Polysaccharide Diphtheria Toxoid Conjugate Vaccine

Menactra®, Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine, is a sterile, intramuscularly administered vaccine that contains Neisseria meningitidis serogroup A, C, Y and W-135 capsular polysaccharide antigens individually conjugated to diphtheria toxoid protein. Nmeningitidis A, C, Y and W-135 strains are cultured on Mueller Hinton agar3 and grown in Watson Scherp4 media. 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. Corynebacterium diphtheriae cultures are grown in a modified Mueller and Miller medium5 and detoxified with 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 vaccine 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 vaccine 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.

There is no latex in any component of the vial.

REFERENCES

3 Mueller JH, et al. A Protein-Free Medium for Primary Isolation of the Gonococcus and Meningococcus. Proc Soc Exp Biol Med 1941;48:330-333.

4 Watson RG, et al. The specific hapten of group C (group IIa) meningococcus. I. Preparation and immunological behavior. J Immunol 1958;81:331-336.

5 Mueller JH, et al. Production of diphtheria toxin of high potency (100 Lf) on a reproducible medium. J Immunol 1941;40:21-32.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine and may not reflect the rates observed in practice.

The safety of Menactra vaccine was evaluated in four clinical studies that enrolled 3721 participants who received Menactra vaccine at 9 and 12 months of age. At 12 months of age these children also received one or more other recommended vaccines [Measles, Mumps, Rubella and Varicella Virus Vaccine Live (MMRV) or Measles, Mumps, and Rubella Virus Vaccine (MMR) and Varicella Virus Vaccine Live (V) each manufactured by Merck & Co., Inc., Pneumococcal 7- valent Conjugate Vaccine (Diphtheria CRM197 Protein) manufactured by Wyeth Pharmaceuticals Inc. (PCV7), Hepatitis A Vaccine manufactured by Merck & Co., Inc. (HepA). A control group of 997 children was enrolled at 12 months of age and received two or more childhood vaccines [MMRV (or MMR + V), PCV7, HepA] at 12 months of age [see Concomitant Vaccine Administration]. Three percent of individuals received MMR and V, instead of MMRV, at 12 months of age.

The primary safety study was a controlled trial that enrolled 1256 children who received Menactra vaccine at 9 and 12 months of age. At 12 months of age these children received MMRV (or MMR + V), PCV7 and HepA. A control group of 522 children received MMRV, PCV7 and HepA. Of the 1778 children, 78% of participants (Menactra vaccine, N=1056; control group, N=322) were enrolled at United States (US) sites and 22% at a Chilean site. (Menactra vaccine, N=200; control group, N=200).

The safety of Menactra vaccine was evaluated in eight clinical studies that enrolled 10,057 participants aged 2-55 years who received Menactra vaccine and 5,266 participants who received Menomune® - A/C/Y/W-135, Meningococcal Polysaccharide Vaccine, Groups A, C, Y and W- 135 Combined. There were no substantive differences in demographic characteristics between the vaccine groups. Among Menactra vaccine recipients 2-55 years of age 24.0%, 16.2%, 40.4% and 19.4% were in the 2-10, 11-14, 15-25 and 26-55-year age groups, respectively. Among Menomune - A/C/Y/W-135 vaccine recipients 2-55 years of age 42.3%, 9.3%, 30.0% and 18.5% were in the 2-10, 11-14, 15-25 and 26-55-year age groups, respectively. The three primary safety studies were randomized, active-controlled trials that enrolled participants 2-10 years of age (Menactra vaccine, N=1713; Menomune - A/C/Y/W-135 vaccine, N=1519), 11-18 years of age (Menactra vaccine, N=2270; Menomune - A/C/Y/W-135 vaccine, N=972) and 18-55 years of age (Menactra vaccine, N=1384; Menomune - A/C/Y/W-135 vaccine, N=1170), respectively. Of the 3232 children 2-10 years of age, 68% of participants (Menactra vaccine, N=1164; Menomune - A/C/Y/W-135 vaccine, N=1031) were enrolled at US sites and 32% (Menactra vaccine, N=549; Menomune - A/C/Y/W-135 vaccine, N=488) of participants at a Chilean site. The median ages in the Chilean and US subpopulations were 5 and 6 years, respectively. All adolescents and adults were enrolled at US sites. As the route of administration differed for the two vaccines (Menactra vaccine given intramuscularly, Menomune - A/C/Y/W-135 vaccine given subcutaneously), study personnel collecting the safety data differed from personnel administering the vaccine.

Participants were monitored after each vaccination for 30 minutes for immediate reactions. Solicited injection site and systemic reactions were recorded in a diary card for 7 consecutive days after each vaccination. Participants were monitored for 28 days (30 days for infants and toddlers) for unsolicited adverse events and for 6 months post-vaccination for visits to an emergency room, unexpected visits to an office physician, and serious adverse events. Unsolicited adverse event information was obtained either by telephone interview or at an interim clinic visit. Information regarding adverse events that occurred in the 6-month post-vaccination time period was obtained via a scripted telephone interview.

Serious adverse events (SAEs) were reported during a 6-month time period following vaccinations in individuals 9 months through 55 years of age. In children who received Menactra vaccine at 9 months and at 12 months of age, SAEs occurred at a rate of 2.0% - 2.5%. In participants who received one or more childhood vaccine(s) (without co-administration of Menactra vaccine) at 12 months of age, SAEs occurred at a rate of 1.6% - 3.6%, depending on the number and type of vaccines received. In children 2-10 years of age, SAEs occurred at a rate of 0.6% following Menactra vaccine and at a rate of 0.7% following Menomune - A/C/Y/W-135 vaccine. In adolescents 11 through 18 years of age and adults 18 years through 55 years of age, SAEs occurred at a rate of 1.0% following Menactra vaccine and at a rate of 1.3% following Menomune - A/C/Y/W-135 vaccine.

The most frequently reported solicited injection site and systemic adverse reactions within 7 days following vaccination in children 9 months and 12 months of age (Table 1) were injection site tenderness and irritability.

The most frequently reported solicited injection site and systemic adverse reactions in US children aged 2 years through 10 years of age (Table 2) were injection site pain and irritability. Diarrhea, drowsiness, and anorexia were also common.

The most commonly reported solicited injection site and systemic adverse reactions in adolescents, ages 11-18 years (Table 3), and adults, ages 18-55 years (Table 4), were injection site pain, headache and fatigue. Except for redness in adults, injection site reactions were more frequently reported after Menactra vaccination than after Menomune - A/C/Y/W-135 vaccination.

Table 1: Percentage of US Participants Reporting Solicited Adverse Reactions Within 7 Days Following Vaccine Administration at 9 Months and 12 Months of Age

Table 2: Percentage of US Participants 2 Years Through 10 Years of Age Reporting  Solicited Adverse Reactions Within 7 Days Following Vaccine Administration

Table 3: Percentage of Participants 11 Years Through 18 Years of Age Reporting Solicited Adverse Reactions Within 7 Days Following Vaccine Administration

Table 4: Percentage of Participants 18 Years Through 55 Years of Age Reporting Solicited Adverse Reactions Within 7 Days Following Vaccine Administration

Solicited Injection site and Systemic Reactions when Given with Routine Pediatric Vaccines

For a description of the study design and number of participants [see Clinical Studies, Concomitant Vaccine Administration]. In the primary safety study, 1378 US children were enrolled to receive Menactra vaccine alone at 9 months of age and Menactra vaccine plus one or more other routinely administered vaccines (MMRV, PCV7 and HepA) at 12 months of age (N=961). Another group of children received two or more routinely administered vaccines (MMRV, PCV7 and HepA vaccines) (control group, n=321) at 12 months of age. The frequency of occurrence of solicited adverse events is presented in Table 1. Participants who received Menactra vaccine and the concomitant vaccines at 12 months of age described above reported similar frequencies of tenderness, redness and swelling at the Menactra vaccine injection site and at the concomitant vaccine injection sites. Tenderness was the most frequent injection site reaction (48%, 39%, 46% and 43% at the Menactra vaccine, MMRV, PCV7 and HepA vaccine sites, respectively). Irritability was the most frequent systemic reaction, reported in 62% of recipients of Menactra vaccine plus concomitant vaccines, and 65% of control group. [See Concomitant Vaccine Administration].

Solicited Injection site and Systemic Reactions when Given with Tetanus and Diphtheria Toxoid Adsorbed Vaccine

In a clinical study, rates of local and systemic reactions after Menactra vaccine and Tetanus and Diphtheria Toxoid Adsorbed (Td) vaccine manufactured by Sanofi Pasteur Inc. were compared [see DRUG INTERACTIONS, and Concomitant Vaccine Administration  for study description]. Injection site pain was reported more frequently after Td vaccination than after Menactra vaccination (71% versus 53%). The overall rate of systemic adverse events was higher when Menactra and Td vaccines were given concomitantly than when Menactra vaccine was administered 28 days after Td (59% versus 36%). In both groups, the most common reactions were headache (Menactra vaccine + Td, 36%; Td + Placebo, 34%; Menactra vaccine alone, 22%) and fatigue (Menactra vaccine + Td, 32%; Td + Placebo, 29%; Menactra vaccine alone, 17%). Fever ≥ 40.0°C occurred at ≤ 0.5% in all groups.

Solicited Injection site and Systemic Reactions when Given with Typhoid Vi Polysaccharide Vaccine

In a clinical study, rates of local and systemic reactions after Menactra vaccine and Typhoid Vi Polysaccharide Vaccine, produced by Sanofi Pasteur SA were compared [see DRUG INTERACTIONS, Concomitant Vaccine Administration] for a description of the concomitantly administered vaccine, study design and number of participants. More participants experienced pain after Typhoid vaccination than after Menactra vaccination (Typhoid + Placebo, 76% versus Menactra vaccine + Typhoid, 47%). The majority (70%-77%) of injection site solicited reactions for both groups at either injection site were reported as Grade 1 and resolved within 3 days postvaccination. In both groups, the most common systemic reaction was headache (Menactra vaccine + Typhoid, 41%; Typhoid + Placebo, 42%; Menactra vaccine alone, 33%) and fatigue (Menactra vaccine + Typhoid, 38%; Typhoid + Placebo, 35%; Menactra vaccine alone, 27%). Fever > 40.0°C and seizures were not reported in either group.

Post-Marketing Experience

In addition to reports in clinical trials, worldwide voluntary adverse events reports received since market introduction of Menactra vaccine 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 vaccine. 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.

• Immune System Disorders
  Hypersensitivity reactions such as anaphylaxis/anaphylactic reaction, wheezing, difficulty breathing, upper airway swelling, urticaria, erythema, pruritus, hypotension
• Nervous System Disorders
  Guillain-Barre syndrome, paraesthesia, vasovagal syncope, dizziness, convulsion, facial palsy, acute disseminated encephalomyelitis, transverse myelitis
• Musculoskeletal and Connective Tissue Disorders
  Myalgia

The risk of GBS following receipt of Menactra vaccine 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 vaccine. Of 72 medical chart-confirmed GBS cases, none had received Menactra vaccine 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.

Included as part of the PRECAUTIONS section.

No information provided.

Vaccine Information Statements are required by the National Childhood Vaccine Injury Act of 1986 to be given prior to immunization to the patient, parent, or guardian. These materials are available free of charge at the Centers for Disease Control and Prevention (CDC) website (www.cdc.gov/vaccines.)

Inform the patients, parents or guardians about:

• Potential benefits and risks of immunization with Menactra vaccine.
• Potential for adverse reactions that have been temporally associated with administration of Menactra vaccine or other vaccines containing similar components.
• Reporting any adverse reactions to their healthcare provider.
• The Sanofi Pasteur Inc. pregnancy registry, as appropriate.

Your doctor or pharmacist can provide more information about this vaccine. Additional information is available from your local health department or the Centers for Disease Control and Prevention.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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