PREVYMIS

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

Letermovir has a molecular formula of

C 29 H 28 F 4 N 4 O and a molecular weight of 572.55.

The chemical name for letermovir is (4 S )-2-{8-Fluoro-2-[4-(3 - methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5 - (trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetic acid.

Letermovir is very slightly soluble in water.

The chemical structure of letermovir is

PREVYMIS is available as 240 mg and 480 mg tablets.

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

Carnauba wax is added as a polishing agent.

PREVYMIS is available as 20 mg and 120 mg packets of oral pellets.

PREVYMIS packets of oral pellets contain either 20 mg or 120 mg of letermovir.

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

PREVYMIS is also available as 240 mg/12 mL (20 mg/mL) and 480 mg/24 mL (20 mg/mL) injection for intravenous infusion.

PREVYMIS injection is a clear, preservative-free sterile solution and may contain a few small translucent or white particles in single-dose vials of either 240 mg or 480 mg per vial.

Each 1 mL of solution contains 20 mg letermovir, hydroxypropyl betadex (150 mg), sodium chloride (3.1 mg), sodium hydroxide (1.2 mg), and Water for Injection.

The amount of sodium hydroxide may be adjusted to achieve a pH of approximately 7.5.

is a CMV DNA terminase complex inhibitor indicated for: Prophylaxis of cytomegalovirus (CMV) infection and disease in adult and pediatric patients 6 months of age and older and weighing at least 6 kg who are CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT).

Prophylaxis of

CMV disease in adult and pediatric patients 12 years of age and older and weighing at least 40 kg who are kidney transplant recipients at high risk (Donor CMV seropositive/Recipient CMV seronegative [D+/R-]). 1.1 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-]).

Mechanism of Action PREVYMIS is an antiviral drug against CMV. 12.2 Pharmacodynamics Cardiac Electrophysiology In a thorough QT trial in healthy adult 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. 12.3 Pharmacokinetics The pharmacokinetic properties of letermovir are displayed in Table 12.

Table 12: Absorption, Distribution, Metabolism, Elimination (ADME), and Pharmacokinetic Properties of PREVYMIS Values were obtained in studies of healthy adult subjects unless otherwise indicated.

Pharmacokinetics in Adult HSCT Recipients Treatment Regimen Steady-state median (90% prediction interval) AUC (ng∙hr/mL) of PREVYMIS 480 mg oral once daily, no cyclosporine 34,400 480 mg IV once daily, no cyclosporine 100,000 240 mg oral once daily, with cyclosporine 60,800 240 mg IV once daily, with cyclosporine 70,300 Pharmacokinetics in Adult Kidney Transplant Recipients Treatment Regimen Steady-state median (90% prediction interval) AUC (ng∙hr/mL) of PREVYMIS 480 mg oral once daily, no cyclosporine 62,700 240 mg oral once daily, with cyclosporine 71,900 Pharmacokinetics in Adult 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 Based on geometric mean data.

Cmax: 1.03 AUC: 1.22 Time to steady-state 9-10 days Absorption Bioavailability Healthy adult subjects administered PREVYMIS without cyclosporine: 94% at an oral dose range of 240 mg to 480 mg Adult HSCT recipients administered PREVYMIS without cyclosporine: 35% with 480 mg oral once daily Adult HSCT recipients administered PREVYMIS with cyclosporine: 85% with 240 mg oral once daily Adult kidney transplant recipients administered PREVYMIS without cyclosporine: 56% 95% CI (46%, 65%) with 480 mg oral once daily Median Tmax (hr) 1.5 to 3.0 hr Effect of food (relative to fasting) 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).

AUC: 99.63% [84.27% - 117.80%] Cmax: 129.82% [104.35% -161.50%] Oral pellets versus tablet (fasting) AUC and Cmax values were comparable when comparing PREVYMIS tablet (240 mg) and PREVYMIS oral pellets (2 X 120 mg) Distribution Mean steady-state volume of distribution 45.5 L following IV administration in adult 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 t 1/2 (hr) 12 hrs after dosing of PREVYMIS 480 mg IV once daily % of dose excreted in feces Single oral administration of radiolabeled letermovir in mass balance study. 93% % of dose excreted in urine <2% % of unchanged drug excreted in feces 70% Specific Populations Pediatric Patients Letermovir AUC in pediatric HSCT recipients was estimated using population pharmacokinetic analysis using Trial P030 data.

Exposures for pediatric

HSCT recipients for body weight bands 6 kg and above are within the range of exposures observed at the recommended doses of PREVYMIS in adults.

Table 13: PREVYMIS AUC (ng•hr/mL) Values Following Once Daily Oral Administration in Pediatric HSCT Recipients Body Weight Oral Dose, No Cyclosporine Steady-state Median (90% Prediction Interval) Medians and 90% prediction intervals are based on simulations using the pediatric HSCT population PK model with inter-individual variability.

Dose, With Cyclosporine Steady-state Median (90% Prediction Interval) 30 kg and above Includes pediatric patients 12 years of age and older or weighing ≥ 30 kg. 480 mg 38,500 240 mg 50,200 15 kg to less than 30 kg 240 mg 39,600 120 mg 53,200 7.5 kg to less than 15 kg 120 mg 32,900 60 mg 42,300 6 kg to less than 7.5 kg Includes pediatric patients 6 months of age and older and weighing 6 kg to < 7.5 kg. 80 mg 29,400 40 mg 39,200 Table 14: PREVYMIS AUC (ng•hr/mL) Values Following Once Daily IV Administration in Pediatric HSCT Recipients Body Weight IV Dose, No Cyclosporine Steady-state Median (90% Prediction Interval) Medians and 90% prediction intervals are based on simulations using the pediatric HSCT population PK model with inter-individual variability.

IV Dose, With Cyclosporine Steady-state Median (90% Prediction Interval) 30 kg and above Includes pediatric patients 12 years of age and older or weighing ≥ 30 kg. 480 mg 114,000 240 mg 61,400 15 kg to less than 30 kg 120 mg 56,400 120 mg 62,300 7.5 kg to less than 15 kg 60 mg 45,900 60 mg 49,900 6 kg to less than 7.5 kg Includes pediatric patients 6 months of age and older and weighing 6 kg to < 7.5 kg. 40 mg 42,800 40 mg 46,400 Age, Gender, Race, and Weight Age (18 to 82 years), gender, race, and body weight (up to 100 kg) did not have a clinically significant effect on the pharmacokinetics of letermovir in adult subjects.

Renal Impairment Clinical Study in a Renally Impaired Population Letermovir AUC was approximately 1.9.

• and 1.4-fold higher in adult subjects with moderate (eGFR greater than or equal to to 59 mL/min/1.73m 2 ) and severe (eGFR less than 30 mL/min/1.73m 2 ) renal impairment, respectively, compared to healthy adult subjects.

Based on population pharmacokinetic analysis, letermovir AUC was approximately 1.1-, 1.3.

• and 1.4-fold higher in adult subjects with mild (CLcr greater than or equal to to less than 90 mL/min), moderate (CLcr greater than or equal to to less than 60 mL/min) and severe (CLcr greater than or equal to to less than 30 mL/min) renal impairment, respectively, compared to adult subjects with CLcr greater than or equal to 90 mL/min. Intravenous Formulation 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.

AUC was approximately 1.6.

• and 3.8-fold higher in adult 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 adult subjects.

Drug interaction studies were performed in healthy adult subjects with PREVYMIS and drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interactions.

In vitro results indicate that letermovir is a substrate of drug metabolizing enzymes CYP3A, CYP2D6, UGT1A1, and UGT1A3, and transporters OATP1B1/3 and P-gp.

Oxidative metabolism is considered to be a minor elimination pathway based on in vivo human data.

Inhibitors of

OATP1B1/3 may result in increases in letermovir plasma concentrations.

Changes in letermovir plasma concentrations due to inhibition of P-gp/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.

Based on these results, co-administration of PREVYMIS with CYP3A substrates may increase the plasma concentrations of the CYP3A substrates.

Letermovir is a reversible inhibitor of

CYP2C8 in vitro.

When co-administered with

PREVYMIS, plasma concentrations of CYP2C8 substrates are predicted to be increased.

PREVYMIS reduced the exposure of voriconazole, most likely due to the induction of voriconazole elimination pathways, CYP2C9 and CYP2C19.

Co-administration of PREVYMIS with

CYP2C9 and CYP2C19 substrates may decrease the plasma concentrations of the CYP2C9 and CYP2C19 substrates.

Letermovir is an inducer of

CYP2B6 in vitro; the clinical relevance is unknown.

Letermovir inhibited efflux transporters

P-gp, breast cancer resistance protein (BCRP), bile salt export pump (BSEP), multidrug resistance-associated protein 2 (MRP2), OAT3, and hepatic uptake transporter OATP1B1/3 in vitro.

Co-administration of PREVYMIS with substrates of

OATP1B1/3 transporters (e.g., atorvastatin, a known substrate of CYP3A, OATP1B1/3, and potentially BCRP) may result in a clinically relevant increase in plasma concentrations of OATP1B1/3 substrates.

There were no clinically relevant changes in plasma concentrations of digoxin, a P-gp substrate, or acyclovir, an OAT3 substrate, following co-administration with PREVYMIS in clinical studies.

The effect of letermovir on

BCRP, BSEP, and MRP2 substrates was not evaluated in clinical studies; the clinical relevance is unknown.

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

Letermovir is not an inhibitor of

OATP2B1, OCT1, OCT2, or OAT1 in vitro.

Table 15: 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 C12hr for tacrolimus Abbreviations: PO= oral Antifungals fluconazole 400 mg single dose PO 480 mg single dose PO 1.11 1.06 1.28 itraconazole 200 mg once daily PO 480 mg once daily PO 1.33 1.21 1.90 Antimycobacterials rifampin 600 mg single dose PO 480 mg single dose PO 2.03 1.59 2.01 600 mg single dose IV 480 mg single dose PO 1.58 1.37 0.78 600 mg once daily PO 480 mg once daily PO 0.81 1.01 0.14 600 mg once daily PO (24 hours after rifampin) These data are the effect of rifampin on letermovir 24 hours after final rifampin dose. 480 mg once daily PO 0.15 0.27 0.09 Immunosuppressants cyclosporine 200 mg single dose PO 240 mg once daily PO 2.11 1.48 2.06 mycophenolate mofetil 1 g single dose PO 480 mg once daily PO 1.18.

Most common adverse events (occurring in at least 10% of subjects in the PREVYMIS group and at a frequency at least 2% greater than placebo) are nausea, diarrhea, vomiting, peripheral edema, cough, headache, fatigue, and abdominal pain.

Most common adverse event (occurring in at least 10% of subjects in the PREVYMIS group and at a frequency greater than valganciclovir) is diarrhea.

Adverse events in pediatric patients are similar to adults.fda.gov/medwatch. 6.1 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.

Recipients [R+] of an Allogeneic HSCT Prophylaxis Through Week 14 (~100 days) Post-HSCT The safety of PREVYMIS was evaluated in a 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-HSCT.

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.

The cardiac adverse event rate 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.

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 8.

Table 8: 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.

Selected laboratory abnormalities reported during treatment or within 2 weeks of stopping treatment are presented in Table 9.

Table 9: 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/mm on 3 consecutive days after transplantation) was 19 days in the PREVYMIS group and 18 days in the placebo group.

Week 14 (~100 days) Through Week 28 (~200 days) Post-HSCT The safety of PREVYMIS was evaluated in a Phase 3 randomized, double-blind, placebo-controlled trial (P040) in which 218 subjects who completed PREVYMIS prophylaxis through ~100 days post-HSCT were randomized to treatment with PREVYMIS (N=144) or placebo (N=74) through Week 28 (~200 days) post-HSCT.

Adverse events were those reported while subjects were on study drug or within two weeks of study drug completion/discontinuation.

The most commonly reported adverse events in P040 were similar to those reported in P001.

Study drug was discontinued due to an adverse event in 5% of PREVYMIS subjects and 1% of placebo subjects.

The cardiac adverse event rate was 4% in the PREVYMIS and placebo groups.

The rates of hematologic laboratory abnormalities were comparable in the PREVYMIS and placebo groups.

Serum creatinine abnormalities > 1.5 mg/dL occurred in 15% of PREVYMIS and 8% of placebo subjects.

Recipients [D+/R-] The safety of PREVYMIS was evaluated in a Phase 3 randomized, double-blind, active comparator-controlled trial (P002) in which 589 subjects were treated with PREVYMIS (N=292) or valganciclovir (N=297) through Week 28 post-transplant.

In these subjects, diarrhea was reported in at least 10% of subjects in the PREVYMIS group and at a frequency greater than valganciclovir (PREVYMIS, 32%; valganciclovir, 29%).

Study drug was discontinued due to an adverse event in 4% of PREVYMIS subjects and 14% of valganciclovir subjects.

The most frequently reported adverse events that led to study drug discontinuation were neutropenia (PREVYMIS, 1%; valganciclovir, 2%) and leukopenia (PREVYMIS, 1%; valganciclovir, 5%).

Selected laboratory abnormalities reported through Week 28 post-transplant are presented in Table 10.

Table 10: Trial P002 Selected Laboratory Abnormalities PREVYMIS N=292 Valganciclovir N=297 Absolute neutrophil count (cells/μL) < 500 2% 7% 500 – < 750 1% 4% 750 – < 1000 1% 8% Total < 1000 5% 18% Hemoglobin (g/dL) < 6.5 2% 0% 6.5 – < 8.0 4% 5% 8.0 – < 9.5 29% 32% Total < 9.5 34% 37% Platelets (cells/μL) < 50000 0% 0% 50000 – < 100000 1% 3% Total < 100000 1% 3% Leukocytes (cells/μL) < 1000 1% 2% 1000 – < 2000 5% 19% 2000 – < 2500 4% 14% Total < 2500 10% 35% Serum creatinine (mg/dL) > 2.5 24% 22% > 1.5 – 2.5 49% 52% Total > 1.5 73% 73% Pediatric Recipients of an Allogeneic HSCT The safety of PREVYMIS was evaluated in 63 pediatric subjects aged 2 months to less than 18 years of age who received an allogeneic HSCT (P030).

PREVYMIS was administered orally (tablet or pellet) or intravenously.

The duration of

PREVYMIS exposure ranged from 3 days to 102 days (median duration 84 days).

The safety profile was consistent with the safety profile observed in clinical trials of PREVYMIS in adults.

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.

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

Ergot alkaloids

Concomitant administration of PREVYMIS in patients receiving ergot alkaloids may result in increased concentrations of ergot alkaloids (ergotamine and dihydroergotamine) due to inhibition of CYP3A by letermovir, which may lead to ergotism.

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.

PREVYMIS is contraindicated with

Pitavastatin and simvastatin when co-administered with cyclosporine.

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.

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

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.

PREVYMIS injection must be diluted prior to administration.

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

Following the completion of

PREVYMIS prophylaxis, monitoring for CMV reactivation in HSCT recipients is recommended.

If PREVYMIS is co-administered with cyclosporine, the dosage of PREVYMIS should be decreased to 240 mg once daily in adult and pediatric patients 12 years of age and older.

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

Instructions for

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

Do not use PREVYMIS injection with

IV bags and infusion set materials containing the plasticizer diethylhexyl phthalate (DEHP). 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.

• Administer orally mixed with soft food or via nasogastric tube (NG tube) or gastric tube (G tube) .

• Do not crush or chew.

• 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.

No dosage adjustment is necessary when switching formulations in adult and pediatric patients 12 years of age and older.

Dosage adjustment may be necessary for pediatric patients less than 12 years of age when switching between oral and intravenous formulations. 2.2 Patient Monitoring Following the completion of PREVYMIS prophylaxis, monitoring for CMV reactivation in HSCT recipients is recommended. 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.

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.

For preparation and administration instructions of intravenous dosing refer to instructions in subsection 2.10.

For pediatric patients less than 12 years of age or weighing less than 30 kg, refer to weight-based dosing in Table and Table 2.

Initiate PREVYMIS between Day and

Day 28 post-HSCT (before or after engraftment) and continue through Day 100 post-HSCT.

CMV infection and disease, PREVYMIS may be continued through Day 200 post-HSCT.

Dosage of

PREVYMIS should be adjusted when co-administered with cyclosporine.

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.

Day 7 post-transplant and continue through Day 200 post-transplant.

PREVYMIS should be adjusted when co-administered with cyclosporine. 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: 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) .

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.

Table 1: Recommended Daily Oral Dosage of PREVYMIS in Pediatric HSCT Recipients 6 Months to Less than 12 Years of Age or 12 Years of Age and Older and Weighing Less than 30 kg Body Weight Daily Oral Dose Tablets Oral Pellets 30 kg and above 480 mg One 480 mg tablet or Two 240 mg tablets Four 120 mg packets of oral pellets 15 kg to less than 30 kg 240 mg One 240 mg tablet Two 120 mg packets of oral pellets 7.5 kg to less than 15 kg 120 mg Not recommended One 120 mg packet of oral pellets 6 kg to less than 7.5 kg 80 mg Not recommended Four 20 mg packets of oral pellets Table 2: Recommended Daily IV Dosage of PREVYMIS in Pediatric HSCT Recipients 6 Months to Less than 12 Years of Age or 12 Years of Age and Older and Weighing Less than 30 kg Body Weight Daily IV Refer to Subsection 2.10 for intravenous preparation and administration dosing instructions Dose 30 kg and above 480 mg 15 kg to less than 30 kg 120 mg 7.5 kg to less than 15 kg 60 mg 6 kg to less than 7.5 kg 40 mg 2.6 Dosage Adjustment When Co-administered with Cyclosporine for Pediatric Patients 6 Months to Less than 12 Years of Age or 12 Years of Age and Older and Weighing Less than 30 kg Who Are HSCT Recipients If oral or intravenous PREVYMIS is co-administered with cyclosporine in pediatric HSCT recipients 6 months to less than 12 years of age, the dosage of PREVYMIS may require adjustment as shown in Table 3.

If cyclosporine is initiated after starting

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

Table 3: Recommended Dosage of PREVYMIS when Co-administered with Cyclosporine in Pediatric HSCT Recipients 6 Months to Less than 12 Years of Age or 12 Years of Age and Older and Weighing Less than 30 kg Body Weight Daily Oral Dose Tablets Oral Pellets Daily IV Refer to Subsection 2.10 for intravenous preparation and administration dosing instructions Dose 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.

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. 2.8 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. 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.

PREVYMIS oral pellets with to 3 teaspoons of soft food (such as applesauce, yogurt, or puddin.

PREVYMIS 240 mg tablet is a yellow oval tablet; each tablet is debossed with "591" on one side and corporate logo on the other side.

PREVYMIS 480 mg tablet is a pink oval, bi-convex tablet debossed with "595" on one side and corporate logo on the other side.

The 240 mg tablets are packaged into a carton (NDC 0006-3075-02) containing four Child Resistant (CR) Dosepaks®, each containing a 7-count blister card for a total of 28 tablets, or into a carton (NDC 0006-3075-04) containing two 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 Child Resistant (CR) Dosepaks®, each containing a 7-count blister card for a total of 28 tablets, or into a carton (NDC 0006-3076-04) containing two unit-dose 7-count blister cards for a total of 14 tablets.

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

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) .

PREVYMIS oral pellets are supplied as beige round pellets in packets.

Each packet contains 20 mg of letermovir.

Each packet contains 120 mg of letermovir.

The 20 mg packets of PREVYMIS oral pellets are packaged into a carton (NDC 0006-5086-01).

Each carton contains 30 child resistant packets.

The 120 mg packets of PREVYMIS oral pellets are packaged into a carton (NDC 0006-5085-01).

PREVYMIS oral pellets in the original packet until use.

PREVYMIS oral pellets at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) .

PREVYMIS is supplied as a sterile, clear and colorless solution for intravenous use of 240 mg/12 mL (20 mg/mL) or 480 mg/24 mL (20 mg/mL) that may contain a few product-related small translucent or white particles.

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).

PREVYMIS injection vials at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) .

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

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

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) .

Risk Summary No adequate human data are available to establish whether PREVYMIS poses a risk to pregnancy outcomes.

In animal reproduction studies, embryo-fetal developmental toxicity (including fetal malformations) was observed in rats during the period of organogenesis at letermovir exposures (AUC) 11 times higher than human exposure at the recommended human dose (RHD).

In rabbits, no embryo-fetal developmental toxicity was noted at exposures that were not maternally toxic (up to letermovir exposures 2 times higher than human exposure at the RHD).

In a rat pre/post-natal development study, total litter loss was observed at maternal letermovir exposures approximately 2 times higher than human exposure at the RHD.

The background risk of major birth defects and miscarriage for the indicated population is unknown.

In the

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

Letermovir was administered orally to pregnant rats at 0, 10, 50 or 250 mg/kg/day from gestation days 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 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 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 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).

The safety and effectiveness of PREVYMIS have been established for: Prophylaxis of CMV infection and disease in pediatric CMV-seropositive recipients of an allogeneic HSCT 6 months of age and older and weighing at least 6 kg, and Prophylaxis of CMV disease in pediatric kidney transplant recipients 12 years of age and older and weighing at least 40 kg who are at high risk [D+/R-. HSCT Recipients: The use of PREVYMIS for prophylaxis of CMV infection and disease in pediatric recipients of an allogeneic HSCT is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data from pediatric patients in Trial P030. The safety and pharmacokinetic results were similar to those in adults. Kidney Transplant Recipients: The use of PREVYMIS for prophylaxis of CMV disease in high-risk [D+/R-] kidney transplant recipients 12 years of age and older and weighing at least 40 kg is supported by evidence from an adequate and well-controlled study in adults and safety data from pediatric HSCT recipients (Trial P030).

Letermovir exposures are expected to be similar between adult and pediatric patients 12 years of age and older and weighing at least 40 kg.

The safety and effectiveness of PREVYMIS have not been established for: HSCT recipients less than 6 months of age or weighing less than 6 kg, or Kidney transplant recipients less than 12 years of age or weighing less than 40 kg.

Of the 373 subjects treated with PREVYMIS in Trial P001, 56 (15%) subjects were 65 years of age or older.

Of the 144 subjects treated with PREVYMIS in Trial P040, 32 (22%) subjects were 65 years of age or older.

Of the 292 subjects treated with PREVYMIS in Trial P002, 48 (16%) subjects were 65 years of age or older.

Safety and efficacy were similar across older and younger subjects in each trial.

No dosage adjustment of

PREVYMIS is required based on age.