Vaccine Information: Menactra (Page 2 of 4)

6.2 Post-Marketing Experience

In addition to reports in clinical trials, worldwide voluntary adverse events reports received since market introduction of Menactra are listed below. This list includes serious events and/or events which were included based on severity, frequency of reporting or a plausible causal connection to Menactra. Because these events were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to vaccination.

  • Blood and Lymphatic System Disorders
    Lymphadenopathy
  • Immune System Disorders
    Hypersensitivity reactions such as anaphylaxis/anaphylactic reaction, wheezing, difficulty breathing, upper airway swelling, urticaria, erythema, pruritus, hypotension
  • Nervous System Disorders
    Guillain-Barré syndrome, paraesthesia, vasovagal syncope, dizziness, convulsion, facial palsy, acute disseminated encephalomyelitis, transverse myelitis
  • Musculoskeletal and Connective Tissue Disorders
    Myalgia
  • General Disorders and Administrative Site Conditions Large injection site reactions, extensive swelling of the injected limb (may be associated with erythema, warmth, tenderness or pain at the injection site).

Post-marketing Safety Study

The risk of GBS following receipt of Menactra was evaluated in a US retrospective cohort study using healthcare claims data from 9,578,688 individuals 11 through 18 years of age, of whom 1,431,906 (15%) received Menactra. Of 72 medical chart-confirmed GBS cases, none had received Menactra within 42 days prior to symptom onset. An additional 129 potential cases of GBS could not be confirmed or excluded due to absent or insufficient medical chart information. In an analysis that took into account the missing data, estimates of the attributable risk of GBS ranged from 0 to 5 additional cases of GBS per 1,000,000 vaccinees within the 6-week period following vaccination.

7 DRUG INTERACTIONS

7.1 Concomitant Administration with Other Vaccines

Menactra vaccine was concomitantly administered with Typhim Vi® [Typhoid Vi Polysaccharide Vaccine] (Typhoid) and Tetanus and Diphtheria Toxoids Adsorbed, For Adult Use (Td) vaccine, in individuals 18 through 55 and 11 through 17 years of age, respectively. In children 4 through 6 years of age, Menactra was co-administered with DAPTACEL, and in children younger than 2 years of age, Menactra was co-administered with one or more of the following vaccines: PCV7, MMR, V, MMRV, or HepA [see Clinical Studies (14) and Adverse Reactions (6)].

When Menactra and DAPTACEL are to be administered to children 4 through 6 years of age, preference should be given to simultaneous administration of the 2 vaccines or administration of Menactra prior to DAPTACEL. Administration of Menactra one month after DAPTACEL has been shown to reduce meningococcal antibody responses to Menactra. Data are not available to evaluate the immune response to Menactra administered to younger children following DAPTACEL or to Menactra administered to persons <11 years of age following other diphtheria toxoid-containing vaccines [see Clinical Studies (14.3)].

Pneumococcal antibody responses to some serotypes in PCV7 were decreased following co-administration of Menactra and PCV7 [see Concomitant Vaccine Administration (14.3)].

Do not mix Menactra with other vaccines in the same syringe. When Menactra is administered concomitantly with other injectable vaccines, the vaccines should be administered with different syringes and given at separate injection sites.

7.2 Immunosuppressive Therapies

Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses) may reduce the immune response to vaccines.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Menactra during pregnancy. To enroll in or obtain information about the registry, call Sanofi Pasteur at 1-800-822-2463.

Risk Summary

All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. There are no adequate and well-controlled studies of Menactra administration in pregnant women in the US. Available data suggest that rates of major birth defects and miscarriage in women who received Menactra 30 days prior to pregnancy or during pregnancy are consistent with estimated background rates.

A developmental toxicity study was performed in female mice given 0.1 mL (in divided doses) of Menactra prior to mating and during gestation (a single human dose is 0.5 mL). The study revealed no evidence of harm to the fetus due to Menactra [see Animal Data (8.1)].

Data

Human Data

A pregnancy registry spanning 11 years (2005-2016) included 222 reports of exposure to Menactra from 30 days before or at any time during pregnancy. Of these reports, 87 had known pregnancy outcomes available and were enrolled in the pregnancy registry prior to the outcomes being known. Outcomes among these prospectively followed pregnancies included 2 major birth defects and 6 miscarriages.

Animal Data

A developmental toxicity study was performed in female mice. The animals were administered 0.1 mL of Menactra (in divided doses) at each of the following time points: 14 days prior to mating, and on Days 6 and 18 of gestation (a single human dose is 0.5 mL). There were no vaccine-related fetal malformations or variations, and no adverse effects on pre-weaning development observed in the study.

8.2 Lactation

Risk Summary

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Menactra and any potential adverse effects on the breastfed child from Menactra. Data are not available to assess the effects of Menactra on the breastfed infant or on milk production/excretion.

8.4 Pediatric Use

Menactra is not approved for use in infants under 9 months of age. Available data show that infants administered three doses of Menactra (at 2, 4, and 6 months of age) had diminished responses to each meningococcal vaccine serogroup compared to older children given two doses at 9 and 12 months of age.

8.5 Geriatric Use

Safety and effectiveness of Menactra in adults older than 55 years of age have not been established.

11 DESCRIPTION

Menactra is a sterile, intramuscularly administered vaccine that contains N meningitidis serogroup A, C, Y and W-135 capsular polysaccharide antigens individually conjugated to diphtheria toxoid protein. N meningitidis A, C, Y and W-135 strains are cultured on Mueller Hinton agar (3) and grown in Watson Scherp (4) media containing casamino acid. The polysaccharides are extracted from the N meningitidis cells and purified by centrifugation, detergent precipitation, alcohol precipitation, solvent extraction and diafiltration. To prepare the polysaccharides for conjugation, they are depolymerized, derivatized, and purified by diafiltration. Diphtheria toxin is derived from Corynebacterium diphtheriae grown in modified culture medium containing hydrolyzed casein (5) and is detoxified using formaldehyde. The diphtheria toxoid protein is purified by ammonium sulfate fractionation and diafiltration. The derivatized polysaccharides are covalently linked to diphtheria toxoid and purified by serial diafiltration. The four meningococcal components, present as individual serogroup-specific glycoconjugates, compose the final formulated vaccine. No preservative or adjuvant is added during manufacture. Each 0.5 mL dose may contain residual amounts of formaldehyde of less than 2.66 mcg (0.000532%), by calculation. Potency of Menactra is determined by quantifying the amount of each polysaccharide antigen that is conjugated to diphtheria toxoid protein and the amount of unconjugated polysaccharide present.

Menactra is manufactured as a sterile, clear to slightly turbid liquid. Each 0.5 mL dose of vaccine is formulated in sodium phosphate buffered isotonic sodium chloride solution to contain 4 mcg each of meningococcal A, C, Y and W-135 polysaccharides conjugated to approximately 48 mcg of diphtheria toxoid protein carrier.

The vial stopper is not made with natural rubber latex.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

13 NON-CLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Menactra has not been evaluated for carcinogenic or mutagenic potential, or for impairment of male fertility. A developmental animal toxicity study showed that Menactra had no effects on female fertility in mice [see Pregnancy (8.1)].

14 CLINICAL STUDIES

14.1 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 participants 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 participants 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 after a single dose 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 SBA.

14.2 Immunogenicity

Children 9 through 12 Months of Age

In a randomized, US, multi-center trial, children received Menactra at 9 months and 12 months of age. The first Menactra dose was administered alone, followed by a second Menactra dose given alone (N=404), or with MMRV (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 * 30 Days Following a Second Dose of Menactra Administered Alone or Concomitantly Administered with MMRV or PCV7 at 12 Months of Age
Vaccinations administered at 12 months of age following a dose of Menactra at 9 months of age
Menactra Menactra + MMRV Menactra + PCV7
(N=272-277) (N=177-180) (N=264-267)
Serogroup (95% CI) (95% CI) (95% CI)
*
Serum bactericidal assay with an exogenous human complement (SBA-H) source.
N=Number of participants with at least one valid serology result from a blood sample obtained between Days 30 to 44 post vaccination.
95% CIs for the proportions are calculated based on the Clopper-Pearson Exact method and normal approximation for that of the GMTs.
§
The proportion of participants achieving an SBA-H titer of at least 1:8 thirty days after the second dose of Menactra.
A % ≥1:8§ 95.6 (92.4; 97.7) 92.7 (87.8; 96.0) 90.5 (86.3; 93.8)
GMT 54.9 (46.8; 64.5) 52.0 (41.8; 64.7) 41.0 (34.6; 48.5)
C % ≥1:8§ 100.0 (98.7; 100.0) 98.9 (96.0; 99.9) 97.8 (95.2; 99.2)
GMT 141.8 (123.5; 162.9) 161.9 (136.3; 192.3) 109.5 (94.1; 127.5)
Y %≥1:8§ 96.4 (93.4; 98.2) 96.6 (92.8; 98.8) 95.1 (91.8; 97.4)
GMT 52.4 (45.4; 60.6) 60.2 (50.4; 71.7) 39.9 (34.4; 46.2)
W-135 %≥1:8§ 86.4 (81.8; 90.3) 88.2 (82.5; 92.5) 81.2 (76.0; 85.7)
GMT 24.3 (20.8; 28.3) 27.9 (22.7; 34.3) 17.9 (15.2; 21.0)

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 SBA-H 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 SBA-H 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 (N=2526) or Menomune – A/C/Y/W-135 (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 participants (2 through 3 years of age, n=52; 4-10 years of age, n=84) and Menomune – A/C/Y/W-135 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 * to Menactra and Menomune – A/C/Y/W-135 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 Menomune – A/C/Y/W-135 Menactra Menomune – A/C/Y/W-135
N =48-52 N =50-53 N =84 N =84
Serogroup (95% CI) (95% CI) (95% CI) (95% CI)
*
Serum bactericidal assay with an exogenous human complement (SBA-H) source.
N=Number of subset participants with at least one valid serology result at Day 0 and Day 28.
The 95% CI for the Geometric Mean Titer (GMT) was calculated based on an approximation to the normal distribution.
§
The proportion of participants achieving an SBA-H titer of at least 1:8 was assessed using a 10% non-inferiority margin and a one-sided Type 1 error rate of 0.025.
A % ≥1:8§ 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§ 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§ 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§ 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)

In the subset of participants 2 through 3 years of age with undetectable pre-vaccination titers (ie, SBA-H titers <1:4 at Day 0), seroconversion rates (defined as the proportions of participants with SBA-H titers ≥1:8 by Day 28) were similar between the Menactra and Menomune – A/C/Y/W-135 recipients. Menactra 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 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, SBA-H titers <1:4 at Day 0), seroconversion rates (defined as the proportions of participants with SBA-H titers ≥1:8 by Day 28) were similar between the Menactra and Menomune – A/C/Y/W-135 recipients. Menactra 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 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 and Menomune – A/C/Y/W-135 were similar for all four serogroups (Table 7).

In participants with undetectable pre-vaccination titers (ie, SBA-BR titers <1:8 at Day 0), seroconversion rates (defined as the proportions of participants achieving a ≥4-fold rise in SBA-BR titers by Day 28) were similar between the Menactra and Menomune – A/C/Y/W-135 recipients. Menactra participants achieved seroconversion rates of: 100%, Serogroup A (n=81/81); 99%, Serogroup C (n=153/155); 98%, Serogroup Y (n=60/61); 98%, Serogroup W-135 (n=161/164). The seroconversion rates for Menomune – A/C/Y/W-135 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 and Menomune – A/C/Y/W-135 were similar for all four serogroups (Table 7).

Table 7: Comparison of Bactericidal Antibody Responses * to Menactra and Menomune – A/C/Y/W-135 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 Menomune – A/C/Y/W-135 Menactra Menomune – A/C/Y/W-135
N =423 N =423 N =1280 N =1098
Serogroup (95% CI) (95% CI) (95% CI) (95% CI)
*
Serum bactericidal assay with baby rabbit complement (SBA-BR).
N=Number of subset participants with at least one valid serology result at Day 0 and Day 28.
The 95% CI for the Geometric Mean Titer (GMT) was calculated based on an approximation to the normal distribution.
§
Menactra was non-inferior to Menomune – A/C/Y/W-135. 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.
A % ≥4-fold rise § 92.7 (89.8, 95.0) 92.4 (89.5, 94.8) 80.5 (78.2, 82.6) 84.6 (82.3, 86.7)
GMT 5483 (4920, 6111) 3246 (2910, 3620) 3897 (3647, 4164) 4114 (3832, 4417)
C % ≥4-fold rise § 91.7 (88.7, 94.2) 88.7 (85.2, 91.5) 88.5 (86.6, 90.2) 89.7 (87.8, 91.4)
GMT 1924 (1662, 2228) 1639 (1406, 1911) 3231 (2955, 3533) 3469 (3148, 3823)
Y % ≥4-fold rise § 81.8 (77.8, 85.4) 80.1 (76.0, 83.8) 73.5 (71.0, 75.9) 79.4 (76.9, 81.8)
GMT 1322 (1162, 1505) 1228 (1088, 1386) 1750 (1597, 1918) 2449 (2237, 2680)
W-135 % ≥4-fold rise § 96.7 (94.5, 98.2) 95.3 (92.8, 97.1) 89.4 (87.6, 91.0) 94.4 (92.8, 95.6)
GMT 1407 (1232, 1607) 1545 (1384, 1725) 1271 (1172, 1378) 1871 (1723, 2032)

In participants with undetectable pre-vaccination titers (ie, SBA-BR titers <1:8 at Day 0), seroconversion rates (defined as the proportions of participants achieving a ≥4-fold rise in SBA-BR titers by Day 28) were similar between the Menactra and Menomune – A/C/Y/W-135 recipients. Menactra 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 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).

Immunogenicity in Adolescents and Adults Following Booster Vaccination

For a description of the study design and number of participants, [see Clinical Trials Experience, Booster Vaccination Study (6.1).] Prior to revaccination, the percentage of participants (n=781) with an SBA-H titer ≥1:8 were 64.5%, 44.2%, 38.7%, and 68.5% for Serogroups A, C, Y and W-135, respectively. Among the subset of trial participants (n=112) for whom SBA-H responses at Day 6 were assessed, 86.6%, 91.1%, 94.6%, and 92.0% achieved a ≥4-fold rise in SBA-H titer for Serogroups A, C, Y and W-135, respectively. The proportions of participants (n=781) who achieved a ≥4-fold rise in SBA-H titer by Day 28 were 95.0%, 95.3%, 97.1%, and 96% for Serogroups A, C, Y and W-135, respectively. The proportions of participants who achieved an SBA-H titer ≥1:8 by Day 28 were >99% for each serogroup.

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