SYNAGIS- palivizumab injection, solution

United States - English - NLM (National Library of Medicine)

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Active ingredient:
PALIVIZUMAB (UNII: DQ448MW7KS) (PALIVIZUMAB - UNII:DQ448MW7KS)
Available from:
Swedish Orphan Biovitrum AB (publ)
Administration route:
INTRAMUSCULAR
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Synagis is indicated for the prevention of serious lower respiratory tract disease caused by respiratory syncytial virus (RSV) in pediatric patients: - with a history of premature birth (less than or equal to 35 weeks gestational age) and who are 6 months of age or younger at the beginning of RSV season, - with bronchopulmonary dysplasia (BPD) that required medical treatment within the previous 6 months and who are 24 months of age or younger at the beginning of RSV season, - with hemodynamically significant congenital heart disease (CHD) and who are 24 months of age or younger at the beginning of RSV season [see Clinical Studies ( 14) ]. Limitations of Use: The safety and efficacy of Synagis have not been established for treatment of RSV disease [see Warnings and Precautions ( 5.4)] . Synagis is contraindicated in children who have had a previous significant hypersensitivity reaction to Synagis
Product summary:
Synagis is supplied in single-dose vials as a preservative-free, sterile liquid solution at 100 mg per mL for intramuscular injection. 50 mg vial NDC 66658-230-01 The 50 mg vial contains 50 mg Synagis in 0.5 mL. 100 mg vial NDC 66658-231-01 The 100 mg vial contains 100 mg Synagis in 1 mL. The rubber stopper used for sealing vials of Synagis is not made with natural rubber latex. Storage Upon receipt and until use, Synagis should be stored between 2°C and 8°C (36°F and 46°F) in its original container. DO NOT freeze. DO NOT use beyond the expiration date.
Authorization status:
Biologic Licensing Application
Authorization number:
66658-230-01, 66658-231-01

Read the complete document

SYNAGIS - palivizumab injection, solution

Swedish Orphan Biovitrum AB (publ)

----------

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use SYNAGIS safely and effectively. See full

prescribing information for SYNAGIS.

SYNAGIS

(palivizumab) injection, for intramuscular use

Initial U.S. Approval: 1998

INDICATIONS AND USAGE

Synagis is a respiratory syncytial virus (RSV) F protein inhibitor monoclonal antibody indicated for the prevention of

serious lower respiratory tract disease caused by respiratory syncytial virus (RSV) in pediatric patients:

with a history of premature birth (less than or equal to 35 weeks gestational age) and who are 6 months of age or

younger at the beginning of RSV season,

with bronchopulmonary dysplasia (BPD) that required medical treatment within the previous 6 months and who are 24

months of age or younger at the beginning of RSV season,

with hemodynamically significant congenital heart disease (CHD) and who are 24 months of age or younger at the

beginning of RSV season.

Limitations of Use: The safety and efficacy of Synagis have not been established for treatment of RSV disease. ( 1)

DOSAGE AND ADMINISTRATION

15 mg per kg of body weight, administered intramuscularly prior to commencement of the RSV season and remaining

doses administered monthly throughout the RSV season. ( 2.1)

Children undergoing cardio-pulmonary bypass should receive an additional dose of Synagis as soon as possible after the

cardio-pulmonary bypass procedure (even if sooner than a month from the previous dose). Thereafter, doses should be

administered monthly as scheduled. ( 2.1, 12.3)

DOSAGE FORMS AND STRENGTHS

Single-dose liquid solution vials: 50 mg per 0.5 mL and 100 mg per 1 mL. ( 3)

CONTRAINDICATIONS

Previous significant hypersensitivity reaction to Synagis. ( 4)

WARNINGS AND PRECAUTIONS

Anaphylaxis and anaphylactic shock (including fatal cases), and other severe acute hypersensitivity reactions have been

reported. Permanently discontinue Synagis and administer appropriate medications if such reactions occur. ( 5.1)

As with any intramuscular injection, Synagis should be given with caution to children with thrombocytopenia or any

coagulation disorder. ( 5.2)

Palivizumab may interfere with immunological-based RSV diagnostic tests such as some antigen detection-based

assays. ( 5.3, 12.4)

ADVERSE REACTIONS

Adverse reactions occurring greater than or equal to 10% and at least 1% more frequently than placebo are fever and rash.

( 6.1)

To report SUSPECTED ADVERSE REACTIONS, contact 1866-773-5274 or FDA at 1-800-FDA-1088 or

www.fda.gov/medwatch.

USE IN SPECIFIC POPULATIONS

Safety and effectiveness in children older than 24 months of age at the start of dosing have not been established. ( 8.4)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 11/2020

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

®

2 DOSAGE AND ADMINISTRATION

2.1 Dosing Information

2.2 Administration Instructions

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions

5.2 Coagulation Disorders

5.3 RSV Diagnostic Test Interference

5.4 Treatment of RSV Disease

5.5 Proper Administration

6 ADVERSE REACTIONS

6.1 Clinical Studies Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

12.4 Microbiology

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

Synagis is indicated for the prevention of serious lower respiratory tract disease caused by respiratory

syncytial virus (RSV) in pediatric patients:

with a history of premature birth (less than or equal to 35 weeks gestational age) and who are 6

months of age or younger at the beginning of RSV season,

with bronchopulmonary dysplasia (BPD) that required medical treatment within the previous 6

months and who are 24 months of age or younger at the beginning of RSV season,

with hemodynamically significant congenital heart disease (CHD) and who are 24 months of age or

younger at the beginning of RSV season [see Clinical Studies ( 14) ].

Limitations of Use:

The safety and efficacy of Synagis have not been established for treatment of RSV disease [see

Warnings and Precautions ( 5.4)] .

Sections or subsections omitted from the full prescribing information are not listed.

2 DOSAGE AND ADMINISTRATION

2.1 Dosing Information

The recommended dose of Synagis is 15 mg per kg of body weight given monthly by intramuscular

injection. The first dose of Synagis should be administered prior to commencement of the RSV season

and the remaining doses should be administered monthly throughout the RSV season. Children who

develop an RSV infection should continue to receive monthly doses throughout the RSV season. In the

northern hemisphere, the RSV season typically commences in November and lasts through April, but it

may begin earlier or persist later in certain communities.

Synagis serum levels are decreased after cardio-pulmonary bypass [see Clinical Pharmacology ( 12.3) ].

Children undergoing cardio-pulmonary bypass should receive an additional dose of Synagis as soon as

possible after the cardio-pulmonary bypass procedure (even if sooner than a month from the previous

dose). Thereafter, doses should be administered monthly as scheduled.

The efficacy of Synagis at doses less than 15 mg per kg, or of dosing less frequently than monthly

throughout the RSV season, has not been established.

2.2 Administration Instructions

DO NOT DILUTE THE PRODUCT.

DO NOT SHAKE OR VIGOROUSLY AGITATE THE VIAL.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior

to administration. Do not use any vials exhibiting particulate matter or discoloration.

Using aseptic techniques, attach a sterile needle to a sterile syringe. Remove the flip top from the

Synagis vial and wipe the rubber stopper with a disinfectant (e.g., 70% isopropyl alcohol). Insert the

needle into the vial and withdraw into the syringe an appropriate volume of solution. Administer

immediately after drawing the dose into the syringe.

Synagis should be administered in a dose of 15 mg per kg intramuscularly using aseptic technique,

preferably in the anterolateral aspect of the thigh. The gluteal muscle should not be used routinely

as an injection site because of the risk of damage to the sciatic nerve. The dose (volume of injection

in mL) per month = patient weight (kg) x 15 mg per kg ÷ 100 mg per mL of Synagis. Injection

volumes over 1 mL should be given as a divided dose.

Synagis is supplied as a single-dose vial and does not contain preservatives. Do not re-enter the vial

after withdrawal of drug; discard unused portion. Only administer one dose per vial.

Use sterile disposable syringes and needles. To prevent the transmission of hepatitis viruses or

other infectious agents from one person to another, DO NOT reuse syringes and needles.

3 DOSAGE FORMS AND STRENGTHS

Single-dose liquid solution vials: 50 mg per 0.5 mL and 100 mg per 1 mL.

4 CONTRAINDICATIONS

Synagis is contraindicated in children who have had a previous significant hypersensitivity reaction to

Synagis [see Warnings and Precautions ( 5.1) ].

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions

Cases of anaphylaxis and anaphylactic shock, including fatal cases, have been reported following initial

exposure or re-exposure to Synagis. Other acute hypersensitivity reactions, which may be severe, have

also been reported on initial exposure or re-exposure to Synagis. Signs and symptoms may include

urticaria, pruritus, angioedema, dyspnea, respiratory failure, cyanosis, hypotonia, hypotension, and

unresponsiveness. The relationship between these reactions and the development of antibodies to

Synagis is unknown. If a significant hypersensitivity reaction occurs with Synagis, its use should be

permanently discontinued. If anaphylaxis or other significant hypersensitivity reaction occurs,

administer appropriate medications (e.g., epinephrine) and provide supportive care as required. If a mild

hypersensitivity reaction occurs, clinical judgment should be used regarding cautious readministration

of Synagis.

5.2 Coagulation Disorders

Synagis is for intramuscular use only. As with any intramuscular injection, Synagis should be given with

caution to children with thrombocytopenia or any coagulation disorder.

5.3 RSV Diagnostic Test Interference

Palivizumab may interfere with immunological-based RSV diagnostic tests such as some antigen

detection-based assays. In addition, palivizumab inhibits virus replication in cell culture, and therefore

may also interfere with viral culture assays. Palivizumab does not interfere with reverse transcriptase-

polymerase chain reaction based assays. Assay interference could lead to false-negative RSV

diagnostic test results. Therefore, diagnostic test results, when obtained, should be used in conjunction

with clinical findings to guide medical decisions [see Microbiology ( 12.4) ].

5.4 Treatment of RSV Disease

The safety and efficacy of Synagis have not been established for treatment of RSV disease.

5.5 Proper Administration

The single-dose vial of Synagis does not contain a preservative. Administration of Synagis should

occur immediately after dose withdrawal from the vial. The vial should not be re-entered. Discard any

unused portion.

6 ADVERSE REACTIONS

The most serious adverse reactions occurring with Synagis are anaphylaxis and other acute

hypersensitivity reactions [see Warnings and Precautions ( 5.1) ].

6.1 Clinical Studies 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.

The data described below reflect exposure to Synagis (n=1639) compared with placebo (n=1143) in

children 3 days to 24.1 months of age at high risk of RSV-related hospitalization in two clinical trials.

Trial 1 was conducted during a single RSV season and studied a total of 1502 children less than or

equal to 24 months of age with BPD or infants with premature birth (less than or equal to 35 weeks

gestation) who were less than or equal to 6 months of age at study entry. Trial 2 was conducted over

four consecutive seasons among a total of 1287 children less than or equal to 24 months of age with

hemodynamically significant congenital heart disease.

In Trials 1 and 2 combined, fever and rash were each reported more frequently among Synagis than

placebo recipients, 27% versus 25%, and 12% versus 10%, respectively. Adverse reactions observed

in the 153-patient crossover study comparing the liquid and lyophilized formulations were comparable

for the two formulations, and were similar to those observed with Synagis in Trials 1 and 2.

Immunogenicity

In Trial 1, the incidence of anti-palivizumab antibody following the fourth injection was 1.1% in the

placebo group and 0.7% in the Synagis group. In children receiving Synagis for a second season, one

of the fifty-six children had transient, low titer reactivity. This reactivity was not associated with

adverse events or alteration in serum concentrations. Immunogenicity was not assessed in Trial 2.

A trial of high-risk preterm children less than or equal to 24 months of age was conducted to evaluate

the immunogenicity of the lyophilized formulation of Synagis (used in Trials 1 and 2 above) and the

liquid formulation of Synagis. Three hundred seventy-nine children contributed to the 4 to 6 months

post-final dose analysis. The rate of anti-palivizumab antibodies at this time point was low in both

formulation groups (anti-palivizumab antibodies were not detected in any subject in the liquid

formulation group and were detected in one subject in the lyophilized group (0.5%), with an overall rate

of 0.3% for both treatment groups combined).

These data reflect the percentage of children whose test results were considered positive for

antibodies to palivizumab in an enzyme-linked immunosorbent assay (ELISA) and are highly dependent

on the sensitivity and specificity of the assay.

The ELISA has substantial limitations in detecting anti-palivizumab antibodies in the presence of

palivizumab. Immunogenicity samples tested with the ELISA assay likely contained palivizumab at levels

that may interfere with the detection of anti-palivizumab antibodies.

An electrochemical luminescence (ECL) based immunogenicity assay, with a higher tolerance for

palivizumab presence compared to the ELISA, was used to evaluate the presence of anti-palivizumab

antibodies in subject samples from two additional clinical trials. The rates of anti-palivizumab antibody

positive results in these trials were 1.1% and 1.5%.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of Synagis. 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.

Blood and Lymphatic System Disorders: severe thrombocytopenia (platelet count less than 50,000 per

microliter)

General Disorders and Administration Site Conditions: injection site reactions

Limited information from post-marketing reports suggests that, within a single RSV season, adverse

events after a sixth or greater dose of Synagis are similar in character and frequency to those after the

initial five doses.

7 DRUG INTERACTIONS

No formal drug-drug interaction studies were conducted. In Trial 1, the proportions of children in the

placebo and Synagis groups who received routine childhood vaccines, influenza vaccine,

bronchodilators, or corticosteroids were similar and no incremental increase in adverse reactions was

observed among children receiving these agents.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Synagis is not indicated for use in females of reproductive potential.

8.2 Lactation

Risk Summary

Synagis is not indicated for use in females of reproductive potential.

8.4 Pediatric Use

The safety and effectiveness of Synagis in children older than 24 months of age at the start of dosing

have not been established [see Clinical Studies ( 14) ].

10 OVERDOSAGE

Overdoses with doses up to 85 mg per kg have been reported in clinical studies and post-marketing

experience with Synagis, and in some cases, adverse reactions were reported. In case of overdosage, it

is recommended that the patient be monitored for any signs or symptoms of adverse reactions and

appropriate symptomatic treatment instituted.

11 DESCRIPTION

Palivizumab is a humanized monoclonal antibody (IgG1κ) produced by recombinant DNA technology,

directed to an epitope in the A antigenic site of the F protein of RSV. Palivizumab is a composite of

human (95%) and murine (5%) antibody sequences. The human heavy chain sequence was derived from

the constant domains of human IgG1 and the variable framework regions of the V

genes Cor and Cess.

The human light chain sequence was derived from the constant domain of Cκ and the variable framework

regions of the V

gene K104 with Jκ -4. The murine sequences were derived from a murine

monoclonal antibody, Mab 1129, in a process that involved the grafting of the murine complementarity

determining regions into the human antibody frameworks. Palivizumab is composed of two heavy chains

and two light chains and has a molecular weight of approximately 148,000 Daltons.

Synagis is supplied as a sterile, preservative-free liquid solution at 100 mg per mL to be administered

by intramuscular injection. Thimerosal or other mercury-containing salts are not used in the production

of Synagis. The solution has a pH of 6.0 and should appear clear or slightly opalescent.

Each 100 mg single-dose vial of Synagis liquid solution contains 100 mg of palivizumab and also

contains chloride (0.5 mg), glycine (0.1 mg), and histidine (3.9 mg), in a volume of 1 mL.

Each 50 mg single-dose vial of Synagis liquid solution contains 50 mg of palivizumab and also contains

chloride (0.2 mg), glycine (0.06 mg), and histidine (1.9 mg), in a volume of 0.5 mL.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Palivizumab is a recombinant humanized monoclonal antibody with anti-RSV activity [see Microbiology (

12.4) ].

12.3 Pharmacokinetics

In children less than or equal to 24 months of age without congenital heart disease (CHD), the mean

half-life of palivizumab was 20 days and monthly intramuscular doses of 15 mg per kg achieved mean

± SD 30 day trough serum drug concentrations of 37 ± 21 mcg per mL after the first injection,

57 ± 41 mcg per mL after the second injection, 68 ± 51 mcg per mL after the third injection, and 72 ± 50

mcg per mL after the fourth injection. Trough concentrations following the first and fourth Synagis

dose were similar in children with CHD and in non-cardiac patients. In children given Synagis for a

second season, the mean ± SD serum concentrations following the first and fourth injections were 61 ±

17 mcg per mL and 86 ± 31 mcg per mL, respectively.

In 139 children less than or equal to 24 months of age with hemodynamically significant CHD who

received Synagis and underwent cardio-pulmonary bypass for open-heart surgery, the mean ± SD serum

palivizumab concentration was 98 ± 52 mcg per mL before bypass and declined to 41 ± 33 mcg per mL

after bypass, a reduction of 58% [see Dosage and Administration ( 2.1) ]. The clinical significance of

this reduction is unknown.

Specific studies were not conducted to evaluate the effects of demographic parameters on palivizumab

systemic exposure. However, no effects of gender, age, body weight, or race on palivizumab serum

trough concentrations were observed in a clinical study with 639 children with CHD (less than or equal

to 24 months of age) receiving five monthly intramuscular injections of 15 mg per kg of Synagis.

The pharmacokinetics and safety of Synagis liquid solution and Synagis lyophilized formulation

administered via intramuscular injection at 15 mg per kg were studied in a cross-over trial of 153 infants

less than or equal to 6 months of age with a history of prematurity. The results of this trial indicated that

the trough serum concentrations of palivizumab were comparable between the liquid solution and the

lyophilized formulation, which was the formulation used in the clinical studies.

A population pharmacokinetic analysis was performed across 22 studies in 1800 patients (1684

pediatric and 116 adult patients) to characterize palivizumab pharmacokinetics and inter-subject

variability in serum concentrations. Palivizumab pharmacokinetics was described by a two-compartment

linear model with an elimination half-life of 24.5 days in pediatric patients. Clearance of palivizumab in

a typical pediatric patient (body weight 4.5 kg) less than or equal to 24 months of age without CHD was

estimated to be 11 mL per day with a bioavailability of 70% following intramuscular administration. The

inter-patient variability in drug clearance was 48.7% (CV%). Covariate analysis did not identify any

factors that could account for the inter-patient variability in order to predict serum concentrations a

priori in an individual patient.

12.4 Microbiology

Mechanism of Action

Palivizumab, a recombinant humanized monoclonal antibody which provides passive immunity against

RSV, acts by binding the RSV envelope fusion protein (RSV F) on the surface of the virus and blocking

a critical step in the membrane fusion process. Palivizumab also prevents cell-to-cell fusion of RSV-

infected cells.

Antiviral Activity

The antiviral activity of palivizumab was assessed in a microneutralization assay in which increasing

concentrations of antibody were incubated with RSV prior to addition of the human epithelial cells

HEp-2. After incubation for 4-5 days, RSV antigen was measured in an ELISA assay. The neutralization

titer (50% effective concentration [EC

]) is expressed as the antibody concentration required to

reduce detection of RSV antigen by 50% compared with untreated virus-infected cells. Palivizumab

exhibited median EC

values of 0.65 mcg per mL (mean 0.75 ± 0.53 mcg per mL; n=69, range 0.07-

2.89 mcg per mL) and 0.28 mcg per mL (mean 0.35 ± 0.23 mcg per mL; n=35, range 0.03-0.88 mcg per

mL) against clinical RSV A and RSV B isolates, respectively. The majority of clinical RSV isolates

tested (n=96) were collected from subjects across the United States (CA, CO, CT, IL, MA, NC, NY,

PA, RI, TN, TX, VA), with the remainder from Japan (n=1), Australia (n=5) and Israel (n=2). These

isolates encoded the most common RSV F sequence polymorphisms found among clinical isolates

worldwide.

Palivizumab serum concentrations of greater than or equal to 40 mcg per mL have been shown to reduce

pulmonary RSV replication in the cotton rat model of RSV infection by 100-fold.

Resistance

Palivizumab binds a highly conserved region on the extracellular domain of mature RSV F, referred to

as antigenic site II or site A, which encompasses amino acids 262 to 275. All RSV mutants that exhibit

resistance to palivizumab have been shown to contain amino acid changes in this region on the F protein.

F protein sequence variations within antigenic site A: Amino acid substitutions in antigenic site A selected

either in cell culture, in animal models, or in human subjects that resulted in palivizumab resistance were

N262D, N268I, K272E/M/N/Q/T, and S275F/L. RSV variants expressing the K272N substitution in F

protein showed a 5164 ± 1731-fold decrease in susceptibility (i.e., fold increase in EC

value) when

compared to the wild-type RSV, while variants containing the N262D, S275F/L, or K272E/M/Q/T

substitutions showed a greater than 25,000-fold decrease in susceptibility to palivizumab. The N268I

substitution conferred partial resistance to palivizumab; however, fold changes in susceptibility were

not quantified for this mutant. Studies carried out to investigate the mechanism of virus escape from

palivizumab showed a correlation between antibody binding and virus neutralization. RSV with

substitutions in antigenic site A that were resistant to neutralization by palivizumab did not bind to

palivizumab.

At least one of the palivizumab resistance-associated substitutions, N262D, K272E/Q, or S275F/L was

identified in 8 of 126 clinical RSV (59 RSV A and 67 RSV B) isolates from subjects who failed

immunoprophylaxis, resulting in a combined resistance-associated mutation frequency of 6.3%. A

review of clinical findings revealed no association between antigenic A site sequence changes and

RSV disease severity among children receiving palivizumab immunoprophylaxis who develop RSV

lower respiratory tract disease.

Analysis of 254 clinical RSV isolates (145 RSV A and 109 RSV B) collected from

immunoprophylaxis-naïve subjects revealed palivizumab resistance-associated substitutions in 2 (1 with

N262D and 1 with S275F), resulting in a resistance-associated mutation frequency of 0.79%.

F protein sequence variations outside antigenic site A: In addition to the sequence variations in antigenic

site A known to confer palivizumab resistance, F protein substitutions T100A, G139S, N165D/V406I;

T326A, V450A in RSV A, and T74I, A147V, I206L, S285G, V450I, T455I in RSV B were identified in

viruses isolated from failures of immunoprophylaxis. These substitutions were not identified in RSV F

sequences derived from 254 clinical isolates from immunoprophylaxis-naïve subjects and thus are

considered treatment-associated and non-polymorphic. Recombinant RSV B encoding the S285G

substitution exhibited palivizumab sensitivity (EC

value = 0.39 ± 0.02 mcg per mL) similar to

recombinant wild-type RSV B (EC

value = 0.17 ± 0.02 mcg per mL).

Palivizumab susceptibility of RSV encoding common F protein sequence polymorphisms located

proximal to antigenic site A was evaluated. Recombinant RSV A encoding N276S (EC

value = 0.72 ±

0.07 mcg per mL), and recombinant RSV B with S276N (EC

value = 0.42 ± 0.04 mcg per mL),

exhibited sensitivities comparable to the corresponding recombinant wild-type RSV A (EC

value = 0.63 ± 0.22 mcg per mL) and RSV B (EC

value = 0.23 ± 0.07 mcg per mL). Likewise, RSV B

clinical isolates containing the polymorphic variation V278A were at least as sensitive to neutralization

by palivizumab (EC

range 0.08-0.45 mcg per mL) as laboratory strains of wild-type RSV B (EC

value = 0.54 ± 0.08 mcg per mL). No known polymorphic or non-polymorphic sequence variations

outside the antigenic site A on RSV F have been demonstrated to render RSV resistant to neutralization

by palivizumab.

Interference of RSV Diagnostic Assays by Palivizumab

Interference with immunologically-based RSV diagnostic assays by palivizumab has been observed in

laboratory studies. Rapid chromatographic/enzyme immunoassays (CIA/EIA), immunofluorescence

assays (IFA), and direct immunofluorescence assays (DFA) using monoclonal antibodies targeting RSV

F protein may be inhibited. Therefore, caution should be used in interpreting negative immunological

assay results when clinical observations are consistent with RSV infection. A reverse transcriptase-

polymerase chain reaction (RT-PCR) assay, which is not inhibited by palivizumab, may prove useful for

laboratory confirmation of RSV infection [see Warnings and Precautions ( 5.3) ].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis, mutagenesis, and reproductive toxicity studies have not been performed.

14 CLINICAL STUDIES

The safety and efficacy of Synagis were assessed in two randomized, double-blind, placebo-controlled

trials of prophylaxis against RSV infection in children at high risk of an RSV-related hospitalization.

Trial 1 was conducted during a single RSV season and studied a total of 1502 children less than or

equal to 24 months of age with BPD or infants with premature birth (less than or equal to 35 weeks

gestation) who were less than or equal to 6 months of age at study entry. Trial 2 was conducted over

four consecutive seasons among a total of 1287 children less than or equal to 24 months of age with

hemodynamically significant congenital heart disease. In both trials participants received 15 mg per kg

Synagis or an equivalent volume of placebo via intramuscular injection monthly for five injections and

were followed for 150 days from randomization. In Trial 1, 99% of all subjects completed the study and

93% completed all five injections. In Trial 2, 96% of all subjects completed the study and 92%

completed all five injections. The incidence of RSV hospitalization is shown in Table 1. The results

were shown to be statistically significant using Fisher's exact test.

Table 1: Incidence of RSV Hospitalization by Treatment Group

T rial

Placebo

Synagis

Difference

Between

Groups

Relative

Reduction

Trial 1

Impact-RSV

1002

Hospitalization

53 (10.6%)

48 (4.8%)

5.8%

Trial 2

CHD

Hospitalization

63 (9.7%)

34 (5.3%)

4.4%

In Trial 1, the reduction of RSV hospitalization was observed both in children with BPD (34/266

[12.8%] placebo versus 39/496 [7.9%] Synagis) and in premature infants without BPD (19/234 [8.1%]

placebo versus 9/506 [1.8%] Synagis). In Trial 2, reductions were observed in acyanotic (36/305

[11.8%] placebo versus 15/300 [5.0%] Synagis) and cyanotic children (27/343 [7.9%] placebo versus

19/339 [5.6%] Synagis).

The clinical studies do not suggest that RSV infection was less severe among children hospitalized

with RSV infection who received Synagis for RSV prophylaxis compared to those who received

placebo.

16 HOW SUPPLIED/STORAGE AND HANDLING

Synagis is supplied in single-dose vials as a preservative-free, sterile liquid solution at 100 mg per mL

for intramuscular injection.

50 mg vial NDC 66658-230-01

The 50 mg vial contains 50 mg Synagis in 0.5 mL.

100 mg vial NDC 66658-231-01

The 100 mg vial contains 100 mg Synagis in 1 mL.

The rubber stopper used for sealing vials of Synagis is not made with natural rubber latex.

Storage

Upon receipt and until use, Synagis should be stored between 2°C and 8°C (36°F and 46°F) in its

original container. DO NOT freeze. DO NOT use beyond the expiration date.

17 PATIENT COUNSELING INFORMATION

Advise the patient's caregiver to read the FDA-approved patient labeling ( Patient Information)

Hypersensitivity Reactions

Inform the patient's caregiver of the signs and symptoms of potential hypersensitivity reactions, and

advise the caregiver to seek medical attention immediately if the child experiences a severe

hypersensitivity reaction to Synagis [see Contraindications ( 4) and Warnings and Precautions ( 5.1) ].

Administration

Advise the patient's caregiver that Synagis should be administered by a healthcare provider once a

month during the RSV season by intramuscular injection and the importance of compliance with the full

course of therapy [see Dosage and Administration ( 2)] .

Synagis® is a registered trademark of Arexis AB c/o Swedish Orphan Biovitrum AB (publ).

s obi

Manufactured by:

Swedish Orphan Biovitrum AB (publ)

Stockholm, Sweden

Distributed by:

Sobi Inc.

890 Winter street

Waltham, MA 02451

U.S License No. 1859

Issued: 11/2020

PATIENT INFORMATION

SYNAGIS

(Si-na-jis)

(palivizumab)

injection

What is SYNAGIS?

SYNAGIS is a prescription medication that is used to help prevent a serious lung disease caused by

Respiratory Syncytial Virus (RSV) in children:

born prematurely (at or before 35 weeks) and who are 6 months of age or less at the beginning of

RSV season,

who have a chronic lung condition called bronchopulmonary dysplasia (BPD), that needed medical

treatment within the last 6 months, and who are 24 months of age or less at the beginning of RSV

season,

born with certain types of heart disease and who are 24 months of age or less at the beginning of

RSV season.

SYNAGIS contains man-made, disease-fighting proteins called antibodies.

It is not known if SYNAGIS is safe and effective to treat the symptoms of RSV in a child who already

has RSV. Synagis is used to help prevent RSV disease.

It is not known if SYNAGIS is safe and effective in children who are older than 24 months of age at the

start of dosing.

Who should not receive SYNAGIS?

Your child should not receive SYNAGIS if they have ever had a severe allergic reaction to it. See the

end of this leaflet for a complete list of ingredients in SYNAGIS. Signs and symptoms of a severe

allergic reaction could include:

severe rash, hives, or itching skin

swelling of the lips, tongue, or face

swelling of the throat, difficulty swallowing

bluish color of skin, lips, or under fingernails

muscle weakness or floppiness

unresponsiveness

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