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GlaxoSmithKline UK

Stockley Park West, Uxbridge, Middlesex, UB11 1BT
Telephone: +44 (0)800 221 441
Fax: +44 (0)208 990 4328
Medical Information e-mail: customercontactuk@gsk.com

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Summary of Product Characteristics last updated on the eMC: 11/03/2014
SPC Nimenrix
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Black Triangle:

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.



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1. Name of the medicinal product

Nimenrix®▼ powder and solvent for solution for injection in pre-filled syringe

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


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2. Qualitative and quantitative composition

After reconstitution, 1 dose (0.5 ml) contains:

Neisseria meningitidis group A polysaccharide1

5 micrograms

Neisseria meningitidis group C polysaccharide1

5 micrograms

Neisseria meningitidis group W-135 polysaccharide1

5 micrograms

Neisseria meningitidis group Y polysaccharide1

5 micrograms

1conjugated to tetanus toxoid carrier protein

44 micrograms

For the full list of excipients, see section 6.1.


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3. Pharmaceutical form

Powder and solvent for solution for injection.

The powder is white.

The solvent is clear and colourless.


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4. Clinical particulars

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4.1 Therapeutic indications

Nimenrix is indicated for active immunisation of individuals from the age of 12 months and above against invasive meningococcal diseases caused by Neisseria meningitidis group A, C, W-135 and Y.


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4.2 Posology and method of administration

Posology

Nimenrix should be used in accordance with available official recommendations.

Primary vaccination:

A single 0.5 ml dose of the reconstituted vaccine is used for immunisation.

Booster vaccination:

Nimenrix may be given in subjects who have previously been vaccinated with a plain polysaccharide meningococcal vaccine (see sections 4.4 and 5.1).

The need for a booster dose in subjects primed with Nimenrix has not yet been established (see sections 4.4 and 5.1).

Paediatric population

The safety and efficacy of Nimenrix in children under 12 months of age has not yet been established. No data are available.

Method of administration

Immunisation should be carried out by intramuscular injection only, preferably into the deltoid muscle.

In children 12 to 23 months of age, the vaccine may also be administered in the anterolateral part of the thigh (see sections 4.4 and 4.5).

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


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4.3 Contraindications

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


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4.4 Special warnings and precautions for use

Nimenrix should under no circumstances be administered intravascularly, intradermally or subcutaneously.

It is good clinical practice to precede vaccination by a review of the medical history (especially with regard to previous vaccination and possible occurrence of undesirable effects) and a clinical examination.

Appropriate medical treatment and supervision should always be readily available in case of a rare anaphylactic event following the administration of the vaccine.

Vaccination with Nimenrix should be postponed in subjects suffering from an acute severe febrile illness. The presence of a minor infection, such as a cold, should not result in the deferral of vaccination.

Syncope (fainting) can occur following, or even before, any vaccination especially in adolescents as a psychogenic response to the needle injection. This can be accompanied by several neurological signs such as transient visual disturbance, paraesthesia and tonic-clonic limb movements during recovery. It is important that procedures are in place to avoid injury from faints.

Nimenrix should be given with caution to individuals with thrombocytopenia or any coagulation disorder since bleeding may occur following an intramuscular administration to these subjects.

Nimenrix will only confer protection against Neisseria meningitidis group A, C, W-135 and Y. The vaccine will not protect against any other Neisseria meningitidis groups.

A protective immune response may not be elicited in all vaccinees.

It may be expected that in patients receiving immunosuppressive treatment or patients with immunodeficiency, an adequate immune response may not be elicited.

Safety and immunogenicity have not been assessed in patients with increased susceptibility to meningococcal infection due to conditions such as terminal complement deficiencies and anatomic or functional asplenia. In these individuals, an adequate immune response may not be elicited.

Subjects previously vaccinated with a plain polysaccharide meningococcal vaccine and vaccinated with Nimenrix 30 to 42 months later had lower Geometric Mean Titres (GMTs) measured with rabbit complement serum bactericidal assay (rSBA) than subjects who had not been vaccinated with any meningococcal vaccine in the preceding 10 years (see section 5.1). Clinical relevance of this observation is unknown.

Effect of pre-vaccination anti-tetanus antibodies

Safety and immunogenicity of Nimenrix was evaluated when sequentially administered or co-administered with a DTaP-HBV-IPV/Hib vaccine in the second year of life. The administration of Nimenrix one month after the DTaP-HBV-IPV/Hib vaccine resulted in lower MenA, MenC and MenW-135 rSBA GMTs (see section 4.5). Clinical relevance of this observation is unknown. The reactogenicity reported either when the vaccines were co-administered or sequentially administered was similar to the reactogenicity reported after a booster dose of a DTaP-HBV-IPV/Hib vaccine given during the second year of life.

Effect of Nimenrix on anti-tetanus antibody concentrations

Although an increase of the anti-tetanus toxoid (TT) antibody concentrations was observed following vaccination with Nimenrix, Nimenrix does not substitute for tetanus immunisation.

Giving Nimenrix with or one month before a TT-containing vaccine in the second year of life does not impair the response to TT or significantly affect safety. No data are available beyond the age of 2 years.

Persistence of serum bactericidal antibody titres

Studies with Nimenrix have shown a waning of serum bactericidal antibody titres against MenA when using human complement in the assay (hSBA) (see section 5.1).

The clinical relevance of the waning of hSBA-MenA antibody titres is unknown. Currently there is limited information available on the safety of a booster dose. However, if an individual is expected to be at particular risk of exposure to MenA and received a dose of Nimenrix more than approximately one year previously, consideration may be given to administering a booster dose.

Persistence of antibodies has been evaluated up to 5 years after vaccination. Similar to the monovalent Men C comparator, a decline in antibody titres over time has been observed. The clinical relevance of the waning antibody titres is unknown. A booster dose might be considered in individuals vaccinated at toddler age remaining at high risk of exposure to meningococcal disease caused by serogroups A, C, W-135 and Y (see section 5.1).


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4.5 Interaction with other medicinal products and other forms of interaction

Nimenrix can be given concomitantly with any of the following vaccines: hepatitis A (HAV) and hepatitis B (HBV) vaccines, measles - mumps - rubella (MMR) vaccine, measles - mumps - rubella - varicella (MMRV) vaccine, 10-valent pneumococcal conjugate vaccine or unadjuvanted seasonal influenza vaccine.

Nimenrix can also be given concomitantly with combined diphtheria - tetanus - acellular pertussis vaccines in the second year of life, including combination DTaP vaccines with hepatitis B, inactivated polio or Haemophilus influenzae type b, such as DTaP-HBV-IPV/Hib vaccine.

Whenever possible, Nimenrix and a TT containing vaccine, such as DTaP-HBV-IPV/Hib vaccine, should be co-administered or Nimenrix should be administered at least one month before the TT containing vaccine. The sequential administration of Nimenrix one month after a DTaP-HBV-IPV/Hib vaccine resulted in lower MenA, MenC and MenW-135 GMTs. Clinical relevance of this observation is unknown, since at least 99.4% of subjects (N=178) had rSBA titres ≥ 8 for each group (A, C, W-135, Y) (see section 4.4).

One month after co-administration with a 10-valent pneumococcal conjugate vaccine, lower Geometric Mean antibody Concentrations (GMCs) and opsonophagocytic assay (OPA) antibody GMTs were observed for one pneumococcal serotype (18C conjugated to tetanus toxoid carrier protein). Clinical relevance of this observation is unknown. There was no impact of co-administration on the other nine pneumococcal serotypes.

If Nimenrix is to be given at the same time as another injectable vaccine, the vaccines should always be administered at different injection sites.

It may be expected that in patients receiving immunosuppressive treatment an adequate response may not be elicited.


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4.6 Fertility, pregnancy and lactation

Pregnancy

There is limited experience with use of Nimenrix in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryo/foetal development, parturition or post-natal development (see section 5.3).

Nimenrix should be used during pregnancy only when clearly needed, and the possible advantages outweigh the potential risks for the foetus.

Breast-feeding

It is unknown whether Nimenrix is excreted in human milk.

Nimenrix should only be used during breast-feeding when the possible advantages outweigh the potential risks.

Fertility

Animal studies do not indicate direct or indirect harmful effects with respect to fertility.


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4.7 Effects on ability to drive and use machines

No studies on the effects of Nimenrix on the ability to drive and use machines have been performed.

However, some of the effects mentioned under section 4.8 “Undesirable effects” may affect the ability to drive or use machines.


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4.8 Undesirable effects

Summary of the safety profile

The safety profile presented below is based on a pooled analysis on 8,108 subjects who have been vaccinated with one dose of Nimenrix in clinical studies. This pooled analysis includes data for 2,237 toddlers (12 months to 23 months), 1,809 children (2 to 10 years), 2,011 adolescents (11 to 17 years) and 2,051 adults ( 18 to 55 years).

In all age groups the most frequently reported local adverse reactions after vaccination were pain (24.1% to 39.9%), redness (14.3% to 33.0%) and swelling (11.2% to 17.9%).

In the 12-23 months and 2-5 years age groups, the most frequently reported general adverse reactions after vaccination were irritability (36.2% and 7.5% respectively), drowsiness (27.8% and 8.8% respectively), loss of appetite (20.7% and 6.3% respectively) and fever (17.6% and 6.5% respectively).

In the 6-10, 11-17 and ≥ 18 years age groups, the most frequently reported general adverse reactions after vaccination were headache (13.3%, 16.1% and 17.6% respectively), fatigue (13.8%, 16.3% and 16.4% respectively), gastrointestinal symptoms (7.5%, 6.4% and 6.3% respectively) and fever (7.5%, 4.1% and 4.0% respectively).

In a separate study a single dose of Nimenrix was administered to 274 individuals aged 56 years and older. All adverse reactions reported in this study were already observed in younger age groups.

Tabulated list of adverse reactions

The adverse reactions observed during clinical studies included in the safety pooled analysis are presented in the table below.

Adverse reactions reported are listed according to the following frequency categories:

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)

System Organ Class

Frequency

Adverse events

Metabolism and nutrition disorders

Very common

Appetite lost

Psychiatric disorders

Very common

Irritability

Uncommon

Insomnia, crying

Nervous system disorders

Very common

Drowsiness, headache

Uncommon

Hypoaesthesia, dizziness

Gastrointestinal disorders

Common

Gastrointestinal symptoms (including diarrhoea, vomiting and nausea)

Skin and subcutaneous tissue disorders

Uncommon

Pruritus, rash

Musculoskeletal and connective tissue disorders

Uncommon

Myalgia, pain in extremity

General disorders and administration site conditions

Very common

Fever, swelling, pain and redness at injection site, fatigue

Common

Injection site haematoma

Uncommon

Malaise, injection site reaction (including induration, pruritus, warmth, anaesthesia)

Reporting of suspected adverse reactions

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. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.


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4.9 Overdose

No case of overdose has been reported.


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5. Pharmacological properties

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5.1 Pharmacodynamic properties

Pharmacotherapeutic group: vaccines, meningococcal vaccines, ATC code: J07AH08

Mechanism of action

Anti-capsular meningococcal antibodies protect against meningococcal diseases via complement mediated bactericidal activity. Nimenrix induces the production of bactericidal antibodies against capsular polysaccharides of group A, C, W-135 and Y when measured by assays using either rabbit complement (rSBA) or human complement (hSBA).

Pharmacodynamic effects

The immunogenicity of one dose of Nimenrix has been evaluated in more than 8,000 subjects aged ≥ 12 months.

Vaccine efficacy was inferred from the demonstration of immunologic non inferiority (based mainly on comparing proportions with rSBA titres at least 8) to licensed meningococcal vaccines. Immunogenicity was measured by using rSBA or hSBA which are biomarkers for protective efficacy against meningococcal groups A, C, W-135 and Y.

Immunogenicity in toddlers aged 12-23 months

In clinical studies MenACWY-TT-039 and MenACWY-TT-040, the immune response to vaccination with either Nimenrix or a licensed meningococcal C-CRM197 conjugate (MenC-CRM) vaccine was evaluated.

Nimenrix elicited a bactericidal antibody response against the four groups, with a response against group C that was comparable to the one elicited by the licensed MenC-CRM vaccine in term of rSBA titres ≥8 (Table 1).

Table 1: Bactericidal antibody responses (rSBA*) in toddlers aged 12-23 months

Group

Response to

Study MenACWY-TT-039

rSBA(1)

Study MenACWY-TT-040

rSBA(2)

N

≥8

(95%CI)

GMT

(95%CI)

N

≥8

(95%CI)

GMT

(95%CI)

A

Nimenrix

354

99.7%

(98.4; 100)

2205.0

(2007.8; 2421.6)

183

98.4%

(95.3; 99.7)

3169.9

(2577.2; 3898.8)

C

Nimenrix

354

99.7%

(98.4; 100)

477.6

(437.3; 521.6)

183

97.3%

(93.7; 99.1)

828.7

(672.4; 1021.4)

MenC-CRM vaccine

121

97.5%

(92.9; 99.5)

212.3

(170.0; 265.2)

114

98.2%

(93.8; 99.8)

691.4

(520.8; 917.9)

W-135

Nimenrix

354

100%

(99.0; 100)

2681.7

(2453.1; 2931.6)

186

98.4%

(95.4; 99.7)

4022.3

(3269.2; 4948.8)

Y

Nimenrix

354

100%

(99.0; 100)

2729.4

(2472.7; 3012.8)

185

97.3%

(93.8; 99.1)

3167.7

(2521.9; 3978.9)

The analysis of immunogenicity was conducted on the according-to-protocol (ATP) cohorts for immunogenicity.

(1) blood sampling performed 42 to 56 days post vaccination

(2) blood sampling performed 30 to 42 days post vaccination

* tested at GSK laboratories

In the study MenACWY-TT-039, the serum bactericidal activity was also measured using human serum as the source of complement (hSBA) as a secondary endpoint (Table 2).

Table 2: Bactericidal antibody responses (hSBA*) in toddlers aged 12-23 months

Group

Response to

N

Study MenACWY-TT-039

hSBA(1)

≥8

(95% CI)

GMT

(95%CI)

A

Nimenrix

338

77.2%

(72.4; 81.6)

19.0

(16.4; 22.1)

C

Nimenrix

341

98.5%

(96.6; 99.5)

196.0

(175.4; 219.0)

MenC-CRM vaccine

116

81.9%

(73.7; 88.4)

40.3

(29.5; 55.1)

W-135

Nimenrix

336

87.5%

(83.5 ; 90.8)

48.9

(41.2; 58.0)

Y

Nimenrix

329

79.3%

(74.5; 83.6)

30.9

(25.8; 37.1)

The analysis of immunogenicity was conducted on ATP cohort for immunogenicity.

(1) blood sampling performed 42 to 56 days post vaccination

* tested at GSK laboratories

Immunogenicity in children aged 2-10 years

In two comparative studies conducted in subjects aged 2-10 years, one group of subjects received a dose of Nimenrix and a second group a dose of either a licensed MenC-CRM vaccine (study MenACWY-TT-081) or the licensed GlaxoSmithKline Biologicals' plain polysaccharide meningococcal group A, C, W-135, Y (ACWY-PS) vaccine (study MenACWY-TT-038 ) as comparator.

In the MenACWY-TT-038 study, Nimenrix was demonstrated to be non-inferior to the licensed ACWY-PS vaccine in terms of vaccine response to the four groups (A, C, W-135 and Y) (See Table 3).

The vaccine response was defined as the proportion of subjects with:

• rSBA titres ≥ 32 for initially seronegative subjects (i.e, pre-vaccination rSBA titre < 8)

• at least a 4-fold increase in rSBA titres from pre- to post-vaccination for initially seropositive subjects (i.e., pre-vaccination rSBA titre ≥ 8)

In the MenACWY-TT-081 study, Nimenrix was demonstrated to be non-inferior to another licensed MenC-CRM vaccine in terms of vaccine response to the Men C group [94.8% (95% CI: 91.4; 97.1) and 95.7% (95% CI: 89.2; 98.8) respectively], GMTs were lower for the Nimenrix group [2794.8 (95% CI: 2393.5; 3263.3)] versus the MenC-CRM vaccine [5291.6 (95% CI: 3814.6; 7340.5)].

Table 3: Bactericidal antibody responses (rSBA*) to Nimenrix and the ACWY-PS vaccine in children aged 2-10 years 1 month after vaccination (study MenACWY-TT-038)

Group

Nimenrix

ACWY-PS vaccine

N

VR

(95%CI)

GMT

(95%CI)

N

VR

(95%CI)

GMT

(95%CI)

A

638

88.6%

(85.8; 90.9)

6309.7

(5979.0; 6658.8)

206

65.5%

(58.6; 72.0)

2309.4

(2055.8; 2594.3)

C

732

95.9%

(94.2; 97.2)

4983.6

(4514.1; 5502.0)

251

89.6%

(85.2; 93.1)

1386.8

(1108.9; 1734.4)

W-135

738

97.4%

(96.0; 98.4)

11569.8

(10910.7; 12268.7)

252

82.5%

(77.3; 87.0)

2150.6

(1823.9; 2535.8)

Y

771

92.5%

(90.4; 94.2)

10886.6

(10310.7; 11494.5)

258

68.6%

(62.6; 74.2)

2544.7

(2178.2; 2972.9)

The analysis of immunogenicity was conducted on ATP cohort for immunogenicity.

VR: vaccine response

* tested at GSK laboratories

Immunogenicity in adolescents aged 11-17 years and adults aged ≥ 18 years

In two clinical studies, conducted in adolescents 11-17 years of age (study MenACWY-TT-036) and in adults 18-55 years of age (study MenACWY-TT-035), either one dose of Nimenrix or one dose of the ACWY-PS vaccine were administered.

In both adolescents and adults, Nimenrix was demonstrated to be immunologically non-inferior to the ACWY-PS vaccine in terms of vaccine response as defined above (Table 4). The response to the four meningococcal groups elicited by Nimenrix was either similar or higher than the one elicited by the ACWY-PS vaccine.

Table 4: Bactericidal antibody responses (rSBA*) to Nimenrix and the ACWY-PS vaccine in adolescents aged 11-17 years and adults aged ≥ 18 years 1 month after vaccination

Study

(Age range)

Group

Nimenrix

ACWY-PS vaccine

N

VR

(95%CI)

GMT

(95%CI)

N

VR

(95%CI)

GMT

(95%CI)

Study MenACWY-TT-036

(11-17 years)

A

615

85.4%

(82.3; 88.1)

6106.8

(5739.5; 6497.6)

215

79.5%

(73.5; 84.7)

3203.0

(2854.1; 3594.6)

C

719

97.1%

(95.6; 98.2)

12645.5

(11531.8; 13866.7)

237

96.6%

(93.5; 98.5)

8271.6

(6937.3; 9862.4)

W-135

717

96.5%

(94.9; 97.7)

8390.1

(7777.8; 9050.7)

242

88.0%

(83.2; 91.8)

2679.3

(2363.7; 3037.2)

Y

737

93.1%

(91.0; 94.8)

13865.2

(12968.1; 14824.4)

246

78.0%

(72.3; 83.1)

5245.3

(4644.2; 5924.1)

Study MenACWY-TT-035

(18-55 years)

A

743

80.1%

(77.0; 82.9)

3624.7

(3371.7; 3896.8)

252

69.8%

(63.8; 75.4)

2127.2

(1909.2; 2370.1)

C

849

91.5%

(89.4; 93.3)

8865.9

(8011.0; 9812.0)

288

92.0%

(88.3; 94.9)

7371.2

(6297.4; 8628.2)

W-135

860

90.2%

(88.1; 92.1)

5136.2

(4698.8; 5614.3)

283

85.5%

(80.9; 89.4)

2461.3

(2081.0; 2911.0)

Y

862

87.0%

(84.6; 89.2)

7710.7

(7100.1; 8373.8)

288

78.8%

(73.6; 83.4)

4314.3

(3782.1; 4921.5)

The analysis of immunogenicity was conducted on ATP cohorts for immunogenicity.

VR: vaccine response

* tested at GSK laboratories

In a separate study (MenACWY-TT-085) a single dose of Nimenrix was administered to 194 Lebanese adults 56 years of age and older (including 133 aged 56-65 years and 61 aged > 65 years). The percentage of subjects with rSBA titres (measured at GSK's laboratories) ≥ 128 before vaccination ranged from 45% (MenC) to 62% (MenY). Overall, at one month post-vaccination the percentage of vaccinees with rSBA titres ≥ 128 ranged from 93% (MenC) to 97% (MenY). In the subgroup aged > 65 years the percentage of vaccinees with rSBA titres ≥ 128 at one month post-vaccination ranged from 90% (MenA) to 97% (MenY).

Persistence of immune response

The persistence of the immune response elicited by Nimenrix was evaluated 12 to 42 months after vaccination in subjects aged 12 months to 55 years.

For all groups (A, C, W-135, Y), the persistence of the antibodies elicited by Nimenrix was similar or higher than those induced by the licensed meningococcal vaccines (i.e. MenC-CRM vaccine in subjects aged 12-23 months and ACWY-PS vaccine in subjects older than 2 years of age).

Persistence of immune response in toddlers

In children primed at toddler ago, the persistence of the immune response was evaluated by rSBA and hSBA in studies MenACWY-TT-048 and MenACWY-TT-032, up to 4 years after priming in study MenACWY-TT-039 (Table 5) and up to 5 years after priming in study MenACWY-TT-027 (Table 6) respectively.

Table 5: 4 year persistence data in toddlers aged 12-23 months at vaccination (study MenACWY-TT-048)

Group

Response to

Time-point

(year)

rSBA*

hSBA**

N

≥8

(95%CI)

GMT

(95%CI)

N

≥8

(95%CI)

GMT

(95%CI)

A***

Nimenrix

3

262

59.9%

(53.7; 65.9)

19.3

(15.7; 23.6)

251

35.9%

(29.9; 42.1)

5.8

(4.8; 7.0)

4

224

74.1%

(67.9; 79.7)

107.3

(77.6; 148.3)

198

28.8%

(22.6; 35.6)

4.9

(4.0; 6.0)

C

Nimenrix

3

262

35.9%

(30.1; 42.0)

9.8

(8.1; 11.7)

253

78.3%

(72.7; 83.2)

37.8

(29.4; 48.6)

4

225

40.4%

(34.0; 47.2)

12.3

(9.8; 15.3)

209

73.2%

(66.7; 79.1)

32.0

(23.8; 43.0)

MenC-CRMvaccine

3

46

13.0%

(4.9; 26.3)

5.7

(4.2; 7.7)

31

41.9%

(24.5; 60.9)

6.2

(3.7; 10.3)

4

45

35.6%

(21.9; 51.2)

13.5

(7.4; 24.5)

32

46.9%

(29.1; 65.3)

11.3

(4.9; 25.6)

W-135

Nimenrix

3

261

49.8%

(43.6; 56.0)

24.9

(19.2; 32.4)

254

82.3%

(77.0; 86.8)

52.0

(41.4; 65.2)

4

225

49.3%

(42.6; 56.1)

30.5

(22.4; 41.5)

165

80.6%

(73.7; 86.3)

47.1

(35.7; 62.2)

Y

Nimenrix

3

262

53.8%

(47.6; 60.0)

22.3

(17.6; 28.4)

250

72.0%

(66.0; 77.5)

33.2

(25.9; 42.5)

4

225

58.2%

(51.5; 64.7)

36.2

(27.1; 48.4)

130

65.4%

(56.5; 73.5)

29.8

(20.2; 44.1)

The analysis of immunogenicity was conducted on ATP cohort for persistence adapted for each time-point.

*rSBA testing performed at Public Health England (PHE) laboratories in UK

** tested at GSK laboratories

*** Similar to the increase in rSBA MenA GMTs, an increase in MenA IgG Geometric Mean Concentrations was observed between Y3 and Y4 time-points

Table 6: 5 year persistence data in toddlers aged 12-23 months at vaccination (study MenACWY-TT-032)

Group

Response to

Time-point

rSBA*

hSBA**

N

≥8

(95%CI)

GMT

(95%CI)

N

≥8

(95%CI)

GMT

(95%CI)

A

Nimenrix

Year 4

152

61.2%

(53.0; 69.0)

25.7

(19.1; 34.7)

140

39.3%

(31.1; 47.9)

6.0

(4.7; 7.7)

Year 5

49

73.5%

(58.9; 85.1)

37.4

(22.1; 63.2)

45

35.6%

(21.9: 51.2)

5.2

(3.4; 7.8)

C

Nimenrix

Year 4

152

30.3%

(23.1; 38.2)

11.2

(8.3; 15.1)

147

85.7%

(79.0;90.9)

51.4

(36.9; 71.7)

Year 5

49

77.6%

(63.4; 88.2)

48.9

(28.5; 84.0)

48

91.7%

(80.0; 97.7)

216.5

(123.6; 379.1)

MenC-CRM vaccine

Year 4

31

25.8%

(11.9; 44.6)

11.4

(5.2; 25.0)

31

77.4%

(58.9; 90.4)

32.4

(14.8; 71.1)

Year 5

11

63.6%

(30.8; 89.1)

26.5

(6.5; 107.2)

11

90.9%

(58.7; 99.8)

108.7

(21.2; 557.2)

W-135

Nimenrix

Year 4

152

51.3%

(43.1; 59.5)

31.3

(21.4; 45.6)

143

81.8%

(74.5; 87.8)

48.3

(36.2; 64.4)

Year 5

49

34.7%

(21.7; 49.6)

18.2

(9.3; 35.3)

46

82.6%

(68.6; 92.2)

59.7

(35.1; 101.4)

Y

Nimenrix

Year 4

152

55.3%

(47.0; 63.3)

29.9

(21.5; 41.6)

129

77.5%

(69.3; 84.4)

42.1

(30.6; 58.1)

Year 5

49

42.9%

(28.8; 57.8)

20.6

(10.9; 39.2)

45

80.0%

(65.4; 90.4)

70.6

(38.7; 128.8)

The analysis of immunogenicity was conducted on ATP cohort for persistence adapted for each time-point.

*rSBA testing performed at PHE laboratories in UK

** tested at GSK laboratories

Persistence of immune response in children aged 2-10 years

Persistence of immune response in children aged 2-10 years

In study MenACWY-TT-088, the persistence of the immune response was evaluated by rSBA and hSBA up to 44 months after vaccination in children 2-10 years of age primed in study MenACWY-TT-081 (Table 7).

Table 7: 44 month persistence data in children 2-10 years of age at vaccination

Group

Response to

Time-point

(months)

rSBA*

hSBA**

N

≥8

(95%CI)

GMT

(95%CI)

N

≥8

(95%CI)

GMT

(95%CI)

A

Nimenrix

32

193

86.5%

(80.9; 91.0)

196.3

(144.1; 267.2)

90

25.6%

(16.9; 35.8)

4.6

(3.3; 6.3)

44

189

85.7%

(79.9; 90.4)

307.5

(223.7; 422.8)

89

25.8%

(17.1; 36.2)

4.8

(3.4; 6.7)

C

Nimenrix

32

192

64.6%

(57.4; 71.3)

34.8

(26.0; 46.4)

90

95.6%

(89.0; 98.8)

75.9

(53.4; 107.9)

44

189

37.0%

(30.1; 44.3)

14.5

(10.9; 19.2)

82

76.8%

(66.2; 85.4)

36.4

(23.1; 57.2)

MenC-CRM vaccine

32

69

76.8%

(65.1; 86.1)

86.5

(47.3; 158.1)

33

90.9%

(75.7; 98.1)

82.2

(34.6; 195.8)

44

66

45.5%

(33.1; 58.2)

31.0

(16.6; 58.0)

31

64.5%

(45.4; 80.8)

38.8

(13.3; 113.2)

W-135

Nimernix

32

193

77.2%

(70.6; 82.9)

213.9

(149.3; 306.6)

86

84.9%

(75.5; 91.7)

69.9

(48.2; 101.5)

44

189

68.3%

(61.1; 74.8)

103.5

(72.5; 147.6)

87

80.5%

(70.6; 88.2)

64.3

(42.7; 96.8)

Y

Nimenrix

32

193

81.3%

(75.1; 86.6)

227.4

(164.8; 313.7)

91

81.3%

(71.8; 88.7)

79.2

(52.5; 119.3)

44

189

62.4%

(55.1; 69.4)

78.9

(54.6; 114.0)

76

82.9%

(72.5; 90.6)

126.7

(78.0; 205.7)

The analysis of immunogenicity was conducted on ATP cohort for persistence adapted for each time-point.

*rSBA testing performed at PHE laboratories in UK

** tested at GSK laboratories

Persistence of immune response in children aged 6-10 years

In study MenACWY-TT-028, the persistence of the immune response was evaluated by hSBA 1 year after vaccination in children 6-10 years of age primed in study MenACWY-TT-027 (Table 6) (see section 4.4).

Table 8: 1 month post-vaccination and 1 year persistence data (hSBA*) in children 6-10 years of age

Group

Response to

1 month post-vaccination

1 year persistence

N

≥8

(95%CI)

GMT

(95%CI)

N

≥8

(95%CI)

GMT

(95%CI)

A

Nimenrix

105

80.0 %

(71.1; 87.2)

53.4

(37.3; 76.2)

104

16.3%

(9.8; 24.9)

3.5

(2.7; 4.4)

ACWY-PS

35

25.7%

(12.5;43.3)

4.1

(2.6;6.5)

35

5.7%

(0.7;19.2)

2.5

(1.9;3.3)

C

Nimenrix

101

89.1%

(81.3;94.4)

155.8

(99.3;244.3)

105

95.2%

(89.2;98.4)

129.5

(95.4;175.9)

ACWY-PS

38

39.5%

(24.0;56.6)

13.1

(5.4;32.0)

31

32.3%

(16.7;51.4)

7.7

(3.5;17.3)

W-135

Nimenrix

103

95.1%

(89.0;98.4)

133.5

(99.9;178.4)

103

100%

(96.5;100)

256.7

(218.2;301.9)

ACWY-PS

35

34.3%

(19.1;52.2)

5.8

(3.3;9.9)

31

12.9%

(3.6;29.8)

3.4

(2.0;5.8)

Y

Nimenrix

89

83.1%

(73.7;90.2)

95.1

(62.4;145.1)

106

99.1%

(94.9;100)

265.0

(213.0;329.6)

ACWY-PS

32

43.8%

(26.4;62.3)

12.5

(5.6;27.7)

36

33.3%

(18.6;51.0)

9.3

(4.3;19.9)

The analysis of immunogenicity was conducted on ATP cohort for persistence.

* tested at GSK laboratories

Persistence of immune response in adolescents

In study MenACWY-TT-043, the persistence of the immune response was evaluated 2 years after vaccination in adolescents primed in study MenACWY-TT-036 (Table 7). See table 4 for primary results in this study.

Table 9: 2 year persistence data (rSBA*) in adolescents aged 11-17 years at vaccination

Group

Nimenrix

ACWY-PS vaccine

N

≥8

(95%CI)

GMT

(95%CI)

N

≥8

(95%CI)

GMT

(95%CI)

A

445

99.8%

(98.8; 100)

1517.4

(1399.7; 1645.1)

144

100%

(97.5; 100)

810.6

(695.9; 944.3)

C

447

99.3%

(98.1; 99.9)

1121.9

(996.9; 1262.6)

145

98.6%

(95.1; 99.8)

1499.0

(1119.6; 2006.8)

W-135

447

99.6%

(98.4; 99.9)

2070.6

(1869.6; 2293.0)

143

95.1%

(90.2; 98.0)

442.6

(341.8; 573.0)

Y

447

100%

(99.2; 100)

3715.9

(3409.3; 4049.9)

142

97.2%

(92.9; 99.2)

1090.3

(857.7; 1386.1)

The analysis of immunogenicity was conducted on ATP cohort for persistence.

*rSBA testing performed at PHE laboratories in UK

Persistence of immune response in adolescents and adults aged 11-25 years

In study MenACWY-TT-059, the persistence of the immune response was evaluated by hSBA 1 and 3 years after vaccination in adolescents and adults 11-25 years of age primed in study MenACWY-TT-052 (Table 10) (see section 4.4).

Table 10: 1 month post-vaccination and 3 year persistence data (hSBA*) in adolescents and adults 11-25 years of age

Group

Response to

Time-point

N

≥8 (95%CI)

GMT (95%CI)

A

Nimenrix

Month 1

356

82.0% (77.6; 85.9)

58.7 (48.6; 70.9)

Year 1

350

29.1% (24.4; 34.2)

5.4 (4.5; 6.4)

Year 3

316

37.3% (32.0; 42.9)

6.2 (5.2; 7.3)

C

Nimenrix

Month 1

359

96.1% (93.5; 97.9)

532.0 (423.8; 667.8)

Year 1

336

94.9% (92.0; 97.0)

172.0 (142.5; 207.4)

Year 3

319

93.1% (89.7; 95.6)

119.3 (95.5; 149.0)

W-135

Nimenrix

Month 1

334

91.0% (87.4; 93.9)

116.8 (96.8; 141.0)

Year 1

327

98.5% (96.5; 99.5)

197.5 (173.0; 225.5)

Year 3

323

95.4% (92.5; 97.4)

143.9 (124.7; 166.2)

Y

Nimenrix

Month 1

364

95.1% (92.3; 97.0)

246.0 (207.7; 291.4)

Year 1

356

97.8% (95.6; 99.0)

271.8 (237.5; 311.2)

Year 3

321

96.0% (93.2; 97.8)

209.2 (180.1; 242.9)

The analysis of immunogenicity was conducted on ATP cohort for persistence adapted for each time-point.

* tested at GSK laboratories

Immune memory

In study MenACWY-TT-014, the induction of immune memory was assessed one month after the administration of a fifth of the dose of ACWY-PS vaccine (10 µg of each polysaccharide) to children in the third year of life previously primed in the study MenACWY-TT-013 with Nimenrix or a licensed MenC-CRM vaccine at the age of 12 to 14 months.

One month after the challenge dose, the GMTs elicited by the subjects primed with Nimenrix increased by 6.5 to 8 fold for groups A, C, W-135 and Y and indicate that Nimenrix induces immune memory to groups A, W-135 and Y. The post-challenge rSBA-MenC GMT was similar in both study groups, indicating that Nimenrix induces an analogous immune memory to group C as the licensed MenC-CRM vaccine (Table 11).

Table 11: Immune response (rSBA*) 1 month after a challenge vaccination in subjects primed with Nimenrix or a MenC-CRM vaccine at the age of 12 to 14 months

Group

Response to

Pre-challenge

Post-challenge

N

GMT

(95%CI)

N

GMT

(95%CI)

A

Nimenrix

32

544.0

(325.0; 910.7)

25

3321.9

(2294.2; 4810.0)

C

Nimenrix

31

174.0

(104.8; 288.9)

32

5965.7

(4128.4; 8620.7)

MenC-CRM vaccine

28

34.4

(15.8; 75.3)

30

5265.2

(3437.3; 8065.1)

W-135

Nimenrix

32

643.8

(394.1; 1051.8)

32

11058.1

(8587.2; 14239.9)

Y

Nimenrix

32

439.8

(274.0; 705.9)

32

5736.6

(4215.9; 7806.0)

The analysis of immunogenicity was conducted on ATP cohort for immunogenicity.

* tested at GSK laboratories

Booster response

In study MenACWY-TT-048, a booster response was evaluated in children vaccinated 4 years earlier (at toddler age) in study MenACWY-TT-039 (Table 2). Children were primed and boosted with the same vaccine: either Nimenrix or a MenC-CRM vaccine. A robust increase in rSBA and hSBA GMTs was observed from pre booster dose to one month post booster dose of Nimenrix (Table 12).

Table 12: Pre-booster and 1 month post-booster data in children vaccinated either with Nimenrix or MenC-CRM vaccine 4 years earlier (at toddler age)

Group

Response to

Time-point

rSBA*

hSBA**

N

≥8

(95%CI)

GMT

(95%CI)

N

≥8

(95%CI)

GMT

(95%CI)

A

Nimenrix

Pre-Booster

212

74.5%

(68.1; 80.2)

111.9

(80.3; 156.1)

187

28.9%

(22.5; 35.9)

4.8

(3.9; 5.9)

Post-booster

214

100%

(98.3; 100)

7173.3

(6389.2; 8053.5)

202

99.5%

(97.3; 100)

1343.2

(1119.3; 1612.0)

C

Nimenrix

Pre-Booster

213

39.9%

(33.3; 46.8)

12.1

(9.6; 15.2)

200

73.0%

(66.3; 79.0)

31.2

(23.0; 42.2)

Post-booster

215

100%

(98.3; 100)

4511.9

(3935.9; 5172.3)

209

100%

(98.3; 100)

15831.4

(13625.8; 18394.0)

MenC-CRM

vaccine

Pre-Booster

43

37.2%

(23.0; 53.3)

14.3

(7.7; 26.5)

31

48.4%

(30.2; 66.9)

11.9

(5.1; 27.6)

Post-booster

43

100%

(91.8; 100)

3718.4

(2596.0; 5326.0)

33

100%

(89.4; 100)

8646.1

(5886.6; 12699.3)

W-135

Nimenrix

Pre-Booster

213

48.8%

(41.9, 55.7)

30.2

(21.9; 41.5)

158

81.6%

(74.7; 87.3)

48.3

(36.5; 63.9)

Post-booster

215

100%

(98.3; 100)

10949.7

(9531.4; 12579.1)

192

100%

(98.1; 100)

14411.2

(12971.8; 16010.2)

Y

Nimenrix

Pre-Booster

213

58.2%

(51.3; 64.9)

37.3

(27.6; 50.4)

123

65.9%

(56.8; 74.2)

30.2

(20.2; 45.0)

Post-booster

215

100%

(98.3; 100)

4585.3

(4128.6; 5092.5)

173

100%

(97.9; 100)

6775.5

(5961.3; 7700.9)

The analysis of immunogenicity was conducted on the booster ATP cohort for immunogenicity.

*rSBA testing performed at PHE laboratories in UK

** tested at GSK laboratories

Subjects previously vaccinated with a plain polysaccharide vaccine against Neisseria meningitidis

In study MenACWY-TT-021 conducted in subjects aged 4.5-34 years, the immunogenicity of Nimenrix administered between 30 and 42 months after vaccination with a ACWY-PS vaccine was compared to the immunogenicity of Nimenrix administered to age-matched subjects who had not been vaccinated with any meningococcal vaccine in the preceding 10 years. An immune response (rSBA titre ≥8) was observed against all groups (A, C, W-135, Y) in all subjects regardless of the meningococcal vaccine history. The rSBA GMTs were significantly lower in the subjects who had received a dose of ACWY-PS vaccine 30-42 months prior to Nimenrix (Table 13) (see section 4.4).

Table 13: Immune response (rSBA) 1 month after Nimenrix vaccination in subjects according to their meningococcal vaccine history

Group

Subjects vaccinated 30 to 42 months previously with ACWY-PS

Subjects who had not received a meningococcal vaccine in the preceding 10 years

N

≥8

(95%CI)

GMT

(95%CI)

N

≥8

(95%CI)

GMT

(95%CI)

A

146

100%

(97.5; 100)

6868.8

(6044.9; 7805.0)

69

100%

(94.8; 100)

13014.9

(10722.2; 15798.0)

C

169

100%

(97.8; 100)

1945.8

(1583.3; 2391.1)

75

100%

(95.2; 100)

5494.6

(4266.3; 7076.5)

W-135

169

100%

(97.8; 100)

4635.7

(3942.5; 5450.7)

75

100%

(95.2; 100)

9078.0

(7087.7; 11627.1)

Y

169

100%

(97.8; 100)

7799.9

(6682.8; 9103.6)

75

100%

(95.2; 100)

13895.5

(11186.2; 17260.9)

The analysis of immunogenicity was conducted on ATP cohort for immunogenicity.

* tested at GSK laboratories

The European Medicines Agency has deferred the obligation to submit the results of studies with Nimenrix in one or more subsets of the paediatric population in the prevention of meningococcal disease caused by Neisseria meningitidis group A, C, W-135 and Y (see section 4.2 for information on paediatric use).


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5.2 Pharmacokinetic properties

Not applicable.


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5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on local tolerance, acute toxicity, repeated dose toxicity, developmental/reproductive toxicity and fertility studies.


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6. Pharmaceutical particulars

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6.1 List of excipients

Powder:

Sucrose

Trometamol

Solvent:

Sodium chloride

Water for injections


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6.2 Incompatibilities

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


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6.3 Shelf life

3 years

After reconstitution:

After reconstitution, the vaccine should be used immediately. However, chemical and physical in-use stability has been demonstrated for 24 hours at 30°C.


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6.4 Special precautions for storage

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 reconstitution of the medicinal product, see section 6.3.


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6.5 Nature and contents of container

Powder in a vial (type I glass) with a stopper (butyl rubber) and solvent in a pre-filled syringe with a stopper (butyl rubber).

Pack sizes of 1 and 10 with or without needles.

Not all pack sizes may be marketed.


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6.6 Special precautions for disposal and other handling

Instructions for reconstitution of the vaccine with the solvent presented in pre-filled syringe

Nimenrix must be reconstituted by adding the entire content of the pre-filled syringe of solvent to the vial containing the powder.

To attach the needle to the syringe, refer to the below picture. However, the syringe provided with Nimenrix might be slightly different (without screw thread) than the syringe described in the picture. In that case, the needle should be attached without screwing.

1. Holding the syringe barrel in one hand (avoid holding the syringe plunger), unscrew the syringe cap by twisting it anticlockwise.

 

2. To attach the needle to the syringe, twist the needle clockwise into the syringe until you feel it lock (See picture).

3. Remove the needle protector, which on occasion can be a little stiff.

 

4. Add the solvent to the powder. After the addition of the solvent to the powder, the mixture should be well shaken until the powder is completely dissolved in the solvent.

The reconstituted vaccine is a clear colourless solution.

The reconstituted vaccine should be inspected visually for any foreign particulate matter and/or variation of physical aspect prior to administration. In the event of either being observed, discard the vaccine.

After reconstitution, the vaccine should be used immediately.

A new needle should be used to administer the vaccine.

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


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7. Marketing authorisation holder

GlaxoSmithKline Biologicals S.A.

Rue de l'Institut 89

B-1330 Rixensart, Belgium


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8. Marketing authorisation number(s)

EU/1/12/767/001

EU/1/12/767/002

EU/1/12/767/003

EU/1/12/767/004


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9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 20/04/2012


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10. Date of revision of the text

20/02/2014

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



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