Letermovir

Brand names: Prevymis
Drug class: Antineoplastic Agents , Antineoplastic Agents

Usage of 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.

Relate drugs

How to use Letermovir

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 Oral or IV

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 Oral or IV

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

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

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

IV

Clcr <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.

Warnings

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 (Clcr ≤10 mL/minute), including those receiving dialysis, not known. Dosage adjustments not needed in patients with Clcr >10 mL/minute.

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

    Common Adverse Effects

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

    What other drugs will affect Letermovir

    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

    Drug

    Interaction

    Comments

    Antiarrhythmic agents (amiodarone, quinidine)

    Amiodarone: Increased amiodarone concentrations expected

    Quinidine: Increased quinidine concentrations expected; magnitude of interaction may be different if cyclosporine also used concomitantly

    Amiodarone: If used concomitantly, closely monitor for amiodarone-associated adverse effects; frequently monitor amiodarone concentrations

    Quinidine: If patient receiving letermovir and cyclosporine, also consider interactions between cyclosporine and quinidine

    Anticonvulsants (phenytoin)

    Phenytoin: Decreased phenytoin concentrations expected

    Phenytoin: Frequently monitor phenytoin concentrations

    Antidiabetic agents (glyburide, repaglinide, rosiglitazone)

    Glyburide, repaglinide, rosiglitazone: Increased concentrations of antidiabetic agent expected

    Glyburide, rosiglitazone: Frequently monitor glucose concentrations

    Repaglinide: Frequently monitor glucose concentrations; if patient receiving letermovir and cyclosporine, concomitant use with repaglinide not recommended

    Antifungal agents (fluconazole, posaconazole, voriconazole)

    Fluconazole: No clinically important pharmacokinetic interactions

    Posaconazole: No clinically important pharmacokinetic interactions

    Voriconazole: Decreased voriconazole concentrations and AUC

    Voriconazole: If concomitant use required, closely monitor for reduced voriconazole efficacy

    Antimycobacterial agents (rifampin)

    Rifampin: Decreased letermovir concentrations expected

    Rifampin: Concomitant use with letermovir not recommended

    Antiviral agents (acyclovir, cidofovir, foscarnet, ganciclovir)

    Acyclovir, cidofovir, foscarnet, ganciclovir: No in vitro evidence of antagonistic anti-CMV effects with letermovir

    Acyclovir: No clinically important pharmacokinetic interactions

    Digoxin

    No clinically important pharmacokinetic interactions

    Ergot alkaloids (ergotamine, dihydroergotamine)

    Ergotamine, dihydroergotamine: Increased concentrations of the ergot alkaloid expected due to inhibition of CYP3A by letermovir; may lead to ergotism

    Ergotamine, dihydroergotamine: Concomitant use with letermovir contraindicated

    Estrogens and progestins (ethinyl estradiol or levonorgestrel)

    Ethinyl estradiol or levonorgestrel: No clinically important pharmacokinetic interactions

    HMG-CoA reductase inhibitors (statins)

    Atorvastatin: Increased atorvastatin AUC and peak plasma concentrations

    Fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin: Increased concentrations of the statin expected

    Atorvastatin: Do not exceed atorvastatin dosage of 20 mg daily and closely monitor for myopathy and rhabdomyolysis; in patient receiving letermovir and cyclosporine, concomitant use with atorvastatin not recommended

    Fluvastatin, pravastatin, rosuvastatin: Dosage reduction of the statin may be required; closely monitor for myopathy and rhabdomyolysis

    Lovastatin: Dosage reduction of lovastatin may be required; closely monitor for myopathy and rhabdomyolysis; in patients receiving letermovir and cyclosporine, concomitant use with lovastatin not recommended

    Pitavastatin, simvastatin: Concomitant use not recommended; in patients receiving letermovir and cyclosporine, concomitant use with pitavastatin or simvastatin contraindicated

    Immunosuppressive agents (cyclosporine, mycophenolate mofetil, sirolimus, tacrolimus)

    Cyclosporine: Increased letermovir AUC and peak plasma concentrations; increased cyclosporine AUC, but no substantial effect on cyclosporine peak plasma concentrations

    Mycophenolate mofetil: No clinically important pharmacokinetic interactions

    Sirolimus: Increased sirolimus AUC and peak plasma concentrations

    Tacrolimus: No substantial effect on letermovir exposures; increased tacrolimus AUC and peak plasma concentrations

    Cyclosporine: Decrease letermovir dosage to 240 mg once daily; during concomitant use and after letermovir discontinued, frequently monitor cyclosporine whole blood concentrations and adjust cyclosporine dosage accordingly

    Sirolimus, tacrolimus: During concomitant use and after letermovir discontinued, frequently monitor immunosuppressive agent whole blood concentrations and adjust dosage accordingly

    Midazolam

    Increased midazolam AUC; magnitude of interaction may be different if patient receiving letermovir and cyclosporine

    If patient receiving letermovir and cyclosporine, also consider interactions between cyclosporine and midazolam

    Opiate agonists (alfentanil, fentanyl)

    Alfentanil, fentanyl: Increased concentrations of the opiate agonist expected; magnitude of interaction may be different if cyclosporine also used concomitantly

    Alfentanil, fentanyl: If patient receiving letermovir and cyclosporine, also consider interactions between cyclosporine and the opiate agonist

    Pimozide

    Increased pimozide concentrations expected due to inhibition of CYP3A by letermovir; may lead to QT interval prolongation and torsades de pointes

    Concomitant use with letermovir contraindicated

    Proton-pump inhibitors (omeprazole, pantoprazole)

    Omeprazole, pantoprazole: Decreased proton-pump inhibitor exposures expected

    Omeprazole, pantoprazole: Clinically monitor and adjust dosage of proton-pump inhibitor if needed

    Warfarin

    Decreased warfarin concentrations expected

    Frequently monitor INR

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