Vaccine Information: QUADRACEL (Page 2 of 3)

6.2 Postmarketing Experience

The following adverse events have been spontaneously reported, during the post-marketing use of Quadracel outside the US, in infants and children from 2 months through 6 years of age. Because these events are reported voluntarily from a population of uncertain size, it is not possible to estimate their frequency reliably or establish a causal relationship to vaccine exposure. This list includes adverse events based on one or more of the following factors: severity, frequency of reporting, or strength of evidence for a causal relationship to Quadracel.

Immune system disorders

Anaphylactic reaction, hypersensitivity and allergic reactions (such as rash, urticaria, dyspnea)

Psychiatric disorders

Screaming

Nervous system disorders

Somnolence, convulsion, febrile convulsion, HHE, hypotonia

Cardiac disorders

Cyanosis

Vascular disorders

Pallor

General disorders and administration site conditions

Listlessness
Injection site reactions (including inflammation, mass, sterile abscess, and edema)
Large injection site reactions (>50 mm), including limb swelling which may extend from the injection site beyond one or both joints

Infections and Infestations

Injection site cellulitis, injection site abscess

7 DRUG INTERACTIONS

7.1 Concomitant Administration with Other Vaccines

In the US clinical trial, Study M5I02, Quadracel was administered concomitantly with one or more of the following US-licensed vaccines: MMR vaccine and varicella vaccine. [See Adverse Reactions (6.1).]

When Quadracel is given at the same time as another injectable vaccine(s), the vaccines should be administered with different syringes and at different injection sites.

7.2 Immunosuppressive Treatments

Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs and corticosteroids (used in greater than physiologic doses), may reduce the immune response to Quadracel. [See Warnings and Precautions (5.5).]

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Quadracel is not approved for use in individuals 7 years of age and older. No human or animal data are available to assess vaccine-associated risks in pregnancy.

8.2 Lactation

Quadracel is not approved for use in individuals 7 years of age and older. No human or animal data are available to assess the impact of Quadracel on milk production, its presence in breast milk, or its effects on the breastfed infant.

8.4 Pediatric Use

The safety and effectiveness of Quadracel has not been established in children less than 4 years of age or children 7 through 16 years of age and is not approved for use in these age groups.

11 DESCRIPTION

Quadracel (Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed and Inactivated Poliovirus Vaccine) is a sterile suspension for intramuscular injection.

Each 0.5 mL dose is formulated to contain 15 Lf diphtheria toxoid, 5 Lf tetanus toxoid, acellular pertussis antigens [20 mcg detoxified pertussis toxin (PT), 20 mcg filamentous hemagglutinin (FHA), 3 mcg pertactin (PRN), 5 mcg fimbriae types 2 and 3 (FIM)], and inactivated polioviruses [40 D-antigen units (DU) Type 1 (Mahoney), 8 DU Type 2 (MEF-1), 32 DU Type 3 (Saukett)].

Corynebacterium diphtheriae is grown in modified Mueller’s growth medium. (1) After purification by ammonium sulfate fractionation, the diphtheria toxin is detoxified with formaldehyde and diafiltered.

Clostridium tetani is grown in modified Mueller-Miller casamino acid medium without beef heart infusion. (2) Tetanus toxin is detoxified with formaldehyde and purified by ammonium sulfate fractionation and diafiltration. Diphtheria and tetanus toxoids are individually adsorbed onto aluminum phosphate.

The acellular pertussis vaccine antigens are produced from Bordetella pertussis cultures grown in Stainer-Scholte medium (3) modified by the addition of casamino acids and dimethyl-beta-cyclodextrin. PT, FHA and PRN are isolated separately from the supernatant culture medium. FIM are extracted and copurified from the bacterial cells. The pertussis antigens are purified by sequential filtration, salt-precipitation, ultrafiltration and chromatography. PT is detoxified with glutaraldehyde. FHA is treated with formaldehyde and the residual aldehydes are removed by ultrafiltration. The individual antigens are adsorbed separately onto aluminum phosphate.

Poliovirus Type 1, Type 2 and Type 3 are each grown in separate cultures of MRC-5 cells, a line of normal human diploid cells, by the microcarrier method. (4) (5) The cells are grown in CMRL (Connaught Medical Research Laboratories) 1969 medium, supplemented with calf serum. For viral growth, the culture medium is replaced by Medium 199, without calf serum. After clarification and filtration, the viral suspensions are concentrated by ultrafiltration, and purified by liquid chromatography steps. The monovalent viral suspensions are inactivated with formaldehyde. Monovalent concentrates of each inactivated poliovirus are combined to produce a trivalent poliovirus concentrate.

The adsorbed diphtheria, tetanus and acellular pertussis antigens are combined with aluminum phosphate, 2-phenoxyethanol (not as a preservative) and water for injection, into an intermediate concentrate. The trivalent poliovirus concentrate is added and the vaccine is diluted to its final concentration.

Each 0.5 mL dose contains 1.5 mg aluminum phosphate (0.33 mg aluminum) as the adjuvant, polysorbate 80 (approximately 10 ppm by calculation), <2 mcg residual formaldehyde, <50 ng residual glutaraldehyde, ≤50 ng residual bovine serum albumin, 3.3 mg (0.6% v/v) 2-phenoxyethanol (not as a preservative), <4 pg of neomycin and <4 pg polymyxin B sulfate.

Quadracel does not contain a preservative.

Both diphtheria and tetanus toxoids induce at least 2 neutralizing units per mL in the guinea pig potency test. The potency of the acellular pertussis antigens is evaluated by the antibody response of immunized mice to detoxified PT, FHA, PRN and FIM as measured by enzyme-linked immunosorbent assay (ELISA). The potency of the inactivated poliovirus antigens is determined by measuring antibody-mediated neutralization of poliovirus in sera from immunized rats.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Diphtheria

Diphtheria is an acute toxin-mediated disease caused by toxigenic strains of C. diphtheriae. Protection against disease is due to the development of neutralizing antibodies to diphtheria toxin. A serum diphtheria antitoxin level of 0.01 IU/mL is the lowest level giving some degree of protection. Antitoxin levels of at least 0.1 IU/mL are generally regarded as protective. (6) Levels of 1.0 IU/mL have been associated with long-term protection. (7)

Tetanus

Tetanus is an acute disease caused by an extremely potent neurotoxin produced by C. tetani. Protection against disease is due to the development of neutralizing antibodies to tetanus toxin. A serum tetanus antitoxin level of at least 0.01 IU/mL, measured by neutralization assay, is considered the minimum protective level. (6) (8). A tetanus antitoxoid level ≥0.1 IU/mL as measured by the ELISA used in clinical studies of Quadracel is considered protective.

Pertussis

Pertussis (whooping cough) is a respiratory disease caused by B. pertussis. This Gram-negative coccobacillus produces a variety of biologically active components, though their role in either the pathogenesis of, or immunity to, pertussis has not been clearly defined.

There is no well-established serological correlate of protection for pertussis. Because DAPTACEL contains the same pertussis antigens manufactured by the same process as those in Quadracel, the effectiveness of Quadracel against pertussis was based on a comparison of pertussis immune responses following Quadracel to those following DAPTACEL (Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed). [See Clinical Studies (14)]. The efficacy of the pertussis component of DAPTACEL was determined in clinical trials of DAPTACEL administered to infants (see DAPTACEL prescribing information). Quadracel contains twice as much detoxified PT and four times as much FHA as DAPTACEL.

Poliomyelitis

Polioviruses, of which there are three serotypes (Types 1, 2, and 3), are enteroviruses. The presence of poliovirus type-specific neutralizing antibodies has been correlated with protection against poliomyelitis. (9)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Quadracel has not been evaluated for carcinogenic or mutagenic potential or impairment of fertility.

14 CLINICAL STUDIES

14.1 Immunogenicity

In Study M5I02, children 4 through 6 years of age received Quadracel or DAPTACEL + IPOL as the fifth dose in the diphtheria, tetanus, and pertussis vaccination series and the fourth or fifth dose in the inactivated poliovirus vaccination series. Subjects also received their second dose of MMR and Varicella vaccines, concomitantly. The immunogenicity subset comprised 263 subjects in the Quadracel group and 253 subjects in the DAPTACEL + IPOL vaccines group. [See study description in Adverse Reactions (6.1)].

Antibody levels to diphtheria, tetanus, pertussis (PT, FHA, PRN and FIM) and poliovirus antigens were measured in sera obtained immediately prior to vaccination and 28 days after vaccination. The co-primary endpoints were booster response rates and antibody geometric mean concentrations/titers (GMCs/GMTs) to diphtheria, tetanus, pertussis and poliovirus antigens elicited after vaccination. Booster response rates and antibody GMCs/GMTs following Quadracel vaccination were compared to those after DAPTACEL + IPOL vaccination.

Quadracel was non-inferior to DAPTACEL + IPOL vaccines administered concomitantly at separate sites, as demonstrated by comparison of the post-vaccination antibody booster response rates and GMCs/GMTs to diphtheria and tetanus (Table 2), to all pertussis antigens (Table 3) and to poliovirus 1, 2 and 3 (Table 4).

Table 2: Booster Response Rates, Pre- and Post-Vaccination Seroprotection Rates and Post-Vaccination Antibody Levels to Diphtheria and Tetanus Antigens Following Quadracel or Concomitant but Separate DAPTACEL and IPOL Vaccines Co-Administered with MMR and Varicella Vaccines *
Quadracel(N =253-262) DAPTACEL + IPOL(N =248-253)
*
ClinicalTrials.gov Identifier: NCT01346293.
N = The number of subjects with available data.
Booster response: In subjects with pre-vaccination antibody concentrations <0.1 IU/mL, a post-vaccination level ≥0.4 IU/mL; in subjects with pre-vaccination antibody concentrations ≥0.1 IU/mL but <2.0 IU/mL, a 4-fold rise in post-vaccination level; in subjects with pre-vaccination antibody level ≥2.0 IU/mL, a 2-fold rise in post-vaccination level.
§
Quadracel was non-inferior to DAPTACEL + IPOL based on the post-vaccination booster response rates for diphtheria and tetanus (lower limits of the 2-sided 95% CIs of the difference [Quadracel minus DAPTACEL + IPOL] were >-10%).
Seroprotection: anti-diphtheria and anti-tetanus antibody concentrations ≥0.1 IU/mL and ≥1.0 IU/mL.
#
Quadracel was non-inferior to DAPTACEL + IPOL based on the post-vaccination GMCs for diphtheria and tetanus (lower limits of the 2-sided 95% CIs of the ratio [Quadracel / DAPTACEL + IPOL] were >2/3).
Anti-Diphtheria
% Booster Response 97.3§ 99.2
Pre-vaccination % ≥0.1 IU/mL 90.7 83.1
Post-vaccination % ≥0.1 IU/mL 100.0 99.6
Post-vaccination % ≥1.0 IU/mL 99.6 99.6
Post-vaccination GMC (IU/mL) 18.6# 15.5
Anti-Tetanus
% Booster Response 84.2§ 84.3
Pre-vaccination % ≥0.1 IU/mL 91.7 89.1
Post-vaccination % ≥0.1 IU/mL 100.0 99.2
Post-vaccination % ≥1.0 IU/mL 98.9 96.8
Post-vaccination GMC (IU/mL) 6.4# 5.5
Table 3: Booster Response Rates and Post-vaccination Antibody Levels to Pertussis Antigens Following Quadracel or Concomitant but Separate DAPTACEL and IPOL Vaccines Co-Administered with MMR and Varicella Vaccines *
Quadracel(N =250-255) DAPTACEL + IPOL(N =247-249)
*
ClinicalTrials.gov Identifier: NCT01346293.
N = The number of subjects with available data.
Booster response: In subjects with pre-vaccination antibody concentrations <LLOQ, a post-vaccination level ≥4×LLOQ; in subjects with pre-vaccination antibody concentrations ≥LLOQ but <4×LLOQ, a 4-fold rise in post-vaccination level; in subjects with pre-vaccination antibody level ≥4×LLOQ, a 2-fold rise in post-vaccination level.
§
Quadracel was non-inferior to DAPTACEL + IPOL based on the post-vaccination booster response rates for all pertussis antigens (lower limits of the 2-sided 95% CIs of the difference [Quadracel minus DAPTACEL + IPOL] were > -10%).
Quadracel was non-inferior to DAPTACEL + IPOL based on the post-vaccination GMCs for all pertussis antigens (lower limits of the 2-sided 95% CIs of the ratio [DTaP-IPV / DAPTACEL + IPOL] were >2/3).
Anti-PT
% Booster Response 95.2§ 89.9
Post-vaccination GMC (EU/mL) 120.7 61.3
Anti-FHA
% Booster Response 94.9§ 87.5
Post-vaccination GMC (EU/mL) 123.5 79.0
Anti-PRN
% Booster Response 96.9§ 93.1
Post-vaccination GMC (EU/mL) 282.6 187.5
Anti-FIM
% Booster Response 97.2§ 92.4
Post-vaccination GMC (EU/mL) 505.8 378.9
Table 4: Booster Response Rates, Pre- and Post-Vaccination Seroprotection Rates and Post-vaccination Antibody Levels to Poliovirus Antigens Following Quadracel or Concomitant but Separate DAPTACEL and IPOL Vaccines Co-Administered with MMR and Varicella Vaccines *
Quadracel(N =247-258) DAPTACEL + IPOL(N =248-253)
*
ClinicalTrials.gov Identifier: NCT01346293.
N = The number of subjects with available data.
Booster response: In subjects with pre-vaccination antibody concentrations <1:8 dilution, post-vaccination levels ≥1:8 dil; in subjects with pre-vaccination antibody concentrations ≥1:8 dilution, a 4-fold rise in post-vaccination antibody levels.
§
Quadracel was non-inferior to DAPTACEL + IPOL based on the post-vaccination booster response rates for polio types 1, 2 and 3 (lower limits of the 2-sided 95% CIs of the difference [Quadracel minus DAPTACEL + IPOL] were > -10%).
Quadracel was non-inferior to DAPTACEL + IPOL based on the post-vaccination GMTs for polio types 1, 2 and 3 (lower limits of the 2-sided 95% CIs of the ratio [Quadracel / DAPTACEL + IPOL] were >2/3).
Anti-Poliovirus 1
% Booster Response 85.9§ 82.3
Pre-vaccination % ≥1:8 dilution 98.4 98.8
Post-vaccination % ≥1:8 dilution 100.0 99.6
Post-vaccination GMT 3,477 2,731
Anti-Poliovirus 2
% Booster Response 78.3§ 79.0
Pre-vaccination % ≥1:8 dilution 99.6 99.6
Post-vaccination % ≥1:8 dilution 100.0 100.0
Post-vaccination GMT 3,491 3,894
Anti-Poliovirus 3
% Booster Response 85.0§ 84.7
Pre-vaccination % ≥1:8 dilution 96.8 93.1
Post-vaccination % ≥1:8 dilution 100.0 100.0
Post-vaccination GMT 4,591 3,419

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