Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed, Hepatitis B Vaccine (Recombinant), and Poliovirus Vaccine Inactivated - Pediarix; DTaP-HepB-IPV; Infanrix + Engerix-B + IPV
Status: approved and marketed in U.S. and EU
Organizations involved:
GlaxoSmithKline Biologicals S.A. – Manuf.; R&D; Tech.; Intl. mark.
GlaxoSmithKline Inc – USA mark.
GlaxoSmithKline plc – Parent
Chiron Behring GmbH & Co. – Manuf. other
Chiron Corp. – Parent
Novartis AG – Parent
Cross ref.: See the entries for the component vaccines of this combination vaccine –Infanrix (DTaP vaccine (#433); itself a 3-component vaccine), Engerix-B (hepatitis B virus vaccine) (#175), and Poliovirus Vaccine (IPV)/GSK (not previously approved in the U.S.) (#520). See the entry below for Infanrix Penta (#442), the comparable vaccine from GSK marketed in Europe. See also the DT Vaccine (#422) from Chiron used for manufacture of this vaccine. See the entries for Acellular Pertussis Vaccine Products entry (#506); Diphtheria and Pertussis Toxoids and Pertussis Vaccine (DTP/DTaP) Products (#429); Hepatitis B Vaccine Products (#468); Polio Vaccine Products (#516); Tetanus Toxoid Products (#543); and Diphtheria Toxoid Products (#418).
Description: Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Hepatitis B (Recombinant) and Inactivated Poliovirus Vaccine Combined or Pediarix is an aqueous pentavalent (5-component) combination vaccine for intramuscular administration. This combination vaccine is designed to protect infants against diphtheria (Corynebacterium diphtheriae bacteria infection), tetanus (Clostridium tetani bacteria infection), pertussis (Bordetella pertussis bacteria infection; whooping cough), poliovirus, and hepatitis B virus (HBV) infections.
Pediarix essentially contains Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, a trivalent DTaP vaccine (marketed as Infanrix); recombinant Saccharomyces cerevisiae (yeast)-expressed hepatitis B virus vaccine (marketed as Engerix-B, except adsorbed onto aluminum phosphate, rather than aluminum hydroxide); and a novel inactivated poliovirus vaccine (IPV). All but the IPV component were previously approved and are currently marketed in the U.S. The Infanrix component is, itself, a combination vaccine containing diphtheria and tetanus toxoids (inactivated toxins) and acellular pertussis vaccine. The novel IPV component vaccine is, itself, composed of three separate inactivated poliovirus vaccine components [Type 1 (Mahoney), Type 2 (MEF-1), and Type 3 (Saukett]. Together these five vaccines provide diphtheria and tetanus toxoids, three pertussis antigens [inactivated pertussis toxin (PT), filamentous hemagglutinin (FHA), and pertactin (69 kDa outer membrane protein), recombinant hepatitis B virus surface antigen (HBsAg), and inactivated poliovirus types 1, 2, and 3 antigens. The diphtheria toxoid, tetanus toxoid, and pertussis antigens are the same as those in Infanrix (Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed), with these components adsorbed onto aluminum hydroxide adjuvant. The polio vaccine components are the only components not adsorbed onto aluminum adjuvant prior to final formulation (mixing) of the various components.
Each 0.5-mL dose contains 25 Lf of diphtheria toxoid, 10 Lf of tetanus toxoid, 25 µg of inactivated PT, 25 µg of FHA, 8 µg of pertactin, 10 µg of HBsAg, 40 D-antigen Units (DU) of Type 1 poliovirus, 8 DU of Type 2 poliovirus, 32 DU of Type 3 poliovirus, and 10 µg of recombinant hepatitis B virus surface antigen. Diphtheria and tetanus toxoid potenc2y 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. Potency of the hepatitis B component is established by HBsAg ELISA. The potency of the poliovirus component is determined using a D--antigen ELISA and by a poliovirus neutralizing cell culture assay on sera from previously immunized rats. The dating period for Pediarix is 24 months from the date of manufacture when stored continuously at 2-8°C. The date of manufacture is the date of initiation of the earliest valid potency test conducted on the final formulated bulk vaccine or final container vaccine, regardless of which component is tested first.
Pediarix is supplied as a turbid white suspension in single-dose (0.5 mL) vials and disposable prefilled Tip-Lok syringes. Each 0.5-mL dose also contains 2.5 mg of 2-phenoxyethanol as a preservative, 4.5 mg of sodium chloride (NaCl), and aluminum adjuvants (not more than 0.85 mg aluminum by assay). Each dose also contains ≤ 100 µg of residual formaldehyde and ≤ 100 µg of polysorbate 80 (Tween 80).
Originally, apparently until after the March 2007 U.S. approval of a thimerosal (mercury-based antimicrobial/preservative)-free formulation, thimerosal (see related entry) was used in the early stages of manufacture of the HBsAg component, and was removed by subsequent purification steps to below the analytical limit of detection (<12.5 ng of mercury/10 µg HBsAg). With the formal approval of a “thimerosal-free” formulation in 2007, the U.S. product insert no longer has any mention of thimerosal/mercury, indicating it is no longer used in manufacture. The HBsAg component contains ≤ 5% yeast protein. Neomycin sulfate and polymyxin B are used for polio vaccine manufacturing and may be present in the final vaccine at ≤ 0.05 ng neomycin and ≤ 0.01 ng polymyxin B per dose.
Nomenclature: DTaP-HBV, rDNA-IPV/GSK [BIO]; Pediarix [TR]; Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Hepatitis B (Recombinant) and Inactivated Poliovirus Vaccine Combined [FDA]; Infanrix + Engerix-B + IPV [SY; TRs for component vaccines]; DTPa-HepB-IPV [SY]; NDC 58160-841-11; NDC 58160-841-46; NDC 58160-841-50; NDC 58160-841-56; and NDC 58160-841-57 [NDC]
Companies.: Pediarix was developed and is manufactured by GlaxoSmithKline Biologicals S.A., CBER/FDA est. no. 1617. The acellular pertussis antigens, the hepatitis B surface antigen, and the inactivated poliovirus antigens are manufactured by this establishment. Combined tetanus and diphtheria toxoids component (DT vaccine; see #422) is manufactured by Chiron Behring GmbH & Co., CBER/FDA est. no. 1222, a subsidiary of Chiron Corp, which merged into Novartis AG in April 2006.
Manufacture: See the entries for each of the individual vaccine components. Purified recombinant hepatitis B surface antigen undergoes dialysis with cysteine to remove any residual thimerosal (mercury preservative). Prior to final mixing and formulation, the diphtheria, tetanus, and pertussis components are individually adsorbed onto aluminum hydroxide; and the hepatitis B virus vaccine component is adsorbed onto aluminum phosphate. These components and the poliovirus vaccine (containing 3 inactivated strains of poliovirus) are then diluted and combined to produce the final formulated vaccine.
FDA class: Biologic; BLA
CBER class: Multiple Antigen Preparations
Approvals: Date = 20021213; BLA (103907)
Date = 20070129; BLA supplement; Indications: = approval of a preservative free (thimerosal-free) formulation
Date = 20070316; BLA supplement; Indications: = unspecified labeling changes
Indications: [first paragraph of the "INDICATIONS AND USAGE” section of product insert/labeling]:
PEDIARIX is indicated for active immunization against diphtheria, tetanus, pertussis (whooping cough), all known subtypes of hepatitis B virus, and poliomyelitis caused by poliovirus Types 1, 2, and 3 as a three-dose primary series in infants born of HBsAg-negative mothers, beginning as early as 6 weeks of age. PEDIARIX should not be administered to any infant before the age of 6 weeks, or to individuals 7 years of age or older.
Status: The BLA was filed on July 15, 1999. The Vaccines and Related Biological Products Advisory Committee, FDA, reviewed the product on March 7, 2001, concluded that the its was not effective when administered to infants in the primary series, and recommended further U.S. studies comparing the vaccine with its component vaccines. The committee was concerned that most of the available data had been collected in German infants using a different regimen (primary immunization with doses at 3, 4 and 5 months of age) than that proposed for the U.S. (2, 4 and 6 months), and that there was an increase in the incidence of fever among infants receiving the combination vaccine vs. component vaccines. Pediarix was approved on Dec. 12, 2002 (approval time = ~2.4 years). The vaccine had previously been approved in many other countries, but has not received European Union approval.
Status: A new thimerosal (mercury)-free formulation received FDA approval in March 2007. As indicated by the product insert (7/2007), which no longer even mentions thimerosal/mercury, the thimerosal-free formulation is now the only one marketed in the U.S.
Medical: Compared to use of its component vaccines, use of pentavalent Pediarix reduces by two-thirds the number of injections a child should receive in the first year of life to gain protection against diphtheria, tetanus, pertussis, hepatitis B, and polio. Currently, up to nine shots are needed to offer this protection; only three shots are needed with Pediarix.
Market:
Based on first-half 2013 sales of $535 million, 2012 sales are estimated to be about $950 million.
As reported by the National Immunization Program (NIP), Centers for Disease Control and Prevention (CDC; 7/2007), the average private-sector cost per dose (Private Sector Cost/Dose) is $70.72 for a package of 10 single dose vials and for a package of 5 prefilled syringes. The cost negotiated by NIP, CDC, for bulk contract purchase for public-sector state and local immunization programs (CDC Cost/Dose ) is $47.25 ($43.75 in 2006; $38.34 in 2005) per package of 10 single dose vials and per package of 5 prefilled syringes. These prices include the $3.75/dose ($.75/covered component vaccine) Federal Excise Tax charged by the manufacturer for the federal vaccine injury compensation program. GSK’s contract with NIP, CDC, expires on March 31, 2008.
The 2007 Average Wholesale Price (AWP) is $420.60 for five single-dose vials and $841.18 for 10 (unchanged since 2004; Red Book, 2007). These prices include the $3.75/dose ($.75/covered component vaccine) federal excise tax charged by the manufacturer for the federal vaccine injury compensation program.
Companies involvement:
Full monograph
441 DTaP-HBV, rDNA-IPV/GSK
Nomenclature:
DTaP-HBV, rDNA-IPV/GSK [BIO]
Pediarix [TR]
Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Hepatitis B (Recombinant) and Inactivated Poliovirus Vaccine Combined [FDA]
DTaP-HBV-IPV [SY]
Infanrix (DTaP) HepB-IPV. [SY]
Infanrix + Engerix-B + IPV [SY]
NDC 58160-841-11; NDC 58160-841-46; NDC 58160-841-50; NDC 58160-841-56; and NDC 58160-841-57 [NDC]
FDA Class: Biologic; BLA
Year of approval (FDA) = 2002
Date of 1st FDA approval = 20021213
(in format YYYYMMDD)
Index Terms:
biopharmaceutical products
recombinant DNA
vaccines, bacterial
vaccines, combination
vaccines, toxoids (inactivated toxins)
vaccines, viral
yeast source materials
yeast source materials
bacterial culture <!-- bacterialculture -->
Clostridium tetani
Corynebacterium diphtheriae
DC5 (RT4376), Saccharomyces cerevisiae (yeast) strain
hepatitis B virus (HBV)
hepatitis B virus (HBV)
media, serum-free
neomycin
polio prophylaxis
poliovirus type 1
poliovirus type 2
polymyxin
Saccharomyces cerevisiae (yeast)
2-phenoxyethanol
aluminum hydroxide
aluminum phosphate
Diphtheria Toxoid
filamentous hemagglutinin (FHA), Bordetella pertussis
formaldehyde
hepatitis B virus (HBV)
indium-111 radioisotope
lactose
neomycin
pertactin (69 kDa protein)
Pertussis Vaccine Adsorbed, Acellular
polio prophylaxis
poliovirus type 3
polymyxin
polysorbate 80 (Tween 80)
Sterile Water for Injection
Tetanus Toxoid
thimerosal (mercury derivative)
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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