These Highlights Do Not Include All The Information Needed To Use Prevymis Safely And Effectively. See Full Prescribing Information For Prevymis.

Preparation Instructions

• PREVYMIS must be diluted prior to intravenous (IV) use. Only 0.9% Sodium Chloride and 5% Dextrose are chemically and physically compatible with PREVYMIS injection.
• Do not shake PREVYMIS vial.
• Inspect vial contents for discoloration and particulate matter prior to dilution. PREVYMIS injection is a clear colorless solution and may contain a few product-related small translucent or white particles.
• Do not use the vial if the solution is cloudy, discolored, or contains matter other than a few small translucent or white particles.
• 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.
• Do not use PREVYMIS injection with IV bags and infusion set materials containing the plasticizer diethylhexyl phthalate (DEHP). Use only with IV bags and infusion set materials that are DEHP-free. Materials that are phthalate-free are also DEHP-free.
• 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:
    
    Tris (2-ethylhexyl) trimellitate (TOTM), benzyl butyl phthalate (BBP)
  • Catheters:
    
    Radiopaque polyurethane
• For the 480 mg or 240 mg dose, add PREVYMIS injection (see Table 6) 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.
• For the 120 mg or 60 mg dose, add PREVYMIS injection into a pre-filled IV bag containing either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP (see Table 6) and mix bag gently. Do not shake.

• For the 40 mg dose, prepare a dilution of PREVYMIS injection according to Table 7 in either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP and mix bag gently. Transfer 20 mL from the prepared dilution into an appropriately sized IV bag or syringe. Do not shake.

Administration Instructions

• Administer the entire contents of the intravenous bag or syringe by intravenous infusion via a peripheral catheter or central venous line at a constant rate over 1 hour [see Dosage and Administration (2.1)].
• The diluted solution must be administered through a sterile 0.2 micron or 0.22 micron polyethersulfone (PES) in-line filter. Do not administer through a filter other than a sterile 0.2 micron or 0.22 micron PES in-line filter.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.
• Discard if the diluted solution is cloudy, discolored, or contains matter other than a few small translucent or white particles.

PREVYMIS is a prescription medicine used to help prevent:

• cytomegalovirus (CMV) infection and disease in adults and children 6 months and older weighing at least 13.2 pounds (lbs) or 6 kilograms (kg) who:
  • have received an allogeneic hematopoietic stem cell (bone marrow) transplant, and
  • have a high risk for getting CMV infection and disease.
• CMV disease in adults and children 12 years of age and older weighing at least 88.2 lbs (40 kg) who:
  • have received a kidney transplant, and
  • have a high risk for getting CMV disease.

It is not known if PREVYMIS is safe and effective in:

• children under 6 months of age or weighing less than 13.2 lbs (6 kg) who received a hematopoietic stem cell transplant, or
• children under 12 years of age or weighing less than 88.2 lbs (40 kg) who received a kidney transplant.

Do not take PREVYMIS if you take:

• pimozide
• ergot alkaloids

If you are taking PREVYMIS with cyclosporine, do not take:

• pitavastatin or simvastatin

Before taking PREVYMIS, tell your healthcare provider about all your medical conditions, including if you:

• have kidney or liver problems.
• are pregnant or plan to become pregnant. It is not known if PREVYMIS will harm your unborn baby.
• are breastfeeding or plan to breastfeed. It is not known if PREVYMIS passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking PREVYMIS.

Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. PREVYMIS may affect the way other medicines work, and other medicines may affect how PREVYMIS works and cause serious side effects.

Know the medicines you take. Keep a list of medicines and show it to your healthcare provider and pharmacist when you get a new medicine. Your healthcare provider or pharmacist will tell you if it is safe to take PREVYMIS with other medicines. Do not start or stop taking another medicine without telling your healthcare provider first.

• PREVYMIS comes as a tablet, oral pellets, or can be given by your healthcare provider through an IV line (intravenously).
• PREVYMIS given intravenously should be used only if you are unable to take PREVYMIS tablets or PREVYMIS oral pellets. You should switch to PREVYMIS tablets or PREVYMIS oral pellets as soon as you are able to.
• Take PREVYMIS tablets or oral pellets exactly as your healthcare provider tells you to take it. Do not stop taking PREVYMIS without talking to your healthcare provider first.
• Take PREVYMIS tablets or oral pellets 1 time a day.
• It is important that you do not miss or skip doses of PREVYMIS.
• If you miss a dose of PREVYMIS tablets or oral pellets, take it as soon as you remember. If you do not remember until it is time for your next dose, skip the missed dose and take your dose at the next scheduled time. Do not take 2 doses of PREVYMIS at the same time or take more than your prescribed dose to make up for a missed dose.
• If you take too much PREVYMIS tablets or oral pellets, call your healthcare provider right away.

• If you take PREVYMIS tablets:
  • Take PREVYMIS with or without food.
  • Swallow PREVYMIS tablets whole.
• If you take PREVYMIS oral pellets:
  • Your healthcare provider will tell you the number of PREVYMIS oral pellet packets to take for your prescribed dose.
  • PREVYMIS oral pellets can be taken by mouth after mixing with soft food or given through a nasogastric tube (NG tube) or gastric tube (G tube).
  • See the Instructions for Use for the right way to prepare and take a dose of PREVYMIS oral pellets. Keep the Instructions for Use and follow it each time you prepare and take PREVYMIS oral pellets.
  • Do not crush or chew PREVYMIS oral pellets.
• If you receive PREVYMIS through an IV line (intravenously):
  • You will receive PREVYMIS 1 time each day given over 1 hour.
  • If you miss or skip your dose of PREVYMIS, call your healthcare provider right away.

The most common side effects of PREVYMIS in adults who have received a hematopoietic stem cell transplant include:

The most common side effect of PREVYMIS in adults who have received a kidney transplant is diarrhea.

The side effects of PREVYMIS in children are similar to the side effects in adults.

These are not all the possible side effects of PREVYMIS.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

• Store PREVYMIS tablets, PREVYMIS oral pellets, and PREVYMIS injection at room temperature between 68°F to 77°F (20°C to 25°C).
• Store PREVYMIS tablets in the original package until you are ready to take it to protect from moisture.
• Store PREVYMIS oral pellets in the original packet until you are ready to take them.
• Store PREVYMIS injection in the original carton to protect from exposure to light.

Keep PREVYMIS and all medicines out of the reach of children.

Medicines are sometimes prescribed for purposes other than those listed in the Patient Information leaflet. Do not use PREVYMIS for a condition for which it was not prescribed. Do not give PREVYMIS to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about PREVYMIS that is written for healthcare professionals.

Active ingredient: letermovir

Inactive ingredients:

Tablets: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and povidone 25.

Film coating: hypromellose 2910, iron oxide red (only for 480 mg tablets), iron oxide yellow, lactose monohydrate, titanium dioxide, and triacetin. Carnauba wax is added as a polishing agent.

Oral Pellets: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and povidone K-29/32.

Film coating: hypromellose 2910, iron oxide red, iron oxide yellow, lactose monohydrate, titanium dioxide, and triacetin.

Injection: hydroxypropyl betadex, sodium chloride, sodium hydroxide, and Water for Injection.

Store PREVYMIS tablets in the original package until use to protect from moisture.

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) [see USP Controlled Room Temperature].

Mixing PREVYMIS oral pellets with soft food



Important information about mixing PREVYMIS oral pellets with soft food

Giving PREVYMIS oral pellets through a gastric tube (G tube) or nasogastric tube (NG tube)



These instructions are for giving PREVYMIS oral pellets through a G tube or NG tube.

Storing PREVYMIS oral pellets packets

• Store PREVYMIS oral pellets at room temperature between 68°F to 77°F (20°C to 25°C).
• Store PREVYMIS oral pellets in the original packet until you are ready to take them.
• Keep PREVYMIS oral pellets and all medicine out of the reach of children.

Learn more about PREVYMIS oral pellets

For more information on how to use PREVYMIS oral pellets, ask your healthcare provider or pharmacist and read the PREVYMIS Patient Information.

For more information about PREVYMIS oral pellets, go to PREVYMIS.com or call 1-800-444-2080.

Distributed by:

Merck Sharp & Dohme LLC

Rahway, NJ 07065, USA

Copyright © 2024 Merck & Co., Inc., Rahway, NJ, USA, and its affiliates. All rights reserved.

usifu-mk8228-op-2408r000

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Approved: 08/2024

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.

PREVYMIS contains letermovir, an inhibitor of the CMV DNA terminase complex, and is administered orally or by intravenous infusion.

Letermovir has a molecular formula of C₂₉H₂₈F₄N₄O₄ and a molecular weight of 572.55. The chemical name for letermovir is (4S)-2-{8-Fluoro-2-[4-(3- methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5- (trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetic acid. Letermovir is very slightly soluble in water.

The chemical structure of letermovir is:

PREVYMIS is available as 240 mg and 480 mg tablets. PREVYMIS tablets contain either 240 mg or 480 mg of letermovir and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, povidone 25, and film-coated with a coating material containing the following inactive ingredients: hypromellose 2910, iron oxide red (only for 480 mg tablets), iron oxide yellow, lactose monohydrate, titanium dioxide, and triacetin. Carnauba wax is added as a polishing agent.

PREVYMIS is available as 20 mg and 120 mg packets of oral pellets. PREVYMIS packets of oral pellets contain either 20 mg or 120 mg of letermovir. PREVYMIS oral pellets contain the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, povidone K-29/32, and are film-coated with a coating material containing the following inactive ingredients: hypromellose 2910, iron oxide red, iron oxide yellow, lactose monohydrate, titanium dioxide, and triacetin.

PREVYMIS is also available as 240 mg/12 mL (20 mg/mL) and 480 mg/24 mL (20 mg/mL) injection for intravenous infusion. PREVYMIS injection is a clear, preservative-free sterile solution and may contain a few small translucent or white particles in single-dose vials of either 240 mg or 480 mg per vial. Each 1 mL of solution contains 20 mg letermovir, hydroxypropyl betadex (150 mg), sodium chloride (3.1 mg), sodium hydroxide (1.2 mg), and Water for Injection. The amount of sodium hydroxide may be adjusted to achieve a pH of approximately 7.5.

The safety and effectiveness of PREVYMIS have been established for:

• Prophylaxis of CMV infection and disease in pediatric CMV-seropositive recipients of an allogeneic HSCT 6 months of age and older and weighing at least 6 kg, and
• Prophylaxis of CMV disease in pediatric kidney transplant recipients 12 years of age and older and weighing at least 40 kg who are at high risk [D+/R-].

HSCT Recipients: The use of PREVYMIS for prophylaxis of CMV infection and disease in pediatric recipients of an allogeneic HSCT is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data from pediatric patients in Trial P030. The safety and pharmacokinetic results were similar to those in adults [see Warnings and Precautions (5.2), Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical studies (14.2, 14.4)].

Kidney Transplant Recipients: The use of PREVYMIS for prophylaxis of CMV disease in high-risk [D+/R-] kidney transplant recipients 12 years of age and older and weighing at least 40 kg is supported by evidence from an adequate and well-controlled study in adults and safety data from pediatric HSCT recipients (Trial P030). Letermovir exposures are expected to be similar between adult and pediatric patients 12 years of age and older and weighing at least 40 kg [see Warnings and Precautions (5.2), Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical studies (14.3, 14.4)].

The safety and effectiveness of PREVYMIS have not been established for:

• HSCT recipients less than 6 months of age or weighing less than 6 kg, or
• Kidney transplant recipients less than 12 years of age or weighing less than 40 kg.

Of the 373 subjects treated with PREVYMIS in Trial P001, 56 (15%) subjects were 65 years of age or older. Of the 144 subjects treated with PREVYMIS in Trial P040, 32 (22%) subjects were 65 years of age or older. Of the 292 subjects treated with PREVYMIS in Trial P002, 48 (16%) subjects were 65 years of age or older. Safety and efficacy were similar across older and younger subjects in each trial. No dosage adjustment of PREVYMIS is required based on age [see Clinical Pharmacology (12.3)].

• 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 [see Warnings and Precautions (5.1) and Drug Interactions (7.2, 7.3)].
  • 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 [see Warnings and Precautions (5.1) and Drug Interactions (7.2, 7.3)].

• Adult HSCT Patients: Most common adverse events (occurring in at least 10% of subjects in the PREVYMIS group and at a frequency at least 2% greater than placebo) are nausea, diarrhea, vomiting, peripheral edema, cough, headache, fatigue, and abdominal pain. (6.1)
• Adult Kidney Transplant Patients: Most common adverse event (occurring in at least 10% of subjects in the PREVYMIS group and at a frequency greater than valganciclovir) is diarrhea. (6.1)
• Pediatric Patients: Adverse events in pediatric patients are similar to adults. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme LLC at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch  .

• Dosage Adjustment: If PREVYMIS is co-administered with cyclosporine, the dosage of PREVYMIS should be decreased to 240 mg once daily in adult and pediatric patients 12 years of age and older. (2.4) If PREVYMIS is co-administered with cyclosporine in pediatric patients less than 12 years of age, dose adjustment may be required. (2.6)
• Co-administration of PREVYMIS may alter the plasma concentrations of other drugs and other drugs may alter the plasma concentrations of PREVYMIS. Consult the full prescribing information prior to and during treatment for potential drug interactions. (2.4, 2.6, 4, 5.1, 7.1, 7.2, 7.3, 7.4, 12.3)

For adult patients with CLcr greater than 10 mL/min (by Cockcroft-Gault equation), and pediatric patients with a similar degree of renal impairment (based on age-appropriate assessment of renal function), no dosage adjustment of PREVYMIS is required based on renal impairment [see Clinical Pharmacology (12.3)]. The safety of PREVYMIS in adult patients with end-stage renal disease (CLcr less than 10 mL/min) or in pediatric patients with a similar degree of renal impairment (based on age-appropriate assessment of renal function), including patients on dialysis, is unknown.

In adult patients with CLcr less than 50 mL/min and in pediatric patients with a similar degree of renal impairment (based on age-appropriate assessment of renal function) receiving PREVYMIS injection, accumulation of the intravenous vehicle, hydroxypropyl betadex, could occur. Closely monitor serum creatinine levels in these patients [see Dosage and Administration (2.7) and Warnings and Precautions (5.2)].

The pharmacokinetic properties of letermovir are displayed in Table 12.

Following the completion of PREVYMIS prophylaxis, monitoring for CMV reactivation in HSCT recipients is recommended [see Clinical Studies (14.2)].

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 [see Clinical Pharmacology (12.3)].

PREVYMIS is a CMV DNA terminase complex inhibitor indicated for:

• Prophylaxis of cytomegalovirus (CMV) infection and disease in adult and pediatric patients 6 months of age and older and weighing at least 6 kg who are CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT). (1.1)
• Prophylaxis of CMV disease in adult and pediatric patients 12 years of age and older and weighing at least 40 kg who are kidney transplant recipients at high risk (Donor CMV seropositive/Recipient CMV seronegative [D+/R-]). (1.2)

PREVYMIS is an antiviral drug against CMV [see Microbiology (12.4)].

• Risk of Adverse Reactions or Reduced Therapeutic Effect Due to Drug Interactions: The concomitant use of PREVYMIS with 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. Consult the full prescribing information for contraindications and dosage recommendations for concomitant drugs. (4, 5.1, 7.1, 7.2, 7.3)
• Risks Associated with Hydroxypropyl Betadex Excipient in Intravenous Formulation: Intravenous formulation of PREVYMIS contains the excipient hydroxypropyl betadex. PREVYMIS injection should be used only in patients unable to take oral therapy. If possible, intravenous administration should not exceed 4 weeks. In patients with renal impairment, accumulation of hydroxypropyl betadex may occur. Animal studies have shown the potential for hydroxypropyl betadex to cause ototoxicity. (5.2, 8.6, 13.2)

• Adult and Pediatric Patients 12 Years of Age and Older and Weighing at least 30 kg Who Are HSCT Recipients or Adult and Pediatric Patients 12 Years of Age and Older and Weighing at least 40 kg Who Are Kidney Transplant Recipients:
  • HSCT: 480 mg administered once daily orally or as an intravenous (IV) infusion over 1 hour through 100 days post-HSCT. In patients at risk for late CMV infection and disease, PREVYMIS may be continued through 200 days post-HSCT. (2.1, 2.3)
  • Kidney Transplant: 480 mg administered once daily orally or as an IV infusion over 1 hour through 200 days post-transplant. (2.1, 2.3)
• Pediatric Patients 6 Months to Less than 12 Years of Age or 12 Years of Age and Older and Weighing Less than 30 kg Who Are HSCT Recipients:
  • HSCT: Dosing based on weight administered once daily orally or as an IV infusion over 1 hour through 100 days post-HSCT. In patients at risk for late CMV infection and disease, PREVYMIS may be continued through 200 days post-HSCT. (2.1, 2.5)
• PREVYMIS injection must be diluted prior to administration. (2.1)
• PREVYMIS injection must be administered through a sterile 0.2 micron or 0.22 micron polyethersulfone (PES) in-line filter. (2.1, 2.10)
• Following the completion of PREVYMIS prophylaxis, monitoring for CMV reactivation in HSCT recipients is recommended. (2.2)
• Dosage Adjustment: If PREVYMIS is co-administered with cyclosporine, the dosage of PREVYMIS should be decreased to 240 mg once daily in adult and pediatric patients 12 years of age and older. (2.4) If PREVYMIS is co-administered with cyclosporine in pediatric patients less than 12 years of age, dose adjustment may be required. (2.6)
• Instructions for Use should be followed for preparation and administration of PREVYMIS oral pellets. (2.9)
• Do not use PREVYMIS injection with IV bags and infusion set materials containing the plasticizer diethylhexyl phthalate (DEHP). (2.10, 2.13)

• Tablet: 240 mg; 480 mg (3)
• Oral Pellets: 20 mg or 120 mg per packet (3)
• Injection: 240 mg/12 mL (20 mg/mL) or 480 mg/24 mL (20 mg/mL) in a single-dose vial (3)

• Renal Impairment: Closely monitor serum creatinine levels in patients with CLcr less than 50 mL/min using PREVYMIS injection. (8.6)
• Hepatic Impairment: PREVYMIS is not recommended for patients with severe (Child-Pugh C) hepatic impairment. (8.7)

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.

An overview of the trials contributing to the assessment of efficacy and safety of PREVYMIS in HSCT and kidney transplant recipients is provided in Table 17.

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

The diluted solutions (as prepared in Table 6 or Table 7) are 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).

• For adult patients with creatinine clearance (CLcr) greater than 10 mL/min and pediatric patients with a similar degree of renal impairment (based on age-appropriate assessment of renal function), no dosage adjustment of PREVYMIS is required based on renal impairment [see Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].
• There are insufficient data in adult patients with CLcr 10 mL/min or less or in patients on dialysis or in pediatric patients with a similar degree of renal impairment (based on age-appropriate assessment of renal function) to make PREVYMIS dosing recommendations.
• In adult patients with CLcr less than 50 mL/min and in pediatric patients with a similar degree of renal impairment (based on age-appropriate assessment of renal function) receiving PREVYMIS injection, accumulation of the intravenous vehicle, hydroxypropyl betadex, may occur. Closely monitor serum creatinine levels in these patients [see Warnings and Precautions (5.2)].

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).

The excipient, hydroxypropyl betadex, present in the IV letermovir formulation, has been associated with hearing loss resulting from damage to the inner ear in multiple animal species. In published studies in rats, a single subcutaneous dose of 2000 mg/kg hydroxypropyl betadex resulted in changes in hearing parameters and associated decreases in outer hair cells in the inner ear. These findings were observed at hydroxypropyl betadex levels approximately 3 times higher than those present in the letermovir IV drug product at the MRHD, based on body surface area (BSA) comparisons. No adverse changes in hearing parameters or hair cell populations in the inner ear were observed in rats following a single subcutaneous dose of 1000 mg/kg hydroxypropyl betadex, which corresponds to levels approximately 1.5 times higher than those present in the letermovir IV drug product at the MRHD, based on BSA comparisons [see Warnings and Precautions (5.2)].

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 [see Use in Specific Populations (8.7)].

NDC 0006-5003-01

Prevymis^®

(letermovir) Injection

240 mg / 12 mL

(20 mg/mL)

For Intravenous Infusion Only

Requires dilution prior to administration.

Use a 0.2 or 0.22 micron in-line filter

during infusion.

See Package Insert.

Rx only

Single-dose vial. Discard unused portion.

NDC 0006-5004-01

Prevymis^®

(letermovir) Injection

480 mg /24 mL

(20 mg/mL)

For Intravenous Infusion Only

Requires dilution prior to administration.

Use a 0.2 or 0.22 micron in-line filter

during infusion.

See Package Insert.

Rx only

Single-dose vial. Discard unused portion.

Letermovir is a substrate of organic anion-transporting polypeptide 1B1/3 (OATP1B1/3) and P-glycoprotein (P-gp) transporters and UDP-glucuronosyltransferase 1A1/3 (UGT1A1/3) enzymes. Co-administration of PREVYMIS with drugs that are inhibitors of OATP1B1/3 transporters may result in increases in letermovir plasma concentrations (Table 11).

Co-administration of PREVYMIS with inducers of transporters (e.g., P-gp) and/or enzymes (e.g., UGTs) is not recommended due to the potential for a decrease in letermovir plasma concentrations (see Table 11).

Co-administration of PREVYMIS with midazolam results in increased midazolam plasma concentrations, indicating that letermovir is a moderate inhibitor of CYP3A [see Clinical Pharmacology (12.3)]. 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 (Table 11) [see Contraindications (4) and Warnings and Precautions (5.1)].

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 (Table 11).

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.

PREVYMIS oral pellets can be administered:

• orally after mixing with soft food or
• via NG tube or G tube.

Preparation and Administration Mixed with Soft Food

• See Instructions for Use for details on the preparation and administration of PREVYMIS oral pellets mixed with soft food.
• Do not crush or chew PREVYMIS oral pellets.
• Mix PREVYMIS oral pellets with 1 to 3 teaspoons of soft food (such as applesauce, yogurt, or pudding) that is at or below room temperature. Do not use hot food.
• Administer entire mixture within 10 minutes of mixing PREVYMIS oral pellets with the soft food.

Preparation and Administration via NG Tube or G Tube

See Instructions for Use , Table 4 (NG tube) and Table 5 (G tube) for details on the preparation and administration of PREVYMIS oral pellets via NG tube or G tube.

• Pour PREVYMIS oral pellets into a medicine cup containing room temperature water (see Initial Volume in Table 4 and Table 5). Do not mix PREVYMIS oral pellets with hot or cold (refrigerated) water.
• Wait 10 minutes. Do not shake or swirl the medicine cup. PREVYMIS oral pellets will not dissolve but will become loose or broken up. The entire mixture should be administered (see steps 3 and 4) within 2 hours.
• Stir the mixture with the syringe and administer entire mixture right away using the syringe and NG tube or G tube.
• Add room temperature water (see Rinse Volume in Table 4 and Table 5) to the medicine cup for rinsing, stir with a syringe and administer the entire rinse mixture using the syringe and NG tube or G tube.
• Flush the NG tube or G tube with the volume of water recommended by the NG or G tube manufacturer.

PREVYMIS is indicated for prophylaxis of CMV disease in adult and pediatric patients 12 years of age and older and weighing at least 40 kg who are kidney transplant recipients at high risk (Donor CMV seropositive/Recipient CMV seronegative [D+/R-]).

• PREVYMIS is available in 3 dosage forms:
  • PREVYMIS Tablets
    • -
      Administer orally with or without food.
    • -
      Swallow tablets whole.
  • PREVYMIS Oral Pellets
    • -
      Administer orally mixed with soft food or via nasogastric tube (NG tube) or gastric tube (G tube) [see Dosage and Administration (2.9)].
    • -
      Do not crush or chew.
  • PREVYMIS Injection
    • -
      PREVYMIS injection must be diluted prior to administration.
    • -
      Administer PREVYMIS through a sterile 0.2 micron or 0.22 micron polyethersulfone (PES) in-line filter.
    • -
      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.
    • -
      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. If possible, intravenous administration should not exceed 4 weeks [see Warnings and Precautions (5.2)].
• No dosage adjustment is necessary when switching formulations in adult and pediatric patients 12 years of age and older [see Dosage and Administration (2.3)].
• Dosage adjustment may be necessary for pediatric patients less than 12 years of age when switching between oral and intravenous formulations (see Table 1 and Table 2) [see Dosage and Administration (2.5)].

NDC 0006-5086-01

PREVYMIS^®

(letermovir) oral pellets

20 mg per packet

Each packet contains 20 mg letermovir.

DIRECTIONS FOR USE: See enclosed

Instructions for Use booklet and

prescribing information.

Rx only

30 packets

NDC 0006-5085-01

PREVYMIS^®

(letermovir) oral pellets

120 mg per packet

Each packet contains 120 mg letermovir

DIRECTIONS FOR USE: See enclosed

Instructions for Use booklet and

prescribing information.

Rx only

30 packets

NDC 0006-3075-04

Prevymis^®

(letermovir) tablets

240 mg

Each tablet contains 240 mg letermovir.

This is a bulk package and not intended for dispensing.

This package is not child resistant.

Rx only

14 tablets: 7 tablets x 2 blister cards

NDC 0006-3076-04

Prevymis^®

(letermovir) tablets

480 mg

Each tablet contains 480 mg letermovir.

This is a bulk package and not intended for dispensing.

This package is not child resistant.

Rx only

14 tablets: 7 tablets x 2 blister cards

NDC 0006-3075-02

PREVYMIS^®

(letermovir) tablets

240 mg per tablet

Rx only

28 Tablets

This carton contains a total of 28 tablets

packaged within 4 dose packs.

Each dose pack contains 7 blister units

with one tablet per blister unit.

NDC 0006-3076-02

PREVYMIS^®

(letermovir) tablets

480 mg per tablet

1 tablet a day

28-day supply

Rx only

28 Tablets

This carton contains a total of 28 tablets

packaged within 4 dose packs.

Each dose pack contains 7 blister units

with one tablet per blister unit.

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).

PREVYMIS vials are for single use only. Discard any unused portion.

Sixty-three children 2 months to less than 18 years of age who had an allogeneic HSCT were enrolled in a multicenter, open-label, single-arm pharmacokinetic, safety and effectiveness study of PREVYMIS (P030, NCT03940586). Subjects received PREVYMIS daily either orally or intravenously for CMV prophylaxis within 28 days post-HSCT through Week 14 post-HSCT. The intravenous formulation was used for up to four weeks in subjects who were unable to take oral therapy. The daily doses of PREVYMIS were based on body weight [see Dosage and Administration (2.3, 2.5)]. Among the 63 treated subjects, 8 were 2 months to less than 2 years of age, 27 were 2 to less than 12 years of age and 28 were 12 to less than 18 years of age. The median age was 11 years; 70% were male; 70% were White; 14% were Asian; 5% were Black; and 22% were Hispanic or Latino [see Use in Specific Populations (8.4)].

The efficacy analyses population consisted of 56 subjects who received at least one dose of study drug and had no detectable CMV DNA at baseline. The proportion of subjects who failed CMV prophylaxis through Week 24 post-HSCT was 25% (14 of the 56 subjects). Six subjects had initiation of pre-emptive therapy based on CMV viremia and 8 subjects discontinued from the study before Week 24. None of the subjects had CMV end-organ disease.

PREVYMIS is indicated for pediatric recipients of an allogeneic HSCT aged 6 months and older and weighing at least 6 kg.

If dose adjustments of concomitant medications are made due to treatment with PREVYMIS, doses should be readjusted after treatment with PREVYMIS is completed.

Table 11 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on adult studies conducted with PREVYMIS or are predicted drug interactions that may occur with PREVYMIS [see Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].

No clinically significant interactions were observed in adult clinical drug-drug interaction studies of letermovir and acyclovir, digoxin, mycophenolate mofetil, fluconazole, itraconazole, posaconazole, ethinyl estradiol, and levonorgestrel.

PREVYMIS^® is indicated for prophylaxis of cytomegalovirus (CMV) infection and disease in adult and pediatric patients 6 months of age and older and weighing at least 6 kg who are CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT).

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 Contraindications (4) and Drug Interactions (7.1, 7.2, 7.3)].

See Table 11 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.

Intravenous formulation of PREVYMIS contains the excipient hydroxypropyl betadex. PREVYMIS injection should be used only in patients unable to take oral therapy and patients should be switched to oral PREVYMIS as soon as they are able to take oral medications. If possible, intravenous administration should not exceed 4 weeks [see Dosage and Administration (2.1)].

In patients with renal impairment, accumulation of hydroxypropyl betadex may occur. In adult patients with CLcr less than 50 mL/min and in pediatric patients with a similar degree of renal impairment (based on age-appropriate assessment of renal function) receiving PREVYMIS injection, closely monitor serum creatinine levels [see Dosage and Administration (2.7) and Use in Specific Populations (8.6)].

Animal studies have shown the potential for hydroxypropyl betadex to cause ototoxicity [see Nonclinical Toxicology (13.2)]. The active ingredient, letermovir, is not known to be associated with ototoxicity.

To evaluate PREVYMIS prophylaxis as a preventive strategy for CMV disease in kidney transplant recipients, the efficacy of PREVYMIS was assessed in a multicenter, double-blind, active comparator-controlled non-inferiority Phase 3 trial (P002, NCT03443869) in adult kidney transplant recipients at high risk [D+/R-]. Subjects were randomized (1:1) to receive either PREVYMIS or valganciclovir. PREVYMIS was administered at a dose of 480 mg once daily (adjusted to 240 mg when co-administered with cyclosporine). PREVYMIS was given concomitantly with acyclovir. Valganciclovir was given concomitantly with a placebo to acyclovir. Randomization was stratified by the use or nonuse of highly cytolytic, anti-lymphocyte immunotherapy during induction. Study drug was initiated between Day 0 and Day 7 post-kidney transplant and continued through Week 28 (~200 days) post-transplant. Study drug was administered either orally or IV; the dose of PREVYMIS was the same regardless of the route of administration. Three subjects received IV PREVYMIS for a mean duration of 1.7 days. Subjects were monitored through Week 52 post-transplant.

Among the 589 treated subjects, 292 subjects received PREVYMIS and 297 received valganciclovir. The median age was 51 years (range: 18 to 82 years); 72% were male; 84% were White; 9% were Black; 3% were multiple; 2% were Asian; 1% Alaskan native or American Indian; 17% were Hispanic or Latino; and 60% received a kidney from a deceased donor. The most common primary reasons for transplant were congenital cystic kidney disease (17%), hypertension (16%), and diabetes/diabetic nephropathy (14%).

CMV Disease

The primary efficacy endpoint of Trial P002 was the incidence of CMV disease (CMV end-organ disease or CMV syndrome, confirmed by an independent adjudication committee) through Week 52 post-transplant. The Observed Failure (OF) approach was used, where subjects who discontinued prematurely from the study for any reason or were missing data at the timepoint were not counted as failures. The number of subjects who discontinued from the study before Week 52 was 32 (11%) in the PREVYMIS arm and 28 (9%) in the valganciclovir arm. The number of subjects with a missing outcome in the Week 52 visit window was 24 (8%) in the PREVYMIS arm and 25 (8%) in the valganciclovir arm.

Efficacy results from Trial P002 are shown in Table 20.

Efficacy was comparable across all subgroups, including the use/nonuse of highly cytolytic, anti-lymphocyte immunotherapy during induction.

In an exploratory analysis of the incidence of CMV disease through Week 28 post-transplant, the difference (PREVYMIS – Valganciclovir) was -1.7% with 95% CI of (-3.4, 0.1). No subjects in the PREVYMIS group experienced CMV disease through Week 28 post-transplant (end of treatment period) compared with 5 subjects in the valganciclovir group.

Prophylaxis Through Week 14 (~100 days) Post-HSCT (Trial P001)

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-HSCT) and continued through Week 14 post-HSCT. 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-HSCT Week 14 and then bi-weekly until post-HSCT 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-HSCT.

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 5% were other (American Indian or Alaska Native, multiple, and missing). 7% were Hispanic or Latino; 89% not Hispanic or Latino; and 4% other (not reported, unknown, and missing).

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%).

HSCT: Adult and Pediatric Patients 12 Years of Age and Older and Weighing at least 30 kg

The recommended dosage of PREVYMIS is 480 mg administered orally or intravenously once daily. When PREVYMIS is administered orally, the recommended dosage is one 480 mg tablet once daily or two 240 mg tablets once daily. Four 120 mg packets of oral pellets once daily can be used for patients who cannot swallow tablets [see Dosage and Administration (2.9)]. For preparation and administration instructions of intravenous dosing refer to instructions in subsection 2.10 [see Dosage and Administration (2.10)]. For pediatric patients less than 12 years of age or weighing less than 30 kg, refer to weight-based dosing in Table 1 and Table 2 [see Dosage and Administration (2.5)].

Initiate PREVYMIS between Day 0 and Day 28 post-HSCT (before or after engraftment) and continue through Day 100 post-HSCT. In patients at risk for late CMV infection and disease, PREVYMIS may be continued through Day 200 post-HSCT [see Clinical Studies (14.2)].

Dosage of PREVYMIS should be adjusted when co-administered with cyclosporine [see Dosage and Administration (2.4)].

Kidney Transplant: Adult and Pediatric Patients 12 Years of Age and Older and Weighing at least 40 kg

The recommended dosage of PREVYMIS is 480 mg administered orally or intravenously once daily. When PREVYMIS is administered orally, the recommended dosage is one 480 mg tablet once daily or two 240 mg tablets once daily. Four 120 mg packets of oral pellets once daily can be used for patients who cannot swallow tablets [see Dosage and Administration (2.9)]. For preparation and administration instructions of intravenous dosing refer to instructions in subsection 2.10 [see Dosage and Administration (2.10)].

Initiate PREVYMIS between Day 0 and Day 7 post-transplant and continue through Day 200 post-transplant.

Dosage of PREVYMIS should be adjusted when co-administered with cyclosporine [see Dosage and Administration (2.4)].

• If oral or intravenous PREVYMIS is co-administered with cyclosporine, the dosage of PREVYMIS should be decreased to 240 mg once daily in the following populations [see Drug Interactions (7.1, 7.2, 7.3) and Clinical Pharmacology (12.3)]:
  • HSCT: adult and pediatric patients 12 years of age and older and weighing at least 30 kg
    
    or
  • Kidney transplant: adult and pediatric patients 12 years of age and older and weighing at least 40 kg.
• 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.

The recommended dosages of PREVYMIS for pediatric HSCT recipients 6 months to less than 12 years of age are based on weight and shown in Table 1 (tablets or oral pellets) and Table 2 (injection) [see Clinical Pharmacology (12.3)]. PREVYMIS can be administered orally (tablet or pellet) or intravenously once daily. Dosage adjustment may be necessary for pediatric patients less than 12 years of age when switching between oral and intravenous formulations (see Table 1 and Table 2).

Initiate PREVYMIS between Day 0 and Day 28 post-HSCT (before or after engraftment) and continue through Day 100 post-HSCT. In patients at risk for late CMV infection and disease, PREVYMIS may be continued through Day 200 post-HSCT [see Clinical Studies (14.2)].

If oral or intravenous PREVYMIS is co-administered with cyclosporine in pediatric HSCT recipients 6 months to less than 12 years of age, the dosage of PREVYMIS may require adjustment as shown in Table 3 [see Drug Interactions (7.1, 7.2, 7.3) and Clinical Pharmacology (12.3)].

• If cyclosporine is initiated after starting PREVYMIS, the next dose of PREVYMIS should be the daily oral or intravenous dose co-administered with cyclosporine (Table 3)
• If cyclosporine is discontinued after starting PREVYMIS, the next dose of PREVYMIS should be the daily oral or intravenous dose administered without cyclosporine (Table 1 or Table 2)
• If cyclosporine dosing is interrupted due to high cyclosporine levels, no dose adjustment of PREVYMIS is needed.

Preparation Instructions

• PREVYMIS must be diluted prior to intravenous (IV) use. Only 0.9% Sodium Chloride and 5% Dextrose are chemically and physically compatible with PREVYMIS injection.
• Do not shake PREVYMIS vial.
• Inspect vial contents for discoloration and particulate matter prior to dilution. PREVYMIS injection is a clear colorless solution and may contain a few product-related small translucent or white particles.
• Do not use the vial if the solution is cloudy, discolored, or contains matter other than a few small translucent or white particles.
• 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.
• Do not use PREVYMIS injection with IV bags and infusion set materials containing the plasticizer diethylhexyl phthalate (DEHP). Use only with IV bags and infusion set materials that are DEHP-free. Materials that are phthalate-free are also DEHP-free.
• 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:
    
    Tris (2-ethylhexyl) trimellitate (TOTM), benzyl butyl phthalate (BBP)
  • Catheters:
    
    Radiopaque polyurethane
• For the 480 mg or 240 mg dose, add PREVYMIS injection (see Table 6) 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.
• For the 120 mg or 60 mg dose, add PREVYMIS injection into a pre-filled IV bag containing either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP (see Table 6) and mix bag gently. Do not shake.

• For the 40 mg dose, prepare a dilution of PREVYMIS injection according to Table 7 in either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP and mix bag gently. Transfer 20 mL from the prepared dilution into an appropriately sized IV bag or syringe. Do not shake.

Administration Instructions

• Administer the entire contents of the intravenous bag or syringe by intravenous infusion via a peripheral catheter or central venous line at a constant rate over 1 hour [see Dosage and Administration (2.1)].
• The diluted solution must be administered through a sterile 0.2 micron or 0.22 micron polyethersulfone (PES) in-line filter. Do not administer through a filter other than a sterile 0.2 micron or 0.22 micron PES in-line filter.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.
• Discard if the diluted solution is cloudy, discolored, or contains matter other than a few small translucent or white particles.

PREVYMIS is a prescription medicine used to help prevent:

• cytomegalovirus (CMV) infection and disease in adults and children 6 months and older weighing at least 13.2 pounds (lbs) or 6 kilograms (kg) who:
  • have received an allogeneic hematopoietic stem cell (bone marrow) transplant, and
  • have a high risk for getting CMV infection and disease.
• CMV disease in adults and children 12 years of age and older weighing at least 88.2 lbs (40 kg) who:
  • have received a kidney transplant, and
  • have a high risk for getting CMV disease.

It is not known if PREVYMIS is safe and effective in:

• children under 6 months of age or weighing less than 13.2 lbs (6 kg) who received a hematopoietic stem cell transplant, or
• children under 12 years of age or weighing less than 88.2 lbs (40 kg) who received a kidney transplant.

Do not take PREVYMIS if you take:

• pimozide
• ergot alkaloids

If you are taking PREVYMIS with cyclosporine, do not take:

• pitavastatin or simvastatin

Before taking PREVYMIS, tell your healthcare provider about all your medical conditions, including if you:

• have kidney or liver problems.
• are pregnant or plan to become pregnant. It is not known if PREVYMIS will harm your unborn baby.
• are breastfeeding or plan to breastfeed. It is not known if PREVYMIS passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking PREVYMIS.

Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. PREVYMIS may affect the way other medicines work, and other medicines may affect how PREVYMIS works and cause serious side effects.

Know the medicines you take. Keep a list of medicines and show it to your healthcare provider and pharmacist when you get a new medicine. Your healthcare provider or pharmacist will tell you if it is safe to take PREVYMIS with other medicines. Do not start or stop taking another medicine without telling your healthcare provider first.

• PREVYMIS comes as a tablet, oral pellets, or can be given by your healthcare provider through an IV line (intravenously).
• PREVYMIS given intravenously should be used only if you are unable to take PREVYMIS tablets or PREVYMIS oral pellets. You should switch to PREVYMIS tablets or PREVYMIS oral pellets as soon as you are able to.
• Take PREVYMIS tablets or oral pellets exactly as your healthcare provider tells you to take it. Do not stop taking PREVYMIS without talking to your healthcare provider first.
• Take PREVYMIS tablets or oral pellets 1 time a day.
• It is important that you do not miss or skip doses of PREVYMIS.
• If you miss a dose of PREVYMIS tablets or oral pellets, take it as soon as you remember. If you do not remember until it is time for your next dose, skip the missed dose and take your dose at the next scheduled time. Do not take 2 doses of PREVYMIS at the same time or take more than your prescribed dose to make up for a missed dose.
• If you take too much PREVYMIS tablets or oral pellets, call your healthcare provider right away.

• If you take PREVYMIS tablets:
  • Take PREVYMIS with or without food.
  • Swallow PREVYMIS tablets whole.
• If you take PREVYMIS oral pellets:
  • Your healthcare provider will tell you the number of PREVYMIS oral pellet packets to take for your prescribed dose.
  • PREVYMIS oral pellets can be taken by mouth after mixing with soft food or given through a nasogastric tube (NG tube) or gastric tube (G tube).
  • See the Instructions for Use for the right way to prepare and take a dose of PREVYMIS oral pellets. Keep the Instructions for Use and follow it each time you prepare and take PREVYMIS oral pellets.
  • Do not crush or chew PREVYMIS oral pellets.
• If you receive PREVYMIS through an IV line (intravenously):
  • You will receive PREVYMIS 1 time each day given over 1 hour.
  • If you miss or skip your dose of PREVYMIS, call your healthcare provider right away.

The most common side effects of PREVYMIS in adults who have received a hematopoietic stem cell transplant include:

The most common side effect of PREVYMIS in adults who have received a kidney transplant is diarrhea.

The side effects of PREVYMIS in children are similar to the side effects in adults.

These are not all the possible side effects of PREVYMIS.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

• Store PREVYMIS tablets, PREVYMIS oral pellets, and PREVYMIS injection at room temperature between 68°F to 77°F (20°C to 25°C).
• Store PREVYMIS tablets in the original package until you are ready to take it to protect from moisture.
• Store PREVYMIS oral pellets in the original packet until you are ready to take them.
• Store PREVYMIS injection in the original carton to protect from exposure to light.

Keep PREVYMIS and all medicines out of the reach of children.

Medicines are sometimes prescribed for purposes other than those listed in the Patient Information leaflet. Do not use PREVYMIS for a condition for which it was not prescribed. Do not give PREVYMIS to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about PREVYMIS that is written for healthcare professionals.

Active ingredient: letermovir

Inactive ingredients:

Tablets: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and povidone 25.

Film coating: hypromellose 2910, iron oxide red (only for 480 mg tablets), iron oxide yellow, lactose monohydrate, titanium dioxide, and triacetin. Carnauba wax is added as a polishing agent.

Oral Pellets: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and povidone K-29/32.

Film coating: hypromellose 2910, iron oxide red, iron oxide yellow, lactose monohydrate, titanium dioxide, and triacetin.

Injection: hydroxypropyl betadex, sodium chloride, sodium hydroxide, and Water for Injection.

Store PREVYMIS tablets in the original package until use to protect from moisture.

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) [see USP Controlled Room Temperature].

Mixing PREVYMIS oral pellets with soft food



Important information about mixing PREVYMIS oral pellets with soft food

Giving PREVYMIS oral pellets through a gastric tube (G tube) or nasogastric tube (NG tube)



These instructions are for giving PREVYMIS oral pellets through a G tube or NG tube.

Storing PREVYMIS oral pellets packets

• Store PREVYMIS oral pellets at room temperature between 68°F to 77°F (20°C to 25°C).
• Store PREVYMIS oral pellets in the original packet until you are ready to take them.
• Keep PREVYMIS oral pellets and all medicine out of the reach of children.

Learn more about PREVYMIS oral pellets

For more information on how to use PREVYMIS oral pellets, ask your healthcare provider or pharmacist and read the PREVYMIS Patient Information.

For more information about PREVYMIS oral pellets, go to PREVYMIS.com or call 1-800-444-2080.

Distributed by:

Merck Sharp & Dohme LLC

Rahway, NJ 07065, USA

Copyright © 2024 Merck & Co., Inc., Rahway, NJ, USA, and its affiliates. All rights reserved.

usifu-mk8228-op-2408r000

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Approved: 08/2024

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.

PREVYMIS contains letermovir, an inhibitor of the CMV DNA terminase complex, and is administered orally or by intravenous infusion.

Letermovir has a molecular formula of C₂₉H₂₈F₄N₄O₄ and a molecular weight of 572.55. The chemical name for letermovir is (4S)-2-{8-Fluoro-2-[4-(3- methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5- (trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetic acid. Letermovir is very slightly soluble in water.

The chemical structure of letermovir is:

PREVYMIS is available as 240 mg and 480 mg tablets. PREVYMIS tablets contain either 240 mg or 480 mg of letermovir and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, povidone 25, and film-coated with a coating material containing the following inactive ingredients: hypromellose 2910, iron oxide red (only for 480 mg tablets), iron oxide yellow, lactose monohydrate, titanium dioxide, and triacetin. Carnauba wax is added as a polishing agent.

PREVYMIS is available as 20 mg and 120 mg packets of oral pellets. PREVYMIS packets of oral pellets contain either 20 mg or 120 mg of letermovir. PREVYMIS oral pellets contain the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, povidone K-29/32, and are film-coated with a coating material containing the following inactive ingredients: hypromellose 2910, iron oxide red, iron oxide yellow, lactose monohydrate, titanium dioxide, and triacetin.

PREVYMIS is also available as 240 mg/12 mL (20 mg/mL) and 480 mg/24 mL (20 mg/mL) injection for intravenous infusion. PREVYMIS injection is a clear, preservative-free sterile solution and may contain a few small translucent or white particles in single-dose vials of either 240 mg or 480 mg per vial. Each 1 mL of solution contains 20 mg letermovir, hydroxypropyl betadex (150 mg), sodium chloride (3.1 mg), sodium hydroxide (1.2 mg), and Water for Injection. The amount of sodium hydroxide may be adjusted to achieve a pH of approximately 7.5.

The safety and effectiveness of PREVYMIS have been established for:

• Prophylaxis of CMV infection and disease in pediatric CMV-seropositive recipients of an allogeneic HSCT 6 months of age and older and weighing at least 6 kg, and
• Prophylaxis of CMV disease in pediatric kidney transplant recipients 12 years of age and older and weighing at least 40 kg who are at high risk [D+/R-].

HSCT Recipients: The use of PREVYMIS for prophylaxis of CMV infection and disease in pediatric recipients of an allogeneic HSCT is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data from pediatric patients in Trial P030. The safety and pharmacokinetic results were similar to those in adults [see Warnings and Precautions (5.2), Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical studies (14.2, 14.4)].

Kidney Transplant Recipients: The use of PREVYMIS for prophylaxis of CMV disease in high-risk [D+/R-] kidney transplant recipients 12 years of age and older and weighing at least 40 kg is supported by evidence from an adequate and well-controlled study in adults and safety data from pediatric HSCT recipients (Trial P030). Letermovir exposures are expected to be similar between adult and pediatric patients 12 years of age and older and weighing at least 40 kg [see Warnings and Precautions (5.2), Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical studies (14.3, 14.4)].

The safety and effectiveness of PREVYMIS have not been established for:

• HSCT recipients less than 6 months of age or weighing less than 6 kg, or
• Kidney transplant recipients less than 12 years of age or weighing less than 40 kg.

Of the 373 subjects treated with PREVYMIS in Trial P001, 56 (15%) subjects were 65 years of age or older. Of the 144 subjects treated with PREVYMIS in Trial P040, 32 (22%) subjects were 65 years of age or older. Of the 292 subjects treated with PREVYMIS in Trial P002, 48 (16%) subjects were 65 years of age or older. Safety and efficacy were similar across older and younger subjects in each trial. No dosage adjustment of PREVYMIS is required based on age [see Clinical Pharmacology (12.3)].

• 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 [see Warnings and Precautions (5.1) and Drug Interactions (7.2, 7.3)].
  • 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 [see Warnings and Precautions (5.1) and Drug Interactions (7.2, 7.3)].

• Adult HSCT Patients: Most common adverse events (occurring in at least 10% of subjects in the PREVYMIS group and at a frequency at least 2% greater than placebo) are nausea, diarrhea, vomiting, peripheral edema, cough, headache, fatigue, and abdominal pain. (6.1)
• Adult Kidney Transplant Patients: Most common adverse event (occurring in at least 10% of subjects in the PREVYMIS group and at a frequency greater than valganciclovir) is diarrhea. (6.1)
• Pediatric Patients: Adverse events in pediatric patients are similar to adults. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme LLC at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch  .

• Dosage Adjustment: If PREVYMIS is co-administered with cyclosporine, the dosage of PREVYMIS should be decreased to 240 mg once daily in adult and pediatric patients 12 years of age and older. (2.4) If PREVYMIS is co-administered with cyclosporine in pediatric patients less than 12 years of age, dose adjustment may be required. (2.6)
• Co-administration of PREVYMIS may alter the plasma concentrations of other drugs and other drugs may alter the plasma concentrations of PREVYMIS. Consult the full prescribing information prior to and during treatment for potential drug interactions. (2.4, 2.6, 4, 5.1, 7.1, 7.2, 7.3, 7.4, 12.3)

For adult patients with CLcr greater than 10 mL/min (by Cockcroft-Gault equation), and pediatric patients with a similar degree of renal impairment (based on age-appropriate assessment of renal function), no dosage adjustment of PREVYMIS is required based on renal impairment [see Clinical Pharmacology (12.3)]. The safety of PREVYMIS in adult patients with end-stage renal disease (CLcr less than 10 mL/min) or in pediatric patients with a similar degree of renal impairment (based on age-appropriate assessment of renal function), including patients on dialysis, is unknown.

In adult patients with CLcr less than 50 mL/min and in pediatric patients with a similar degree of renal impairment (based on age-appropriate assessment of renal function) receiving PREVYMIS injection, accumulation of the intravenous vehicle, hydroxypropyl betadex, could occur. Closely monitor serum creatinine levels in these patients [see Dosage and Administration (2.7) and Warnings and Precautions (5.2)].

The pharmacokinetic properties of letermovir are displayed in Table 12.

Following the completion of PREVYMIS prophylaxis, monitoring for CMV reactivation in HSCT recipients is recommended [see Clinical Studies (14.2)].

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 [see Clinical Pharmacology (12.3)].

PREVYMIS is a CMV DNA terminase complex inhibitor indicated for:

• Prophylaxis of cytomegalovirus (CMV) infection and disease in adult and pediatric patients 6 months of age and older and weighing at least 6 kg who are CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT). (1.1)
• Prophylaxis of CMV disease in adult and pediatric patients 12 years of age and older and weighing at least 40 kg who are kidney transplant recipients at high risk (Donor CMV seropositive/Recipient CMV seronegative [D+/R-]). (1.2)

PREVYMIS is an antiviral drug against CMV [see Microbiology (12.4)].

• Risk of Adverse Reactions or Reduced Therapeutic Effect Due to Drug Interactions: The concomitant use of PREVYMIS with 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. Consult the full prescribing information for contraindications and dosage recommendations for concomitant drugs. (4, 5.1, 7.1, 7.2, 7.3)
• Risks Associated with Hydroxypropyl Betadex Excipient in Intravenous Formulation: Intravenous formulation of PREVYMIS contains the excipient hydroxypropyl betadex. PREVYMIS injection should be used only in patients unable to take oral therapy. If possible, intravenous administration should not exceed 4 weeks. In patients with renal impairment, accumulation of hydroxypropyl betadex may occur. Animal studies have shown the potential for hydroxypropyl betadex to cause ototoxicity. (5.2, 8.6, 13.2)

• Adult and Pediatric Patients 12 Years of Age and Older and Weighing at least 30 kg Who Are HSCT Recipients or Adult and Pediatric Patients 12 Years of Age and Older and Weighing at least 40 kg Who Are Kidney Transplant Recipients:
  • HSCT: 480 mg administered once daily orally or as an intravenous (IV) infusion over 1 hour through 100 days post-HSCT. In patients at risk for late CMV infection and disease, PREVYMIS may be continued through 200 days post-HSCT. (2.1, 2.3)
  • Kidney Transplant: 480 mg administered once daily orally or as an IV infusion over 1 hour through 200 days post-transplant. (2.1, 2.3)
• Pediatric Patients 6 Months to Less than 12 Years of Age or 12 Years of Age and Older and Weighing Less than 30 kg Who Are HSCT Recipients:
  • HSCT: Dosing based on weight administered once daily orally or as an IV infusion over 1 hour through 100 days post-HSCT. In patients at risk for late CMV infection and disease, PREVYMIS may be continued through 200 days post-HSCT. (2.1, 2.5)
• PREVYMIS injection must be diluted prior to administration. (2.1)
• PREVYMIS injection must be administered through a sterile 0.2 micron or 0.22 micron polyethersulfone (PES) in-line filter. (2.1, 2.10)
• Following the completion of PREVYMIS prophylaxis, monitoring for CMV reactivation in HSCT recipients is recommended. (2.2)
• Dosage Adjustment: If PREVYMIS is co-administered with cyclosporine, the dosage of PREVYMIS should be decreased to 240 mg once daily in adult and pediatric patients 12 years of age and older. (2.4) If PREVYMIS is co-administered with cyclosporine in pediatric patients less than 12 years of age, dose adjustment may be required. (2.6)
• Instructions for Use should be followed for preparation and administration of PREVYMIS oral pellets. (2.9)
• Do not use PREVYMIS injection with IV bags and infusion set materials containing the plasticizer diethylhexyl phthalate (DEHP). (2.10, 2.13)

• Tablet: 240 mg; 480 mg (3)
• Oral Pellets: 20 mg or 120 mg per packet (3)
• Injection: 240 mg/12 mL (20 mg/mL) or 480 mg/24 mL (20 mg/mL) in a single-dose vial (3)

• Renal Impairment: Closely monitor serum creatinine levels in patients with CLcr less than 50 mL/min using PREVYMIS injection. (8.6)
• Hepatic Impairment: PREVYMIS is not recommended for patients with severe (Child-Pugh C) hepatic impairment. (8.7)

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.

An overview of the trials contributing to the assessment of efficacy and safety of PREVYMIS in HSCT and kidney transplant recipients is provided in Table 17.

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

The diluted solutions (as prepared in Table 6 or Table 7) are 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).

• For adult patients with creatinine clearance (CLcr) greater than 10 mL/min and pediatric patients with a similar degree of renal impairment (based on age-appropriate assessment of renal function), no dosage adjustment of PREVYMIS is required based on renal impairment [see Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].
• There are insufficient data in adult patients with CLcr 10 mL/min or less or in patients on dialysis or in pediatric patients with a similar degree of renal impairment (based on age-appropriate assessment of renal function) to make PREVYMIS dosing recommendations.
• In adult patients with CLcr less than 50 mL/min and in pediatric patients with a similar degree of renal impairment (based on age-appropriate assessment of renal function) receiving PREVYMIS injection, accumulation of the intravenous vehicle, hydroxypropyl betadex, may occur. Closely monitor serum creatinine levels in these patients [see Warnings and Precautions (5.2)].

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).

The excipient, hydroxypropyl betadex, present in the IV letermovir formulation, has been associated with hearing loss resulting from damage to the inner ear in multiple animal species. In published studies in rats, a single subcutaneous dose of 2000 mg/kg hydroxypropyl betadex resulted in changes in hearing parameters and associated decreases in outer hair cells in the inner ear. These findings were observed at hydroxypropyl betadex levels approximately 3 times higher than those present in the letermovir IV drug product at the MRHD, based on body surface area (BSA) comparisons. No adverse changes in hearing parameters or hair cell populations in the inner ear were observed in rats following a single subcutaneous dose of 1000 mg/kg hydroxypropyl betadex, which corresponds to levels approximately 1.5 times higher than those present in the letermovir IV drug product at the MRHD, based on BSA comparisons [see Warnings and Precautions (5.2)].

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 [see Use in Specific Populations (8.7)].

NDC 0006-5003-01

Prevymis^®

(letermovir) Injection

240 mg / 12 mL

(20 mg/mL)

For Intravenous Infusion Only

Requires dilution prior to administration.

Use a 0.2 or 0.22 micron in-line filter

during infusion.

See Package Insert.

Rx only

Single-dose vial. Discard unused portion.

NDC 0006-5004-01

Prevymis^®

(letermovir) Injection

480 mg /24 mL

(20 mg/mL)

For Intravenous Infusion Only

Requires dilution prior to administration.

Use a 0.2 or 0.22 micron in-line filter

during infusion.

See Package Insert.

Rx only

Single-dose vial. Discard unused portion.

Letermovir is a substrate of organic anion-transporting polypeptide 1B1/3 (OATP1B1/3) and P-glycoprotein (P-gp) transporters and UDP-glucuronosyltransferase 1A1/3 (UGT1A1/3) enzymes. Co-administration of PREVYMIS with drugs that are inhibitors of OATP1B1/3 transporters may result in increases in letermovir plasma concentrations (Table 11).

Co-administration of PREVYMIS with inducers of transporters (e.g., P-gp) and/or enzymes (e.g., UGTs) is not recommended due to the potential for a decrease in letermovir plasma concentrations (see Table 11).

Co-administration of PREVYMIS with midazolam results in increased midazolam plasma concentrations, indicating that letermovir is a moderate inhibitor of CYP3A [see Clinical Pharmacology (12.3)]. 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 (Table 11) [see Contraindications (4) and Warnings and Precautions (5.1)].

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 (Table 11).

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.

PREVYMIS oral pellets can be administered:

• orally after mixing with soft food or
• via NG tube or G tube.

Preparation and Administration Mixed with Soft Food

• See Instructions for Use for details on the preparation and administration of PREVYMIS oral pellets mixed with soft food.
• Do not crush or chew PREVYMIS oral pellets.
• Mix PREVYMIS oral pellets with 1 to 3 teaspoons of soft food (such as applesauce, yogurt, or pudding) that is at or below room temperature. Do not use hot food.
• Administer entire mixture within 10 minutes of mixing PREVYMIS oral pellets with the soft food.

Preparation and Administration via NG Tube or G Tube

See Instructions for Use , Table 4 (NG tube) and Table 5 (G tube) for details on the preparation and administration of PREVYMIS oral pellets via NG tube or G tube.

• Pour PREVYMIS oral pellets into a medicine cup containing room temperature water (see Initial Volume in Table 4 and Table 5). Do not mix PREVYMIS oral pellets with hot or cold (refrigerated) water.
• Wait 10 minutes. Do not shake or swirl the medicine cup. PREVYMIS oral pellets will not dissolve but will become loose or broken up. The entire mixture should be administered (see steps 3 and 4) within 2 hours.
• Stir the mixture with the syringe and administer entire mixture right away using the syringe and NG tube or G tube.
• Add room temperature water (see Rinse Volume in Table 4 and Table 5) to the medicine cup for rinsing, stir with a syringe and administer the entire rinse mixture using the syringe and NG tube or G tube.
• Flush the NG tube or G tube with the volume of water recommended by the NG or G tube manufacturer.

PREVYMIS is indicated for prophylaxis of CMV disease in adult and pediatric patients 12 years of age and older and weighing at least 40 kg who are kidney transplant recipients at high risk (Donor CMV seropositive/Recipient CMV seronegative [D+/R-]).

• PREVYMIS is available in 3 dosage forms:
  • PREVYMIS Tablets
    • -
      Administer orally with or without food.
    • -
      Swallow tablets whole.
  • PREVYMIS Oral Pellets
    • -
      Administer orally mixed with soft food or via nasogastric tube (NG tube) or gastric tube (G tube) [see Dosage and Administration (2.9)].
    • -
      Do not crush or chew.
  • PREVYMIS Injection
    • -
      PREVYMIS injection must be diluted prior to administration.
    • -
      Administer PREVYMIS through a sterile 0.2 micron or 0.22 micron polyethersulfone (PES) in-line filter.
    • -
      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.
    • -
      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. If possible, intravenous administration should not exceed 4 weeks [see Warnings and Precautions (5.2)].
• No dosage adjustment is necessary when switching formulations in adult and pediatric patients 12 years of age and older [see Dosage and Administration (2.3)].
• Dosage adjustment may be necessary for pediatric patients less than 12 years of age when switching between oral and intravenous formulations (see Table 1 and Table 2) [see Dosage and Administration (2.5)].

NDC 0006-5086-01

PREVYMIS^®

(letermovir) oral pellets

20 mg per packet

Each packet contains 20 mg letermovir.

DIRECTIONS FOR USE: See enclosed

Instructions for Use booklet and

prescribing information.

Rx only

30 packets

NDC 0006-5085-01

PREVYMIS^®

(letermovir) oral pellets

120 mg per packet

Each packet contains 120 mg letermovir

DIRECTIONS FOR USE: See enclosed

Instructions for Use booklet and

prescribing information.

Rx only

30 packets

NDC 0006-3075-04

Prevymis^®

(letermovir) tablets

240 mg

Each tablet contains 240 mg letermovir.

This is a bulk package and not intended for dispensing.

This package is not child resistant.

Rx only

14 tablets: 7 tablets x 2 blister cards

NDC 0006-3076-04

Prevymis^®

(letermovir) tablets

480 mg

Each tablet contains 480 mg letermovir.

This is a bulk package and not intended for dispensing.

This package is not child resistant.

Rx only

14 tablets: 7 tablets x 2 blister cards

NDC 0006-3075-02

PREVYMIS^®

(letermovir) tablets

240 mg per tablet

Rx only

28 Tablets

This carton contains a total of 28 tablets

packaged within 4 dose packs.

Each dose pack contains 7 blister units

with one tablet per blister unit.

NDC 0006-3076-02

PREVYMIS^®

(letermovir) tablets

480 mg per tablet

1 tablet a day

28-day supply

Rx only

28 Tablets

This carton contains a total of 28 tablets

packaged within 4 dose packs.

Each dose pack contains 7 blister units

with one tablet per blister unit.

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).

PREVYMIS vials are for single use only. Discard any unused portion.

Sixty-three children 2 months to less than 18 years of age who had an allogeneic HSCT were enrolled in a multicenter, open-label, single-arm pharmacokinetic, safety and effectiveness study of PREVYMIS (P030, NCT03940586). Subjects received PREVYMIS daily either orally or intravenously for CMV prophylaxis within 28 days post-HSCT through Week 14 post-HSCT. The intravenous formulation was used for up to four weeks in subjects who were unable to take oral therapy. The daily doses of PREVYMIS were based on body weight [see Dosage and Administration (2.3, 2.5)]. Among the 63 treated subjects, 8 were 2 months to less than 2 years of age, 27 were 2 to less than 12 years of age and 28 were 12 to less than 18 years of age. The median age was 11 years; 70% were male; 70% were White; 14% were Asian; 5% were Black; and 22% were Hispanic or Latino [see Use in Specific Populations (8.4)].

The efficacy analyses population consisted of 56 subjects who received at least one dose of study drug and had no detectable CMV DNA at baseline. The proportion of subjects who failed CMV prophylaxis through Week 24 post-HSCT was 25% (14 of the 56 subjects). Six subjects had initiation of pre-emptive therapy based on CMV viremia and 8 subjects discontinued from the study before Week 24. None of the subjects had CMV end-organ disease.

PREVYMIS is indicated for pediatric recipients of an allogeneic HSCT aged 6 months and older and weighing at least 6 kg.

If dose adjustments of concomitant medications are made due to treatment with PREVYMIS, doses should be readjusted after treatment with PREVYMIS is completed.

Table 11 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on adult studies conducted with PREVYMIS or are predicted drug interactions that may occur with PREVYMIS [see Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].

No clinically significant interactions were observed in adult clinical drug-drug interaction studies of letermovir and acyclovir, digoxin, mycophenolate mofetil, fluconazole, itraconazole, posaconazole, ethinyl estradiol, and levonorgestrel.

PREVYMIS^® is indicated for prophylaxis of cytomegalovirus (CMV) infection and disease in adult and pediatric patients 6 months of age and older and weighing at least 6 kg who are CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT).

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 Contraindications (4) and Drug Interactions (7.1, 7.2, 7.3)].

See Table 11 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.

Intravenous formulation of PREVYMIS contains the excipient hydroxypropyl betadex. PREVYMIS injection should be used only in patients unable to take oral therapy and patients should be switched to oral PREVYMIS as soon as they are able to take oral medications. If possible, intravenous administration should not exceed 4 weeks [see Dosage and Administration (2.1)].

In patients with renal impairment, accumulation of hydroxypropyl betadex may occur. In adult patients with CLcr less than 50 mL/min and in pediatric patients with a similar degree of renal impairment (based on age-appropriate assessment of renal function) receiving PREVYMIS injection, closely monitor serum creatinine levels [see Dosage and Administration (2.7) and Use in Specific Populations (8.6)].

Animal studies have shown the potential for hydroxypropyl betadex to cause ototoxicity [see Nonclinical Toxicology (13.2)]. The active ingredient, letermovir, is not known to be associated with ototoxicity.

To evaluate PREVYMIS prophylaxis as a preventive strategy for CMV disease in kidney transplant recipients, the efficacy of PREVYMIS was assessed in a multicenter, double-blind, active comparator-controlled non-inferiority Phase 3 trial (P002, NCT03443869) in adult kidney transplant recipients at high risk [D+/R-]. Subjects were randomized (1:1) to receive either PREVYMIS or valganciclovir. PREVYMIS was administered at a dose of 480 mg once daily (adjusted to 240 mg when co-administered with cyclosporine). PREVYMIS was given concomitantly with acyclovir. Valganciclovir was given concomitantly with a placebo to acyclovir. Randomization was stratified by the use or nonuse of highly cytolytic, anti-lymphocyte immunotherapy during induction. Study drug was initiated between Day 0 and Day 7 post-kidney transplant and continued through Week 28 (~200 days) post-transplant. Study drug was administered either orally or IV; the dose of PREVYMIS was the same regardless of the route of administration. Three subjects received IV PREVYMIS for a mean duration of 1.7 days. Subjects were monitored through Week 52 post-transplant.

Among the 589 treated subjects, 292 subjects received PREVYMIS and 297 received valganciclovir. The median age was 51 years (range: 18 to 82 years); 72% were male; 84% were White; 9% were Black; 3% were multiple; 2% were Asian; 1% Alaskan native or American Indian; 17% were Hispanic or Latino; and 60% received a kidney from a deceased donor. The most common primary reasons for transplant were congenital cystic kidney disease (17%), hypertension (16%), and diabetes/diabetic nephropathy (14%).

CMV Disease

The primary efficacy endpoint of Trial P002 was the incidence of CMV disease (CMV end-organ disease or CMV syndrome, confirmed by an independent adjudication committee) through Week 52 post-transplant. The Observed Failure (OF) approach was used, where subjects who discontinued prematurely from the study for any reason or were missing data at the timepoint were not counted as failures. The number of subjects who discontinued from the study before Week 52 was 32 (11%) in the PREVYMIS arm and 28 (9%) in the valganciclovir arm. The number of subjects with a missing outcome in the Week 52 visit window was 24 (8%) in the PREVYMIS arm and 25 (8%) in the valganciclovir arm.

Efficacy results from Trial P002 are shown in Table 20.

Efficacy was comparable across all subgroups, including the use/nonuse of highly cytolytic, anti-lymphocyte immunotherapy during induction.

In an exploratory analysis of the incidence of CMV disease through Week 28 post-transplant, the difference (PREVYMIS – Valganciclovir) was -1.7% with 95% CI of (-3.4, 0.1). No subjects in the PREVYMIS group experienced CMV disease through Week 28 post-transplant (end of treatment period) compared with 5 subjects in the valganciclovir group.

Prophylaxis Through Week 14 (~100 days) Post-HSCT (Trial P001)

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-HSCT) and continued through Week 14 post-HSCT. 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-HSCT Week 14 and then bi-weekly until post-HSCT 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-HSCT.

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 5% were other (American Indian or Alaska Native, multiple, and missing). 7% were Hispanic or Latino; 89% not Hispanic or Latino; and 4% other (not reported, unknown, and missing).

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%).

HSCT: Adult and Pediatric Patients 12 Years of Age and Older and Weighing at least 30 kg

The recommended dosage of PREVYMIS is 480 mg administered orally or intravenously once daily. When PREVYMIS is administered orally, the recommended dosage is one 480 mg tablet once daily or two 240 mg tablets once daily. Four 120 mg packets of oral pellets once daily can be used for patients who cannot swallow tablets [see Dosage and Administration (2.9)]. For preparation and administration instructions of intravenous dosing refer to instructions in subsection 2.10 [see Dosage and Administration (2.10)]. For pediatric patients less than 12 years of age or weighing less than 30 kg, refer to weight-based dosing in Table 1 and Table 2 [see Dosage and Administration (2.5)].

Initiate PREVYMIS between Day 0 and Day 28 post-HSCT (before or after engraftment) and continue through Day 100 post-HSCT. In patients at risk for late CMV infection and disease, PREVYMIS may be continued through Day 200 post-HSCT [see Clinical Studies (14.2)].

Dosage of PREVYMIS should be adjusted when co-administered with cyclosporine [see Dosage and Administration (2.4)].

Kidney Transplant: Adult and Pediatric Patients 12 Years of Age and Older and Weighing at least 40 kg

The recommended dosage of PREVYMIS is 480 mg administered orally or intravenously once daily. When PREVYMIS is administered orally, the recommended dosage is one 480 mg tablet once daily or two 240 mg tablets once daily. Four 120 mg packets of oral pellets once daily can be used for patients who cannot swallow tablets [see Dosage and Administration (2.9)]. For preparation and administration instructions of intravenous dosing refer to instructions in subsection 2.10 [see Dosage and Administration (2.10)].

Initiate PREVYMIS between Day 0 and Day 7 post-transplant and continue through Day 200 post-transplant.

Dosage of PREVYMIS should be adjusted when co-administered with cyclosporine [see Dosage and Administration (2.4)].

• If oral or intravenous PREVYMIS is co-administered with cyclosporine, the dosage of PREVYMIS should be decreased to 240 mg once daily in the following populations [see Drug Interactions (7.1, 7.2, 7.3) and Clinical Pharmacology (12.3)]:
  • HSCT: adult and pediatric patients 12 years of age and older and weighing at least 30 kg
    
    or
  • Kidney transplant: adult and pediatric patients 12 years of age and older and weighing at least 40 kg.
• 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.

The recommended dosages of PREVYMIS for pediatric HSCT recipients 6 months to less than 12 years of age are based on weight and shown in Table 1 (tablets or oral pellets) and Table 2 (injection) [see Clinical Pharmacology (12.3)]. PREVYMIS can be administered orally (tablet or pellet) or intravenously once daily. Dosage adjustment may be necessary for pediatric patients less than 12 years of age when switching between oral and intravenous formulations (see Table 1 and Table 2).

Initiate PREVYMIS between Day 0 and Day 28 post-HSCT (before or after engraftment) and continue through Day 100 post-HSCT. In patients at risk for late CMV infection and disease, PREVYMIS may be continued through Day 200 post-HSCT [see Clinical Studies (14.2)].

If oral or intravenous PREVYMIS is co-administered with cyclosporine in pediatric HSCT recipients 6 months to less than 12 years of age, the dosage of PREVYMIS may require adjustment as shown in Table 3 [see Drug Interactions (7.1, 7.2, 7.3) and Clinical Pharmacology (12.3)].

• If cyclosporine is initiated after starting PREVYMIS, the next dose of PREVYMIS should be the daily oral or intravenous dose co-administered with cyclosporine (Table 3)
• If cyclosporine is discontinued after starting PREVYMIS, the next dose of PREVYMIS should be the daily oral or intravenous dose administered without cyclosporine (Table 1 or Table 2)
• If cyclosporine dosing is interrupted due to high cyclosporine levels, no dose adjustment of PREVYMIS is needed.