Introduction

Antiviral; DNA terminase complex inhibitor active against cytomegalovirus (CMV).

Uses for Letermovir

Prevention of CMV Infection and Disease

Prophylaxis to prevent CMV infection and disease in adult CMV-seropositive recipients (R⁺) of an allogeneic hematopoietic stem cell transplant (HSCT). Designated an orphan drug by FDA for prevention of CMV viremia and disease in at-risk populations.

Letermovir Dosage and Administration

Administration

Administer orally or by IV infusion.

Use IV letermovir only in patients unable to receive the drug orally. In those receiving IV letermovir, switch to oral tablet as soon as patient is able to receive oral drugs.

Oral Administration

Administer orally without regard to food. Swallow tablet whole.

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by IV infusion through peripheral catheter or central venous line. Do not administer by rapid IV injection.

Available as preservative-free, sterile concentrate for injection that must be diluted prior to IV infusion.

Dilution

The concentrate should appear clear and colorless; do not use if it appears discolored or contains particles.

To prepare a 240- or 480- mg dose, withdraw entire contents of single-dose vial containing 240 or 480 mg, respectively, and add to a 250-mL prefilled IV bag containing either 0.9% sodium chloride injection or 5% dextrose injection. Mix gently; do not shake.

Diluted solution should appear clear and may range from colorless to yellow in color; discard if it contains particles.

Letermovir is compatible only with 0.9% sodium chloride or 5% dextrose; do not dilute using any other infusion fluids.

Must be used with compatible IV bag materials, infusion set materials, plasticizers, and catheters.

Compatible IV bag materials: Polyvinyl chloride (PVC), ethylene vinyl acetate (EVA), polyolefin (polypropylene and polyethylene).

Compatible infusion set materials: PVC, polyethylene (PE), polybutadiene (PBD), silicone rubber (SR), styrene-butadiene copolymer (SBC), styrene-butadiene-styrene copolymer (SBS), polystyrene (PS). Use with polyurethane-containing IV administration set tubing not recommended.

Compatible plasticizers: Diethylhexyl phthalate (DEHP), tris [2-ethylhexyl] trimelliatate (TOTM), benzyl butyl phthalate (BBP).

Compatible catheters: Radiopaque polyurethane.

Rate of Administration

Administer by IV infusion over 1 hour.

Dosage

Adults

Prevention of CMV Infection and Disease

CMV-seropositive Allogeneic HSCT Recipients

480 mg once daily.

Initiate within 28 days after HSCT (before or after engraftment) and continue through day 100 posttransplantation. Monitor for CMV reactivation after letermovir discontinued.

CMV-seropositive Allogeneic HSCT Recipients Receiving Cyclosporine

240 mg once daily.

If cyclosporine initiated in patient receiving letermovir 480 mg once daily, decrease letermovir dosage to 240 mg once daily.

If cyclosporine discontinued in patient receiving letermovir 240 mg once daily, increase letermovir dosage to 480 mg once daily.

If cyclosporine regimen interrupted due to high cyclosporine plasma concentrations in a patient receiving letermovir 240 mg once daily, continue same letermovir dosage.

Special Populations

Hepatic Impairment

Oral or IV

Mild or moderate hepatic impairment (Child-Pugh class A or B): Dosage adjustments not needed based on hepatic function.

Severe hepatic impairment (Child-Pugh class C): Not recommended.

Renal Impairment

Oral or IV

Cl_cr >10 mL/minute: Dosage adjustments not needed based on renal function.

End-stage renal disease (Cl_cr ≤10 mL/minute), including those receiving dialysis: Data insufficient to make dosage recommendations; safety not known.

IV

Cl_cr <50 mL/minute: Accumulation of the IV vehicle (i.e., hydroxypropyl betadex) may occur. (See Renal Impairment under Cautions.)

Geriatric Patients

Dosage adjustments based on age not needed.

Contraindications

• Concomitant use with pimozide or ergot alkaloids. (See Interactions.)

• Concomitant use with pitavastatin or simvastatin in patients also receiving concomitant cyclosporine. (See Interactions.)

Warnings/Precautions

Interactions

Concomitant use with certain drugs may result in clinically important drug interactions, which could lead to adverse effects or reduced therapeutic effect of letermovir or concomitant drugs. (See Interactions.)

Consider potential for drug interactions prior to and during therapy. Review concomitant drugs and monitor for adverse effects associated with letermovir and concomitant drugs.

Specific Populations

Pregnancy

No adequate human data to assess if letermovir adversely affects pregnancy outcomes.

In animal studies, embryofetal developmental toxicity (including fetal malformations) observed in rats during organogenesis. No embryofetal developmental toxicity observed in rabbits at exposures that were not maternally toxic. In a rat pre- and post-natal development study, total litter loss observed at maternal letermovir exposures approximately twofold higher than human exposures at recommended human dosage.

Lactation

Distributed into milk in lactating rats and present in blood of nursing pups.

Not known if distributed into human milk, affects milk production, or affects breast-fed child.

Consider developmental and health benefits of breast-feeding along with the mother's clinical need for the drug and potential adverse effects on the breast-fed child from letermovir or the underlying maternal condition.

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age. Pharmacokinetics not evaluated in pediatric patients.

Geriatric Use

Safety and efficacy similar between older and younger adults.

Data indicate age (18–78 years of age) does not have a clinically important effect on pharmacokinetics. Dosage adjustments based on age not needed.

Hepatic Impairment

Not recommended in patients with severe hepatic impairment (Child-Pugh class C).

Dosage adjustments not needed in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).

Renal Impairment

Safety in patients with end-stage renal disease (Cl_cr ≤10 mL/minute), including those receiving dialysis, not known. Dosage adjustments not needed in patients with Cl_cr >10 mL/minute.

If IV letermovir used in patients with Cl_cr <50 mL/minute, closely monitor S_cr concentrations; accumulation of IV vehicle (i.e., hydroxypropyl betadex) could occur.

Common Adverse Effects

Nausea, diarrhea, vomiting, peripheral edema, cough, headache, fatigue, abdominal pain.

Administration

Administer orally or by IV infusion.

Use IV letermovir only in patients unable to receive the drug orally. In those receiving IV letermovir, switch to oral tablet as soon as patient is able to receive oral drugs.

Oral Administration

Administer orally without regard to food. Swallow tablet whole.

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by IV infusion through peripheral catheter or central venous line. Do not administer by rapid IV injection.

Available as preservative-free, sterile concentrate for injection that must be diluted prior to IV infusion.

Dilution

The concentrate should appear clear and colorless; do not use if it appears discolored or contains particles.

To prepare a 240- or 480- mg dose, withdraw entire contents of single-dose vial containing 240 or 480 mg, respectively, and add to a 250-mL prefilled IV bag containing either 0.9% sodium chloride injection or 5% dextrose injection. Mix gently; do not shake.

Diluted solution should appear clear and may range from colorless to yellow in color; discard if it contains particles.

Letermovir is compatible only with 0.9% sodium chloride or 5% dextrose; do not dilute using any other infusion fluids.

Must be used with compatible IV bag materials, infusion set materials, plasticizers, and catheters.

Compatible IV bag materials: Polyvinyl chloride (PVC), ethylene vinyl acetate (EVA), polyolefin (polypropylene and polyethylene).

Compatible infusion set materials: PVC, polyethylene (PE), polybutadiene (PBD), silicone rubber (SR), styrene-butadiene copolymer (SBC), styrene-butadiene-styrene copolymer (SBS), polystyrene (PS). Use with polyurethane-containing IV administration set tubing not recommended.

Compatible plasticizers: Diethylhexyl phthalate (DEHP), tris [2-ethylhexyl] trimelliatate (TOTM), benzyl butyl phthalate (BBP).

Compatible catheters: Radiopaque polyurethane.

Rate of Administration

Administer by IV infusion over 1 hour.

Dosage

Adults

Prevention of CMV Infection and Disease

CMV-seropositive Allogeneic HSCT Recipients

480 mg once daily.

Initiate within 28 days after HSCT (before or after engraftment) and continue through day 100 posttransplantation. Monitor for CMV reactivation after letermovir discontinued.

CMV-seropositive Allogeneic HSCT Recipients Receiving Cyclosporine

240 mg once daily.

If cyclosporine initiated in patient receiving letermovir 480 mg once daily, decrease letermovir dosage to 240 mg once daily.

If cyclosporine discontinued in patient receiving letermovir 240 mg once daily, increase letermovir dosage to 480 mg once daily.

If cyclosporine regimen interrupted due to high cyclosporine plasma concentrations in a patient receiving letermovir 240 mg once daily, continue same letermovir dosage.

Special Populations

Hepatic Impairment

Oral or IV

Mild or moderate hepatic impairment (Child-Pugh class A or B): Dosage adjustments not needed based on hepatic function.

Severe hepatic impairment (Child-Pugh class C): Not recommended.

Renal Impairment

Oral or IV

Cl_cr >10 mL/minute: Dosage adjustments not needed based on renal function.

End-stage renal disease (Cl_cr ≤10 mL/minute), including those receiving dialysis: Data insufficient to make dosage recommendations; safety not known.

IV

Cl_cr <50 mL/minute: Accumulation of the IV vehicle (i.e., hydroxypropyl betadex) may occur. (See Renal Impairment under Cautions.)

Geriatric Patients

Dosage adjustments based on age not needed.

Substrate of CYP3A and 2D6. Moderate inhibitor of CYP3A; also induces CYP3A. Reversible inhibitor of CYP2C8. Expected to induce CYP2C9 and 2C19. Not metabolized by CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2E1, or 4A11; does not inhibit CYP1A2, 2A6, 2C9, 2C19, 2D6, or 2E1; and does not induce CYP1A2.

Substrate of organic anion transporter polypeptide (OATP) 1B1 and 1B3. Inhibits OATP1B1, 1B3, and renal organic anion transporter (OAT) 3; does not inhibit OAT2B1 or OAT1. Transport not mediated by OATP2B1 or OAT1.

Metabolized by UGT1A1 and 1A3 to a minor extent. Not metabolized by UGT1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B15, or 2B17; does not inhibit UGT1A4, 1A6, 1A9, or 2B7.

Substrate and inhibitor of P-glycoprotein (P-gp) transport.

Inhibits breast cancer resistance protein (BCRP), bile salt export pump (BSEP), and multidrug resistance-associated protein (MRP) 2. Does not inhibit renal organic cation transporter (OCT) 1 or 2 and is not transported by OCT1, BCRP, or MRP2.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

CYP3A substrates: Clinically important increased concentrations of such substrates may occur. Magnitude of CYP3A-mediated drug interactions may be different when letermovir used concomitantly with cyclosporine.

CYP2C8 substrates: Possible increased concentrations of such substrates.

CYP2C9 or 2C19 substrates: Possible decreased concentrations of such substrates.

Drugs Affecting or Affected by Organic Anion Transporters

OATP1B1 or 1B3 inhibitors: Possible increased letermovir concentrations.

OATP1B1 or 1B3 substrates: Clinically important increased concentrations of such substrates may occur. Magnitude of OATP1B1- or 1B3-mediated drug interactions may be different when letermovir used concomitantly with cyclosporine.

Drugs Affecting or Metabolized by UGT

UGT inhibitors: Clinically important changes in letermovir concentrations not expected.

Drugs Affected by P-glycoprotein Transport

P-gp inhibitors: Clinically important changes in letermovir concentrations not expected.

Drugs Affecting or Affected by Other Membrane Transporters

BCRP, BSEP, and MRP2 substrates: Concomitant use not evaluated; clinical effect of letermovir on such substrates not known.

Specific Drugs