Nirsevimab

1 INDICATIONS AND USAGE BEYFORTUS is indicated for the prevention of Respiratory Syncytial Virus (RSV) lower respiratory tract disease in: Neonates and infants born during or entering their first RSV season. Children up to 24 months of age who remain vulnerable to severe RSV disease through their second RSV season. BEYFORTUS is a respiratory syncytial virus (RSV) F protein-directed fusion inhibitor indicated for the prevention of RSV lower respiratory tract disease in: Neonates and infants born during or entering their first RSV season. ( 1 ) Children up to 24 months of age who remain vulnerable to severe RSV disease through their second RSV season. ( 1 )

2 DOSAGE AND ADMINISTRATION Administer as an intramuscular injection. ( 2.1 ) Recommended dosage: Neonates and infants born during or entering their first RSV season: 50 mg if less than 5 kg in body weight. ( 2.1 ) 100 mg if greater than or equal to 5 kg in body weight. ( 2.1 ) Children who remain vulnerable through their second RSV season: 200 mg (2 × 100 mg injections). ( 2.1 ) 2.1 Recommended Dosage First RSV Season for Neonates and Infants For neonates and infants born during the RSV season, administer BEYFORTUS starting from birth. For neonates and infants born outside the RSV season, administer BEYFORTUS once prior to the start of the RSV season considering duration of protection provided by BEYFORTUS [see Clinical Pharmacology (12.2) ] . The recommended dosage of BEYFORTUS for neonates and infants born during or entering their first RSV season is based on body weight (see Table 1 ) and is administered as a single intramuscular (IM) injection. Table 1 Recommended Dosage of BEYFORTUS for the First RSV Season Body Weight at Time of Dosing Recommended Dosage Less than 5 kg 50 mg by IM injection 5 kg and greater 100 mg by IM injection Second RSV Season for Children Who Remain at Increased Risk for Severe RSV Disease For children up to 24 months of age, regardless of body weight, who remain at increased risk for severe RSV disease in their second RSV season, refer to Table 2 below for recommended dosage. Table 2 Recommended Dosage of BEYFORTUS for the Second RSV Season for Children Who Remain at Increased Risk for Severe RSV Disease Child's Age at Time of Dosing Recommended Dosage Up to 24 months of age Regardless of body weight 200 mg administered as two IM injections of (2 × 100 mg) First and Second RSV Season for Children Undergoing Cardiac Surgery with Cardiopulmonary Bypass For children undergoing cardiac surgery with cardiopulmonary bypass, an additional dose of BEYFORTUS is recommended as soon as the child is stable after surgery to ensure adequate nirsevimab-alip serum levels. The recommended dosage of BEYFORTUS is administered as an IM injection. First RSV season: If surgery is within 90 days after receiving BEYFORTUS, the additional dose should be based on body weight at the time of the additional dose. Refer to Table 1 for weight-based dosing. If more than 90 days have elapsed since receiving BEYFORTUS, the additional dose should be 50 mg regardless of body weight. Second RSV season: If surgery is within 90 days after receiving BEYFORTUS, the additional dose should be 200 mg, regardless of body weight. If more than 90 days have elapsed since receiving BEYFORTUS, the additional dose should be 100 mg, regardless of body weight. 2.2 Administration Instructions BEYFORTUS must be administered by a healthcare provider. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. BEYFORTUS is a clear to opalescent, colorless to yellow solution. Do not inject BEYFORTUS if the liquid is cloudy, discolored, or it contains large particles or foreign particulate matter. Do not use if the BEYFORTUS pre-filled syringe has been dropped or damaged, the security seal on the carton has been broken, or the expiration date has passed. BEYFORTUS is available in a 50 mg and a 100 mg pre-filled syringe. Check the labels on the BEYFORTUS carton and pre-filled syringe to ensure the correct 50 mg or 100 mg product is being used. Co-administration with Childhood Vaccines and Immunoglobulin Products BEYFORTUS can be given concomitantly with childhood vaccines [see Clinical Pharmacology (12.3) ] . When administered concomitantly with injectable vaccines, they should be given with separate syringes and at different injection sites. Do not mix BEYFORTUS with any vaccines or medications in the same syringe or vial. There is no information regarding co-administration of BEYFORTUS with other immunoglobulin products. Palivizumab should not be administered to infants who have already received BEYFORTUS in the same season. There are no data regarding substitution of BEYFORTUS for palivizumab once prophylaxis treatment is initiated with palivizumab for the RSV season. BEYFORTUS may be administered prior to or during the second RSV season to children up to 24 months of age who remain vulnerable to severe RSV disease, and who received palivizumab in their first RSV season [see Adverse Reactions (6.1) and Clinical Studies (14.3) ] . Administration Instructions for Single-Dose Pre-filled Syringe BEYFORTUS 50 mg (50 mg/0.5 mL) pre-filled syringe with a purple plunger rod. BEYFORTUS 100 mg (100 mg/mL) pre-filled syringe with a light blue plunger rod. Refer to Figure 1 for pre-filled syringe components. Figure 1 Luer Lock Syringe Components Step 1: Holding the Luer lock in one hand (avoid holding the plunger rod or syringe body), unscrew the syringe cap by twisting it counter-clockwise with the other hand. Step 2: Attach a Luer lock needle to the pre-filled syringe by gently twisting the needle clockwise onto the pre-filled syringe until slight resistance is felt. Step 3: Hold the syringe body with one hand and carefully pull the needle cover straight off with the other hand. Do not hold the plunger rod while removing the needle cover or the rubber stopper may move. Do not touch the needle or let it touch any surface. Do not recap the needle or detach it from the syringe. Step 4: Administer the entire contents of the BEYFORTUS pre-filled syringe as an IM injection, preferably in the anterolateral aspect of the thigh. The gluteal muscle should not be used as an injection site because of the risk of damage to the sciatic nerve. Step 5: Discard syringe into a sharps container. If two injections are required, repeat Steps 1–5 in a different injection site. Image Image Figure 1

6 ADVERSE REACTIONS Most common adverse reactions were rash (0.9%) and injection site reactions (0.3%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sanofi at 1-855-239-3678 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. A total of 3,224 pediatric subjects received the recommended dose of BEYFORTUS in Phase 2 and Phase 3 clinical trials (Trials 03, 04, and 05) including 2,119 infants who were born at 35 weeks gestational age (GA) or older, and 1,105 infants who were born at less than 35 weeks GA. A total of 247 infants of any GA with chronic lung disease (CLD) of prematurity or hemodynamically significant congenital heart disease (CHD) in Trial 05 received the recommended dose of BEYFORTUS. Neonates and Infants Entering Their First RSV Season (Trial 03 and Trial 04) Trial 03 was a randomized, double-blind placebo-controlled trial conducted in preterm infants born at a GA of greater than or equal to 29 weeks to less than 35 weeks. Subjects were randomized 2:1 to receive BEYFORTUS (N=968) or placebo (N=479) by IM injection. All subjects randomized to BEYFORTUS received a single 50 mg IM dose regardless of body weight. Safety data in Trial 03 are presented only for the infants in the BEYFORTUS arm who received the recommended dose [infants who weighed less than 5 kg and who received a single dose of 50 mg BEYFORTUS IM (N=572) or placebo (N=288)]. Trial 04 was a Phase 3, randomized, double-blind, placebo-controlled trial conducted in late preterm and term infants born at greater than or equal to 35 weeks GA. Trial 04 enrolled subjects sequentially into two cohorts: the Primary Cohort was used for the primary efficacy analysis [see Clinical Studies (14.3) ] and for assessment of safety, and the Safety Cohort was used primarily for safety assessment. All subjects from both cohorts of Trial 04 were included in the safety analysis (BEYFORTUS N=1,997 and placebo N=997). Subjects in Trial 04 weighing less than 5 kg received a single 50 mg IM dose of BEYFORTUS and infants weighing greater than or equal to 5 kg received a single 100 mg IM dose. Infants who received the recommended dose in Trial 03 and infants in Trial 04 were pooled to evaluate the safety of BEYFORTUS (N=2,570) compared to placebo (N=1,284). At randomization, in this pooled Safety Population from Trials 03 and 04 cohorts, 22% of infants were born at less than 35 weeks GA, 10% of infants were GA greater than or equal to 35 weeks and less than 37 weeks; 68% were GA greater than or equal to 37 weeks; 52% were male; 57% were White; 15% were Black; 4% were American Indian/Alaskan native; 4% were Asian; 1% were Pacific Islander; and 19% were Other or Mixed Race; 30% were Hispanic or Latino; 73% were from Northern Hemisphere; and 53% weighed less than 5 kg. The median age was 2 months; 65% were less than or equal to 3 months; 28% were greater than 3 to less than or equal to 6 months, and 7% were greater than 6 months of age. (Refer to Sections 14.2 and 14.3, Clinical Studies, for a description of the efficacy populations in Trials 03 and 04). In both trials, infants received a single dose of IM BEYFORTUS or placebo on Study Day 1 and were monitored for at least 60 minutes post-dose. Subjects were followed for 360 days post-dose to assess safety. Adverse reactions were reported in 1.2% of subjects who received BEYFORTUS; most (97%) of adverse reactions were mild to moderate in intensity. Table 3 summarizes the adverse reactions that occurred in Trial 03 and Trial 04 (Safety Population) in subjects who received the recommended dose of BEYFORTUS. Table 3 Adverse Reactions Reported at an Incidence Higher Than Placebo in the Safety Population The Safety Population includes all subjects who received the recommended dose of BEYFORTUS in Trials 03 and 04: Primary and Safety cohorts from Trial 04; infants who weighed less than 5 kg and who received the recommended dose of BEYFORTUS (single 50 mg IM dose) in Trial 03. (Trials 03 and 04) Adverse Reaction BEYFORTUS N=2,570 % Placebo N=1,284 % Rash Rash was defined by the following grouped preferred terms: rash, rash macular, rash maculo-papular, rash papular. (occurring within 14 days post-dose) 0.9 0.6 Injection site reaction Injection site reaction was defined by the following grouped preferred terms: injection site reaction, injection site pain, injection site induration, injection site edema, injection site swelling. (occurring within 7 days post-dose) 0.3 0 Infants Born at <35 Weeks Gestational Age and Infants and Children with CLD of Prematurity or Hemodynamically Significant CHD (Trial 05) RSV Season One The safety of BEYFORTUS was evaluated in Trial 05, a randomized, double-blind, palivizumab-controlled multicenter trial in infants at high risk for severe RSV disease. These subjects were randomized 2:1 to receive BEYFORTUS (N=614) or palivizumab (N=304) by IM injection. The 614 infants who received BEYFORTUS included 128 preterm infants born at GA less than 29 weeks, 390 preterm infants who were born at 29 weeks or older to less than 35 weeks GA, and 96 late preterm and term infants born at 35 weeks GA or older. Among infants enrolled during their first RSV season, the number of infants with CLD of prematurity or hemodynamically significant CHD were overall 214 and 103, respectively, regardless of gestational age. Of these, 12 infants had both CLD and CHD. Subjects in Trial 05 weighing less than 5 kg received a single 50 mg IM dose of BEYFORTUS and infants weighing greater than or equal to 5 kg received a single 100 mg IM dose. BEYFORTUS was administered once on Study Day 1 followed by 4 monthly IM doses of placebo; palivizumab was administered IM monthly for 5 months. All subjects were monitored for at least 60 minutes post-dose. Subjects were followed for 360 days post-dose to assess safety. Adverse reactions reported among Trial 05 subjects who received BEYFORTUS in their first RSV season were similar to those reported in subjects who received BEYFORTUS in Trials 03 and 04. RSV Season Two (Subjects with CLD of Prematurity and Hemodynamically Significant CHD) Subjects with CLD of prematurity or hemodynamically significant CHD could continue in Trial 05 and receive BEYFORTUS or palivizumab prior to their second RSV season. All subjects who received BEYFORTUS in the first RSV season also received BEYFORTUS in the second RSV season (N=180). Subjects who received palivizumab in the first RSV season were re-randomized to receive BEYFORTUS (N=40) or palivizumab (N=42) in the second RSV season. Safety data were available for 150 days after dosing in children with CLD or CHD who received BEYFORTUS (N=220) or palivizumab (N=42) in their second RSV season. The safety profile of BEYFORTUS in these children during their second RSV season was consistent with the safety profile of BEYFORTUS observed during their first RSV season. Term and Preterm Infants Entering Their First RSV Season (Trial 09) The safety of BEYFORTUS was evaluated in Trial 09, a randomized open-label multicenter trial in 8,034 term and preterm infants (GA greater than or equal to 29 weeks) entering their first RSV season (not eligible for palivizumab), who received BEYFORTUS (N=4,016) or no intervention (N=4,018) for the prevention of RSV LRTI hospitalization. Subjects were followed for 365 days post-dose (BEYFORTUS arm) or post-randomization (no intervention arm) to assess safety. The safety profile of BEYFORTUS administered in the first RSV season was consistent with the safety profile of BEYFORTUS in the placebo-controlled Trials 03 and 04. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of BEYFORTUS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypersensitivity reactions [see Warnings and Precautions (5.1) ] .

12.3 Pharmacokinetics The PK of nirsevimab-alip is dose-proportional following a single IM administration of doses ranging from 25 mg (0.5 times the lowest approved recommended dosage) to 200 mg in pediatric subjects. Following the recommended dose, the nirsevimab-alip serum exposures were similar in neonates and infants born during or entering their first RSV season (Trials 03 and 04), and in neonates and infants born at less than 35 weeks GA (including less than 29 weeks GA) in their first RSV season (Trial 05), and in pediatric subjects up to 24 months of age with CLD or CHD in their first and second RSV season (Trial 05). Absorption The estimated nirsevimab-alip absolute bioavailability is 84% and the median time (range) to maximum concentration is 6 (1, 28) days. Distribution The estimated nirsevimab-alip total volume of distribution is 477 mL, for an infant weighing 5 kg. Elimination The nirsevimab-alip terminal half-life is approximately 71 days and the estimated clearance is 3.42 mL/day for an infant weighing 5 kg. Metabolism Nirsevimab-alip is degraded into small peptides by catabolic pathways. Specific Populations No clinically significant differences in the pharmacokinetics of nirsevimab-alip were observed based on race or vulnerability to severe RSV disease (i.e., CLD, CHD, GA <29 weeks). The mean and median serum nirsevimab-alip concentrations in Trial 08 were lower than the concentrations in Trials 04 and 05. However, Trial 08 exposures were within the range shown to be effective in those who received the recommended dosage in Trials 03, 04, and 05 [see Pediatric Use (8.4) ] . Drug Interaction Studies No formal drug interaction studies have been performed with BEYFORTUS. Nirsevimab-alip is not predicted to be a substrate of, inhibitor or inducer of cytochrome P450 enzymes or transporter systems based on a mechanistic understanding of monoclonal antibodies. Clinical Studies Vaccines : There is limited experience with co-administration of BEYFORTUS with vaccines. In clinical trials, when BEYFORTUS was given concomitantly with routine childhood vaccines, the safety and reactogenicity profile of the co-administered regimen was similar to the childhood vaccines given alone.