Letermovir

1 INDICATIONS AND USAGE PREVYMIS is a CMV DNA terminase complex inhibitor indicated for: Prophylaxis of cytomegalovirus (CMV) infection and disease in adult and pediatric patients 6 months of age and older and weighing at least 6 kg who are CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT). ( 1.1 ) Prophylaxis of CMV disease in adult and pediatric patients 12 years of age and older and weighing at least 40 kg who are kidney transplant recipients at high risk (Donor CMV seropositive/Recipient CMV seronegative [D+/R-]). ( 1.2 ) 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-]).

2 DOSAGE AND ADMINISTRATION Adult and Pediatric Patients 12 Years of Age and Older and Weighing at least 30 kg Who Are HSCT Recipients or Adult and Pediatric Patients 12 Years of Age and Older and Weighing at least 40 kg Who Are Kidney Transplant Recipients: HSCT : 480 mg administered once daily orally or as an intravenous (IV) infusion over 1 hour through 100 days post-HSCT. In patients at risk for late CMV infection and disease, PREVYMIS may be continued through 200 days post-HSCT. ( 2.1 , 2.3 ) Kidney Transplant : 480 mg administered once daily orally or as an IV infusion over 1 hour through 200 days post-transplant. ( 2.1 , 2.3 ) Pediatric Patients 6 Months to Less than 12 Years of Age or 12 Years of Age and Older and Weighing Less than 30 kg Who Are HSCT Recipients: HSCT : Dosing based on weight administered once daily orally or as an IV infusion over 1 hour through 100 days post-HSCT. In patients at risk for late CMV infection and disease, PREVYMIS may be continued through 200 days post-HSCT. ( 2.1 , 2.5 ) PREVYMIS injection must be diluted prior to administration. ( 2.1 ) PREVYMIS injection must be administered through a sterile 0.2 micron or 0.22 micron polyethersulfone (PES) in-line filter. ( 2.1 , 2.10 ) Following the completion of PREVYMIS prophylaxis, monitoring for CMV reactivation in HSCT recipients is recommended. ( 2.2 ) Dosage Adjustment: If PREVYMIS is co-administered with cyclosporine, the dosage of PREVYMIS should be decreased to 240 mg once daily in adult and pediatric patients 12 years of age and older. ( 2.4 ) If PREVYMIS is co-administered with cyclosporine in pediatric patients less than 12 years of age, dose adjustment may be required. ( 2.6 ) Instructions for Use should be followed for preparation and administration of PREVYMIS oral pellets. ( 2.9 ) Do not use PREVYMIS injection with IV bags and infusion set materials containing the plasticizer diethylhexyl phthalate (DEHP). ( 2.10 , 2.13 ) 2.1 Important Dosing and Administration Information PREVYMIS is available in 3 dosage forms: PREVYMIS Tablets - Administer orally with or without food. - Swallow tablets whole. PREVYMIS Oral Pellets - Administer orally mixed with soft food or via nasogastric tube (NG tube) or gastric tube (G tube) [see Dosage and Administration (2.9) ] . - Do not crush or chew. PREVYMIS Injection - PREVYMIS injection must be diluted prior to administration. - Administer PREVYMIS through a sterile 0.2 micron or 0.22 micron polyethersulfone (PES) in-line filter. - Administer by intravenous infusion via a peripheral catheter or central venous line at a constant rate over 1 hour. - Do not administer as an intravenous bolus injection. - PREVYMIS injection, which contains hydroxypropyl betadex, should be used only in patients unable to take oral therapy. Patients should be switched to oral PREVYMIS as soon as they are able to take oral medications. If possible, intravenous administration should not exceed 4 weeks [see Warnings and Precautions (5.2) ] . No dosage adjustment is necessary when switching formulations in adult and pediatric patients 12 years of age and older [see Dosage and Administration (2.3) ] . Dosage adjustment may be necessary for pediatric patients less than 12 years of age when switching between oral and intravenous formulations (see Table 1 and Table 2 ) [see Dosage and Administration (2.5) ] . 2.2 Patient Monitoring Following the completion of PREVYMIS prophylaxis, monitoring for CMV reactivation in HSCT recipients is recommended [see Clinical Studies (14.2) ] . 2.3 Recommended Dosage for Adult and Pediatric Patients 12 Years of Age and Older Who Are HSCT or Kidney Transplant Recipients HSCT: Adult and Pediatric Patients 12 Years of Age and Older and Weighing at least 30 kg The recommended dosage of PREVYMIS is 480 mg administered orally or intravenously once daily. When PREVYMIS is administered orally, the recommended dosage is one 480 mg tablet once daily or two 240 mg tablets once daily. Four 120 mg packets of oral pellets once daily can be used for patients who cannot swallow tablets [see Dosage and Administration (2.9) ] . For preparation and administration instructions of intravenous dosing refer to instructions in subsection 2.10 [see Dosage and Administration (2.10) ]. For pediatric patients less than 12 years of age or weighing less than 30 kg, refer to weight-based dosing in Table 1 and Table 2 [see Dosage and Administration (2.5) ] . Initiate PREVYMIS between Day 0 and Day 28 post-HSCT (before or after engraftment) and continue through Day 100 post-HSCT. In patients at risk for late CMV infection and disease, PREVYMIS may be continued through Day 200 post-HSCT [see Clinical Studies (14.2) ] . Dosage of PREVYMIS should be adjusted when co-administered with cyclosporine [see Dosage and Administration (2.4) ] . Kidney Transplant: Adult and Pediatric Patients 12 Years of Age and Older and Weighing at least 40 kg The recommended dosage of PREVYMIS is 480 mg administered orally or intravenously once daily. When PREVYMIS is administered orally, the recommended dosage is one 480 mg tablet once daily or two 240 mg tablets once daily. Four 120 mg packets of oral pellets once daily can be used for patients who cannot swallow tablets [see Dosage and Administration (2.9) ] . For preparation and administration instructions of intravenous dosing refer to instructions in subsection 2.10 [see Dosage and Administration (2.10) ]. Initiate PREVYMIS between Day 0 and Day 7 post-transplant and continue through Day 200 post-transplant. Dosage of PREVYMIS should be adjusted when co-administered with cyclosporine [see Dosage and Administration (2.4) ] . 2.4 Dosage Adjustment When Co-administered with Cyclosporine for Adult and Pediatric Patients 12 Years of Age and Older Who Are HSCT or Kidney Transplant Recipients If oral or intravenous PREVYMIS is co-administered with cyclosporine, the dosage of PREVYMIS should be decreased to 240 mg once daily in the following populations [see Drug Interactions (7.1 , 7.2 , 7.3) and Clinical Pharmacology (12.3) ] : HSCT: adult and pediatric patients 12 years of age and older and weighing at least 30 kg or Kidney transplant: adult and pediatric patients 12 years of age and older and weighing at least 40 kg. If cyclosporine is initiated after starting PREVYMIS, the next dose of PREVYMIS should be decreased to 240 mg once daily. If cyclosporine is discontinued after starting PREVYMIS, the next dose of PREVYMIS should be increased to 480 mg once daily. If cyclosporine dosing is interrupted due to high cyclosporine levels, no dose adjustment of PREVYMIS is needed. 2.5 Recommended Dosage for Pediatric Patients 6 Months to Less than 12 Years of Age or 12 Years of Age and Older and Weighing Less than 30 kg Who Are HSCT Recipients The recommended dosages of PREVYMIS for pediatric HSCT recipients 6 months to less than 12 years of age are based on weight and shown in Table 1 (tablets or oral pellets) and Table 2 (injection) [see Clinical Pharmacology (12.3) ] . PREVYMIS can be administered orally (tablet or pellet) or intravenously once daily. Dosage adjustment may be necessary for pediatric patients less than 12 years of age when switching between oral and intravenous formulations (see Table 1 and Table 2 ) . Initiate PREVYMIS between Day 0 and Day 28 post-HSCT (before or after engraftment) and continue through Day 100 post-HSCT. In patients at risk for late CMV infection and disease, PREVYMIS may be continued through Day 200 post-HSCT [see Clinical Studies (14.2) ] . 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 [see Drug Interactions (7.1 , 7.2 , 7.3) and Clinical Pharmacology (12.3) ] . If cyclosporine is initiated after starting PREVYMIS, the next dose of PREVYMIS should be the daily oral or intravenous dose co-administered with cyclosporine (Table 3) If cyclosporine is discontinued after starting PREVYMIS, the next dose of PREVYMIS should be the daily oral or intravenous dose administered without cyclosporine (Table 1 or Table 2) If cyclosporine dosing is interrupted due to high cyclosporine levels, no dose adjustment of PREVYMIS is needed. Table 3: Recommended Dosage of PREVYMIS when Co-administered with Cyclosporine in Pediatric HSCT Recipients 6 Months to Less than 12 Years of Age or 12 Years of Age and Older and Weighing Less than 30 kg Body Weight Daily Oral Dose Tablets Oral Pellets Daily IV 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 [see Use in Specific Populations (8.6) , and Clinical Pharmacology (12.3) ] . There are insufficient data in adult patients with CLcr 10 mL/min or less or in patients on dialysis or in pediatric patients with a similar degree of renal impairment (based on age-appropriate assessment of renal function) to make PREVYMIS dosing recommendations. In adult patients with CLcr less than 50 mL/min and in pediatric patients with a similar degree of renal impairment (based on age-appropriate assessment of renal function) receiving PREVYMIS injection, accumulation of the intravenous vehicle, hydroxypropyl betadex, may occur. Closely monitor serum creatinine levels in these patients [see Warnings and Precautions (5.2) ] . 2.8 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 [see Use in Specific Populations (8.7) ] . 2.9 Preparation and Administration of Oral Pellets PREVYMIS oral pellets can be administered: orally after mixing with soft food or via NG tube or G tube. Preparation and Administration Mixed with Soft Food See Instructions for Use for details on the preparation and administration of PREVYMIS oral pellets mixed with soft food. Do not crush or chew PREVYMIS oral pellets. Mix PREVYMIS oral pellets with 1 to 3 teaspoons of soft food (such as applesauce, yogurt, or pudding) that is at or below room temperature. Do not use hot food. Administer entire mixture within 10 minutes of mixing PREVYMIS oral pellets with the soft food. Preparation and Administration via NG Tube or G Tube See Instructions for Use , Table 4 (NG tube) and Table 5 (G tube) for details on the preparation and administration of PREVYMIS oral pellets via NG tube or G tube. Pour PREVYMIS oral pellets into a medicine cup containing room temperature water (see Initial Volume in Table 4 and Table 5). Do not mix PREVYMIS oral pellets with hot or cold (refrigerated) water. Wait 10 minutes. Do not shake or swirl the medicine cup. PREVYMIS oral pellets will not dissolve but will become loose or broken up. The entire mixture should be administered (see steps 3 and 4) within 2 hours. Stir the mixture with the syringe and administer entire mixture right away using the syringe and NG tube or G tube. Add room temperature water (see Rinse Volume in Table 4 and Table 5) to the medicine cup for rinsing, stir with a syringe and administer the entire rinse mixture using the syringe and NG tube or G tube. Flush the NG tube or G tube with the volume of water recommended by the NG or G tube manufacturer. Table 4: Recommendations for Administration of PREVYMIS Oral Pellets Via NG Tube Dosage NG Tube Fr = French; PUR = polyurethane Syringe Type With ENFit syringe, a medicine straw (large bore) is needed to aid withdrawal of the mixture from the medicine cup. Mixing Container Initial Volume (mL) Rinse Volume (mL) 120 mg to 480 mg Any ≥ 8 Fr NG tube Appropriately sized ENFit or catheter-tipped syringe Medicine Cup 15 15 40 mg to 80 mg 5 Fr PUR NG tube or Any ≥ 6 Fr NG tube 3 2 Table 5: Recommendations for Administration of PREVYMIS Oral Pellets Via G Tube Dosage G Tube Fr = French; PUR = polyurethane Syringe Type With ENFit syringe, a medicine straw (large bore) is needed to aid withdrawal of the mixture from the medicine cup. Mixing Container Initial Volume (mL) Rinse Volume (mL) 120 mg to 480 mg Any G tube Appropriately sized ENFit or catheter-tipped syringe Medicine Cup 15 15 40 mg to 80 mg Any 12 Fr G tube 3 2 2.10 Preparation and Administration of Intravenous Solution PREVYMIS injection is supplied in 30 mL single-dose vials containing either 240 mg/12 mL per vial (20 mg/mL) or 480 mg/24 mL per vial (20 mg/mL). PREVYMIS vials are for single use only. Discard any unused portion. Preparation Instructions PREVYMIS must be diluted prior to intravenous (IV) use. Only 0.9% Sodium Chloride and 5% Dextrose are chemically and physically compatible with PREVYMIS injection. Do not shake PREVYMIS vial. Inspect vial contents for discoloration and particulate matter prior to dilution. PREVYMIS injection is a clear colorless solution and may contain a few product-related small translucent or white particles. Do not use the vial if the solution is cloudy, discolored, or contains matter other than a few small translucent or white particles. Once diluted, the solution of PREVYMIS is clear, and ranges from colorless to yellow. Variations of color within this range do not affect the quality of the product. Do not use PREVYMIS injection with IV bags and infusion set materials containing the plasticizer diethylhexyl phthalate (DEHP). Use only with IV bags and infusion set materials that are DEHP-free. Materials that are phthalate-free are also DEHP-free. Use compatible IV bags and infusion set materials. PREVYMIS injection is compatible with the following IV bags and infusion set materials. PREVYMIS injection is not recommended with any IV bags or infusion set materials not listed below (note that PREVYMIS injection is not recommended for use with polyurethane-containing IV administration set tubing). IV Bags Materials: Polyvinyl chloride (PVC), ethylene vinyl acetate (EVA) and polyolefin (polypropylene and polyethylene) Infusion Sets Materials: PVC, polyethylene (PE), polybutadiene (PBD), silicone rubber (SR), styrene–butadiene copolymer (SBC), styrene-butadiene-styrene copolymer (SBS), polystyrene (PS) Plasticizers: Tris (2-ethylhexyl) trimellitate (TOTM), benzyl butyl phthalate (BBP) Catheters: Radiopaque polyurethane For the 480 mg or 240 mg dose , add PREVYMIS injection (see Table 6 ) into a 250 mL pre-filled IV bag containing either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP and mix bag gently. Do not shake. For the 120 mg or 60 mg dose , add PREVYMIS injection into a pre-filled IV bag containing either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP (see Table 6 ) and mix bag gently. Do not shake. Table 6: Preparation of PREVYMIS Intravenous Solution for Doses of 60 mg or Greater PREVYMIS Dose Volume of PREVYMIS 20 mg/mL to be Withdrawn from Vial Volume of Diluent 480 mg 24 mL 250 mL 240 mg 12 mL 250 mL 120 mg 6 mL 100 mL 60 mg 3 mL 50 mL For the 40 mg dose , prepare a dilution of PREVYMIS injection according to Table 7 in either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP and mix bag gently. Transfer 20 mL from the prepared dilution into an appropriately sized IV bag or syringe. Do not shake. Table 7: Preparation of PREVYMIS Intravenous Solution for Doses of 40 mg PREVYMIS Dose Preparation of 2 mg/mL PREVYMIS Dilution Final Infusion Volume of the Prepared 2 mg/mL PREVYMIS Dilution 40 mg Add 5 mL of 20 mg/mL PREVYMIS to 45 mL of diluent (0.9% Sodium Chloride Injection or 5% Dextrose Injection) and mix gently 20 mL Administration Instructions Administer the entire contents of the intravenous bag or syringe by intravenous infusion via a peripheral catheter or central venous line at a constant rate over 1 hour [see Dosage and Administration (2.1) ] . The diluted solution must be administered through a sterile 0.2 micron or 0.22 micron polyethersulfone (PES) in-line filter. Do not administer through a filter other than a sterile 0.2 micron or 0.22 micron PES in-line filter. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Discard if the diluted solution is cloudy, discolored, or contains matter other than a few small translucent or white particles. 2.11 Storage of the Diluted Solution The diluted solutions (as prepared in Table 6 or Table 7) are stable for up to 24 hours at room temperature or up to 48 hours under refrigeration at 2°C to 8°C (36°F to 46°F) (this time includes storage of the diluted solution in the intravenous bag through the duration of infusion). 2.12 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) Amphotericin B (lipid complex) is compatible with PREVYMIS. However, Amphotericin B (liposomal) is incompatible [see Dosage and Administration (2.13) ] . , 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. 2.13 Incompatible Drug Products and Other Materials Used for Intravenous Administration Incompatible Drug Products PREVYMIS injection is physically incompatible with amiodarone hydrochloride, amphotericin B (liposomal), aztreonam, cefepime hydrochloride, ciprofloxacin, cyclosporine, diltiazem hydrochloride, filgrastim, gentamicin sulfate, levofloxacin, linezolid, lorazepam, midazolam HCl, mycophenolate mofetil hydrochloride, ondansetron, palonosetron. Incompatible IV Bags and Infusion Set Materials PREVYMIS injection is incompatible with diethylhexyl phthalate (DEHP) plasticizers and polyurethane-containing IV administration set tubing.

6 ADVERSE REACTIONS Adult HSCT Patients: Most common adverse events (occurring in at least 10% of subjects in the PREVYMIS group and at a frequency at least 2% greater than placebo) are nausea, diarrhea, vomiting, peripheral edema, cough, headache, fatigue, and abdominal pain. ( 6.1 ) Adult Kidney Transplant Patients: Most common adverse event (occurring in at least 10% of subjects in the PREVYMIS group and at a frequency greater than valganciclovir) is diarrhea. ( 6.1 ) Pediatric Patients: Adverse events in pediatric patients are similar to adults. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme LLC at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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. Adult CMV-seropositive 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. Cardiac Adverse Events 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. 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 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. Laboratory Abnormalities 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 3 on 3 consecutive days after transplantation) was 19 days in the PREVYMIS group and 18 days in the placebo group. Prophylaxis From 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. Adult Kidney Transplant 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. Adverse events were those reported while subjects were on study medication or within two weeks of study medication completion/discontinuation. 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%). Laboratory Abnormalities 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 [see Use in Specific Populations (8.4) and Clinical Studies (14.4) ].

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 (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 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 (17,500, 139,000) 240 mg oral once daily, with cyclosporine 71,900 (42,400, 125,000) 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 (see Table 13 and Table 14 ). 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 (see Table 12 ). 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. Oral 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 (18,100, 78,100) 240 mg 50,200 (24,100, 102,000) 15 kg to less than 30 kg 240 mg 39,600 (21,300, 71,800) 120 mg 53,200 (27,800, 102,000) 7.5 kg to less than 15 kg 120 mg 32,900 (16,800, 61,200) 60 mg 42,300 (22,300, 81,500) 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 (16,600, 54,100) 40 mg 39,200 (20,900, 71,800) 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 (53,900, 230,000) 240 mg 61,400 (29,300, 128,000) 15 kg to less than 30 kg 120 mg 56,400 (29,100, 110,000) 120 mg 62,300 (32,100, 114,000) 7.5 kg to less than 15 kg 60 mg 45,900 (24,500, 86,400) 60 mg 49,900 (26,300, 96,300) 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. 40 mg 42,800 (23,800, 79,200) 40 mg 46,400 (26,300, 86,500) 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 30 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. Post-kidney Transplant 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 60 to less than 90 mL/min), moderate (CLcr greater than or equal to 30 to less than 60 mL/min) and severe (CLcr greater than or equal to 15 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. Hepatic Impairment Letermovir 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 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 (see Table 15 and Table 16 ) . 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 (see Table 16 ) . Based on these results, co-administration of PREVYMIS with CYP3A substrates may increase the plasma concentrations of the CYP3A substrates [see Contraindications (4) , Warnings and Precautions (5.1) , Drug Interactions (7.2 , 7.3) , and Table 11 ] . 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 11 in Drug Interactions (7.3) ]. 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 11 in Drug Interactions (7.3) ] . 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 11 in Drug Interactions (7.3) ] . 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 16 ) . 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 (1.01, 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) These data are the effect of rifampin on letermovir 24 hours after final rifampin dose. 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) Table 16: 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 PK with/without Letermovir (No Effect=1.00) AUC Cmax C24hr C12hr reported for voriconazole. Abbreviations: PO=oral 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) 2 mg single dose PO 240 mg once daily PO 2.25 (2.04, 2.48) 1.72 (1.55, 1.92) Not available 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)