INFANRIX: Package Insert and Label Information (Page 2 of 2)

6.2 Postmarketing Experience

In addition to reports in clinical trials for INFANRIX, the following adverse reactions have been identified during postapproval use of INFANRIX. 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.

Infections and Infestations

Bronchitis, cellulitis, respiratory tract infection.

Blood and Lymphatic System Disorders

Lymphadenopathy, thrombocytopenia.

Immune System Disorders

Anaphylactic reaction, hypersensitivity.

Nervous System Disorders

Encephalopathy, headache, hypotonia, syncope.

Ear and Labyrinth Disorders

Ear pain.

Cardiac Disorders

Cyanosis.

Respiratory, Thoracic, and Mediastinal Disorders

Apnea, cough.

Skin and Subcutaneous Tissue Disorders

Angioedema, erythema, pruritus, rash, urticaria.

General Disorders and Administration Site Conditions

Fatigue, injection site induration, injection site reaction, Sudden Infant Death Syndrome.

7 DRUG INTERACTIONS

7.1 Concomitant Vaccine Administration

In clinical trials, INFANRIX was given concomitantly with Hib conjugate vaccine, pneumococcal 7-valent conjugate vaccine, hepatitis B vaccine, IPV, and the second dose of MMR vaccine [see Adverse Reactions (6.1), Clinical Studies (14.3)].

When INFANRIX is administered concomitantly with other injectable vaccines, they should be given with separate syringes. INFANRIX 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 INFANRIX.

8 USE IN SPECIFIC POPULATIONS

8.4 Pediatric Use

Safety and effectiveness of INFANRIX in infants aged younger than 6 weeks and children aged 7 to 16 years have not been established. INFANRIX is not approved for use in these age groups.

11 DESCRIPTION

INFANRIX (Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed) 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), and 8 mcg of pertactin (69 kiloDalton outer membrane protein).

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 present an undue risk for 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 (PT, FHA, and pertactin) are individually adsorbed onto aluminum hydroxide.

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 (PT, FHA, and pertactin) is determined by enzyme-linked immunosorbent assay (ELISA) on sera from previously immunized mice.

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).

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

INFANRIX is formulated without preservatives.

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 infectious 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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

14 CLINICAL STUDIES

14.1 Diphtheria and Tetanus

Efficacy of diphtheria toxoid used in INFANRIX was determined on the basis of immunogenicity studies. A VERO cell toxin-neutralizing test confirmed the ability of infant sera (N = 45), obtained one month after a 3-dose primary series, to neutralize diphtheria toxin. Levels of diphtheria antitoxin ≥0.01 IU/mL were achieved in 100% of the sera tested.

Efficacy of tetanus toxoid used in INFANRIX was determined on the basis of immunogenicity studies. An in vivo mouse neutralization assay confirmed the ability of infant sera (N = 45), obtained1 month after a 3-dose primary series, to neutralize tetanus toxin. Levels of tetanus antitoxin ≥0.01 IU/mL were achieved in 100% of the sera tested.

14.2 Pertussis

Efficacy of a 3-dose primary series of INFANRIX has been assessed in 2 clinical studies.

A double-blind, randomized, active Diphtheria and Tetanus Toxoids (DT)-controlled trial conducted in Italy assessed the absolute protective efficacy of INFANRIX when administered at 2, 4, and 6 months of age. The population used in the primary analysis of the efficacy of INFANRIX included 4,481 infants vaccinated with INFANRIX and 1,470 DT vaccinees. The mean length of follow-up was 17 months, beginning 30 days after the third dose of vaccine. After 3 doses, the absolute protective efficacy of INFANRIX against WHO-defined typical pertussis (21 days or more of paroxysmal cough with infection confirmed by culture and/or serologic testing) was 84% (95% CI: 76, 89). When the definition of pertussis was expanded to include clinically milder disease with respect to type and duration of cough, with infection confirmed by culture and/or serologic testing, the efficacy of INFANRIX was calculated to be 71% (95% CI: 60, 78) against >7 days of any cough and 73% (95% CI: 63, 80) against ≥14 days of any cough. Vaccine efficacy after 3 doses and with no booster dose in the second year of life was assessed in 2 subsequent follow-up periods. A follow-up period from 24 months to a mean age of 33 months was conducted in a partially unblinded cohort (children who received DT were offered pertussis vaccine and those who declined were retained in the study cohort). During this period, the efficacy of INFANRIX against WHO-defined pertussis was 78% (95% CI: 62, 87). During the third follow-up period, which was conducted in an unblinded manner among children aged 3 to 6 years, the efficacy of INFANRIX against WHO-defined pertussis was 86% (95% CI: 79, 91). Thus, protection against pertussis in children administered 3 doses of INFANRIX in infancy was sustained to 6 years of age.

A prospective efficacy trial was also conducted in Germany employing a household contact study design. In preparation for this study, 3 doses of INFANRIX were administered at 3, 4, and 5 months of age to more than 22,000 children living in 6 areas of Germany in a safety and immunogenicity study. Infants who did not participate in the safety and immunogenicity study could have received a DTwP vaccine or DT vaccine. Index cases were identified by spontaneous presentation to a physician. Households with at least one other member (i.e., besides index case) aged 6 through 47 months were enrolled. Household contacts of index cases were monitored for incidence of pertussis by a physician who was blinded to the vaccination status of the household. Calculation of vaccine efficacy was based on attack rates of pertussis in household contacts classified by vaccination status. Of the 173 household contacts who had not received a pertussis vaccine, 96 developed WHO-defined pertussis, as compared with 7 of 112 contacts vaccinated with INFANRIX. The protective efficacy of INFANRIX was calculated to be 89% (95% CI: 77, 95), with no indication of waning of protection up until the time of the booster vaccination. The average age of infants vaccinated with INFANRIX at the end of follow-up in this trial was 13 months (range: 6 to 25 months). When the definition of pertussis was expanded to include clinically milder disease, with infection confirmed by culture and/or serologic testing, the efficacy of INFANRIX against ≥7 days of any cough was 67% (95% CI: 52, 78) and against ≥7 days of paroxysmal cough was 81% (95% CI: 68, 89). The corresponding efficacy of INFANRIX against ≥14 days of any cough or paroxysmal cough were 73% (95% CI: 59, 82) and 84% (95% CI: 71, 91), respectively.

Pertussis Immune Response to INFANRIX Administered as a 3-Dose Primary Series

The immune responses to each of the 3 pertussis antigens contained in INFANRIX were evaluated in sera obtained 1 month after the third dose of vaccine in each of 3 studies (schedule of administration: 2, 4, and 6 months of age in the Italian efficacy study and one U.S. study; 3, 4, and 5 months of age in the German efficacy study). One month after the third dose of INFANRIX, the response rates to each pertussis antigen were similar in all 3 studies. Thus, although a serologic correlate of protection for pertussis has not been established, the antibody responses to these 3 pertussis antigens (PT, FHA, and pertactin) in a U.S. population were similar to those achieved in 2 populations in which efficacy of INFANRIX was demonstrated.

14.3 Immune Response to Concomitantly Administered Vaccines

In a U.S. study, INFANRIX was given concomitantly, at separate sites, with Hib conjugate vaccine (Sanofi Pasteur SA) at 2, 4, and 6 months of age. Subjects also received ENGERIX-B and oral poliovirus vaccine (OPV). One month after the third dose of Hib conjugate vaccine, 90% of 72 infants had anti-PRP (polyribosyl-ribitol-phosphate) ≥1.0 mcg/mL.

In a U.S. study, INFANRIX was given concomitantly, at separate sites, with ENGERIX-B, IPV (Sanofi Pasteur SA), pneumococcal 7-valent conjugate (PCV7), and Hib conjugate vaccines (Wyeth Pharmaceuticals Inc.; no longer licensed in the United States) at 2, 4, and 6 months of age. Immune responses were measured in sera obtained approximately 1 month after the third dose of vaccines. Among 121 subjects who had not received a birth dose of hepatitis B vaccine, 99.2% had anti-HBsAg (hepatitis B surface antigen) ≥10 mIU/mL following the third dose of ENGERIX-B. Among 153 subjects, 100% had anti-poliovirus 1, 2, and 3, ≥1:8 following the third dose of IPV. Although serological correlates for protection have not been established for the pneumococcal serotypes, a threshold level of ≥0.3 mcg/mL was evaluated. Following the third dose of PCV7 vaccine, 91.8% to 99.4% of subjects (n = 146-156) had anti-pneumococcal polysaccharide ≥0.3 mcg/mL for serotypes 4, 9V, 14, 18C, 19F, and 23F, and 73.0% had a level ≥0.3 mcg/mL for serotype 6B.

15 REFERENCES

1.
Vitek CR and Wharton M. Diphtheria Toxoid. In: Plotkin SA, Orenstein WA, and Offit PA, eds. Vaccines. 5th ed. Saunders; 2008:139-156.
2.
Wassilak SGF, Roper MH, Kretsinger K, and Orenstein WA. Tetanus Toxoid. In: Plotkin SA, Orenstein WA, and Offit PA, eds. Vaccines. 5th ed. Saunders; 2008:805-839.
3.
Department of Health and Human Services, Food and Drug Administration. Biological products; Bacterial vaccines and toxoids; Implementation of efficacy review; Proposed rule. Federal Register. December 13, 1985;50(240):51002-51117.
4.
Centers for Disease Control and Prevention. General Recommendations on Immunization. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 2006;55(RR-15):1-48.

16 HOW SUPPLIED/STORAGE AND HANDLING

INFANRIX is available in 0.5-mL single-dose, disposable, prefilled TIP‑LOK syringes (packaged without needles):

NDC 58160-810-43 Syringe in Package of 10: NDC 58160-810-52

Store refrigerated between 2° and 8°C (36° and 46°F). Do not freeze. Discard if the vaccine has been frozen.

17 PATIENT COUNSELING INFORMATION

Provide the following information to the parent or guardian:

Inform of the potential benefits and risks of immunization with INFANRIX, and of the importance of completing the immunization series.
Inform about the potential for adverse reactions that have been temporally associated with administration of INFANRIX or other vaccines containing similar components.
Instruct to report any adverse events to their healthcare provider.
Give the Vaccine Information Statements, which are required by the National Childhood Vaccine Injury Act of 1986 to be given prior to immunization. These materials are available free of charge at the Centers for Disease Control and Prevention (CDC) website (www.cdc.gov/vaccines).

ENGERIX-B, INFANRIX, PEDIARIX, and TIP-LOK are trademarks owned by or licensed to the GSK group of companies.

Manufactured by GlaxoSmithKline Biologicals

Rixensart, Belgium, U.S. License 1617

GSK Vaccines GmbH

Marburg, Germany, U.S. License 1617

Distributed by GlaxoSmithKline

Durham, NC 27701

©2023 GSK group of companies or its licensor.

INF:31PI

PRINCIPAL DISPLAY PANEL

NDC 58160-810-52

INFANRIX

Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed

DTaP

Rx only

For Use from 6 Weeks to 7 Years of Age

10 Disposable Single-Dose Prefilled TIP-LOK Syringes each containing one 0.5-mL dose

TIP-LOK syringes are compatible with LUER-LOK needles

NEEDLES NOT INCLUDED

GSK

INFANRIX and TIP-LOK are trademarks owned by or licensed to the GSK group of companies.

LUER-LOK is a trademark owned by or licensed to Becton, Dickinson, and Company.

Made in Belgium

©2019 GSK group of companies or its licensor.

Rev. 3/19

496045

Infanrix Prefilled Syringe 10 count carton
(click image for full-size original)
INFANRIX diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed suspension
Product Information
Product Type VACCINE Item Code (Source) NDC:58160-810
Route of Administration INTRAMUSCULAR DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
CLOSTRIDIUM TETANI TOXOID ANTIGEN (FORMALDEHYDE INACTIVATED) (CLOSTRIDIUM TETANI TOXOID ANTIGEN (FORMALDEHYDE INACTIVATED)) CLOSTRIDIUM TETANI TOXOID ANTIGEN (FORMALDEHYDE INACTIVATED) 10 [iU] in 0.5 mL
CORYNEBACTERIUM DIPHTHERIAE TOXOID ANTIGEN (FORMALDEHYDE INACTIVATED) (CORYNEBACTERIUM DIPHTHERIAE TOXOID ANTIGEN (FORMALDEHYDE INACTIVATED)) CORYNEBACTERIUM DIPHTHERIAE TOXOID ANTIGEN (FORMALDEHYDE INACTIVATED) 25 [iU] in 0.5 mL
BORDETELLA PERTUSSIS TOXOID ANTIGEN (FORMALDEHYDE, GLUTARALDEHYDE INACTIVATED) (BORDETELLA PERTUSSIS TOXOID ANTIGEN (FORMALDEHYDE, GLUTARALDEHYDE INACTIVATED)) BORDETELLA PERTUSSIS TOXOID ANTIGEN (FORMALDEHYDE, GLUTARALDEHYDE INACTIVATED) 25 ug in 0.5 mL
BORDETELLA PERTUSSIS FILAMENTOUS HEMAGGLUTININ ANTIGEN (FORMALDEHYDE INACTIVATED) (BORDETELLA PERTUSSIS FILAMENTOUS HEMAGGLUTININ ANTIGEN (FORMALDEHYDE INACTIVATED)) BORDETELLA PERTUSSIS FILAMENTOUS HEMAGGLUTININ ANTIGEN (FORMALDEHYDE INACTIVATED) 25 ug in 0.5 mL
BORDETELLA PERTUSSIS PERTACTIN ANTIGEN (FORMALDEHYDE INACTIVATED) (BORDETELLA PERTUSSIS PERTACTIN ANTIGEN (FORMALDEHYDE INACTIVATED)) BORDETELLA PERTUSSIS PERTACTIN ANTIGEN (FORMALDEHYDE INACTIVATED) 8 ug in 0.5 mL
Inactive Ingredients
Ingredient Name Strength
ALUMINUM HYDROXIDE
FORMALDEHYDE
SODIUM CHLORIDE
POLYSORBATE 80
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:58160-810-52 10 SYRINGE in 1 CARTON contains a SYRINGE (58160-810-43)
1 NDC:58160-810-43 0.5 mL in 1 SYRINGE This package is contained within the CARTON (58160-810-52)
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
BLA BLA103647 07/24/2009
Labeler — GlaxoSmithKline Biologicals SA (372748392)

Revised: 01/2023 GlaxoSmithKline Biologicals SA

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