PREVYMIS LETERMOVIR 480 mg Tablet, Film Coated

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 )

5.1Risk 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.

5.2Risks 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.

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 .

6.1Clinical 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…

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 )

7.1Potential 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 ) .

7.2Potential 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.

7.3Established 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…