SYNAGIS 50mg powder+solvent for injection medication leaflet

Synagis 50 mg/0.5 ml solution for injection

Synagis 100 mg/1 ml solution for injection

1 ml of Synagis solution contains 100 mg of palivizumab*.

Each 0.5 ml vial contains 50 mg of palivizumab.

Each 1 ml vial contains 100 mg of palivizumab.

*Palivizumab is a recombinant humanised monoclonal antibody produced by DNA technology inmouse myeloma host cells.

For the full list of excipients, see section 6.1.

Solution for injection.

The solution is clear or slightly opalescent.

Synagis is indicated for the prevention of serious lower respiratory tract disease requiringhospitalisation caused by respiratory syncytial virus (RSV) in children at high risk for RSV disease:

- Children born at 35 weeks of gestation or less and less than 6 months of age at the onset of the

RSV season.

- Children less than 2 years of age and requiring treatment for bronchopulmonary dysplasiawithin the last 6 months.

- Children less than 2 years of age and with haemodynamically significant congenital heartdisease.

The recommended dose of palivizumab is 15 mg/kg of body weight, given once a month duringanticipated periods of RSV risk in the community.

The volume (expressed in ml) of // Palivizumab // to be administered at one-monthly intervals =[patient weight in kg] multiplied by 0.15.

Where possible, the first dose should be administered prior to commencement of the RSV season.

Subsequent doses should be administered monthly throughout the RSV season. The efficacy ofpalivizumab at doses other than 15 mg per kg or of dosing differently from monthly throughout the

RSV season, has not been established.

The majority of experience including the pivotal phase III clinical trials with palivizumab has beengained with 5 injections during one season (see section 5.1). Data, although limited, are available ongreater than 5 doses (see sections 4.8 and 5.1), therefore the benefit in terms of protection beyond5 doses has not been established.

To reduce risk of rehospitalisation, it is recommended that children receiving palivizumab who arehospitalised with RSV continue to receive monthly doses of palivizumab for the duration of the RSVseason.

For children undergoing cardiac bypass, it is recommended that a 15 mg/kg of body weight injectionof palivizumab be administered as soon as stable after surgery to ensure adequate palivizumab serumlevels. Subsequent doses should resume monthly through the remainder of the RSV season forchildren that continue to be at high risk of RSV disease (see section 5.2).

Palivizumab is administered intramuscularly, preferably in the anterolateral aspect of the thigh. Thegluteal muscle should not be used routinely as an injection site because of the risk of damage to thesciatic nerve. The injection should be given using standard aseptic technique.

Injection volumes over 1 ml should be given as a divided dose.

Synagis solution for injection is a ready to use formulation. For instructions on special handlingrequirements, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1, or to otherhumanised monoclonal antibodies.

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

Allergic reactions including very rare cases of anaphylaxis and anaphylactic shock have been reportedfollowing palivizumab administration. In some cases, fatalities have been reported (see section 4.8).

Medicinal products for the treatment of severe hypersensitivity reactions, including anaphylaxis andanaphylactic shock, should be available for immediate use following administration of palivizumab.

A moderate to severe acute infection or febrile illness may warrant delaying the use of palivizumab,unless, in the opinion of the physician, withholding palivizumab entails a greater risk. A mild febrileillness, such as mild upper respiratory infection, is not usually reason to defer administration ofpalivizumab.

Palivizumab should be given with caution to patients with thrombocytopenia or any coagulationdisorder.

The efficacy of palivizumab when administered to patients as a second course of treatment during anensuing RSV season has not been formally investigated in a study performed with this objective. Thepossible risk of enhanced RSV infection in the season following the season in which the patients weretreated with palivizumab has not been conclusively ruled out by studies performed aiming at thisparticular point.

No formal interactions studies with other medicinal products were conducted. In the phase III IMpact-

RSV study in the premature and bronchopulmonary dysplasia paediatric populations, the proportionsof patients in the placebo and palivizumab groups who received routine childhood vaccines, influenzavaccine, bronchodilators or corticosteroids were similar and no incremental increase in adversereactions was observed among patients receiving these agents.

Since the monoclonal antibody is specific for RSV, palivizumab is not expected to interfere with theimmune response to vaccines.

Palivizumab may interfere with immune-based RSV diagnostic tests, such as some antigen detectionbased assays. In addition, palivizumab inhibits virus replication in cell culture and, therefore, mayalso interfere with viral culture assays. Palivizumab does not interfere with reverse transcriptasepolymerase chain reaction-based assays. Assay interference could lead to false-negative RSVdiagnostic test results. Therefore, diagnostic test results, when obtained, should be used in conjunctionwith clinical findings to guide medical decisions.

Not relevant. Synagis is not indicated for use in adults. Data on fertility, pregnancy and lactation arenot available.

Not relevant.

The most serious adverse reactions occurring with palivizumab are anaphylaxis and other acutehypersensitivity reactions. Common adverse reactions occurring with palivizumab are fever, rash, andinjection site reaction.

Adverse reactions both clinical and laboratory, are displayed by system organ class and frequency(very common ≥ 1/10; common ≥ 1/100 to < 1/10; uncommon ≥ 1/1,000 to < 1/100; rare ≥ 1/10,000to <1/1,000 ) in studies conducted in premature and bronchopulmonary dysplasia paediatric patients,and paediatric congenital heart disease patients.

The adverse reactions identified via post-marketing surveillance are reported voluntarily from apopulation of uncertain size; it is not always possible to reliably estimate their frequency or establish acausal relationship to palivizumab exposure. The frequency for these 'ADRs' as presented in thetable below was estimated using the safety data of the two registration clinical studies. The incidencesof these reactions in these studies showed no difference between the palivizumab and placebo groupsand the reactions were not drug related.

Undesirable effects in clinical studies* and post-marketing reports in paediatric patients

MedDRA system organ Frequency ADRclass

Blood and lymphatic Uncommon Thrombocytopenia#system disorders

Immune system disorders Not known Anaphylaxis, anaphylacticshock (in some cases,fatalities have beenreported.)#

Nervous system disorders Uncommon Convulsion#

Respiratory, thoracic and Common Apnoea#mediastinal disorders

Skin and subcutaneous Very common Rashtissue disorders

Uncommon Urticaria#

General disorders and Very common Pyrexiaadministrative siteconditions Common Injection site reaction

*For full study description, see Section 5.1 Clinical studies# ADRs identified from post-marketing surveillance

Post-marketing serious spontaneous adverse reactions reported during palivizumab treatment between1998 and 2002 covering four RSV seasons were evaluated. A total of 1,291 serious reports werereceived where palivizumab had been administered as indicated and the duration of therapy was withinone season. The onset of the adverse reactions occurred after the sixth or greater dose in only 22 ofthese reports (15 after the sixth dose, 6 after the seventh doses and 1 after the eight dose). Theseadverse reactions are similar in character to those after the initial five doses.

Palivizumab treatment schedule and adverse reactions were monitored in a group of nearly20,000 infants tracked through a patient compliance registry between 1998 and 2000. Of this group1,250 enrolled infants had 6 injections, 183 infants had 7 injections, and 27 infants had either8 or 9 injections. Adverse reactions observed in patients after a sixth or greater dose were similar incharacter and frequency to those after the initial 5 doses.

In an observational, post-marketing, database study, a small increase in the frequency of asthma wasobserved among preterm palivizumab recipients; however, the causal relationship is uncertain.

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.

In clinical studies, three children received an overdose of more than 15 mg/kg. These doses were20.25 mg/kg, 21.1 mg/kg and 22.27 mg/kg. No medical consequences were identified in theseinstances.

From the post-marketing experience, overdoses with doses up to 85 mg/kg have been reported and insome cases, adverse reactions were reported which did not differ from those observed with 15 mg/kgdose (see section 4.8). In case of overdose, it is recommended that the patient be monitored for anysigns or symptoms of adverse reactions or effects and appropriate symptomatic treatment institutedimmediately.

Pharmacotherapeutic group: immune sera immunoglobulins, specific immunoglobulins; ATC Code:

J06BB16.

Palivizumab is a humanised IgG1 monoclonal antibody directed to an epitope in the A antigenic siteof the fusion protein of respiratory syncytial virus (RSV). This humanised monoclonal antibody iscomposed of human (95%) and murine (5%) antibody sequences. It has potent neutralising andfusion-inhibitory activity against both RSV subtype A and B strains.

Palivizumab serum concentrations of approximately 30 g/ml have been shown to produce a 99%reduction in pulmonary RSV replication in the cotton rat model.

In vitro studies of antiviral activity

The antiviral activity of palivizumab was assessed in a microneutralization assay in which increasingconcentrations 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 enzyme-linkedimmunosorbent assay (ELISA). The neutralization titre (50% effective concentration [EC50]) isexpressed as the antibody concentration required to reduce detection of RSV antigen by 50%compared with untreated virus-infected cells. Palivizumab exhibited median EC50 values of0.65 g/ml (mean [standard deviation] = 0.75 [0.53] g/ml; n=69, range 0.07-2.89 g/ml) and0.28 g/ml (mean [standard deviation] = 0.35 [0.23] g/ml; n=35, range 0.03-0.88 g/ml) againstclinical RSV A and RSV B isolates, respectively. The majority of clinical RSV isolates tested (n=96)were collected from subjects in the United States.

Palivizumab binds a highly conserved region on the extracellular domain of mature RSV F protein,referred to as antigenic site II or A antigenic site, which encompasses amino acids 262 to 275. In agenotypic analysis of 126 clinical isolates from 123 children who failed immunoprophylaxis, all RSVmutants that exhibited resistance to palivizumab (n=8) were shown to contain amino acid changes inthis region of the F protein. No polymorphic or non-polymorphic sequence variations outside of the Aantigenic site on the RSV F protein were shown to render RSV resistant to neutralisation bypalivizumab. At least one of the palivizumab resistance-associated substitutions, N262D, K272E/Q, or

S275F/L was identified in these 8 clinical RSV isolates resulting in a combined resistance-associatedmutation frequency of 6.3% in these patients. A review of clinical findings did not reveal anassociation between A antigenic site sequence changes and RSV disease severity among childrenreceiving palivizumab immunoprophylaxis who develop RSV lower respiratory tract disease.

Analysis of 254 clinical RSV isolates collected from immunoprophylaxis-naïve subjects revealedpalivizumab resistance-associated substitutions in 2 (1 with N262D and 1 with S275F), resulting in aresistance associated mutation frequency of 0.79%.

Antibody to palivizumab was observed in approximately 1% of patients in the IMpact-RSV during thefirst course of therapy. This was transient, low titre, resolved despite continued use (first and secondseason), and could not be detected in 55 of 56 infants during the second season (including 2 with titresduring the first season). Immunogenicity was not studied in the congenital heart disease study.

Antibody to palivizumab was evaluated in four additional studies in 4337 patients (children born at 35weeks of gestation or less and 6 months of age or less, or 24 months of age or less withbronchopulmonary dysplasia, or with haemodynamically significant congenital heart disease wereincluded in these studies) and was observed in 0% - 1.5% of patients at different study timepoints.

There was no association observed between the presence of antibody and adverse events. Therefore,anti-drug antibody (ADA) responses appear to be of no clinical relevance.

Studies using lyophilised palivizumab

In a placebo-controlled trial of RSV disease prophylaxis in (IMpact-RSV trial) 1502 high-risk children(1002 Synagis; 500 placebo), 5 monthly doses of 15 mg/kg reduced the incidence of RSV relatedhospitalisation by 55% (p = < 0.001). The RSV hospitalisation rate was 10.6% in the placebo group.

On this basis, the absolute risk reduction is 5.8% which means the number needed to treat is 17 toprevent one hospitalisation. The severity of RSV disease in children hospitalised despite prophylaxiswith palivizumab in terms of days in ICU stay per 100 children and days of mechanical ventilation per100 children was not affected.

A total of 222 children were enrolled in two separate studies to examine the safety of palivizumabwhen it is administered for a second RSV season. One hundred and three (103) children receivedmonthly palivizumab injections for the first time, and 119 children received palivizumab fortwo consecutive seasons. No difference between groups regarding immunogenicity was observed ineither study. However, as the efficacy of palivizumab when administered to patients as a secondcourse of treatment during an ensuing RSV season has not been formally investigated in a studyperformed with this objective, the relevance of these data in terms of efficacy is unknown.

In an open label prospective trial designed to evaluate pharmacokinetics, safety, and immunogenicityafter administration of 7 doses of palivizumab within a single RSV season, pharmacokinetic dataindicated that adequate mean palivizumab levels were achieved in all 18 children enrolled. Transient,low levels of antipalivizumab antibody were observed in one child after the second dose ofpalivizumab that dropped to undetectable levels at the fifth and seventh dose.

In a placebo-controlled trial in 1,287 patients  24 months of age with haemodynamically significantcongenital heart disease (639 Synagis; 648 placebo), 5 monthly doses of 15 mg/kg Synagis; reducedthe incidence of RSV hospitalisations by 45% (p = 0.003) (congenital heart disease study). Groupswere equally balanced between cyanotic and acyanotic patients. The RSV hospitalisation rate was9.7% in the placebo group and 5.3% in the Synagis group. Secondary efficacy endpoints showedsignificant reductions in the Synagis group compared to placebo in total days of RSV hospitalisation(56% reduction, p = 0.003) and total RSV days with increased supplemental oxygen (73% reduction,p = 0.014) per 100 children.

A retrospective observational study was conducted in young children with hemodynamicallysignificant congenital heart disease (HSCHD) comparing the occurrence of primary serious adverseevents (PSAEs: infection, arrhythmia, and death) between those who did (1009) and did not receive

Synagis prophylaxis (1009) matched by age, type of cardiac lesion, and prior corrective surgery. Theincidence of arrhythmia and death PSAEs was similar in children who did and did not receiveprophylaxis. The incidence of infection PSAEs was lower in children who received prophylaxis ascompared to those children who did not receive prophylaxis. The results of the study indicate noincreased risk of serious infection, serious arrhythmia, or death in children with HSCHD associatedwith Synagis prophylaxis compared with children who did not receive prophylaxis.

Studies using liquid palivizumab

Two clinical studies were conducted to directly compare liquid and lyophilised formulations ofpalivizumab. In the first study, all 153 premature infants received both formulations in differentsequences. In the second study, 211 and 202 premature infants or children with chronic lung diseasereceived liquid and lyophilised palivizumab, respectively. In two additional studies, liquidpalivizumab was used as an active control (3918 paediatric subjects) to evaluate an investigationalmonoclonal antibody for prophylaxis of serious RSV disease in premature infants or children with

BPD or hemodynamically significant CHD (see below for further details of these two studies). Theoverall rate and pattern of adverse events, study drug discontinuation due to AEs, and the number ofdeaths reported in these clinical studies were consistent with those observed during the clinicaldevelopment programs for the lyophilised formulation. No deaths were considered related topalivizumab and no new ADRs were identified in these studies.

Pre-term infants and children with Chronic Lung Disease of Prematurity (CLDP): this trial, conductedat 347 centers in the North America, European Union and 10 other countries, studied patients less thanor equal to 24 months of age with CLDP and patients with premature birth (less than or equal to35 weeks gestation) who were less than or equal to 6 months of age at study entry. Patients withhemodynamically significant congenital heart disease were excluded from enrollment in this study andwere studied in a separate study. In this trial, patients were randomized to receive 5 monthlyinjections of 15 mg/kg of liquid palivizumab (N=3306) used as active control for an investigationalmonoclonal antibody (N=3329). Subjects were followed for safety and efficacy for 150 days. Ninety-eight percent of all subjects receiving palivizumab completed the study and 97% received allfive injections. The primary endpoint was the incidence of RSV hospitalisation. RSV hospitalisationsoccurred among 62 of 3306 (1.9%) patients in the palivizumab group. The RSV hospitalisation rateobserved in patients enrolled with a diagnosis of CLDP was 28/723 (3.9%) and in patients enrolledwith a diagnosis of prematurity without CLDP was 34/2583 (1.3%).

CHD Study 2: this trial, conducted at 162 centers in North America, European Union and 4 othercountries over two RSV seasons, studied patients less than or equal to 24 months of age withhemodynamically significant CHD. In this trial, patients were randomized to receive 5 monthlyinjections of 15 mg/kg of liquid palivizumab (N=612) used as active control for an investigationalmonoclonal antibody (N=624). Subjects were stratified by cardiac lesion (cyanotic vs. other) and werefollowed for safety and efficacy for 150 days. Ninety-seven percent of all subjects receivingpalivizumab completed the study and 95% received all five injections. The primary endpoint was asummary of adverse events and serious adverse events, and the secondary endpoint was the incidenceof RSV hospitalisation. The incidence of RSV hospitalisation was 16 of 612 (2.6%) in thepalivizumab group.

Lyophilised formulation of palivizumab

In studies in adult volunteers, palivizumab had a pharmacokinetic profile similar to a human IgG1antibody with regard to volume of distribution (mean 57 ml/kg) and half-life (mean 18 days). Inprophylactic studies in premature and bronchopulmonary dysplasia paediatric populations, the meanhalf-life of palivizumab was 20 days and monthly intramuscular doses of 15 mg/kg achieved mean30 day trough serum active substance concentrations of approximately 40 g/ml after the firstinjection, approximately 60 g/ml after the second injection, approximately 70 g/ml after the thirdinjection and fourth injection. In the congenital heart disease study, monthly intramuscular doses of15 mg/kg achieved mean 30 day trough serum active substance concentrations of approximately55 µg/ml after the first injection and approximately 90 µg/ml after the fourth injection.

Among 139 children in the congenital heart disease study receiving palivizumab who hadcardio-pulmonary bypass and for whom paired serum samples were available, the mean serumpalivizumab concentration was approximately 100 g/ml pre-cardiac bypass and declined toapproximately 40 g/ml after bypass.

Liquid formulation of palivizumab

The pharmacokinetics and safety of palivizumab liquid formulation and palivizumab lyophilisedformulation, following 15 mg/kg intramuscular administration, were compared in a cross-over trial of153 infants less than or equal to 6 months of age with a history of prematurity (less than or equal to35 weeks gestational age). The results of this trial indicated that the trough serum concentrations ofpalivizumab were similar between the liquid formulation and the lyophilised formulation andbioequivalence of the liquid and the lyophilised formulation was demonstrated.

Single dose toxicology studies have been conducted in cynomolgus monkeys (maximum dose30 mg/kg), rabbits (maximum dose 50 mg/kg) and rats (maximum dose 840 mg/kg). No significantfindings were observed.

Studies carried out in rodents gave no indication of enhancement of RSV replication, or RSV-inducedpathology or generation of virus escape mutants in the presence of palivizumab under the chosenexperimental conditions.

Histidine

Glycine

Water for injections

This medicinal product should not be mixed with other medicinal products.

3 years.

Store in a refrigerator (2ºC to 8ºC).

Do not freeze.

Keep the vial in the carton in order to protect from light.

Single-use vials: 3 ml capacity, clear, colourless type I glass vial with a chlorobutyl stopper and flip-off seal containing either 0.5 ml or 1 ml of solution for injection.

Pack size of 1.

Do not dilute the product.

Do not shake the vial.

Both the 0.5 ml and 1 ml vials contain an overfill to allow the withdrawal of 50 mg or 100 mg,respectively.

To administer, remove the tab portion of the vial cap and clean the stopper with 70 % ethanol orequivalent. Insert the needle into the vial and withdraw into the syringe an appropriate volume ofsolution.

Palivizumab solution for injection does not contain a preservative, is for single use and should beadministered immediately after drawing the dose into the syringe.

Any unused product or waste material should be disposed of in accordance with local requirements.

AstraZeneca AB

SE-151 85 Södertälje

Sweden

EU/1/99/117/003

EU/1/99/117/004

Date of first authorisation: 13 August 1999

Date of latest renewal: 27 July 2009

Detailed information on this product is available on the website of the European Medicines Agency:http://www.ema.europa.eu.