Prevymis

What is Prevymis and how is it used?

Prevymis is a prescription medicine used to treat the symptoms of Cytomegalovirus Infection Prophylaxis (CMV). Prevymis may be used alone or with other medications.

Prevymis belongs to a class of drugs called Antivirals, CMV; CYP3A4 Inhibitor, Moderate.

It is not known if Prevymis is safe and effective in children younger than 18 years of age.

What are the possible side effects of Prevymis?

Prevymis may cause serious side effects including:

• hives,
• difficulty breathing,
• swelling of your face, lips, tongue, or throat,
• fast or irregular heartbeat,
• rash,
• itching, and
• severe dizziness

Get medical help right away, if you have any of the symptoms listed above.

The most common side effects of Prevymis include:

• nausea,
• diarrhea,
• vomiting,
• swelling of the ankles or feet,
• cough, and
• headache

Tell the doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Prevymis. For more information, ask your doctor or pharmacist.

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

DESCRIPTION

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

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

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

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

The chemical structure of letermovir is:

INDICATIONS

PREVYMIS™ is indicated for prophylaxis of cytomegalovirus (CMV) infection and disease in adult CMVseropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT).

DOSAGE AND ADMINISTRATION

Important Dosing And Administration Information

PREVYMIS™ Tablets

• Administer with or without food.
• Swallow tablets whole.

PREVYMIS™ Injection

• PREVYMIS injection must be administered 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.

Recommended Dosage For Adult Patients

The recommended dosage of PREVYMIS is 480 mg administered orally or intravenously once daily. Initiate PREVYMIS between Day 0 and Day 28 post-transplantation (before or after engraftment), and continue through Day 100 post-transplantation. Dosage of PREVYMIS should be adjusted when co-administered with cyclosporine [see Dosage Adjustment When Co-Administered With Cyclosporine].

PREVYMIS injection, which contains hydroxypropyl betadex, should be used only in patients unable to take oral therapy. Patients should be switched to oral PREVYMIS as soon as they are able to take oral medications. PREVYMIS tablet and injection may be used interchangeably at the discretion of the physician, and no dosage adjustment is necessary when switching formulations.

Patient Monitoring

Following the completion of PREVYMIS prophylaxis, monitoring for CMV reactivation is recommended.

Dosage Adjustment When Co-Administered With Cyclosporine

If oral or intravenous PREVYMIS is co-administered with cyclosporine, the dosage of PREVYMIS should be decreased to 240 mg once daily [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].

• If cyclosporine is initiated after starting PREVYMIS, the next dose of PREVYMIS should be decreased to 240 mg once daily.
• If cyclosporine is discontinued after starting PREVYMIS, the next dose of PREVYMIS should be increased to 480 mg once daily.
• If cyclosporine dosing is interrupted due to high cyclosporine levels, no dose adjustment of PREVYMIS is needed.

Use In Patients With Renal Impairment

• For patients with creatinine clearance (CLcr) greater than 10 mL/min, no dosage adjustment of PREVYMIS is required based on renal impairment [see Use In Specific Populations, and CLINICAL PHARMACOLOGY].
• There are insufficient data in patients with CLcr 10 mL/min or less or in patients on dialysis to make PREVYMIS dosing recommendations.
• In patients with CLcr less than 50 mL/min receiving PREVYMIS injection, accumulation of the intravenous vehicle, hydroxypropyl betadex, may occur. Closely monitor serum creatinine levels in these patients.

Use In Patients With Hepatic Impairment

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

Preparation And Administration Of Intravenous Solution

PREVYMIS injection is supplied in 30 mL single-dose vials containing either 240 mg/12 mL per vial (20 mg/mL) or 480 mg/24 mL per vial (20 mg/mL). The preparation and administration instructions are the same for either dose.

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

Preparation And Administration Instructions

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

• PREVYMIS must be diluted prior to intravenous (IV) use.
• Inspect vial contents for discoloration and particulate matter prior to dilution. PREVYMIS injection is a clear colorless solution 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.
• 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.
• Do not shake PREVYMIS vial.
• Add one single-dose vial of PREVYMIS injection into a 250 mL pre-filled IV bag containing either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP and mix bag gently. Do not shake. Only 0.9% Sodium Chloride and 5% Dextrose are chemically and physically compatible with PREVYMIS injection.
• Use compatible IV bags and infusion set materials. PREVYMIS injection is compatible with the following IV bags and infusion set materials. PREVYMIS injection is not recommended with any IV bags or infusion set materials not listed below (note that PREVYMIS injection is not recommended for use with polyurethane-containing IV administration set tubing).
• Once diluted, the solution of PREVYMIS is clear, and ranges from colorless to yellow. Variations of color within this range do not affect the quality of the product.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.
• Discard if the diluted solution is cloudy, discolored, or contains matter other than a few small translucent or white particles.
• The diluted solution is stable for up to 24 hours at room temperature or up to 48 hours under refrigeration at 2°C to 8°C (36°F to 46°F) (this time includes storage of the diluted solution in the intravenous bag through the duration of infusion).
• 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.
• Administer the entire contents of the intravenous bag by intravenous infusion via a peripheral catheter or central venous line at a constant rate over 1 hour [see Important Dosing And Administration Information].

Compatible Drug Products Used For Intravenous Administration

Compatible Drug Products

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

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

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

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

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

*Amphotericin B (lipid complex) is compatible with PREVYMIS. However, Amphotericin B (liposomal) is incompatible [see Incompatible Drug Products And Other Materials Used For Intravenous Administration].

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 concentrate for solution for infusion is incompatible with diethylhexyl phthalate (DEHP) plasticizers and polyurethane-containing IV administration set tubing.

HOW SUPPLIED

Dosage Forms And Strengths

Tablets

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

Injection

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

Storage And Handling

Tablets

Each PREVYMIS 240 mg tablet is a yellow oval tablet; each tablet is debossed with “591” on one side and Merck logo on the other side. Each PREVYMIS 480 mg tablet is a pink oval, bi-convex tablet debossed with “595” on one side and Merck logo on the other side.

The 240 mg tablets are packaged into a carton (NDC 0006-3075-02) containing four (4) Child Resistant (CR) Dosepaks^®, each containing a 7-count blister card for a total of 28 tablets, or into a carton (NDC 00063075-04) containing two (2) unit-dose 7-count blister cards for a total of 14 tablets.

The 480 mg tablets are packaged into a carton (NDC 0006-3076-02) containing four (4) Child Resistant (CR) Dosepaks^®, each containing a 7-count blister card for a total of 28 tablets, or into a carton (NDC 00063076-04) containing two (2) unit-dose 7-count blister cards for a total of 14 tablets.

Store PREVYMIS tablets in the original package until use.

Store PREVYMIS tablets at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Injection

PREVYMIS is supplied as a sterile, clear solution for intravenous use of 240 mg (12 mL per vial) or 480 mg (24 mL per vial) that may contain a few product-related small translucent or white particles. The final solutions for infusion are obtained by dilution with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP.

The single dose vials are supplied in cartons that contain a 240 mg single-dose vial (NDC 0006-5003-01) or a 480 mg single-dose vial (NDC 0006-5004-01).

Store PREVYMIS injection vials at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Store in the original carton to protect from exposure to light.

Distributed by: Merck Sharp & Dohme Corp., a subsidiary of MERCK & CO.,INC., Whitehouse Station, NJ 08889, USA. Revised: Mar 2020

SIDE EFFECTS

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adult CMV-Seropositive Recipients [R+] Of An Allogeneic HSCT

The safety of PREVYMIS was evaluated in one Phase 3 randomized, double-blind, placebo-controlled trial (P001) in which 565 subjects were randomized and treated with PREVYMIS (N=373) or placebo (N=192) through Week 14 post-transplant. Adverse events were those reported while subjects were on study medication or within two weeks of study medication completion/discontinuation. The mean time for reporting adverse events and laboratory abnormalities was approximately 22% longer in the PREVYMIS arm compared to the placebo arm.

Cardiac Adverse Events

The cardiac adverse event rate (regardless of investigator-assessed causality) was higher in subjects receiving PREVYMIS (13%) compared to subjects receiving placebo (6%). The most common cardiac adverse events were tachycardia (reported in 4% of PREVYMIS subjects and in 2% of placebo subjects) and atrial fibrillation (reported in 3% of PREVYMIS subjects and in 1% of placebo subjects). Among those subjects who experienced one or more cardiac adverse events, 85% of PREVYMIS and 92% of placebo subjects had events reported as mild or moderate in severity.

Common Adverse Events

The rate of adverse events occurring in at least 10% of subjects in the PREVYMIS group and at a frequency at least 2% greater than placebo are outlined in Table 1.

Table 1: Trial P001 All Grade Adverse Events Reported in ≥ 10% of PREVYMIS-Treated HSCT Recipients at a Frequency at least 2% Greater than Placebo

Adverse Events	PREVYMIS (N=373)	Placebo (N=192)
nausea	27%	23%
diarrhea	26%	24%
vomiting	19%	14%
peripheral edema	14%	9%
cough	14%	10%
headache	14%	9%
fatigue	13%	11%
abdominal pain	12%	9%

Overall, similar proportions of subjects in each group discontinued study medication due to an adverse event (13% of PREVYMIS subjects vs. 12% of placebo subjects). The most frequently reported adverse event that led to study drug discontinuation was nausea, occurring in 2% of PREVYMIS subjects and 1% of placebo subjects. Hypersensitivity reaction, with associated moderate dyspnea, occurred in one subject following the first infusion of IV PREVYMIS after switching from oral PREVYMIS, leading to treatment discontinuation.

Laboratory Abnormalities

Selected laboratory abnormalities reported during treatment or within 2 weeks of stopping treatment are presented in the table below.

Table 2: Trial P001 Selected Laboratory Abnormalities

	PREVYMIS N=373	Placebo N=192
Absolute neutrophil count (cells/μL)
< 500	19%	19%
500 – < 750	4%	7%
750 – < 1000	8%	9%
Hemoglobin (g/dL)
< 6.5	2%	1%
6.5 – < 8.0	14%	15%
8.0 – < 9.5	41%	43%
Platelets (cells/μL)
< 25000	27%	21%
25000 – < 50000	17%	18%
50000 – < 100000	20%	30%
Serum creatinine (mg/dL)
> 2.5	2%	3%
> 1.5 – 2.5	17%	20%

The median time to engraftment (defined as absolute neutrophil count ≥ 500/mm³ on 3 consecutive days after transplantation) was 19 days in the PREVYMIS group and 18 days in the placebo group.

DRUG INTERACTIONS

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 3).

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 3).

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]. 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 3) [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].

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 3).

The magnitude of CYP3A-and OATP1B1/3-mediated drug interactions on co-administered drugs may be different when PREVYMIS is co-administered with cyclosporine. See the prescribing information for cyclosporine for information on drug interactions with cyclosporine.

Established And Other Potentially Significant Drug Interactions

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

Table 3 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with PREVYMIS or are predicted drug interactions that may occur with PREVYMIS [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and CLINICAL PHARMACOLOGY].

Table 3: Potentially Significant Drug Interactions: Alteration in Dose May Be Recommended Based on Results from Drug Interaction Studies or Predicted Interactions* (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†	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) ‡.
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
voriconazole§	↓ 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].
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].
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].
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 [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY]. 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].
* This table is not all inclusive. † ↓ =decrease, ↑=increase ‡ Refer to the respective prescribing information. § These interactions have been studied [see CLINICAL PHARMACOLOGY].

Drugs Without Clinically Significant Interactions With PREVYMIS

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

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

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 and DRUG INTERACTIONS].

See Table 3 for steps to prevent or manage these possible or known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during PREVYMIS therapy; review concomitant medications during PREVYMIS therapy; and monitor for adverse reactions associated with PREVYMIS and concomitant medications.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).

Drug Interactions

Inform patients that PREVYMIS may interact with some drugs; therefore, advise patients to report the use of any prescription, non-prescription medication, or herbal products to their healthcare provider [see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and DRUG INTERACTIONS].

Administration

Inform patients that it is important not to miss or skip doses and to take PREVYMIS for the duration that is recommended by the healthcare provider. Instruct patients that if they miss a dose of PREVYMIS, they should take it as soon as they remember. If they do not remember until it is time for the next dose, instruct them to skip the missed dose and go back to the regular schedule. Instruct patients not to double their next dose or take more than the prescribed dose.

Storage

Advise patients to store PREVYMIS tablets in the original package until use [see HOW SUPPLIED].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis And Mutagenesis

Letermovir was not genotoxic in in vitro or in vivo assays, including microbial mutagenesis assays, chromosomal aberration in Chinese hamster ovary cells, and in an in vivo mouse micronucleus study.

Carcinogenicity studies with letermovir have not been conducted.

Impairment Of Fertility

In a fertility and early embryonic development study in rats, no effects of letermovir on female fertility were observed at letermovir exposures (AUC) approximately 5 times higher than human exposure at the RHD.

In male rat fertility studies, decreased fertility associated with irreversible testicular toxicity was observed at ≥180 mg/kg/day (greater than or equal to 3 times the human exposure at the RHD). No fertility or testicular effects were observed at dose levels resulting in letermovir exposures (AUC) similar to human exposure at the RHD [see Nonclinical Toxicology].

Use In Specific Populations

Pregnancy

Risk Summary

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

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

Data

Animal Data

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

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

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

Lactation

Risk Summary

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

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

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

Data

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

Females And Males Of Reproductive Potential

Infertility

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

Pediatric Use

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

Geriatric Use

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

Renal Impairment

For patients with CLcr greater than 10 mL/min (by Cockcroft-Gault equation), no dosage adjustment of PREVYMIS is required based on renal impairment [see CLINICAL PHARMACOLOGY]. The safety of PREVYMIS in patients with end-stage renal disease (CLcr less than 10 mL/min), including patients on dialysis, is unknown.

In patients with CLcr less than 50 mL/min receiving PREVYMIS injection, accumulation of the intravenous vehicle, hydroxypropyl betadex, could occur. Closely monitor serum creatinine levels in these patients.

Hepatic Impairment

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

OVERDOSE

There is no specific antidote for overdose with PREVYMIS. In case of overdose, it is recommended that the patient be monitored for adverse reactions and appropriate symptomatic treatment be instituted.

It is unknown whether dialysis will result in meaningful removal of PREVYMIS from systemic circulation.

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 and DRUG INTERACTIONS].
  • 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 and DRUG INTERACTIONS].
• 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 and DRUG INTERACTIONS].

CLINICAL PHARMACOLOGY

Mechanism Of Action

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

Pharmacodynamics

Cardiac Electrophysiology

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

Pharmacokinetics

The pharmacokinetic properties of letermovir are displayed in Table 4.

Table 4: Absorption, Distribution, Metabolism, Elimination (ADME), and Pharmacokinetic Properties of PREVYMIS*

Pharmacokinetics in HSCT Recipients
Treatment Regimen	Steady-state median (90% prediction interval) AUC (ng•hr/mL) of PREVYMIS
480 mg oral once daily, no cyclosporine	34,400 (16,900, 73,700)
480 mg IV once daily, no cyclosporine	100,000 (65,300, 148,000)
240 mg oral once daily, with cyclosporine	60,800 (28,700, 122,000)
240 mg IV once daily, with cyclosporine	70,300 (46,200, 106,000)
Pharmacokinetics in Healthy Subjects
Treatment Regimen	Steady-state geometric mean AUC and Cmax of PREVYMIS
480 mg oral once daily	Cmax: 13,000 ng/mL AUC: 71,500 ng•hr/mL
Dose proportionality	Greater than proportional following single and multiple oral or IV doses of PREVYMIS 240 mg and 480 mg
Accumulation ratio†	Cmax: 1.03 AUC: 1.22
Time to steady-state	9-10 days
Absorption
Bioavailability	Healthy subjects administered PREVYMIS without cyclosporine: 94% at an oral dose range of 240 mg to 480 mg HSCT recipients administered PREVYMIS without cyclosporine: 35% with 480 mg oral once daily HSCT recipients administered PREVYMIS with cyclosporine: 85% with 240 mg oral once daily
Median Tmax (hr)	1.5 to 3.0 hr
Effect of food (relative to fasting) ‡	AUC: 99.63% [84.27% -117.80%] Cmax: 129.82% [104.35% -161.50%]
Distribution
Mean steady-state volume of distribution	45.5 L following IV administration in HSCT recipients
% In vitro bound to human plasma proteins	99% across the concentration range of 0.2 to 50 mg/L
In vitro blood-to plasma ratio	0.56 across the concentration range of 0.1 to 10 mg/L
Metabolism
In vitro metabolism	UGT1A1/1A3 (minor)
Drug-related component in plasma	97% unchanged parent No major metabolites detected in plasma
Elimination
Route of elimination	Hepatic uptake (OATP1B1/3)
Mean terminal t1/2 (hr)	12 hrs after dosing of PREVYMIS 480 mg IV once daily
% of dose excreted in feces§	93%
% of dose excreted in urine§	<2%
% of unchanged drug excreted in feces§	70%
* Values were obtained in studies of healthy subjects unless otherwise indicated. † Based on geometric mean data. ‡ Values refer to geometric mean ratio [fed/fasted] percentage and 90% confidence interval back transformed from linear mixed-effects model performed on natural log-transformed values. The meal administered was a standard high fat and high calorie meal (33 grams protein, 65 grams carbohydrates, 58 grams fat; 920 total calories). § Single oral administration of radiolabeled letermovir in mass balance study.

Specific Populations

Pediatric Population

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

Age, Gender, Race, And Weight

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

Renal Impairment

Letermovir AUC was approximately 1.9-and 1.4-fold higher in subjects with moderate (eGFR greater than or equal to 30 to 59 mL/min/1.73m²) and severe (eGFR less than 30 mL/min/1.73m²) renal impairment, respectively, compared to healthy subjects.

Hydroxypropyl betadex present in the intravenous letermovir formulation is mainly eliminated by glomerular filtration. Decreased elimination of hydroxypropyl betadex has been reported in the literature in patients with severe renal impairment.

Hepatic Impairment

Letermovir AUC was approximately 1.6-and 3.8-fold higher in subjects with moderate (Child-Pugh Class B [CP-B], score of 7-9) and severe (Child-Pugh Class C [CP-C], score of 10-15) hepatic impairment, respectively, compared to healthy subjects.

Drug Interaction Studies

Drug interaction studies were performed in healthy subjects with PREVYMIS and drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interactions (see Table 5 and Table 6).

In vitro results indicate that letermovir is a substrate of drug metabolizing enzymes CYP3A, CYP2D6, UGT1A1, and UGT1A3, and transporters OATP1B1/3 and P-gp. Oxidative metabolism is considered to be a minor elimination pathway based on in vivo human data. Inhibitors of OATP1B1/3 may result in increases in letermovir plasma concentrations. Changes in letermovir plasma concentrations due to inhibition of Pgp/BCRP by itraconazole were not clinically relevant. Changes in letermovir plasma concentrations due to inhibition of UGTs are not anticipated to be clinically relevant.

Based on in vitro studies, the metabolism of letermovir is not mediated by CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2E1, CYP4A11, UGT1A4, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B4, UGT2B7, UGT2B15, or UGT2B17. The transport of letermovir is not mediated by OATP2B1, OCT1, OAT1, BCRP, or MRP2 in vitro.

Letermovir is a time-dependent inhibitor and inducer of CYP3A in vitro. Co-administration of PREVYMIS with midazolam resulted in increased exposure of midazolam, indicating that the net effect of letermovir on CYP3A is moderate inhibition (see Table 6). Based on these results, co-administration of PREVYMIS with CYP3A substrates may increase the plasma concentrations of the CYP3A substrates [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS, and Table 3]. Letermovir is a reversible inhibitor of CYP2C8 in vitro. When co-administered with PREVYMIS, plasma concentrations of CYP2C8 substrates are predicted to be increased [see Table 3 in DRUG INTERACTIONS]. Co-administration of PREVYMIS reduced the exposure of voriconazole, most likely due to the induction of voriconazole elimination pathways, CYP2C9 and CYP2C19. Co-administration of PREVYMIS with CYP2C9 and CYP2C19 substrates may decrease the plasma concentrations of the CYP2C9 and CYP2C19 substrates [see Table 3 in DRUG INTERACTIONS]. Letermovir is an inducer of CYP2B6 in vitro; the clinical relevance is unknown.

Letermovir inhibited efflux transporters P-gp, breast cancer resistance protein (BCRP), bile salt export pump (BSEP), multidrug resistance-associated protein 2 (MRP2), OAT3, and hepatic uptake transporter OATP1B1/3 in vitro. Co-administration of PREVYMIS with substrates of OATP1B1/3 transporters (e.g. atorvastatin, a known substrate of CYP3A, OATP1B1/3, and potentially BCRP) may result in a clinically relevant increase in plasma concentrations of OATP1B1/3 substrates [see Table 3 in DRUG INTERACTIONS]. There were no clinically relevant changes in plasma concentrations of digoxin, a P-gp substrate, or acyclovir, an OAT3 substrate, following co-administration with PREVYMIS in clinical studies (see Table 6). The effect of letermovir on BCRP, BSEP, and MRP2 substrates was not evaluated in clinical studies; the clinical relevance is unknown.

Based on in vitro results letermovir is not an inhibitor of CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, UGT1A4, UGT1A6, UGT1A9, or UGT2B7 and is not an inducer of CYP1A2. Letermovir is not an inhibitor of OATP2B1, OCT1, OCT2, or OAT1 in vitro.

Table 5: Drug Interactions: Changes in Pharmacokinetics of Letermovir in the Presence of Co-administered Drug

Co-administered Drug	Regimen of Co-administered Drug	Letermovir Regimen	Geometric Mean Ratio [90% CI] of Letermovir PK with/without Co-administered Drug (No Effect=1.00)
			AUC	Cmax	C24hr*
Antifungals
fluconazole	400 mg single dose PO	480 mg single dose PO	1.11 (1.01, 1.23)	1.06 (0.93, 1.21)	1.28 (1.15, 1.43)
itraconazole	200 mg once daily PO	480 mg once daily PO	1.33 (1.17, 1.51)	1.21 (1.05, 1.39)	1.90 (1.58, 2.28)
Antimycobacterials
rifampin	600 mg single dose PO	480 mg single dose PO	2.03 (1.84, 2.26)	1.59 (1.46, 1.74)	2.01 (1.59, 2.54)
	600 mg single dose IV	480 mg single dose PO	1.58 (1.38, 1.81)	1.37 (1.16, 1.61)	0.78 (0.65, 0.93)
	600 mg once daily PO	480 mg once daily PO	0.81 (0.67, 0.98)	1.01 (0.79, 1.28)	0.14 (0.11, 0.19)
	600 mg once daily PO (24 hours after rifampin)†	480 mg once daily PO	0.15 (0.13, 0.17)	0.27 (0.22, 0.31)	0.09 (0.06, 0.12)
Immunosuppressants
cyclosporine	200 mg single dose PO	240 mg once daily PO	2.11 (1.97, 2.26)	1.48 (1.33, 1.65)	2.06 (1.81, 2.35)
mycophenolate mofetil	1 g single dose PO	480 mg once daily PO	1.18 (1.04, 1.32)	1.11 (0.92, 1.34)	1.39 (1.12, 1.74)
tacrolimus	5 mg single dose PO	80 mg twice daily PO	1.02 (0.97, 1.07)	0.92 (0.84, 1.00)	1.02 (0.93, 1.12)
Abbreviations: PO= oral * C12hr for tacrolimus † These data are the effect of rifampin on letermovir 24 hours after final rifampin dose.

Table 6: Drug Interactions: Changes in Pharmacokinetics for Co-administered Drug in the Presence of Letermovir

Co-administered Drug	Regimen of Co-administered Drug	Letermovir Regimen	Geometric Mean Ratio [90% CI] of Co-administered Drug PKwith/without Letermovir (No Effect=1.00)
			AUC	Cmax	C24hr*
CYP3A Substrates
midazolam	1 mg single dose IV	240 mg once daily PO	1.47 (1.37, 1.58)	1.05 (0.94, 1.17)	2.74 (2.16, 3.49)
P-gp Substrates
digoxin	0.5 mg single dose PO	240 mg twice daily PO	0.88 (0.80, 0.96)	0.75 (0.63, 0.89)	0.90 (0.84, 0.96)
Immunosuppressants
cyclosporine	50 mg single dose PO	240 mg once daily PO	1.66 (1.51, 1.82)	1.08 (0.97, 1.19)	2.19 (1.80, 2.66)
mycophenolate mofetil	1 g single dose PO	480 mg once daily PO	1.08 (0.97, 1.20)	0.96 (0.82, 1.12)	1.04 (0.86, 1.27)
tacrolimus	5 mg single dose PO	480 mg once daily PO	2.42 (2.04, 2.88)	1.57 (1.32, 1.86)	2.53 (2.12, 3.03)
sirolimus	2 mg single dose PO	480 mg once daily PO	3.40 (3.01, 3.85)	2.76 (2.48, 3.06)	3.15 (2.80, 3.55)
Antifungals and Antivirals
acyclovir	400 mg single dose PO	480 mg once daily PO	1.02 (0.87, 1.2)	0.82 (0.71, 0.93)	1.13 (0.94, 1.36)
fluconazole	400 mg single dose PO	480 mg single dose PO	1.03 (0.99, 1.08)	0.95 (0.92, 0.99)	1.04 (1.00, 1.08)
itraconazole	200 mg once daily PO	480 mg once daily PO	0.76 (0.71, 0.81)	0.84 (0.76, 0.92)	0.67 (0.61, 0.73)
posaconazole	300 mg single dose PO	480 mg once daily PO	0.98 (0.82, 1.17)	1.11 (0.95, 1.29)	1.10 (0.94, 1.30)
voriconazole	200 mg twice daily PO	480 mg once daily PO	0.56 (0.51, 0.62)	0.61 (0.53, 0.71)	0.49 (0.42, 0.57)
HMG-CoA Reductase Inhibitors
atorvastatin	20 mg single dose PO	480 mg once daily PO	3.29 (2.84, 3.82)	2.17 (1.76, 2.67)	3.62 (2.87, 4.55)
Oral Contraceptives
ethinyl estradiol (EE) /levonorgestrel (LNG)	0.03 mg EE single dose PO	480 mg once daily PO	1.42 (1.32, 1.52)	0.89 (0.83, 0.96)	1.57 (1.45, 1.70)
	0.15 mg LNG single dose PO		1.36 (1.30, 1.43)	0.95 (0.86, 1.04)	1.38 (1.32, 1.46)
Abbreviations: PO=oral * C12hr reported for voriconazole.

Microbiology

Mechanism Of Action

Letermovir inhibits the CMV DNA terminase complex (pUL51, pUL56, and pUL89) which is required for viral DNA processing and packaging. Biochemical characterization and electron microscopy demonstrated that letermovir affects the production of proper unit length genomes and interferes with virion maturation. Genotypic characterization of virus resistant to letermovir confirmed that letermovir targets the terminase complex.

Antiviral Activity

The median EC₅₀ value of letermovir against a collection of clinical CMV isolates in a cell-culture model of infection was 2.1 nM (range = 0.7 nM to 6.1 nM, n = 74). There was no significant difference in EC₅₀ value by CMV gB genotype (gB1=29; gB2=27; gB3=11; and gB4=3).

Combination Antiviral Activity

No antagonism of the antiviral activity was seen when letermovir was combined with CMV DNA polymerase inhibitors (cidofovir, foscarnet, or ganciclovir).

Viral Resistance

In Cell Culture

CMV mutants with reduced susceptibility to letermovir have been selected in cell culture and the resistance mutations map to UL51, UL56, and UL89. Resistance-associated substitutions were found in pUL51 (P91S), pUL56 (C25F, S229F, V231A/L, N232Y, V236A/L/M, E237D, L241P, T244K/R, L254F, L257F/I, K258E, F261C/L/S, Y321C, C325F/R/W/Y, L328V, M329T, A365S, N368D, R369G/M/S), and pUL89 (N320H, D344E). EC₅₀ values for recombinant CMV mutants expressing these substitutions are 1.6-to 9,300-fold higher than those for the wild-type reference virus.

In Clinical Studies

In a Phase 2b trial evaluating letermovir or placebo in 131 HSCT recipients, DNA sequence analysis of a select region of UL56 (amino acids 231 to 369) was performed on samples obtained from 12 letermovirtreated subjects who experienced prophylaxis failure and for whom on-treatment samples were available for analysis. One subject had a letermovir resistance substitution, pUL56 V236M.

In a Phase 3 trial (P001), DNA sequence analysis of the entire coding regions of UL56 and UL89 was performed on samples obtained from 50 letermovir-treated subjects who had received at least one dose of study drug and experienced prophylaxis failure and for whom samples were available for analysis. The pUL56 substitutions V236M, E237G, C325W, and R369T were detected in 3 subjects; however, no 2 subjects had substitutions at the same positions.

Cross Resistance

Cross resistance is not likely with drugs outside of this class. Letermovir is fully active against viral populations with substitutions conferring resistance to CMV DNA polymerase inhibitors (cidofovir, foscarnet, and ganciclovir). These DNA polymerase inhibitors are expected to be fully active against viral populations with substitutions conferring resistance to letermovir.

Animal Toxicology And/Or Pharmacology

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

Clinical Studies

Adult CMV-Seropositive Recipients [R+] Of An Allogeneic Hematopoietic Stem Cell Transplant

To evaluate PREVYMIS prophylaxis as a preventive strategy for CMV infection or disease in transplant recipients at high risk for CMV reactivation, the efficacy of PREVYMIS was assessed in a multicenter, double-blind, placebo-controlled Phase 3 Trial (P001, NCT02137772) in adult CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT). Subjects were randomized (2:1) to receive either PREVYMIS at a dose of 480 mg once daily adjusted to 240 mg when co-administered with cyclosporine, or placebo. Randomization was stratified by investigational site and risk level for CMV reactivation at the time of study entry. Study drug was initiated after HSCT (at any time from Day 0 to Day 28 post-transplant) and continued through Week 14 post-transplant. Study drug was administered either orally or intravenously; the dose of PREVYMIS was the same regardless of the route of administration. Subjects received CMV DNA monitoring weekly until post-transplant Week 14 and then bi-weekly until post-transplant Week 24, with initiation of standard-of-care CMV pre-emptive therapy if CMV viremia was considered clinically significant. Subjects had continued follow-up through Week 48 post-transplant.

Among the 565 treated subjects, 70 subjects were found to have CMV viremia prior to study drug initiation and were therefore excluded from the efficacy analyses. The efficacy population consisted of 325 subjects who received PREVYMIS (including 91 subjects who received at least one IV dose) and 170 who received placebo (including 41 subjects who received at least one IV dose). The IV formulation of PREVYMIS was used at investigators’ discretion in subjects who were unable to take oral therapy (e.g., unable to tolerate oral intake). The median time to starting study drug was 8 days after transplantation. Thirty-four percent (34%) of subjects were engrafted at baseline. The median age was 55 years (range: 18 to 76 years); 57% were male; 84% were White; 9% were Asian; 2% were Black or African American; and 7% were Hispanic or Latino.

At baseline, 30% of all subjects had one or more of the following factors associated with increased risk for CMV reactivation (high risk stratum): Human Leukocyte Antigen (HLA)-related donor with at least one mismatch at one of the following three HLA-gene loci: HLA-A, -B or –DR; haploidentical donor; unrelated donor with at least one mismatch at one of the following four HLA-gene loci: HLA-A, -B, -C and -DRB1; use of umbilical cord blood as stem cell source; use of ex vivo T-cell-depleted grafts; Grade 2 or greater GraftVersus-Host Disease (GVHD) requiring systemic corticosteroids. The remaining 70% of subjects did not meet any of these high risk stratum criteria and were therefore included in the low risk stratum. Additionally, 48% of subjects received a myeloablative regimen, 51% were receiving cyclosporine, and 43% were receiving tacrolimus. The most common primary reasons for transplant were acute myeloid leukemia (38%), myelodysplastic syndrome (16%), and lymphoma (12%).

Clinically Significant CMV Infection

The primary efficacy endpoint of Trial P001 was the incidence of clinically significant CMV infection through Week 24 post-transplant (prophylaxis failure). Clinically significant CMV infection was defined as the occurrence of either CMV end-organ disease, or initiation of anti-CMV pre-emptive therapy (PET) based on documented CMV viremia (using the Roche COBAS^® AmpliPrep/COBAS TaqMan^® assay, LLoQ is 137 IU/mL, which is approximately 150 copies/mL) and the clinical condition of the subject. The protocol-specified guidance for CMV DNA thresholds for the initiation of PET during the treatment period was ≥ 150 copies/mL or > 300 copies/mL for subjects in the high and low risk strata, respectively. From Week 14 through Week 24, the threshold was >300 copies/mL for both high and low risk strata subjects. The Non-Completer=Failure (NC=F) approach was used, where subjects who discontinued from the trial prior to Week 24 post-transplant or had a missing outcome at Week 24 post-transplant were counted as failures.

Efficacy results from Trial P001 are shown in Table 7.

Table 7: Trial P001 Efficacy Results in HSCT Recipients (NC=F Approach, FAS Population) Through Week 24

Parameter	Letermovir (N=325)	Placebo (N=170)
Proportion of subjects who failed prophylaxis	38%	61%
Reasons for failures*
Clinically significant CMV infection by Week 24†	18%	42%
Initiation of PET based on documented CMV viremia	16%	40%
CMV end-organ disease	2%	2%
Discontinued from study before Week 24‡	17%	16%
Missing outcome in Week 24 visit window	3%	3%
Stratum-adjusted treatment difference(Letermovir-Placebo)§
Difference (95% CI)	-23.5 (-32.5, -14.6)¶
* The categories of failure are mutually exclusive and based on the hierarchy of categories in the order listed. † Through Week 14, 8% of subjects in the PREVYMIS group and 39% of subjects in the placebo group experienced clinically significant CMV infection. ‡ Reasons for discontinuation included adverse event, death, lost to follow-up, physician decision, and withdrawal by subject. § 95% CI and p-value for the treatment differences in percent response were calculated using stratum-adjusted Mantel-Haenszel method with the difference weighted by the harmonic mean of sample size per arm for each stratum (high or low risk). ¶ p-value <0.0001. Note: FAS=Full analysis set; FAS includes randomized subjects who received at least one dose of study medication, and excludes subjects with detectable CMV DNA at baseline. Approach to handling missing values: Non-Completer=Failure (NC=F) approach. With NC=F approach, failure was defined as all subjects who developed clinically significant CMV infection or prematurely discontinued from the study or had a missing outcome through Week 24 post-transplant visit window.

Efficacy results were consistent across high and low risk strata for CMV reactivation. The time to clinically significant CMV infection is shown in Figure 1.

Figure 1: P001: Kaplan-Meier Plot of Time to Onset of Clinically Significant CMV Infection Through Week 24 Post-Transplant in HSCT Recipients (FAS Population)

Post-hoc analysis demonstrated that among PREVYMIS-treated subjects, inclusion in the high risk stratum for CMV reactivation at baseline, occurrence of GVHD, and steroid use at any time after randomization may be associated with the development of clinically significant CMV infection between Week 14 and Week 24 post-transplant.

Mortality

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

PATIENT INFORMATION

PREVYMIS™
(PREH-vih-miss)
(letermovir) tablets
(letermovir) injection, for intravenous use

What is PREVYMIS?

PREVYMIS is a prescription medicine to help to prevent cytomegalovirus (CMV) infection and disease in adults who have received an allogeneic hematopoietic stem cell (bone marrow) transplant.

It is not known if PREVYMIS is safe and effective in children under 18 years of age.

Who should not take PREVYMIS?

Do not take PREVYMIS if you take:

• Pimozide
• Ergot alkaloids

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

• Pitavastatin or simvastatin

What should I tell my doctor before taking PREVYMIS?

Tell your doctor about all your medical conditions, including if you:

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

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

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

How should I take PREVYMIS?

PREVYMIS comes as a tablet or can be given by your doctor through an IV line (intravenously).

• If you take PREVYMIS tablets:
  • Take PREVYMIS exactly as your doctor tells you to take it. Do not stop taking PREVYMIS without talking to your doctor first.
  • Take 1 PREVYMIS tablet once a day.
  • Take PREVYMIS with or without food.
  • Swallow PREVYMIS tablets whole.
  • It is important that you do not miss or skip doses of PREVYMIS.
  • If you miss a dose, take it as soon as you remember. If you do not remember until it is time for your next dose, skip the missed dose and take your dose at the next scheduled time. Do not take 2 doses of PREVYMIS at the same time to make up for a missed dose.
  • If you take too much PREVYMIS, call your doctor right away.
• If you receive PREVYMIS through an IV line (intravenously):
  • You will receive PREVYMIS 1 time each day given over 1 hour.
  • If you miss or skip your dose of PREVYMIS, call your doctor right away.

What are the possible side effects of PREVYMIS?

The most common side effects while taking PREVYMIS include:

• nausea
• diarrhea
• vomiting
• swelling in your arms and legs
• cough
• headache
• tiredness
• stomach (abdominal) pain

These are not all the possible side effects of PREVYMIS.

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

How should I store PREVYMIS?

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

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

General information about the safe and effective use of PREVYMIS

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

What are the ingredients in PREVYMIS?

Active ingredient: letermovir

Inactive ingredients:
Tablets: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and povidone 25. Film coating: hypromellose 2910, iron oxide red (only for 480 mg tablets), iron oxide yellow, lactose monohydrate, titanium dioxide, triacetin. Carnauba wax is added as a polishing agent.

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

This Patient Information has been approved by the U.S. Food and Drug Administration.