PREVYMIS

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 o…

5 WARNINGS AND PRECAUTIONS Risk of Adverse Reactions or Reduced Therapeutic Effect Due to Drug Interactions: The concomitant use of PREVYMIS with certain drugs may result in potentially significant drug interactions, some of which may lead to adverse reactions (PREVYMIS or concomitant drugs) or reduced therapeutic effect of PREVYMIS or the concomitant drug. Consult the full prescribing information for contraindications and dosage recommendations for concomitant drugs. ( 4 , 5.1 , 7.1 , 7.2 , 7.3 ) Risks Associated with Hydroxypropyl Betadex Excipient in Intravenous Formulation: Intravenous formulation of PREVYMIS contains the excipient hydroxypropyl betadex. PREVYMIS injection should be used only in patients unable to take oral therapy. If possible, intravenous administration should not exceed 4 weeks. In patients with renal impairment, accumulation of hydroxypropyl betadex may occur. Animal studies have shown the potential for hydroxypropyl betadex to cause ototoxicity. ( 5.2 , 8.6 , 13.2 ) 5.1 Risk of Adverse Reactions or Reduced Therapeutic Effect Due to Drug Interactions The concomitant use of PREVYMIS and certain drugs may result in potentially significant drug interactions, some of which may lead to adverse reactions (PREVYMIS or concomitant drugs) or reduced therapeutic effect of PREVYMIS or the concomitant drug [see Contraindications (4) and Drug Interactions (7.1 , 7.2 , 7.3) ] . See Table 11 for steps to prevent or manage these possible or known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during PREVYMIS therapy; review concomitant medications during PREVYMIS therapy; and monitor for adverse reactions associated with PREVYMIS and concomitant medications. 5.2 Risks Associated with Hydroxypropyl Betadex Excipient in Intravenous Formulation Intravenous formulation of PREVYMIS contains the excipient hydroxypropyl betadex. PREVYMIS injection should be used only in patients unable to take oral therapy and patients should be switched to oral PREVYMIS as soon as they are able to take oral medications. If possible, intravenous administration should not exceed 4 weeks [see Dosage and Administration (2.1) ]. In patients with renal impairment, accumulation of hydroxypropyl betadex may occur. In adult patients with CLcr less than 50 mL/min and in pediatric patients with a similar degree of renal impairment (based on age-appropriate assessment of renal function) receiving PREVYMIS injection, closely monitor serum creatinine levels [see Dosage and Administration (2.7) and Use in Specific Populations (8.6) ] . Animal studies have shown the potential for hydroxypropyl betadex to cause ototoxicity [see Nonclinical Toxicology (13.2) ]. The active ingredient, letermovir, is not known to be associated with ototoxicity.

4 CONTRAINDICATIONS PREVYMIS is contraindicated in patients receiving pimozide or ergot alkaloids: Pimozide: Concomitant administration of PREVYMIS in patients receiving pimozide may result in increased concentrations of pimozide due to inhibition of cytochrome P450 3A (CYP3A) by letermovir, which may lead to QT prolongation and torsades de pointes [see Warnings and Precautions (5.1) and Drug Interactions (7.2 , 7.3) ] . Ergot alkaloids: Concomitant administration of PREVYMIS in patients receiving ergot alkaloids may result in increased concentrations of ergot alkaloids (ergotamine and dihydroergotamine) due to inhibition of CYP3A by letermovir, which may lead to ergotism [see Warnings and Precautions (5.1) and Drug Interactions (7.2 , 7.3) ] . PREVYMIS is contraindicated with pitavastatin and simvastatin when co-administered with cyclosporine. Concomitant administration of PREVYMIS in combination with cyclosporine may result in significantly increased pitavastatin or simvastatin concentrations, which may lead to myopathy or rhabdomyolysis [see Warnings and Precautions (5.1) and Drug Interactions (7.2 , 7.3) ] . PREVYMIS is contraindicated with: Pimozide. ( 4 ) Ergot Alkaloids. ( 4 ) Pitavastatin and simvastatin when co-administered with cyclosporine. ( 4 )

7 DRUG INTERACTIONS 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 ) Co-administration of PREVYMIS may alter the plasma concentrations of other drugs and other drugs may alter the plasma concentrations of PREVYMIS. Consult the full prescribing information prior to and during treatment for potential drug interactions. ( 2.4 , 2.6 , 4 , 5.1 , 7.1 , 7.2 , 7.3 , 7.4 , 12.3 ) 7.1 Potential for Other Drugs to Affect PREVYMIS Letermovir is a substrate of organic anion-transporting polypeptide 1B1/3 (OATP1B1/3) and P-glycoprotein (P-gp) transporters and UDP-glucuronosyltransferase 1A1/3 (UGT1A1/3) enzymes. Co-administration of PREVYMIS with drugs that are inhibitors of OATP1B1/3 transporters may result in increases in letermovir plasma concentrations (Table 11). Co-administration of PREVYMIS with inducers of transporters (e.g., P-gp) and/or enzymes (e.g., UGTs) is not recommended due to the potential for a decrease in letermovir plasma concentrations (see Table 11 ) . 7.2 Potential for PREVYMIS to Affect Other Drugs Co-administration of PREVYMIS with midazolam results in increased midazolam plasma concentrations, indicating that letermovir is a moderate inhibitor of CYP3A [see Clinical Pharmacology (12.3) ] . Co-administration of PREVYMIS with drugs that are CYP3A substrates may result in clinically relevant increases in the plasma concentrations of co-administered CYP3A substrates (Table 11) [see Contraindications (4) and Warnings and Precautions (5.1) ] . Letermovir is an inhibitor of OATP1B1/3 transporters. Co-administration of PREVYMIS with drugs that are substrates of OATP1B1/3 transporters may result in a clinically relevant increase in plasma concentrations of co-administered OATP1B1/3 substrates (Table 11). The magnitude of CYP3A- and OATP1B1/3-mediated drug interactions on co-administered drugs may be different when PREVYMIS is co-administered with cyclosporine. See the prescribing information for cyclosporine for information on drug interactions with cyclosporine. 7.3 Established and Other Potentially Significant Drug Interactions If dose adjustments of concomitant medications are made due to treatment with PREVYMIS, doses should be readjusted after treatment with PREVYMIS is completed. Table 11 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on adult studies conducted with PREVYMIS or are predicted drug interactions that may occur with PREVYMIS [see Contraindications (4) , Warnings and Precautions (5.1) , and Clinical Pharmacology (12.3) ] . Table 11: Potentially Significant Drug Interactions: Alteration in Dose May Be Recommended Based on Results from Adult Drug Interaction Studies or Predicted Interactions This table is not all inclusive. (Information in the Table Applies to Co-administration of PREVYMIS and the Concomitant Drug without Cyclosporine, Unless Otherwise Indicated) Concomitant Drug Class and/or Clearance Pathway: Drug Name Effect on Concentration ↓ =decrease, ↑ =increase Clinical Comments Anti-arrhythmic Agents amiodarone ↑ amiodarone Close clinical monitoring for adverse events related to amiodarone is recommended during co-administration. Frequently monitor amiodarone concentrations when amiodarone is co-administered with PREVYMIS. Antibiotics nafcillin ↓ letermovir Co-administration of PREVYMIS and nafcillin is not recommended due to potential for loss of efficacy of PREVYMIS. Anticoagulants warfarin ↓ warfarin When PREVYMIS is co-administered with warfarin, frequently monitor International Normalized Ratio (INR) Refer to the respective prescribing information. . Anticonvulsants carbamazepine ↓ letermovir Co-administration of PREVYMIS and…

8.1 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).

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 d…