BEYFORTUS 100mg injection solution in pre-filled syringe medication leaflet

Beyfortus 50 mg solution for injection in pre-filled syringe

Beyfortus 100 mg solution for injection in pre-filled syringe

Beyfortus 50 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 50 mg of nirsevimab in 0.5 mL (100 mg/mL).

Beyfortus 100 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 100 mg of nirsevimab in 1 mL (100 mg/mL).

Nirsevimab is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody produced in Chinesehamster ovary (CHO) cells by recombinant DNA technology.

This medicine contains 0.1 mg of polysorbate 80 (E433) in each 50 mg (0.5 mL) dose and 0.2 mg ineach 100 mg (1 mL) dose (see section 4.4).

For the full list of excipients, see section 6.1.

Solution for injection (injection).

Clear to opalescent, colourless to yellow, pH 6.0 solution.

Beyfortus is indicated for the prevention of Respiratory Syncytial Virus (RSV) lower respiratory tractdisease in:

i. Neonates and infants during their first RSV season.

ii. Children up to 24 months of age who remain vulnerable to severe RSV disease through theirsecond RSV season (see section 5.1).

Beyfortus should be used in accordance with official recommendations.

Infants during their first RSV season

The recommended dose is a single dose of 50 mg administered intramuscularly for infants with bodyweight <5 kg and a single dose of 100 mg administered intramuscularly for infants with body weight≥5 kg.

Beyfortus should be administered from birth for infants born during the RSV season. For others bornoutside the season Beyfortus should be administered ideally prior to the RSV season.

Dosing in infants with a body weight from 1.0 kg to <1.6 kg is based on extrapolation, no clinical dataare available. Exposure in infants <1 kg is anticipated to yield higher exposures than in those weighingmore. The benefits and risks of nirsevimab use in infants <1 kg should be carefully considered.

There are limited data available in extremely preterm infants (Gestational Age [GA] <29 weeks) lessthan 8 weeks of age. No clinical data available in infants with a postmenstrual age (gestational age atbirth plus chronological age) of less than 32 weeks (see section 5.1).

Children who remain vulnerable to severe RSV disease through their second RSV season

The recommended dose is a single dose of 200 mg given as two intramuscular injections (2 x 100 mg).

Beyfortus should be administered ideally prior to the start of the second RSV season.

For individuals undergoing cardiac surgery with cardiopulmonary bypass, an additional dose may beadministered as soon as the individual is stable after surgery to ensure adequate nirsevimab serumlevels. If within 90 days after receiving the first dose of Beyfortus, the additional dose during the first

RSV season should be 50 mg or 100 mg according to body weight, or 200 mg during the second RSVseason. If more than 90 days have elapsed since the first dose, the additional dose could be a singledose of 50 mg regardless of body weight during the first RSV season, or 100 mg during the second

RSV season, to cover the remainder of the RSV season.

The safety and efficacy of nirsevimab in children aged 2 to 18 years have not been established. Nodata are available.

Beyfortus is for intramuscular injection only.

It is administered intramuscularly, preferably in the anterolateral aspect of the thigh. The glutealmuscle should not be used routinely as an injection site because of the risk of damage to the sciaticnerve. If two injections are required, different injection sites should be used.

For instructions on special handling requirements, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Hypersensitivity including anaphylaxis

Serious hypersensitivity reactions have been reported following Beyfortus administration.

Anaphylaxis has been observed with human immunoglobulin G1 (IgG1) monoclonal antibodies. Ifsigns and symptoms of anaphylaxis or other clinically significant hypersensitivity reaction occur,immediately discontinue administration and initiate appropriate medicinal products and/or supportivetherapy.

Clinically significant bleeding disorders

As with any other intramuscular injections, nirsevimab should be given with caution to individualswith thrombocytopenia or any coagulation disorder.

Immunocompromised children

In some immunocompromised children with protein-losing conditions, a high clearance of nirsevimabhas been observed in clinical trials (see section 5.2), and nirsevimab may not provide the same level ofprotection in those individuals.

Polysorbate 80 (E433)

This medicine contains 0.1 mg of polysorbate 80 in each 50 mg (0.5 mL) dose and 0.2 mg in each 100mg (1 mL) dose. Polysorbates may cause allergic reactions.

No interaction studies have been performed. Monoclonal antibodies do not typically have significantinteraction potential, as they do not directly affect cytochrome P450 enzymes and are not substrates ofhepatic or renal transporters. Indirect effects on cytochrome P450 enzymes are unlikely as the target ofnirsevimab is an exogenous virus.

Nirsevimab does not interfere with reverse transcriptase polymerase chain reaction (RT-PCR) or rapidantigen detection RSV diagnostic assays that employ commercially available antibodies targetingantigenic site I, II, or IV on the RSV fusion (F) protein.

Concomitant administration with vaccines

Since nirsevimab is a monoclonal antibody, a passive immunisation specific for RSV, it is notexpected to interfere with the active immune response to co-administered vaccines.

There is limited experience of co-administration with vaccines. In clinical trials, when nirsevimab wasgiven with routine childhood vaccines, the safety and reactogenicity profile of the co-administeredregimen was similar to the childhood vaccines given alone. Nirsevimab can be given concomitantlywith childhood vaccines.

Nirsevimab should not be mixed with any vaccine in the same syringe or vial (see section 6.2). Whenadministered concomitantly with injectable vaccines, they should be given with separate syringes andat different injection sites.

Not applicable.

Not applicable.

The most frequent adverse reaction was rash (0.7%) occurring within 14 days post dose. The majorityof cases were mild to moderate in intensity. Additionally, pyrexia and injection site reactions werereported at a rate of 0.5% and 0.3% within 7 days post dose, respectively. Injection site reactions werenon-serious.

Table 1 presents the adverse reactions reported in 2 966 term and preterm infants (GA ≥29 weeks)who received nirsevimab in clinical trials, and in post-marketing setting (see section 4.4).

Adverse reactions reported from controlled clinical trials are classified by MedDRA System Organ

Class (SOC). Within each SOC, preferred terms are arranged by decreasing frequency and then bydecreasing seriousness. Frequencies of occurrence of adverse reactions are defined as: very common(≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000);very rare (<1/10 000) and not known (cannot be estimated from available data).

Table 1: Adverse reactions

MedDRA SOC MedDRA Preferred Term Frequency

Immune system disorders Hypersensitivitya Not known

Skin and subcutaneous tissue disorders Rashb Uncommon

General disorders and administration Injection site reactionc Uncommonsite conditions

Pyrexia Uncommona Adverse reaction from spontaneous reporting.b Rash was defined by the following grouped preferred terms: rash, rash maculo-papular, rash macular.c Injection site reaction was defined by the following grouped preferred terms: injection site reaction, injectionsite pain, injection site induration, injection site oedema, injection site swelling.

Infants at higher risk for severe RSV disease in their first season

Safety was evaluated in MEDLEY in 918 infants at higher risk for severe RSV disease, including196 extremely preterm infants (GA <29 weeks) and 306 infants with chronic lung disease ofprematurity, or haemodynamically significant congenital heart disease entering their first RSV season,who received nirsevimab (n=614) or palivizumab (n=304). The safety profile of nirsevimab in infantswho received nirsevimab in their first RSV season was comparable to the palivizumab comparator andconsistent with the safety profile of nirsevimab in term and preterm infants GA ≥29 weeks(D5290C00003 and MELODY).

Infants who remain vulnerable to severe RSV disease in their second season

Safety was evaluated in MEDLEY in 220 children with chronic lung disease of prematurity orhaemodynamically significant congenital heart disease who received nirsevimab or palivizumab intheir first RSV season and went on to receive nirsevimab entering their second RSV season (180subjects received nirsevimab in both Season 1 and 2, 40 received palivizumab in Season 1 andnirsevimab in Season 2). The safety profile of nirsevimab in children who received nirsevimab in theirsecond RSV season was consistent with the safety profile of nirsevimab in term and preterm infants

GA ≥29 weeks (D5290C00003 and MELODY).

Safety was also evaluated in MUSIC, an open label, uncontrolled, single dose trial in100 immunocompromised infants and children ≤24 months, who received nirsevimab in their first orsecond RSV season. This included subjects with at least one of the following conditions:

immunodeficiency (combined, antibody, or other etiology) (n=33); systemic high-dose corticosteroidtherapy (n=29); organ or bone marrow transplantation (n=16); receiving immunosuppressivechemotherapy (n=20); other immunosuppressive therapy (n=15), and HIV infection (n=8). The safetyprofile of nirsevimab was consistent with that expected for a population of immunocompromisedchildren and with the safety profile of nirsevimab in term and preterm infants GA ≥29 weeks(D5290C00003 and MELODY).

The safety profile of nirsevimab in children during their second RSV season was consistent with thesafety profile of nirsevimab observed during their first RSV season.

Term and Preterm Infants entering their first RSV season

Safety of nirsevimab was also evaluated in HARMONIE, a randomised open-label multicentre trial in8 034 term and preterm infants (GA ≥29 weeks) entering their first RSV season (not eligible forpalivizumab), who received nirsevimab (n=4 016) or no intervention (n=4 018) for the prevention of

RSV LRTI hospitalisation. The safety profile of nirsevimab administered in the first RSV season wasconsistent with the safety profile of nirsevimab in the placebo-controlled trials (D5290C00003 and

MELODY).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no specific treatment for an overdose with nirsevimab. In the event of an overdose, theindividual should be monitored for the occurrence of adverse reactions and provided withsymptomatic treatment as appropriate.

Pharmacotherapeutic group: Immune sera and immunoglobulins, antiviral monoclonal antibodies,

ATC code: J06BD08

Nirsevimab is a recombinant neutralising human IgG1ĸ long-acting monoclonal antibody to theprefusion conformation of the RSV F protein which has been modified with a triple amino acidsubstitution (YTE) in the Fc region to extend serum half-life. Nirsevimab binds to a highly conservedepitope in antigenic site Ø on the prefusion protein with dissociation constants KD = 0.12 nM and

KD = 1.22 nM for RSV subtype A and B strains, respectively. Nirsevimab inhibits the essentialmembrane fusion step in the viral entry process, neutralising the virus and blocking cell-to-cell fusion.

The cell culture neutralisation activity of nirsevimab against RSV was measured in a dose-responsemodel using cultured Hep-2 cells. Nirsevimab neutralised RSV A and RSV B isolates with median

EC50 values of 3.2 ng/mL (range 0.48 to 15 ng/mL) and 2.9 ng/mL (range 0.3 to 59.7 ng/mL),respectively. The clinical RSV isolates (70 RSV A and 49 RSV B) were collected between 2003 and2017 from subjects across the United States, Australia, Netherlands, Italy, China and Israel andencoded the most common RSV F sequence polymorphisms found among circulating strains.

Nirsevimab demonstrated in vitro binding to immobilised human FcγRs (FcγRI, FcγRIIA, FcγRIIB,and FcγRIII) and equivalent neutralising activity compared to parental monoclonal antibodies, IG7and IG7-TM (Fc region modified to reduce FcR binding and effector function). In a cotton rat modelof RSV infection, IG7 and IG7-TM exhibited comparable dose-dependent reduction in RSVreplication in the lungs and nasal turbinates, strongly suggesting that protection from RSV infection isdependent on nirsevimab neutralisation activity rather than Fc-mediated effector function.

Escape variants were selected following three passages in cell culture of RSV A2 and B9320 strains inthe presence of nirsevimab. Recombinant RSV A variants that showed reduced susceptibility tonirsevimab included those with identified substitutions N67I+N208Y (103-fold as compared toreference). Recombinant RSV B variants that showed reduced susceptibility to nirsevimab includedthose with identified substitutions N208D (>90,000-fold), N208S (>24,000-fold), K68N+N201S(>13,000-fold), or K68N+N208S (>90,000-fold). All resistance-associated substitutions identifiedamong neutralisation escape variants were located in the nirsevimab binding site (amino acids 62-69and 196-212) and were shown to reduce binding affinity to RSV F protein.

In clinical trials

In MELODY, MEDLEY and MUSIC, no subject with medically attended RSV lower respiratory tractinfection (MA RSV LRTI) had an RSV isolate containing nirsevimab resistance-associatedsubstitutions in any treatment group.

In D5290C00003 (subjects who received a single dose of 50 mg nirsevimab irrespective of weight attime of dosing), 2 of 40 subjects in the nirsevimab group with MA RSV LRTI had an RSV isolatecontaining nirsevimab resistance-associated substitutions. No subjects in the placebo group had an

RSV isolate containing nirsevimab resistance-associated substitution. Recombinant RSV B variantsharbouring the identified I64T+K68E+I206M+Q209R (>447.1-fold) or N208S (>386.6-fold) F proteinsequence variations in the nirsevimab binding site conferred reduced susceptibility to nirsevimabneutralisation.

Nirsevimab retained activity against recombinant RSV harbouring palivizumab resistance-associatedsubstitutions identified in molecular epidemiology studies and in neutralisation escape variants ofpalivizumab. It is possible that variants resistant to nirsevimab could have cross-resistance to othermonoclonal antibodies targeting the F protein of RSV.

Anti-drug antibodies (ADA) were commonly detected.

The employed immunogenicity assay has limitations in detecting ADAs at early onset (prior to Day361) in the presence of high concentrations of drug, therefore, the incidence of ADA might not havebeen conclusively determined. The impact on clearance of nirsevimab is uncertain. Subjects who were

ADA positive at Day 361 had reduced nirsevimab concentrations at Day 361 compared to subjectswho received nirsevimab and were ADA-negative.

The impact of ADA on the efficacy of nirsevimab has not been determined. No evidence of ADAimpact on safety was observed.

The efficacy and safety of nirsevimab were evaluated in two randomised, double-blind, placebocontrolled multicentre trials (D5290C00003 [Phase IIb] and MELODY [Phase III]) for the preventionof MA RSV LRTI in term and preterm infants (GA ≥29 weeks) entering their first RSV season. Safetyand pharmacokinetics of nirsevimab were also evaluated in a randomised, double-blind,palivizumab-controlled multicentre trial (MEDLEY [Phase II/III]) in infants GA <35 weeks at higherrisk for severe RSV disease, including extremely preterm infants (GA <29 weeks) and infants withchronic lung disease of prematurity, or haemodynamically significant congenital heart disease,entering their first RSV season and children with chronic lung disease of prematurity orhaemodynamically significant congenital heart disease entering their second RSV season.

Safety and pharmacokinetics of nirsevimab were also evaluated in an open-label, uncontrolled, singledose multicentre trial (MUSIC [Phase II]) in immunocompromised infants and children ≤24 months ofage.

Efficacy and safety of nirsevimab were also evaluated in one randomised open-label multicentre trial(HARMONIE, Phase IIIb), compared to no intervention, for the prevention of RSV LRTIhospitalisation in term and preterm infants (GA ≥29 weeks) born during or entering their first RSVseason (not eligible to palivizumab).

Efficacy against MA RSV LRTI, MA RSV LRTI hospitalisation, and very severe MA RSV LRTI in termand preterm infants (D5290C00003 and MELODY)

D5290C00003 randomised a total of 1 453 very and moderately preterm infants (GA ≥29 to<35 weeks) entering their first RSV season (2:1) to receive a single intramuscular dose of 50 mgnirsevimab or placebo. At randomisation, 20.3% were GA ≥29 to <32 weeks; 79.7% were GA ≥32 to<35 weeks; 52.4% were male; 72.2% were White; 17.6% were of African origin; 1.0% were Asian;59.5% weighed <5 kg (17.0% <2.5 kg); 17.3% of infants were ≤1.0 month of age, 35.9% were >1.0 to≤3.0 months, 32.6% were >3.0 to ≤6.0 months, and 14.2% were >6.0 months.

MELODY (Primary cohort) randomised a total of 1 490 term and late preterm infants (GA ≥35 weeks)entering their first RSV season (2:1) to receive a single intramuscular dose of nirsevimab (50 mgnirsevimab if <5 kg weight or 100 mg nirsevimab if ≥5 kg weight at the time of dosing) or placebo. Atrandomisation, 14.0% were GA ≥35 to <37 weeks; 86.0% were GA ≥37 weeks; 51.6% were male;53.5% were White; 28.4% were of African origin; 3.6% were Asian; 40.0% weighed <5 kg (2.5%<2.5 kg); 24.5% of infants were ≤1.0 month of age, 33.4% were >1.0 to ≤3.0 months, 32.1% were>3.0 to ≤6.0 months, and 10.0% were >6.0 months.

The trials excluded infants with a history of chronic lung disease of prematurity/bronchopulmonarydysplasia or haemodynamically significant congenital heart disease (except for infants withuncomplicated congenital heart disease). Demographic and baseline characteristics were comparablebetween the nirsevimab and placebo group in both trials.

The primary endpoint for D5290C00003 and MELODY (Primary cohort) was the incidence ofmedically attended lower respiratory tract infection (inclusive of hospitalisation) caused by

RT-PCR-confirmed RSV (MA RSV LRTI), characterised predominantly as bronchiolitis orpneumonia, through 150 days after dosing. Signs of LRTI were defined by having one of the followingfindings at physical examination indicating lower respiratory tract involvement (e.g., rhonchi, rales,crackles, or wheeze); and at least one sign of clinical severity (increased respiratory rate, hypoxemia,acute hypoxic or ventilatory failure, new onset apnoea, nasal flaring, retractions, grunting, ordehydration due to respiratory distress). The secondary endpoint was the incidence of hospitalisation ininfants with MA RSV LRTI. RSV hospitalisation was defined as hospitalisation for LRTI with apositive RSV test, or worsening of respiratory status and positive RSV test in an already hospitalisedpatient. Very severe MA RSV LRTI was also evaluated, defined as MA RSV LRTI withhospitalisation and requirement for supplemental oxygen or intravenous fluids.

The efficacy of nirsevimab in term and preterm infants (GA ≥29 weeks) entering their first RSVseason against MA RSV LRTI, MA RSV LRTI with hospitalisation and very severe MA RSV LRTIare shown in Table 2.

Table 2: Efficacy in term and preterm infants against MA RSV LRTI, MA RSV LRTI withhospitalisation and very severe MA RSV LRTI through 150 days post dose, D5290C00003 and

MELODY (Primary cohort)

Incidence

Group Treatment N Efficacya (95% CI)% (n)

Efficacy in infants against MA RSV LRTI through 150 days post dose

Very and moderately preterm GA ≥29 Nirsevimab 969 2.6 (25)to <35 weeks (D5290C00003)b 70.1% (52.3, 81.2)c

Placebo 484 9.5 (46)

Term and late preterm GA ≥35 weeks Nirsevimab 994 1.2 (12)74.5% (49.6, 87.1)c(MELODY Primary cohort) Placebo 496 5.0 (25)

Efficacy in infants against MA RSV LRTI with hospitalisation through 150 days post dose

Very and moderately preterm GA ≥29 Nirsevimab 969 0.8 (8)b 78.4% (51.9, 90.3)cto <35 weeks (D5290C00003) Placebo 484 4.1 (20)

Term and late preterm GA ≥35 weeks Nirsevimab 994 0.6 (6)62.1% (-8.6, 86.8)(MELODY Primary cohort) Placebo 496 1.6 (8)

Efficacy in infants against very severe MA RSV LRTI through 150 days post dose

Very and moderately preterm GA ≥29 Nirsevimab 969 0.4 (4)dto <35 weeks (D5290C00003)b 87.5% (62.9, 95.8)

Placebo 484 3.3 (16)

Term and late preterm GA ≥35 weeks Nirsevimab 994 0.5 (5)64.2% (-12.1, 88.6)d(MELODY Primary cohort) Placebo 496 1.4 (7)a Based on relative risk reduction versus placebo.b All subjects who received 50 mg irrespective of weight at the time of dosing.c Prespecified multiplicity controlled; p-value =<0.001.d Not multiplicity controlled.

Subgroup analyses of the primary efficacy endpoint by gestational age, gender, race and regionshowed results were consistent with the overall population.

The severity of breakthrough cases of subjects hospitalised for MA RSV LRTI was assessed. Thepercentage of subjects who required supplementary oxygen was 44.4% (4/9) vs. 81.0% (17/21),subjects who required continuous positive airway pressure [CPAP]/high flow nasal cannula [HFNC]was 11.1% (1/9) vs. 23.8% (5/21), and 0% (0/9) vs. 28.6% (6/21) subjects were admitted to intensivecare unit, for nirsevimab vs. placebo, respectively.

MELODY continued to enrol infants following the primary analysis, and overall, 3 012 infants wererandomised to receive Beyfortus (n=2 009) or placebo (n=1 003). Efficacy of nirsevimab against

MA RSV LRTI, MA RSV LRTI with hospitalisation, and very severe MA RSV LRTI through150 days post dose was a relative risk reduction of 76.4% (95% CI 62.3, 85.2), 76.8% (95% CI 49.4,89.4) and 78.6% (95% CI 48.8, 91.0), respectively.

The rates of MA RSV LRTI events in the second season (day 361 to day 510 post-dose) were similarin both treatment groups [19 (1.0%) nirsevimab recipients and 10 (1.0%) placebo recipients].

Efficacy against MA RSV LRTI in infants at higher risk and children who remain vulnerable to severe

RSV disease in their second season (MEDLEY and MUSIC)

MEDLEY randomised a total of 925 infants at higher risk for severe RSV disease including infantswith chronic lung disease of prematurity or haemodynamically significant congenital heart disease andpreterm infants GA <35 weeks, entering their first RSV season. Infants received a single intramusculardose (2:1) of nirsevimab (50 mg nirsevimab if <5 kg weight or 100 mg nirsevimab if ≥5 kg weight atthe time of dosing), followed by 4 once-monthly intramuscular doses of placebo, or 5 once-monthlyintramuscular doses of 15 mg/kg palivizumab. At randomisation, 21.6% were GA <29 weeks; 21.5%were GA≥29 to <32 weeks; 41.9% were GA ≥32 to <35 weeks; 14.9% were GA ≥35 weeks. Of theseinfants 23.5% had chronic lung disease of prematurity; 11.2% had haemodynamically significantcongenital heart disease; 53.5% were male; 79.2% were White; 9.5% were of African origin; 5.4%were Asian; 56.5% weighed <5 kg (9.7% were <2.5 kg); 11.4% of infants were ≤1.0 month of age,33.8% were >1.0 to ≤3.0 months 33.6% were >3.0 months to ≤6.0 months, and 21.2% were>6.0 months.

Children at higher risk of severe RSV disease with chronic lung disease of prematurity orhaemodynamically significant congenital heart disease ≤24 months of age who remain vulnerablecontinued in the trial for a second RSV season. Subjects who received nirsevimab during their first

RSV season received a second single dose of 200 mg nirsevimab entering their second RSVseason (n=180) followed by 4 once-monthly intramuscular doses of placebo. Subjects who receivedpalivizumab during their first RSV season were re-randomised 1:1 to either the nirsevimab or thepalivizumab group entering their second RSV season. Subjects in the nirsevimab group (n=40)received a single fixed dose of 200 mg followed by 4 once-monthly intramuscular doses of placebo.

Subjects in the palivizumab group (n=42) received 5 once-monthly intramuscular doses of 15 mg/kgpalivizumab. Of these children 72.1% had chronic lung disease of prematurity, 30.9% hadhaemodynamically significant congenital heart disease; 57.6% were male; 85.9% were White; 4.6%were of African origin; 5.7% were Asian; and 2.3% weighed <7 kg. Demographic and baselinecharacteristics were comparable between the nirsevimab/nirsevimab, palivizumab/nirsevimab andpalivizumab/palivizumab groups.

The efficacy of nirsevimab in infants at higher risk for severe RSV disease, including extremelypreterm infants (GA <29 weeks) entering their first RSV season and children with chronic lungdisease of prematurity or haemodynamically significant congenital heart disease ≤24 months of ageentering their first or second RSV season, is established by extrapolation from the efficacy ofnirsevimab in D5290C00003 and MELODY (Primary cohort) based on pharmacokinetic exposure (seesection 5.2). In MEDLEY, the incidence of MA RSV LRTI through 150 days post dose was 0.6%(4/616) in the nirsevimab group and 1.0% (3/309) in the palivizumab group in the first RSV season.

There were no cases of MA RSV LRTI through 150 days post dose in the second RSV season.

In MUSIC, the efficacy in 100 immunocompromised infants and children ≤24 months who receivedthe recommended dose of nirsevimab is established by extrapolation from the efficacy of nirsevimabin D5290C00003 and MELODY (Primary cohort) based on pharmacokinetic exposure (seesection 5.2). There were no cases of MA RSV LRTI through 150 days post dose.

Efficacy against RSV LRTI hospitalisation in term and pre-term infants (HARMONIE)

HARMONIE randomised a total of 8 058 in term and preterm infants (GA ≥29) born during orentering their first RSV season to receive a single IM dose of nirsevimab (50 mg if <5 kg weight or100 mg if ≥5 kg weight at the time of dosing) or no intervention. At randomisation, the median agewas 4 months (range: 0 to 12 months). 48.6% of infants were aged ≤3 months; 23.7% were aged >3 to≤6 months; and 27.7% were aged >6 months. Of these infants, 52.1% were male and 47.9% werefemale. Half of the infants were born during the RSV season. Most participants were term infants,with a gestational age at birth of ≥37 weeks (85.2%).

The primary endpoint for HARMONIE was the overall incidence of RSV LRTI hospitalisationthrough the RSV season in term and preterm infants caused by confirmed RSV infection. The efficacyof nirsevimab in preventing RSV LRTI hospitalisation compared to no intervention was estimatedaccounting for the follow-up time to emulate use in real world conditions. The median follow-up timeof participants was 2.3 months (range: 0 to 7.0 months) in the nirsevimab group and 2.0 months(range: 0 to 6.8 months) in the no intervention group.

RSV LRTI hospitalisations occurred in 11 of 4 037 infants in the nirsevimab group (incidencerate = 0.001) and in 60 of 4 021 infants in the no intervention group (incidence rate = 0.006),corresponding to an efficacy of 83.2% (95% CI, 67.8 to 92.0) in preventing RSV LRTIhospitalisations through the RSV season, and the efficacy sustained through 180 days post-dosing/randomisation (82.7%; 95% CI, 67.8 to 91.5).

Based on clinical and pharmacokinetic data, the duration of protection afforded by nirsevimab is atleast 5 to 6 months.

The pharmacokinetic properties of nirsevimab are based on data from individual studies andpopulation pharmacokinetic analyses. The pharmacokinetics of nirsevimab were dose-proportional inchildren and adults following administration of clinically relevant intramuscular doses over a doserange of 25 mg to 300 mg.

Following intramuscular administration, the maximum concentration was reached within 6 days (range1 to 28 days) and the estimated absolute bioavailability was 84%.

The estimated central and peripheral volume of distribution of nirsevimab were 216 mL and 261 mL,respectively, for an infant weighing 5 kg. The volume of distribution increases with increasing bodyweight.

Nirsevimab is a human IgG1κ monoclonal antibody that is degraded by proteolytic enzymes widelydistributed in the body and not metabolised by hepatic enzymes.

As a typical monoclonal antibody, nirsevimab is eliminated by intracellular catabolism and there is noevidence of target-mediated clearance at the doses tested clinically.

The estimated clearance of nirsevimab was 3.42 mL/day for an infant weighing 5 kg and the terminalhalf-life was approximately 71 days. Nirsevimab clearance increases with increasing body weight.

There was no clinically relevant effect of race.

As a typical IgG monoclonal antibody, nirsevimab is not cleared renally due to its large molecularweight, change in renal function is not expected to influence nirsevimab clearance. However, in oneindividual with nephrotic syndrome, an increased clearance of nirsevimab was observed in clinicaltrials.

IgG monoclonal antibodies are not primarily cleared via the hepatic pathway. However, in someindividuals with chronic liver disease which may be associated with protein loss, an increasedclearance of nirsevimab was observed in clinical trials.

Infants at higher risk and children who remain vulnerable to severe RSV disease in their secondseason

There was no significant influence of chronic lung disease of prematurity or haemodynamicallysignificant congenital heart disease on the pharmacokinetics of nirsevimab. Serum concentrations atday 151 in MEDLEY were comparable to those in MELODY.

In children with chronic lung disease of prematurity or haemodynamically significant congenital heartdisease (MEDLEY) and those that are immunocompromised (MUSIC), receiving a 200 mgintramuscular dose of nirsevimab in their second season, nirsevimab serum exposures were slightlyhigher with substantial overlap compared to those in MELODY (see Table 3).

Table 3: Nirsevimab intramuscular dose exposures, mean (standard deviation) [range], derivedbased on individual population pharmacokinetic parameters

N Day 151

Study/Season N AUC0-365 AUCbaseline CL(Day 151 serum conc(AUC) mg*day/mL mg*day/mLserum conc) µg/mL

MELODY 954 12.2 (3.5) 21.3 (6.5) 636 26.6 (11.1)(Primary cohort) [3.3-24.9] [5.2-48.7] [2.1-76.6]

MEDLEY/Season 1 591 12.3 (3.3) 22.6 (6.2) 457 27.8 (11.1)[4.1-23.4] [7-43.8] [2.1-66.2]

MEDLEY/Season 2 189 21.5 (5.5) 23.6 (7.8) 163 55.6 (22.8)[7.5-41.9] [8.2-56.4] [11.2-189.3]

MUSIC/Season 1 46 11.2 (4.3) 16.7 (7.3) 37 25.6 (13.4)[1.2-24.6] [3.1-43.4] [5.1-67.4]

MUSIC/Season 2 50 16 (6.3) 21 (8.4) 42 33.2 (19.3)[2.2-25.5] [5.6-35.5] [0.9-68.5]

AUC0-365= area under the concentration time curve from 0-365 days post dose, AUCbaseline CL = area under theserum concentration-time curve derived from post hoc clearance values at dosing, Day 151 serum conc =concentration at day 151, visit day 151 ± 14 days.

In D5290C00003 and MELODY (Primary cohort) a positive correlation was observed between aserum AUC (Area Under the Curve), based on clearance at baseline, above 12.8 mg*day/mL and alower incidence of MA RSV LRTI. The recommended dosing regimen consisting of a 50 mg or100 mg intramuscular dose for infants in their first RSV season and a 200 mg intramuscular dose forchildren entering their second RSV season was selected on the basis of these results.

In MEDLEY, >80% of infants at higher risk for severe RSV disease, including infants born extremelypreterm (GA <29 weeks) entering their first RSV season and infants/children with chronic lungdisease of prematurity or haemodynamically significant congenital heart disease entering their first orsecond RSV season, achieved nirsevimab exposures associated with RSV protection (serum AUCabove 12.8 mg*day/mL) following a single dose (see section 5.1).

In MUSIC, 75% (72/96) of immunocompromised infants/children entering their first or second RSVseason achieved nirsevimab exposures associated with RSV protection. When excluding 14 childrenwith increased clearance of nirsevimab, 87% (71/82) achieved nirsevimab exposures associated with

RSV protection.

Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology,repeated dose toxicity and tissue cross-reactivity studies.

L-histidine

L-histidine hydrochloride

L-arginine hydrochloride

Sucrose

Polysorbate 80 (E433)

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

3 years

Beyfortus may be kept at room temperature (20°C - 25°C) when protected from light for a maximumof 8 hours. After this time, the syringe must be discarded.

Store in a refrigerator (2°C - 8°C).

Do not freeze.

Do not shake or expose to direct heat.

Keep the pre-filled syringe in the outer carton in order to protect from light.

For storage conditions of the medicinal product, see section 6.3.

Siliconised Luer lock Type I glass pre-filled syringe with a FluroTec-coated plunger stopper.

Each pre-filled syringe contains 0.5 mL or 1 mL solution.

* 1 or 5 pre-filled syringe(s) without needles.

* 1 pre-filled syringe packaged with two separate needles of different sizes.

Not all pack sizes may be marketed.

This medicinal product should be administered by a trained healthcare professional using aseptictechniques to ensure sterility.

Visually inspect the medicinal product for particulate matter and discolouration prior toadministration. The medicinal product is a clear to opalescent, colourless to yellow solution. Do notinject if the liquid is cloudy, discoloured, or it contains large particles or foreign particulate matter.

Do not use if the pre-filled syringe has been dropped or damaged or the security seal on the carton hasbeen broken.

Instructions for administration

Beyfortus is available in a 50 mg and a 100 mg pre-filled syringe. Check the labels on the carton andpre-filled syringe to make sure you have selected the correct 50 mg or 100 mg presentation asrequired.

Beyfortus 50 mg (50 mg/0.5 mL) pre-filled Beyfortus 100 mg (100 mg/1 mL) pre-filledsyringe with a purple plunger rod. syringe with a light blue plunger rod.

Purple Light Blue

Refer to Figure 1 for pre-filled syringe components.

Figure 1: Luer lock syringe components

Finger grip Rubber stopper Syringe cap

Plunger rod Syringe body Luer lock

Step 1: Holding the Luer lock in one hand (avoid holding the plunger rod or syringe body), unscrewthe 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 clockwiseonto 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 theother hand. Do not hold the plunger rod while removing the needle cover or the rubber stopper maymove. Do not touch the needle or let it touch any surface. Do not recap the needle or detach it from thesyringe.

Step 4: Administer the entire contents of the pre-filled syringe as an intramuscular injection,preferably in the anterolateral aspect of the thigh. The gluteal muscle should not be used routinely asan injection site because of the risk of damage to the sciatic nerve.

Step 5: Dispose of the used syringe immediately, together with the needle, in a sharps disposalcontainer or in accordance with local requirements.

If two injections are required, repeat steps 1-5 in a different injection site.

Each pre-filled syringe is for single-use only. Any unused medicinal product or waste material shouldbe disposed of in accordance with local requirements.

Sanofi Winthrop Industrie82 avenue Raspail94250 Gentilly

France

EU/1/22/1689/001 50 mg, 1 single-use pre-filled syringe

EU/1/22/1689/002 50 mg, 1 single-use pre-filled syringe with needles

EU/1/22/1689/003 50 mg, 5 single-use pre-filled syringe

EU/1/22/1689/004 100 mg, 1 single-use pre-filled syringe

EU/1/22/1689/005 100 mg, 1 single-use pre-filled syringe with needles

EU/1/22/1689/006 100 mg, 5 single-use pre-filled syringe

Date of first authorisation: 31 October 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.