What is the dosage of Prevymis?

Prevymis is available in 6 dosages, including 20 mg Pellet, 240 mg Tab, 20 mg/ml Injection 12 ml, 120 mg Pellet, 20 mg/ml Injection 24 ml and 480 mg Tab

What is Prevymis made of?

Prevymis contains letermovir which is a Cytomegalovirus DNA Terminase Complex Inhibitor

How is Prevymis administered?

Prevymis is administered as a Oral Pellet, Oral Pill or Injectable

What is Prevymis mechanism of action?

Prevymis mechanism of action is Cytochrome P450 2C9 Inducers, Cytochrome P450 2C19 Inducers, Cytochrome P450 2C8 Inhibitors, Organic Anion Transporting Polypeptide 1B1 Inhibitors, Organic Anion Transporting Polypeptide 1B3 Inhibitors, Cytochrome P450 3A Inhibitors or DNA Terminase Complex Inhibitors

Prevymis

(letermovir)

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Dosage & Administration

* 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.
* Kidney Transplant: 480 mg administered once daily orally or as an IV infusion over 1 hour through 200 days post-transplant.

* 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.

* PREVYMIS injection must be diluted prior to administration.
* PREVYMIS injection must be administered through a sterile 0.2 micron or 0.22 micron polyethersulfone (PES) in-line filter.
* Following the completion of PREVYMIS prophylaxis, monitoring for CMV reactivation in HSCT recipients is recommended.
* 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. If PREVYMIS is co-administered with cyclosporine in pediatric patients less than 12 years of age, dose adjustment may be required.
* Instructions for Use should be followed for preparation and administration of PREVYMIS oral pellets.
* Do not use PREVYMIS injection with IV bags and infusion set materials containing the plasticizer diethylhexyl phthalate (DEHP).

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Prevymis Prescribing Information

1.1 CMV Prophylaxis in Hematopoietic Stem Cell Transplant (HSCT) Recipients

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).

1.2 CMV Prophylaxis in Kidney Transplant Recipients

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-]).

Important Dosing and Administration Information

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)].

Patient Monitoring

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

2.3 Recommended Dosage for Adult and Pediatric Patients 12 Years of Age and Older Who Are HSCT or Kidney Transplant Recipients

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

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)].

2.4 Dosage Adjustment When Co-administered with Cyclosporine for Adult and Pediatric Patients 12 Years of Age and Older Who Are HSCT or Kidney Transplant Recipients

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.

2.5 Recommended Dosage for 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

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).

Table 1: Recommended Daily Oral Dosage of PREVYMIS in Pediatric HSCT Recipients 6 Months to Less than 12 Years of Age or 12 Years of Age and Older and Weighing Less than 30 kg
Body Weight	Daily Oral Dose	Tablets	Oral Pellets
30 kg and above	480 mg	One 480 mg tablet or Two 240 mg tablets	Four 120 mg packets of oral pellets
15 kg to less than 30 kg	240 mg	One 240 mg tablet	Two 120 mg packets of oral pellets
7.5 kg to less than 15 kg	120 mg	Not recommended	One 120 mg packet of oral pellets
6 kg to less than 7.5 kg	80 mg	Not recommended	Four 20 mg packets of oral pellets

Table 2: Recommended Daily IV Dosage of PREVYMIS in Pediatric HSCT Recipients 6 Months to Less than 12 Years of Age or 12 Years of Age and Older and Weighing Less than 30 kg
Body Weight	Daily IV * Dose
* Refer to Subsection 2.10 for intravenous preparation and administration dosing instructions
30 kg and above	480 mg
15 kg to less than 30 kg	120 mg
7.5 kg to less than 15 kg	60 mg
6 kg to less than 7.5 kg	40 mg

2.6 Dosage Adjustment When Co-administered with Cyclosporine for 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

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.

Table 3: Recommended Dosage of PREVYMIS when Co-administered with Cyclosporine in Pediatric HSCT Recipients 6 Months to Less than 12 Years of Age or 12 Years of Age and Older and Weighing Less than 30 kg
Body Weight	Daily Oral Dose	Tablets	Oral Pellets	Daily IV * Dose
* Refer to Subsection 2.10 for intravenous preparation and administration dosing instructions
30 kg and above	240 mg	One 240 mg tablet	Two 120 mg packets of oral pellets	240 mg
15 kg to less than 30 kg	120 mg	Not recommended	One 120 mg packet of oral pellets	120 mg
7.5 kg to less than 15 kg	60 mg	Not recommended	Three 20 mg packets of oral pellets	60 mg
6 kg to less than 7.5 kg	40 mg	Not recommended	Two 20 mg packets of oral pellets	40 mg

2.7 Use in Patients with Renal Impairment

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)].

Use in Patients with Hepatic Impairment

No dosage adjustment of PREVYMIS is required for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. PREVYMIS is not recommended for patients with severe (Child-Pugh Class C) hepatic impairment [see Use in Specific Populations (8.7)].

2.9 Preparation and Administration of Oral Pellets

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.

Table 4: Recommendations for Administration of PREVYMIS Oral Pellets Via NG Tube
Dosage	NG Tube *	Syringe Type †	Mixing Container	Initial Volume (mL)	Rinse Volume (mL)
* Fr = French; PUR = polyurethane † With ENFit syringe, a medicine straw (large bore) is needed to aid withdrawal of the mixture from the medicine cup.
120 mg to 480 mg	Any ≥ 8 Fr NG tube	Appropriately sized ENFit or catheter-tipped syringe	Medicine Cup	15	15
40 mg to 80 mg	5 Fr PUR NG tube or Any ≥ 6 Fr NG tube	Appropriately sized ENFit or catheter-tipped syringe	Medicine Cup	3	2

Table 5: Recommendations for Administration of PREVYMIS Oral Pellets Via G Tube
Dosage	G Tube *	Syringe Type †	Mixing Container	Initial Volume (mL)	Rinse Volume (mL)
* Fr = French; PUR = polyurethane † With ENFit syringe, a medicine straw (large bore) is needed to aid withdrawal of the mixture from the medicine cup.
120 mg to 480 mg	Any G tube	Appropriately sized ENFit or catheter-tipped syringe	Medicine Cup	15	15
40 mg to 80 mg	Any 12 Fr G tube	Appropriately sized ENFit or catheter-tipped syringe	Medicine Cup	3	2

Preparation and Administration of Intravenous Solution

PREVYMIS injection is supplied in 30 mL single-dose vials containing either 240 mg/12 mL per vial (20 mg/mL) or 480 mg/24 mL per vial (20 mg/mL).

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

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.

Table 6: Preparation of PREVYMIS Intravenous Solution for Doses of 60 mg or Greater
PREVYMIS Dose	Volume of PREVYMIS 20 mg/mL to be Withdrawn from Vial	Volume of Diluent
480 mg	24 mL	250 mL
240 mg	12 mL	250 mL
120 mg	6 mL	100 mL
60 mg	3 mL	50 mL

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.

Table 7: Preparation of PREVYMIS Intravenous Solution for Doses of 40 mg
PREVYMIS Dose	Preparation of 2 mg/mL PREVYMIS Dilution	Final Infusion Volume of the Prepared 2 mg/mL PREVYMIS Dilution
40 mg	Add 5 mL of 20 mg/mL PREVYMIS to 45 mL of diluent (0.9% Sodium Chloride Injection or 5% Dextrose Injection) and mix gently	20 mL

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.

Storage of the Diluted Solution

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).

Compatible Drug Products Used for Intravenous Administration

Compatible Drug Products

The physical compatibility of PREVYMIS injection with selected injectable drug products was evaluated in two commonly available diluents. PREVYMIS should not be co-administered through the same intravenous line (or cannula) with other drug products and diluent combinations except those listed below. Refer to the respective prescribing information of the co-administered drug(s) to confirm compatibility of simultaneous co-administration.

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

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

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

: Amphotericin B (lipid complex) 1, anidulafungin, cefazolin sodium, ceftaroline, ceftriaxone sodium, doripenem, famotidine, folic acid, ganciclovir sodium, hydrocortisone sodium succinate, morphine sulfate, norepinephrine bitartrate, pantoprazole sodium, potassium chloride, potassium phosphate, tacrolimus, telavancin, tigecycline.

1: Amphotericin B (lipid complex) is compatible with PREVYMIS. However, Amphotericin B (liposomal) is incompatible [see Dosage and Administration (2.13)].

Incompatible Drug Products and Other Materials Used for Intravenous Administration

Incompatible Drug Products

PREVYMIS injection is physically incompatible with amiodarone hydrochloride, amphotericin B (liposomal), aztreonam, cefepime hydrochloride, ciprofloxacin, cyclosporine, diltiazem hydrochloride, filgrastim, gentamicin sulfate, levofloxacin, linezolid, lorazepam, midazolam HCl, mycophenolate mofetil hydrochloride, ondansetron, palonosetron.

Incompatible IV Bags and Infusion Set Materials

PREVYMIS injection is incompatible with diethylhexyl phthalate (DEHP) plasticizers and polyurethane-containing IV administration set tubing.

Tablets

PREVYMIS 240 mg tablet: yellow oval tablet with "591" on one side and corporate logo on the other side.
PREVYMIS 480 mg tablet: pink oval, bi-convex tablet with "595" on one side and corporate logo on the other side.

Oral Pellets

PREVYMIS oral pellets: beige round pellets in packets. Each packet contains 20 mg letermovir.
PREVYMIS oral pellets: beige round pellets in packets. Each packet contains 120 mg letermovir.

Injection

PREVYMIS 240 mg/12 mL (20 mg/mL) injection: clear and colorless solution in a single-dose vial.
PREVYMIS 480 mg/24 mL (20 mg/mL) injection: clear and colorless solution in a single-dose vial.

Pregnancy

Risk Summary

No adequate human data are available to establish whether PREVYMIS poses a risk to pregnancy outcomes. In animal reproduction studies, embryo-fetal developmental toxicity (including fetal malformations) was observed in rats during the period of organogenesis at letermovir exposures (AUC) 11 times higher than human exposure at the recommended human dose (RHD). In rabbits, no embryo-fetal developmental toxicity was noted at exposures that were not maternally toxic (up to letermovir exposures 2 times higher than human exposure at the RHD). In a rat pre/post-natal development study, total litter loss was observed at maternal letermovir exposures approximately 2 times higher than human exposure at the RHD (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

Letermovir was administered orally to pregnant rats at 0, 10, 50 or 250 mg/kg/day from gestation days 6 to 17. Developmental toxicities, including skeletal malformations and umbilical cord shortening, were observed at 250 mg/kg/day (approximately 11 times higher than human exposure at the RHD). In addition, decreased fetal body weight and skeletal variations (due to maternal toxicity) were observed at this dose. No embryo-fetal toxicities were observed at 50 mg/kg/day (approximately 3 times higher than human exposure at the RHD).

Letermovir was administered orally to pregnant rabbits at 0, 25, 75 or 225 mg/kg/day from gestation days 6 to 20. Developmental toxicities, including spontaneous abortion, increased post-implantation loss, and skeletal variations, were observed at a maternally toxic dose (225 mg/kg/day; approximately 2 times higher than human exposure at the RHD). No embryo-fetal toxicities were observed at 75 mg/kg/day (less than human exposure at the RHD).

In the pre/post-natal development study, letermovir was administered orally to pregnant rats at 0, 10, 45 or 180 mg/kg/day from gestation day 6 to lactation day 22. At 180 mg/kg/day (approximately 2 times higher than human exposure at the RHD), total litter loss due to stillbirth or possible maternal neglect was observed in 5 of 23 pregnant females by post-partum/lactation day 4. In surviving offspring, slight developmental delays in vaginal opening and pinna unfolding were accompanied by reduced body weight gain at this dose. No toxicities were observed at 45 mg/kg/day (similar to human exposure at the RHD).

Lactation

Risk Summary

It is not known whether letermovir is present in human breast milk, affects human milk production, or has effects on the breastfed child.

When administered to lactating rats, letermovir was present in the milk of lactating rats as well as the blood of nursing pups (see Data).

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

Data

In a lactation study, letermovir was excreted in milk when administered intravenously (at 10 mg/kg) to lactating rats on post-partum/lactation day 10. Letermovir was also detected in the blood of nursing pups on post-partum/lactation day 21 in the pre/post-natal developmental study.

Females and Males of Reproductive Potential

Infertility

There are no data on the effect of letermovir on human fertility. Decreased fertility due to testicular toxicity was observed in male rats [see Nonclinical Toxicology (13.1, 13.2)].

Pediatric Use

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.

Geriatric Use

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)].

Renal Impairment

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)].

Hepatic Impairment

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)].

Risk of Adverse Reactions or Reduced Therapeutic Effect Due to Drug Interactions

The concomitant use of PREVYMIS and certain drugs may result in potentially significant drug interactions, some of which may lead to adverse reactions (PREVYMIS or concomitant drugs) or reduced therapeutic effect of PREVYMIS or the concomitant drug [see 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.

5.2 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 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.