor increased clarithromycin exposure (AUC) by 94%, and decreased AUC of 14-OH clarithromycin by 70%. (Moderate) Monitor for reduced omeprazole efficacy and adjust the dose of omeprazole if needed during concurrent use of letermovir. Coadministration may result in a clinically relevant decrease in the plasma concentration of omeprazole. Omeprazole is a sensitive substrate of CYP2C19. Letermovir is a CYP2C19 inducer.
Apalutamide: (Major) Concurrent administration of letermovir and apalutamide is not recommended. Use of these drugs together may decrease letermovir plasma concentrations, resulting in a potential loss of letermovir efficacy. Letermovir is a substrate of UDP-glucuronosyltransferase 1A1/3 (UGT1A1/3) and P-glycoprotein (P-gp). Apalutamide may induce UGT and is a weak inducer of P-gp. Also, plasma concentrations of apalutamide could be increased when administered concurrently with letermovir. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Apalutamide is metabolized by CYP3A4. Letermovir is a moderate inhibitor of CYP3A4; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Consider reducing the dose of apalutamide if necessary based on tolerability in patients experiencing grade 3 or higher adverse reactions of intolerable toxicities.
Aprepitant, Fosaprepitant: (Major) Avoid concurrent administration of aprepitant with letermovir due to substantially increased exposure of aprepitant. Fosaprepitant is rapidly converted to aprepitant; therefore, a similar interaction is likely. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Aprepitant is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. The AUC of aprepitant was increased by 2-fold in the presence of a moderate CYP3A4 inhibitor and by approximately 5-fold with a strong inhibitor.
Aripiprazole: (Moderate) Because aripiprazole is partially metabolized by CYP3A4, patients should be carefully monitored for aripiprazole-related adverse reactions during concurrent use of a moderate CYP3A4 inhibitor such as letermovir. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions. In addition, because aripiprazole is also metabolized by CYP2D6, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 inhibitor. During coadministration of letermovir and cyclosporine, letermovir may exhibit more potent CYP3A4 inhibitory properties. When letermovir and cyclosporine are used concurrently with aripiprazole, consult the aripiprazole product information for dosage adjustments of aripiprazole necessary during use of a potent CYP3A4 inhibitor.
Artemether; Lumefantrine: (Moderate) A moderate increase in the plasma concentration of artemether may occur if given concurrently with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. No dosage adjustments are required; however, due to the potential for increased concentrations of artemether which could lead to QT prolongation, these drugs should be administered together with caution. Artemether is metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. (Moderate) A moderate increase in the plasma concentration of lumefantrine may occur if given concurrently with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. No dosage adjustments are required; however, due to the potential for increased concentrations of lumefantrine which could lead to QT prolongation, these drugs should be administered together with caution. Lumefantrine is metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with letermovir may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of letermovir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If letermovir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Letermovir is a moderate inhibitor of CYP3A4.
Aspirin, ASA; Omeprazole: (Moderate) Monitor for reduced omeprazole efficacy and adjust the dose of omeprazole if needed during concurrent use of letermovir. Coadministration may result in a clinically relevant decrease in the plasma concentration of omeprazole. Omeprazole is a sensitive substrate of CYP2C19. Letermovir is a CYP2C19 inducer.
Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of letermovir is necessary. If letermovir is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a CYP3A4 inhibitor like letermovir can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If letermovir is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Atazanavir: (Moderate) Administering atazanavir concurrently with letermovir may result in elevated concentrations of both drugs. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Closely monitor for adverse events, including tachycardia, atrial fibrillation, hepatotoxicity, kidney stones, and gastrointestinal events. Atazanavir is an inhibitor of the organic anion-transporting polypeptides (OATP1B1), and a substrate of CYP3A4. Letermovir is an OATP1B1 substrate and a moderate CYP3A4 inhibitor. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Atazanavir; Cobicistat: (Moderate) Administering atazanavir concurrently with letermovir may result in elevated concentrations of both drugs. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Closely monitor for adverse events, including tachycardia, atrial fibrillation, hepatotoxicity, kidney stones, and gastrointestinal events. Atazanavir is an inhibitor of the organic anion-transporting polypeptides (OATP1B1), and a substrate of CYP3A4. Letermovir is an OATP1B1 substrate and a moderate CYP3A4 inhibitor. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. (Moderate) Administering cobicistat concurrently with letermovir may result in increased concentrations of both drugs. The impact on the concentration of cobicistat may be increased in patients who are receiving letermovir with cyclosporine. Closely monitor for adverse events, including tachycardia, atrial fibrillation, and gastrointestinal events. Cobicistat is an inhibitor of the organic anion-transporting polypeptides (OATP1B1/3), and a substrate of CYP3A4. Letermovir is an OATP1B1/3 substrate and a moderate CYP3A4 inhibitor. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Atogepant: (Major) Limit the dose of atogepant to 10 or 30 mg PO once daily for episodic migraine or 30 mg PO once daily for chronic migraine if coadministered with letermovir. Avoid use of atogepant and combination letermovir plus cyclosporine when atogepant is used for chronic migraine. Limit the dose of atogepant to 10 mg PO once daily for episodic migraine if coadministered with combination letermovir plus cyclosporine. Concurrent use may increase atogepant exposure and the risk of adverse effects. Atogepant is a substrate of CYP3A and OATP1B1/3; letermovir is an OATP1B1/3 inhibitor and combination letermovir plus cyclosporine is a strong CYP3A inhibitor. Coadministration with an OATP1B1/3 inhibitor resulted in a 2.85-fold increase in atogepant overall exposure and a 2.23-fold increase in atogepant peak concentration. Coadministration with a strong CYP3A inhibitor resulted in a 5.5-fold increase in atogepant overall exposure and a 2.15-fold increase in atogepant peak concentration.
Atorvastatin: (Major) Do not exceed an atorvastatin dosage of 20 mg daily and closely monitor for myopathy and rhabdomyolysis if coadministration with letermovir is necessary. Concurrent use is not recommended for patients who are also receiving cyclosporine, as the magnitude of this interaction may be amplified. A clinically relevant increase in the plasma concentration of atorvastatin may occur during concurrent administration with letermovir. Atorvastatin is a substrate of CYP3A4 and the organic anion-transporting polypeptides 1B1 and 1B3 (OATP1B1/3). Both letermovir and cyclosporine are moderate inhibitors of CYP3A4 and inhibitors of OATP1B1; letermovir is also an OATP1B3 inhibitor. Coadministration of letermovir increased the AUC and Cmax of atorvastatin by 3.29-fold and 2.17-fold, respectively. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Atorvastatin; Ezetimibe: (Major) Do not exceed an atorvastatin dosage of 20 mg daily and closely monitor for myopathy and rhabdomyolysis if coadministration with letermovir is necessary. Concurrent use is not recommended for patients who are also receiving cyclosporine, as the magnitude of this interaction may be amplified. A clinically relevant increase in the plasma concentration of atorvastatin may occur during concurrent administration with letermovir. Atorvastatin is a substrate of CYP3A4 and the organic anion-transporting polypeptides 1B1 and 1B3 (OATP1B1/3). Both letermovir and cyclosporine are moderate inhibitors of CYP3A4 and inhibitors of OATP1B1; letermovir is also an OATP1B3 inhibitor. Coadministration of letermovir increased the AUC and Cmax of atorvastatin by 3.29-fold and 2.17-fold, respectively. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Avanafil: (Major) Do not exceed an avanafil dose of 50 mg every 24 hours when administered concurrently with letermovir due to increased avanafil exposure. Concurrent use should be avoided if the patient is also receiving cyclosporine, because the magnitude of the interaction may be increased. Avanafil is a sensitive substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. The AUC of avanafil was increased by approximately 3-fold in the presence of a moderate CYP3A4 inhibitor and by 13-fold with a strong inhibitor.
Avapritinib: (Major) Avoid coadministration of avapritinib with letermovir due to the risk of increased avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avoid concomitant use in patients also receiving cyclosporine because the magnitude of the interaction may be increased. Avapritinib is a CYP3A4 substrate and letermovir is a moderate CYP3A4 inhibitor; however, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 210% at steady-state. Coadministration of avapritinib 300 mg PO once daily with a strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Axitinib: (Moderate) Avoid coadministration of axitinib with letermovir if the patient is also taking cyclosporine due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after letermovir or cyclosporine is discontinued. Axitinib is a CYP3A4/5 substrate. Letermovir is a moderate CYP3A4 inhibitor which requires no dose adjustment with axitinib; however, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Azelastine; Fluticasone: (Moderate) A clinically relevant increase in the plasma concentration of fluticasone may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Concurrent use of all 3 drugs together is not recommended because increased systemic corticosteroid adverse events may develop. Fluticasone is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor. In a drug interaction study, use of fluticasone with another strong CYP3A4 inhibitor resulted in a 1.9-fold increase in plasma fluticasone exposure and a 45% decrease in plasma cortisol exposure, but had no effect on urinary excretion of cortisol.
Bedaquiline: (Moderate) Administering letermovir with bedaquiline may increase bedaquiline concentration and risk for adverse events. Avoid coadministration if the patient is also receiving cyclosporine, because the magnitude of the interaction may be increased. Bedaquiline is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent administration of strong CYP3A4 inhibitors increased bedaquiline exposure by 22%.
Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with letermovir may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Consider a dose reduction of benzhydrocodone until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of letermovir in a patient taking benzhydrocodone may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If letermovir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a substrate for CYP3A4. Letermovir is an inhibitor of CYP3A4.
Bortezomib: (Moderate) Administering letermovir with bortezomib may increase bortezomib concentration and risk for adverse events. Consider a bortezomib dose reduction and monitor for signs of bortezomib toxicity if the patient is also receiving cyclosporine, because the magnitude of the interaction may be increased. Bortezomib is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent administration with a strong CYP3A4 inhibitor increased exposure of bortezomib by 35%.
Bosentan: (Major) Concurrent administration of letermovir and bosentan is not recommended. Use of these drugs together may decrease letermovir plasma concentrations, resulting in a potential loss of letermovir efficacy. Also, the risk for bosentan-related adverse reactions may increase during cocurrent administration with letermovir. Do not administer bosentan to patients receiving letermovir with cyclosporine as bosentan is contraindicated for use with cyclosporine; bosentan plasma concentrations were markedly increased by cyclosporine. Additionally, treatment with bosentan and letermovir with a CYP2C9 inhibitor is not recommended. Letermovir is a moderate inhibitor of CYP3A4. Bosentan is a CYP3A substrate and letermovir is a moderate CYP3A4 inhibitor. Because bosentan is also metabolized by CYP2C9, a large increase in bosentan plasma concentrations may occur if the patient is receiving concomitant treatment with a CYP2C9 inhibitor in addition to letermovir.
Bosutinib: (Major) Avoid concurrent use of letermovir and bosutinib, as taking these drugs together may increase bosutinib concentration and risk for adverse events. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Bosutinib is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent use with another strong CYP3A inhibitor increased bosutinib maximum plasma concentration by 5.2-fold and exposure by 8.6-fold. The maximum plasma concentrations and exposure increased by 1.5- and 2-fold, respectively, when administered with a moderate CYP3A inhibitor.
Brentuximab vedotin: (Moderate) A clinically relevant increase in the plasma concentration of brentuximab vedotin may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Brentuximab vedotin is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent administration with a strong CYP3A4 inhibitor increased exposure to a component of brentuximab vedotin (monomethyl auristatin E), by approximately 34%.
Brexpiprazole: (Moderate) Administering letermovir with brexpiprazole may increase brexpiprazole concentration and risk for adverse events. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. When administering brexpiprazole with letermovir and cyclosporine, the dose should be reduced to one-half of the normal dose. In patients who are 2D6 poor metabolizers, the brexpiprazole dose should be reduced to one-quarter of the normal dose when administered with letermovir with or without cyclosporine. The dose should be reduced to one-quarter of the normal dose in patients who are receiving brexpiprazole and letermovir with a strong or moderate CY2D6 inhibitor. Brexpiprazole is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Brigatinib: (Major) Avoid coadministration of brigatinib with letermovir if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable and the patient is also taking cyclosporine, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg). If the patient is not receiving concomitant cyclosporine, reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg). After discontinuation of letermovir, resume the brigatinib dose that was tolerated prior to initiation of letermovir. Brigatinib is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the AUC of brigatinib by approximately 40%.
Brincidofovir: (Moderate) Postpone the administration of letermovir for at least three hours after brincidofovir administration and increase monitoring for brincidofovir-related adverse reactions (i.e., elevated hepatic enzymes and bilirubin, diarrhea, other gastrointestinal adverse events) if concomitant use of brincidofovir and letermovir is necessary. Brincidofovir is an OATP1B1/3 substrate and letermovir is an OATP1B1/3 inhibitor. In a drug interaction study, the mean AUC and Cmax of brincidofovir increased by 374% and 269%, respectively, when administered with another OATP1B1/3 inhibitor.
Bromocriptine: (Major) When bromocriptine is used for diabetes, do not exceed a dose of 1.6 mg once daily during concomitant use of letermovir. If the patient is also receiving cyclosporine, avoid coadministration ensuring adequate washout before initiating bromocriptine; the addition of cyclosporine may increase the magnitude of the interaction. When bromocriptine is used for other indications, use caution during coadministration of letermovir with or without cyclosporine. Concurrent use may increase bromocriptine concentrations. Bromocriptine is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. The AUC of bromocriptine was increased by 3.7-fold in the presence of a moderate CYP3A4 inhibitor.
Budesonide: (Moderate) A clinically relevant increase in the plasma concentration of budesonide may occur when given concurrently with letermovir; monitor for adverse events. Avoid coadministration of oral budesonide and letermovir in patients who are also receiving treatment with cyclosporine, because the magnitude of this interaction may be amplified. Budesonide is a sensitive CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent use of a strong inhibitor increased the AUC of oral budesonide by 8-fold.
Budesonide; Formoterol: (Moderate) A clinically relevant increase in the plasma concentration of budesonide may occur when given concurrently with letermovir; monitor for adverse events. Avoid coadministration of oral budesonide and letermovir in patients who are also receiving treatment with cyclosporine, because the magnitude of this interaction may be amplified. Budesonide is a sensitive CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent use of a strong inhibitor increased the AUC of oral budesonide by 8-fold.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) A clinically relevant increase in the plasma concentration of budesonide may occur when given concurrently with letermovir; monitor for adverse events. Avoid coadministration of oral budesonide and letermovir in patients who are also receiving treatment with cyclosporine, because the magnitude of this interaction may be amplified. Budesonide is a sensitive CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent use of a strong inhibitor increased the AUC of oral budesonide by 8-fold.
Bupivacaine; Lidocaine: (Moderate) An increase in the plasma concentration of lidocaine may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Lidocaine is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Buprenorphine: (Moderate) Concomitant use of buprenorphine and letermovir can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when letermovir is added after a stable buprenorphine dose is achieved. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping letermovir, the buprenorphine concentration will decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If letermovir is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Buprenorphine; Naloxone: (Moderate) Concomitant use of buprenorphine and letermovir can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when letermovir is added after a stable buprenorphine dose is achieved. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping letermovir, the buprenorphine concentration will decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If letermovir is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Buspirone: (Moderate) Administering letermovir with buspirone may increase buspirone concentration and risk for adverse events. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. If a patient has been titrated to a stable dosage of buspirone, a dose adjustment of buspirone may be necessary to avoid adverse events attributable to buspirone. Consequently, when administered with both letermovir and cyclosporine, a low dose of buspirone used cautiously is recommended. Buspirone is a sensitive substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concomitant use of codeine with letermovir may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of letermovir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If letermovir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Letermovir is a moderate inhibitor of CYP3A4.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Concomitant use of codeine with letermovir may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of letermovir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If letermovir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Letermovir is a moderate inhibitor of CYP3A4.
Cabazitaxel: (Moderate) A clinically significant increase in cabazitaxel exposure is not expected when coadministered with letermovir; however, if the patient is also receiving cyclosporine, increased cabazitaxel concentrations are possible. Consider a 25% reduction in the dose of cabazitaxel in patients who are also receiving cyclosporine. Cabazitaxel is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration of cabazitaxel with a moderate CYP3A4 inhibitor did not modify cabazitaxel exposure; however, when given with a strong CYP3A4 inhibitor, the cabazitaxel exposure increased by 25%.
Cabotegravir; Rilpivirine: (Moderate) A clinically relevant increase in the plasma concentration of rilpivirine may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Rilpivirine is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Cabozantinib: (Moderate) Avoid coadministration of letermovir and cabozantinib in patients also receiving cyclosporine due to the risk of increased cabozantinib exposure; an interaction is not expected in patients taking letermovir and cabozantinib without cyclosporine. If concomitant use of cabozantinib with both letermovir and cyclosporine is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg (e.g., 60 mg/day to 40 mg/day; 40 mg/day to 20 mg/day); for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg (e.g., 140 mg/day to 100 mg/day or 100 mg/day to 60 mg/day). Resume the cabozantinib dose that was used prior to initiating treatment with letermovir and cyclosporine 2 to 3 days after discontinuation of either letermovir or cyclosporine. Cabozantinib is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased single-dose cabozantinib exposure by 38%.
Carbamazepine: (Major) Concurrent administration of letermovir and carbamazepine is not recommended. Use of these drugs together may decrease letermovir plasma concentrations, resulting in a potential loss of letermovir efficacy. Letermovir is a substrate of UDP-glucuronosyltransferase 1A1/3 (UGT1A1/3) and P-glycoprotein (P-gp). Carbamazepine is a strong inducer of UGTA1 and P-gp. Also, plasma concentrations of carbamazepine could be increased when administered concurrently with letermovir. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Carbamazepine is metabolized by CYP3A4. Letermovir is a moderate inhibitor of CYP3A4; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Cariprazine: (Moderate) Administering letermovir with cariprazine may increase cariprazine concentration and risk for adverse events. The dose of cariprazine should be reduced in patients also receiving cyclosporine, because the magnitude of this interaction may be increased. When letermovir and cyclosporine are initiated in a patient who is on a stable dose of cariprazine, reduce the cariprazine dosage by half. For adult patients taking cariprazine 4.5 mg daily, the dosage should be reduced to 1.5 mg or 3 mg daily. For patients taking cariprazine 1.5 mg daily, the dosing frequency should be adjusted to every other day. When initiating cariprazine in a patient who is stable on letermovir and cyclosporine, the patient should be administered 1.5 mg of cariprazine on Day 1 and on Day 3 with no dose administered on Day 2. From Day 4 onward, the dose should be administered at 1.5 mg daily, and then increased to a maximum dose of 3 mg daily. When both letermovir and cyclosporine are withdrawn, the cariprazine dosage may need to be increased. Cariprazine is metabolized by CYP3A4 to its major active metabolite. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent use with another strong CYP3A4 inhibitor increased the maximum plasma concentration (Cmax) and exposure (AUC) of cariprazine by about 3.5- and 4-fold, respectively; increased the Cmax and AUC of DDCAR metabolite by about 1.5-fold; and decreased DCAR metabolite Cmax and AUC by about one-third. The impact of moderate CYP3A4 inhibitors has not been studied.
Carvedilol: (Moderate) Monitor for decreased carvedilol efficacy during concurrent use of letermovir. Taking these drugs together may cause a reduction in carvedilol plasma concentrations. Letermovir is a CYP2C9 inducer; carvedilol is a substrate of CYP2C9.
Celecoxib; Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with letermovir is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of letermovir, a CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Ceritinib: (Moderate) Avoid coadministration of ceritinib with letermovir if the patient is also taking cyclosporine. If this combination (ceritinib/letermovir/cyclosporine) is unavoidable, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg; monitor for ceritinib-related adverse reactions. No dose adjustment or special precautions are necessary if ceritinib and letermovir are coadministered without cyclosporine. Ceritinib is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor, but the combined effect when given with cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ceritinib exposure by 2.9-fold after a single dose in healthy subjects.
Chlordiazepoxide: (Moderate) Closely monitor for chlordiazepoxide-related adverse events if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. A clinically relevant increase in the plasma concentration of chlordiazepoxide, a CYP3A4 substrate, may occur during concurrent administration with letermovir, a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Chlordiazepoxide; Amitriptyline: (Moderate) Closely monitor for chlordiazepoxide-related adverse events if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. A clinically relevant increase in the plasma concentration of chlordiazepoxide, a CYP3A4 substrate, may occur during concurrent administration with letermovir, a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Chlordiazepoxide; Clidinium: (Moderate) Closely monitor for chlordiazepoxide-related adverse events if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. A clinically relevant increase in the plasma concentration of chlordiazepoxide, a CYP3A4 substrate, may occur during concurrent administration with letermovir, a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with letermovir may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of letermovir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If letermovir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Letermovir is a moderate inhibitor of CYP3A4.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with letermovir may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of letermovir could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If letermovir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Letermovir is a moderate inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of letermovir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like letermovir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If letermovir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Cilostazol: (Major) Reduce the dose of cilostazol to 50 mg PO twice daily if coadministered with letermovir due to increased cilostazol exposure and risk for adverse events. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Cilostazol is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor. The combined effect of letermovi

r and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. The AUC of cilostazol and its metabolite 4-trans-hydroxycilostazol have been increased by up to 73% and 141%, respectively in the presence of moderate CYP3A4 inhibitors; a strong CYP3A4 inhibitor increased the cilostazol AUC by 117%.
Cinacalcet: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of letermovir and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and letermovir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Cisapride: (Moderate) Closely monitor for cisapride-related adverse events if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. A clinically relevant increase in the plasma concentration of cisapride, a CYP3A4 substrate, may occur during concurrent administration with letermovir, a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Clarithromycin: (Moderate) Administering clarithromycin concurrently with letermovir may result in elevated concentrations of both drugs. The impact on the serum concentration of clarithromycin may be increased in patients receiving letermovir with cyclosporine. Closely monitor for adverse events including tachycardia, atrial fibrillation, gastrointestinal events, dizziness, or confusion. Clarithromycin is an inhibitor of the organic anion-transporting polypeptides (OATP1B1/3), and a substrate of CYP3A4. Letermovir is an OATP1B1/3 substrate and a moderate CYP3A4 inhibitor. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In a drug interaction study, concurrent use with another CYP3A inhibitor increased clarithromycin exposure (AUC) by 94%, and decreased AUC of 14-OH clarithromycin by 70%.
Clindamycin: (Moderate) Monitor for an increase in clindamycin-related adverse reactions with coadministration of letermovir as concurrent use may increase clindamycin exposure. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Clindamycin is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Clobazam: (Moderate) Plasma concentrations of clobazam could be increased when administered concurrently with letermovir. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Monitor for clobazam-related adverse events. Clobazam is a substrate of CYP3A4. Letermovir is a moderate inhibitor of CYP3A4; however, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Clonazepam: (Moderate) A clinically relevant increase in the plasma concentration of clonazepam may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Clonazepam is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor.
Clorazepate: (Moderate) Plasma concentrations of clorazepate could be increased when administered concurrently with letermovir. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. If these drugs are given together, monitor for clorazepate-related adverse events. Clorazepate is a pro-drug converted to N-desmethyldiazepam in the GI tract; N-desmethyldiazepam is metabolized by CYP3A4. Letermovir is a moderate inhibitor of CYP3A4. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Clozapine: (Moderate) Consider a clozapine dose reduction if coadministered with letermovir and monitor for adverse reactions. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Clozapine is partially metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor.
Cobicistat: (Moderate) Administering cobicistat concurrently with letermovir may result in increased concentrations of both drugs. The impact on the concentration of cobicistat may be increased in patients who are receiving letermovir with cyclosporine. Closely monitor for adverse events, including tachycardia, atrial fibrillation, and gastrointestinal events. Cobicistat is an inhibitor of the organic anion-transporting polypeptides (OATP1B1/3), and a substrate of CYP3A4. Letermovir is an OATP1B1/3 substrate and a moderate CYP3A4 inhibitor. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Cobimetinib: (Moderate) Avoid coadministration of letermovir with cobimetinib, as concurrent use may increase cobimetinib concentration and risk for adverse events. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Cobimetinib is a sensitive substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Codeine: (Moderate) Concomitant use of codeine with letermovir may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of letermovir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If letermovir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Letermovir is a moderate inhibitor of CYP3A4.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with letermovir may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of letermovir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If letermovir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Letermovir is a moderate inhibitor of CYP3A4.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with letermovir may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of letermovir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If letermovir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Letermovir is a moderate inhibitor of CYP3A4.
Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with letermovir may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of letermovir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If letermovir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Letermovir is a moderate inhibitor of CYP3A4.
Codeine; Promethazine: (Moderate) Concomitant use of codeine with letermovir may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of letermovir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If letermovir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Letermovir is a moderate inhibitor of CYP3A4.
Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and letermovir in patients with normal renal and hepatic function unless the use of both agents is imperative. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Letermovir, a moderate CYP3A4 inhibitor, can inhibit colchicine's metabolism, resulting in increased colchicine exposure. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine; the combined effect of letermovir and cyclosporine may be similar to a strong CYP3A4 inhibitor. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations for the Colcrys product for patients who have taken a moderate CYP3A4 inhibitor including letermovir in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg twice daily or 0.6 mg once daily or if the original dose is 0.6 mg once daily, decrease the dose to 0.3 mg once daily; for treatment of gout flares, give 1.2 mg as a single dose and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed 1.2 mg/day. For patients who have taken a strong CYP3A4 inhibitor including letermovir plus cyclosporine in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg once daily or if the original dose is 0.6 mg once daily, decrease to 0.3 mg once every other day; for treatment of gout flares, give 0.6 mg as a single dose, then 0.3 mg 1 hour later, and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed a 0.6 mg/day.
Conivaptan: (Moderate) A clinically relevant increase in the plasma concentration of conivaptan may occur during concurrent administration with letermovir. Concurrent use is contraindicated if the patient is also receiving cyclosporine because the magnitude of the interaction may be amplified. Conivaptan is a sensitive CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when letermovir is given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration of oral conivaptan with another strong CYP3A inhibitor increased conivaptan maximum concentration and exposure by 4- and 11-fold, respectively.
Conjugated Estrogens; Medroxyprogesterone: (Moderate) An increase in the plasma concentration of medroxyprogesterone may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Avoid coadministration of medroxyprogesterone in patient receiving both letermovir and cyclosporine as this may increase the risk for adverse reactions. Medroxyprogesterone is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Copanlisib: (Moderate) Administering letermovir with copanlisib may increase copanlisib concentration and risk for adverse events. Avoid coadministration in patients who are also receiving treatment with cyclosporine, because the magnitude of this interaction may be amplified. If concurrent use of copanlisib with both letermovir and cyclosporine cannot be avoided, reduce the copanlisib dose to 45 mg and monitor for toxicity. Copanlisib is predominately metabolized by CYP3A4. Letermovir a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of copanlisib by 53% with no effect on Cmax.
Crizotinib: (Moderate) Crizotinib may be used without a dose reduction in patients receiving letermovir without cyclosporine. Avoid concomitant use of crizotinib and letermovir when also used in combination with cyclosporine due to increased plasma concentrations of crizotinib, which may increase the incidence and severity of adverse reactions. If concomitant use is necessary for adults with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), reduce the dose of crizotinib to 250 mg PO once daily. If concomitant use is necessary for young adult or pediatric patients with anaplastic large cell lymphoma or pediatric patients with IMT, reduce the dose of crizotinib to 250 mg PO twice daily for BSA of 1.7 m2 or more; 200 mg PO twice daily for BSA of 1.17 to 1.69 m2; and 250 mg PO once daily for BSA of 0.81 to 1.16 m2; do not use this combination in patients with a BSA of 0.6 to 0.8 m2. Resume the original crizotinib dose after discontinuation of cyclosporine. Crizotinib is a CYP3A substrate. Letermovir is a moderate CYP3A4 inhibitor; however, the combined effect of letermovir and cyclosporine on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor. Coadministration with one strong CYP3A inhibitor increased the AUC of single-dose crizotinib by 216%. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC of crizotinib by 57% compared to crizotinib alone.
Cyclosporine: (Major) Decrease the dose of letermovir to 240 mg once daily if coadministered with cyclosporine. Frequently monitor cyclosporine whole blood concentrations during treatment and after discontinuation of letermovir and adjust the dose of cyclosporine accordingly. Coadministration result in increased exposure to both drugs. If cyclosporine is initiated after starting letermovir, decrease the next dose of letermovir to 240 mg once daily. If cyclosporine is discontinued after starting letermovir, increase the next dose of letermovir to 480 mg once daily. If cyclosporine dosing is interrupted due to high cyclosporine concentrations, no dose adjustment of letermovir is needed.
Dabrafenib: (Moderate) Administering letermovir with dabrafenib may increase dabrafenib concentration and risk for adverse events. Avoid coadministration in patients who are also receiving cyclosporine because the magnitude of this interaction may be increased. Closely monitor the patient for adverse reactions if coadministration of dabrafenib with both letermovir and cyclosporine cannot be avoided. Dabrafenib is primarily metabolized by CYP3A4 and CYP2C8. Letermovir is a moderate inhibitor of CYP3A4 and inhibits CYP2C8 in vitro. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent administration with a strong CYP3A4 inhibitor resulted in the exposure of dabrafenib, hydroxy-dabrafenib, and desmethyl-dabrafenib to be increased by 71%, 82%, and 68%, respectively. Administration with a strong CYP2C8 inhibitor increased dabrafenib exposure by 47%, but did not change the exposure of dabrafenib metabolites.
Daclatasvir: (Moderate) Administering daclatasvir concurrently with letermovir may result in elevated concentrations of both drugs; dosage adjustments are not required for either drug. However in patients who are also receiving cyclosporine, the dose of daclatasvir should be reduced to 30 mg once daily. Closely monitor for adverse events, including tachycardia, atrial fibrillation, headache, tiredness, and gastrointestinal events. Daclatasvir is an inhibitor of the organic anion-transporting polypeptides (OATP1B1/3), and is primarily metabolized by CYP3A4. Letermovir is an OATP1B1/3 substrate and a moderate CYP3A4 inhibitor. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Dapagliflozin; Saxagliptin: (Moderate) An increase in the plasma concentration of saxagliptin may occur if given with letermovir. Limit the saxagliptin dose to 2.5 mg once per day if the patient is also receiving cyclosporine because the magnitude of this interaction may be increased. Saxagliptin is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent administration with another strong CYP3A4 inhibitor increased the maximum plasma concentration and exposure of saxagliptin by 1.62- and 2.45-fold, respectively.
Dapsone: (Moderate) A clinically relevant increase in the plasma concentration of dapsone may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Dapsone is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Daridorexant: (Major) Limit the daridorexant dose to 25 mg if coadministered with letermovir. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and letermovir is a moderate CYP3A inhibitor. Concomitant use of another moderate CYP3A inhibitor increased daridorexant overall exposure 2.4-fold. Letermovir/cyclosporine combinations are strong 3A inhibitors and should not be used in combination with daridorexant.
Darifenacin: (Moderate) An increase in the plasma concentration of darifenacin is expected when given with letermovir. Do not exceed a maximum daily darifenacin dose of 7.5 mg in patients who are also receiving treatment with cyclosporine, because the magnitude of this interaction may be amplified. No dosing adjustments are required when darifenacin and letermovir are given together without cyclosporine. Darifenacin is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. The mean Cmax and AUC of darifenacin were increased by 128% and 95%, respectively, when in the presence of another moderate CYP3A4 inhibitor.
Darunavir: (Moderate) A clinically relevant increase in the plasma concentration of darunavir may occur if given with letermovir; monitor for darunavir-related adverse events. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Darunavir is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Darunavir; Cobicistat: (Moderate) A clinically relevant increase in the plasma concentration of darunavir may occur if given with letermovir; monitor for darunavir-related adverse events. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Darunavir is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. (Moderate) Administering cobicistat concurrently with letermovir may result in increased concentrations of both drugs. The impact on the concentration of cobicistat may be increased in patients who are receiving letermovir with cyclosporine. Closely monitor for adverse events, including tachycardia, atrial fibrillation, and gastrointestinal events. Cobicistat is an inhibitor of the organic anion-transporting polypeptides (OATP1B1/3), and a substrate of CYP3A4. Letermovir is an OATP1B1/3 substrate and a moderate CYP3A4 inhibitor. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) A clinically relevant increase in the plasma concentration of darunavir may occur if given with letermovir; monitor for darunavir-related adverse events. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Darunavir is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. (Moderate) Administering cobicistat concurrently with letermovir may result in increased concentrations of both drugs. The impact on the concentration of cobicistat may be increased in patients who are receiving letermovir with cyclosporine. Closely monitor for adverse events, including tachycardia, atrial fibrillation, and gastrointestinal events. Cobicistat is an inhibitor of the organic anion-transporting polypeptides (OATP1B1/3), and a substrate of CYP3A4. Letermovir is an OATP1B1/3 substrate and a moderate CYP3A4 inhibitor. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Dasatinib: (Moderate) Administering letermovir with dasatinib may increase dasatinib concentration and risk for adverse events. Avoid this combination in patients also receiving cyclosporine, because the magnitude of the interaction may be increased. If use of dasatinib with both letermovir and cyclosporine cannot be avoided, consider a dose decrease of dasatinib. If on 140 mg per day dasatinib, decrease to 40 mg per day. If on 100 mg per day or 70 mg per day of dasatinib, decrease to 20 mg per day. In patients on dasatinib doses of 60 mg or 40 mg daily, do not coadminister with both letermovir and cyclosporine. Dasatinib is a sensitive substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Deflazacort: (Major) Give 1/3 of the recommended dose of deflazacort when given with letermovir due to increased deflazacort exposure and risk for adverse events. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Deflazacort is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the mean geometric exposure of deflazacort by up to 3.4-fold.
Delavirdine: (Moderate) An increase in the plasma concentration of delavirdine may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Delavirdine is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Dexlansoprazole: (Moderate) Plasma concentrations of dexlansoprazole could be increased when administered concurrently with letermovir. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. If these drugs are given together, monitor for dexlansoprazole-related adverse events. Dexlansoprazole is a CYP3A4 substrate. Letermovir is a moderate inhibitor of CYP3A4. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Dextromethorphan; Quinidine: (Moderate) Closely monitor for quinidine-related adverse events including arrhythmias, if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. A clinically relevant increase in the plasma concentration of quinidine, a CYP3A4 substrate, may occur during concurrent administration with letermovir, a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Diazepam: (Moderate) Plasma concentrations of diazepam could be increased when administered concurrently with letermovir. The magnitude of this interaction may be elevated in patients who are also receiving cyclosporine. If these drugs are given together, closely monitor for reduced diazepam efficacy and diazepam-related adverse events. Diazepam is a substrate of CYP3A4. Letermovir is a moderate inhibitor of CYP3A4. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Dihydroergotamine: (Contraindicated) Concurrent administration of ergot alkaloids and letermovir is contraindicated due to the risk of ergotism. Taking these drugs together may result in increased concentrations of ergot alkaloids due to inhibition of CYP3A4 by letermovir.
Diltiazem: (Moderate) A clinically relevant increase in the plasma concentration of diltiazem may occur during concurrent administration with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. If these drugs are given together, closely monitor for diltiazem-related adverse events (e.g., bradycardia, hypotension, hepatotoxicity). Diltiazem is metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor.
Disopyramide: (Moderate) A clinically relevant increase in the plasma concentration of disopyramide may occur during concurrent administration with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. If these drugs are given together, closely monitor for disopyramide-related adverse events (e.g., QT prolongation). In vitro metabolic studies indicated that disopyramide is metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor.
Docetaxel: (Moderate) Administering letermovir with docetaxel may increase docetaxel concentration and risk for adverse events. Avoid coadministration if the patient is also receiving cyclosporine, because the magnitude of this interaction may be increased. Consider a 50% dose reduction of docetaxel if all 3 drugs must be administered concurrently. Docetaxel is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent administration with a strong CYP3A4 inhibitor increased docetaxel exposure by 2.2-fold and reduced drug clearance by 49%.
Dofetilide: (Moderate) A clinically relevant increase in the plasma concentration of dofetilide may occur if given with letermovir; monitor patient closely for dofetilide-related adverse events. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Dofetilide is metabolized to a small degree by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor.
Dolutegravir: (Moderate) A clinically relevant increase in the plasma concentration of dolutegravir may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Dolutegravir is partially metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor.
Dolutegravir; Lamivudine: (Moderate) A clinically relevant increase in the plasma concentration of dolutegravir may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Dolutegravir is partially metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor.
Dolutegravir; Rilpivirine: (Moderate) A clinically relevant increase in the plasma concentration of dolutegravir may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Dolutegravir is partially metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor. (Moderate) A clinically relevant increase in the plasma concentration of rilpivirine may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Rilpivirine is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Donepezil: (Moderate) A clinically relevant increase in the plasma concentration of donepezil may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Donepezil is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor. Concurrent administration with a strong CYP3A inhibitor increased the mean donepezil concentration by 36%. The clinical relevance of this increase in concentration is unknown.
Donepezil; Memantine: (Moderate) A clinically relevant increase in the plasma concentration of donepezil may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Donepezil is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor. Concurrent administration with a strong CYP3A inhibitor increased the mean donepezil concentration by 36%. The clinical relevance of this increase in concentration is unknown.
Doxorubicin Liposomal: (Major) Avoid use of letermovir with doxorubicin, as concurrent use may increase doxorubicin concentration and risk for adverse events. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Doxorubicin is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Doxorubicin: (Major) Avoid use of letermovir with doxorubicin, as concurrent use may increase doxorubicin concentration and risk for adverse events. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Doxorubicin is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Dronabinol: (Moderate) Plasma concentrations of dronabinol could be increased when administered concurrently with letermovir. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. If these drugs are given together, monitor for dronabinol-related adverse events. Dronabinol is a substrate of CYP3A4. Letermovir is a moderate inhibitor of CYP3A4. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Dronedarone: (Moderate) A clinically relevant increase in the plasma concentration of dronedarone is expected if given with letermovir. Coadministration is contraindicated in patients who are also receiving treatment with cyclosporine, because the magnitude of this interaction may be amplified.
Dutasteride: (Moderate) An increase in the plasma concentration of dutasteride may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Dutasteride is extensively metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor. The effects of strong CYP3A4 inhibitors on dutasteride have not been evaluated.
Dutasteride; Tamsulosin: (Moderate) An increase in the plasma concentration of dutasteride may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Dutasteride is extensively metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor. The effects of strong CYP3A4 inhibitors on dutasteride have not been evaluated. (Moderate) An increase in the plasma concentration of tamsulosin may occur when given with letermovir. Avoid this combination in patients who are also receiving treatment with cyclosporine because the magnitude of this interaction may be amplified. Tamsulosin is partially metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor. In a drug interaction study, concomitant use of tamsulosin with another strong CYP3A4 inhibitor resulted in increase in the maximum plasma concentration and exposure of tamsulosin by a factor of 2.2 and 2.8, respectively. The effects of concurrent use with moderate CYP3A4 inhibitors have not been evaluated.
Duvelisib: (Moderate) In patients receiving duvelisib and letermovir WITHOUT concomitant cyclosporine, monitor for an increase in duvelisib-related adverse reactions. In patients who are also receiving treatment with cyclosporine, reduce the dose of duvelisib to 15 mg PO twice daily because the magnitude of this interaction may be amplified. Duvelisib is a CYP3A4 substrate and letermovir is a moderate CYP3A4 inhibitor; however, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. The increase in exposure to duvelisib is estimated to be approximately 2-fold when used concomitantly with strong CYP3A inhibitors.
Efavirenz: (Major) Concurrent administration of letermovir and efavirenz is not recommended. Use of these drugs together may decrease letermovir plasma concentrations, resulting in a potential loss of letermovir efficacy. Also, a clinically relevant increase in the plasma concentration of efavirenz may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Efavirenz is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Concurrent administration of letermovir and efavirenz is not recommended. Use of these drugs together may decrease letermovir plasma concentrations, resulting in a potential loss of letermovir efficacy. Also, a clinically relevant increase in the plasma concentration of efavirenz may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Efavirenz is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Concurrent administration of letermovir and efavirenz is not recommended. Use of these drugs together may decrease letermovir plasma concentrations, resulting in a potential loss of letermovir efficacy. Also, a clinically relevant increase in the plasma concentration of efavirenz may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Efavirenz is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor.
Elacestrant: (Major) Avoid concomitant use of elacestrant and letermovir due to the risk of increased elacestrant exposure which may increase the risk for adverse effects. Elacestrant is a CYP3A substrate and letermovir is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased elacestrant overall exposure by 2.3-fold. Elacestrant overall exposure may be further increased if letermovir is used in combination with cyclosporine as the combination of letermovir plus cyclosporine acts as a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased elacestrant overall exposure by 5.3-fold.
Elagolix: (Contraindicated) Concomitant use of elagolix and strong organic anion transporting polypeptide (OATP) 1B1 inhibitors such as letermovir is contraindicated. Use of elagolix with drugs that inhibit OATP1B1 may increase elagolix plasma concentrations. Elagolix is a substrate of CYP3A, P-gp, and OATP1B1. Letermovir inhibits OATP1B1 and is expected to increase concentrations of drugs that are substrates for OATP1B1. Another OATP1B1 potent inhibitor increased elagolix AUC in the range of 2- to 5.58-fold. Increased elagolix concentrations increase the risk for dose-related side effects, including loss of bone mineral density.
Elagolix; Estradiol; Norethindrone acetate: (Contraindicated) Concomitant use of elagolix and strong organic anion transporting polypeptide (OATP) 1B1 inhibitors such as letermovir is contraindicated. Use of elagolix with drugs that inhibit OATP1B1 may increase elagolix plasma concentrations. Elagolix is a substrate of CYP3A, P-gp, and OATP1B1. Letermovir inhibits OATP1B1 and is expected to increase concentrations of drugs that are substrates for OATP1B1. Another OATP1B1 potent inhibitor increased elagolix AUC in the range of 2- to 5.58-fold. Increased elagolix concentrations increase the risk for dose-related side effects, including loss of bone mineral density.
Elbasvir; Grazoprevir: (Moderate) An increase in the plasma concentration of elbasvir may occur during concurrent administration with letermovir; closely monitor for elbasvir-related adverse events, such as liver toxicity. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Elbasvir is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor. (Moderate) An increase in the plasma concentration of grazoprevir may occur during concurrent administration with letermovir; closely monitor for grazoprevir-related adverse events, such as liver toxicity. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Grazoprevir is a substrate of CYP3A4and the organic anion-transporting polypeptides (OATP1B1/3). Both letermovir and cyclosporine are CYP3A4 inhibitors and inhibitors of OATP1B1; letermovir is also an OATP1B3 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Eletriptan: (Moderate) Eletriptan and letermovir may be administered concurrently with caution; however, if the patient is also receiving cyclosporine, eletriptan is contraindicated for use within 72 hours of receiving letermovir and cyclosporine because the magnitude of this interaction may be increased. Eletriptan is a sensitive substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent use with a strong CYP3A4 inhibitor increased the maximum plasma concentration (Cmax) and exposure (AUC) of eletriptan by 3- and 6-fold, respectively. When eletriptan was given with a moderate CYP3A4 inhibitor, the Cmax and AUC of eletriptan increased by 2- and 4-fold, respectively.
Elexacaftor; tezacaftor; ivacaftor: (Major) Adjust the tezacaftor; ivacaftor dosing schedule when coadministered with letermovir; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet every other day in the morning and 1 ivacaftor tablet every other day in the morning on alternate days (i.e., tezacaftor/ivacaftor tablet on Day 1 and ivacaftor tablet on Day 2). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); letermovir is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor increased ivacaftor exposure 3-fold. Simulation suggests a moderate inhibitor may increase tezacaftor exposure 2-fold. (Major) If letermovir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. In patients also receiving cyclosporine, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly, because the magnitude of the interaction may be increased. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate. Letermovir is a moderate CYP3A inhibitor; however, when given with cyclosporine, the combined effect on CYP3A substrates may be similar to a strong CYP3A inhibitor. Coadministration with other moderate and strong CYP3A inhibitors increased ivacaftor exposure by 3- and 8.5-fold, respectively. (Moderate) Monitor for an increase in letermovir-related adverse reactions if coadministration with elexacaftor is necessary. Concomitant use may increase letermovir exposure. Letermovir is a substrate of OATP1B1/3; elexacaftor is an OATP1B1/3 inhibitor.
Eliglustat: (Major) In intermediate or poor CYP2D6 metabolizers (IMs or PMs), coadministration of letermovir and eliglustat is not recommended; this combination is contraindicated in this population if the patient is also receiving cyclosporine. In extensive CYP2D6 metabolizers (EMs), coadministration of letermovir and eliglustat requires dosage reduction of eliglustat to 84 mg PO once daily. The coadministration of eliglustat with both letermovir and a moderate or strong CYP2D6 inhibitor is contraindicated in all patients. Letermovir is a moderate CYP3A inhibitor; eliglustat is a CYP3A and CYP2D6 substrate. Coadministration of eliglustat with CYP3A inhibitors may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias); this risk is the highest in CYP2D6 IMs and PMs because a larger portion of the eliglustat dose is metabolized via CYP3A. The magnitude of this interaction may be further amplified in patients receiving concurrent treatment with cyclosporine, as the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Eltrombopag: (Moderate) Closely monitor for letermovir-related adverse events (i.e., tachycardia, atrial fibrillation, and gastrointestinal events) if administered with eltrombopag, as use of these drugs together may result in elevated letermovir plasma concentration. Letermovir is a substrate of the organic anion-transporting polypeptide (OATP1B1); eltrombopag is an inhibitor of OATP1B1.
Eluxadoline: (Moderate) Concurrent administration of eluxadoline and letermovir may increase the plasma concentration of both drugs. In patients receiving both letermovir and cyclosporine, administer eluxadoline at a dose of 75 mg twice daily, because cyclosporine increases the inhibitory potential of letermovir. If these drugs are given together, closely monitor for adverse events including impaired mental or physical abilities, tachycardia, atrial fibrillation, and gastrointestinal events. Both eluxadoline and letermovir are substrates and inhibitors of the organic anion-transporting polypeptide (OATP1B1).
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Administering cobicistat concurrently with letermovir may result in increased concentrations of both drugs. The impact on the concentration of cobicistat may be increased in patients who are receiving letermovir with cyclosporine. Closely monitor for adverse events, including tachycardia, atrial fibrillation, and gastrointestinal events. Cobicistat is an inhibitor of the organic anion-transporting polypeptides (OATP1B1/3), and a substrate of CYP3A4. Letermovir is an OATP1B1/3 substrate and a moderate CYP3A4 inhibitor. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Administering cobicistat concurrently with letermovir may result in increased concentrations of both drugs. The impact on the concentration of cobicistat may be increased in patients who are receiving letermovir with cyclosporine. Closely monitor for adverse events, including tachycardia, atrial fibrillation, and gastrointestinal events. Cobicistat is an inhibitor of the organic anion-transporting polypeptides (OATP1B1/3), and a substrate of CYP3A4. Letermovir is an OATP1B1/3 substrate and a moderate CYP3A4 inhibitor. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) A clinically relevant increase in the plasma concentration of rilpivirine may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Rilpivirine is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) A clinically relevant increase in the plasma concentration of rilpivirine may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Rilpivirine is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Enasidenib: (Moderate) Monitor for an increase in letermovir-related adverse reactions if coadministration with enasidenib is necessary. Concomitant use may increase letermovir exposure. Letermovir is a substrate of OATP1B1/3; enasidenib is an OATP1B1/3 inhibitor.
Encorafenib: (Major) Avoid coadministration of encorafenib and letermovir due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of letermovir. If letermovir is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of letermovir. Because concomitant use may also increase letermovir exposure, monitor for an increase in letermovir-related adverse reactions if coadministration with encorafenib is necessary. Encorafenib is a CYP3A4 substrate and an OATP1B1/3 inhibitor; letermovir is a moderate CYP3A4 inhibitor and a substrate of OATP1B1/3. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
Entrectinib: (Major) Avoid coadministration of entrectinib with letermovir due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 200 mg PO once daily. If letermovir is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of letermovir. Entrectinib is a CYP3A4 substrate; letermovir is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor is predicted to increase the AUC of entrectinib by 3-fold.
Eplerenone: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with a CYP3A4 inhibitor in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving a concurrent CYP3A4 inhibitor, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. In addition, measure serum creatinine and serum potassium within 3 to 7 days of initiating a CYP3A4 inhibitor and periodically thereafter. Eplerenone is a CYP3A4 substrate. Coadministration is contraindicated in patients also receiving cyclosporine, because the magnitude of the interaction may be amplified. Eplerenone is predominately metabolized by CYP3A. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor. Concurrent administration with a strong CYP3A inhibitor increased the maximum plasma concentration (Cmax) and exposure (AUC) of eplerenone by 1.7- and 5.4-fold, respectively. When given with a moderate CYP3A inhibitor, the Cmax and AUC of eplerenone increased by 40% to 60% and 100% to 190%, respectively.
Ergoloid Mesylates: (Contraindicated) Concurrent administration of ergot alkaloids and letermovir is contraindicated due to the risk of ergotism. Taking these drugs together may result in increased concentrations of ergot alkaloids due to inhibition of CYP3A4 by letermovir.
Ergot alkaloids: (Contraindicated) Concurrent administration of ergot alkaloids and letermovir is contraindicated due to the risk of ergotism. Taking these drugs together may result in increased concentrations of ergot alkaloids due to inhibition of CYP3A4 by letermovir.
Ergotamine: (Contraindicated) Concurrent administration of ergot alkaloids and letermovir is contraindicated due to the risk of ergotism. Taking these drugs together may result in increased concentrations of ergot alkaloids due to inhibition of CYP3A4 by letermovir.
Ergotamine; Caffeine: (Contraindicated) Concurrent administration of ergot alkaloids and letermovir is contraindicated due to the risk of ergotism. Taking these drugs together may result in increased concentrations of ergot alkaloids due to inhibition of CYP3A4 by letermovir.
Erlotinib: (Moderate) An increase in the plasma concentration of erlotinib may occur if given with letermovir. Avoid coadministration in patients also receiving cyclosporine, because the magnitude of the interaction may be amplified. If erlotinib must be coadministered with both letermovir and cyclosporine and the patient experiences a severe reaction, reduce the erlotinib dose by 50 mg decrements. Erlotinib is predominately metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor. Concurrent administration with a strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
Erythromycin: (Moderate) Caution is warranted with the concurrent administration of erythromycin and letermovir, as this may result in increased concentrations of letermovir. Closely monitor for adverse events, including gastrointestinal events. Erythromycin is an inhibitor of the organic anion-transporting polypeptides (OATP1B1/3). Letermovir is an OATP1B1/3 substrate.
Estazolam: (Moderate) An increase in the plasma concentration of estazolam may occur during concurrent administration with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Closely monitor for estazolam-related adverse events, and reduce the estazolam dose if needed. Estazolam is metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor.
Eszopiclone: (Moderate) Administering letermovir with eszopiclone may increase eszopiclone concentration and risk for adverse events. In patients also receiving cyclosporine, the total dose of eszopiclone should not exceed 2 mg, because the magnitude of the interaction may be increased. Eszopiclone is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent administration with a strong CYP3A4 inhibitor increased eszopiclone exposure, maximum plasma concentration, and half-life by 2.2-, 1.4-, and 1.3-fold, respectively.
Ethosuximide: (Moderate) A clinically relevant increase in the plasma concentration of ethosuximide may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Ethosuximide is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor.
Etravirine: (Major) Concurrent administration of letermovir and etravirine is not recommended. Use of these drugs together may decrease letermovir plasma concentrations, resulting in a potential loss of letermovir efficacy. Letermovir is a substrate of UDP-glucuronosyltransferase 1A1/3 (UGT1A1/3). Etravirine induces UGT1A1. Also, plasma concentrations of etravirine could be altered (increased or decreased) when administered concurrently with letermovir. Etravirine is a substrate of the enzymes CYP3A4, CYP2C9, and CYP2C19. Letermovir is an inducer of CYP2C9 and CYP2C19, and a moderate inhibitor of CYP3A4. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with letermovir is necessary. The dose of everolimus may need to be reduced. In patients also receiving cyclosporine, avoid coadministration of everolimus with letermovir. If concomitant use of both letermovir and cyclosporine is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Letermovir is a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration with moderate CYP3A4/P-gp inhibitors increased the AUC of everolimus by 3.5 to 4.4-fold. Coadministration with a strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
Ezetimibe; Simvastatin: (Major) Use of simvastatin with letermovir is not recommended due to increased simvastatin exposure. Concurrent use is contraindicated if the patient is also receiving cyclosporine. Administering letermovir with simvastatin significantly increases simvastatin concentration and risk for myopathy or rhabdomyolysis. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Simvastatin is a sensitive substrate of CYP3A4 and the organic anion-transporting polypeptide (OATP1B1). Both letermovir and cyclosporine are moderate CYP3A4 inhibitors and inhibitors of OATP1B1.
Felodipine: (Moderate) Monitor patients for exaggerated felodipine effects (i.e., lower blood pressure and increased heart rate) if coadministered with felodipine. Caution and a conservative approach are recommended in patients who are also receiving treatment with cyclosporine, because the magnitude of this interaction may be amplified. Felodipine is a sensitive CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor. Concurrent administration with a strong CYP3A4 inhibitor increased the exposure (AUC) and maximum plasma concentration (Cmax) of felodipine by 8- and 6-fold, respectively. When given with a moderate CYP3A4 inhibitor, the AUC and Cmax of felodipine increased by 2.5-fold.
Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of letermovir is necessary; the magnitude of this interaction may be amplified if the patient is also receiving cyclosporine. If letermovir is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like letermovir can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If letermovir is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Finasteride; Tadalafil: (Moderate) An increase in the plasma concentration of tadalafil may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Avoid coadministration of tadalafil for pulmonary hypertension if the patient is receiving letermovir and cyclosporine. When used for erectile dysfunction in patients receiving letermovir with cyclosporine, the as needed (PRN) dose of tadalafil should not exceed 10 mg once every 72 hours and the daily dose should not exceed 2.5 mg. Tadalafil is predominately metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect CYP3A4 substrates is similar to a strong CYP3A4 inhibitor. In a drug interaction study, the exposure and maximum plasma concentration of tadalafil increased by up to 312% and 22%, respectively, when administered with another potent CYP3A4 inhibitor. Studies with moderate CYP3A4 inhibitors have not been conducted.
Finerenone: (Moderate) Monitor serum potassium during initiation or dose adjustment of either finerenone or letermovir; a finerenone dosage reduction may be necessary. This combi nation is contraindicated if the patient is also receiving cyclosporine because the magnitude of the interaction may be amplified. Concomitant use may increase finerenone exposure and the risk of hyperkalemia. Finerenone is a CYP3A substrate. Letermovir is a moderate CYP3A inhibitor; however, when given with cyclosporine, the combined effect on CYP3A substrates is similar to a strong CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased overall exposure to finerenone by 248%; a strong CYP3A inhibitor increased overall exposure to finerenone by more than 400%.
Flibanserin: (Contraindicated) Concurrent use of letermovir and flibanserin is contraindicated. Coadministration may increase flibanserin concentration and risk for adverse events including hypotension and syncope. If initiating flibanserin following use of letermovir, start flibanserin at least 2 weeks after the last dose of letermovir. If initiating letermovir following flibanserin use, start letermovir at least 2 days after the last dose of flibanserin. Flibanserin is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor.
Flurazepam: (Moderate) A clinically relevant increase in the plasma concentration of flurazepam may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Flurazepam is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor.
Fluticasone: (Moderate) A clinically relevant increase in the plasma concentration of fluticasone may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Concurrent use of all 3 drugs together is not recommended because increased systemic corticosteroid adverse events may develop. Fluticasone is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor. In a drug interaction study, use of fluticasone with another strong CYP3A4 inhibitor resulted in a 1.9-fold increase in plasma fluticasone exposure and a 45% decrease in plasma cortisol exposure, but had no effect on urinary excretion of cortisol.
Fluticasone; Salmeterol: (Moderate) A clinically relevant increase in the plasma concentration of fluticasone may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Concurrent use of all 3 drugs together is not recommended because increased systemic corticosteroid adverse events may develop. Fluticasone is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor. In a drug interaction study, use of fluticasone with another strong CYP3A4 inhibitor resulted in a 1.9-fold increase in plasma fluticasone exposure and a 45% decrease in plasma cortisol exposure, but had no effect on urinary excretion of cortisol.
Fluticasone; Umeclidinium; Vilanterol: (Moderate) A clinically relevant increase in the plasma concentration of fluticasone may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Concurrent use of all 3 drugs together is not recommended because increased systemic corticosteroid adverse events may develop. Fluticasone is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor. In a drug interaction study, use of fluticasone with another strong CYP3A4 inhibitor resulted in a 1.9-fold increase in plasma fluticasone exposure and a 45% decrease in plasma cortisol exposure, but had no effect on urinary excretion of cortisol. (Moderate) An increase in the plasma concentration of vilanterol may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Monitor patients receiving vilanterol with both letermovir and cyclosporine for cardiovascular adverse effects (i.e., increased pulse, increased blood pressure, fast or irregular heartbeat). Vilanterol is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Fluticasone; Vilanterol: (Moderate) A clinically relevant increase in the plasma concentration of fluticasone may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Concurrent use of all 3 drugs together is not recommended because increased systemic corticosteroid adverse events may develop. Fluticasone is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor. In a drug interaction study, use of fluticasone with another strong CYP3A4 inhibitor resulted in a 1.9-fold increase in plasma fluticasone exposure and a 45% decrease in plasma cortisol exposure, but had no effect on urinary excretion of cortisol. (Moderate) An increase in the plasma concentration of vilanterol may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Monitor patients receiving vilanterol with both letermovir and cyclosporine for cardiovascular adverse effects (i.e., increased pulse, increased blood pressure, fast or irregular heartbeat). Vilanterol is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Fluvastatin: (Moderate) Closely monitor for fluvastatin-related adverse events (myopathy, rhabdomyolysis) and consider a fluvastatin dose reduction if administered with letermovir. Do not exceed a fluvastatin dose of 20 mg daily if the patient is also receiving cyclosporine. The magnitude of this interaction may be increased if letermovir is given with cyclosporine. Concurrent administration of letermovir, an organic anion-transporting polypeptide (OATP1B1) inhibitor, with fluvastatin, an OATP1B1 substrate, may result in a clinically relevant increase in fluvastatin plasma concentration.
Fosamprenavir: (Moderate) Monitor for increased fosamprenavir toxicity if coadministered with letermovir. Concurrent use may increase the plasma concentrations of fosamprenavir. Fosamprenavir is a CYP3A substrate and letermovir is a moderate CYP3A inhibitor. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine.
Fosphenytoin: (Major) Concurrent administration of letermovir and fosphenytoin is not recommended. Use of these drugs together may decrease letermovir plasma concentrations, resulting in a potential loss of letermovir efficacy. Letermovir is a substrate of UDP-glucuronosyltransferase 1A1/3 (UGT1A1/3) and P-glycoprotein (P-gp). Fosphenytoin is an inducer of UGT and P-gp. Also, clinically relevant decrease in the plasma concentration of fosphenytoin, a CYP2C9 and CYP2C19 substrate, may occur during concurrent administration with letermovir, an inducer of CYP2C9 and CYP2C19. If these drugs are used together, frequently monitor phenytoin plasma concentrations.
Fostemsavir: (Moderate) Closely monitor for letermovir-related adverse events (i.e., tachycardia, atrial fibrillation, and gastrointestinal events) if administered with fostemsavir, as use of these drugs together may result in increased letermovir plasma concentrations. Letermovir is a substrate of OATP1B1/3 and fostemsavir is an inhibitor of OATP1B1/3.
Gefitinib: (Moderate) A clinically relevant increase in the plasma concentration of gefitinib may occur if given with letermovir. Closely monitor for gefitinib-related adverse reactions in patients who are also receiving treatment with cyclosporine, because the magnitude of this interaction may be amplified. Gefitinib is predominately metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor. Concurrent administration with a strong CYP3A4 inhibitor increased mean exposure of gefitinib by 80%.
Gemfibrozil: (Moderate) Closely monitor for letermovir-related adverse events (i.e., tachycardia, atrial fibrillation, and gastrointestinal events) if administered with gemfibrozil, as use of these drugs together may result in increased letermovir plasma concentration. Letermovir is a substrate of the organic anion-transporting polypeptide (OATP1B1); gemfibrozil is an inhibitor of OATP1B1.
Gilteritinib: (Moderate) Consider an alternative to letermovir in patients also receiving cyclosporine during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration of all 3 drugs is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; letermovir is a moderate CYP3A4 inhibitor; however, when administered with cyclosporine the effect may be similar to a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
Glasdegib: (Moderate) Concurrent use of letermovir with glasdegib may increase glasdegib exposure resulting in treatment-related adverse events including QT prolongation. Consider an alternative to letermovir if administered with cyclosporine during treatment with glasdegib. If coadministration of glasdegib with both letermovir and cyclosporine cannot be avoided, monitor for increased adverse events; more frequent ECG monitoring is recommended. Glasdegib is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when administered with cyclosporine is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
Glecaprevir; Pibrentasvir: (Moderate) Administering glecaprevir concurrently with letermovir may result in elevated concentrations of both drugs. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Closely monitor for adverse events, including tachycardia, atrial fibrillation, hepatotoxicity, and gastrointestinal events. Glecaprevir and letermovir are substrates and inhibitors of the organic anion-transporting polypeptides (OATP1B1/3). Glecaprevir is also a substrate of CYP3A4, while letermovir is a moderate CYP3A4 inhibitor. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In addition, cyclosporine is an OATP1B1 inhibitor, which could further amplify this interaction. (Moderate) Closely monitor for letermovir-related adverse events (i.e., tachycardia, atrial fibrillation, and gastrointestinal events) if administered with pibrentasvir, as use of these drugs together may result in elevated letermovir plasma concentration. Letermovir is a substrate of the organic anion-transporting polypeptides (OATP1B1/3); pibrentasvir is an inhibitor of OATP1B1/3.
Glyburide: (Moderate) Frequently monitor glucose concentrations when glyburide is given with letermovir. The magnitude of this interaction may be increased if letermovir is given with cyclosporine. Concurrent administration of letermovir, an organic anion-transporting polypeptide (OATP1B1/3) inhibitor, with glyburide, an OATP1B1/3 substrate, may result in a clinically relevant increase in glyburide plasma concentration.
Glyburide; Metformin: (Moderate) Frequently monitor glucose concentrations when glyburide is given with letermovir. The magnitude of this interaction may be increased if letermovir is given with cyclosporine. Concurrent administration of letermovir, an organic anion-transporting polypeptide (OATP1B1/3) inhibitor, with glyburide, an OATP1B1/3 substrate, may result in a clinically relevant increase in glyburide plasma concentration.
Granisetron: (Moderate) A clinically relevant increase in the plasma concentration of granisetron may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Granisetron is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor.
Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of letermovir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like letermovir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If letermovir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Guanfacine: (Major) FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. Upon letermovir discontinuation, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Haloperidol: (Moderate) A clinically relevant increase in the plasma concentration of haloperidol may occur if given with letermovir. Haloperidol dose reductions may be needed in patients also receiving cyclosporine, because the magnitude of the interaction may be increased. Haloperidol is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor. In a drug interaction study, administration with another strong CYP3A4 inhibitor resulted in QT prolongation.
Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of letermovir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like letermovir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If letermovir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of letermovir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like letermovir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If letermovir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of letermovir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like letermovir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If letermovir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of letermovir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like letermovir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If letermovir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Ibrutinib: (Major) If ibrutinib is coadministered with letermovir, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if letermovir is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Avoid coadministration in patients also receiving cyclosporine, because the magnitude of the interaction may be increased. Ibrutinib is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold. A strong CYP3A4 inhibitor increased the Cmax and AUC of ibrutinib by 29- and 24-fold, respectively.
Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of letermovir is necessary. If letermovir is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a CYP3A4 inhibitor like letermovir can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If letermovir is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Idelalisib: (Moderate) An increase in the plasma concentration of idelalisib may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. If idelalisib is coadministered with both letermovir and cyclosporine, monitor for adverse reactions and modify idelalisib dose as needed. Idelalisib is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent use with a strong CYP3A inhibitor increased exposure of idelalisib by 1.8-fold.
Ifosfamide: (Moderate) Closely monitor for reduced ifosfamide efficacy if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Metabolism of ifosfamide, a CYP3A4 substrate, to its active alkylating metabolite may be decreased during concurrent administration with letermovir, a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Iloperidone: (Moderate) A clinically relevant increase in the plasma concentration of iloperidone may occur if given with letermovir. Reduce the iloperidone dose by one-half in patients also receiving cyclosporine, because the magnitude of the interaction may be increased. When treatment with letermovir and/or cyclosporine is withdrawn from combination therapy, iloperidone dose should be increased to where it was previously. Iloperidone is partially metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent administration with strong CYP3A4 inhibitors increased exposure (AUC) of iloperidone and its metabolites P88 and P95 by 57%, 55%, and 35%, respectively. Administration of iloperidone with weak or moderate CYP3A4 inhibitors has not been evaluated.
Imatinib: (Moderate) Plasma concentrations of imatinib could be significantly elevated when administered concurrently with letermovir. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. If these drugs are given together, closely monitor for imatinib-related adverse events. Imatinib is primarily metabolized by CYP3A4. Letermovir is a moderate inhibitor of CYP3A4; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In a drug interaction study, concurrent administration with another strong CYP3A4 inhibitor significantly increased the mean Cmax and AUC of imatinib by 26% and 40%, respectively.
Indinavir: (Moderate) Concurrent use of indinavir and letermovir may result in elevated indinavir plasma concentrations. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Indinavir is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Infigratinib: (Major) Avoid concomitant use of infigratinib and letermovir. Coadministration may increase infigratinib exposure, increasing the risk of adverse effects. Infigratinib is a CYP3A4 substrate and letermovir is a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor; coadministration with another strong CYP3A4 inhibitor increased the AUC of infigratinib by 622%.
Irinotecan Liposomal: (Moderate) An increase in the plasma concentration of irinotecan or its active metabolite, SN-38, may occur if given with letermovir. Do not administer this combination unless there are no alternative treatment options if the patient is also receiving treatment with cyclosporine, because the magnitude of this interaction may be amplified. If possible, discontinue letermovir, cyclosporine, or both drugs at least 1 week prior to starting irinotecan. Irinotecan is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Irinotecan: (Moderate) An increase in the plasma concentration of irinotecan or its active metabolite, SN-38, may occur if given with letermovir. Do not administer this combination unless there are no alternative treatment options if the patient is also receiving treatment with cyclosporine, because the magnitude of this interaction may be amplified. If possible, discontinue letermovir, cyclosporine, or both drugs at least 1 week prior to starting irinotecan. Irinotecan is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Isavuconazonium: (Moderate) Concurrent use of isavuconazonium and letermovir may result in elevated isavuconazonium plasma concentrations. Coadministration is contraindicated in patients also receiving cyclosporine, because the magnitude of this interaction may be amplified. Isavuconazonium is a sensitive CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent administration with a strong CYP3A4 inhibitor increased exposure of isavuconazole by more than 5-fold.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Concurrent administration of letermovir and rifampin is not recommended. Use of these drugs together may decrease letermovir plasma concentrations, resulting in a potential loss of letermovir efficacy. Letermovir is a substrate of UDP-glucuronosyltransferase 1A1/3 (UGT1A1/3) and P-glycoprotein (P-gp). Rifampin induces UGT and P-gp.
Isoniazid, INH; Rifampin: (Major) Concurrent administration of letermovir and rifampin is not recommended. Use of these drugs together may decrease letermovir plasma concentrations, resulting in a potential loss of letermovir efficacy. Letermovir is a substrate of UDP-glucuronosyltransferase 1A1/3 (UGT1A1/3) and P-glycoprotein (P-gp). Rifampin induces UGT and P-gp.
Isradipine: (Moderate) A clinically relevant increase in the plasma concentration of isradipine may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Isradipine is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Ivabradine: (Major) Avoid concurrent use of ivabradine and letermovir as increased concentrations of ivabradine are possible, which may result in bradycardia exacerbation and conduction disturbances. Concurrent use is contraindicated if the patient is also receiving cyclosporine because the magnitude of the interaction may be amplified. Ivabradine is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor increased ivabradine exposure by 7.7-fold, while concomitant use of moderate CYP3A4 inhibitors increased exposure of ivabradine by 2-fold to 3-fold.
Ivacaftor: (Major) If letermovir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. In patients also receiving cyclosporine, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly, because the magnitude of the interaction may be increased. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate. Letermovir is a moderate CYP3A inhibitor; however, when given with cyclosporine, the combined effect on CYP3A substrates may be similar to a strong CYP3A inhibitor. Coadministration with other moderate and strong CYP3A inhibitors increased ivacaftor exposure by 3- and 8.5-fold, respectively.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with letermovir due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. In patients receiving the combination of letermovir and cyclosporine who require ivosidenib therapy, reduce the dose of ivosidenib to 250 mg PO once daily. If letermovir or cyclosporine is discontinued, wait at least 5 half-lives of letermovir or cyclosporine before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate and letermovir is a moderate CYP3A4 inhibitor; however, when letermovir is combined with cyclosporine the effect may be similar to a strong CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling, with no change in Cmax. Multiple doses of the moderate CYP3A4 inhibitor are predicted to increase the ivosidenib steady-state AUC to 152% of control and AUC to 190% of control. Coadministration with a strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax.
Ixabepilone: (Moderate) Monitor for ixabepilone toxicity and reduce the ixabepilone dose as needed if concurrent use of letermovir WITHOUT concomitant cyclosporine is necessary. Avoid concurrent use of ixabepilone and letermovir WITH concomitant cyclosporine; if unavoidable, reduce the dose of ixabepilone to 20 mg/m2. Concomitant use may increase ixabepilone exposure and the risk of adverse reactions. Ixabepilone is a CYP3A substrate and letermovir is a moderate CYP3A inhibitor; however, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Ketoconazole: (Moderate) A clinically relevant increase in the plasma concentration of ketoconazole may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, monitor closely for increased or prolonged pharmacologic effects of ketoconazole; the ketoconazole dose should be decreased as deemed necessary. When appropriate, ketoconazole plasma concentrations should be measured. Ketoconazole is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor; therefore, the magnitude of the interaction may be amplified.
Lacosamide: (Moderate) The plasma concentration of lacosamide may be increased during concurrent use with letermovir. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. If lacosamide is administered to a patient with hepatic impairment receiving both letermovir and cyclosporine, a lacosamide dose reduction may be needed. Lacosamide is a CYP3A4 substrate. Letermovir is a moderate inhibitor of CYP3A4. However, when given with cyclosporine, the combined effect of letermovir and cyclosporine on a CYP3A4 substrate is similar to a strong CYP3A4 inhibitor.
Lansoprazole: (Moderate) Plasma concentrations of lansoprazole could be increased when administered concurrently with letermovir. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. If these drugs are given together, monitor for lansoprazole-related adverse events. Lansoprazole is a CYP3A4 substrate. Letermovir is a moderate inhibitor of CYP3A4. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Lansoprazole; Amoxicillin; Clarithromycin: (Moderate) Administering clarithromycin concurrently with letermovir may result in elevated concentrations of both drugs. The impact on the serum concentration of clarithromycin may be increased in patients receiving letermovir with cyclosporine. Closely monitor for adverse events including tachycardia, atrial fibrillation, gastrointestinal events, dizziness, or confusion. Clarithromycin is an inhibitor of the organic anion-transporting polypeptides (OATP1B1/3), and a substrate of CYP3A4. Letermovir is an OATP1B1/3 substrate and a moderate CYP3A4 inhibitor. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In a drug interaction study, concurrent use with another CYP3A inhibitor increased clarithromycin exposure (AUC) by 94%, and decreased AUC of 14-OH clarithromycin by 70%. (Moderate) Plasma concentrations of lansoprazole could be increased when administered concurrently with letermovir. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. If these drugs are given together, monitor for lansoprazole-related adverse events. Lansoprazole is a CYP3A4 substrate. Letermovir is a moderate inhibitor of CYP3A4. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Larotrectinib: (Moderate) Monitor for an increase in larotrectinib-related adverse reactions if concomitant use with letermovir is necessary. Avoid concomitant use in patients who are also receiving treatment with cyclosporine, because the magnitude of this interaction may be amplified. If concomitant use of combination letermovir plus cyclosporine is necessary, reduce the dose of larotrectinib by 50%. After combination letermovir plus cyclosporine has been discontinued for 3 to 5 elimination half-lives, resume the larotrectinib dose taken prior to initiating letermovir plus cyclosporine. Concomitant use may increase larotrectinib exposure. Larotrectinib is a CYP3A substrate. Letermovir is a moderate CYP3A inhibitor; however, when given with cyclosporine, the combined effect on CYP3A substrates may be similar to a strong CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase larotrectinib exposure by 2.7-fold. Coadministration with a strong CYP3A inhibitor increased larotrectinib exposure by 4.3-fold.
Lefamulin: (Moderate) Monitor for lefamulin-related adverse effects if oral lefamulin is administered with letermovir as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Avoid coadministration in patients also receiving cyclosporine. Lefamulin is a CYP3A4 substrate; letermovir is a moderate CYP3A4 inhibitor. If the regimen also contains cyclosporine, the inhibitory effect is expected to be similar to a strong CYP3A4 inhibitor.
Lemborexant: (Major) Avoid coadministration of lemborexant and letermovir as concurrent use is expected to significantly increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; letermovir is a moderate CYP3A4 inhibitor. Coadministration of lemborexant with another moderate CYP3A4 inhibitor increased the lemborexant AUC by up to 4.5-fold.
Leniolisib: (Major) Avoid concomitant use of leniolisib and combination letermovir plus cyclosporine due to the risk for increased leniolisib exposure which may increase the risk for adverse effects. Additionally, concomitant use may increase letermovir concentrations. Leniolisib is a CYP3A substrate and OATP1B1/3 inhibitor; combination letermovir plus cyclosporine is a strong CYP3A inhibitor and letermovir is a substrate of OATP1B1/3. Concomitant use with another strong CYP3A inhibitor increased leniolisib overall exposure by 2-fold.
Levamlodipine: (Moderate) Amlodipine dose reductions may be required during concurrent administration with letermovir; monitor for symptoms of hypotension and edema to determine the need for dose adjustment. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Administering these drugs together may increase amlodipine concentration and risk for adverse events. Amlodipine is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent administration with a moderate CYP3A inhibitor increased amlodipine exposure by 60%; however, another moderate inhibitor did not significantly change amlodipine exposure. Strong CYP3A4 inhibitors may increase amlodipine exposure to a greater extent.
Levoketoconazole: (Moderate) A clinically relevant increase in the plasma concentration of ketoconazole may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, monitor closely for increased or prolonged pharmacologic effects of ketoconazole; the ketoconazole dose should be decreased as deemed necessary. When appropriate, ketoconazole plasma concentrations should be measured. Ketoconazole is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor; therefore, the magnitude of the interaction may be amplified.
Levomilnacipran: (Moderate) Administering letermovir with levomilnacipran may increase levomilnacipran concentration and risk for adverse events. Do not exceed a levomilnacipran adult dose of 80 mg per day in patients also receiving cyclosporine because the magnitude of this interaction may be increased. Levomilnacipran is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Lidocaine: (Moderate) An increase in the plasma concentration of lidocaine may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Lidocaine is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Lidocaine; Epinephrine: (Moderate) An increase in the plasma concentration of lidocaine may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Lidocaine is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Lidocaine; Prilocaine: (Moderate) An increase in the plasma concentration of lidocaine may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Lidocaine is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Lomitapide: (Contraindicated) Concurrent use of lomitapide and letermovir is contraindicated due to the potential for increased lomitapide exposure and adverse events. If treatment with letermovir is unavoidable, lomitapide should be stopped during letermovir treatment. Coadministration may increase lomitapide concentration and risk for adverse events. Lomitapide is a sensitive substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor.
Lonafarnib: (Contraindicated) Coadministration of lonafarnib and letermovir is contraindicated; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and letermovir is a moderate CYP3A4 inhibitor.
Lopinavir; Ritonavir: (Moderate) A clinically relevant increase in the plasma concentration of ritonavir may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Ritonavir is primarily metabolized by CYP3A. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. (Moderate) Administering lopinavir concurrently with letermovir may result in elevated concentrations of both drugs. The exposure to lopinavir may be further increased if the patient is receiving letermovir combined with cyclosporine. Closely monitor for adverse events, including fast or irregular heartbeats, severe rash, hepatotoxicity, and gastrointestinal events. Lopinavir is an inhibitor of the organic anion-transporting polypeptide (OATP1B1), and a substrate of CYP3A4. Letermovir is an OATP1B1 substrate and a moderate CYP3A4 inhibitor. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Lorlatinib: (Major) Concurrent administration of letermovir and lorlatinib is not recommended due to the risk of decreased lorlatinib exposure which may reduce its efficacy. Letermovir is a P-glycoprotein (P-gp) substrate and lorlatinib is a P-gp inducer.
Lovastatin: (Major) Close monitoring for lovastatin-related adverse events (i.e., myopathy, rhabdomyolysis) and consideration of a lovastatin dose reduction is recommended if administered concurrently with letermovir. Concurrent use is contraindicated if the patient is also receiving cyclosporine. A clinically relevant increase in the plasma concentration of lovastatin may occur during concurrent administration with letermovir. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Lovastatin is a sensitive substrate of CYP3A4 and the organic anion-transporting polypeptide (OATP1B1). Both letermovir and cyclosporine are moderate CYP3A4 inhibitors and inhibitors of OATP1B1. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Lumacaftor; Ivacaftor: (Major) Concurrent administration of letermovir and lumacaftor; ivacaftor is not recommended. Use of these drugs together may alter letermovir plasma concentrations; decreased letermovir exposure may result in potential loss of letermovir efficacy. Letermovir is a substrate of the drug transporter P-glycoprotein (P-gp). Lumacaftor; ivacaftor has potential to both inhibit and induce P-gp. Also, concurrent use may increase ivacaftor plasma concentrations. Ivacaftor is a CYP3A substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration with other moderate and strong CYP3A inhibitors increased ivacaftor exposure by 3- and 8.5-fold, respectively. (Major) If letermovir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. In patients also receiving cyclosporine, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly, because the magnitude of the interaction may be increased. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate. Letermovir is a moderate CYP3A inhibitor; however, when given with cyclosporine, the combined effect on CYP3A substrates may be similar to a strong CYP3A inhibitor. Coadministration with other moderate and strong CYP3A inhibitors increased ivacaftor exposure by 3- and 8.5-fold, respectively.
Lumacaftor; Ivacaftor: (Major) Concurrent administration of letermovir and lumacaftor; ivacaftor is not recommended. Use of these drugs together may alter letermovir plasma concentrations; decreased letermovir exposure may result in potential loss of letermovir efficacy. Letermovir is a substrate of the drug transporter P-glycoprotein (P-gp). Lumacaftor; ivacaftor has potential to both inhibit and induce P-gp. Also, concurrent use may increase ivacaftor plasma concentrations. Ivacaftor is a CYP3A substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration with other moderate and strong CYP3A inhibitors increased ivacaftor exposure by 3- and 8.5-fold, respectively.
Lumateperone: (Major) Reduce the dose of lumateperone to 21 mg once daily if concomitant use of letermovir is necessary. If using a combination of letermovir/cyclosporine, reduce the dose of lumateperone to 10.5 mg once daily. Concurrent use may increase lumateperone exposure and the risk of adverse effects. Lumateperone is a CYP3A4 substrate; letermovir is a moderate CYP3A4 inhibitor. The combination of letermovir/cyclosporine is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased lumateperone exposure by approximately 2-fold, while coadministration with a strong CYP3A4 inhibitors increased lumateperone exposure by approximately 4-fold.
Lurasidone: (Moderate) Dosage reductions are required during concomitant administration of lurasidone and letermovir due to the potential for increased lurasidone exposure. In patients receiving lurasidone, reduce the lurasidone dose by one-half if letermovir is added to therapy. If a patient is receiving letermovir and lurasidone is added to therapy, the recommended lurasidone starting dose is 20 mg per day, not to exceed 80 mg per day. Coadministration is contraindicated if the patient is also receiving cyclosporine, because the magnitude of this interaction may be amplified in patients. Lurasidone is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Lurbinectedin: (Major) Avoid coadministration of lurbinectedin and letermovir due to the risk of increased lurbinectedin exposure which may increase the incidence of lurbinectedin-related adverse reactions. If concomitant use is unavoidable, consider reducing the dose of lurbinectedin if clinically indicated. Lurbinectedin is a CYP3A substrate and letermovir is a moderate CYP3A inhibitor.
Macitentan: (Moderate) An increase in the plasma concentration of macitentan may occur if given with letermovir. Avoid coadministration in patients who are also receiving treatment with cyclosporine, because the magnitude of this interaction may be amplified. If treatment with letermovir and cyclosporine must be continued, consider use of an alternative pulmonary artery hypertension medication. Macitentan is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent use with a strong CYP3A4 inhibitor resulted in a doubling of macitentan exposure.
Maraviroc: (Moderate) Administering letermovir with maraviroc may increase maraviroc concentration and risk for adverse events. In patients also receiving cyclosporine, reduce maraviroc adult dose to 150 mg twice daily (weight based dose reductions also recommended for pediatric patients), because the magnitude of the interaction may be amplified. In patients with severe renal impairment, use of maraviroc with both letermovir and cyclosporine is contraindicated. Maraviroc is primarily metabolized by CYP3A4 and is a substrate of organic anion-transporting polypeptide (OATP1B). Letermovir is a moderate CYP3A4 and OATP1B1 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Mavacamten: (Major) Mavacamten is contraindicated for use with combination letermovir/cyclosporine due to risk of heart failure due to systolic dysfunction. Reduce the mavacamten dose by 1 level (i.e., 15 to 10 mg, 10 to 5 mg, or 5 to 2.5 mg) in patients receiving mavacamten and starting letermovir therapy without cyclosporine. Avoid initiation of letermovir in patients who are on stable treatment with mavacamten 2.5 mg per day because a lower dose of mavacamten is not available. Initiate mavacamten at the recommended starting dose of 5 mg PO once daily in patients who are on stable letermovir therapy without cyclosporine. Concomitant use increases mavacamten exposure, which may increase the risk of adverse drug reactions. Mavacamten is a CYP3A substrate and combination letermovir/cyclosporine is a strong CYP3A inhibitor and letermovir is a moderate CYP3A inhibitor. The impact that a CYP3A inhibitor may have on mavacamten overall exposure varies based on the patient's CYP2C19 metabolizer status. Concomitant use with a strong CYP3A inhibitor is predicted to increase mavacamten overall exposure up to 130%. Concomitant use of a moderate CYP3A inhibitor increased mavacamten overall exposure by 15% in CYP2C19 normal and intermediate metabolizers; concomitant use in poor metabolizers is predicted to increase mavacamten exposure by up to 55%.
Medroxyprogesterone: (Moderate) An increase in the plasma concentration of medroxyprogesterone may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Avoid coadministration of medroxyprogesterone in patient receiving both letermovir and cyclosporine as this may increase the risk for adverse reactions. Medroxyprogesterone is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Mefloquine: (Moderate) An increase in the plasma concentration of mefloquine may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Mefloquine is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In a drug interaction study, concurrent administration of mefloquine with a strong CYP3A4 inhibitor resulted in an increase in the mean maximum plasma concentration and exposure of mefloquine by 64% and 79%, respectively; in addition, the mean elimination half-life increased from 322 hours to 448 hours.
Metformin; Repaglinide: (Moderate) Frequently monitor blood glucose concentrations and for evidence of hypoglycemia during concurrent use of repaglinide and letermovir. Concurrent use is not recommended in patients also receiving cyclosporine as the magnitude of this interaction may be amplified. A clinically relevant increase in the plasma concentration of repaglinide may occur during concurrent administration with letermovir. Repaglinide is a substrate of CYP3A4 and the organic anion-transporting polypeptides 1B1 and 1B3 (OATP1B1/3). Both letermovir and cyclosporine are moderate inhibitors of CYP3A4 and inhibitors of OATP1B1; letermovir is also an OATP1B3 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Metformin; Rosiglitazone: (Moderate) Frequently monitor blood glucose concentrations when rosiglitazone is given with letermovir. Concurrent administration of letermovir, a CYP2C8 inhibitor, with rosiglitazone, a CYP2C8 substrate, may result in a clinically relevant increase in rosiglitazone plasma concentration.
Metformin; Saxagliptin: (Moderate) An increase in the plasma concentration of saxagliptin may occur if given with letermovir. Limit the saxagliptin dose to 2.5 mg once per day if the patient is also receiving cyclosporine because the magnitude of this interaction may be increased. Saxagliptin is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent administration with another strong CYP3A4 inhibitor increased the maximum plasma concentration and exposure of saxagliptin by 1.62- and 2.45-fold, respectively.
Methadone: (Moderate) Plasma concentrations of methadone could be altered (increased or decreased) when administered concurrently with letermovir. In patients who are also receiving cyclosporine, the impact on the increase in methadone exposure may be increased. If these drugs are given together, closely monitor for reduced methadone efficacy and methadone-related adverse events. Consider a methadone dose increase if the patient shows signs or symptoms of opioid withdrawal. Conversely, consider reducing the methadone dose if patient show signs of respiratory depression or sedation. Methadone is a substrate of the enzymes CYP3A4, CYP2C9, and CYP2C19. Letermovir is an inducer of CYP2C9 and CYP2C19, and a moderate inhibitor of CYP3A4. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Methylergonovine: (Contraindicated) Concurrent administration of ergot alkaloids and letermovir is contraindicated due to the risk of ergotism. Taking these drugs together may result in increased concentrations of ergot alkaloids due to inhibition of CYP3A4 by letermovir.
Methylprednisolone: (Moderate) An increase in the plasma concentration of methylprednisolone may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Methylprednisolone is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In a drug interaction study, concurrent administration of certain corticosteroids with another potent CYP3A4 inhibitor significantly decreased the corticosteroid metabolism (up to 60% reduction).
Midazolam: (Moderate) Closely monitor for midazolam-related adverse events if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Midazolam is a sensitive CYP3A4 substrate and letermovir is a moderate CYP3A4 inhibitor. Concurrent use of letermovir increased the midazolam AUC and Cmax by 1.47-fold and 1.05-fold, respectively. The combined effect of letermovir and cyclosporine on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor.
Midostaurin: (Moderate) Monitor for an increase in letermovir-related adverse reactions in patients who are NOT also receiving cyclosporine if concomitant use with midostaurin is necessary due to increased letermovir concentrations which may increase the incidence and severity of adverse reactions. Avoid the concomitant use of midostaurin and letermovir WITH cyclosporine due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions. If unavoidable, monitor for signs and symptoms of midostaurin toxicity, particularly during the first week of therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Midostaurin is a CYP3A4 substrate and an OATP1B1 inhibitor. Letermovir is a OATP1B1/3 substrate and a moderate CYP3A4 inhibitor; however, when given together with cyclosporine, the combined effect may be similar to a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
Mifepristone: (Moderate) An increase in the plasma concentration of mifepristone may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Mifepristone is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Mirtazapine: (Moderate) Monitor for mirtazapine-related adverse events if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Mirtazapine is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In a drug interaction study, administration with another strong CYP3A4 inhibitor increased the maximum plasma concentration and exposure of mirtazapine by approximately 40% and 50%, respectively.
Mitapivat: (Moderate) In patients receiving mitapivat and letermovir WITHOUT concomitant cyclosporine, do not exceed mitapivat 20 mg PO twice daily during coadministration and monitor hemoglobin and for adverse reactions from mitapivat. In patients who are also receiving treatment with cyclosporine, avoid coadministration due to increased risk of adverse reactions from mitapivat. Coadministration increases mitapivat concentrations. Mitapivat is a CYP3A substrate and letermovir is a moderate CYP3A inhibitor; however, combination letermovir/cyclosporine is a strong CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased mitapivat overall exposure by 2.6-fold. Concomitant use with other strong CYP3A inhibitors increased mitapivat overall exposure by 3.6 to 4.9-fold.
Mobocertinib: (Major) Avoid concomitant use of mobocertinib and letermovir; reduce the dose of mobocertinib by approximately 50% and monitor the QT interval more frequently if use is necessary. Concomitant use may increase mobocertinib exposure and the risk for adverse reactions. Mobocertinib is a CYP3A substrate and letermovir is a moderate CYP3A inhibitor. If the patient is also receiving cyclosporine, avoid concomitant use. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Use of a moderate CYP3A inhibitor is predicted to increase the overall exposure of mobocertinib and its active metabolites by 100% to 200%, while use with a strong CYP3A inhibitor is predicted to increase the overall exposure of mobocertinib and its active metabolites by 374% to 419%.
Modafinil: (Major) Concurrent administration of letermovir and modafinil is not recommended. Use of these drugs together may decrease letermovir plasma concentrations, resulting in a potential loss of letermovir efficacy.
Nafcillin: (Major) Concurrent administration of letermovir and nafcillin is not recommended. Use of these drugs together may decrease letermovir plasma concentrations, resulting in a potential loss of letermovir efficacy.
Naldemedine: (Moderate) Administering letermovir with naldemedine may increase naldemedine concentration and risk for adverse events. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Naldemedine is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Naloxegol: (Major) Avoid concomitant administration of naloxegol and letermovir due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Concurrent use is contraindicated if the patient is also receiving cyclosporine because the magnitude of the interaction may be amplified. Naloxegol is a CYP3A4 substrate; letermovir is a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased naloxegol exposure by approximately 3.4-fold. Coadministration of a strong CYP3A4 inhibitor increased naloxegol exposure by more than 12-fold.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of nab-paclitaxel with letermovir is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor. In vitro, coadministration with both strong and moderate CYP3A4 inhibitors increased paclitaxel exposure; however, the concentrations used exceeded those found in vivo following normal therapeutic doses. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with CYP3A4 inhibitors.
Nanoparticle Albumin-Bound Sirolimus: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 during concomitant use of letermovir. Avoid the us e of nab-sirolimus with letermovir plus cyclosporine. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and letermovir is a moderate CYP3A inhibitor; combination letermovir plus cyclosporine has a net effect similar to that of a strong CYP3A inhibitor.
Nelfinavir: (Moderate) Plasma concentrations of nelfinavir could be altered increased when administered concurrently with letermovir. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. If these drugs are given together, closely monitor for nelfinavir-related adverse events. Nelfinavir is metabolized by CYP3A4. Letermovir is a moderate inhibitor of CYP3A4. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Neratinib: (Major) Avoid concomitant use of letermovir with neratinib in patients who are also receiving treatment with cyclosporine due to an increased risk of neratinib-related toxicity; an interaction is not expected in patients tatking letermovir without cyclosporine. Neratinib is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
Netupitant, Fosnetupitant; Palonosetron: (Moderate) An increase in the plasma concentration of netupitant may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. However, when these drugs are given together, no dosage adjustments are needed for a single dose of netupitant. Netupitant is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In a drug interaction study, administration with another strong CYP3A4 inhibitor increased the mean maximum plasma concentration and exposure of netupitant by 25% and 140%, respectively.
Nevirapine: (Moderate) Monitor for an increase in nevirapine-related adverse reactions if coadministration with letermovir and cyclosporine is necessary. Nevirapine is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased nevirapine exposure by 100%; concomitant use with a strong CYP3A4 inhibitor may also increase nevirapine exposure.
Niacin; Simvastatin: (Major) Use of simvastatin with letermovir is not recommended due to increased simvastatin exposure. Concurrent use is contraindicated if the patient is also receiving cyclosporine. Administering letermovir with simvastatin significantly increases simvastatin concentration and risk for myopathy or rhabdomyolysis. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Simvastatin is a sensitive substrate of CYP3A4 and the organic anion-transporting polypeptide (OATP1B1). Both letermovir and cyclosporine are moderate CYP3A4 inhibitors and inhibitors of OATP1B1.
Nifedipine: (Moderate) Closely monitor for nifedipine-related adverse events if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. A clinically relevant increase in the plasma concentration of nifedipine, a CYP3A4 substrate, may occur during concurrent administration with letermovir, a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Nilotinib: (Moderate) Coadministration of letermovir and nilotinib may increase nilotinib exposure. Avoid this combination if the patient is also receiving cyclosporine, because the magnitude of the interaction may be increased. If the use of letermovir with cyclosporine is necessary, interrupt nilotinib therapy. If the use of nilotinib with letermovir and cyclosporine cannot be avoided, consider a nilotinib dose reduction (to nilotinib 200 mg PO once daily in adult patients with newly diagnosed Ph+ CML or to nilotinib 300 mg PO once daily in adult patients with resistant or intolerant Ph+ CML); close monitoring of the QT interval is recommended. If letermovir with cyclosporine is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period. Nilotinib is a CYP3A4 substrate and letermovir is a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Nimodipine: (Moderate) A clinically relevant increase in the plasma concentration of nimodipine may occur if given with letermovir. A nimodipine dose reduction may be necessary. Avoid this combination in patients who are also receiving treatment with cyclosporine because the magnitude of this interaction may be amplified. Nimodipine is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Nirmatrelvir; Ritonavir: (Moderate) A clinically relevant increase in the plasma concentration of ritonavir may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Ritonavir is primarily metabolized by CYP3A. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Nisoldipine: (Major) Avoid concurrent administration of letermovir and nisoldipine, as taking these drugs together may increase nisoldipine concentrations and risk for adverse events. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Nisoldipine is a sensitive substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Olaparib: (Major) Avoid coadministration of olaparib with letermovir due to the risk of increased olaparib-related adverse reactions. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. If concomitant use is unavoidable, reduce the dose of olaparib to 150 mg twice daily if patients are taking letermovir without cyclosporine. If olaparib must be given with both letermovir and cyclosporine, reduce the dose of olaparib to 100 mg twice daily. The original dose of olaparib may be resumed 3 to 5 elimination half-lives after letermovir is discontinued. Olaparib is a CYP3A substrate. Letermovir is a moderate CYP3A4 inhibitor; however, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the olaparib Cmax by 14% and the AUC by 121%. Coadministration with another strong CYP3A inhibitor increased the olaparib Cmax by 42% and the AUC by 170%.
Oliceridine: (Moderate) Monitor patients closely for respiratory depression and sedation at frequent intervals and base subsequent doses on the patient's severity of pain and response to treatment if concomitant administration of oliceridine and letermovir is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and letermovir may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects. If letermovir is discontinued, consider increasing the oliceridine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oliceridine is a CYP3A4 substrate and letermovir is a moderate CYP3A4 inhibitor.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Amlodipine dose reductions may be required during concurrent administration with letermovir; monitor for symptoms of hypotension and edema to determine the need for dose adjustment. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Administering these drugs together may increase amlodipine concentration and risk for adverse events. Amlodipine is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent administration with a moderate CYP3A inhibitor increased amlodipine exposure by 60%; however, another moderate inhibitor did not significantly change amlodipine exposure. Strong CYP3A4 inhibitors may increase amlodipine exposure to a greater extent.
Omaveloxolone: (Major) Avoid concomitant use of omaveloxolone and letermovir. If concomitant use is necessary, decrease omaveloxolone dose to 100 mg once daily; additional dosage reductions may be necessary. If also used with cyclosporine, decrease omaveloxolone dose to 50 mg once daily. Concomitant use may increase omaveloxolone exposure and the risk for omaveloxolone-related adverse effects. Omaveloxolone is a CYP3A substrate. Letermovir is a moderate CYP3A inhibitor, however, when given with cyclosporine, the combined effect on CYP3A substrates is similar to a strong CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased omaveloxolone overall exposure by 1.25-fold while concomitant use with another strong CYP3A inhibitor increased omaveloxolone overall exposure by 4-fold.
Omeprazole: (Moderate) Monitor for reduced omeprazole efficacy and adjust the dose of omeprazole if needed during concurrent use of letermovir. Coadministration may result in a clinically relevant decrease in the plasma concentration of omeprazole. Omeprazole is a sensitive substrate of CYP2C19. Letermovir is a CYP2C19 inducer.
Omeprazole; Amoxicillin; Rifabutin: (Major) Concurrent administration of letermovir and rifabutin is not recommended. Use of these drugs together may decrease letermovir plasma concentrations, resulting in a potential loss of letermovir efficacy. Also, an increase in the plasma concentration of rifabutin may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Rifabutin is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. (Moderate) Monitor for reduced omeprazole efficacy and adjust the dose of omeprazole if needed during concurrent use of letermovir. Coadministration may result in a clinically relevant decrease in the plasma concentration of omeprazole. Omeprazole is a sensitive substrate of CYP2C19. Letermovir is a CYP2C19 inducer.
Omeprazole; Sodium Bicarbonate: (Moderate) Monitor for reduced omeprazole efficacy and adjust the dose of omeprazole if needed during concurrent use of letermovir. Coadministration may result in a clinically relevant decrease in the plasma concentration of omeprazole. Omeprazole is a sensitive substrate of CYP2C19. Letermovir is a CYP2C19 inducer.
Ospemifene: (Moderate) Plasma concentrations of ospemifene could be increased when administered concurrently with letermovir. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. If these drugs are given together, closely monitor for ospemifene-related adverse events. Ospemifene is primarily metabolized by CYP3A4. Letermovir is a moderate inhibitor of CYP3A4. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In a drug interaction study, concurrent administration with another strong CYP3A4 inhibitor increased ospemifene systemic exposure (AUC) by 1.4-fold.
Oxybutynin: (Moderate) A clinically relevant increase in the plasma concentration of oxybutynin may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Oxybutynin is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In a drug interaction study, concurrent administration with another strong CYP3A4 inhibitor increased mean oxybutynin plasma concentrations by approximately 2-fold.
Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of letermovir is necessary. If letermovir is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a CYP3A4 inhibitor like letermovir can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If letermovir is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Paclitaxel: (Moderate) An increase in the plasma concentration of paclitaxel may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Paclitaxel is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Pacritinib: (Major) Avoid concurrent use of pacritinib with letermovir due to the risk of increased pacritinib exposure which increases the risk of adverse reactions. Concurrent use of pacritinib with combination letermovir/cyclosporine is contraindicated. Pacritinib is a CYP3A substrate. Letermovir is a moderate CYP3A inhibitor and combination letermovir/cyclosporine is a strong CYP3A inhibitor.
Palbociclib: (Moderate) Caution is advised when administering palbociclib with letermovir, as taking these drugs together may increase palbociclib concentration and risk for adverse events. Avoid coadministration in patients also receiving cyclosporine because the magnitude of this interaction may be increased. If coadministration cannot be avoided, reduce the palbociclib dose to 75 mg/day. If letermovir or cyclosporine is discontinued, resume the prior palbociclib dose after 3 to 5 half-lives of the discontinued drug. Palbociclib is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent administration with a strong CYP3A inhibitor increased the exposure (AUC) and maximum plasma concentration (Cmax) of palbociclib by 87% and 34%, respectively.
Palovarotene: (Major) Avoid concomitant use of palovarotene and letermovir due to the risk for increased palovarotene exposure which may increase the risk for adverse effects. If concomitant use is necessary, decrease the palovarotene dose by half. Coadministration is not recommended if the patient is also receiving cyclosporine because the magnitude of the interaction may be amplified. Palovarotene is a CYP3A substrate and letermovir is a moderate CYP3A inhibitor; combination letermovir plus cyclosporine is a strong CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased palovarotene overall exposure by 2.5-fold while concomitant use with another strong CYP3A inhibitor increased palovarotene overall exposure by 3-fold.
Panobinostat: (Moderate) An increase in the plasma concentration of panobinostat may occur if given with letermovir. Reduce the starting dose of panobinostat to 10 mg in patients who are also receiving treatment with cyclosporine, because the magnitude of this interaction may be amplified. Panobinostat is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent administration with a strong CYP3A inhibitor increased the maximum plasma concentration (Cmax) and exposure (AUC) of panobinostat by 62% and 73%, respectively.
Pantoprazole: (Moderate) Monitor for reduced pantoprazole efficacy and adjust the dose of pantoprazole if needed during concurrent use of letermovir. Coadministration may result in a clinically relevant decrease in the plasma concentration of pantoprazole. Pantoprazole is a substrate of CYP2C19. Letermovir is a CYP2C19 inducer.
Paricalcitol: (Moderate) An increase in in the plasma concentration of paricalcitol may occur if given with letermovir. Dosage adjustment of paricalcitol may be necessary in patients also receiving cyclosporine, because the magnitude of the interaction may be increased. Closely monitor serum intact parathyroid hormone (iPTH) and calcium concentrations. Paricalcitol is a CYP3A4 substrate and letermovir is a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In one pharmacokinetic study, paricalcitol exposure approximately doubled and the half-life increased from 9.8 hours to 17 hours in the presence of a strong CYP3A4 inhibitor.
Pazopanib: (Moderate) An increase in the plasma concentration of pazopanib may occur if given with letermovir. Avoid coadministration in patients also receiving cyclosporine, because the magnitude of this interaction may be increased. If coadministration of pazopanib with both letermovir and cyclosporine cannot be avoided, reduce the pazopanib dose to 400 mg. Pazopanib is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent administration with a strong CYP3A4 inhibitor increased the exposure (AUC) and maximum plasma concentration of pazopanib by up to 2- and 1.5-fold, respectively.
Pemigatinib: (Major) Avoid coadministration of pemigatinib and letermovir due to the risk of increased pemigatinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of pemigatinib to 9 mg PO once daily if original dose was 13.5 mg per day and to 4.5 mg PO once daily if original dose was 9 mg per day. If letermovir is discontinued, resume the original pemigatinib dose after 3 elimination half-lives of letermovir. Pemigatinib is a CYP3A4 substrate and letermovir is a moderate CYP3A4 inhibitor. If the regimen also contains cyclosporine, the inhibitory effect is expected to be similar to a strong CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase pemigatinib exposure by approximately 50% to 80%. Coadministration with a strong CYP3A4 inhibitor increased pemigatinib exposure by 88%.
Perindopril; Amlodipine: (Moderate) Amlodipine dose reductions may be required during concurrent administration with letermovir; monitor for symptoms of hypotension and edema to determine the need for dose adjustment. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Administering these drugs together may increase amlodipine concentration and risk for adverse events. Amlodipine is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent administration with a moderate CYP3A inhibitor increased amlodipine exposure by 60%; however, another moderate inhibitor did not significantly change amlodipine exposure. Strong CYP3A4 inhibitors may increase amlodipine exposure to a greater extent.
Pexidartinib: (Major) Avoid concomitant use of pexidartinib and letermovir due to the risk of increased pexidartinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pexidartinib dosage as follows: 500 mg/day or 375 mg/day of pexidartinib, reduce to 125 mg twice daily; 250 mg/day of pexidartinib, reduce to 125 mg once daily. If letermovir is discontinued, increase the pexidartinib dose to the original dose after 3 plasma half-lives of letermovir. Pexidartinib is a CYP3A substrate; letermovir is a moderate CYP3A inhibitor. Coadministration of another moderate CYP3A inhibitor increased pexidartinib overall exposure by 67%.
Phenobarbital: (Major) Concurrent administration of letermovir and phenobarbital is not recommended. Use of these drugs together may decrease letermovir plasma concentrations, resulting in a potential loss of letermovir efficacy. Letermovir is a substrate of UDP-glucuronosyltransferase 1A1/3 (UGT1A1/3) and P-glycoprotein (P-gp). Phenobarbital induces UGT and P-gp.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Concurrent administration of letermovir and phenobarbital is not recommended. Use of these drugs together may decrease letermovir plasma concentrations, resulting in a potential loss of letermovir efficacy. Letermovir is a substrate of UDP-glucuronosyltransferase 1A1/3 (UGT1A1/3) and P-glycoprotein (P-gp). Phenobarbital induces UGT and P-gp.
Phenytoin: (Major) Concurrent administration of letermovir and phenytoin is not recommended. Use of these drugs together may decrease letermovir plasma concentrations, resulting in a potential loss of letermovir efficacy. Letermovir is a substrate of UDP-glucuronosyltransferase 1A1/3 (UGT1A1/3) and P-glycoprotein (P-gp). Phenytoin is an inducer of UGT and P-gp. Also, a clinically relevant decrease in the plasma concentration of phenytoin, a CYP2C9 and CYP2C19 substrate, may occur during concurrent administration with letermovir, an inducer of CYP2C9 and CYP2C19. If these drugs are used together, frequently monitor phenytoin plasma concentrations.
Pimavanserin: (Moderate) An increase in the plasma concentration of pimavanserin, a primary CYP3A4 substrate, may occur if given with letermovir, a moderate CYP3A4 inhibitor. Reduce the dose of pimavanserin to 10 mg PO once daily in patients who are also receiving treatment with cyclosporine because the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to use of a strong CYP3A4 inhibitor alone. In a drug interaction study, administration with another strong CYP3A4 inhibitor increased pimavanserin maximum plasma concentration and exposure by 1.5- and 3-fold, respectively.
Pimozide: (Contraindicated) Concurrent administration of letermovir and pimozide is contraindicated. Taking these drugs together may result in increased concentrations of pimozide due to inhibition of CYP3A4 by letermovir, which could lead to QT prolongation and torsade de pointes.
Pioglitazone: (Moderate) Plasma concentrations of pioglitazone could be increased when administered concurrently with letermovir. If these drugs are given together, closely monitor for pioglitazone-related adverse events. Letermovir is an inhibitor of CYP2C8; pioglitazone is a CYP2C8 substrate.
Pioglitazone; Glimepiride: (Moderate) Plasma concentrations of pioglitazone could be increased when administered concurrently with letermovir. If these drugs are given together, closely monitor for pioglitazone-related adverse events. Letermovir is an inhibitor of CYP2C8; pioglitazone is a CYP2C8 substrate.
Pioglitazone; Metformin: (Moderate) Plasma concentrations of pioglitazone could be increased when administered concurrently with letermovir. If these drugs are given together, closely monitor for pioglitazone-related adverse events. Letermovir is an inhibitor of CYP2C8; pioglitazone is a CYP2C8 substrate.
Pirtobrutinib: (Major) Avoid concomitant use of pirtobrutinib and combination letermovir plus cyclosporine due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of combination letermovir plus cyclosporine use. Resume the previous dose of pirtobrutinib after combination letermovir plus cyclosporine is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and combination letermovir plus cyclosporine is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Pitavastatin: (Major) Use of pitavastatin with letermovir is not recommended due to increased pitavastatin exposure. Concurrent use is contraindicated if the patient is also receiving cyclosporine. Administering letermovir with pitavastatin significantly increases pitavastatin concentration and risk for myopathy or rhabdomyolysis. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Pitavastatin is a substrate of the organic anion-transporting polypeptides 1B1 and 1B3 (OATP1B1/3). Both letermovir and cyclosporine are inhibitors of OATP1B1; letermovir is also an OATP1B3 inhibitor.
Ponatinib: (Moderate) Avoid coadministration of ponatinib and letermovir in patients who are also taking cyclosporine due to the potential for increased ponatinib exposure; ponatinib may be taken with letermovir in patients who are not taking cyclosporine. If concurrent use of ponatinib and letermovir in combination with cyclosporine cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of letermovir with cyclosporine and consider alternative therapy. After cyclosporine has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting letermovir with cyclosporine. Ponatinib is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Pralsetinib: (Major) Avoid concomitant use of letermovir with pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the daily dose of pralsetinib by 100 mg. Pralsetinib is a CYP3A substrate and letermovir is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the overall exposure of pralsetinib by 71%.
Pravastatin: (Moderate) Closely monitor for pravastatin-related adverse events (myopathy, rhabdomyolysis) and consider a pravastatin dose reduction if administered with letermovir. Do not exceed a pravastatin dose of 20 mg daily if the patient is also receiving cyclosporine. The magnitude of this interaction may be increased if letermovir is given with cyclosporine. Concurrent administration of letermovir, an organic anion-transporting polypeptide (OATP1B1/3) inhibitor, with pravastatin, an OATP1B1/3 substrate, may result in a clinically relevant increase in pravastatin plasma concentration.
Prednisolone: (Moderate) An increase in the plasma concentration of prednisolone may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Prednisolone is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent administration with a strong CYP3A4 inhibitor decreased the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects.
Prednisone: (Moderate) A clinically relevant increase in the plasma concentration of prednisolone (the active metabolite of prednisone) may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Prednisolone is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent administration with a strong CYP3A4 inhibitor decreased the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects.
Primidone: (Major) Concurrent administration of letermovir and primidone is not recommended. Use of these drugs together may decrease letermovir plasma concentrations, resulting in a potential loss of letermovir efficacy. Letermovir is a substrate of the drug transporter P-glycoprotein (P-gp). Primidone induces P-gp.
Probenecid; Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and letermovir in patients with normal renal and hepatic function unless the use of both agents is imperative. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Letermovir, a moderate CYP3A4 inhibitor, can inhibit colchicine's metabolism, resulting in increased colchicine exposure. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine; the combined effect of letermovir and cyclosporine may be similar to a strong CYP3A4 inhibitor. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations for the Colcrys product for patients who have taken a moderate CYP3A4 inhibitor including letermovir in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg twice daily or 0.6 mg once daily or if the original dose is 0.6 mg once daily, decrease the dose to 0.3 mg once daily; for treatment of gout flares, give 1.2 mg as a single dose and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed 1.2 mg/day. For patients who have taken a strong CYP3A4 inhibitor including letermovir plus cyclosporine in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg once daily or if the original dose is 0.6 mg once daily, decrease to 0.3 mg once every other day; for treatment of gout flares, give 0.6 mg as a single dose, then 0.3 mg 1 hour later, and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed a 0.6 mg/day.
Propafenone: (Moderate) A clinically relevant increase in the plasma concentration of propafenone may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Propafenone is partially metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Quetiapine: (Moderate) Caution is advised when administering quetiapine with letermovir, as taking these drugs together may increase quetiapine concentration and risk for adverse events. Reduce the quetiapine dose to 1/6 the original dose in patients also receiving cyclosporine, because the magnitude of this interaction may be increased. If letermovir or cyclosporine are discontinued, the quetiapine dose should be increased by 6-fold. Quetiapine is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent administration with another strong CYP3A4 inhibitors decreased quetiapine clearance by 84%, thereby resulting in a 6.2-fold increase in quetiapine exposure (AUC).
Quinidine: (Moderate) Closely monitor for quinidine-related adverse events including arrhythmias, if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. A clinically relevant increase in the plasma concentration of quinidine, a CYP3A4 substrate, may occur during concurrent administration with letermovir, a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Quinine: (Moderate) Plasma concentrations of quinine could increase when administered concurrently with letermovir. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. If these drugs are given together, closely monitor for quinine-related adverse events. Quinine is primarily metabolized by CYP3A4. Letermovir is moderate inhibitor of CYP3A4. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In a drug interaction study, concurrent use with another strong CYP3A4 inhibitor increased quinine AUC by 45%, and decreased the mean oral clearance of quinine by 31%; no change in quinine dosage regimen was needed.
Ramelteon: (Moderate) Plasma concentrations of ramelteon could be increased when administered concurrently with letermovir. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. If these drugs are given together, closely monitor for reduced ramelteon efficacy and ramelteon-related adverse events. Ramelteon is a substrate of CYP3A4. Letermovir a moderate inhibitor of CYP3A4. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In a drug interaction study, administration of ramelteon with another strong CYP3A4 inhibitor increased the exposure and maximum plasma concentration of ramelteon by approximately 84% and 36%, respectively.
Ranolazine: (Major) Limit the maximum dose of ranolazine to 500 mg twice daily if coadministered with letermovir. Concurrent use is contraindicated if the patient is also receiving cyclosporine, because the magnitude of the interaction may be increased. A clinically relevant increase in the plasma concentration of ranolazine may occur if given with letermovir. Ranolazine is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent administration with another strong CYP3A inhibitor increased ranolazine plasma concentrations by 220%. When given with another moderate CYP3A inhibitor, ranolazine plasma concentrations increased by 50% to 130%.
Regorafenib: (Moderate) Avoid coadministration of regorafenib with letermovir in patients who are also receiving treatment with cyclosporine due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib may be administered with letermovir if the patient is not receiving concomitant cyclosporine. Regorafenib is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
Repaglinide: (Moderate) Frequently monitor blood glucose concentrations and for evidence of hypoglycemia during concurrent use of repaglinide and letermovir. Concurrent use is not recommended in patients also receiving cyclosporine as the magnitude of this interaction may be amplified. A clinically relevant increase in the plasma concentration of repaglinide may occur during concurrent administration with letermovir. Repaglinide is a substrate of CYP3A4 and the organic anion-transporting polypeptides 1B1 and 1B3 (OATP1B1/3). Both letermovir and cyclosporine are moderate inhibitors of CYP3A4 and inhibitors of OATP1B1; letermovir is also an OATP1B3 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Revefenacin: (Major) Coadministration of revefenacin is not recommended with letermovir because it may result in clinically relevant increases in plasma concentrations of the active metabolite of revefenacin and an increased potential for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; letermovir is an inhibitor of OATP1B1 and OATP1B3.
Ribociclib: (Moderate) Coadministration of letermovir and ribociclib may increase ribociclib exposure. This combination should be avoided in patients also taking cyclosporine, because the magnitude of the interaction may be increased. If the use of ribociclib cannot be avoided in patients receiving both letermovir and cyclosporine, reduce the ribociclib dose to 400 mg once per day. Ribociclib is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. The AUC of ribociclib was increased by 3.2-fold when coadministered with a strong CYP3A4 inhibitor. A moderate inhibitor is predicted to increase the ribociclib AUC by 1.9-fold.
Ribociclib; Letrozole: (Moderate) Coadministration of letermovir and ribociclib may increase ribociclib exposure. This combination should be avoided in patients also taking cyclosporine, because the magnitude of the interaction may be increased. If the use of ribociclib cannot be avoided in patients receiving both letermovir and cyclosporine, reduce the ribociclib dose to 400 mg once per day. Ribociclib is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. The AUC of ribociclib was increased by 3.2-fold when coadministered with a strong CYP3A4 inhibitor. A moderate inhibitor is predicted to increase the ribociclib AUC by 1.9-fold.
Rifabutin: (Major) Concurrent administration of letermovir and rifabutin is not recommended. Use of these drugs together may decrease letermovir plasma concentrations, resulting in a potential loss of letermovir efficacy. Also, an increase in the plasma concentration of rifabutin may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Rifabutin is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Rifampin: (Major) Concurrent administration of letermovir and rifampin is not recommended. Use of these drugs together may decrease letermovir plasma concentrations, resulting in a potential loss of letermovir efficacy. Letermovir is a substrate of UDP-glucuronosyltransferase 1A1/3 (UGT1A1/3) and P-glycoprotein (P-gp). Rifampin induces UGT and P-gp.
Rilpivirine: (Moderate) A clinically relevant increase in the plasma concentration of rilpivirine may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Rilpivirine is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Rimegepant: (Major) Avoid a second dose of rimegepant within 48 hours if coadministered with letermovir; concurrent use may increase rimegepant exposure. Avoid concomitant use in patients also receiving cyclosporine because the magnitude of the interaction may be increased. Rimegepant is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Ritonavir: (Moderate) A clinically relevant increase in the plasma concentration of ritonavir may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Ritonavir is primarily metabolized by CYP3A. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Roflumilast: (Moderate) An increase in the plasma concentration of roflumilast may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. The risk of such concurrent use should be weighed carefully against benefit. Roflumilast is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In a drug interaction study, concurrent administration with another strong CYP3A4 inhibitor increased the maximum plasma concentration (Cmax) and exposure (AUC) of roflumilast by 23% and 99%, respectively. In addition, the Cmax of the metabolite, roflumilast N-oxide, was decrease by 38% and the AUC was increased by 3%. Similarly, when administered with another moderate CYP3A4 inhibitor the Cmax and AUC of roflumilast increased by 40% and 70%, respectively; while the Cmax of roflumilast N-oxide decreased by 34% and the AUC increased by 4%.
Romidepsin: (Moderate) A clinically relevant increase in the plasma concentration of romidepsin may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Romidepsin is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In a drug interaction study, administration of romidepsin with another strong CYP3A4 inhibitor increased romidepsin concentration by approximately 25%.
Rosiglitazone: (Moderate) Frequently monitor blood glucose concentrations when rosiglitazone is given with letermovir. Concurrent administration of letermovir, a CYP2C8 inhibitor, with rosiglitazone, a CYP2C8 substrate, may result in a clinically relevant increase in rosiglitazone plasma concentration.
Rosuvastatin: (Moderate) Closely monitor for rosuvastatin-related adverse events (myopathy, rhabdomyolysis) and consider a rosuvastatin dose reduction if administered with letermovir. Do not exceed a rosuvastatin dose of 5 mg daily if the patient is also receiving cyclosporine. The magnitude of this interaction may be increased if letermovir is given with cyclosporine. Concurrent administration of letermovir, an organic anion-transporting polypeptide (OATP1B1/3) inhibitor, with rosuvastatin, an OATP1B1/3 substrate, may result in a clinically relevant increase in rosuvastatin plasma concentration.
Rosuvastatin; Ezetimibe: (Moderate) Closely monitor for rosuvastatin-related adverse events (myopathy, rhabdomyolysis) and consider a rosuvastatin dose reduction if administered with letermovir. Do not exceed a rosuvastatin dose of 5 mg daily if the patient is also receiving cyclosporine. The magnitude of this interaction may be increased if letermovir is given with cyclosporine. Concurrent administration of letermovir, an organic anion-transporting polypeptide (OATP1B1/3) inhibitor, with rosuvastatin, an OATP1B1/3 substrate, may result in a clinically relevant increase in rosuvastatin plasma concentration.
Ruxolitinib: (Moderate) Plasma concentrations of ruxolitinib could increase when administered concurrently with letermovir. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Frequently monitor safety and efficacy of ruxolitinib, and modify dose as needed. Ruxolitinib is a substrate of the enzymes CYP3A4. Letermovir is moderate inhibitor of CYP3A4. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In a drug interaction study, administration of ruxolitinib with another strong CYP3A4 inhibitor increased ruxolitinib maximum plasma concentration (Cmax) and exposure (AUC) by 33% and 91%, respectively. In addition, ruxolitinib half-life was increased from 3.7 to 6 hours. In another study, administration with a moderate CYP3A4 inhibitor increased ruxolitinib Cmax and AUC by 8% and 27%, respectively.
Saquinavir: (Moderate) An increase in the plasma concentration of saquinavir may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Saquinavir is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Saxagliptin: (Moderate) An increase in the plasma concentration of saxagliptin may occur if given with letermovir. Limit the saxagliptin dose to 2.5 mg once per day if the patient is also receiving cyclosporine because the magnitude of this interaction may be increased. Saxagliptin is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent administration with another strong CYP3A4 inhibitor increased the maximum plasma concentration and exposure of saxagliptin by 1.62- and 2.45-fold, respectively.
Segesterone Acetate; Ethinyl Estradiol: (Minor) Coadministration of segesterone and moderate CYP3A4 inhibitors such as letermorvir may increase the serum concentration of segesterone.
Selexipag: (Moderate) Increased exposure to the active metabolite of selexipag may occur when administered concurrently with letermovir. In vitro data suggests letermovir is a CYP2C8 inhibitor; however, the magnitude of inhibition is unknown. According to the selexipag manufacturer, strong CYP2C8 inhibitors are contraindicated with selexipag, a CYP2C8 substrate, and a dosage reduction should be considered with moderate CYP2C8 inhibitors. Specifically, consider a less frequent dosing regimen (e.g., once daily) when initiating selexipag in patients on a moderate CYP2C8 inhibitor. Reduce selexipag dose when a moderate CYP2C8 inhibitor is initiated.
Selpercatinib: (Major) Avoid coadministration of selpercatinib and letermovir due to the risk of increased selpercatinib exposure which may increase the risk of adverse reactions, including QT prolongation. If concomitant use is unavoidable and the patient is also taking cyclosporine, reduce the dose of selpercatinib to 40 mg PO twice daily if original dose was 120 mg twice daily, and to 80 mg PO twice daily if original dose was 160 mg twice daily. If the patient is not receiving concomitant cyclosporine, reduce the dose of selpercatinib to 80 mg PO twice daily if original dose was 120 mg twice daily, and to 120 mg PO twice daily if original dose was 160 mg twice daily. Monitor ECGs for QT prolongation more frequently. If letermovir is discontinued, resume the original selpercatinib dose after 3 to 5 elimination half-lives of letermovir. Selpercatinib is a CYP3A4 substrate; letermovir is a moderate CYP3A4 inhibitor; however, if the regimen also contains cyclosporine, the inhibitory effect is expected to be similar to a strong CYP3A4 inhibitor. Coadministration with other moderate CYP3A4 inhibitors is predicted to increase selpercatinib exposure by 60% to 99%, while coadministration with other strong CYP3A4 inhibitors increased selpercatinib exposure by 133%.
Selumetinib: (Major) Avoid coadministration of selumetinib and letermovir due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If letermovir is discontinued, resume the original selumetinib dose after 3 elimination half-lives of letermovir. Selumetinib is a CYP3A4 substrate and letermovir is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase selumetinib exposure by 41%.
Sildenafil: (Major) Monitor for an increase in sildenafil-related adverse reactions if coadministration with letermovir is necessary; a dose reduction of sildenafil may be necessary when prescribed for erectile dysfunction. Concurrent use is not recommended in patients receiving sildenafil for pulmonary arterial hypertension and taking cyclosporine, because the magnitude of the interaction may be amplified. Consider a starting dose of 25 mg of sildenafil for erectile dysfunction in patients receiving letermovir with cyclosporine. Concurrent use is expected to substantially increase the sildenafil plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Sildenafil is metabolized principally by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor.
Silodosin: (Moderate) A clinically relevant increase in the plasma concentration of silodosin may occur if given with letermovir; exercise caution and monitor patients for adverse events if these drugs are given together. Coadministration is contraindicated in patients who are also receiving treatment with cyclosporine, because the magnitude of this interaction may be amplified. Silodosin is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent administration with a strong CYP3A4 inhibitor caused a 3.8-fold increase in the maximum plasma silodosin concentration (Cmax) and 3.2-fold increase in silodosin exposure (AUC). The effect of moderate CYP3A4 inhibitors on the pharmacokinetics of silodosin has not been evaluated.
Simvastatin: (Major) Use of simvastatin with letermovir is not recommended due to increased simvastatin exposure. Concurrent use is contraindicated if the patient is also receiving cyclosporine. Administering letermovir with simvastatin significantly increases simvastatin concentration and risk for myopathy or rhabdomyolysis. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Simvastatin is a sensitive substrate of CYP3A4 and the organic anion-transporting polypeptide (OATP1B1). Both letermovir and cyclosporine are moderate CYP3A4 inhibitors and inhibitors of OATP1B1.
Siponimod: (Moderate) Concomitant use of siponimod and letermovir may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; letermovir is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of letermovir. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and letermovir is a moderate CYP3A inhibitor. Concomitant use has been observed to increase sirolimus overall exposure by 3.4-fold.
Sodium Phenylbutyrate; Taurursodiol: (Major) Avoid coadministration of sodium phenylbutyrate; taurursodiol and letermovir. Concomitant use may increase plasma concentrations of sodium phenylbutyrate; taurursodiol. Sodium phenylbutyrate; taurursodiol is an OATP1B3 substrate and letermovir is an OATP1B3 inhibitor.
Sofosbuvir; Velpatasvir: (Moderate) Administering velpatasvir concurrently with letermovir may result in elevated concentrations of letermovir. Monitor for increased letermovir adverse effects. Velpatasvir is an inhibitor of the organic anion-transporting polypeptides (OATP1B1/3). Letermovir is an OATP1B1/3 substrate.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Concomitant administration of voxilaprevir and letermovir is not recommended, as concurrent use may result in significantly elevated concentrations of both drugs. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Voxilaprevir and letermovir are substrates and inhibitors of the organic anion-transporting polypeptides (OATP1B1/3). In addition, cyclosporine is an OATP1B1 inhibitor, which could further amplify this interaction. (Moderate) Administering velpatasvir concurrently with letermovir may result in elevated concentrations of letermovir. Monitor for increased letermovir adverse effects. Velpatasvir is an inhibitor of the organic anion-transporting polypeptides (OATP1B1/3). Letermovir is an OATP1B1/3 substrate.
Solifenacin: (Major) Do not exceed a dose of 5 mg per day of solifenacin in patients receiving letermovir plus cyclosporine as concurrent use may increase solifenacin exposure; no dosage adjustment is required in patients receiving letermovir alone. Solifenacin is a CYP3A substrate and letermovir plus cyclosporine behaves as a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased solifenacin exposure by 2.7-fold.
Sonidegib: (Major) Avoid concurrent use of sonidegib with letermovir, as taking these drugs together may increase sonidegib concentration and risk for adverse events. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Sonidegib is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A4 inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days. Coadministration of a strong CYP3A4 inhibitor increased the mean Cmax and AUC of sonidegib by 2.2-fold and 1.5-fold, respectively.
Sparsentan: (Moderate) Monitor for an increase in sparsentan-related adverse effects if concomitant use with letermovir is necessary. Avoid concomitant use of sparsentan and combination letermovir plus cyclosporine. Concomitant use may increase sparsentan exposure. Sparsentan is a CYP3A substrate and letermovir is a moderate CYP3A inhibitor. When letermovir is given with cyclosporine the combined effect on CYP3A substrates is similar to a strong CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased sparsentan overall exposure by 70%. Concomitant use with a strong CYP3A inhibitor increased sparsentan overall exposure by 174%.
St. John's Wort, Hypericum perforatum: (Major) Concurrent administration of letermovir and St. John's Wort is not recommended. Use of these drugs together may decrease letermovir plasma concentrations, resulting in a potential loss of letermovir efficacy. Letermovir is a substrate of the drug transporter P-glycoprotein (P-gp). St. John's Wort induces P-gp.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if letermovir must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of letermovir is necessary. If letermovir is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A4 substrate, and coadministration with a CYP3A4 inhibitor like letermovir can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If letermovir is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
Sunitinib: (Moderate) If possible, avoid coadministration of letermovir with sunitinib in patients who are also receiving cyclosporine due to increased sunitinib exposure, which may increase the risk of QT prolongation. If concomitant use of letermovir, cyclosporine, and sunitinib is unavoidable, monitor the QT interval more frequently and consider reducing the daily dose of sunitinib to 37.5 mg for patients with GIST or RCC, and to 25 mg for patients with pNET. Sunitinib is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased exposure to sunitinib and its primary active metabolite by 51%.
Suvorexant: (Major) The recommended dose of suvorexant is 5 mg and may be increased to a maximum of 10 mg if necessary for efficacy when coadministered with letermovir. Concurrent use is not recommended in patients also receiving cyclosporine, because the magnitude of the interaction may be amplified. Suvorexant is a CYP3A4 substrate. A clinically relevant increase in the plasma concentration of suvorexant may occur if given with letermovir. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor.
Tacrolimus: (Moderate) Frequently monitor tacrolimus whole blood concentrations during concurrent treatment and after discontinuation of letermovir, and adjust the tacrolimus dose accordingly. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Concurrent use of letermovir increased the AUC and Cmax of tacrolimus by 2.42-fold and 1.57-fold, respectively. Tacrolimus is a sensitive CYP3A4 substrate; letermovir is a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Tadalafil: (Moderate) An increase in the plasma concentration of tadalafil may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Avoid coadministration of tadalafil for pulmonary hypertension if the patient is receiving letermovir and cyclosporine. When used for erectile dysfunction in patients receiving letermovir with cyclosporine, the as needed (PRN) dose of tadalafil should not exceed 10 mg once every 72 hours and the daily dose should not exceed 2.5 mg. Tadalafil is predominately metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect CYP3A4 substrates is similar to a strong CYP3A4 inhibitor. In a drug interaction study, the exposure and maximum plasma concentration of tadalafil increased by up to 312% and 22%, respectively, when administered with another potent CYP3A4 inhibitor. Studies with moderate CYP3A4 inhibitors have not been conducted.
Tamsulosin: (Moderate) An increase in the plasma concentration of tamsulosin may occur when given with letermovir. Avoid this combination in patients who are also receiving treatment with cyclosporine because the magnitude of this interaction may be amplified. Tamsulosin is partially metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor. In a drug interaction study, concomitant use of tamsulosin with another strong CYP3A4 inhibitor resulted in increase in the maximum plasma concentration and exposure of tamsulosin by a factor of 2.2 and 2.8, respectively. The effects of concurrent use with moderate CYP3A4 inhibitors have not been evaluated.
Tasimelteon: (Moderate) An increase in the plasma concentration of tasimelteon may occur during concurrent administration with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Tasimelteon is partially metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor. In a drug interaction study, administration of tasimelteon with another strong CYP3A4 inhibitor increased tasimelteon exposure by approximately 50%.
Tazemetostat: (Major) Avoid coadministration of tazemetostat with letermovir as concurrent use may increase tazemetostat exposure and the frequency and severity of adverse reactions. If concomitant use of tazemetostat and letermovir WITHOUT cyclosporine is unavoidable, decrease current tazemetostat daily dosage by 50% (e.g., decrease 800 mg PO twice daily to 400 mg PO twice daily; 600 mg PO twice daily to 400 mg PO for first dose and 200 mg PO for second dose; 400 mg PO twice daily to 200 mg PO twice daily). If letermovir is discontinued, wait at least 3 half-lives of letermovir before increasing the dose of tazemetostat to the previous tolerated dose. Tazemetostat is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased tazemetostat exposure by 3.1-fold.
Telmisartan; Amlodipine: (Moderate) Amlodipine dose reductions may be required during concurrent administration with letermovir; monitor for symptoms of hypotension and edema to determine the need for dose adjustment. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Administering these drugs together may increase amlodipine concentration and risk for adverse events. Amlodipine is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent administration with a moderate CYP3A inhibitor increased amlodipine exposure by 60%; however, another moderate inhibitor did not significantly change amlodipine exposure. Strong CYP3A4 inhibitors may increase amlodipine exposure to a greater extent.
Temsirolimus: (Moderate) Concurrent administration of temsirolimus with letermovir may result in a clinically relevant increase in sirolimus plasma concentration, the active metabolite of temsirolimus. Avoid coadministration in patients also receiving cyclosporine, because the magnitude of this interaction may be increased. If temsirolimus must be coadministered with both letermovir and cyclosporine, a temsirolimus dose reduction to 12.5 mg per week should be considered. If letermovir or cyclosporine is discontinued, a washout period of approximately 1 week should be allowed before the temsirolimus dose is adjusted back to the dose used prior to initiation of concurrent treatment. Temsirolimus is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor. In a drug interaction study, concurrent administration with another strong CYP3A4 inhibitor had no significant effect on temsirolimus maximum plasma concentration (Cmax) or exposure (AUC); however, sirolimus AUC increased 3.1-fold and Cmax increased 2.2-fold.
Teriflunomide: (Moderate) Closely monitor for letermovir-related adverse events (i.e., tachycardia, atrial fibrillation, and gastrointestinal events) if administered with teriflunomide, as use of these drugs together may result in elevated letermovir plasma concentration. Letermovir is a substrate of the organic anion-transporting polypeptides (OATP1B1/3); teriflunomide is an inhibitor of OATP1B1/3.
Tezacaftor; Ivacaftor: (Major) Adjust the tezacaftor; ivacaftor dosing schedule when coadministered with letermovir; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet every other day in the morning and 1 ivacaftor tablet every other day in the morning on alternate days (i.e., tezacaftor/ivacaftor tablet on Day 1 and ivacaftor tablet on Day 2). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); letermovir is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor increased ivacaftor exposure 3-fold. Simulation suggests a moderate inhibitor may increase tezacaftor exposure 2-fold. (Major) If letermovir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. In patients also receiving cyclosporine, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly, because the magnitude of the interaction may be increased. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate. Letermovir is a moderate CYP3A inhibitor; however, when given with cyclosporine, the combined effect on CYP3A substrates may be similar to a strong CYP3A inhibitor. Coadministration with other moderate and strong CYP3A inhibitors increased ivacaftor exposure by 3- and 8.5-fold, respectively.
Theophylline, Aminophylline: (Moderate) An increase in the plasma concentration of theophylline may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Theophylline is partially metabolized by CYP3A3. Letermovir is a moderate CYP3A inhibitor; however, when given with cyclosporine, the combined effect on CYP3A substrates may be similar to a strong CYP3A inhibitor. In drug interaction studies, concurrent administration with other moderate CYP3A inhibitors resulted in increased theophylline effect ranging from 25% to 35%.
Thioridazine: (Major) Concurrent administration of letermovir and thioridazine is not recommended. Use of these drugs together may decrease letermovir plasma concentrations, resulting in a potential loss of letermovir efficacy.
Thiotepa: (Moderate) The concomitant use of thiotepa and letermovir may result in reduced metabolism to the active thiotepa metabolite and decreased thiotepa efficacy. Avoid concomitant use if letermovir is used in combination with cyclosporine and consider an alternative agent with no or minimal potential to inhibit CYP3A4; monitor patients for signs of reduced thiotepa efficacy if coadministration is necessary, In vitro, thiotepa is metabolized via CYP3A4 to the active metabolite, TEPA. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Ticagrelor: (Moderate) Administering letermovir with ticagrelor may increase ticagrelor concentration and risk for adverse events (e.g., dyspnea, bleeding). Avoid coadministration in patients also receiving cyclosporine, because the magnitude of this interaction may be increased. Ticagrelor is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Tinidazole: (Moderate) An increase in the plasma concentration of tinidazole may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Tinidazole is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Tipranavir: (Major) Concurrent administration of letermovir and tipranavir is not recommended. Use of these drugs together may decrease letermovir plasma concentrations, resulting in a potential loss of letermovir efficacy. Letermovir is a substrate of the drug transporter P-glycoprotein (P-gp). Tipranavir is a strong P-gp inducer. Also, concurrent administration may increase plasma concentrations of tipranavir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Tipranavir is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor, however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Tisotumab Vedotin: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with letermovir in combination with cyclosporine is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate. Letermovir is a moderate CYP3A4 inhibitor; however, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Tofacitinib: (Major) A clinically relevant increase in the plasma concentration of tofacitinib may occur if given with letermovir. A dosage reduction of tofacitinib is necessary if coadministered with letermovir and cyclosporine because the magnitude of this interaction may be amplified. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Tolterodine: (Moderate) An increase in the plasma concentration of tolterodine may occur if given with letermovir. Do not exceed tolterodine 2 mg per day in patients who are also receiving treatment with cyclosporine, because the magnitude of this interaction may be amplified. Tolterodine is metabolized by CYP3A4 in patients who are poor metabolizers of CYP2D6. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In a drug interaction study involving poor CYP2D6 metabolizers, concurrent administration of tolterodine with another strong CYP3A4 inhibitor increased the mean maximum plasma concentration and exposure of tolterodine by 2- and 2.5-fold, respectively.
Tolvaptan: (Major) Concurrent use is contraindicated if the patient is also receiving cyclosporine, because the magnitude of the interaction may be increased. Otherwise, avoid coadministration of letermovir when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with letermovir. In ADPKD patients receiving tolvaptan 90mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Tolvaptan is a sensitive CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
Toremifene: (Moderate) An increase in the plasma concentration of toremifene may occur if given with letermovir. Avoid coadministration in patients who are also receiving treatment with cyclosporine because the magnitude of this interaction may be amplified. If both letermovir and cyclosporine must be continued, it is recommended that therapy with toremifene be interrupted. If interruption of treatment is not possible and all 3 drugs must be given together, patients should be closely monitored for prolongation of the QT interval. Toremifene is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In a drug interaction study, administration of toremifene with another strong CYP3A4 inhibitor increased toremifene maximum plasma concentration (Cmax) and exposure (AUC) by 1.4- and 2.9-fold, respectively. The Cmax and AUC of toremifene metabolite (N-demethyltoremifene) were reduced by 56% and 20%, respectively.
Trabectedin: (Moderate) An increase in the plasma concentration of trabectedin may occur if given with letermovir. Avoid coadministration in patients who are also receiving treatment with cyclosporine because the magnitude of this interaction may be amplified. Trabectedin is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In a drug interaction study, concurrent administration of trabectedin and another strong CYP3A inhibitor increased systemic exposure of trabectedin by 66%.
Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with letermovir is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of letermovir, a CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Tramadol; Acetaminophen: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with letermovir is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of letermovir, a CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Trandolapril; Verapamil: (Moderate) Plasma concentrations of verapamil are expected to be elevated when administered concurrently with letermovir. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. If these drugs are given together, closely monitor for verapamil-related adverse events. Verapamil is a CYP3A4 substrate. Letermovir is a moderate inhibitor of CYP3A4. However, when given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Clinically significant interactions with verapamil have been reported with other moderate and strong inhibitors of CYP3A4.
Trazodone: (Moderate) An increase in the plasma concentration of trazodone may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, consider reducing the trazodone dose based on tolerability and monitor for cardiac arrhythmias or other trazodone toxicities because the magnitude of this interaction may be amplified. Trazodone is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Triazolam: (Moderate) Monitor for signs of triazolam toxicity during triazolam coadministration with letermovir and consider appropriate dose reduction of triazolam if clinically indicated. Use together may increase triazolam exposure. Concurrent use is contraindicated if the patient is also receiving cyclosporine because the magnitude of the interaction may be amplified. Triazolam is a sensitive CYP3A substrate and letermovir is a moderate CYP3A inhibitor. Combining letermovir with cyclosporine will further increase the inhibitory effects. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Trofinetide: (Moderate) Monitor for an increase in letermovir-related adverse reactions if coadministration with trofinetide is necessary. Concomitant use may increase letermovir exposure. Letermovir is a substrate of OATP1B1/3; trofinetide is an OATP1B1/3 inhibitor.
Ubrogepant: (Major) Limit the initial dose of ubrogepant to 50 mg and avoid a second dose within 24 hours if coadministered with letermovir. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4 substrate; letermovir is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor resulted in a 3.5-fold increase in the exposure of ubrogepant.
Ulipristal: (Moderate) An increase in the plasma concentration of ulipristal may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Ulipristal is predominately metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In a drug interaction study, concurrent administration with another strong CYP3A4 inhibitor increased the maximum plasma concentration (Cmax) and exposure (AUC) of ulipristal by 2- and 5.9-fold, respectively; while the AUC of monodemethyl-ulipristal acetate increased by 2.4-fold and the Cmax decreased by 47%.
Umeclidinium; Vilanterol: (Moderate) An increase in the plasma concentration of vilanterol may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Monitor patients receiving vilanterol with both letermovir and cyclosporine for cardiovascular adverse effects (i.e., increased pulse, increased blood pressure, fast or irregular heartbeat). Vilanterol is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Valbenazine: (Moderate) Caution is advised when administering valbenazine with letermovir, as taking these drugs together may increase valbenazine concentration and risk for adverse events, such as QT prolongation. Reduce the valbenazine dose to 40 mg once per day in patients who are also receiving cyclosporine, because the magnitude of this interaction may be increased. Valbenazine is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Vardenafil: (Major) Do not use vardenafil orally disintegrating tablets with letermovir due to increased vardenafil exposure; do not exceed a single dose of 5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; letermovir is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the AUC of vardenafil by 4-fold.
Vemurafenib: (Moderate) Caution is advised when administering vemurafenib with letermovir. If the patient is also receiving cyclosporine, use of vemurafenib should be avoided. Administering letermovir with vemurafenib may increase vemurafenib concentration and risk for adverse events. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Vemurafenib is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Venetoclax: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with letermovir due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of letermovir. If the patient is also receiving cyclosporine, concurrent use is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity in patients receiving a steady daily dose of venetoclax if concurrent use with both letermovir and cyclosporine is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use of all 3 drugs. Resume the original dose of venetoclax 2 to 3 days after letermovir or letermovir and cyclosporine is discontinued. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies.
Venlafaxine: (Moderate) An increase in the plasma concentration of venlafaxine may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Venlafaxine is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Verapamil: (Moderate) Plasma concentrations of verapamil are expected to be elevated when administered concurrently with letermovir. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. If these drugs are given together, closely monitor for verapamil-related adverse events. Verapamil is a CYP3A4 substrate. Letermovir is a moderate inhibitor of CYP3A4. However, when given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Clinically significant interactions with verapamil have been reported with other moderate and strong inhibitors of CYP3A4.
Vilazodone: (Moderate) Administering letermovir with vilazodone may increase vilazodone concentration. Do not exceed a vilazodone dose of 20 mg daily in patients who are also receiving cyclosporine, because the magnitude of this interaction may be increased. The original vilazodone dose may be resumed if letermovir or cyclosporine is discontinued. Vilazodone is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect may be similar to a strong CYP3A4 inhibitor.
Vinblastine: (Moderate) Monitor for an earlier onset and/or increased severity of vinblastine-related adverse reactions, including myelosuppression, constipation, and peripheral neuropathy, if coadministration with letermovir is necessary; the magnitude of this interaction may be amplified in patients who are also receiving treatment with cyclosporine. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Enhanced vinblastine toxicity was reported with coadministration of another moderate CYP3A4 inhibitor.
Vincristine Liposomal: (Major) Avoid coadministration of letermovir and vincristine in patients additionally receiving cyclosporine due to increased plasma concentrations of vincristine. Vinorelbine is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor that may be administered with vincristine; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. An increase in plasma concentrations of vincristine may occur during concurrent administration with letermovir; in patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified.
Vincristine: (Major) Avoid coadministration of letermovir and vincristine in patients additionally receiving cyclosporine due to increased plasma concentrations of vincristine. Vinorelbine is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor that may be administered with vincristine; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. An increase in plasma concentrations of vincristine may occur during concurrent administration with letermovir; in patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified.
Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with letermovir is necessary; in patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Vinorelbine is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Voclosporin: (Major) Reduce the voclosporin dosage to 15.8 mg PO in the morning and 7.9 mg PO in the evening if coadministered with letermovir. Concomitant use may increase voclosporin exposure and the risk of voclosporin-related adverse effects such as nephrotoxicity, hypertension, and QT prolongation. Concomitant use may also increase letermovir exposure and adverse effects. Voclosporin is a sensitive CYP3A4 substrate and OATP1B1 inhibitor and letermovir is a moderate CYP3A4 inhibitor and OATP1B1 substrate. Coadministration with moderate CYP3A4 inhibitors is predicted to increase voclosporin exposure by 3-fold.
Vonoprazan; Amoxicillin; Clarithromycin: (Moderate) Administering clarithromycin concurrently with letermovir may result in elevated concentrations of both drugs. The impact on the serum concentration of clarithromycin may be increased in patients receiving letermovir with cyclosporine. Closely monitor for adverse events including tachycardia, atrial fibrillation, gastrointestinal events, dizziness, or confusion. Clarithromycin is an inhibitor of the organic anion-transporting polypeptides (OATP1B1/3), and a substrate of CYP3A4. Letermovir is an OATP1B1/3 substrate and a moderate CYP3A4 inhibitor. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In a drug interaction study, concurrent use with another CYP3A inhibitor increased clarithromycin exposure (AUC) by 94%, and decreased AUC of 14-OH clarithromycin by 70%.
Vorapaxar: (Moderate) Administering letermovir with vorapaxar may increase vorapaxar concentration. Avoid coadministration in patients who are also receiving treatment with cyclosporine, because the magnitude of this interaction may be amplified. Vorapaxar is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Voriconazole: (Major) Closely monitor for reduced voriconazole effectiveness and breakthrough fungal infections if coadministration with letermovir is necessary. Coadministration decreased the AUC and Cmax of voriconazole by 44% and 39%, respectively. Voriconazole is a substrate of CYP2C9 and CYP2C19. Letermovir is a CYP2C9 and CYP2C19 inducer.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with letermovir is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Letermovir is a moderate CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Zanubrutinib: (Major) Decrease the zanubrutinib dose to 80 mg PO twice daily if coadministered with letermovir. Decrease the zanubrutinib dose to 80 mg PO once daily in patients also receiving cyclosporine because the magnitude of the interaction may be increased. Coadministration may result in increased zanubrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Further decrease the zanubrutinib dose as recommended if adverse reactions occur. After discontinuation of letermovir, resume the previous dose of zanubrutinib. Zanubrutinib is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. The AUC of zanubrutinib is predicted to increase by 157% to 317% when coadministered with other moderate CYP3A4 inhibitors. The AUC of zanubrutinib was increased by 278% when coadministered with a strong CYP3A4 inhibitor.
Zavegepant: (Major) Avoid concomitant use of zavegepant and letermovir. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is an OATP1B3 substrate and letermovir is an OATP1B3 inhibitor. Concomitant use with another OATP1B3 inhibitor increased zavegepant overall exposure by 2.3-fold.
Ziprasidone: (Moderate) An increase in the plasma concentration of ziprasidone may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Ziprasidone is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent use of ziprasidone with a strong CYP3A4 inhibitor increased the AUC and Cmax of ziprasidone by 35% to 40%.
Zolpidem: (Moderate) Plasma concentrations and pharmacodynamic effect of zolpidem could be increased when administered concurrently with letermovir. Closely monitor for adverse events and consider zolpidem dose reductions if appropriate in patients also receiving cyclosporine because the magnitude of the interaction may increase. Zolpidem is primarily metabolized by CYP3A4. Letermovir is a moderate inhibitor of CYP3A4; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent use with a strong CYP3A4 inhibitor increased the zolpidem Cmax and AUC by 30% and 70%, respectively. In addition, concurrent use prolonged zolpidem half-life by 30% and increased the pharmacodynamic effects of zolpidem.

Prevymis Intravenous Inj: 1mL, 20mg
Prevymis Oral Tab: 240mg, 480mg

Adults

480 mg/day PO or IV.

Geriatric

480 mg/day PO or IV.

Adolescents

Safety and efficacy have not been established.

Children

Safety and efficacy have not been established.

Infants

Safety and efficacy have not been established.

Neonates

Safety and efficacy have not been established.

Letermovir is an antiviral that inhibits the cytomegalovirus (CMV) DNA terminase complex (pUL51, pUL56, pUL89) which is required for viral DNA processing and packaging. Letermovir affects the production of proper unit length genomes and interferes with virion maturation.
 
CMV mutants with reduced susceptibility to letermovir have been selected in cell culture with resistance mutations to UL51, UL56, and UL89. Specific resistance-associated substitutions were found in: pUL51 (P91S, A95V); pUL56 (C25F, S229F, V231A/L, N232Y, V236A/L/M, E237D, L241P, T244K/R, L254F, L257F/I, K258E, F261C/L/S, Y321C, C325F/R/W/Y, L328V, M329T, A365S, N368D, R369G/M/S); and pUL89 (N320H, D344E). The EC50 for viruses expressing these substitutions are 1.6- to 9,300-fold higher than those for wild-type viruses.
 
No antagonism of antiviral activity was demonstrated when letermovir was combined with CMV DNA polymerase inhibitors (cidofovir, foscarnet, or ganciclovir). Cross resistance is not likely with drugs outside this class. Letermovir is fully active against viral populations resistant to CMV DNA polymerase inhibitors and these DNA polymerase inhibitors are fully active against viral populations resistant to letermovir.

Letermovir is administered orally and intravenously. Once in systemic circulation, the drug has a volume of distribution of 45.5 L and is 99% protein-bound across the concentration range of 0.2 to 50 mg/L. The blood to plasma ratio is 0.56 across the concentration range of 0.1 to 10 mg/L. Letermovir is primarily eliminated from circulation by hepatic uptake via organic anion-transporting polypeptide 1B1/3 (OATP1B1/3) transporters. Metabolism via UDP-glucuronosyltransferase 1A1/3 (UGT1A1/1A3) is considered to be a minor elimination pathway, with 97% of the drug remaining unchanged and no major metabolites detected in the plasma. The majority of the drug is excreted in the feces (93%) with 70% excreted as unchanged drug. Less than 2% of letermovir is eliminated in the urine. The intravenous vehicle, hydroxypropyl betadex, is mainly eliminated by glomerular filtration. The mean terminal half-life is 12 hours.[62611]
 
Affected cytochrome P450 isoenzymes or transporters: OATP1B1/3, CYP3A, UGT1A1, CYP2C8, CYP2C9, CYP2C19, UGT1A3, CYP2D6, CYP 2B6, P-gp, BCRP, BSEP, MRP2, OAT3
Letermovir is a substrate of organic anion-transporting polypeptide 1B1/3 (OATP1B1/3) transporters. Inhibitors of OATP1B1/3 transporters may increase letermovir serum concentrations. The drug is also a substrate of UDP-glucuronosyltransferase 1A1/3 (UGT1A1/1A3) and P-glycoprotein (P-gp). Administration with inducers of UGT1A1/3 or P-gp is not recommended as concurrent administration may decrease letermovir plasma concentrations; however, changes in letermovir plasma concentrations due to inhibition of UGT1A1/3 or P-gp are not anticipated to be clinically relevant. In vitro studies suggest the letermovir is also a substrate of CYP3A and CYP2D6.[62611]
 
Letermovir is time-dependent inhibitor and inducer of CYP3A in vitro. Studies with midazolam resulted in increased exposure of midazolam, indicating a net effect of letermovir as a moderate inhibitor of CYP3A. Administration with CYP3A substrates may result in clinically relevant increases in serum concentrations of the substrates. Letermovir is a reversible inhibitor of CYP2C8 in vitro; plasma concentrations of CYP2C8 substrates are predicted to be increased if used concomitantly. Letermovir may also induce CYP2C9 and CYP2C19 as coadministration with voriconazole reduced the exposure of voriconazole. Substrates of these pathways may demonstrate decreased plasma concentrations when administered with letermovir. Letermovir is an inducer of CYP2B6 in vitro, but the clinical significance is unknown.[62611]
 
Letermovir is an inhibitor of OATP1B1/3 transporters and administration with OATP1B1/3 substrates may result in clinically relevant increases in serum concentrations of the substrates. Letermovir is also an in vitro inhibitor of efflux transporters P-gp, breast cancer resistance protein (BCRP), bile salt export pump (BSEP), multidrug resistance-associated protein 2 (MRP2), and OAT3. There were no clinically relevant changes on P-gp or OAT3 substrates in studies. The effect of letermovir on BCRP, BSEP, and MRP2 substrates was not evaluated and the clinical relevance is unknown.[62611]
 
The magnitude of CYP3A- and OATP1B1/3-mediated drug interactions may be different when letermovir is administered with cyclosporine. When letermovir and cyclosporine are coadministered with a CYP3A substrate, the combined effect may be similar to a strong CYP3A inhibitor.[62611]

Oral Route

In hematopoietic stem cell transplant (HSCT) and kidney transplant recipients, administration of letermovir with cyclosporine increases letermovir oral bioavailability and steady-state concentrations. The oral bioavailability of letermovir, when administered without cyclosporine, is 94% in healthy subjects (dose range 240 to 480 mg), 35% in HSCT recipients (480 mg), and 56% in kidney transplant recipients (480 mg); however, the bioavailability increases to 85% in HSCT recipients when given with cyclosporine (240 mg). The median time to maximum plasma concentration (Tmax) is 1.5 to 3 hours. The time to reach steady-state is 9 to 10 days. In HSCT recipients, the median steady-state concentration for a dose of 480 mg PO daily without cyclosporine is 34,400 ng x hour/mL compared to a median steady-state concentration of 60,800 ng x hour/mL for a dose of 240 mg PO daily with cyclosporine. In kidney transplant recipients, the median steady-state concentration for 480 mg PO daily without cyclosporine is 62,700 ng x hour/mL compared to a median steady-state concentration of 71,900 ng x hour/mL for 240 mg PO daily with cyclosporine. Food does not significantly alter the AUC (99.63%) or Cmax (129.82%) of letermovir.[62611]

Intravenous Route

In healthy subjects, the median steady-state AUC for a dose of 480 mg IV daily without cyclosporine is 100,000 ng x hour/mL compared to a median steady-state AUC of 70,300 ng x hour/mL for a dose of 240 mg PO daily with cyclosporine.

Pregnancy

There are no adequate and well-controlled studies of the use of letermovir during human pregnancy. Studies in animals showed embryo-fetal development toxicities at 11 times the human exposure at recommended doses, but no toxicity with doses that were not maternally toxic (up to 2 times higher than human exposure at recommended doses).

It is not known whether letermovir is present in human breast milk, affects human milk production, or has effects on the breastfed child. Letermovir was present in breast milk during animal studies. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.