letermovir (Rx)

Brand and Other Names:Prevymis
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

tablet

  • 240mg
  • 480mg

solution for injection

  • 20mg/mL (vials contain 240mg/12mL or 480mg/24mL)
  • Further dilution required

Cytomegalovirus Infection Prophylaxis

Indicated for prophylaxis of cytomegalovirus (CMV) infection and disease in adult CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT)

480 mg PO/IV qDay; initiate between Day 0 and Day 28 posttransplantation (before or after engraftment) and continue through Day 100

Following the completion of prophylaxis, monitoring for CMV reactivation recommended

Use IV only in patients unable to take oral therapy; switch to oral administration as soon as feasible

Tablet and injection may be used interchangeably at the discretion of the physician; no dosage adjustment is necessary when switching formulations

Also see Administration

Dosage Modifications

Coadministration with cyclosporine

  • Decrease letermovir dose to 240 mg/day if coadministered with cyclosporine (monitor cyclosporine levels)
  • If cyclosporine initiated after letermovir, decrease the next letermovir dose to 240 mg/day
  • If cyclosporine discontinued after starting letermovir, increase the next letermovir dose to 480 mg/day
  • If cyclosporine dosing is interrupted because of high cyclosporine levels, no dose adjustment of letermovir is needed

Renal impairment

  • CrCl >10 mL/min: No dosage adjustment required
  • CrCl ≤10 mL/min or patient on dialysis: Data are insufficient to make dosing recommendations
  • Hydroxypropyl betadex (IV vehicle) may accumulate if CrCl <50 mL/min; closely monitor serum creatinine levels in patients receiving IV letermovir

Hepatic impairment

  • Mild or moderate (Child-Pugh A or B): No dosage adjustment required
  • Severe (Child-Pugh C): Not recommended

<18 years: Safety and efficacy not established

No dosage adjustment is required based on age

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Interactions

Interaction Checker

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            Adverse Effects

            >10%

            Nausea (27%)

            Diarrhea (26%)

            Vomiting (19%)

            Peripheral edema (14%)

            Cough (14%)

            Headache (14%)

            Fatigue (13%)

            Abdominal pain (12%)

            Laboratory abnormalities with incidence greater than placebo

            • Platelets <25,000 cells/mcL 27% (placebo 21%)

            1-10%

            Tachycardia (4%)

            Atrial fibrillation (3%)

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            Warnings

            Contraindications

            Pimozide, ergot alkaloids (see Cautions)

            Pitavastatin or simvastatin when coadministered with cyclosporine (see Cautions)

            Cautions

            Coadministration of letermovir with certain drugs may result in potentially significant drug interactions, some of which may lead to adverse reactions or reduced therapeutic effect of either drug (see Contraindications)

            Drug interaction overview

            • Cyclosporine and letermovir may increase plasma concentrations of each other (see Dosage Modifications)
            • Contraindicated drug interactions
              • Pimozide: Coadministration with pimozide may result in increased concentrations of pimozide, owing to inhibition of CYP3A4 by letermovir, which may lead to QT prolongation and torsades de pointes
              • Ergot alkaloids: Coadministration with ergot alkaloids may result in increased concentrations of ergot alkaloids (ergotamine and dihydroergotamine), owing to inhibition of CYP3A by letermovir, which may lead to ergotism
              • Pitavastatin or simvastatin when coadministered with cyclosporine: Coadministration of letermovir in combination with cyclosporine may result in significantly increased pitavastatin or simvastatin concentrations, which may lead to myopathy or rhabdomyolysis
            • Potential for other drugs to affect letermovir
              • Letermovir is a substrate of CYP3A, CYP2D6, UGT1A1, and UGT1A3, and transporters OATP1B1/3 and P-gp; oxidative metabolism is considered to be a minor elimination pathway based on in vivo human data
              • Inhibitors of OATP1B1/3 may result in increases in letermovir plasma concentrations
              • Changes in letermovir plasma concentrations due to inhibition of P-gp or UGTs are not anticipated to be clinically relevant
            • Potential for letermovir to affect other drugs
              • Letermovir is a time-dependent inhibitor and inducer of CYP3A in vitro; drug interaction studies showed a net effect of letermovir on CYP3A is moderate inhibition
              • Letermovir is a reversible inhibitor of CYP2C8 in vitro; if coadministered, plasma concentrations of CYP2C8 substrates are predicted to increase
              • Letermovir induces CYP2C9 and CYP2C19; if coadministered, plasma concentrations of CYP2C9 and CYP2C19 substrates may decrease
              • Letermovir induces CYP2B6 in vitro; clinical relevance unknown
              • Letermovir inhibits efflux transporters P-gp, breast cancer resistance protein (BCRP), bile salt export pump (BSEP), multidrug resistance-associated protein 2 (MRP2), OAT3, and hepatic uptake transporter OATP1B1/3 in vitro; coadministration with substrates of OATP1B1/3 transporters (eg, atorvastatin, a known substrate of CYP3A, OATP1B1/3, and potentially BCRP) may result in a clinically relevant increase in plasma concentrations of OATP1B1/3 substrates
              • Note: There were no clinically relevant changes in plasma concentrations of digoxin, a P-gp substrate, or acyclovir, an OAT3 substrate
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            Pregnancy & Lactation

            Pregnancy

            No data are available regarding use in pregnant women

            In animal reproduction studies, embryo-fetal developmental toxicity (including fetal malformations) was observed in rats during the period of organogenesis at letermovir exposures (AUC) 11 times higher than human exposure at the recommended human dose (RHD); in rabbits, no embryo-fetal developmental toxicity was noted at exposures that were not maternally toxic (up to letermovir exposures 2 times higher than human exposure at the RHD)

            Infertility: No data are available on the effect of letermovir on human fertility; decreased fertility due to testicular toxicity observed in male rats

            Lactation

            Unknown if present in human breast milk, affects human milk production, or has effects on the breastfed child

            When administered to lactating rats, letermovir was present in the milk of lactating rats as well as the blood of nursing pups

            The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for the drug and any potential adverse effects on the breastfed child or from the underlying maternal condition

            Pregnancy Categories

            A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA:Information not available.

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            Pharmacology

            Mechanism of Action

            Antiviral drug against CMV; inhibits the CMV DNA terminase complex (pUL51, pUL56, and pUL89), which is required for viral DNA processing and packaging by affecting the production of proper unit length genomes and interfering with virion maturation

            Absorption

            Peak plasma time, PO: 0.75-2.25 hr

            Peak plasma concentration, 480 mg/day PO: 13,000 ng/mL

            Time to steady-state: 9-10 days

            Bioavailability

            • Healthy subjects, no cyclosporine: 94%
            • HSCT recipients, no cyclosporine: 35% (480 mg/day)
            • HSCT recipients, with cyclosporine: 85% (240 mg/day)

            AUC

            • Accumulation ratio: 1.22
            • HSCT recipients
              • 480 mg/day PO, no cyclosporine: 34,400 ng·hr/mL
              • 480 mg/day IV, no cyclosporine: 100,000 ng·hr/mL
              • 240 mg/day PO, with cyclosporine: 60,800 ng·hr/mL
              • 240 mg/day IV, with cyclosporine: 70,300 ng·hr/mL
            • Healthy subjects
              • 480 mg PO/day: 71,500 ng·hr/mL

            Distribution

            Vd, HSCT recipients (IV): 45.5 L

            Protein bound: 99% across concentration range of 0.2-50 mg/L

            Blood-to-plasma ratio: 0.56 across concentration range of 0.1-10 mg/L

            Metabolism

            UGT1A1/1A3 (minor)

            CYP3A, CYP2D6 (minor)

            Elimination

            Route: Hepatic uptake (OATP1B1/3)

            Half-life: 12 hr (480 mg/day IV)

            Excretion: 93% feces (70% unchanged); <2% urine

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            Administration

            Oral Administration

            May take with or without food

            Swallow tablets whole; do not crush or chew

            IV Compatibilities

            0.9% NaCl

            D5W

            Compatible drugs when letermovir prepared with 0.9% NaCl

            • Ampicillin sodium, ampicillin sodium/sulbactam sodium, antithymocyte globulin, caspofungin, daptomycin, fentanyl citrate, fluconazole, furosemide, human insulin, magnesium sulfate, methotrexate, micafungin

            Compatible drugs when letermovir prepared with D5W

            • Amphotericin B (lipid complex)*, anidulafungin, cefazolin sodium, ceftaroline, ceftriaxone sodium, doripenem, famotidine, folic acid, ganciclovir sodium, hydrocortisone sodium succinate, morphine sulfate, norepinephrine bitartrate, pantoprazole sodium, potassium chloride, potassium phosphate, tacrolimus, telavancin, tigecycline
            • *Amphotericin B (lipid complex; Abelcet) is compatible with letermovir; however, amphotericin B (liposomal; AmBisome) is incompatible

            Compatible IV bags

            • Polyvinyl chloride (PVC), ethylene vinyl acetate (EVA), and polyolefin (polypropylene and polyethylene)

            Compatible infusion sets

            • PVC, polyethylene (PE), polybutadiene (PBD), silicone rubber (SR), styrene–butadiene copolymer (SBC), styrene-butadiene-styrene copolymer (SBS), polystyrene (PS)

            Compatible plasticizers

            • Diethylhexyl phthalate (DEHP), tris (2-ethylhexyl) trimellitate (TOTM), benzyl butyl phthalate (BBP)

            Compatible catheters

            • Radiopaque polyurethane

            IV Incompatibilities

            Amiodarone, amphotericin B (liposomal), aztreonam, cefepime hydrochloride, ciprofloxacin, cyclosporine, diltiazem hydrochloride, filgrastim, gentamicin sulfate, levofloxacin, linezolid, lorazepam, midazolam HCl, mycophenolate mofetil hydrochloride, ondansetron, palonosetron

            IV Preparation

            Vials are for single use only; discard any unused portion

            Letermovir solution must be further diluted before IV administration

            Inspect vial contents for discoloration and particulate matter before dilution; should appear as a clear, colorless solution

            Do not use the vial if the solution is discolored or contains visible particles

            Do not shake vial

            Add one single-dose vial into a 250-mL prefilled IV bag containing either 0.9% NaCl or D5W; mix bag gently, do not shake

            Use compatible IV bags and infusion set materials (see IV Compatibilities); note that letermovir is not recommended for use with polyurethane-containing IV administration set tubing

            Once diluted, the solution is clear and ranges from colorless to yellow; variations of color within this range do not affect the quality of the product

            Inspect visually for particulate matter and discoloration before administration, whenever solution and container permit

            Discard if discoloration or visible particles are observed

            IV Administration

            Administer the entire contents of the IV bag by IV infusion via a peripheral catheter or central venous line at a constant rate over 1 hr

            Do not administer as IV bolus

            Storage

            Tablets

            • Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F)
            • Store in original package until use

            Solution for injection

            • Unopened vials
              • Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F)
              • Store in the original carton to protect from light
            • Diluted IV solution
              • Room temperature (20-25°C [68-77°F]): Stable for up to 24 hr
              • Refrigerated (2-8°C [36-46°F]): Stable for up to 48 hr
              • Note: These times includes storage of the diluted solution in the IV bag through the duration of infusion
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            Formulary

            FormularyPatient Discounts

            Adding plans allows you to compare formulary status to other drugs in the same class.

            To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

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            • View the formulary and any restrictions for each plan.
            • Manage and view all your plans together – even plans in different states.
            • Compare formulary status to other drugs in the same class.
            • Access your plan list on any device – mobile or desktop.

            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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