SYNFLORIX 0.5ml suspension for injection in pre-filled syringe medication leaflet

Synflorix suspension for injection in pre-filled syringe

Synflorix suspension for injection

Synflorix suspension for injection in multidose container (2 doses)

Synflorix suspension for injection in multidose container (4 doses)

Pneumococcal polysaccharide conjugate vaccine (adsorbed)

1 dose (0.5 ml) contains:

Pneumococcal polysaccharide serotype 11,2 1 microgram

Pneumococcal polysaccharide serotype 41,2 3 micrograms

Pneumococcal polysaccharide serotype 51,2 1 microgram

Pneumococcal polysaccharide serotype 6B1,2 1 microgram

Pneumococcal polysaccharide serotype 7F1,2 1 microgram

Pneumococcal polysaccharide serotype 9V1,2 1 microgram

Pneumococcal polysaccharide serotype 141,2 1 microgram

Pneumococcal polysaccharide serotype 18C1,3 3 micrograms

Pneumococcal polysaccharide serotype 19F1,4 3 micrograms

Pneumococcal polysaccharide serotype 23F1,2 1 microgram1 adsorbed on aluminium phosphate 0.5 milligram Al3+ in total2 conjugated to protein D (derived from non-typeable Haemophilus influenzae) carrier protein9-16 micrograms3 conjugated to tetanus toxoid carrier protein 5-10 micrograms4 conjugated to diphtheria toxoid carrier protein 3-6 micrograms

For the full list of excipients, see section 6.1.

Suspension for injection (injection).

The vaccine is a turbid white suspension.

Active immunisation against invasive disease, pneumonia and acute otitis media caused by

Streptococcus pneumoniae in infants and children from 6 weeks up to 5 years of age. See sections 4.4and 5.1 for information on protection against specific pneumococcal serotypes.

The use of Synflorix should be determined on the basis of official recommendations taking intoconsideration the impact on pneumococcal diseases in different age groups as well as the variability ofthe epidemiology in different geographical areas.

The immunisation schedules for Synflorix should be based on official recommendations.

It is recommended that individuals who receive a first dose of Synflorix complete the full vaccinationcourse with Synflorix.

Infants from 6 weeks to 6 months of age

Three-dose primary series

The recommended immunisation series to ensure optimal protection consists of four doses, each of0.5 ml. The primary infant series consists of three doses with the first dose usually given at 2 monthsof age and with an interval of at least 1 month between doses. The first dose may be given as early as6 weeks of age. A booster (fourth) dose is recommended at least 6 months after the last primary doseand may be given from the age of 9 months onwards (preferably between 12 and 15 months of age)(see sections 4.4 and 5.1).

Two-dose primary series

Alternatively, when Synflorix is given as part of a routine infant immunisation programme, a seriesconsisting of three doses, each of 0.5 ml may be given. The first dose may be given as early as 6weeks of age with a second dose administered 2 months later. A booster (third) dose is recommendedat least 6 months after the last primary dose and may be given from the age of 9 months onwards(preferably between 12 and 15 months of age) (see section 5.1).

Preterm newborn infants (born between 27-36 weeks gestation)

In preterm infants born after at least 27 weeks of gestational age, the recommended immunisationseries consists of four doses, each of 0.5 ml. The primary infant series consists of three doses with thefirst dose given at 2 months of age and with an interval of at least 1 month between doses. A booster(fourth) dose is recommended at least 6 months after the last primary dose (see sections 4.4 and 5.1).

Unvaccinated infants and children ≥ 7 months of age- infants aged 7-11 months: The vaccination schedule consists of two primary doses of 0.5 ml withan interval of at least 1 month between doses. A booster (third) dose is recommended in the secondyear of life with an interval of at least 2 months after the last primary dose.

- children aged 12 months -5 years: The vaccination schedule consists of two doses of 0.5 ml with aninterval of at least 2 months between doses.

In individuals who have underlying conditions predisposing them to invasive pneumococcal disease(such as Human Immunodeficiency Virus (HIV) infection, sickle cell disease (SCD) or splenicdysfunction), Synflorix may be given according to the above mentioned schedules except that a 3-doseschedule should be given as primary vaccination in infants starting vaccination from 6 weeks to 6months of age (see sections 4.4 and 5.1).

The safety and efficacy of Synflorix in children over 5 years of age have not been established.

Use of Synflorix and other pneumococcal conjugate vaccines

Limited clinical data are available on the use of both Synflorix and 13-valent pneumococcal conjugatevaccine (PCV13) in the immunisation course of an individual (see section 5.1).

The vaccine should be given by intramuscular injection. The preferred sites are anterolateral aspect ofthe thigh in infants or the deltoid muscle of the upper arm in young children.

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1, or to any ofthe carrier proteins.

As with other vaccines, the administration of Synflorix should be postponed in subjects suffering fromacute severe febrile illness. However, the presence of a minor infection, such as a cold, should notresult in the deferral of vaccination.

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

Prior to immunisation

As with all injectable vaccines, appropriate medical treatment and supervision should always bereadily available in case of a rare anaphylactic reaction following the administration of the vaccine.

The potential risk of apnoea and the need for respiratory monitoring for 48-72 h should be consideredwhen administering the primary immunisation series to very premature infants (born ≤ 28 weeks ofgestation) and particularly for those with a previous history of respiratory immaturity. As the benefitof vaccination is high in this group of infants, vaccination should not be withheld or delayed.

Synflorix should under no circumstances be administered intravascularly or intradermally. No data areavailable on subcutaneous administration of Synflorix.

In children as of 2 years of age, syncope (fainting) can occur following, or even before, anyvaccination as a psychogenic response to the needle injection. It is important that procedures are inplace to avoid injury from faints.

As for other vaccines administered intramuscularly, Synflorix should be given with caution toindividuals with thrombocytopenia or any coagulation disorder since bleeding may occur following anintramuscular administration to these subjects.

Information on protection conferred by the vaccine

Official recommendations for the immunisation against diphtheria, tetanus and Haemophilusinfluenzae type b should also be followed.

There is insufficient evidence that Synflorix provides protection against pneumococcal serotypes notcontained in the vaccine except the cross-reactive serotype 19A (see section 5.1) or against non-typeable Haemophilus influenzae. Synflorix does not provide protection against other micro-organisms.

As with any vaccine, Synflorix may not protect all vaccinated individuals against invasivepneumococcal disease, pneumonia or otitis media caused by the serotypes in the vaccine and thecross-reactive serotype 19A. In addition, as otitis media and pneumonia are caused by many micro-organisms other than the Streptococcus pneumoniae serotypes represented by the vaccine, the overallprotection against these diseases is expected to be limited and substantially lower than protectionagainst invasive disease caused by the serotypes in the vaccine and serotype 19A (see section 5.1).

In clinical trials, Synflorix elicited an immune response to all ten serotypes included in the vaccine,but the magnitude of the responses varied between serotypes. The functional immune response toserotypes 1 and 5 was lower in magnitude than the response against all other vaccine serotypes. It isnot known whether this lower functional immune response against serotypes 1 and 5 will result inlower protective efficacy against invasive disease, pneumonia or otitis media caused by theseserotypes (see section 5.1).

Children should receive the dose regimen of Synflorix that is appropriate to their age at the time ofcommencing the vaccination series (see section 4.2).

Immunosuppressive therapy and immunodeficiency

Children with impaired immune responsiveness, whether due to the use of immunosuppressivetherapy, a genetic defect, HIV infection, prenatal exposure to anti-retroviral therapy and/or to HIV, orother causes, may have reduced antibody response to vaccination.

Safety and immunogenicity data are available for HIV infected infants (asymptomatic or with mildsymptoms according to WHO classification), HIV negative infants born from HIV positive mothers,children with sickle cell disease and children with splenic dysfunction (see sections 4.8 and 5.1).

Safety and immunogenicity data for Synflorix are not available for individuals in other specificimmunocompromised groups and vaccination should be considered on an individual basis (see section4.2).

The use of pneumococcal conjugate vaccine does not replace the use of 23-valent pneumococcalpolysaccharide vaccines in children ≥ 2 years of age with conditions (such as sickle cell disease,asplenia, HIV infection, chronic illness, or those who have other immunocompromising conditions)placing them at higher risk for invasive disease due to Streptococcus pneumoniae. Wheneverrecommended, children at risk who are ≥ 24 months of age and already primed with Synflorix shouldreceive 23-valent pneumococcal polysaccharide vaccine. The interval between the pneumococcalconjugate vaccine (Synflorix) and the 23-valent pneumococcal polysaccharide vaccine should not beless than 8 weeks. There are no data available to indicate whether the administration of pneumococcalpolysaccharide vaccine to Synflorix primed children may result in hyporesponsiveness to further dosesof pneumococcal polysaccharide or to pneumococcal conjugate vaccine.

Prophylactic use of antipyretics

Prophylactic administration of antipyretics before or immediately after vaccine administration canreduce the incidence and intensity of post-vaccination febrile reactions. Clinical data generated withparacetamol and ibuprofen suggest that the prophylactic use of paracetamol might reduce the feverrate, while prophylactic use of ibuprofen showed a limited effect in reducing fever rate. The clinicaldata suggest that paracetamol might reduce the immune response to Synflorix. However, the clinicalrelevance of this observation is not known.

The use of prophylactic antipyretic medicinal products is recommended:

- for all children receiving Synflorix simultaneously with vaccines containing whole cell pertussisbecause of higher rate of febrile reactions (see section 4.8).

- for children with seizure disorders or with a prior history of febrile seizures.

Antipyretic treatment should be initiated according to local treatment guidelines.

This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

Synflorix can be given concomitantly with any of the following monovalent or combination vaccines[including DTPa-HBV-IPV/Hib and DTPw-HBV/Hib]: diphtheria-tetanus-acellular pertussis vaccine(DTPa), hepatitis B vaccine (HBV), inactivated polio vaccine (IPV), Haemophilus influenzae type bvaccine (Hib), diphtheria-tetanus-whole cell pertussis vaccine (DTPw), measles-mumps-rubellavaccine (MMR), varicella vaccine (V), meningococcal serogroup C conjugate vaccine (CRM197 and

TT conjugates), meningococcal serogroups A, C, W-135 and Y conjugate vaccine (TT conjugate),oral polio vaccine (OPV) and oral rotavirus vaccine. Different injectable vaccines should always begiven at different injection sites.

Clinical studies demonstrated that the immune responses and the safety profiles of the co-administeredvaccines were unaffected, with the exception of the inactivated poliovirus type 2 response, for whichinconsistent results were observed across studies (seroprotection ranging from 78% to 100%). Inaddition when the meningococcal serogroups A, C, W-135 and Y vaccine (TT conjugate) was co-administered with a booster dose of Synflorix during the second year of life in children primed with 3doses of Synflorix, lower antibody geometric mean concentration (GMC) and opsonophagocytic assaygeometric mean titre (OPA GMT) were observed for one pneumococcal serotype (18 C). There was noimpact of co-administration on the other nine pneumococcal serotypes. Enhancement of antibodyresponse to Hib-TT conjugate, diphtheria and tetanus antigens was observed. The clinical relevance ofthe above observations is unknown.

As with other vaccines, it may be expected that in patients receiving immunosuppressive treatment anadequate response may not be elicited.

Use with prophylactic administration of antipyretics

Clinical data suggest that prophylactic administration of paracetamol, used to reduce the rate ofpossible post-vaccination febrile reactions, might reduce the immune response to Synflorix. However,the clinical relevance of this observation is not known. See section 4.4.

Synflorix is not intended for use in adults. Human data on the use during pregnancy or breast-feedingand animal reproduction studies are not available.

Not relevant.

Safety assessment of Synflorix was based on clinical trials involving the administration of 63,905doses of Synflorix to 22,429 healthy children and 137 preterm infants as primary vaccination.

Furthermore, 19,466 children and 116 preterm infants received a booster dose of Synflorix in thesecond year of life.

Safety was also assessed in 435 previously unvaccinated children from 2 to 5 years old of which 285subjects received 2 doses of Synflorix.

In all trials, Synflorix was administered concurrently with the recommended childhood vaccines.

In infants, the most common adverse reactions observed after primary vaccination were redness atthe injection site and irritability which occurred after approximately 41% and 55% of all dosesrespectively. Following booster vaccination, the most common adverse reactions were pain at theinjection site and irritability, which occurred at approximately 51% and 53% respectively. Themajority of these reactions were of mild to moderate severity and were not long lasting.

No increase in the incidence or severity of the adverse reactions was seen with subsequent doses ofthe primary vaccination series.

Local reactogenicity of primary vaccination course was similar in infants < 12 months of age and inchildren > 12 months of age except for injection site pain for which the incidence increased withincreasing age: pain was reported by more than 39% of the infants < 12 months of age and by morethan 58% of the children > 12 months of age.

Following booster vaccination, children > 12 months of age are more likely to experience injection sitereactions compared to the rates observed in infants during the primary series with Synflorix.

Following catch-up vaccination in children 12 to 23 months of age, urticaria was reported morefrequently (uncommon) compared to the rates observed in infants during primary and boostervaccination.

Reactogenicity was higher in children receiving whole cell pertussis vaccines concomitantly. In aclinical study children received either Synflorix (N=603) or 7-valent Prevenar (N=203) concomitantlywith a DTPw containing vaccine. After the primary vaccination course, fever ≥38 °C and >39 °C wasreported respectively in 86.1% and 14.7% of children receiving Synflorix and in 82.9% and 11.6% ofchildren vaccinated with 7-valent Prevenar.

In comparative clinical studies, the incidence of local and general adverse events reported within 4days after each vaccination dose was within the same range as after vaccination with 7-valent

Prevenar.

Adverse reactions (for all age groups) have been categorised by frequency.

Frequencies are reported 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)

Within each frequency grouping the adverse reactions are presented in the order of decreasingseriousness.

System Organ Class Frequency Adverse reactions

Immune system disorders Rare Allergic reactions (such as eczema, allergicdermatitis, atopic dermatitis)

Very rare Angioedema

Metabolism and nutrition Very common Appetite lostdisorders

Psychiatric disorders Very common Irritability

Uncommon Crying abnormal

Nervous system disorders Very common Drowsiness

Rare Convulsions (including febrile convulsions)

Vascular disorders Very rare Kawasaki disease

Respiratory, thoracic and Uncommon Apnoea in very premature infants (≤ 28 weeksmediastinal disorders of gestation) (see section 4.4)

Gastrointestinal disorders Uncommon Diarrhoea, vomiting

Skin and subcutaneous tissue Uncommon Rashdisorders Rare Urticaria

General disorders and Very common Fever ≥ 38 °C rectally (age < 2 years), pain,administration site conditions redness, swelling at the injection site.

Common Fever > 39 °C rectally (age < 2 years),injection site reactions like injection siteinduration

Uncommon Injection site reactions like injection sitehaematoma, haemorrhage and nodule

Adverse reactions additionally reported after booster vaccination of primary series and/or catch-upvaccination:

Nervous system disorders Uncommon Headache (age 2 to 5 years)

Gastrointestinal disorders Uncommon Nausea (age 2 to 5 years)

General disorders and Common Fever ≥ 38 °C rectally (age 2 to 5 years)administration site conditions Uncommon Fever > 40 °C rectally (age < 2 years), fever> 39 °C rectally (age 2 to 5 years), injectionsite reactions like diffuse swelling of theinjected limb, sometimes involving theadjacent joint, pruritus.

Immune system disorders Very rare Anaphylaxis

Nervous system disorders Rare Hypotonic-hyporesponsive episode

Safety of Synflorix was assessed in 83 HIV positive (HIV+/+) infants (asymptomatic or with mildsymptoms according to WHO classification), 101 HIV negative infants born from HIV positivemothers (HIV+/-) and 50 infants with sickle cell disease (SCD), receiving primary vaccination. Ofthese, 76, 96 and 49 infants, respectively, received a booster dose. Safety of Synflorix was alsoassessed in 50 children with SCD starting vaccination at 7-11 months of age, all of them receivingthe booster vaccination, and in 50 children with SCD starting vaccination at 12-23 months of age.

Results suggest comparable reactogenicity and safety profile of Synflorix between these high riskgroups and healthy children.

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.

No case of overdose has been reported.

Pharmacotherapeutic group: vaccines, pneumococcal vaccines, ATC code: J07AL52

Epidemiological data

The 10 pneumococcal serotypes included in this vaccine represent the major disease-causing serotypesin Europe covering approximately 56% to 90% of invasive pneumococcal disease (IPD) in children <5years of age. In this age group, serotypes 1, 5 and 7F account for 3.3% to 24.1% of IPD depending onthe country and time period studied.

Pneumonia of different aetiologies is a leading cause of childhood morbidity and mortality globally. Inprospective studies, Streptococcus pneumoniae was estimated to be responsible for 30-50% ofpneumonia cases.

Acute otitis media (AOM) is a common childhood disease with different aetiologies. Bacteria can beresponsible for 60-70% of clinical episodes of AOM. Streptococcus pneumoniae and Non-Typeable

Haemophilus influenzae (NTHi) are the most common causes of bacterial AOM worldwide.

Efficacy and effectiveness in clinical trials

In a large-scale phase III/IV, double-blind, cluster-randomized, controlled, clinical trial in Finland(FinIP), children were randomised into 4 groups according to the two infant vaccination schedules[2-dose (3, 5 months of age) or 3-dose (3, 4, 5 months of age) primary schedule followed by a boosterdose as of 11 months of age] to receive either Synflorix (2/3rd of clusters) or hepatitis vaccines ascontrol (1/3rd of clusters). In the catch-up cohorts, children between 7-11 months of age at firstvaccine dose received Synflorix or hepatitis B control vaccine according to a 2-dose primary schedulefollowed by a booster dose and children between 12-18 months of age at first vaccine dose received2 doses of either Synflorix or hepatitis A control vaccine. Average follow-up, from first vaccination,was 24 to 28 months for invasive disease and hospital-diagnosed pneumonia. In a nested study, infantswere followed up till approximately 21 months of age to assess impact on nasopharyngeal carriage andphysician-diagnosed AOM reported by parents.

In a large-scale phase III, randomized, double-blind clinical trial (Clinical Otitis Media and

Pneumonia Study - COMPAS) conducted in Argentina, Panama and Colombia, healthy infants aged6 to 16 weeks received either Synflorix or hepatitis B control vaccine at 2, 4 and 6 months of agefollowed respectively by either Synflorix or hepatitis A control vaccine at 15 to 18 months of age.

Invasive pneumococcal disease (which includes sepsis, meningitis, bacteraemic pneumonia andbacteraemia)

Effectiveness/efficacy in infant cohort below 7 months of age at enrolment

Vaccine effectiveness or efficacy (VE) was demonstrated in preventing culture-confirmed IPD due tovaccine pneumococcal serotypes when Synflorix was given to infants in either 2+1 or 3+1 schedulesin FinIP or 3+1 schedule in COMPAS (see Table 1).

Table 1: Number of vaccine serotype IPD cases and vaccine effectiveness (FinIP) or efficacy(COMPAS) in infants below 7 months of age at enrolment receiving at least one vaccine dose(Infant total vaccinated cohort)

FinIP COMPAS

No. of IPD cases VE(95% CI) No. of IPD cases VE(95% CI)

Type of Synflorix Synflorix (2) Synflorix

IPD 3+1 2+1 Control 3+1 Controlschedule schedule 3+1 2+1 3+1

N N N schedule schedule schedule

N N schedule10,273 10,054 10,200 11,798 11,799

Vaccine 100%(3) 91.8%(4) (5)serotype 0 1 12 0 18 100%

IPD(1) (82.8; 100) (58.3; 99.6) (77.3; 100)

Serotype 0 0 5 100% 100%6B IPD (54.9; 100) (54.5; 100) 0 2 -

Serotype 0 0 4 100% 100% 100%14 IPD (39.6; 100) (43.3; 100) 0 9 (49.5; 100)

IPD Invasive Pneumococcal Disease

VE Vaccine effectiveness (FinIP) or efficacy (COMPAS)

N number of subjects per group

CI Confidence Interval(1) In FinIP apart from serotypes 6B and 14, culture-confirmed vaccine serotype IPD casesincluded 7F (1 case in the Synflorix 2+1 clusters), 18C, 19F and 23F (1 case of each in thecontrol clusters). In COMPAS, serotypes 5 (2 cases), 18C (4 cases) and 23F (1 case) weredetected in control group in addition to serotypes 6B and 14.

(2) the 2 groups of control clusters of infants were pooled(3) p-value<0.0001(4) p-value=0.0009(5) in the ATP cohort VE was 100% (95% CI: 74.3; 100; 0 versus 16 cases)

In FinIP the overall observed VE against culture-confirmed IPD was 100% (95% CI: 85.6; 100; 0versus 14 cases) for the 3+1 schedule, 85.8% (95% CI: 49.1; 97.8; 2 versus 14 cases) for the 2+1schedule and 93.0% (95% CI: 74.9; 98.9; 2 versus 14 cases) regardless of the primary vaccinationschedule. In COMPAS it was 66.7% (95% CI: 21.8; 85.9; 7 versus 21 cases).

Effectiveness following catch-up immunisation

Among the 15,447 children in the catch-up vaccinated cohorts, there were no culture-confirmed IPDcases in the Synflorix groups while 5 vaccine serotype IPD cases were observed in the control groups(serotypes 4, 6B, 7F, 14 and 19F).

Efficacy against pneumonia was assessed in COMPAS. The mean duration follow-up from 2 weekspost-dose 3 in the ATP cohort was 23 months (range from 0 to 34 months) for the interim analysis(IA) and 30 months (range from 0 to 44 months) for the end-of-study analysis. At the end of this IA orend-of-study ATP follow-up period, the mean age was 29 months (range from 4 to 41 months) and 36months (range from 4 to 50 months), respectively. The proportion of subjects who received the boosterdose in the ATP cohort was 92.3% in both analyses.

Efficacy of Synflorix against first episodes of likely bacterial Community Acquired Pneumonia (CAP)occurring from 2 weeks after the administration of the 3rd dose was demonstrated in the ATP cohort(P value ≤ 0.002) in the interim analysis (event-driven; primary objective).

Likely bacterial CAP (B-CAP) is defined as radiologically confirmed CAP cases with either alveolarconsolidation/pleural effusion on the chest X-ray, or with non-alveolar infiltrates but with C reactiveprotein (CRP) ≥ 40 mg/l.

The vaccine efficacy against B-CAP observed at the interim analysis is presented below (table 2).

Table 2: Numbers and percentages of subjects with first episodes of B-CAP occurring from2 weeks after the administration of the 3rd dose of Synflorix or control vaccine and vaccineefficacy (ATP cohort)

Synflorix Control vaccine

N=10,295 N=10,201 Vaccine efficacyn % (n/N) n % (n/N)240 2.3% 304 3.0% 22.0%(95% CI: 7.7; 34.2)

N number of subjects per groupn/% number/percentage of subjects reporting a first episode of B-CAP anytime from 2 weeks afterthe administration of the 3rd dose

CI Confidence Interval

In the interim analysis (ATP cohort), the vaccine efficacy against first episodes of CAP with alveolarconsolidation or pleural effusion (C-CAP, WHO definition) was 25.7% (95% CI: 8.4; 39.6) andagainst first episodes of clinically suspected CAP referred for X-ray was 6.7% (95% CI: 0.7; 12.3).

At the end-of-study analysis (ATP cohort), the vaccine efficacy (first episodes) against B-CAP was18.2% (95% CI: 4.1; 30.3), against C-CAP 22.4% (95% CI: 5.7; 36.1) and against clinically suspected

CAP referred for X-ray 7.3% (95% CI: 1.6; 12.6). Efficacy was 100% (95% CI: 41.9; 100) againstbacteraemic pneumococcal pneumonia or empyema due to vaccine serotypes. The protection against

B-CAP before booster dose and at the time or after booster dose was 13.6% (95% CI: -11.3; 33.0) and21.7% (95% CI: 3.4; 36.5) respectively. For C-CAP it was 15.1% (95% CI: -15.5; 37.6) and 26.3%(95% CI: 4.4; 43.2) respectively.

The reduction in B-CAP and C-CAP was greatest in children < 36 months of age (vaccine efficacy of20.6% (95% CI: 6.5; 32.6) and 24.2% (95% CI: 7.4; 38.0) respectively). Vaccine efficacy results inchildren > 36 months of age suggest a waning of protection. The persistence of protection against

B-CAP and C-CAP beyond the age of 36 months is currently not established.

The results of the COMPAS study, which was performed in Latin America, should be interpreted withcaution due to possible differences in epidemiology of pneumonia in different geographical locations.

In the FinIP study, vaccine effectiveness in reducing hospital-diagnosed pneumonia cases (identifiedbased on the ICD 10 codes for pneumonia) was 26.7% (95% CI: 4.9; 43.5) in the 3+1 infant scheduleand 29.3% (95% CI: 7.5; 46.3) in the 2+1 infant schedule. For catch-up vaccination, vaccineeffectiveness was 33.2% (95% CI: 3.0; 53.4) in the 7-11 month cohort and 22.4% (95% CI: -8.7; 44.8)in the 12-18 month cohort.

Acute Otitis Media (AOM)

Two efficacy studies, COMPAS and POET (Pneumococcal Otitis Media Efficacy Trial), wereconducted with pneumococcal conjugate vaccines containing protein D: Synflorix and aninvestigational 11-valent conjugate vaccine (which in addition contained serotype 3), respectively.

In COMPAS, 7,214 subjects [Total Vaccinated cohort (TVC)] were included in the AOM efficacyanalysis of which 5,989 subjects were in the ATP cohort (Table 3).

Table 3: Vaccine efficacy against AOM(1) in COMPAS

Vaccine efficacy

Type or cause of AOM (95% CI)

ATP(2)

Clinical AOM 16.1%(-1.1; 30.4)(3)

Any pneumococcal serotype 56.1%(13.4; 77.8)10 pneumococcal vaccine serotypes 67.1%(17.0; 86.9)(4)

Non-typeable Haemophilus influenzae (NTHi) 15.0%(-83.8; 60.7)

CI Confidence Interval(1) First episode(2) Follow up period for a maximum of 40 months from 2 weeks after third primary dose(3) Not statistically significant by pre-defined criteria (One sided p=0.032). However, in TVCcohort, vaccine efficacy against first clinical AOM episode was 19% (95% CI: 4.4; 31.4).(4) Not statistically significant.

In another large randomised double-blind trial (POET) conducted in the Czech Republic and in

Slovakia, 4,907 infants (ATP cohort) received either the 11-valent investigational vaccine (11Pn-PD)containing the 10 serotypes of Synflorix (along with serotype 3 for which efficacy was notdemonstrated) or a control vaccine (hepatitis A vaccine) according to a 3, 4, 5 and 12-15 monthsvaccination schedule.

Efficacy of the 11 Pn-PD vaccine against the first occurrence of vaccine serotype AOM episode was52.6% (95% CI: 35.0; 65.5). Serotype specific efficacy against the first AOM episode wasdemonstrated for serotypes 6B (86.5%, 95% CI: 54.9; 96.0), 14 (94.8%, 95% CI: 61.0; 99.3), 19F(43.3%, 95% CI: 6.3; 65.4) and 23F (70.8%, 95% CI: 20.8; 89.2). For other vaccine serotypes, thenumber of AOM cases was too limited to allow any efficacy conclusion to be drawn. Efficacy againstany AOM episode due to any pneumococcal serotype was 51.5% (95% CI: 36.8; 62.9). The vaccineefficacy against the first episode of NTHi AOM was 31.1% (95% CI: -3.7; 54.2, not significant).

Efficacy against any NTHi AOM episode was 35.3% (95% CI: 1.8; 57.4). The estimated vaccineefficacy against any clinical episodes of otitis media regardless of aetiology was 33.6% (95% CI: 20.8;44.3).

Based on immunological bridging of the functional vaccine response (OPA) of Synflorix with the11-valent formulation used within POET, it is expected that Synflorix provides similar protectiveefficacy against pneumococcal AOM.

No increase in the incidence of AOM due to other bacterial pathogens or non-vaccine/non-vaccinerelated serotypes was observed in either COMPAS (based on the few cases reported) or POET trial.

Effectiveness against physician-diagnosed AOM reported by parents was studied in the nested studywithin the FinIP trial. Vaccine effectiveness was 6.1% (95% CI: -2.7; 14.1) for the 3+1 schedule and7.4% (95% CI -2.8; 16.6) for 2+1 schedule for this AOM endpoint in the infant vaccinated cohort.

Impact on nasopharyngeal carriage (NPC)

The effect of Synflorix on nasopharyngeal carriage was studied in 2 double-blind randomised studiesusing an inactive control: in the nested study of FinIP in Finland (5,023 subjects) and in COMPAS(1,700 subjects).

In both COMPAS and the nested Finnish study, Synflorix reduced vaccine type carriage with anapparent increase in non-vaccine (excluding vaccine-related) serotypes observed after booster. Theresults were not statistically significant across all analyses in COMPAS. However, taken togetherthere was a trend for decrease in overall pneumococcal carriage.

In both studies there were significant decrease of individual serotypes 6B and 19F. In the nested

Finnish study, a significant reduction was also observed for individual serotypes 14, 23F and, in the3 dose primary schedule, for the cross-reactive serotype 19A.

In a clinical study NPC was assessed in HIV positive infants (N = 83) and HIV negative infants bornfrom HIV positive mothers (N = 101) and compared to HIV negative infants born from HIV negativemothers (N = 100). The HIV exposure or infection did not appear to alter the effect of Synflorix onpneumococcal carriage up to 24-27 months of age, i.e. up to 15 months following booster vaccination.

Effectiveness in post-marketing surveillance

In Brazil, Synflorix was introduced into the national immunisation programme (NIP) using a 3+1schedule in infants (2, 4, 6 months of age and a booster dose at 12 months) with a catch-up campaignin children up to 2 years of age. Based on almost 3 years of surveillance following Synflorixintroduction, a matched case-control study reported a significant decrease in culture or PCR confirmed

IPD due to any vaccine serotype, and IPD due to individual serotypes 6B, 14 and 19A.

Table 4: Summary of effectiveness of Synflorix for IPD in Brazil

Types of IPD(1) Adjusted Effectiveness(2)% (95% CI)

Any vaccine serotype IPD(3) 83.8% (65.9; 92.3)

- Invasive pneumonia or bacteraemia 81.3% (46.9; 93.4)

- Meningitis 87.7% (61.4; 96.1)

IPD due to individual serotypes(4)

- 6B 82.8% (23.8; 96.1)

- 14 87.7% (60.8; 96.1)

- 19A 82.2% (10.7; 96.4)(1) Culture or PCR confirmed IPD(2) The adjusted effectiveness represents the percent reduction in IPD in the Synflorix vaccinatedgroup compared to the unvaccinated group, controlling for confounding factors.(3) Culture or PCR confirmed cases for serotypes 4, 6B, 7F, 9V, 14, 18C, 19F and 23F contributed tothe analysis.(4) Individual serotypes for which statistical significance was reached in the effectiveness analysiscontrolling for confounding factors (no adjustment for multiplicity performed).

In Finland, Synflorix was introduced into NIP with a 2+1 schedule in infants (3, 5 months of age and abooster dose at 12 months) without catch-up campaign. Before and after NIP comparison suggests asignificant decrease in the incidence of any culture confirmed IPD, any vaccine serotype IPD and IPDdue to serotype 19A.

Table 5: Rates of IPD and the corresponding rate reductions in Finland

IPD Incidence per 100,000 person years Relative rate reduction(1)% (95% CI)

Before NIP After NIP

Any culture confirmed 62.9 12.9 80% (72; 85)

Any vaccine serotype(2) 49.1 4.2 92% (86; 95)

Serotype 19A 5.5 2.1 62% (20; 85)(1) The relative rate reduction indicates how much the incidence of IPD in children of ≤5 years of agewas reduced in the Synflorix cohort (followed for 3 years after NIP introduction) versus age andseason matched non-vaccinated historical cohorts (each followed for 3 year periods beforeintroduction of Synflorix into NIP).(2) Culture confirmed cases for serotypes 1, 4, 6B, 7F, 9V, 14, 18C, 19F and 23F contributed to theanalysis.

In Quebec, Canada, Synflorix was introduced into the infant immunisation programme (2 primarydoses to infants less than 6 months of age and a booster dose at 12 months) following 4.5 years of useof 7-valent Prevenar. Based on 1.5 years of surveillance following Synflorix introduction, with over90% coverage in the vaccine-eligible age group, a decrease in vaccine serotype IPD incidence (largelydue to changes in serotype 7F disease) was observed with no concomitant increase in non-vaccineserotype IPD incidence. Overall, the incidence of IPD was 35/100,000 person-years in those cohortsexposed to Synflorix, and 64/100,000 person-years in those exposed to 7-valent Prevenar, representinga statistically significant difference (p = 0.03). No direct cause-and-effect can be inferred fromobservational studies of this type.

Immunogenicity data

Immunologic non-inferiority to 7-valent Prevenar

The assessment of potential efficacy against IPD pre-licensure was based on a comparison of immuneresponses to the seven serotypes shared between Synflorix and another pneumococcal conjugatevaccine for which protective efficacy was evaluated previously (i.e. 7-valent Prevenar), asrecommended by the WHO. Immune responses to the extra three serotypes in Synflorix were alsomeasured.

In a head-to-head comparative trial with 7-valent Prevenar, non-inferiority of the immune response to

Synflorix measured by ELISA was demonstrated for all serotypes, except for 6B and 23F (upper limitof the 96.5% CI around the difference between groups >10%) (Table 6). For serotypes 6B and 23F,respectively, 65.9% and 81.4% of infants vaccinated at 2, 3 and 4 months reached the antibodythreshold (i.e. 0.20 µg/ml) one month after the third dose of Synflorix versus 79.0% and 94.1%respectively, after three doses of 7-valent Prevenar. The clinical relevance of these differences isunclear, as Synflorix was observed to be effective against IPD caused by serotype 6B in a double-blind, cluster-randomized clinical study (see Table 1).

The percentage of vaccinees reaching the threshold for the three additional serotypes in Synflorix (1, 5and 7F) was respectively 97.3%, 99.0% and 99.5% and was at least as good as the aggregate 7-valent

Prevenar response against the 7 common serotypes (95.8%).

Table 6: Comparative analysis between 7-valent Prevenar and Synflorix in percentage ofsubjects with antibody concentrations > 0.20 µg/ml one month post-dose 3

Antibody Synflorix 7-valent Prevenar Difference in % ≥ 0.20µg/ml (7-valent Prevenar minus Synflorix)

N % N % % 96.5% CI

Anti-4 1106 97.1 373 100 2.89 1.71 4.16

Anti-6B 1100 65.9 372 79.0 13.12 7.53 18.28

Anti-9V 1103 98.1 374 99.5 1.37 -0.28 2.56

Anti-14 1100 99.5 374 99.5 -0.08 -1.66 0.71

Anti-18C 1102 96.0 374 98.9 2.92 0.88 4.57

Anti-19F 1104 95.4 375 99.2 3.83 1.87 5.50

Anti-23F 1102 81.4 374 94.1 12.72 8.89 16.13

Post-primary antibody geometric mean concentrations (GMCs) elicited by Synflorix against the sevenserotypes in common were lower than those elicited by 7-valent Prevenar. Pre-booster GMCs (8 to 12months after the last primary dose) were generally similar for the two vaccines. After the booster dosethe GMCs elicited by Synflorix were lower for most serotypes in common with 7-valent Prevenar.

In the same study, Synflorix was shown to elicit functional antibodies to all vaccine serotypes. Foreach of the seven serotypes in common, 87.7% to 100% of Synflorix vaccinees and 92.1% to 100% of7-valent Prevenar vaccinees reached an OPA titre ≥ 8 one month after the third dose. The differencebetween both vaccines in terms of percentage of subjects with OPA titres ≥ 8 was <5% for allserotypes in common, including 6B and 23F. Post-primary and post-booster OPA antibody geometricmean titres (GMTs) elicited by Synflorix were lower than those elicited by 7-valent Prevenar for theseven shared serotypes, except for serotype 19F.

For serotypes 1, 5 and 7F, the percentages of Synflorix vaccinees reaching an OPA titre ≥ 8 wererespectively 65.7%, 90.9% and 99.6% after the primary vaccination course and 91.0%, 96.3% and100% after the booster dose. The OPA response for serotypes 1 and 5 was lower in magnitude than theresponse for each of the other serotypes. The implications of these findings for protective efficacy arenot known. The response to serotype 7F was in the same range as for the seven serotypes in commonbetween the two vaccines.

It has also been demonstrated that Synflorix induces an immune response to the cross-reactiveserotype 19A with 48.8% (95% CI: 42.9; 54.7) of vaccinees reaching an OPA titre ≥ 8 one month aftera booster dose.

The administration of a fourth dose (booster dose) in the second year of life elicited an anamnesticantibody response as measured by ELISA and OPA for the vaccine serotypes and the cross-reactiveserotype 19A demonstrating the induction of immune memory after the three-dose primary course.

Additional immunogenicity data

Infants from 6 weeks to 6 months of age:

3-dose primary schedule

In clinical studies the immunogenicity of Synflorix was evaluated after a 3-dose primary vaccinationseries (6941 subjects) according to different schedules (including 6-10-14 weeks, 2-3-4, 3-4-5 or 2-4-6months of age) and after a fourth (booster) dose (5645 subjects) given at least 6 months after the lastprimary dose and from the age of 9 months onwards. In general, comparable vaccine responses wereobserved for the different schedules, although somewhat higher immune responses were noted for the2-4-6 month schedule.

2-dose primary schedule

In clinical studies the immunogenicity of Synflorix was evaluated after a 2-dose primary vaccinationseries (470 subjects) according to different schedules (including 6-14 weeks, 2-4 or 3-5 months of age)and after a third (booster) dose (470 subjects) given at least 6 months after the last primary dose andfrom the age of 9 months onwards.

A clinical study evaluated the immunogenicity of Synflorix in 2-dose or 3-dose primed subjects infour European countries. Although there was no significant difference between the two groups in thepercentages of subjects with antibody concentration ≥ 0.20 µg/ml (ELISA), the percentages of subjectsfor serotypes 6B and 23F were lower than for the other vaccine serotypes (Table 7 and Table 8). Thepercentage of subjects with OPA titres ≥ 8 in 2-dose primed subjects compared to 3-dose primedsubjects were lower for serotypes 6B, 18C and 23F (74.4%, 82.8%, 86.3% respectively for the 2-doseschedule and 88.9%, 96.2%, 97.7% respectively for the 3-dose schedule). Overall, the persistence ofthe immune response until the booster at 11 months of age was lower in the 2-dose primed subjects. Inboth schedules, a booster response indicative of immunological priming was observed for eachvaccine serotype (Table 7 and Table 8). After the booster dose a lower percentage of subjects with

OPA titres ≥ 8 was observed in the 2-dose schedule for serotypes 5 (87.2% versus 97.5% for the 3-dose primed subjects) and 6B (81.1% versus 90.3%), all other responses were comparable.

Table 7: Percentage of 2-dose primed subjects with antibody concentrations ≥ 0.20 µg/ml onemonth post-primary and one month post-booster≥ 0.20 µg/ml (ELISA)

Antibody Post-primary Post-booster% 95% CI % 95% CI

Anti-1 97.4 93.4 99.3 99.4 96.5 100

Anti-4 98.0 94.4 99.6 100 97.6 100

Anti-5 96.1 91.6 98.5 100 97.6 100

Anti-6B 55.7 47.3 63.8 88.5 82.4 93.0

Anti-7F 96.7 92.5 98.9 100 97.7 100

Anti-9V 93.4 88.2 96.8 99.4 96.5 100

Anti-14 96.1 91.6 98.5 99.4 96.5 100

Anti-18C 96.1 91.6 98.5 100 97.7 100

Anti-19F 92.8 87.4 96.3 96.2 91.8 98.6

Anti-23F 69.3 61.3 76.5 96.1 91.7 98.6

Table 8: Percentage of 3-dose primed subjects with antibody concentrations ≥ 0.20 µg/ml onemonth post-primary and one month post-booster≥ 0.20 µg/ml (ELISA)

Antibody Post-primary Post-booster% 95% CI % 95% CI

Anti-1 98.7 95.3 99.8 100 97.5 100

Anti-4 99.3 96.4 100 100 97.5 100

Anti-5 100 97.6 100 100 97.5 100

Anti-6B 63.1 54.8 70.8 96.6 92.2 98.9

Anti-7F 99.3 96.4 100 100 97.5 100

Anti-9V 99.3 96.4 100 100 97.5 100

Anti-14 100 97.6 100 98.6 95.2 99.8

Anti-18C 99.3 96.4 100 99.3 96.3 100

Anti-19F 96.1 91.6 98.5 98.0 94.2 99.6

Anti-23F 77.6 70.2 84.0 95.9 91.3 98.5

For the cross-reactive serotype 19A, similar ELISA antibody GMCs were observed post-primary andpost-booster for the 2-dose schedule [0.14 µg/ml (95% CI: 0.12; 0.17) and 0.73 µg/ml (95% CI: 0.58;0.92)] and the 3-dose schedule [0.19 µg/ml (95% CI: 0.16; 0.24) and 0.87 µg/ml (95% CI: 0.69;1.11)]. The percentage of subjects with OPA titres ≥ 8 and GMTs observed post-primary and post-booster were lower in the 2-dose schedule than that in the 3-dose schedule. In both schedules, abooster response indicative of immunological priming was observed.

The clinical consequences of the lower post-primary and post-booster immune responses observedafter the 2-dose primary schedule are not known.

A clinical study conducted in South Africa assessed the immunogenicity of Synflorix after 3-dose (6-10-14 weeks of age) or 2-dose (6-14 weeks of age) priming followed by a booster dose at 9-10 monthsof age. After primary vaccination, for the vaccine serotypes the percentages of subjects reachingantibody threshold and with OPA titres ≥ 8 were similar after 2-dose compared to 3-dose except lower

OPA percentage for serotype 14. The antibody GMCs and OPA GMTs were lower after 2-dose formost vaccine serotypes.

For the cross-reactive serotype 19A, similar percentages of subjects reaching antibody threshold and

OPA titres ≥ 8 and similar antibody GMC and OPA GMT were observed post-primary in both groups.

Overall, the pre-booster persistence of immune responses was lower in the 2-dose compared to the3-dose priming group for most vaccine serotypes and was similar for serotype 19A.

Booster dose at 9-10 months of age

In the study conducted in South Africa, the booster dose given at 9-10 months of age induced markedincreases in antibody GMCs and OPA GMTs for each vaccine serotype and serotype 19A in both 2-dose and 3-dose priming groups indicative of immunological priming.

Booster dose at 9-12 versus 15-18 months of age

A clinical study conducted in India assessing a booster dose given at 9-12 or 15-18 months of age in66 and 71 children, respectively, following primary vaccination at 6, 10 and 14 weeks of age, did notsuggest differences between groups in terms of antibody GMCs. Higher OPA GMTs in the groupboosted at 15-18 months of age were observed for most of the vaccine serotypes and serotype 19A.

However, the clinical relevance of this observation is not known.

Immune memory

In the follow-up of the European study evaluating the 2-dose and 3-dose primary vaccinationschedules, the persistence of antibodies at 36-46 months of age was demonstrated in subjects that hadreceived a 2-dose primary series followed by a booster dose with at least 83.7% of subjects remainingseropositive for vaccine serotypes and the cross-reactive serotype 19A. In subjects that had received a3-dose primary series followed by a booster dose, at least 96.5% of the subjects remained seropositivefor vaccine serotypes and 86.4% for serotype 19A. After a single dose of Synflorix, administeredduring the 4th year of life, as a challenge dose, the fold increase in ELISA antibody GMCs and OPA

GMTs, pre to post vaccination, was similar in 2-dose primed subjects to that in 3-dose primedsubjects. These results are indicative of immunological memory in primed subjects for all vaccineserotypes and the cross-reactive serotype 19A.

Unvaccinated infants and children ≥ 7 months of age:

The immune responses elicited by Synflorix in previously unvaccinated older children were evaluatedin three clinical studies.

The first clinical study evaluated the immune responses for vaccine serotypes and the cross-reactiveserotype 19A in children aged 7-11 months, 12-23 months and 2 to 5 years:

* Children aged 7-11 months received 2 primary doses followed by a booster dose in thesecond year of life. The immune responses after the booster dose in this age group weregenerally similar to those observed after the booster dose in infants who had been primedwith 3 doses below 6 months of age.

* In children aged 12-23 months, the immune responses elicited after two doses werecomparable to the responses elicited after three doses in infants below 6 months of age,except for vaccine serotypes 18C and 19F as well as serotype 19A for which responseswere higher in the 12-23 months children.

* In children aged 2 to 5 years that received 1 dose, the ELISA antibody GMCs were similarfor 6 vaccine serotypes as well as serotype 19A than those achieved following a 3-dosevaccination schedule in infants below 6 months of age while they were lower for4 vaccine serotypes (serotypes 1, 5, 14 and 23F). The OPA GMTs were similar or higherfollowing a single dose than a 3-dose primary course in infants below 6 months of age,except for serotype 5.

In the second clinical study, a single dose administered four months after two catch-up doses at 12-20months of age elicited a marked increase of ELISA GMCs and OPA GMTs (when comparing theresponses pre and post the last dose), indicating that two catch-up doses provide adequate priming.

The third clinical study showed that the administration of 2 doses with a 2 month interval starting at36-46 months of age resulted in higher ELISA antibody GMCs and OPA GMTs than those observedone month after a 3-dose primary vaccination for each vaccine serotype and the cross-reactiveserotype 19A. The proportion of subjects with an ELISA antibody concentration ≥ 0.20 µg/ml or an

OPA titre ≥ 8 for each vaccine serotype was comparable or higher in the catch-up group than in the 3-dose primed infants.

Long-term persistence of antibodies has not been investigated after administration of a primary seriesin infants plus booster or after a 2-dose priming in older children.

In a clinical study, it has been demonstrated that Synflorix can be safely administered as a boosterdose in the second year of life to children who had received 3 primary doses of 7-valent Prevenar. Thisstudy has shown that the immune responses against the 7 common serotypes were comparable to thoseelicited by a booster dose of 7-valent Prevenar. However, children who received 7-valent Prevenar forthe primary series would not be primed against the additional serotypes contained in Synflorix (1, 5,7F). Therefore the degree and duration of protection against invasive pneumococcal disease and otitismedia due to these three serotypes in children of this age group following a single dose of Synflorixcannot be predicted.

Immunogenicity data in preterm infants

Immunogenicity of Synflorix in very preterm (gestation period of 27-30 weeks) (N=42), preterm(gestation period of 31-36 weeks) (N=82) and full term (gestation period > 36 weeks) (N=132) infantswas evaluated following a 3-dose primary vaccination course at 2, 4, 6 months of age.

Immunogenicity following a fourth dose (booster dose) at 15 to 18 months of age was evaluated in44 very preterm, 69 preterm and 127 full term infants.

One month after primary vaccination (i.e. after the third dose), for each vaccine serotype at least92.7% of subjects achieved ELISA antibody concentrations ≥ 0.20 µg/ml and at least 81.7% achieved

OPA titres ≥ 8 except serotype 1 (at least 58.8% with OPA titres ≥ 8). Similar antibody GMCs and

OPA GMTs were observed for all infants except lower antibody GMCs for serotypes 4, 5, 9V and thecross-reactive serotype 19A in very preterms and serotype 9V in preterms and lower OPA GMT forserotype 5 in very preterms. The clinical relevance of these differences is not known.

One month after the booster dose increases of ELISA antibody GMCs and OPA GMTs were seen foreach vaccine serotype and the cross-reactive serotype 19A, indicative of immunological memory.

Similar antibody GMCs and OPA GMTs were observed for all infants except a lower OPA GMT forserotype 5 in very preterm infants. Overall, for each vaccine serotype at least 97.6% of subjectsachieved ELISA antibody concentrations ≥ 0.20 µg/ml and at least 91.9% achieved OPA titres ≥ 8.

Immunogenicity in special population

HIV positive (HIV+/+) infants and HIV negative infants born from HIV positive mothers (HIV+/-)

In a clinical study conducted in South Africa the immunogenicity of Synflorix administered as a3-dose primary vaccination course (at 6, 10 and 14 weeks of age) followed by a booster dose (at 9 to10 months of age) was assessed in 70 HIV positive (HIV+/+) infants, 91 HIV negative infants bornfrom HIV positive mothers (HIV+/-) and 93 HIV negative infants born from HIV negative mothers(HIV-/-). Only HIV+/+ infants with WHO classification stage 1 (asymptomatic) or 2 (mild symptoms)were to be enrolled.

For most vaccine serotypes, group comparisons did not suggest any differences in post-primaryimmune responses between the HIV+/+ and HIV-/- groups, or the HIV+/- and HIV-/- groups, exceptfor a trend towards a lower percentage of subjects reaching OPA titres ≥ 8 and lower OPA GMTs inthe HIV+/+ group. The clinical relevance of this lower post-primary OPA response is not known. Forthe cross-reactive serotype 19A, the results did not suggest any differences in ELISA antibody GMCsand OPA GMTs between groups.

The booster dose of Synflorix in HIV+/+ and HIV+/- infants induced robust increases in ELISAantibody GMCs and OPA GMTs for each vaccine serotype and serotype 19A indicative ofimmunological priming. For most vaccine serotypes and serotype 19A, group comparisons did notsuggest any differences post-booster dose in ELISA antibody GMCs and OPA GMTs between the

HIV+/+ and HIV-/- groups, or the HIV+/- and HIV-/- groups.

The results for protein D suggested comparable post-primary and post-booster immune responsesbetween groups.

In each group, persistence of the immune responses was observed at 24-27 months of age, i.e. up to 15months following booster vaccination.

Children with sickle cell disease

A clinical study conducted in Burkina Faso assessed the immunogenicity of Synflorix administered to146 children with SCD (haemoglobin SS disease, haemoglobin SC disease or with β-thalassemia)compared to 143 age-matched children without SCD. Among children with SCD, 48 children<6 months of age received primary vaccination at 8, 12 and 16 weeks of age, followed by a boosterdose at 9-10 months of age, 50 children aged 7-11 months and 48 aged 12-23 months startedcatch-up vaccination according to their age. The immune response to Synflorix for each of the vaccineserotypes and serotype 19A, as well as for protein D, did not appear to be influenced by SCD.

Children with splenic dysfunction

Immunogenicity and safety of Synflorix were assessed in a limited number of primed or unprimedsubjects with congenital or acquired asplenia, splenic dysfunction or complement deficiencies:6 subjects 2-5 years of age and 40 subjects 6-17 years of age (Synflorix is indicated up to 5 years ofage). Synflorix was shown to be immunogenic and no new safety concerns were observed in thisstudy.

Immunogenicity of Synflorix containing the preservative 2-phenoxyethanol (2-PE)

Immunogenicity of Synflorix containing the preservative 2-PE (presented in a 4-dose container) wasassessed in healthy infants vaccinated at 6, 10 and 18 weeks of age and compared to those receiving

Synflorix without added preservative (160 enrolled subjects per group).

Immune responses were compared using non-inferiority criteria in terms of antibody GMC ratio(GMC from group of subjects receiving Synflorix without 2-PE over GMC from group of subjectsreceiving Synflorix with 2-PE) for each of the 10 vaccine serotypes and for the cross-reactive serotype19A.

Non-inferiority was demonstrated as the upper limit of the 2-sided 95% CI of the antibody GMC ratioswas below 2 for each of the 10 vaccine serotypes and for serotype 19A. In addition, OPA GMTs werein same ranges for both groups.

Use of Synflorix and 13-valent PCV in the immunisation course of an individual

The use of Synflorix and PCV13 in the immunisation course of an individual (interchangeability) wasassessed in a clinical study conducted in Mexico. Infants were primed with 2 doses of PCV13 (86subjects) or 1 dose of PCV13 and 1 dose of Synflorix (89 subjects), followed by a booster dose of

Synflorix at 12-15 months of age, and compared to infants administered with a 2+1 Synflorixvaccination schedule.

For most of the 10 common serotypes 1 month post-priming and post-booster, observed percentages ofinfants reaching antibody concentrations ≥ 0.2 µg/mL and OPA titers above cutoffs were high forinfants receiving both Synflorix and PCV13: ≥ 97.7% for 8 out of 10 serotypes for antibodyconcentrations ≥ 0.2 µg/mL and ≥ 92.0% for 7 out of 10 serotypes for OPA titers above cutoffs.

For cross-reactive serotype 19A, these percentages were at least 86.5% and 88.0%, respectively.

No safety concern was identified when the vaccine was changed from PCV13 to Synflorix at the timeof priming or boosting.

Not applicable.

Studies with an 11-valent vaccine formulation representative for Synflorix revealed no special hazardfor humans based on conventional studies of safety pharmacology, single and repeated dose toxicity.

1-dose and 2-dose containers

Sodium chloride

Water for injections4-dose container

Sodium chloride2-phenoxyethanol

Water for injections

For adsorbent, see section 2.

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

1-dose and 2-dose containers4 years4-dose container3 years

After first opening of multidose vial:

2-dose vial

After first opening of the 2-dose vial, immediate use is recommended. If not used immediately, thevaccine should be stored in a refrigerator (2 °C - 8 °C). If not used within 6 hours it should bediscarded.

4-dose vial

After first opening of the 4-dose vial, the vaccine may be stored for a maximum of 28 days in arefrigerator (2 °C - 8 °C). If not used within 28 days it should be discarded.

Store in a refrigerator (2 °C - 8 °C).

Do not freeze.

Store in the original package in order to protect from light.

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

Pre-filled syringe0.5 ml of suspension in a pre-filled syringe (type I glass) with a plunger stopper (butyl rubber) andwith a rubber tip cap.

Pack sizes of 1, 10 and 50, with or without needles.

Vial0.5 ml of suspension in a vial (type I glass) for 1 dose with a stopper (butyl rubber).

Pack sizes of 1, 10 and 100.

Multidose vial1 ml of suspension in a vial (type I glass) for 2 doses with a stopper (butyl rubber).

Pack size of 100.2 ml of suspension in a vial (type I glass) for 4 doses with a stopper (butyl rubber).

Pack sizes of 10 and 100.

The tip cap and rubber plunger stopper of the pre-filled syringe and the stopper of the vial are madewith synthetic rubber.

Not all pack sizes may be marketed.

A fine white deposit with a clear colourless supernatant may be observed upon storage of the pre-filledsyringe. This does not constitute a sign of deterioration.

The content of the pre-filled syringe should be inspected visually both before and after shaking for anyforeign particulate matter and/or abnormal physical appearance prior to administration. In the event ofeither being observed, discard the vaccine.

The vaccine should be allowed to reach room temperature before use.

The vaccine should be well shaken before use.

Instructions for the pre-filled syringe

Luer Lock Adaptor

Hold the syringe by the barrel, not by theplunger.

Plunger Unscrew the syringe cap by twisting it

Barrel anticlockwise.

Cap

Needle hub

To attach the needle, connect the hub to the

Luer Lock Adaptor and rotate a quarter turnclockwise until you feel it lock.

Do not pull the syringe plunger out of thebarrel. If it happens, do not administer thevaccine.

Vial

A fine white deposit with a clear colourless supernatant may be observed upon storage of the vial. Thisdoes not constitute a sign of deterioration.

The content of the vial should be inspected visually both before and after shaking for any foreignparticulate matter and/or abnormal physical appearance prior to administration. In the event of eitherbeing observed, discard the vaccine.

The vaccine should be allowed to reach room temperature before use.

The vaccine should be well shaken before use.

A fine white deposit with a clear colourless supernatant may be observed upon storage of the vial. Thisdoes not constitute a sign of deterioration.

The content of the vial should be inspected visually both before and after shaking for any foreignparticulate matter and/or abnormal physical appearance prior to administration. In the event of eitherbeing observed, discard the vaccine.

The vaccine should be allowed to reach room temperature before use.

The vaccine should be well shaken before use.

When using a multidose vial, each 0.5 ml dose should be withdrawn using a sterile needle and syringe;precautions should be taken to avoid contamination of the contents.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

GlaxoSmithKline Biologicals S.A.

Rue de l’Institut 89

B-1330 Rixensart, Belgium

EU/1/09/508/001

EU/1/09/508/002

EU/1/09/508/003

EU/1/09/508/004

EU/1/09/508/005

EU/1/09/508/010

Vial

EU/1/09/508/006

EU/1/09/508/007

EU/1/09/508/008

Multidose vial2-dose vial

EU/1/09/508/0094-dose vial

EU/1/09/508/012

EU/1/09/508/013

Date of first authorisation: 30 March 2009

Date of latest renewal: 22 November 2018

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

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