What is mechanism of action?

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

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. (

2.1 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 1and Table 2)

[see Dosage and Administration (2.5)]

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

[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)]

)
*

Kidney Transplant

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

2.1 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)]

[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 1and Table 2)

[see Dosage and Administration (2.5)]

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

[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)]

[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

[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)]

)

*

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 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)]

[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 1and Table 2)

[see Dosage and Administration (2.5)]

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 1and Table 2)

[see Clinical Studies (14.2)]

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 IVRefer to Subsection 2.10for intravenous preparation and administration dosing instructionsDose
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

)

* PREVYMIS injection must be diluted prior to administration. (

2.1 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)]

[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 1and Table 2)

[see Dosage and Administration (2.5)]

)
* PREVYMIS injection must be administered through a sterile 0.2 micron or 0.22 micron polyethersulfone (PES) in-line filter. (

2.1 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)]

[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 1and Table 2)

[see Dosage and Administration (2.5)]

2.10 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.

)
* Following the completion of PREVYMIS prophylaxis, monitoring for CMV reactivation in HSCT recipients is recommended. (

2.2 Patient Monitoring

Following the completion of PREVYMIS prophylaxis, monitoring for CMV reactivation in HSCT recipients is recommended

[see Clinical Studies (14.2)]

)
* 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 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.

) If PREVYMIS is co-administered with cyclosporine in pediatric patients less than 12 years of age, dose adjustment may be required. (

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 IVRefer to Subsection 2.10for intravenous preparation and administration dosing instructionsDose
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

)
* Instructions for Use should be followed for preparation and administration of PREVYMIS oral pellets. (

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 TubeFr = French; PUR = polyurethane	Syringe TypeWith ENFit syringe, a medicine straw (large bore) is needed to aid withdrawal of the mixture from the medicine cup.	Mixing Container	Initial Volume (mL)	Rinse Volume (mL)
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 TubeFr = French; PUR = polyurethane	Syringe TypeWith ENFit syringe, a medicine straw (large bore) is needed to aid withdrawal of the mixture from the medicine cup.	Mixing Container	Initial Volume (mL)	Rinse Volume (mL)
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

)
* Do not use PREVYMIS injection with IV bags and infusion set materials containing the plasticizer diethylhexyl phthalate (DEHP). (

2.10 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

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

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)]

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.

)

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Prevymis Prescribing Information

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.

[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 1and Table 2)

[see Dosage and Administration (2.5)]

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

[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)]

[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

[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)]

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)]

(see Table 1and Table 2)

[see Clinical Studies (14.2)]

-
Indications and Usage ( 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-]). )	08/2024
Dosage and Administration ( 2.1 Important Dosing and Administration Information PREVYMIS is available in 3 dosage forms: PREVYMIS Tablets

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 IVRefer to Subsection 2.10for intravenous preparation and administration dosing instructionsDose
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

[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 IVRefer to Subsection 2.10for intravenous preparation and administration dosing instructionsDose
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)]
.

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 TubeFr = French; PUR = polyurethane	Syringe TypeWith ENFit syringe, a medicine straw (large bore) is needed to aid withdrawal of the mixture from the medicine cup.	Mixing Container	Initial Volume (mL)	Rinse Volume (mL)
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 TubeFr = French; PUR = polyurethane	Syringe TypeWith ENFit syringe, a medicine straw (large bore) is needed to aid withdrawal of the mixture from the medicine cup.	Mixing Container	Initial Volume (mL)	Rinse Volume (mL)
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

2.10 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.

)08/2024Warnings and Precautions (

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.

)08/2024

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 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 1and Table 2)
  [see Dosage and Administration (2.5)]
  .
  ,
  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
  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)]
  .
  )
- Kidney Transplant
  : 480 mg administered once daily orally or as an IV infusion over 1 hour through 200 days post-transplant. (
  2.1 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 1and Table 2)
  [see Dosage and Administration (2.5)]
  .
  ,
  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
  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)]
  .
  )

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

2.1 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 1and Table 2)
[see Dosage and Administration (2.5)]
.

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)]

(see Table 1and Table 2)

[see Clinical Studies (14.2)]

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 IVRefer to Subsection 2.10for intravenous preparation and administration dosing instructionsDose
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

)

PREVYMIS injection must be diluted prior to administration. (
2.1 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 1and Table 2)
  [see Dosage and Administration (2.5)]
  .
)

PREVYMIS injection must be administered through a sterile 0.2 micron or 0.22 micron polyethersulfone (PES) in-line filter. (

2.1 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 1and Table 2)
[see Dosage and Administration (2.5)]
.

2.10 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.

)

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

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 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.

) If PREVYMIS is co-administered with cyclosporine in pediatric patients less than 12 years of age, dose adjustment may be required. (

[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 IVRefer to Subsection 2.10for intravenous preparation and administration dosing instructionsDose
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

)

Instructions for Use should be followed for preparation and administration of PREVYMIS oral pellets. (

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 TubeFr = French; PUR = polyurethane	Syringe TypeWith ENFit syringe, a medicine straw (large bore) is needed to aid withdrawal of the mixture from the medicine cup.	Mixing Container	Initial Volume (mL)	Rinse Volume (mL)
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 TubeFr = French; PUR = polyurethane	Syringe TypeWith ENFit syringe, a medicine straw (large bore) is needed to aid withdrawal of the mixture from the medicine cup.	Mixing Container	Initial Volume (mL)	Rinse Volume (mL)
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

)

Do not use PREVYMIS injection with IV bags and infusion set materials containing the plasticizer diethylhexyl phthalate (DEHP). (

2.10 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.

2.13 Incompatible Drug Products and Other Materials Used for Intravenous Administration

Incompatible Drug Products

Incompatible IV Bags and Infusion Set Materials

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

)

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

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

5.1 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 11for 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.

and

7.2 Potential for PREVYMIS to Affect Other Drugs

Co-administration of PREVYMIS with midazolam results in increased midazolam plasma concentrations, indicating that letermovir is a moderate inhibitor of CYP3A

[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.

7.3 Established and Other Potentially Significant Drug Interactions

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

Table 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)]

Table 11: Potentially Significant Drug Interactions: Alteration in Dose May Be Recommended Based on Results from Adult Drug Interaction Studies or Predicted InteractionsThis table is not all inclusive.(Information in the Table Applies to Co-administration of PREVYMIS and the Concomitant Drug without Cyclosporine, Unless Otherwise Indicated)
Concomitant Drug Class and/or Clearance Pathway: Drug Name	Effect on Concentration↓ =decrease, ↑ =increase	Clinical Comments
Anti-arrhythmic Agents
amiodarone	↑ amiodarone	Close clinical monitoring for adverse events related to amiodarone is recommended during co-administration. Frequently monitor amiodarone concentrations when amiodarone is co-administered with PREVYMIS.
Antibiotics
nafcillin	↓ letermovir	Co-administration of PREVYMIS and nafcillin is not recommended due to potential for loss of efficacy of PREVYMIS.
Anticoagulants
warfarin	↓ warfarin	When PREVYMIS is co-administered with warfarin, frequently monitor International Normalized Ratio (INR)Refer to the respective prescribing information..
Anticonvulsants
carbamazepine	↓ letermovir	Co-administration of PREVYMIS and carbamazepine is not recommended due to potential for loss of efficacy of PREVYMIS.
phenobarbital	↓ letermovir	Co-administration of PREVYMIS and phenobarbital is not recommended due to potential for loss of efficacy of PREVYMIS.
phenytoin	↓ letermovir ↓ phenytoin	Co-administration of PREVYMIS and phenytoin is not recommended due to potential for loss of efficacy of PREVYMIS.
Antidiabetic Agents
Examples: glyburide, repaglinide, rosiglitazone	↑ glyburide ↑ repaglinide ↑ rosiglitazone	When PREVYMIS is co-administered with glyburide, repaglinide, or rosiglitazone, frequently monitor glucose concentrations . When PREVYMIS is co-administered with cyclosporine, use of repaglinide is not recommended.
Antifungals
voriconazoleThese interactions have been studied [see Clinical Pharmacology (12.3)] .	↓ voriconazole	If concomitant administration of voriconazole is necessary, closely monitor for reduced effectiveness of voriconazole .
Antimycobacterials
rifabutin	↓ letermovir	Co-administration of PREVYMIS and rifabutin is not recommended due to potential for loss of efficacy of PREVYMIS.
rifampin	↓ letermovir	Co-administration of PREVYMIS and rifampin is not recommended due to potential for loss of efficacy of PREVYMIS.
Antipsychotics
pimozide	↑ pimozide	Co-administration is contraindicated due to risk of QT prolongation and torsades de pointes [see Contraindications (4)] .
thioridazine	↓ letermovir	Co-administration of PREVYMIS and thioridazine is not recommended due to potential for loss of efficacy of PREVYMIS.
Endothelin Antagonists
bosentan	↓ letermovir	Co-administration of PREVYMIS and bosentan is not recommended due to potential for loss of efficacy of PREVYMIS.
Ergot Alkaloids
ergotamine, dihydroergotamine	↑ ergotamine, dihydroergotamine	Co-administration is contraindicated due to risk of ergotism [see Contraindications (4)] .
Herbal Products
St. John's wort ( Hypericum perforatum )	↓ letermovir	Co-administration of PREVYMIS and St. John's wort is not recommended due to potential for loss of efficacy of PREVYMIS.
HIV Medications
efavirenz	↓ letermovir	Co-administration of PREVYMIS and efavirenz is not recommended due to potential for loss of efficacy of PREVYMIS.
etravirine	↓ letermovir	Co-administration of PREVYMIS and etravirine is not recommended due to potential for loss of efficacy of PREVYMIS.
nevirapine	↓ letermovir	Co-administration of PREVYMIS and nevirapine is not recommended due to potential for loss of efficacy of PREVYMIS.
HMG-CoA Reductase Inhibitors
atorvastatin	↑ atorvastatin	When PREVYMIS is co-administered with atorvastatin, do not exceed an atorvastatin dosage of 20 mg daily . Closely monitor patients for myopathy and rhabdomyolysis. When PREVYMIS is co-administered with cyclosporine, use of atorvastatin is not recommended.
pitavastatin, simvastatin	↑ HMG-CoA reductase inhibitors	Co-administration of PREVYMIS and pitavastatin or simvastatin is not recommended. When PREVYMIS is co-administered with cyclosporine, use of either pitavastatin or simvastatin is contraindicated due to significantly increased pitavastatin or simvastatin concentrations and risk of myopathy or rhabdomyolysis [see Contraindications (4)] .
fluvastatin, lovastatin, pravastatin, rosuvastatin	↑ HMG-CoA reductase inhibitors	When PREVYMIS is co-administered with these statins, a statin dosage reduction may be necessary . Closely monitor patients for myopathy and rhabdomyolysis. When PREVYMIS is co-administered with cyclosporine, use of lovastatin is not recommended. When PREVYMIS is co-administered with cyclosporine, refer to the statin prescribing information for specific statin dosing recommendations.
Immunosuppressants
cyclosporine	↑ cyclosporine ↑ letermovir	Decrease the dosage of PREVYMIS to 240 mg once daily in adult and pediatric patients 12 years of age and older [see Dosage and Administration (2.4)and Clinical Pharmacology (12.3)] . Dose adjustment may be required in pediatric patients less than 12 years of age [see Dosage and Administration (2.6)and Clinical Pharmacology (12.3)] . Frequently monitor cyclosporine whole blood concentrations during treatment and after discontinuation of PREVYMIS and adjust the dose of cyclosporine accordingly .
sirolimus	↑ sirolimus	When PREVYMIS is co-administered with sirolimus, frequently monitor sirolimus whole blood concentrations during treatment and after discontinuation of PREVYMIS and adjust the dose of sirolimus accordingly . When PREVYMIS is co-administered with cyclosporine and sirolimus, refer to the sirolimus prescribing information for specific sirolimus dosing recommendations .
tacrolimus	↑ tacrolimus	Frequently monitor tacrolimus whole blood concentrations during treatment and after discontinuation of PREVYMIS and adjust the dose of tacrolimus accordingly .
Proton Pump Inhibitors
omeprazole	↓ omeprazole	Clinical monitoring and dose adjustment may be needed.
pantoprazole	↓ pantoprazole	Clinical monitoring and dose adjustment may be needed.
Wakefulness-Promoting Agents
modafinil	↓ letermovir	Co-administration of PREVYMIS and modafinil is not recommended due to potential for loss of efficacy of PREVYMIS.
CYP3A Substrates
Examples: alfentanil, fentanyl, midazolam, and quinidine	↑ CYP3A substrate	When PREVYMIS is co-administered with a CYP3A substrate, refer to the prescribing information for dosing of the CYP3A substrate with a moderate CYP3A inhibitor . When PREVYMIS is co-administered with cyclosporine, the combined effect on CYP3A substrates may be similar to a strong CYP3A inhibitor. Refer to the prescribing information for dosing of the CYP3A substrate with a strong CYP3A inhibitor . CYP3A substrates pimozide and ergot alkaloids are contraindicated [see Contraindications (4)] .

]

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

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

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

and

7.2 Potential for PREVYMIS to Affect Other Drugs

Co-administration of PREVYMIS with midazolam results in increased midazolam plasma concentrations, indicating that letermovir is a moderate inhibitor of CYP3A

[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)]

7.3 Established and Other Potentially Significant Drug Interactions

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

[see Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)]

Table 11: Potentially Significant Drug Interactions: Alteration in Dose May Be Recommended Based on Results from Adult Drug Interaction Studies or Predicted InteractionsThis table is not all inclusive.(Information in the Table Applies to Co-administration of PREVYMIS and the Concomitant Drug without Cyclosporine, Unless Otherwise Indicated)
Concomitant Drug Class and/or Clearance Pathway: Drug Name	Effect on Concentration↓ =decrease, ↑ =increase	Clinical Comments
Anti-arrhythmic Agents
amiodarone	↑ amiodarone	Close clinical monitoring for adverse events related to amiodarone is recommended during co-administration. Frequently monitor amiodarone concentrations when amiodarone is co-administered with PREVYMIS.
Antibiotics
nafcillin	↓ letermovir	Co-administration of PREVYMIS and nafcillin is not recommended due to potential for loss of efficacy of PREVYMIS.
Anticoagulants
warfarin	↓ warfarin	When PREVYMIS is co-administered with warfarin, frequently monitor International Normalized Ratio (INR)Refer to the respective prescribing information..
Anticonvulsants
carbamazepine	↓ letermovir	Co-administration of PREVYMIS and carbamazepine is not recommended due to potential for loss of efficacy of PREVYMIS.
phenobarbital	↓ letermovir	Co-administration of PREVYMIS and phenobarbital is not recommended due to potential for loss of efficacy of PREVYMIS.
phenytoin	↓ letermovir ↓ phenytoin	Co-administration of PREVYMIS and phenytoin is not recommended due to potential for loss of efficacy of PREVYMIS.
Antidiabetic Agents
Examples: glyburide, repaglinide, rosiglitazone	↑ glyburide ↑ repaglinide ↑ rosiglitazone	When PREVYMIS is co-administered with glyburide, repaglinide, or rosiglitazone, frequently monitor glucose concentrations . When PREVYMIS is co-administered with cyclosporine, use of repaglinide is not recommended.
Antifungals
voriconazoleThese interactions have been studied [see Clinical Pharmacology (12.3)] .	↓ voriconazole	If concomitant administration of voriconazole is necessary, closely monitor for reduced effectiveness of voriconazole .
Antimycobacterials
rifabutin	↓ letermovir	Co-administration of PREVYMIS and rifabutin is not recommended due to potential for loss of efficacy of PREVYMIS.
rifampin	↓ letermovir	Co-administration of PREVYMIS and rifampin is not recommended due to potential for loss of efficacy of PREVYMIS.
Antipsychotics
pimozide	↑ pimozide	Co-administration is contraindicated due to risk of QT prolongation and torsades de pointes [see Contraindications (4)] .
thioridazine	↓ letermovir	Co-administration of PREVYMIS and thioridazine is not recommended due to potential for loss of efficacy of PREVYMIS.
Endothelin Antagonists
bosentan	↓ letermovir	Co-administration of PREVYMIS and bosentan is not recommended due to potential for loss of efficacy of PREVYMIS.
Ergot Alkaloids
ergotamine, dihydroergotamine	↑ ergotamine, dihydroergotamine	Co-administration is contraindicated due to risk of ergotism [see Contraindications (4)] .
Herbal Products
St. John's wort ( Hypericum perforatum )	↓ letermovir	Co-administration of PREVYMIS and St. John's wort is not recommended due to potential for loss of efficacy of PREVYMIS.
HIV Medications
efavirenz	↓ letermovir	Co-administration of PREVYMIS and efavirenz is not recommended due to potential for loss of efficacy of PREVYMIS.
etravirine	↓ letermovir	Co-administration of PREVYMIS and etravirine is not recommended due to potential for loss of efficacy of PREVYMIS.
nevirapine	↓ letermovir	Co-administration of PREVYMIS and nevirapine is not recommended due to potential for loss of efficacy of PREVYMIS.
HMG-CoA Reductase Inhibitors
atorvastatin	↑ atorvastatin	When PREVYMIS is co-administered with atorvastatin, do not exceed an atorvastatin dosage of 20 mg daily . Closely monitor patients for myopathy and rhabdomyolysis. When PREVYMIS is co-administered with cyclosporine, use of atorvastatin is not recommended.
pitavastatin, simvastatin	↑ HMG-CoA reductase inhibitors	Co-administration of PREVYMIS and pitavastatin or simvastatin is not recommended. When PREVYMIS is co-administered with cyclosporine, use of either pitavastatin or simvastatin is contraindicated due to significantly increased pitavastatin or simvastatin concentrations and risk of myopathy or rhabdomyolysis [see Contraindications (4)] .
fluvastatin, lovastatin, pravastatin, rosuvastatin	↑ HMG-CoA reductase inhibitors	When PREVYMIS is co-administered with these statins, a statin dosage reduction may be necessary . Closely monitor patients for myopathy and rhabdomyolysis. When PREVYMIS is co-administered with cyclosporine, use of lovastatin is not recommended. When PREVYMIS is co-administered with cyclosporine, refer to the statin prescribing information for specific statin dosing recommendations.
Immunosuppressants
cyclosporine	↑ cyclosporine ↑ letermovir	Decrease the dosage of PREVYMIS to 240 mg once daily in adult and pediatric patients 12 years of age and older [see Dosage and Administration (2.4)and Clinical Pharmacology (12.3)] . Dose adjustment may be required in pediatric patients less than 12 years of age [see Dosage and Administration (2.6)and Clinical Pharmacology (12.3)] . Frequently monitor cyclosporine whole blood concentrations during treatment and after discontinuation of PREVYMIS and adjust the dose of cyclosporine accordingly .
sirolimus	↑ sirolimus	When PREVYMIS is co-administered with sirolimus, frequently monitor sirolimus whole blood concentrations during treatment and after discontinuation of PREVYMIS and adjust the dose of sirolimus accordingly . When PREVYMIS is co-administered with cyclosporine and sirolimus, refer to the sirolimus prescribing information for specific sirolimus dosing recommendations .
tacrolimus	↑ tacrolimus	Frequently monitor tacrolimus whole blood concentrations during treatment and after discontinuation of PREVYMIS and adjust the dose of tacrolimus accordingly .
Proton Pump Inhibitors
omeprazole	↓ omeprazole	Clinical monitoring and dose adjustment may be needed.
pantoprazole	↓ pantoprazole	Clinical monitoring and dose adjustment may be needed.
Wakefulness-Promoting Agents
modafinil	↓ letermovir	Co-administration of PREVYMIS and modafinil is not recommended due to potential for loss of efficacy of PREVYMIS.
CYP3A Substrates
Examples: alfentanil, fentanyl, midazolam, and quinidine	↑ CYP3A substrate	When PREVYMIS is co-administered with a CYP3A substrate, refer to the prescribing information for dosing of the CYP3A substrate with a moderate CYP3A inhibitor . When PREVYMIS is co-administered with cyclosporine, the combined effect on CYP3A substrates may be similar to a strong CYP3A inhibitor. Refer to the prescribing information for dosing of the CYP3A substrate with a strong CYP3A inhibitor . CYP3A substrates pimozide and ergot alkaloids are contraindicated [see Contraindications (4)] .

]

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

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

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

and

7.2 Potential for PREVYMIS to Affect Other Drugs

Co-administration of PREVYMIS with midazolam results in increased midazolam plasma concentrations, indicating that letermovir is a moderate inhibitor of CYP3A

[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)]

7.3 Established and Other Potentially Significant Drug Interactions

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

[see Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)]

Table 11: Potentially Significant Drug Interactions: Alteration in Dose May Be Recommended Based on Results from Adult Drug Interaction Studies or Predicted InteractionsThis table is not all inclusive.(Information in the Table Applies to Co-administration of PREVYMIS and the Concomitant Drug without Cyclosporine, Unless Otherwise Indicated)
Concomitant Drug Class and/or Clearance Pathway: Drug Name	Effect on Concentration↓ =decrease, ↑ =increase	Clinical Comments
Anti-arrhythmic Agents
amiodarone	↑ amiodarone	Close clinical monitoring for adverse events related to amiodarone is recommended during co-administration. Frequently monitor amiodarone concentrations when amiodarone is co-administered with PREVYMIS.
Antibiotics
nafcillin	↓ letermovir	Co-administration of PREVYMIS and nafcillin is not recommended due to potential for loss of efficacy of PREVYMIS.
Anticoagulants
warfarin	↓ warfarin	When PREVYMIS is co-administered with warfarin, frequently monitor International Normalized Ratio (INR)Refer to the respective prescribing information..
Anticonvulsants
carbamazepine	↓ letermovir	Co-administration of PREVYMIS and carbamazepine is not recommended due to potential for loss of efficacy of PREVYMIS.
phenobarbital	↓ letermovir	Co-administration of PREVYMIS and phenobarbital is not recommended due to potential for loss of efficacy of PREVYMIS.
phenytoin	↓ letermovir ↓ phenytoin	Co-administration of PREVYMIS and phenytoin is not recommended due to potential for loss of efficacy of PREVYMIS.
Antidiabetic Agents
Examples: glyburide, repaglinide, rosiglitazone	↑ glyburide ↑ repaglinide ↑ rosiglitazone	When PREVYMIS is co-administered with glyburide, repaglinide, or rosiglitazone, frequently monitor glucose concentrations . When PREVYMIS is co-administered with cyclosporine, use of repaglinide is not recommended.
Antifungals
voriconazoleThese interactions have been studied [see Clinical Pharmacology (12.3)] .	↓ voriconazole	If concomitant administration of voriconazole is necessary, closely monitor for reduced effectiveness of voriconazole .
Antimycobacterials
rifabutin	↓ letermovir	Co-administration of PREVYMIS and rifabutin is not recommended due to potential for loss of efficacy of PREVYMIS.
rifampin	↓ letermovir	Co-administration of PREVYMIS and rifampin is not recommended due to potential for loss of efficacy of PREVYMIS.
Antipsychotics
pimozide	↑ pimozide	Co-administration is contraindicated due to risk of QT prolongation and torsades de pointes [see Contraindications (4)] .
thioridazine	↓ letermovir	Co-administration of PREVYMIS and thioridazine is not recommended due to potential for loss of efficacy of PREVYMIS.
Endothelin Antagonists
bosentan	↓ letermovir	Co-administration of PREVYMIS and bosentan is not recommended due to potential for loss of efficacy of PREVYMIS.
Ergot Alkaloids
ergotamine, dihydroergotamine	↑ ergotamine, dihydroergotamine	Co-administration is contraindicated due to risk of ergotism [see Contraindications (4)] .
Herbal Products
St. John's wort ( Hypericum perforatum )	↓ letermovir	Co-administration of PREVYMIS and St. John's wort is not recommended due to potential for loss of efficacy of PREVYMIS.
HIV Medications
efavirenz	↓ letermovir	Co-administration of PREVYMIS and efavirenz is not recommended due to potential for loss of efficacy of PREVYMIS.
etravirine	↓ letermovir	Co-administration of PREVYMIS and etravirine is not recommended due to potential for loss of efficacy of PREVYMIS.
nevirapine	↓ letermovir	Co-administration of PREVYMIS and nevirapine is not recommended due to potential for loss of efficacy of PREVYMIS.
HMG-CoA Reductase Inhibitors
atorvastatin	↑ atorvastatin	When PREVYMIS is co-administered with atorvastatin, do not exceed an atorvastatin dosage of 20 mg daily . Closely monitor patients for myopathy and rhabdomyolysis. When PREVYMIS is co-administered with cyclosporine, use of atorvastatin is not recommended.
pitavastatin, simvastatin	↑ HMG-CoA reductase inhibitors	Co-administration of PREVYMIS and pitavastatin or simvastatin is not recommended. When PREVYMIS is co-administered with cyclosporine, use of either pitavastatin or simvastatin is contraindicated due to significantly increased pitavastatin or simvastatin concentrations and risk of myopathy or rhabdomyolysis [see Contraindications (4)] .
fluvastatin, lovastatin, pravastatin, rosuvastatin	↑ HMG-CoA reductase inhibitors	When PREVYMIS is co-administered with these statins, a statin dosage reduction may be necessary . Closely monitor patients for myopathy and rhabdomyolysis. When PREVYMIS is co-administered with cyclosporine, use of lovastatin is not recommended. When PREVYMIS is co-administered with cyclosporine, refer to the statin prescribing information for specific statin dosing recommendations.
Immunosuppressants
cyclosporine	↑ cyclosporine ↑ letermovir	Decrease the dosage of PREVYMIS to 240 mg once daily in adult and pediatric patients 12 years of age and older [see Dosage and Administration (2.4)and Clinical Pharmacology (12.3)] . Dose adjustment may be required in pediatric patients less than 12 years of age [see Dosage and Administration (2.6)and Clinical Pharmacology (12.3)] . Frequently monitor cyclosporine whole blood concentrations during treatment and after discontinuation of PREVYMIS and adjust the dose of cyclosporine accordingly .
sirolimus	↑ sirolimus	When PREVYMIS is co-administered with sirolimus, frequently monitor sirolimus whole blood concentrations during treatment and after discontinuation of PREVYMIS and adjust the dose of sirolimus accordingly . When PREVYMIS is co-administered with cyclosporine and sirolimus, refer to the sirolimus prescribing information for specific sirolimus dosing recommendations .
tacrolimus	↑ tacrolimus	Frequently monitor tacrolimus whole blood concentrations during treatment and after discontinuation of PREVYMIS and adjust the dose of tacrolimus accordingly .
Proton Pump Inhibitors
omeprazole	↓ omeprazole	Clinical monitoring and dose adjustment may be needed.
pantoprazole	↓ pantoprazole	Clinical monitoring and dose adjustment may be needed.
Wakefulness-Promoting Agents
modafinil	↓ letermovir	Co-administration of PREVYMIS and modafinil is not recommended due to potential for loss of efficacy of PREVYMIS.
CYP3A Substrates
Examples: alfentanil, fentanyl, midazolam, and quinidine	↑ CYP3A substrate	When PREVYMIS is co-administered with a CYP3A substrate, refer to the prescribing information for dosing of the CYP3A substrate with a moderate CYP3A inhibitor . When PREVYMIS is co-administered with cyclosporine, the combined effect on CYP3A substrates may be similar to a strong CYP3A inhibitor. Refer to the prescribing information for dosing of the CYP3A substrate with a strong CYP3A inhibitor . CYP3A substrates pimozide and ergot alkaloids are contraindicated [see Contraindications (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 CONTRAINDICATIONS

PREVYMIS is contraindicated in patients receiving pimozide or ergot alkaloids:
- Pimozide: Concomitant administration of PREVYMIS in patients receiving pimozide may result in increased concentrations of pimozide due to inhibition of cytochrome P450 3A (CYP3A) by letermovir, which may lead to QT prolongation and torsades de pointes
  [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)]
.

PREVYMIS is contraindicated with:

Pimozide.
Ergot Alkaloids.
Pitavastatin and simvastatin when co-administered with cyclosporine.

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

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

7.1 Potential for Other Drugs to Affect PREVYMIS

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)

7.2 Potential for PREVYMIS to Affect Other Drugs

Co-administration of PREVYMIS with midazolam results in increased midazolam plasma concentrations, indicating that letermovir is a moderate inhibitor of CYP3A

[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)]

7.3 Established and Other Potentially Significant Drug Interactions

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

[see Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)]

Table 11: Potentially Significant Drug Interactions: Alteration in Dose May Be Recommended Based on Results from Adult Drug Interaction Studies or Predicted InteractionsThis table is not all inclusive.(Information in the Table Applies to Co-administration of PREVYMIS and the Concomitant Drug without Cyclosporine, Unless Otherwise Indicated)
Concomitant Drug Class and/or Clearance Pathway: Drug Name	Effect on Concentration↓ =decrease, ↑ =increase	Clinical Comments
Anti-arrhythmic Agents
amiodarone	↑ amiodarone	Close clinical monitoring for adverse events related to amiodarone is recommended during co-administration. Frequently monitor amiodarone concentrations when amiodarone is co-administered with PREVYMIS.
Antibiotics
nafcillin	↓ letermovir	Co-administration of PREVYMIS and nafcillin is not recommended due to potential for loss of efficacy of PREVYMIS.
Anticoagulants
warfarin	↓ warfarin	When PREVYMIS is co-administered with warfarin, frequently monitor International Normalized Ratio (INR)Refer to the respective prescribing information..
Anticonvulsants
carbamazepine	↓ letermovir	Co-administration of PREVYMIS and carbamazepine is not recommended due to potential for loss of efficacy of PREVYMIS.
phenobarbital	↓ letermovir	Co-administration of PREVYMIS and phenobarbital is not recommended due to potential for loss of efficacy of PREVYMIS.
phenytoin	↓ letermovir ↓ phenytoin	Co-administration of PREVYMIS and phenytoin is not recommended due to potential for loss of efficacy of PREVYMIS.
Antidiabetic Agents
Examples: glyburide, repaglinide, rosiglitazone	↑ glyburide ↑ repaglinide ↑ rosiglitazone	When PREVYMIS is co-administered with glyburide, repaglinide, or rosiglitazone, frequently monitor glucose concentrations . When PREVYMIS is co-administered with cyclosporine, use of repaglinide is not recommended.
Antifungals
voriconazoleThese interactions have been studied [see Clinical Pharmacology (12.3)] .	↓ voriconazole	If concomitant administration of voriconazole is necessary, closely monitor for reduced effectiveness of voriconazole .
Antimycobacterials
rifabutin	↓ letermovir	Co-administration of PREVYMIS and rifabutin is not recommended due to potential for loss of efficacy of PREVYMIS.
rifampin	↓ letermovir	Co-administration of PREVYMIS and rifampin is not recommended due to potential for loss of efficacy of PREVYMIS.
Antipsychotics
pimozide	↑ pimozide	Co-administration is contraindicated due to risk of QT prolongation and torsades de pointes [see Contraindications (4)] .
thioridazine	↓ letermovir	Co-administration of PREVYMIS and thioridazine is not recommended due to potential for loss of efficacy of PREVYMIS.
Endothelin Antagonists
bosentan	↓ letermovir	Co-administration of PREVYMIS and bosentan is not recommended due to potential for loss of efficacy of PREVYMIS.
Ergot Alkaloids
ergotamine, dihydroergotamine	↑ ergotamine, dihydroergotamine	Co-administration is contraindicated due to risk of ergotism [see Contraindications (4)] .
Herbal Products
St. John's wort ( Hypericum perforatum )	↓ letermovir	Co-administration of PREVYMIS and St. John's wort is not recommended due to potential for loss of efficacy of PREVYMIS.
HIV Medications
efavirenz	↓ letermovir	Co-administration of PREVYMIS and efavirenz is not recommended due to potential for loss of efficacy of PREVYMIS.
etravirine	↓ letermovir	Co-administration of PREVYMIS and etravirine is not recommended due to potential for loss of efficacy of PREVYMIS.
nevirapine	↓ letermovir	Co-administration of PREVYMIS and nevirapine is not recommended due to potential for loss of efficacy of PREVYMIS.
HMG-CoA Reductase Inhibitors
atorvastatin	↑ atorvastatin	When PREVYMIS is co-administered with atorvastatin, do not exceed an atorvastatin dosage of 20 mg daily . Closely monitor patients for myopathy and rhabdomyolysis. When PREVYMIS is co-administered with cyclosporine, use of atorvastatin is not recommended.
pitavastatin, simvastatin	↑ HMG-CoA reductase inhibitors	Co-administration of PREVYMIS and pitavastatin or simvastatin is not recommended. When PREVYMIS is co-administered with cyclosporine, use of either pitavastatin or simvastatin is contraindicated due to significantly increased pitavastatin or simvastatin concentrations and risk of myopathy or rhabdomyolysis [see Contraindications (4)] .
fluvastatin, lovastatin, pravastatin, rosuvastatin	↑ HMG-CoA reductase inhibitors	When PREVYMIS is co-administered with these statins, a statin dosage reduction may be necessary . Closely monitor patients for myopathy and rhabdomyolysis. When PREVYMIS is co-administered with cyclosporine, use of lovastatin is not recommended. When PREVYMIS is co-administered with cyclosporine, refer to the statin prescribing information for specific statin dosing recommendations.
Immunosuppressants
cyclosporine	↑ cyclosporine ↑ letermovir	Decrease the dosage of PREVYMIS to 240 mg once daily in adult and pediatric patients 12 years of age and older [see Dosage and Administration (2.4)and Clinical Pharmacology (12.3)] . Dose adjustment may be required in pediatric patients less than 12 years of age [see Dosage and Administration (2.6)and Clinical Pharmacology (12.3)] . Frequently monitor cyclosporine whole blood concentrations during treatment and after discontinuation of PREVYMIS and adjust the dose of cyclosporine accordingly .
sirolimus	↑ sirolimus	When PREVYMIS is co-administered with sirolimus, frequently monitor sirolimus whole blood concentrations during treatment and after discontinuation of PREVYMIS and adjust the dose of sirolimus accordingly . When PREVYMIS is co-administered with cyclosporine and sirolimus, refer to the sirolimus prescribing information for specific sirolimus dosing recommendations .
tacrolimus	↑ tacrolimus	Frequently monitor tacrolimus whole blood concentrations during treatment and after discontinuation of PREVYMIS and adjust the dose of tacrolimus accordingly .
Proton Pump Inhibitors
omeprazole	↓ omeprazole	Clinical monitoring and dose adjustment may be needed.
pantoprazole	↓ pantoprazole	Clinical monitoring and dose adjustment may be needed.
Wakefulness-Promoting Agents
modafinil	↓ letermovir	Co-administration of PREVYMIS and modafinil is not recommended due to potential for loss of efficacy of PREVYMIS.
CYP3A Substrates
Examples: alfentanil, fentanyl, midazolam, and quinidine	↑ CYP3A substrate	When PREVYMIS is co-administered with a CYP3A substrate, refer to the prescribing information for dosing of the CYP3A substrate with a moderate CYP3A inhibitor . When PREVYMIS is co-administered with cyclosporine, the combined effect on CYP3A substrates may be similar to a strong CYP3A inhibitor. Refer to the prescribing information for dosing of the CYP3A substrate with a strong CYP3A inhibitor . CYP3A substrates pimozide and ergot alkaloids are contraindicated [see Contraindications (4)] .

)

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 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.
,
8.6 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)]
.
,
13.2 Animal Toxicology and/or Pharmacology
Testicular toxicity in rats observed at ≥180 mg/kg/day (greater than or equal to 3 times the human exposure at the RHD) was characterized by decreased testis weight, bilateral seminiferous tubular degeneration, decreased sperm count and motility, and resultant decreased male fertility. Male reproductive system toxicities were not observed in either a monkey testicular toxicity study up to 240 mg/kg/day (approximately 2 times higher than human exposure at the RHD), or a general toxicology study in mice up to 250 mg/kg/day (approximately 3 times higher than human exposure at the RHD).
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)]
.
)

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