Letermovir: Difference between revisions

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|genericName=generic name
|genericName=generic name
|aOrAn=a
|aOrAn=a
|drugClass=Acetylcholine release inhibitor, Adrenergic receptor agonist
|drugClass= [[antiviral]] drug
|indicationType=(type of indication of drug)
|indicationType= [[prophylaxis]]
|indication=a list of indications, separated by commas.
|indication= [[cytomegalovirus]] (CMV) [[infection]] and [[disease]] in adult [[CMV]]-[[seropositive]] recipients [R+] of an [[allogeneic]] [[hematopoietic]] [[stem cell transplant]] ([[HSCT]])
|adverseReactions=a list of adverse reactions, separated by commas.
|adverseReactions= [[nausea]], [[diarrhea]], [[vomiting]], [[peripheral edema]], [[cough]], [[headache]], [[fatigue]], and [[abdominal pain]]
|fdaLIADAdult======Condition 1=====
|fdaLIADAdult=
 
=====Indication=====
* Dosing Information
*PREVYMIS™ is indicated for prophylaxis of cytomegalovirus (CMV) infection and disease in adult CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT).
 
=====Recommended Dosage for Adult Patients=====
:* (Dosage)
*The recommended dosage of PREVYMIS is 480 mg administered orally or intravenously once daily. Initiate PREVYMIS between Day 0 and Day 28 post-transplantation (before or after engraftment), and continue through Day 100 post-transplantation. Dosage of PREVYMIS should be adjusted when co-administered with cyclosporine.
 
*PREVYMIS injection, which contains hydroxypropyl betadex, should be used only in patients unable to take oral therapy. Patients should be switched to oral PREVYMIS as soon as they are able to take oral medications. PREVYMIS tablet and injection may be used interchangeably at the discretion of the physician, and no dosage adjustment is necessary when switching formulations.
=====Condition 2=====
=====Dosage Adjustment When Co-administered with Cyclosporine=====
 
*If oral or intravenous PREVYMIS is co-administered with cyclosporine, the dosage of PREVYMIS should be decreased to 240 mg once daily.
* Dosing Information
*If cyclosporine is initiated after starting PREVYMIS, the next dose of PREVYMIS should be decreased to 240 mg once daily.
 
*If cyclosporine is discontinued after starting PREVYMIS, the next dose of PREVYMIS should be increased to 480 mg once daily.
:* (Dosage)
*If cyclosporine dosing is interrupted due to high cyclosporine levels, no dose adjustment of PREVYMIS is needed.
|offLabelAdultGuideSupport======Condition 1=====
=====Use in Patients with Renal Impairment=====
 
*For patients with creatinine clearance (CLcr) greater than 10 mL/min, no dosage adjustment of PREVYMIS is required based on renal impairment.
* Developed by: (Organisation)
*There are insufficient data in patients with CLcr 10 mL/min or less or in patients on dialysis to make PREVYMIS dosing recommendations.
 
*In patients with CLcr less than 50 mL/min receiving PREVYMIS injection, accumulation of the intravenous vehicle, hydroxypropyl betadex, may occur. Closely monitor serum creatinine levels in these patients.
* Class of Recommendation: (Class) (Link)
=====Use in Patients with Hepatic Impairment=====
 
*No dosage adjustment of PREVYMIS is required for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. PREVYMIS is not recommended for patients with severe (Child-Pugh Class C) hepatic impairment.
* Strength of Evidence: (Category A/B/C) (Link)
=====Dosage Forms and Strengths=====
 
*Tablets
* Dosing Information/Recommendation
:*PREVYMIS 240 mg tablet: yellow oval tablet with "591" on one side and Merck logo on the other side.
 
:*PREVYMIS 480 mg tablet: pink oval, bi-convex tablet with "595" on one side and Merck logo on the other side.
:* (Dosage)
*Injection
 
:*PREVYMIS 240 mg/12 mL (20 mg/mL) injection: clear solution in a single-dose vial.
=====Condition 2=====
:*PREVYMIS 480 mg/24 mL (20 mg/mL) injection: clear solution in a single-dose vial.
 
|offLabelAdultGuideSupport=
* Developed by: (Organisation)
There is limited information regarding letermovir Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
 
|offLabelAdultNoGuideSupport=
* Class of Recommendation: (Class) (Link)
There is limited information regarding letermovir Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
 
|fdaLIADPed=
* Strength of Evidence: (Category A/B/C) (Link)
|offLabelPedGuideSupport=
 
There is limited information regarding letermovir Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
* Dosing Information/Recommendation
|offLabelPedNoGuideSupport=
 
There is limited information regarding letermovir Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
:* (Dosage)
|contraindications=
|offLabelAdultNoGuideSupport======Condition 1=====
*PREVYMIS is contraindicated in patients receiving pimozide or ergot alkaloids:
 
:*Pimozide: Concomitant administration of PREVYMIS in patients receiving pimozide may result in increased concentrations of pimozide due to inhibition of cytochrome P450 3A (CYP3A) by letermovir, which may lead to QT prolongation and torsades de pointes.
* Dosing Information
:*Ergot alkaloids: Concomitant administration of PREVYMIS in patients receiving ergot alkaloids may result in increased concentrations of ergot alkaloids (ergotamine and dihydroergotamine) due to inhibition of CYP3A by letermovir, which may lead to ergotism [see WARNINGS AND PRECAUTIONS (5.1) and DRUG INTERACTIONS (7.2, 7.3)].
 
*PREVYMIS is contraindicated with pitavastatin and simvastatin when co-administered with cyclosporine. Concomitant administration of PREVYMIS in combination with cyclosporine may result in significantly increased pitavastatin or simvastatin concentrations, which may lead to myopathy or rhabdomyolysis
:* (Dosage)
|warnings=
 
=====Risk of Adverse Reactions or Reduced Therapeutic Effect Due to Drug Interactions=====
=====Condition 2=====
*The concomitant use of PREVYMIS and certain drugs may result in potentially significant drug interactions, some of which may lead to adverse reactions (PREVYMIS or concomitant drugs) or reduced therapeutic effect of PREVYMIS or the concomitant drug.
 
*See TABLE 3 for steps to prevent or manage these possible or known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during PREVYMIS therapy; review concomitant medications during PREVYMIS therapy; and monitor for adverse reactions associated with PREVYMIS and concomitant medications.
* Dosing Information
 
:* (Dosage)
 
=====Condition 3=====
 
* Dosing Information
 
:* (Dosage)
|fdaLIADPed======Condition 1=====
 
* Dosing Information
 
:* (Dosage)
 
=====Condition 2=====
 
* Dosing Information
 
:* (Dosage)
|offLabelPedGuideSupport======Condition 1=====
 
* Developed by: (Organisation)
 
* Class of Recommendation: (Class) (Link)
 
* Strength of Evidence: (Category A/B/C) (Link)
 
* Dosing Information/Recommendation
 
:* (Dosage)
 
=====Condition 2=====
 
* Developed by: (Organisation)
 
* Class of Recommendation: (Class) (Link)
 
* Strength of Evidence: (Category A/B/C) (Link)
 
* Dosing Information/Recommendation
 
:* (Dosage)
|offLabelPedNoGuideSupport======Condition 1=====
 
* Dosing Information
 
:* (Dosage)
 
=====Condition 2=====
 
* Dosing Information
 
:* (Dosage)
 
=====Condition 3=====
 
* Dosing Information
 
:* (Dosage)
|contraindications=CONTRAINDICATIONS
|warnings======Conidition 1=====
 
(Description)
 
=====Conidition 2=====
 
(Description)
 
=====Conidition 3=====
 
(Description)
|clinicalTrials=
|clinicalTrials=
*Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
=====Adult CMV-seropositive Recipients [R+] of an Allogeneic HSCT=====
*The safety of PREVYMIS was evaluated in one Phase 3 randomized, double-blind, placebo-controlled trial (P001) in which 565 subjects were randomized and treated with PREVYMIS (N=373) or placebo (N=192) through Week 14 post-transplant. Adverse events were those reported while subjects were on study medication or within two weeks of study medication completion/discontinuation. The mean time for reporting adverse events and laboratory abnormalities was approximately 22% longer in the PREVYMIS arm compared to the placebo arm.
=====Cardiac Adverse Events:=====
*The cardiac adverse event rate (regardless of investigator-assessed causality) was higher in subjects receiving PREVYMIS (13%) compared to subjects receiving placebo (6%). The most common cardiac adverse events were tachycardia (reported in 4% of PREVYMIS subjects and in 2% of placebo subjects) and atrial fibrillation (reported in 3% of PREVYMIS subjects and in 1% of placebo subjects). Among those subjects who experienced one or more cardiac adverse events, 85% of PREVYMIS and 92% of placebo subjects had events reported as mild or moderate in severity.
=====Common Adverse Events=====
*The rate of adverse events occurring in at least 10% of subjects in the PREVYMIS group and at a frequency at least 2% greater than placebo are outlined in Table 1.
[[image:letermovirclinexp1.png|none|thumb|400px|This image is provided by the National Library of Medicine.]]
*Overall, similar proportions of subjects in each group discontinued study medication due to an adverse event (13% of PREVYMIS subjects vs. 12% of placebo subjects). The most frequently reported adverse event that led to study drug discontinuation was nausea, occurring in 2% of PREVYMIS subjects and 1% of placebo subjects. Hypersensitivity reaction, with associated moderate dyspnea, occurred in one subject following the first infusion of IV PREVYMIS after switching from oral PREVYMIS, leading to treatment discontinuation.
''Laboratory Abnormalities''
*Selected laboratory abnormalities reported during treatment or within 2 weeks of stopping treatment are presented in the table below.
[[image:letermovirclinexp2.png|none|thumb|400px|This image is provided by the National Library of Medicine.]]
*The median time to engraftment (defined as absolute neutrophil count ≥ 500/mm3 on 3 consecutive days after transplantation) was 19 days in the PREVYMIS group and 18 days in the placebo group.
|postmarketing=
|postmarketing=
|drugInteractions=
|drugInteractions=

Revision as of 14:58, 18 July 2018

Letermovir
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sonya Gelfand

Disclaimer

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Overview

Letermovir is a antiviral drug that is FDA approved for the prophylaxis of cytomegalovirus (CMV) infection and disease in adult CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT). Common adverse reactions include nausea, diarrhea, vomiting, peripheral edema, cough, headache, fatigue, and abdominal pain.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Indication
  • PREVYMIS™ is indicated for prophylaxis of cytomegalovirus (CMV) infection and disease in adult CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT).
Recommended Dosage for Adult Patients
  • The recommended dosage of PREVYMIS is 480 mg administered orally or intravenously once daily. Initiate PREVYMIS between Day 0 and Day 28 post-transplantation (before or after engraftment), and continue through Day 100 post-transplantation. Dosage of PREVYMIS should be adjusted when co-administered with cyclosporine.
  • PREVYMIS injection, which contains hydroxypropyl betadex, should be used only in patients unable to take oral therapy. Patients should be switched to oral PREVYMIS as soon as they are able to take oral medications. PREVYMIS tablet and injection may be used interchangeably at the discretion of the physician, and no dosage adjustment is necessary when switching formulations.
Dosage Adjustment When Co-administered with Cyclosporine
  • If oral or intravenous PREVYMIS is co-administered with cyclosporine, the dosage of PREVYMIS should be decreased to 240 mg once daily.
  • If cyclosporine is initiated after starting PREVYMIS, the next dose of PREVYMIS should be decreased to 240 mg once daily.
  • If cyclosporine is discontinued after starting PREVYMIS, the next dose of PREVYMIS should be increased to 480 mg once daily.
  • If cyclosporine dosing is interrupted due to high cyclosporine levels, no dose adjustment of PREVYMIS is needed.
Use in Patients with Renal Impairment
  • For patients with creatinine clearance (CLcr) greater than 10 mL/min, no dosage adjustment of PREVYMIS is required based on renal impairment.
  • There are insufficient data in patients with CLcr 10 mL/min or less or in patients on dialysis to make PREVYMIS dosing recommendations.
  • In patients with CLcr less than 50 mL/min receiving PREVYMIS injection, accumulation of the intravenous vehicle, hydroxypropyl betadex, may occur. Closely monitor serum creatinine levels in these patients.
Use in Patients with Hepatic Impairment
  • No dosage adjustment of PREVYMIS is required for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. PREVYMIS is not recommended for patients with severe (Child-Pugh Class C) hepatic impairment.
Dosage Forms and Strengths
  • Tablets
  • PREVYMIS 240 mg tablet: yellow oval tablet with "591" on one side and Merck logo on the other side.
  • PREVYMIS 480 mg tablet: pink oval, bi-convex tablet with "595" on one side and Merck logo on the other side.
  • Injection
  • PREVYMIS 240 mg/12 mL (20 mg/mL) injection: clear solution in a single-dose vial.
  • PREVYMIS 480 mg/24 mL (20 mg/mL) injection: clear solution in a single-dose vial.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding letermovir Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.

Non–Guideline-Supported Use

There is limited information regarding letermovir Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Letermovir FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding letermovir Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.

Non–Guideline-Supported Use

There is limited information regarding letermovir Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.

Contraindications

  • PREVYMIS is contraindicated in patients receiving pimozide or ergot alkaloids:
  • Pimozide: Concomitant administration of PREVYMIS in patients receiving pimozide may result in increased concentrations of pimozide due to inhibition of cytochrome P450 3A (CYP3A) by letermovir, which may lead to QT prolongation and torsades de pointes.
  • Ergot alkaloids: Concomitant administration of PREVYMIS in patients receiving ergot alkaloids may result in increased concentrations of ergot alkaloids (ergotamine and dihydroergotamine) due to inhibition of CYP3A by letermovir, which may lead to ergotism [see WARNINGS AND PRECAUTIONS (5.1) and DRUG INTERACTIONS (7.2, 7.3)].
  • PREVYMIS is contraindicated with pitavastatin and simvastatin when co-administered with cyclosporine. Concomitant administration of PREVYMIS in combination with cyclosporine may result in significantly increased pitavastatin or simvastatin concentrations, which may lead to myopathy or rhabdomyolysis

Warnings

Risk of Adverse Reactions or Reduced Therapeutic Effect Due to Drug Interactions
  • The concomitant use of PREVYMIS and certain drugs may result in potentially significant drug interactions, some of which may lead to adverse reactions (PREVYMIS or concomitant drugs) or reduced therapeutic effect of PREVYMIS or the concomitant drug.
  • See TABLE 3 for steps to prevent or manage these possible or known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during PREVYMIS therapy; review concomitant medications during PREVYMIS therapy; and monitor for adverse reactions associated with PREVYMIS and concomitant medications.

Adverse Reactions

Clinical Trials Experience

  • Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adult CMV-seropositive Recipients [R+] of an Allogeneic HSCT
  • The safety of PREVYMIS was evaluated in one Phase 3 randomized, double-blind, placebo-controlled trial (P001) in which 565 subjects were randomized and treated with PREVYMIS (N=373) or placebo (N=192) through Week 14 post-transplant. Adverse events were those reported while subjects were on study medication or within two weeks of study medication completion/discontinuation. The mean time for reporting adverse events and laboratory abnormalities was approximately 22% longer in the PREVYMIS arm compared to the placebo arm.
Cardiac Adverse Events:
  • The cardiac adverse event rate (regardless of investigator-assessed causality) was higher in subjects receiving PREVYMIS (13%) compared to subjects receiving placebo (6%). The most common cardiac adverse events were tachycardia (reported in 4% of PREVYMIS subjects and in 2% of placebo subjects) and atrial fibrillation (reported in 3% of PREVYMIS subjects and in 1% of placebo subjects). Among those subjects who experienced one or more cardiac adverse events, 85% of PREVYMIS and 92% of placebo subjects had events reported as mild or moderate in severity.
Common Adverse Events
  • The rate of adverse events occurring in at least 10% of subjects in the PREVYMIS group and at a frequency at least 2% greater than placebo are outlined in Table 1.
This image is provided by the National Library of Medicine.
  • Overall, similar proportions of subjects in each group discontinued study medication due to an adverse event (13% of PREVYMIS subjects vs. 12% of placebo subjects). The most frequently reported adverse event that led to study drug discontinuation was nausea, occurring in 2% of PREVYMIS subjects and 1% of placebo subjects. Hypersensitivity reaction, with associated moderate dyspnea, occurred in one subject following the first infusion of IV PREVYMIS after switching from oral PREVYMIS, leading to treatment discontinuation.

Laboratory Abnormalities

  • Selected laboratory abnormalities reported during treatment or within 2 weeks of stopping treatment are presented in the table below.
This image is provided by the National Library of Medicine.
  • The median time to engraftment (defined as absolute neutrophil count ≥ 500/mm3 on 3 consecutive days after transplantation) was 19 days in the PREVYMIS group and 18 days in the placebo group.

Postmarketing Experience

There is limited information regarding Letermovir Postmarketing Experience in the drug label.

Drug Interactions

  • Potential for Other Drugs to Affect PREVYMIS
  • Potential for PREVYMIS to Affect Other Drugs
  • Established and Other Potentially Significant Drug Interactions
  • Drugs without Clinically Significant Interactions with PREVYMIS
Potential for Other Drugs to Affect PREVYMIS
  • Letermovir is a substrate of organic anion-transporting polypeptide 1B1/3 (OATP1B1/3) transporters. Co-administration of PREVYMIS with drugs that are inhibitors of OATP1B1/3 transporters may result in increases in letermovir plasma concentrations.
Potential for PREVYMIS to Affect Other Drugs
  • Co-administration of PREVYMIS with midazolam results in increased midazolam plasma concentrations, indicating that letermovir is a moderate inhibitor of CYP3A. Co-administration of PREVYMIS with drugs that are CYP3A substrates may result in clinically relevant increases in the plasma concentrations of co-administered CYP3A substrates.
  • Letermovir is an inhibitor of OATP1B1/3 transporters. Co-administration of PREVYMIS with drugs that are substrates of OATP1B1/3 transporters may result in a clinically relevant increase in plasma concentrations of co-administered OATP1B1/3 substrates.
  • The magnitude of CYP3A- and OATP1B1/3-mediated drug interactions on co-administered drugs may be different when PREVYMIS is co-administered with cyclosporine. See the prescribing information for cyclosporine for information on drug interactions with cyclosporine.
Established and Other Potentially Significant Drug Interactions
  • If dose adjustments of concomitant medications are made due to treatment with PREVYMIS, doses should be readjusted after treatment with PREVYMIS is completed.
  • Table 3 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with PREVYMIS or are predicted drug interactions that may occur with PREVYMIS
This image is provided by the National Library of Medicine.
Drugs without Clinically Significant Interactions with PREVYMIS
  • No clinically significant interactions were observed in clinical drug-drug interaction studies of letermovir and acyclovir, digoxin, mycophenolate mofetil, posaconazole, ethinyl estradiol, and levonorgestrel.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

Risk Summary
  • No adequate human data are available to establish whether PREVYMIS poses a risk to pregnancy outcomes. 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). In a rat pre/post-natal development study, total litter loss was observed at maternal letermovir exposures approximately 2 times higher than human exposure at the RHD.
  • The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Data (Animal)
  • Letermovir was administered orally to pregnant rats at 0, 10, 50 or 250 mg/kg/day from gestation days 6 to 17. Developmental toxicities, including skeletal malformations and umbilical cord shortening, were observed at 250 mg/kg/day (approximately 11 times higher than human exposure at the RHD). In addition, decreased fetal body weight and skeletal variations (due to maternal toxicity) were observed at this dose. No embryo-fetal toxicities were observed at 50 mg/kg/day (approximately 3 times higher than human exposure at the RHD).
  • Letermovir was administered orally to pregnant rabbits at 0, 25, 75 or 225 mg/kg/day from gestation days 6 to 20. Developmental toxicities, including spontaneous abortion, increased post-implantation loss, and skeletal variations, were observed at a maternally toxic dose (225 mg/kg/day; approximately 2 times higher than human exposure at the RHD). No embryo-fetal toxicities were observed at 75 mg/kg/day (less than human exposure at the RHD).
  • In the pre/post-natal development study, letermovir was administered orally to pregnant rats at 0, 10, 45 or 180 mg/kg/day from gestation day 6 to lactation day 22. At 180 mg/kg/day (approximately 2 times higher than human exposure at the RHD), total litter loss due to stillbirth or possible maternal neglect was observed in 5 of 23 pregnant females by post-partum/lactation day 4. In surviving offspring, slight developmental delays in vaginal opening and pinna unfolding were accompanied by reduced body weight gain at this dose. No toxicities were observed at 45 mg/kg/day (similar to human exposure at the RHD).


Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Letermovir in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Letermovir during labor and delivery.

Nursing Mothers

Risk Summary
  • It is not known whether letermovir is 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 developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for PREVYMIS and any potential adverse effects on the breastfed child from PREVYMIS or from the underlying maternal condition.
Data
  • In a lactation study, letermovir was excreted in milk when administered intravenously (at 10 mg/kg) to lactating rats on post-partum/lactation day 10. Letermovir was also detected in the blood of nursing pups on post-partum/lactation day 21 in the pre/post-natal developmental study.

Pediatric Use

  • Safety and efficacy of PREVYMIS in patients below 18 years of age have not been established.

Geriatic Use

  • Of the 373 subjects treated with PREVYMIS in Trial P001, 56 (15%) subjects were 65 years of age or older. Safety and efficacy were similar across older and younger subjects. No dosage adjustment of PREVYMIS is required based on age.

Gender

There is no FDA guidance on the use of Letermovir with respect to specific gender populations.

Race

There is no FDA guidance on the use of Letermovir with respect to specific racial populations.

Renal Impairment

  • For patients with CLcr greater than 10 mL/min (by Cockcroft-Gault equation), no dosage adjustment of PREVYMIS is required based on renal impairment. The safety of PREVYMIS in patients with end-stage renal disease (CLcr less than 10 mL/min), including patients on dialysis, is unknown.
  • In patients with CLcr less than 50 mL/min receiving PREVYMIS injection, accumulation of the intravenous vehicle, hydroxypropyl betadex, could occur. Closely monitor serum creatinine levels in these patients.

Hepatic Impairment

  • No dosage adjustment of PREVYMIS is required for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. PREVYMIS is not recommended for patients with severe (Child-Pugh Class C) hepatic impairment.

Females of Reproductive Potential and Males

Infertility
  • There are no data on the effect of letermovir on human fertility. Decreased fertility due to testicular toxicity was observed in male rats.

Immunocompromised Patients

There is no FDA guidance one the use of Letermovir in patients who are immunocompromised.

Administration and Monitoring

Administration

Important Dosing and Administration Information
  • PREVYMIS™ Tablets
  • Administer with or without food.
  • Swallow tablets whole.
  • PREVYMIS™ Injection
  • Administer by intravenous infusion via a peripheral catheter or central venous line at a constant rate over 1 hour.
  • Do not administer as an intravenous bolus injection.
Preparation and Administration of Intravenous Solution
  • PREVYMIS injection is supplied in 30 mL single-dose vials containing either 240 mg/12 mL per vial (20 mg/mL) or 480 mg/24 mL per vial (20 mg/mL). The preparation and administration instructions are the same for either dose.
  • PREVYMIS vials are for single use only. Discard any unused portion.
Preparation and Administration Instructions
  • PREVYMIS must be diluted prior to intravenous (IV) use.
  • Inspect vial contents for discoloration and particulate matter prior to dilution. PREVYMIS injection is a clear colorless solution. Do not use the vial if the solution is discolored or contains visible particles.
  • Do not shake PREVYMIS vial.
  • Add one single-dose vial of PREVYMIS injection into a 250 mL pre-filled IV bag containing either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP and mix bag gently. Do not shake. Only 0.9% Sodium Chloride and 5% Dextrose are chemically and physically compatible with PREVYMIS injection.
  • Use compatible IV bags and infusion set materials. PREVYMIS injection is compatible with the following IV bags and infusion set materials. PREVYMIS injection is not recommended with any IV bags or infusion set materials not listed below (note that PREVYMIS injection is not recommended for use with polyurethane-containing IV administration set tubing).
  • IV Bags Materials:
  • Polyvinyl chloride (PVC), ethylene vinyl acetate (EVA) and polyolefin (polypropylene and polyethylene)
  • Infusion Sets Materials:
  • PVC, polyethylene (PE), polybutadiene (PBD), silicone rubber (SR), styrene–butadiene copolymer (SBC), styrene-butadiene-styrene copolymer (SBS), polystyrene (PS)
  • Plasticizers:
  • Diethylhexyl phthalate (DEHP), tris (2-ethylhexyl) trimellitate (TOTM), benzyl butyl phthalate (BBP)
  • Catheters:
  • Radiopaque polyurethane
  • Once diluted, the solution of PREVYMIS is clear, and ranges from colorless to yellow. Variations of color within this range do not affect the quality of the product. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard if discoloration or visible particles are observed.
  • The diluted solution is stable for up to 24 hours at room temperature or up to 48 hours under refrigeration at 2°C to 8°C (36°F to 46°F) (this time includes storage of the diluted solution in the intravenous bag through the duration of infusion).
  • Administer the entire contents of the intravenous bag by intravenous infusion via a peripheral catheter or central venous line at a constant rate over 1 hour.
Compatible Drug Products Used for Intravenous Administration
Compatible Drug Products
  • The physical compatibility of PREVYMIS injection with selected injectable drug products was evaluated in two commonly available diluents. PREVYMIS should not be co-administered through the same intravenous line (or cannula) with other drug products and diluent combinations except those listed below. Refer to the respective prescribing information of the co-administered drug(s) to confirm compatibility of simultaneous co-administration.

List of Compatible Drug Products when PREVYMIS and Drug Products are Prepared in 0.9% Sodium Chloride Injection, USP:

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

List of Compatible Drug Products when PREVYMIS and Drug Products are Prepared in 5% Dextrose Injection, USP:

  • Amphotericin B (lipid complex)1, 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.
  • 1= Amphotericin B (lipid complex) is compatible with PREVYMIS. However, Amphotericin B (liposomal) is incompatible.
Incompatible Drug Products for Intravenous Administration
Incompatible Drug Products
  • PREVYMIS injection is physically incompatible with amiodarone hydrochloride, amphotericin B (liposomal), aztreonam, cefepime hydrochloride, ciprofloxacin, cyclosporine, diltiazem hydrochloride, filgrastim, gentamicin sulfate, levofloxacin, linezolid, lorazepam, midazolam HCl, mycophenolate mofetil hydrochloride, ondansetron, palonosetron.

Monitoring

  • Following the completion of PREVYMIS prophylaxis, monitoring for CMV reactivation is recommended.
  • Prophylaxis of clinically significant cytomegalovirus infection is indicative of efficacy.
  • Serum creatinine levels: Closely in patients with CrCl less than 50 mL/min receiving IV formulation.
  • Reactivation of cytomegalovirus.

IV Compatibility

There is limited information regarding the compatibility of Letermovir and IV administrations.

Overdosage

  • There is no specific antidote for overdose with PREVYMIS. In case of overdose, it is recommended that the patient be monitored for adverse reactions and appropriate symptomatic treatment be instituted.
  • It is unknown whether dialysis will result in meaningful removal of PREVYMIS from systemic circulation.

Pharmacology

Template:Px
Letermovir
Systematic (IUPAC) name
{(4S)-8-Fluoro-2-[4-(3-methoxyphenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetic acid
Identifiers
CAS number ?
ATC code None
PubChem 45138674
Chemical data
Formula Template:OrganicBox atomTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox 
Mol. mass ?
SMILES eMolecules & PubChem
Synonyms AIC246; MK-8228
Pharmacokinetic data
Bioavailability ?
Metabolism ?
Half life ?
Excretion ?
Therapeutic considerations
Pregnancy cat.

?

Legal status

[[Prescription drug|Template:Unicode-only]](US)

Routes Oral

Mechanism of Action

  • PREVYMIS is an antiviral drug against CMV.

Structure

This image is provided by the National Library of Medicine.

Pharmacodynamics

Cardiac Electrophysiology
  • In a thorough QT trial in healthy subjects, letermovir at the therapeutic IV dose or at a dose of 2 times the approved IV dose did not prolong QTc to any clinically relevant extent.

Pharmacokinetics

  • The pharmacokinetic properties of letermovir are displayed in Table 4.
This image is provided by the National Library of Medicine.
Specific Populations

Pediatric Population

  • The pharmacokinetics of letermovir in patients less than 18 years of age have not been evaluated.

Age, Gender, Race, and Weight

  • Age (18 to 78 years), gender, race (White vs. non-White), and body weight (up to 100 kg) did not have a clinically significant effect on the pharmacokinetics of letermovir.

Renal Impairment

  • Letermovir AUC was approximately 1.9- and 1.4-fold higher in subjects with moderate (eGFR greater than or equal to 30 to 59 mL/min/1.73m2) and severe (eGFR less than 30 mL/min/1.73m2) renal impairment, respectively, compared to healthy subjects.
  • Hydroxypropyl betadex present in the intravenous letermovir formulation is mainly eliminated by glomerular filtration. Decreased elimination of hydroxypropyl betadex has been reported in the literature in patients with severe renal impairment.

Hepatic Impairment

  • Letermovir AUC was approximately 1.6- and 3.8-fold higher in subjects with moderate (Child-Pugh Class B [CP-B], score of 7-9) and severe (Child-Pugh Class C [CP-C], score of 10-15) hepatic impairment, respectively, compared to healthy subjects.
Drug Interaction Studies
  • Drug interaction studies were performed in healthy subjects with PREVYMIS and drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interactions.
  • In vitro results indicate that letermovir is a substrate of drug metabolizing enzymes 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.
  • Based on in vitro studies, the metabolism of letermovir is not mediated by CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2E1, CYP4A11, UGT1A4, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B4, UGT2B7, UGT2B15, or UGT2B17. The transport of letermovir is not mediated by OATP2B1, OCT1, OAT1, BCRP, or MRP2 in vitro.
  • Letermovir is a time-dependent inhibitor and inducer of CYP3A in vitro. Co-administration of PREVYMIS with midazolam resulted in increased exposure of midazolam, indicating that the net effect of letermovir on CYP3A is moderate inhibition. Based on these results, co-administration of PREVYMIS with CYP3A substrates may increase the plasma concentrations of the CYP3A substrates. Letermovir is a reversible inhibitor of CYP2C8 in vitro. When co-administered with PREVYMIS, plasma concentrations of CYP2C8 substrates are predicted to be increased. Co-administration of PREVYMIS reduced the exposure of voriconazole, most likely due to the induction of voriconazole elimination pathways, CYP2C9 and CYP2C19. Co-administration of PREVYMIS with CYP2C9 and CYP2C19 substrates may decrease the plasma concentrations of the CYP2C9 and CYP2C19 substrates. Letermovir is an inducer of CYP2B6 in vitro; the clinical relevance is unknown.
  • Letermovir inhibited 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. Co-administration of PREVYMIS with substrates of OATP1B1/3 transporters (e.g. 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. There were no clinically relevant changes in plasma concentrations of digoxin, a P-gp substrate, or acyclovir, an OAT3 substrate, following co-administration with PREVYMIS in clinical studies. The effect of letermovir on BCRP, BSEP, and MRP2 substrates was not evaluated in clinical studies; the clinical relevance is unknown.
  • Based on in vitro results letermovir is not an inhibitor of CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, UGT1A4, UGT1A6, UGT1A9, or UGT2B7 and is not an inducer of CYP1A2. Letermovir is not an inhibitor of MRP2, OATP2B1, BSEP, OCT1, OCT2, or OAT1 in vitro.
This image is provided by the National Library of Medicine.
This image is provided by the National Library of Medicine.
Microbiology
Mechanism of Action
  • Letermovir inhibits the CMV DNA terminase complex (pUL51, pUL56, and pUL89) which is required for viral DNA processing and packaging. Biochemical characterization and electron microscopy demonstrated that letermovir affects the production of proper unit length genomes and interferes with virion maturation. Genotypic characterization of virus resistant to letermovir confirmed that letermovir targets the terminase complex.
Antiviral Activity
  • The median EC50 value of letermovir against a collection of clinical CMV isolates in a cell-culture model of infection was 2.1 nM (range = 0.7 nM to 6.1 nM, n = 74). There was no significant difference in EC50 value by CMV gB genotype (gB1=29; gB2=27; gB3=11; and gB4=3).
Combination Antiviral Activity
  • No antagonism of the antiviral activity was seen when letermovir was combined with CMV DNA polymerase inhibitors (cidofovir, foscarnet, or ganciclovir).
Viral Resistance

In Cell Culture

  • CMV mutants with reduced susceptibility to letermovir have been selected in cell culture and the resistance mutations map to UL56. Resistance-associated substitutions occur between amino acid positions pUL56 231 and 369 (V231A/L, V236L/M, E237D, L241P, T244K/R, L257I, F261C/L/S, Y321C, C325F/R/Y, M329T, R369G/M/S). EC50 values for virus expressing these substitutions are 13- to 5,870-fold higher than those for the wild-type reference virus.

In Clinical Studies

  • In a Phase 2b trial evaluating letermovir or placebo in 131 HSCT recipients, DNA sequence analysis of a select region of UL56 (amino acids 231 to 369) was performed on samples obtained from 12 letermovir-treated subjects who experienced prophylaxis failure and for whom on-treatment samples were available for analysis. One subject had a letermovir resistance substitution, pUL56 V236M.
  • In a Phase 3 trial (P001), DNA sequence analysis of the entire coding regions of UL56 and UL89 was performed on samples obtained from 28 letermovir-treated subjects who had received at least one dose of study drug and experienced prophylaxis failure and for whom samples were available for analysis. Two subjects were identified as having a letermovir-resistance substitution, pUL56 V236M or C325W. These substitutions were identified from on-treatment samples. A virus from a third subject who experienced prophylaxis failure had a pUL56 E237G substitution at low frequency (<5%), and while pUL56 E237D was associated with resistance in cell culture, the clinical significance of this substitution at this frequency is unknown.
Cross Resistance
  • Cross resistance is not likely with drugs outside of this class. Letermovir is fully active against viral populations with substitutions conferring resistance to CMV DNA polymerase inhibitors (cidofovir, foscarnet, and ganciclovir). These DNA polymerase inhibitors are fully active against viral populations with substitutions conferring resistance to letermovir.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis and Mutagenesis
  • Letermovir was not genotoxic in in vitro or in vivo assays, including microbial mutagenesis assays, chromosomal aberration in Chinese hamster ovary cells, and in an in vivo mouse micronucleus study.
  • Carcinogenicity studies with letermovir have not been conducted.
Impairment of Fertility
  • In a fertility and early embryonic development study in rats, no effects of letermovir on female fertility were observed at letermovir exposures (AUC) approximately 5 times higher than human exposure at the RHD.
  • In male rat fertility studies, decreased fertility associated with irreversible testicular toxicity was observed at ≥180 mg/kg/day (greater than or equal to 3 times the human exposure at the RHD). No fertility or testicular effects were observed at dose levels resulting in letermovir exposures (AUC) similar to human exposure at the RHD.
Animal Toxicology and/or Pharmacology
  • Testicular toxicity in rats observed at ≥180 mg/kg/day (greater than or equal to 3 times the human exposure at the RHD) was characterized by decreased testis weight, bilateral seminiferous tubular degeneration, decreased sperm count and motility, and resultant decreased male fertility. Male reproductive system toxicities were not observed in either a monkey testicular toxicity study up to 240 mg/kg/day (approximately 2 times higher than human exposure at the RHD), or a general toxicology study in mice up to 250 mg/kg/day (approximately 3 times higher than human exposure at the RHD).

Clinical Studies

Adult CMV-seropositive Recipients [R+] of an Allogeneic Hematopoietic Stem Cell Transplant
  • To evaluate PREVYMIS prophylaxis as a preventive strategy for CMV infection or disease in transplant recipients at high risk for CMV reactivation, the efficacy of PREVYMIS was assessed in a multicenter, double-blind, placebo-controlled Phase 3 Trial (P001, NCT02137772) in adult CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT). Subjects were randomized (2:1) to receive either PREVYMIS at a dose of 480 mg once daily adjusted to 240 mg when co-administered with cyclosporine, or placebo. Randomization was stratified by investigational site and risk level for CMV reactivation at the time of study entry. Study drug was initiated after HSCT (at any time from Day 0 to Day 28 post-transplant) and continued through Week 14 post-transplant. Study drug was administered either orally or intravenously; the dose of PREVYMIS was the same regardless of the route of administration. Subjects received CMV DNA monitoring weekly until post-transplant Week 14 and then bi-weekly until post-transplant Week 24, with initiation of standard-of-care CMV pre-emptive therapy if CMV viremia was considered clinically significant. Subjects had continued follow-up through Week 48 post-transplant.
  • Among the 565 treated subjects, 70 subjects were found to have CMV viremia prior to study drug initiation and were therefore excluded from the efficacy analyses. The efficacy population consisted of 325 subjects who received PREVYMIS (including 91 subjects who received at least one IV dose) and 170 who received placebo (including 41 subjects who received at least one IV dose). The IV formulation of PREVYMIS was used at investigators' discretion in subjects who were unable to take oral therapy (e.g., unable to tolerate oral intake). The median time to starting study drug was 8 days after transplantation. Thirty-four percent (34%) of subjects were engrafted at baseline. The median age was 55 years (range: 18 to 76 years); 57% were male; 84% were White; 9% were Asian; 2% were Black or African American; and 7% were Hispanic or Latino.
  • At baseline, 30% of all subjects had one or more of the following factors associated with increased risk for CMV reactivation (high risk stratum): Human Leukocyte Antigen (HLA)-related donor with at least one mismatch at one of the following three HLA-gene loci: HLA-A, -B or –DR; haploidentical donor; unrelated donor with at least one mismatch at one of the following four HLA-gene loci: HLA-A, -B, -C and -DRB1; use of umbilical cord blood as stem cell source; use of ex vivo T-cell-depleted grafts; Grade 2 or greater Graft-Versus-Host Disease (GVHD) requiring systemic corticosteroids. The remaining 70% of subjects did not meet any of these high risk stratum criteria and were therefore included in the low risk stratum. Additionally, 48% of subjects received a myeloablative regimen, 51% were receiving cyclosporine, and 43% were receiving tacrolimus. The most common primary reasons for transplant were acute myeloid leukemia (38%), myelodysplastic syndrome (16%), and lymphoma (12%).

Clinically Significant CMV Infection

  • The primary efficacy endpoint of Trial P001 was the incidence of clinically significant CMV infection through Week 24 post-transplant (prophylaxis failure). Clinically significant CMV infection was defined as the occurrence of either CMV end-organ disease, or initiation of anti-CMV pre-emptive therapy (PET) based on documented CMV viremia (using the Roche COBAS® AmpliPrep/COBAS TaqMan® assay, LLoQ is 137 IU/mL, which is approximately 150 copies/mL) and the clinical condition of the subject. The protocol-specified guidance for CMV DNA thresholds for the initiation of PET during the treatment period was ≥ 150 copies/mL or > 300 copies/mL for subjects in the high and low risk strata, respectively. From Week 14 through Week 24, the threshold was >300 copies/mL for both high and low risk strata subjects. The Non-Completer=Failure (NC=F) approach was used, where subjects who discontinued from the trial prior to Week 24 post-transplant or had a missing outcome at Week 24 post-transplant were counted as failures.
  • Efficacy results from Trial P001 are shown in Table 7.
This image is provided by the National Library of Medicine.
  • Efficacy results were consistent across high and low risk strata for CMV reactivation. The time to clinically significant CMV infection is shown in Figure 1.
This image is provided by the National Library of Medicine.
  • Post-hoc analysis demonstrated that among PREVYMIS-treated subjects, inclusion in the high risk stratum for CMV reactivation at baseline, occurrence of GVHD, and steroid use at any time after randomization may be associated with the development of clinically significant CMV infection between Week 14 and Week 24 post-transplant.

Mortality

  • The Kaplan-Meier event rate for all-cause mortality in the letermovir vs. placebo groups was 12% vs. 17% at Week 24 post-transplant, and 24% vs. 28% at Week 48 post-transplant.

How Supplied

Tablets
  • Each PREVYMIS 240 mg tablet is a yellow oval tablet; each tablet is debossed with "591" on one side and Merck logo on the other side. Each PREVYMIS 480 mg tablet is a pink oval, bi-convex tablet debossed with "595" on one side and Merck logo on the other side.
  • The 240 mg tablets are packaged into a carton (NDC 0006-3075-02) containing four (4) Child Resistant (CR) Dosepaks®, each containing a 7-count blister card for a total of 28 tablets, or into a carton (NDC 0006-3075-04) containing two (2) unit-dose 7-count blister cards for a total of 14 tablets.
  • The 480 mg tablets are packaged into a carton (NDC 0006-3076-02) containing four (4) Child Resistant (CR) Dosepaks®, each containing a 7-count blister card for a total of 28 tablets, or into a carton (NDC 0006-3076-04) containing two (2) unit-dose 7-count blister cards for a total of 14 tablets.
Injection
  • PREVYMIS is supplied as a sterile, clear solution for intravenous use of 240 mg (12 mL per vial) or 480 mg (24 mL per vial). The final solutions for infusion are obtained by dilution with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP.
  • The single dose vials are supplied in cartons that contain a 240 mg single-dose vial (NDC 0006-5003-01) or a 480 mg single-dose vial (NDC 0006-5004-01).

Storage

Tablets
  • Store PREVYMIS tablets in the original package until use.
  • Store PREVYMIS tablets at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
Injection
  • Store PREVYMIS injection vials at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
  • Store in the original carton to protect from exposure to light.

Images

Drug Images

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Package and Label Display Panel

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This image is provided by the National Library of Medicine.
This image is provided by the National Library of Medicine.
This image is provided by the National Library of Medicine.

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Patient Counseling Information

  • Advise the patient to read the FDA-approved patient labeling (Patient Information).
Drug Interactions
  • Inform patients that PREVYMIS may interact with some drugs; therefore, advise patients to report the use of any prescription, non-prescription medication, or herbal products to their healthcare provider.
Administration
  • Inform patients that it is important not to miss or skip doses and to take PREVYMIS for the duration that is recommended by the healthcare provider. Instruct patients that if they miss a dose of PREVYMIS, they should take it as soon as they remember. If they do not remember until it is time for the next dose, instruct them to skip the missed dose and go back to the regular schedule. Instruct patients not to double their next dose or take more than the prescribed dose.
Storage
  • Advise patients to store PREVYMIS tablets in the original package until use.

Precautions with Alcohol

Alcohol-Letermovir interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

Brand Names

  • Prevymis

Look-Alike Drug Names

There is limited information regarding Letermovir Look-Alike Drug Names in the drug label.

Drug Shortage Status

Drug Shortage

Price

References

The contents of this FDA label are provided by the National Library of Medicine.