MENVEO powder + solvent for injection medication leaflet

Menveo powder and solution for solution for injection

Meningococcal Group A, C, W-135 and Y conjugate vaccine

One dose (0.5 mL of the reconstituted vaccine) contains:

(Originally contained in the powder)

* Meningococcal group A oligosaccharide 10 micrograms

Conjugated to Corynebacterium diphtheriae CRM197 protein 16.7 to 33.3 micrograms(Originally contained in the solution)

* Meningococcal group C oligosaccharide 5 micrograms

Conjugated to Corynebacterium diphtheriae CRM197 protein 7.1 to 12.5 micrograms

* Meningococcal group W-135 oligosaccharide 5 micrograms

Conjugated to Corynebacterium diphtheriae CRM197 protein 3.3 to 8.3 micrograms

* Meningococcal group Y oligosaccharide 5 micrograms

Conjugated to Corynebacterium diphtheriae CRM197 protein 5.6 to 10.0 micrograms

For the full list of excipients, see section 6.1.

Powder and solution for solution for injection (powder and solution for injection).

The powder is a white to off- white cake.

The solution is a colourless clear solution.

Menveo is indicated for active immunization of children (from 2 years of age), adolescents and adultsat risk of exposure to Neisseria meningitidis groups A, C, W-135 and Y, to prevent invasive disease.

The use of this vaccine should be in accordance with official recommendations.

Children (from 2 years of age), adolescents and adults

Menveo should be administered as a single dose (0.5 mL).

To ensure optimal antibody levels against all vaccine serogroups, the primary vaccination schedulewith Menveo should be completed one month prior to risk of exposure to Neisseria meningitidisgroups A, C, W-135 and Y. Bactericidal antibodies (hSBA≥1:8) were observed in at least 64% ofsubjects at 1 week post vaccination (see section 5.1 for immunogenicity data per individualserogroups).

Older people

There are limited data in individuals aged 56-65 and there are no data in individuals aged >65 years.

Booster vaccination

Long-term antibody persistence data following vaccination with Menveo are available up to 5 yearsafter vaccination (see section 4.4 and 5.1).

Menveo may be given as a booster dose in subjects who have previously received primary vaccinationwith Menveo, other conjugated meningococcal vaccine or meningococcal unconjugatedpolysaccharide vaccine. The need for and timing of a booster dose in subjects previously vaccinatedwith Menveo is to be defined based on national recommendations.

Paediatric population (under 2 years of age)

The safety and efficacy of Menveo in children under 2 years of age has not yet been established.

Currently available data are described in section 5.1 but no recommendation on a posology canbe made.

Menveo is given as an intramuscular injection, preferably into the deltoid muscle.

It must not be administered intravascularly, subcutaneously or intradermally.

Separate injection sites must be used if more than one vaccine is being administered at the same time.

For instructions on preparation and reconstitution of the medicinal product before administration,see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1, or diphtheriatoxoid (CRM197), or a life-threatening reaction after previous administration of a vaccine containingsimilar components (see section 4.4).

As with other vaccines, Menveo should be postponed in individuals suffering from an acute severefebrile illness. The presence of a minor infection is not a contraindication.

Before the injection of any vaccine, the person responsible for administration must take all precautionsknown for the prevention of allergic or any other reactions including thorough medical history andcurrent health status. As with all injectable vaccines, appropriate medical treatment and supervisionmust always be readily available in case of a rare anaphylactic event following administration of thevaccine.

Anxiety‐related reactions, including vasovagal reactions (syncope), hyperventilation or stress‐relatedreactions may occur in association with vaccination as a psychogenic response to the needle injection(see section 4.8 Undesirable effects). It is important that procedures are in place to avoid injury fromfainting.

Menveo should under no circumstances be administered intravascularly.

Menveo will not protect against infections caused by any other serogroups of N. meningitidis notpresent in the vaccine.

As with any vaccine, a protective immune response may not be elicited in all vaccinees(see section 5.1).

Studies with Menveo have shown a waning of serum bactericidal antibody titers against serogroup Awhen using human complement in the assay (hSBA) (see section 5.1). The clinical relevance of thewaning of hSBA serogroup A antibody titers is unknown. If an individual is expected to be atparticular risk of exposure to Men A and received a dose of Menveo more than approximately oneyear previously, consideration may be given to administering a booster dose.

There are no data on the applicability of the vaccine for post-exposure prophylaxis.

In immunocompromised individuals, vaccination may not result in an appropriate protective antibodyresponse. While Human Immunodeficiency Virus (HIV) infection is not a contraindication, Menveohas not been specifically evaluated in immunocompromised people. Individuals with complementdeficiencies and individuals with functional or anatomical asplenia may not mount an immuneresponse to meningococcal group A, C, W-135 and Y conjugate vaccines.

Individuals with familial complement deficiencies (for example, C3 or C5 deficiencies) andindividuals receiving treatments that inhibit terminal complement activation (for example,eculizumab) are at increased risk for invasive disease caused by Neisseria meningitidis group A, C,

W-135 and Y, even if they develop antibodies following vaccination with Menveo.

Menveo has not been evaluated in persons with thrombocytopenia, bleeding disorders or that arereceiving anticoagulant therapy, because of the risk of haematoma. The risk-benefit ratio for personsat risk of haematoma following intramuscular injection must be evaluated by health care professionals.

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

This medicinal product contains less than 1 mmol potassium (39 mg) per dose, that is to sayessentially ‘potassium-free’.

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

Menveo can be given concomitantly with any of the following vaccines: monovalent and combinedhepatitis A and B, yellow fever, typhoid fever (Vi polysaccharide), Japanese encephalitis, rabies andmeningococcal group B (Bexsero).

In adolescents (11 to 18 years of age), Menveo has been evaluated in two co-administration studieswith either Tetanus, Reduced Diphtheria and Acellular Pertussis Vaccine, Adsorbed (Tdap) alone or

Tdap and Human Papillomavirus Quadrivalent (Types 6, 11, 16 and 18) Vaccine, Recombinant(HPV), both of which support the co-administration of the vaccines.

There was no evidence of an increased rate of reactogenicity or change in the safety profile of thevaccines in either study. Antibody responses to Menveo and the diphtheria, tetanus or HPV vaccinecomponents were not negatively affected by co-administration.

The administration of Menveo one month after Tdap resulted in statistically significantly lowerserogroup W-135 seroresponses. Since there was no direct impact on the seroprotection rate,the clinical consequences are presently unknown. There was evidence of some suppression of antibodyresponse to two of the three pertussis antigens. The clinical relevance of this observation is unknown.

After vaccination, over 97% of subjects had detectable pertussis titers to all three pertussis antigens.

For children 2 to 10 years of age, no data are available for evaluating safety and immunogenicityof other childhood vaccines when administered concomitantly with Menveo.

Concomitant administration of Menveo and other vaccines than those listed above has not beenstudied. Concomitant vaccines should always be administered at separate injection sites and preferablycontralateral. It should be checked if the adverse reactions may be intensified by anyco-administration.

If a vaccine recipient is undergoing immunosuppressant treatment, the immunological response maybe diminished.

Insufficient clinical data on exposed pregnancies are available.

In non-clinical studies, Menveo had no direct or indirect harmful effects with respect to pregnancy,embryonal/foetal development, parturition or postnatal development. Considering the severity ofinvasive meningococcal disease caused by Neisseria meningitidis serogroups A, C, W-135 and Y,pregnancy should not preclude vaccination when the risk of exposure is clearly defined.

Although insufficient clinical data on the use of Menveo during breast-feeding are available, it isunlikely that secreted antibodies in milk would be harmful when ingested by a breastfed infant.

Therefore, Menveo may be used during breast feeding.

No studies on the effects on the ability to drive and use machines have been performed. Dizziness hasbeen very rarely reported following vaccination. This may temporarily affect the ability to drive or usemachines.

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

Frequencies are defined as follows:

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)

Not known (cannot be estimated from the available data)

Adverse reactions from clinical trials

Children 2 to 10 years of age

Overall 3464 subjects aged 2 to10 years were exposed to Menveo in completed clinical trials. Thecharacterization of the safety profile of Menveo in children 2 to 10 years of age is based on data fromfour clinical trials in which 3181 subjects received Menveo.

The most common adverse reactions during the clinical trials generally persisted for one to two daysand were not severe. These adverse reactions were:

Common: eating disorder

Very common: sleepiness, headache

Common: nausea, vomiting, diarrhea

Common: rash

Common: myalgia, arthralgia

Very common: irritability, malaise, injection site pain, injection site erythema (≤50 mm), injection siteinduration (≤50 mm)

Common: injection site erythema (>50mm), injection site induration (>50mm), chills, fever ≥38oC

Uncommon: injection site pruritus

Individuals 11 to 65 years of age

The characterization of the safety profile of Menveo in adolescents and adults is based on data fromfive randomised controlled clinical trials including 6401 participants (from 11-65 years of age) whoreceived Menveo. Among Menveo recipients, 58.9%, 16.4%, 21.3% and 3.4% were in the 11-18 year,19-34 year, 35-55 year and 56-65 year age groups, respectively. The two primary safety studies wererandomised, active-controlled trials that enrolled participants aged 11 to 55 years (N=2663)and 19 to 55 years (N=1606), respectively.

The incidence and severity of any, local, systemic, and other reactions were generally similar in the

Menveo groups across all studies and within the adolescent and adult age groups. The reactogenicityprofile and rates of adverse events among subjects aged 56-65 years who received Menveo (N=216),were similar to that observed in Menveo recipient subjects aged 11-55.

The most common local and systemic adverse reactions observed in clinical trials were pain at theinjection site and headache.

The list provided below presents adverse reactions reported in three pivotal and two supportive clinicaltrials per system organ class. The most common side effects reported during clinical trials usuallylasted only one to two days and were not usually severe.

Very common: headache

Uncommon: dizziness

Very common: nausea

Common: rash

Very common: myalgia

Common: arthralgia

Very common: injection site pain, injection site erythema (≤50 mm), injection site induration(≤50 mm), malaise

Common: injection site erythema (>50 mm), injection site induration (>50 mm), fever ≥38°C, chills

Uncommon: injection site pruritus

In the adolescent age group, the safety and tolerability of the vaccine was favourable relative to Tdapand did not substantially change with concomitant or sequential administration of other vaccines.

Post-marketing experience (all age groups)

Rare: lymphadenopathy

Not known: hypersensitivity including anaphylaxis

Not known: tonic convulsion, febrile convulsion, syncope

Ear and labyrinth disorders

Not known: vertigo

Not known: injection site cellulitis, injection site swelling, including extensive swelling of the injectedlimb

Reporting suspected adverse reactions after authorisation of the medicinal product is important.

It allows 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: Meningococcal vaccines, ATC code: J07AH08.

The efficacy of Menveo has been inferred by measuring the production of serogroup-specificanti-capsular antibodies with bactericidal activity. Serum bactericidal activity (SBA) was measuredusing human serum as the source of exogenous complement (hSBA). The hSBA was the originalcorrelate of protection against meningococcal disease.

Immunogenicity was evaluated in randomised, multicenter, active controlled clinical trials thatenrolled children (2-10 years of age), adolescents (11-18 years of age), adults (19-55 years of age)and older adults (56-65 years of age).

Immunogenicity in children 2 to 10 years of age

In the pivotal study V59P20 immunogenicity of Menveo was compared to ACWY-D; 1170 childrenwere vaccinated with Menveo and 1161 received the comparator vaccine in the per protocolpopulations. In two supportive studies V59P8 and V59P10 immunogenicity of Menveo was comparedto ACWY-PS.

In the pivotal, randomised, observer-blind study V59P20, in which participants were stratified by age(2 through 5 years and 6 through 10 years), the immunogenicity of a single dose of Menveo one monthpost vaccination was compared with the single dose of ACWY-D. Immunogenicity results one monthafter Menveo vaccination among subjects aged 2-5 years and 6-10 years are summarized belowin Table 1

Table 1: Serum bactericidal antibody responses following Menveo one month aftervaccination among subjects aged 2-5 years and 6-10 years2-5 years 6-10 years

Serogroup hSBA ≥1:8 hSBA GMTs hSBA ≥1:8 hSBA GMTs(95% CI) (95% CI) (95% CI) (95% CI)

A N=606 N=606 N=551 N=55172% 26 77% 35(68, 75) (22, 30) (74, 81) (29, 42)

C N=607 N=607 N=554 N=55468% 18 77% 36(64, 72) (15, 20) (73, 80) (29, 45)

W-135 N=594 N=594 N=542 N=54290% 43 91% 61(87, 92) (38, 50) (88, 93) (52, 72)

Y N=593 N=593 N=545 N=54576% 24 79% 34(72, 79) (20, 28) (76, 83) (28, 41)

In another randomised, observer-blind study (V59P8) US children were immunized with a single doseof either Menveo (N=284) or ACWY-PS (N=285). In the children 2-10 years of age, as well as in eachage strata (2-5 and 6-10 years), immune response as measured by percentage of subjects withseroresponse, hSBA≥1:8 and GMTs were not only non-inferior to comparator vaccine ACWY-PS,but all were statistically higher than the comparator for all serogroups and all immune measurementsat 1 month post vaccination. At 1 year post vaccination, Menveo continued to be statistically higherthan ACWY-PS for serogroups A, W-135 and Y, as measured by percentage of subjects withhSBA≥1:8 and GMTs. Menveo was non-inferior on these endpoints for serogroup C (Table 2).

The clinical relevance of higher post-vaccination immune responses is not known.

Table 2: Immunogenicity of one dose of Menveo or ACWY-PS in subjects 2 through 10 yearsof age, measured at one month and twelve months post-vaccination1 month post-vaccination 12 months post-vaccination

Sero hSBA ≥1:8 hSBA GMTs hSBA ≥1:8 hSBA GMTsgrou (95% CI) (95% CI) (95% CI) (95% CI)p ACWY- ACWY-P ACWY-

Menveo Menveo Menveo Menveo ACWY-PS

PS S PS

A N=280 N=281 N=280 N=281 N=253 N=238 N=253 N=2386.31 3.8879% 37% 36 23% 13% 3(5.21, 7.6 (3.39, pct. 4.4(74, 84) (31, 43) (30, 44) (18, 29) (9, 18) (2.61, 3.44)4) 4)

C N=281 N=283 N=281 N=283 N=252 N=240 N=252 N=24073% 54% 26 15 53% 44% 11 9.02(68, 78) (48, 60) (21, 34) (12, 20) (47, 59) (38, 51) (8.64, 13) (7.23, 11)

W-

N=279 N=282 N=279 N=282 N=249 N=237 N=249 N=23792% 66% 60 14 90% 45% 42 7.57(88, 95) (60, 71) (50, 71) (12, 17) (86, 94) (38, 51) (35, 50) (6.33, 9.07)

Y N=280 N=282 N=280 N=282 N=250 N=239 N=250 N=23988% 53% 54 11 77% 32% 27 5.29(83, 91) (47, 59) (44, 66) (9.29, 14) (71, 82) (26, 38) (22, 33) (4.34, 6.45)

In a randomised, observer-blind study (V59P10) conducted in Argentina, children wereimmunized with a single dose of either Menveo (N=949) or ACWY-PS (N=551). Immunogenicitywas assessed in a subset of 150 subjects in each vaccine group. The immune response observed inthe children 2-10 years of age was very similar to those observed in the V59P8 study shown above:

immune response to Menveo at 1 month post vaccination, as measured by percentage of subjectswith seroresponse, hSBA≥1:8 and GMTs, was non-inferior to ACWY-PS.

A randomised, observer-blind study was conducted in children 12 to 59 months of age in Finlandand Poland (V59P7). A total of 199 subjects 2-5 years of age were in the Menveo per protocolimmunogenicity population and 81 subjects 3-5 years of age were in the ACWY-PS group.

At 1 month post-first vaccination, the percentages of subjects with hSBA ≥ 1:8 were consistentlyhigher in the Menveo group for all four serogroups (63% vs 39%, 46% vs 39%, 78% vs 59%, and 65%vs 57% for Menveo as compared to ACWY-PS for serogroups A, C, W-135, and Y, respectively).

In a randomized, observer-blind study (V59_57) conducted in US, immunogenicity of a 2-dose seriesand a single dose of Menveo was compared in children 2 through 5 and 6 through 10 years of age(N=715).

At baseline, the percentage of subjects with hSBA ≥1:8 across the two age strata was 1%-5% forserogroup A, 13%-28% for serogroup C, 42%-64% for serogroup W-135, and 6%-19% for serogroup

Y. At 1 month post last vaccination, the percentages of subjects with hSBA ≥1:8 in the 2-dose groupand in the single dose group across the two age strata were: 90%-95% vs 76%-80% for serogroup A,98%-99% vs 76%-87% for serogroup C, 99% vs 93%-96% for serogroup W-135, and 96% vs 65%-69% for serogroup Y. GMTs were higher in the 2-dose group than the single dose group at 1 monthafter vaccination in both age strata; however, this difference was less pronounced in the older agestratum.

At 1 year post last vaccination, the percentages of subjects with hSBA ≥1:8 after the 2-dose series andthe single dose were both lower than at 1 month post-vaccination (30% after the 2-dose series, 11%-20% after the single dose for serogroup A; 61%-81% and 41%-55% for serogroup C; 92%-94% and90%-91% for serogroup W-135; 67%-75% and 57%-65% for serogroup Y). The differences betweenhSBA GMTs in the 2-dose and the single dose groups at 1 year after vaccination were lower thanthose seen at 1 month post-vaccination.

The clinical benefit of a 2-dose vaccination series in children 2 through 10 years of age is not known.

Persistence of immune response and booster response in children 2 to 10 years of age

Antibody persistence at 5 years after primary vaccination was assessed in study V59P20E1, this wasan extension of study V59P20. There was antibody persistence observed against serogroups C, W-135and Y, with the percentages of subjects with hSBA ≥ 1:8 being 32% and 56% against serogroup C insubjects 2-5 and 6-10 years of age, respectively, 74% and 80% against serogroup W-135, and 48% and53% against serogroup Y. GMTs were respectively 6.5 and 12 for serogroup C, 19 and 26 forserogroup W-135, and 8.13 and 10 for serogroup Y. For serogroup A, 14% and 22% of subjects 2-5and 6-10 years of age, respectively, had hSBA ≥ 1:8 (GMTs 2.95 and 3.73).

The children also received a booster dose of Menveo, 5 years after a single dose primary vaccination.

All subjects in both age groups had hSBA ≥ 1:8 across all serogroups, with antibody titers several foldhigher than seen after the primary vaccination (Table 3).

Table 3: Persistence of immune responses 5 years after primary vaccination with Menveo, andimmune responses 1 month after a booster dose among subjects aged 2 - 5 years and 6 -10 yearsat the time of primary vaccination

Serogr2-5 years 6-10 yearsoup1 month after 1 month after5 year persistence 5 year persistencebooster boosterhSBA hSBA hSBA hSBA hSBA hSBA hSBA hSBA≥1:8 GMTs ≥1:8 GMTs ≥1:8 GMTs ≥1:8 GMTs(95% (95% (95% (95% (95% (95% (95% (95%

CI) CI) CI) CI) CI) CI) CI) CI)

A N=96 N=96 N=95 N=95 N=64 N=64 N=60 N=602.95 100% 361 3.73 100% 35014% 22%(2.42, (96, (299, (2.74, (94, (265,(7, 22) (13, 34)3.61) 100) 436) 5.06) 100) 463)

C N=96 N=96 N=94 N=94 N=64 N=64 N=60 N=606.5 100% 498 12 100% 71232% 56%(4.75, (96, (406, (7.72, (94, (490,(23, 43) (43, 69)8.9) 100) 610) 19) 100) 1036)

W-135 N=96 N=96 N=95 N=95 N=64 N=64 N=60 N=60100% 1534 100% 155674% 19 80% 26(96, (1255, (94, (1083,(64, 82) (14, 25) (68, 89) (18, 38)100) 1873) 100) 2237)

Y N=96 N=96 N=94 N=94 N=64 N=64 N=59 N=598.13 100% 1693 10 100% 144248% 53%(6.11, (96, (1360, (6.51, (94, (1050,(38, 58) (40, 66)11) 100) 2107) 16) 100) 1979)

Immunogenicity in individuals 11 years of age and above

In the pivotal study (V59P13), adolescents or adults received either a dose of Menveo (N = 2649)comparator vaccine ACWY-D (N = 875). Sera were obtained both before vaccination and 1 monthafter vaccination.

In another study (V59P6) conducted in 524 adolescents, the immunogenicity of Menveo wascompared to that of ACWY-PS.

Immunogenicity in adolescents

In the 11-18 year old population of the pivotal study, V59P13, the immunogenicity of a single dose of

Menveo one month post vaccination is compared with the ACWY-D. Immunogenicity results at onemonth after Menveo are summarized below in Table 4.

Table 4: Serum bactericidal antibody responses following Menveo one month aftervaccination among subjects aged 11-18 years

GMT hSBA ≥ 1:8

Serogroup N(95% CI) (95% CI)

A 1075 29 (24, 35) 75% (73, 78)

C 1396 50 (39, 65) 85% (83, 87)

W-135 1024 87 (74, 102) 96% (95, 97)

Y 1036 51 (42, 61) 88% (85, 90)

In the subset of subjects aged 11-18 years who were seronegative at baseline (hSBA < 1:4),the proportion of subjects who achieved a hSBA ≥ 1:8 after a dose of Menveo were as follows:

serogroup A 75% (780/1039); serogroup C 80% (735/923); serogroup W-135 94% (570/609);serogroup Y 81% (510/630).

In the non-inferiority study, V59P6, immunogenicity was assessed among adolescentsaged 11-17 years who had been randomised to receive either Menveo or ACWY-PS. Menveo wasshown to be non-inferior to ACWY-PS vaccine for all four serogroups (A, C, W-135 and Y) based onseroresponse, proportions achieving hSBA ≥1:8, and GMTs.

Table 5: Immunogenicity of one dose of Menveo or ACWY-PS in adolescents, measured atone month post vaccinationhSBA ≥1:8 hSBA GMTs

Serogroup (95% CI) (95% CI)

Menveo ACWY-PS Menveo ACWY-PS

A N=140 N=149 N=140 N=14981% 41% 33 7.31(74, 87) (33, 49) (25, 44) (5.64, 9.47)

C N=140 N=147 N=140 N=14784% 61% 59 28(77, 90) (53, 69) (39, 89) (19, 41)

W-135 N=138 N=141 N=138 N=14191% 84% 48 28(84, 95) (77, 89) (37, 62) (22, 36)

Y N=139 N=147 N=139 N=14795% 82% 92 35(90, 98) (75, 88) (68, 124) (27, 47)

At one year post vaccination in these same subjects, compared with ACWY-PS, a higher proportion ofsubjects vaccinated with Menveo had hSBA ≥1:8 for serogroups C, W-135, and Y, with comparablelevels for serogroup A. Similar findings were observed in the comparison of hSBA GMTs.

Persistence of immune response and booster response in adolescents

In study V59P13E1, the persistence of immune responses against serogroups A, C, W-135 and Y wasassessed at 21 months, 3 years and 5 years post primary vaccination among subjects aged 11-18 yearsat the time of vaccination. The percentages of subjects with hSBA ≥ 1:8 remained constant againstserogroups C, W-135, and Y from 21 months to 5 years postvaccination in the Menveo group anddecreased slightly over time against serogroup A (Table 6). At 5 years after primary vaccination, therewere significantly higher percentages of subjects with hSBA ≥ 1:8 in the Menveo group than in thevaccine-naive control subjects against all the four serogroups.

Table 6: Persistence of immune responses approximately 21 months, 3 years and 5 yearsafter vaccination with Menveo (subjects were aged 11-18 years at the time of vaccination)

Percentages of subjects withhSBA GMTs

Serogroup Timepoint hSBA≥1:8

Menveo Menveo

N=100 N=10045 6.57 (4.77-9.05)21 months(35, 55)

A 38 5.63 (3.97-7.99)3 years(28, 48)35 4.43 (3.13-6.26)5 years(26, 45)

N=100 N=10061 11 (8.12-15)21 months(51, 71)

C 68 16 (11-25)3 years(58, 77)64 14 (8.83-24)5 years(54, 73)

N=99 N=9986 18 (14-25)21 months(77, 92)

W-135 85 31 (21-46)3 years(76, 91)85 32 (21-47)5 years(76, 91)

N=100 N=10071 14 (10-19)21 months(61, 80)

Y 69 14 (9.68-20)3 years(59, 78)67 13 (8.8-20)5 years(57, 76)

A booster dose of Menveo was administered 3 years after primary vaccination with Menveo or

ACWY-D. Both groups showed a robust response to the booster dose of Menveo at one month aftervaccination (100% of subjects had hSBA ≥ 1:8 across serogroups) and this response largely persistedthrough 2 years after the booster dose for serogroups C, W-135 and Y (with 87% to 100% of subjectswith hSBA ≥ 1:8 across serogroups). A small decline was observed in percentages of subjects withhSBA ≥ 1:8 against serogroup A, although percentages were still high (77% to 79%). GMTs declinedover time as expected but remained between 2- and 8-fold higher than prebooster values (Table 8).

In study V59P6E1, at one year post vaccination, the percentage of Menveo recipients with hSBA≥ 1:8 remained significantly higher compared with ACWY-PS recipients for serogroups C, W-135 and

Y, and similar between the two study groups for serogroup A. hSBA GMTs for serogroups W-135 and

Y were higher among Menveo recipients. In 5 years post vaccination, the percentage of Menveorecipients with hSBA ≥ 1:8 remained significantly higher compared with ACWY-PS recipients forserogroups C and Y. Higher hSBA GMTs were observed for serogroups W-135 and Y (Table 7).

Table 7: Persistence of immune responses approximately 12 months and 5 years aftervaccination with Menveo and ACWY-PS (subjects were aged 11-18 years at the time ofvaccination)

Percentages of subjects withhSBA GMTshSBA≥1:8

P Value P Value

Serogrou Timepo

Menveo Menveop int ACWY-P

Menveo vs Menveo ACWY-PS vs

S

ACWY- ACWY-

PS PS

N=50 N=50 N=50 N=5012 mont 41% 43% 5.19 6.190.73 0.54

A hs (27, 56) (28, 59) (3.34, 8.09) (3.96, 9.66)30% 44% 5.38 7.755 years 0.15 0.24(18, 45) (30, 59) (3.29, 8.78) (4.83, 12)

N=50 N=50 N=50 N=5012 mont 82% 52% 29 17<0.001 0.22

C hs (68, 91) (37, 68) (15, 57) (8.55, 33)76% 62% 21 205 years 0.042 0.92(62, 87) (47, 75) (12, 37) (12, 35)

N=50 N=50 N=50 N=5012 mont 92% 52% 41 10<0.001 <0.001

W-135 hs (80, 98) (37, 68) (26, 64) (6.41, 16)72% 56% 30 135 years 0.093 0.012(58, 84) (41, 70) (18, 52) (7.65, 22)

N=50 N=50 N=50 N=5012 mont 78% 50% 34 9.280.001 <0.001

Y hs (63, 88) (35, 65) (20, 57) (5.5, 16)76% 50% 30 8.255 years 0.002 <0.001(62, 87) (36, 64) (18, 49) (5.03, 14)

A booster dose of Menveo was administered 5 years after primary vaccination with Menveo or

ACWY-PS. At 7 days after the booster dose, 98%-100% of subjects who previously received Menveoand 73%-84% of subjects who previously received ACWY-PS achieved hSBA ≥1:8 againstserogroups A, C, W-135 and Y. At one month post vaccination, the percentages of subjects withhSBA≥1:8 were 98%-100% and 84%-96%, respectively.

A significant increase in the hSBA GMTs against all four serogroups was also observedat 7 and 28 days after the booster dose (Table 8).

Table 8: Response to Booster: bactericidal antibody responses to Menveo boosteradministered at 3 or 5 years after the primary vaccination with Menveo or ACWY-PS insubjects aged 11-17 years

Percentages of subjects withhSBA GMTshSBA≥1:8

V59P13E

V59P6E1 V59P13E1 V59P6E1

Serog Time (3 years(5 years post (3 years post (5 years postroup point postvaccination) vaccination) vaccination)vaccination)

ACWY-P ACWY-

Menveo Menveo Menveo Menveo

S PS

N=42 N=49 N=49 N=42 N=49 N=49

Pre-boo 21% 29% 43% 2.69 5.16 7.31ster (10, 37) (17, 43) (29, 58) (1.68, pct. 4.31) (3.46, 7.7) (4.94, 11)100% 73% 457 days - - (585, 191(93, 100) (59, 85) (25, 80)

A 7)100% 98% 94% 326 14728 days (514, 130(92, 100) (89, 100) (83, 99) (215, 494) (94, 232)5)79% 222 years - - - -(63, 90) (12, 41)

N=42 N=49 N=49 N=42 N=49 N=49

Pre-boo 55% 78% 61% 16 20 19ster (39, 70) (63, 88) (46, 75) (8.66, 31) (13, 33) (12, 31)100% 78% 367 days - - (893, 287(93, 100) (63, 88) (20, 64)

C 7)100% 100% 84% 597 5128 days (717, 206(92, 100) (93, 100) (70, 93) (352, 1014) (30, 86)6)95% 1242 years - - - -(84-99) (62-250)

N=41 N=49 N=49 N=41 N=49 N=49

Pre-boo 88% 73% 55% 37 29 12ster (74, 96) (59, 85) (40, 69) (21, 65) (17, 49) (7.02, 19)100% 84% 347 days - - (1042, 27(93, 100) (70, 93) (21, 54)

W-135 25)100% 100% 92% 673 4728 days (1090, 24(91, 100) (93, 100) (80, 98) (398, 1137) (32, 71)81)100% 932 years - - -(91, 100) (58, 148)

N=42 N=49 N=49 N=42 N=49 N=49

Pre-boo 74% 78% 51% 14 28 7.8ster (58, 86) (63, 88) (36, 66) (8.15, 26) (18, 45) (4.91, 12)98% 76% 217 days - - (1526, 42(89, 100) (61, 87) (13, 35)

Y 98)100% 100% 96% 532 6328 days (1340, 32(92, 100) (93, 100) (86, 100) (300, 942) (41, 98)68)95% 552 years - - - -(84, 99) (30, 101)

Immunogenicity in adults

In the pivotal immunogenicity trial, V59P13, immune responses to Menveo were assessed amongadults aged 19 to 55 years. Results are presented in Table 9. In the subset of subjects aged 19-55 yearswho were seronegative at baseline, the proportion of subjects who achieved a hSBA ≥ 1:8 after a doseof Menveo were as follows: serogroup A 67% (582/875); serogroup C 71% (401/563); serogroup W-135 82% (131/160); serogroup Y 66% (173/263).

Table 9: Serum bactericidal antibody responses following Menveo one month aftervaccination among subjects aged 19-55 years

GMT hSBA ≥ 1:8

Serogroup N(95% CI) (95% CI)

A 963 31 (27, 36) 69% (66, 72)

C 902 50 (43, 59) 80% (77, 83)

W-135 484 111 (93, 132) 94% (91, 96)

Y 503 44 (37, 52) 79% (76, 83)

The onset of immune response after the primary vaccination with Menveo in healthysubjects 18 through 22 years of age was evaluated in study V59P6E1. At 7 days post vaccination, 64%of subjects achieved hSBA ≥1:8 against serogroup A and 88% through 90% of subjects hadbactericidal antibodies against serogroups C, W-135 and Y. At one month post vaccination, 92%through 98% of subjects had hSBA ≥1:8 against serogroups A, C, W-135 and Y. A robust immuneresponse as measured by hSBA GMTs against all serogroups was also observed at 7 days(GMTs 34 through 70) and 28 days (GMTs 79 through 127) after a single dose vaccination.

Immunogenicity in older adults

The comparative immunogenicity of Menveo vs. ACWY-PS was evaluated in subjectsaged 56-65 years, in study V59P17. The proportion of subjects with hSBA ≥ 1:8 was non-inferior to

ACWY-PS for all four serogroups and statistically superior for serogroups A and Y (Table 10).

Table 10: Immunogenicity of one dose of Menveo or ACWY-PS in adults aged 56-65 years,measured at one month post vaccination.

Menveo ACWY-PS

Serogroup hSBA ≥ 1:8 hSBA ≥ 1:8(95% CI) (95% CI)

N=83 N=41

A 87% 63%(78, 93) (47, 78)

N=84 N=41

C 90% 83%(82, 96) (68, 93)

N=82 N=39

W-135 94% 95%(86, 98) (83, 99)

N=84 N=41

Y 88% 68%(79, 94) (52, 82)

Available data in children 2 to 23 months of age

The immunogenicity of Menveo in children 2 to 23 months of age was evaluated in several studies.

Although a high percentage of subjects achieved hSBA titers above 1:8 following 4-dose series of

Menveo, with lower percentages in studies of 2-dose series and of a single dose, Menveo wascompared to another meningococcal vaccine in only one pivotal study, where it failed to show aresponse at least equivalent to a monovalent conjugated serotype C vaccine (after a single dose at theage of 12 months). Currently available data are not sufficient to establish the efficacy of Menveo inchildren under 2 years of age. See section 4.2 for information on paediatric use.

Not applicable.

Non-clinical data reveal no special hazard for humans based on conventional repeated-dose andreproductive and developmental toxicity studies.

In laboratory animals, no adverse reactions were seen in vaccinated maternal rabbits or in theiroffspring through postnatal day 29.

No effects on fertility were observed in female rabbits receiving Menveo pre-mating and duringpregnancy.

Sucrose

Potassium dihydrogen phosphate

Solution

Sodium dihydrogen phosphate monohydrate

Disodium phosphate dihydrate

Sodium chloride

Water for injections

This medicinal product must not be mixed with other medicinal products except those mentionedin section 6.6.

4 years.

After reconstitution, the medicinal product should be used immediately. However, chemical andphysical stability after reconstitution was demonstrated for 8 hours below 25°C.

Store in a refrigerator (2°C - 8°C). Do not freeze.

Keep the vials in the outer carton in order to protect from light.

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

Powder in vial (type I glass) with a stopper (butyl rubber with fluoropolymer coated surface) andsolution in vial (type I glass) with a stopper (butyl rubber).

Pack size of one dose (2 vials), five doses (10 vials) or ten doses (20 vials).

Not all pack sizes may be marketed.

Menveo must be prepared for administration by reconstituting powder (in vial) with solution (in vial).

The contents in the two different vials (MenA powder and MenCWY solution) are to be mixed prior tovaccination providing 1 dose of 0.5 mL.

The components of the vaccine should be visually inspected before and after reconstitution.

Using a syringe and suitable needle (21G, 40 mm length or 21G, 1 ½ inch length), withdraw the entirecontents of the vial of solution and inject into the vial of powder to reconstitute the MenA conjugatecomponent.

Invert and shake the vial vigorously and then withdraw 0.5 mL of reconstituted product. Please notethat it is normal for a small amount of liquid to remain in the vial following withdrawal of the dose.

Following reconstitution, the vaccine is a clear, colourless to light yellow solution, free from visibleforeign particles. In the event of any foreign particulate matter and/or variation of physical aspectbeing observed, discard the vaccine.

Prior to injection, change the needle for one suitable for the administration. Ensure that no air bubblesare present in the syringe before injecting the vaccine.

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

GSK Vaccines S.r.l.

Via Fiorentina 153100 Siena, Italy

EU/1/10/614/002

EU/1/10/614/003

EU/1/10/614/004

Date of first authorisation: 15 March 2010

Date of latest renewal: 04 December 2014

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

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