### Menactra

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## Menactra

### CLINICAL PHARMACOLOGY

#### Mechanism Of Action

The presence of bactericidal anti-capsular meningococcal
antibodies has been associated with protection from invasive meningococcal
disease.^{6,7} Menactra vaccine induces the production of bactericidal
antibodies specific to the capsular polysaccharides of serogroups A, C, Y and
W-135.

#### Non-Clinical Toxicology

#### Carcinogenesis, Mutagenesis, Impairment Of Fertility

Menactra vaccine has not been evaluated for carcinogenic or mutagenic potential, or for impairment of fertility.

#### Clinical Studies

#### Efficacy

The Serum Bactericidal Assay (SBA) used to test sera
contained an exogenous complement source that was either human (SBA-H) or baby
rabbit (SBA-BR).^{8}

The response to vaccination following two doses of vaccine administered to children 9 and 12 months of age and following one dose of vaccine administered to children 2 through 10 years of age was evaluated by the proportion of subjects having an SBA-H antibody titer of 1:8 or greater, for each serogroup. In individuals 11 through 55 years of age, the response to vaccination with a single dose of vaccine was evaluated by the proportion of subjects with a 4-fold or greater increase in bactericidal antibody to each serogroup as measured by SBA-BR. For individuals 2 through 55 years of age, vaccine efficacy was inferred from the demonstration of immunologic equivalence to a US-licensed meningococcal polysaccharide vaccine, Menomune - A/C/Y/W-135 vaccine as assessed by Serum Bactericidal Assay (SBA).

#### Immunogenicity

##### Children 9 through 12 Months of Age

In a randomized, US, multi-center trial, children received Menactra vaccine at 9 months and 12 months of age. The first Menactra dose was administered alone, followed by a second Menactra vaccine dose given alone (N=404), or with MMRV vaccine (N=302), or with PCV7 (N=422). For all participants, sera were obtained approximately 30 days after last vaccination. There were no substantive differences in demographic characteristics between the vaccine groups. The median age range for administration of the first dose of Menactra was 278-279 days of age.

**Table 5: Bactericidal Antibody Responses ^{a} 30 Days
Following a Second Dose of Menactra Vaccine Administered Alone or Concomitantly
Administered with MMRV or PCV7 Vaccines at 12 Months of Age**

Vaccinations administered at 12 months of age following a dose of Menactra at 9 months of age | |||||||

Menactra vaccine | Menactra + MMRV vaccines | Menactra + PCV7 vaccines | |||||

(N=272-277)^{b} |
(N=177-180)^{b} |
(N=264-267)^{b} |
|||||

Serogroup | (95% CI)^{c} |
(95% CI)^{c} |
(95% CI)^{c} |
||||

A | % ≥ 1:8^{d} GMT |
95.6 54.9 | (92.4; 97.7) (46.8; 64.5) | 92.7 52.0 | (87.8; 96.0) (41.8; 64.7) | 90.5 41.0 | (86.3; 93.8) (34.6; 48.5) |

C | % ≥ 1:8^{d} GMT |
100.0 141.8 | (98.7; 100.0) (123.5; 162.9) | 98.9 161.9 | (96.0; 99.9) (136.3; 192.3) | 97.8 109.5 | (95.2; 99.2) (94.1; 127.5) |

Y | % ≥ 1:8^{d} GMT |
96.4 52.4 | (93.4; 98.2) (45.4; 60.6) | 96.6 60.2 | (92.8; 98.8) (50.4; 71.7) | 95.1 39.9 | (91.8; 97.4) (34.4; 46.2) |

W-135 | % ≥ 1:8^{d }GMT |
86.4 24.3 | (81.8; 90.3) (20.8; 28.3) | 88.2 27.9 | (82.5; 92.5) (22.7; 34.3) | 81.2 17.9 | (76.0; 85.7) (15.2; 21.0) |

^{a} Serum Bactericidal Assay with an exogenous
human complement (SBA-H) source.^{b} N=Number of participants with at least one valid serology result
from a blood sample obtained between Days 30 to44 post vaccination.^{c} 95% CIs for the proportions are calculated based on the
Clopper-Pearson Exact method and normal approximation for that of the GMTs.^{d} The proportion of participants achieving at
least an SBA-H titer of 1:8 thirty days after the second dose of Menactra. |

Administration of Menactra to children at 12 months and 15 months of age was evaluated in a US study. Prior to the first dose, 33.3% [n=16/48] of participants had an hSBA titer ≥ 1:8 to Serogroup A, and 0-2% [n=0-1 of 50-51] to Serogroups C, Y and W-135. After the second dose, percentages of participants with an hSBA titer ≥ 1:8 were: 85.2%, Serogroup A [n=46/54]; 100.0%, Serogroup C [n=54/54]; 96.3%, Serogroup Y [n=52/54]; 96.2%, Serogroup W-135 [n=50/52].

##### Individuals 2 through 55 Years of Age

Immunogenicity was evaluated in three comparative, randomized, US, multi-center, active controlled clinical trials that enrolled children (2 through 10 years of age), adolescents (11 through 18 years of age), and adults (18 through 55 years of age). Participants received a single dose of Menactra vaccine (N=2526) or Menomune - A/C/Y/W-135 vaccine (N=2317). For all age groups studied, sera were obtained before and approximately 28 days after vaccination. [Blinding procedures for safety assessments are described in Adverse Reactions (6).]

In each of the trials, there were no substantive differences in demographic characteristics between the vaccine groups, between immunogenicity subsets or the overall study population. In the study of children 2 through 10 years of age, the median age of participants was 3 years; 95% completed the study. In the adolescent trial, the median age for both groups was 14 years; 99% completed the study. In the adult trial, the median age for both groups was 24 years; 94% completed the study.

##### Immunogenicity in Children 2 through 10 Years of Age

Of 1408 enrolled children 2 through 10 years of age, immune responses evaluated in a subset of Menactra vaccine participants (2 through 3 years of age, n=52; 4-10 years of age, n=84) and Menomune - A/C/Y/W-135 vaccine participants (2 through 3 years of age, n=53; 4-10 years of age, n=84) were comparable for all four serogroups (Table 6).

**Table 6: Comparison of Bactericidal Antibody Responses ^{a}
to Menactra Vaccine and Menomune - A/C/Y/W-135 Vaccine 28 Days after
Vaccination for a Subset of Participants 2 through 3 Years of Age and 4 through
10 Years of Age**

Ages 2 through 3 Years | Ages 4 through 10 Years | ||||||||

Menactra vaccine | Menomune -A/C/Y/W-135 vaccine | Menactra vaccine | Menomune -A/C/Y/W-135 vaccine | ||||||

N^{b}=48-52 |
N^{b}=50-53 |
N^{b}=84 |
N^{b}=84 |
||||||

Serogroup | (95% CI)^{c} |
(95% CI)^{c} |
(95% CI)^{c} |
(95% CI)^{c} |
|||||

A | % ≥ 1:8^{d} |
73 | (59,84) | 64 | (50,77) | 81 | (71,89) | 55 | (44,66) |

GMT | 10 | (8,13) | 10 | (7,12) | 19 | (14,26) | 7 | (6,9) | |

C | % ≥ 1:8^{d} |
63 | (48,76) | 38 | (25,53) | 79 | (68,87) | 48 | (37,59) |

GMT | 27 | (14,52) | 11 | (5,21) | 28 | (19,41) | 12 | (7,18) | |

Y | % ≥ 1:8^{d} |
88 | (75,95) | 73 | (59,84) | 99 | (94,100) | 92 | (84,97) |

GMT | 51 | (31,84) | 18 | (11,27) | 99 | (75,132) | 46 | (33,66) | |

W-135 | % ≥ 1:8^{d} |
63 | (47,76) | 33 | (20,47) | 85 | (75,92) | 79 | (68,87) |

GMT | 15 | (9,25) | 5 | (3,6) | 24 | (18,33) | 20 | (14,27) | |

^{a} Serum Bactericidal Assay with an exogenous
human complement (SBA-H) source.^{b} N=Number of subset participants with at least one valid serology
result at Day 0 and Day 28.^{c} The 95% CI for the Geometric Mean Titer (GMT) was calculated based
on an approximation to the normal distribution.^{d} The proportion of participants achieving at least an SBA-H titer
of 1:8 was assessed using a 10% non-inferiority margin and a one-sided Type 1
error rate of 0.025. |

In the subset of participants 2 through 3 years of age with undetectable pre-vaccination titers (ie, < 1:4 at Day 0), seroconversion rates (defined as ≥ 1:8 at Day 28) were similar between the Menactra vaccine and Menomune - A/C/Y/W-135 vaccine recipients. Menactra vaccine participants achieved seroconversion rates of: 57%, Serogroup A (n=12/21); 62%, Serogroup C (n=29/47); 84%, Serogroup Y (n=26/31); 53%, Serogroup W-135 (n=20/38). The seroconversion rates for Menomune - A/C/Y/W-135 vaccine recipients were: 55%, Serogroup A (n=16/29); 30%, Serogroup C (n=13/43); 57%, Serogroup Y (n=17/30); 26%, Serogroup W-135 (n=11/43).

In the subset of participants 4 through 10 years of age with undetectable pre-vaccination titers (ie, < 1:4 at Day 0), seroconversion rates (defined as ≥ 1:8 at Day 28) were similar between the Menactra vaccine and Menomune - A/C/Y/W-135 vaccine recipients. Menactra vaccine participants achieved seroconversion rates of: 69%, Serogroup A (n=11/16); 81%, Serogroup C (n=50/62); 98%, Serogroup Y (n=45/46); 69%, Serogroup W-135 (n=27/39). The seroconversion rates for Menomune - A/C/Y/W-135 vaccine recipients were: 48%, Serogroup A (n=10/21); 38%, Serogroup C (n=19/50); 84%, Serogroup Y (n=38/45); 68%, Serogroup W-135 (n=26/38).

##### Immunogenicity in Adolescents 11 through 18 Years of Age

Results from the comparative clinical trial conducted in 881 adolescents aged 11 through 18 years showed that the immune responses to Menactra vaccine and Menomune - A/C/Y/W-135 vaccine were similar for all four serogroups (Table 7).

In participants with undetectable pre-vaccination titers (ie, less than 1:8 at Day 0), seroconversion rates (defined as a ≥ 4-fold rise in Day 28 SBA-BR titers) were similar between the Menactra vaccine and Menomune - A/C/Y/W-135 vaccine recipients. Menactra vaccine participants achieved seroconversion rates of: 100%, Serogroup A (n=81/81); 99%, Serogroup C (n=153/155); 98%, Serogroup Y (n=60/61); 99%, Serogroup W-135 (n=161/164). The seroconversion rates for Menomune - A/C/Y/W-135 vaccine recipients were: 100%, Serogroup A (n=93/93); 99%, Serogroup C (n=151/152); 100%, Serogroup Y (n=47/47); 99%, Serogroup W-135 (n=138/139).

##### Immunogenicity in Adults 18 through 55 Years of Age

Results from the comparative clinical trial conducted in 2554 adults aged 18 through 55 years showed that the immune responses to Menactra vaccine and Menomune - A/C/Y/W-135 vaccine were similar for all four serogroups (Table 7).

**Table 7: Comparison of Bactericidal Antibody Responsesa
to Menactra Vaccine and Menomune - A/C/Y/W-135 Vaccine 28 Days after
Vaccination for Participants 11 through 18 Years of Age and 18 through 55 Years
of Age**

Ages 11 through 18 Years | Ages 18 through 55 Years | ||||||||

Menactra vaccine | Menomune -A/C/Y/W-135 vaccine | Menactra vaccine | Menomune -A/C/Y/W-135 vaccine | ||||||

N^{b}=423 |
N^{b}=423 |
N^{b}=1280 |
N^{b}=1098 |
||||||

Serogroup | (95% CI)^{c} |
(95% CI)^{c} |
(95% CI)^{c} |
(95% CI)^{c} |
|||||

A | % ≥ 4-fold rise^{d} GMT |
92.7 5483 | (89.8, 95.0) (4920, 6111) | 92.4 3246 | (89.5, 94.8) (2910, 3620) | 80.5 3897 | (78.2, 82.6) (3647, 4164) | 84.6 4114 | (82.3, 86.7) (3832, 4417) |

C | % ≥ 4-fold rise^{d} GMT |
91.7 1924 | (88.7, 94.2) (1662, 2228) | 88.7 1639 | (85.2, 91.5) (1406, 1911) | 88.5 3231 | (86.6, 90.2) (2955, 3533) | 89.7 3469 | (87.8, 91.4) (3148, 3823) |

Y | % ≥ 4-fold rise^{d} GMT |
81.8 1322 | (77.8, 85.4) (1162, 1505) | 80.1 1228 | (76.0, 83.8) (1088, 1386) | 73.5 1750 | (71.0, 75.9) (1597, 1918) | 79.4 2449 | (76.9, 81.8) (2237, 2680) |

W-135 | % ≥ 4-fold rise^{d} GMT |
96.7 1407 | (94.5, 98.2) (1232, 1607) | 95.3 1545 | (92.8, 97.1) (1384, 1725) | 89.4 1271 | (87.6, 91.0) (1172, 1378) | 94.4 1871 | (92.8, 95.6) (1723, 2032) |

^{a} Serum Bactericidal Assay with baby rabbit
complement (SBA-BR).^{b} N=Number of subset participants with at least one valid serology
result at Day 0 and Day 28.^{c} The 95% CI for the Geometric Mean Titer (GMT) was calculated based
on an approximation to the normal distribution.^{d} Menactra vaccine was non-inferior to Menomune - A/C/Y/W-135
vaccine. Non-inferiority was assessed by the proportion of participants with a
4-fold or greater rise in SBA-BR titer for N meningitidis serogroups A,
C, Y and W-135 using a 10% non-inferiority margin and a one-sided Type I error
rate of 0.05. |

In participants with undetectable pre-vaccination titers (ie, less than 1:8 at Day 0), seroconversion rates (defined as a ≥ 4-fold rise in Day 28 SBA-BR titers) were similar between the Menactra vaccine and Menomune - A/C/Y/W-135 vaccine recipients. Menactra vaccine participants achieved seroconversion rates of: 100%, Serogroup A (n=156/156); 99%, Serogroup C (n=343/345); 91%, Serogroup Y (n=253/279); 97%, Serogroup W-135 (n=360/373). The seroconversion rates for Menomune - A/C/Y/W-135 vaccine recipients were: 99%, Serogroup A (n=143/144); 98%, Serogroup C (n=297/304); 97%, Serogroup Y (n=221/228); 99%, Serogroup W-135 (n=325/328).

#### Concomitant Vaccine Administration

##### MMR V (or MMR + V) or PCV7

In a US, active-controlled trial, 1179 children received Menactra vaccine at 9 months and 12 months of age. At 12 months of age these children received Menactra concomitantly with MMRV (N=616), or MMR + V (N=48), or PCV7 (N=250). Another group of 12-month old children received MMRV + PCV7 (N=485). Sera were obtained approximately 30 days after the last vaccinations. Measles, mumps, rubella and varicella antibody responses among children who received Menactra vaccine and MMRV (or MMR and V) were comparable to corresponding antibody responses among children who received MMRV and PCV7.

When Menactra was given concomitantly with PCV7, the non-inferiority criteria for comparisons of pneumococcal IgG GMCs (upper limit of the two-sided 95% CI of the GMC ratio ≤ 2) were not met for 3 of 7 serotypes (4, 6B, 18C). In a subset of subjects with available sera, pneumococcal opsonophagocytic assay GMT data were consistent with IgG GMC data.

##### Td

In a double-blind, randomized, controlled trial, 1021 participants aged 11 through 17 years received Td and Menactra vaccines concomitantly (N=509), or Td followed one month later by Menactra vaccine (N=512). Sera were obtained approximately 28 days after each respective vaccination. The proportion of participants with a 4-fold or greater increase in SBA-BR titer to meningococcal Serogroups C, Y and W-135 was higher when Menactra vaccine was given concomitantly with Td (86-96%) than when Menactra vaccine was given one month following Td (65-91%). Anti-tetanus and anti-diphtheria antibody responses were similar in both study groups.

##### Typhim Vi

In a double-blind, randomized, controlled trial, 945 participants aged 18 through 55 years received Typhim Vi and Menactra vaccines concomitantly (N=469), or Typhim Vi vaccine followed one month later by Menactra vaccine (N=476). Sera were obtained approximately 28 days after each respective vaccination. The antibody responses to Menactra vaccine and to Typhim Vi vaccine components were similar in both study groups.

**REFERENCES**

6 Makela PH, et al. Evolution of conjugate vaccines. Expert Rev Vaccines 2002;1(3):399- 410.

7 Goldschneider I, et al. Human immunity to the meningococcus. I. The Role of Humoral Antibodies. J Exp Med 1969;129:1307-1326.

8 Maslanka SE, et al. Standardization and a Multilaboratory Comparison of Neisseria meningitidis Serogroup A and C Serum Bactericidal Assays. Clin and Diag Lab Immunol 1997;156-167.

*Last reviewed on RxList: 9/12/2014*

This monograph has been modified to include the generic and brand name in many instances.

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### Menactra FDA Prescribing Information

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## Menactra - User Reviews

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