Vaccine Information: KINRIX (Page 2 of 3)

6.2 Postmarketing Experience

In addition to reports in clinical trials for KINRIX, the following adverse reactions have been identified during postapproval use of KINRIX. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to vaccination.

General Disorders and Administration Site Conditions

Injection site vesicles.

Nervous System Disorders

Syncope.

Skin and Subcutaneous Tissue Disorders

Pruritus.

Additional adverse reactions reported following postmarketing use of INFANRIX, for which a causal relationship to vaccination is plausible, are: Allergic reactions, including anaphylactoid reactions, anaphylaxis, angioedema, and urticaria; apnea; collapse or shock-like state (hypotonic-hyporesponsive episode); convulsions (with or without fever); lymphadenopathy; and thrombocytopenia.

7 DRUG INTERACTIONS

7.1 Concomitant Vaccine Administration

In U.S. clinical trials, KINRIX was administered concomitantly with the second dose of MMR vaccine (Merck & Co., Inc.); in one of these trials (Study 055), KINRIX was also administered concomitantly with varicella vaccine (Merck & Co., Inc.) [see Clinical Studies (14.2)].

When KINRIX is administered concomitantly with other injectable vaccines, they should be given with separate syringes. KINRIX should not be mixed with any other vaccine in the same syringe.

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 KINRIX.

8 USE IN SPECIFIC POPULATIONS

8.4 Pediatric Use

Safety and effectiveness of KINRIX in children younger than 4 years and children aged 7 to 16 years have not been evaluated. KINRIX is not approved for use in persons in these age groups.

11 DESCRIPTION

KINRIX (Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed and Inactivated Poliovirus Vaccine) is a noninfectious, sterile vaccine for intramuscular administration. Each 0.5-mL dose is formulated to contain 25 Lf of diphtheria toxoid, 10 Lf of tetanus toxoid, 25 mcg of inactivated pertussis toxin (PT), 25 mcg of filamentous hemagglutinin (FHA), 8 mcg of pertactin (69 kiloDalton outer membrane protein), 40 D-antigen Units (DU) of Type 1 poliovirus (Mahoney), 8 DU of Type 2 poliovirus (MEF-1), and 32 DU of Type 3 poliovirus (Saukett). The diphtheria, tetanus, and pertussis components of KINRIX are the same as those in INFANRIX and PEDIARIX and the poliovirus component is the same as that in PEDIARIX.

The diphtheria toxin is produced by growing Corynebacterium diphtheriae (C. diphtheriae) in Fenton medium containing a bovine extract. Tetanus toxin is produced by growing Clostridium tetani (C. tetani) in a modified Latham medium derived from bovine casein. The bovine materials used in these extracts are sourced from countries which the United States Department of Agriculture (USDA) has determined neither have nor are at risk of bovine spongiform encephalopathy (BSE). Both toxins are detoxified with formaldehyde, concentrated by ultrafiltration, and purified by precipitation, dialysis, and sterile filtration.

The acellular pertussis antigens (PT, FHA, and pertactin) are isolated from Bordetella pertussis (B. pertussis) culture grown in modified Stainer-Scholte liquid medium. PT and FHA are isolated from the fermentation broth; pertactin is extracted from the cells by heat treatment and flocculation. The antigens are purified in successive chromatographic and precipitation steps. PT is detoxified using glutaraldehyde and formaldehyde. FHA and pertactin are treated with formaldehyde.

Diphtheria and tetanus toxoids and pertussis antigens (inactivated PT, FHA, and pertactin) are individually adsorbed onto aluminum hydroxide.

The inactivated poliovirus component of KINRIX is an enhanced potency component. Each of the 3 strains of poliovirus is individually grown in VERO cells, a continuous line of monkey kidney cells, cultivated on microcarriers. Calf serum and lactalbumin hydrolysate are used during VERO cell culture and/or virus culture. Calf serum is sourced from countries the USDA has determined neither have nor are at risk of BSE. After clarification, each viral suspension is purified by ultrafiltration, diafiltration, and successive chromatographic steps, and inactivated with formaldehyde. The 3 purified viral strains are then pooled to form a trivalent concentrate.

Diphtheria and tetanus toxoid potency is determined by measuring the amount of neutralizing antitoxin in previously immunized guinea pigs. The potency of the acellular pertussis components (inactivated PT, FHA, and pertactin) is determined by enzyme-linked immunosorbent assay (ELISA) on sera from previously immunized mice. The potency of the inactivated poliovirus component is determined by using the D-antigen ELISA and by a poliovirus-neutralizing cell culture assay on sera from previously immunized rats.

Each 0.5-mL dose contains aluminum hydroxide as adjuvant (formulated to contain 0.5 mg aluminum) and ≤4.4 mg of sodium chloride. The aluminum content is measured by assay. Each dose also contains ≤100 mcg of residual formaldehyde and ≤100 mcg of polysorbate 80 (Tween 80). Neomycin sulfate and polymyxin B sulfate are used in the poliovirus vaccine manufacturing process and may be present in the final vaccine at ≤0.05 ng neomycin and ≤0.01 ng polymyxin B per dose.

The tip caps of the prefilled syringes contain natural rubber latex; the plungers are not made with natural rubber latex.

KINRIX does not contain a preservative.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Diphtheria

Diphtheria is an acute toxin-mediated infectious disease caused by toxigenic strains of C. diphtheriae. Protection against disease is due to the development of neutralizing antibodies to the diphtheria toxin. A serum diphtheria antitoxin level of 0.01 IU/mL is the lowest level giving some degree of protection; a level of 0.1 IU/mL is regarded as protective.1

Tetanus

Tetanus is an acute toxin-mediated disease caused by a potent exotoxin released by C. tetani. Protection against disease is due to the development of neutralizing antibodies to the tetanus toxin. A serum tetanus antitoxin level of at least 0.01 IU/mL, measured by neutralization assays, is considered the minimum protective level.2,3 A level of ≥0.1 IU/mL is considered protective.4

Pertussis

Pertussis (whooping cough) is a disease of the respiratory tract caused by B. pertussis. The role of the different components produced by B. pertussis in either the pathogenesis of, or the immunity to, pertussis is not well understood. There is no well-established serological correlate of protection for pertussis. The efficacy of the pertussis component of KINRIX was determined in clinical trials of INFANRIX administered as a 3-dose series in infants (see INFANRIX prescribing information).

Poliomyelitis

Poliovirus is an enterovirus that belongs to the picornavirus family. Three serotypes of poliovirus have been identified (Types 1, 2, and 3). Neutralizing antibodies against the 3 poliovirus serotypes are recognized as conferring protection against poliomyelitis disease.5

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

14 CLINICAL STUDIES

14.1 Immunological Evaluation

In a U.S. multicenter study (Study 048), 4,209 children were randomized in a 3:1 ratio to receive either KINRIX or INFANRIX and IPV (Sanofi Pasteur SA) administered concomitantly at separate sites. Subjects also received MMR vaccine (Merck & Co., Inc.) administered concomitantly at a separate site. Subjects were children aged 4 through 6 years who previously received 4 doses of INFANRIX, 3 doses of IPV, and 1 dose of MMR vaccine. Among subjects in both vaccine groups combined, 49.6% were female; 45.6% of subjects were White, 18.8% Hispanic, 13.6% Asian, 7.0% Black, and 15.0% were of other racial/ethnic groups.

Levels of antibodies to the diphtheria, tetanus, pertussis (PT, FHA, and pertactin), and poliovirus antigens were measured in sera obtained immediately prior to vaccination and 1 month (range: 31 to 48 days) after vaccination (Table 2). The co-primary immunogenicity endpoints were anti-diphtheria toxoid, anti-tetanus toxoid, anti-PT, anti-FHA, and anti-pertactin booster responses, and anti-poliovirus Type 1, Type 2, and Type 3 geometric mean antibody titers (GMTs) 1 month after vaccination. KINRIX was shown to be non-inferior to INFANRIX and IPV administered separately, in terms of booster responses to DTaP antigens and post-vaccination GMTs for anti-poliovirus antibodies (Table 2).

Table 2. Pre-Vaccination Antibody Levels and Post-Vaccinationa Antibody Responses following KINRIX Compared with Separate Concomitant Administration of INFANRIX and IPV in Children Aged 4 to 6 Years when Coadministered with MMR Vaccine (Study 048) (ATP Cohort for Immunogenicity)
ATP = According-to-protocol; CI = Confidence Interval; GMT = Geometric mean antibody titer; IPV = Inactivated poliovirus vaccine (Sanofi Pasteur SA); MMR = Measles, mumps, and rubella vaccine (Merck & Co., Inc.).
n = Number of subjects with available results.
a One-month blood sampling, range 31 to 48 days.
b Seroprotection defined as anti-diphtheria toxoid and anti-tetanus toxoid antibody concentrations ≥0.1 IU/mL by ELISA and as anti-poliovirus Type 1, Type 2, and Type 3 antibody titer ≥1:8 by micro-neutralization assay for poliovirus.
c Booster response: In subjects with pre-vaccination <0.1 IU/mL, post-vaccination concentration ≥0.4 IU/mL. In subjects with pre-vaccination concentration ≥0.1 IU/mL, an increase of at least 4 times the pre-vaccination concentration.
d KINRIX was non-inferior to INFANRIX + IPV based on booster response rates (upper limit of 2-sided 95% CI on the difference of INFANRIX + IPV minus KINRIX ≤10%).
e Booster response: In subjects with pre-vaccination <5 EL.U./mL, post-vaccination concentration ≥20 EL.U./mL. In subjects with pre-vaccination ≥5 EL.U./mL and <20 EL.U./mL, an increase of at least 4 times the pre-vaccination concentration. In subjects with pre-vaccination ≥20 EL.U./mL, an increase of at least 2 times the pre-vaccination concentration.
f KINRIX was non-inferior to INFANRIX + IPV based on post-vaccination anti-poliovirus antibody GMTs adjusted for baseline titer (upper limit of 2-sided 95% CI for the GMT ratio [INFANRIX + IPV:KINRIX] ≤1.5).

KINRIX

INFANRIX + IPV

n = 787-851

n = 237-262

Antidiphtheria Toxoid

Pre-vaccination % ≥0.1 IU/mL (95% CI)b

87.7 (85.3, 89.9)

85.5 (80.6, 89.5)

Post-vaccination % ≥0.1 IU/mL (95% CI)b

100 (99.6, 100)

100 (98.6, 100)

% Booster Response (95% CI)c

99.5 (98.8, 99.9)d

100 (98.6, 100)

Antitetanus Toxoid

Pre-vaccination % ≥0.1 IU/mL (95% CI)b

87.8 (85.4, 90.0)

88.2 (83.6, 91.8)

Post-vaccination % ≥0.1 IU/mL (95% CI)b

100 (99.6, 100)

100 (98.6, 100)

% Booster Response (95% CI)c

96.7 (95.2, 97.8)d

93.9 (90.2, 96.5)

AntiPT

% Booster Response (95% CI)e

92.2 (90.2, 94.0)d

92.6 (88.7, 95.5)

AntiFHA

% Booster Response (95% CI)e

95.4 (93.7, 96.7)d

96.2 (93.1, 98.1)

Antipertactin

% Booster Response (95% CI)e

97.8 (96.5, 98.6)d

96.9 (94.1, 98.7)

Antipoliovirus 1

Pre-vaccination % ≥1:8 (95% CI)b

88.3 (85.9, 90.4)

85.1 (80.1, 89.2)

Post-vaccination % ≥1:8 (95% CI)b

99.9 (99.3, 100)

100 (98.5, 100)

Post-vaccination GMT (95% CI)

2,127 (1,976, 2,290)f

1,685 (1,475, 1,925)

Antipoliovirus 2

Pre-vaccination % ≥1:8 (95% CI)b

91.8 (89.7, 93.6)

87.0 (82.3, 90.8)

Post-vaccination % ≥1:8 (95% CI)b

100 (99.6, 100)

100 (98.5, 100)

Post-vaccination GMT (95% CI)

2,265 (2,114, 2,427)f

1,818 (1,606, 2,057)

Antipoliovirus 3

Pre-vaccination % ≥1:8 (95% CI)b

84.7 (82.0, 87.0)

85.0 (80.1, 89.1)

Post-vaccination % ≥1:8 (95% CI)b

100 (99.5, 100)

100 (98.5, 100)

Post-vaccination GMT (95% CI)

3,588 (3,345, 3,849)f

3,365 (2,961, 3,824)

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