Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed - Infanrix; DTaP
Status: approved; marketed
Organizations involved:
GlaxoSmithKline Biologicals S.A. – Manuf.; Tech.; Intl. Mark.
GlaxoSmithKline Inc. – USA mark.
GlaxoSmithKline plc – Parent
SmithKline Biologicals S.A. – R&D; Tech.; Former
Chiron Behring GmbH & Co. KG – Manuf.; R&D; Tech.
Chiron Corp. – Patent dispute; Parent
Novartis AG – Parent
Evans Vaccines Ltd. – R&D; Tech.; Former
PowderJect Pharmaceuticals plc – Former
Cross ref: See the entries for Acellular Pertussis Vaccine Products entry (#506) and the Diphtheria and Pertussis Toxoids and Pertussis Vaccine (DTP/DTaP) Products (#429). See the entry for the DT components of this vaccine – Diphtheria & Tetanus Toxoids Adsorbed Combined Bulk (For Further Manufacturing Use) (#422) from Chiron Beh-ring GmbH & Co.; and for Infanrix combined with inactivated polio vaccine (IPV) and recombinant hepatitis B vaccine (DTaP-IPV-Hep B; Pediarix) (#441). See the entries for Tetanus Toxoid Products (#543); and Diphtheria Toxoid Products (#418).
Description: Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed or Infanrix is an aqueous DTaP vaccine formulation containing conventional diphtheria and tetanus toxoids (formaldehyde-inactivated toxins) plus an acellular Bordetella pertussis component including three antigens – pertussis toxoid (PT; formaldehyde-inactivated pertussis toxin), filamentous hemagglutinin antigen (FHA), and pertac-tin (69 kDa outer membrane protein) – with each component vaccine individually adsorbed onto aluminum hydroxide adjuvant. Infanrix is formulated without addition of thimerosal (a mercury derivative) as a preservative.
The acellular pertussis component, the innovative component of the vaccine, contains 40 µg inactivated pertussis toxin (PT), 8 µg pertactin (69 kDa protein), and 25 µg filamentous hemagglutinin (FHA) per 0.5 mL dose. Each 0.5 mL dose of Infanrix also contains 2.5 mg 2-phenoxyethanol as a preservative, 4.5 mg sodium chloride, Water for Injection, and ≤0.02% (w/v) residual formaldehyde. The inactivated acellular pertussis component contributes less than 5 endotoxin units (EU) per 0.5 mL dose.
Infanrix is packaged in vials containing a 0.5 mL single dose, in packages of 10 vials, for intramuscular injection only; and in prefilled Tip-Lok syringes. The dating period is 30 months from the date of manufacture when stored at 2-8˚C (refrigerated), including 12 months in manu-facturer’s storage and up to 24 months in distribution. The dating period for the final combination is based on the component with the shortest dating period and/or first valid potency test, whichever period is the shortest. [See 21 CFR 610.50(a) and 610.53(b)].
Nomenclature: DTaP Vaccine/GSK [BIO]; Infanrix [TR]; Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed [FDA]; DTaP vaccine [SY]; DTPa [CDC]; NDC 58160-840-1 [NDC]
Companies.: The acellular pertussis component and the combination vaccine are manufactured by GlaxoSmithKline Biologicals S.A., CBER/FDA est. no. 1617, a subsidiary of Glaxo Wellcome plc. The component diphtheria and tetanus toxoids (DT vaccine) are produced in Germany by Chiron Behring GmbH & Co., CBER/FDA est. no. 1222, a subsidiary of Chiron Corp., which merged into Novartis AG in Oct. 2005. Infanrix was developed by SmithKline Beecham Biologicals S.A., which merged with Glaxo Wellcome plc to form GlaxoSmithKline plc (GSK) in Dec. 2000.
Infanrix is marketed in the U.S. by GlaxoSmithKline Inc. (GSK) and marketed internationally by GlaxoSmithKline Biologicals S.A. and affiliates.
FDA class: Biologic BLA 103647
CBER class: Multiple Antigen Preparations
Approvals: Date = 19970129, first approval, BLA; Indication = use for first three of the recommended five series of DTaP/DTP vaccine injections
Date = 20020514; Indication = use for first four of the recommended five series of DTaP/DTP vaccine injections
Date = 20030707; BLA supplement; Indication = approval as the fifth consecutive DTaP dose for children ages 4-6 years old
Date = 20090312; BLA supplement: indications: = revisions to the package insert to include safety data on the use of INFANRIX following three doses of PEDIARIX and updated safety and immunogenicity data on the concomitant administration of INFANRIX with other recommended vaccines
Indications: [portion of the "INDICATIONS AND USAGE” section from product insert/labeling]:
INFANRIX is indicated for active immunization against diphtheria, tetanus, and pertussis (whooping cough) as a 5-dose series in infants and children 6 weeks to 7 years of age (prior to seventh birthday). Because of the substantial risks of complications from pertussis disease in infants, completion of the primary series of 3 doses of vaccine early in life is strongly recommended (see DOSAGE AND ADMINISTRATION). INFANRIX should not be administered to any infant before the age of 6 weeks, or to individuals 7 years of age or older. When passive protection against tetanus or diphtheria is required, Tetanus Immune Globulin or Diphtheria Antitoxin, respectively, should be administered at separate sites. As with any vaccine, INFANRIX may not protect 100% of individuals receiving the vaccine, and is not recommended for treatment of actual infections.
Status: The BLA was submitted on Nov. 10, 1995, and approved on Jan. 29, 1997; review time = ~14.5 months (~1.2 years). Infanrix had previously been available in some European countries, and was first launched in Germany in 1994. As of mid-2003, Infanrix was approved in over 80 countries.
GlaxoSmithKline filed a BLA supplement in Feb. 2001 for use of Infanrix as the fifth consecutive dose in the currently recommended DTaP/DTP vaccine schedule. Approval was granted on July 7, 2003. With this approval, Infanrix may be used for the entire five-dose series of diphtheria, pertussis and tetanus vaccination. Since Pediarix (DTaP plus hepatitis B virus vaccine) also from GlaxoSmithKline, can be administered for the first three inoculations, followed by two Infanrix inoculations. Essentially all organizations promulgating vaccination guidelines recommend use of a single brand (manu-facturer’s) DTaP vaccine for all five doses of the pediatric vaccination regimen.
In Dec. 2000, CBER/FDA reported that the Diphtheria Toxoid component of Infanrix from Chiron Behring GmbH & Co. was being manufactured using bovine-derived materials from a country (or countries) on the official USDA list of countries known to have cattle with BSE. See the Vaccine Products entry (#400) for further information on BSE concerns.
Infanrix Hep B (DTaP-Hep B), i.e., Infanrix combined with recombinant hepatitis B virus vaccine (Engerix-B) from GSK, is marketed in the European Union. Infanrix plus Haemophilus influenzae type b (Hib) vaccine (DTaP-Hib) is marketed in Germany and, perhaps, other European countries. Infanrix plus Inactivated Polio Vaccine (IPV) plus recombinant hepatitis B virus (DTaP-IPV-Hep B) pentavalent vaccine is marketed by GSK in the U.S. (see Pediarix, #441), and is marketed in Scandinavian/Baltic countries by SBL Vaccine AB, now part of Crucell N.V.
GSK launched Infanrix in prefilled Tip-Lok syringes in the U.S. in April 2002.
In Jan. 2008, GSK launched Infanrix in India.
Tech. transfer: The pertussis component containing three antigens – pertussis toxoid, filamentous hemagglutinin and pertactin (69 kDa protein) – was exclusively licensed from Evans Medical, which became Celltech Medeva Pharma Ltd., then Evans Vaccines Ltd., which was acquired by PowderJect Pharmaceuticals plc. which was acquired by Chiron Corp., which was acquired by Novartis AG in Oct. 2005.
In March 1998, Chiron won a patent dispute resulting in revocation of European Patent 0-162,639 assigned to Evans/Medeva concerning B. pertussis-derived pertactin, exclusively licensed by to GlaxoSmithKline Biologicals and used in Infanrix (#433). Evans/Medeva had alleged that Chiron’s acellular pertussis component-containing combination vaccines (marketed in Europe) infringed this patent. Chiron, presumably, receives royalties from sales of Infanrix.
In April 2009, GlaxoSmithKline and Medeva jointly filed five SPC
applications in European countries for several vaccines, referencing the basic patent
EP1,666,057 and referencing marketing
authorizations for different DTPa-IPV/Hib vaccines, including Infanrix. The UK’s
intellectual property office (IPO) rejected the applications. Medeva
appealed against the IPO’s decision to a UK Court of Appeal, which
referred the case to the European Court of Justice (ECJ).
Interpreting Article 3(a) of the European Union’s (EU’s)
SPC Regulation 469/2009 – which requires that, to qualify for a
monopoly extension, a product be protected by a basic patent – the
The ECJ ruled SPCs could only be granted to products solely containing
active ingredients specified in the claims of the basic patent. This 'Medeva’ ruling could render invalid up to a third of European SPCs for
combination products.
Trials: Two large German and Italian studies in infants demonstrated that the prophylactic efficacy of Infanrix against pertussis was significantly better or comparable to that of two DTP (whole cell pertussis) vaccines, with Infanrix providing effective protection against pertussis, even under conditions of household contact with symptomatic pertussis. Infanrix demonstrated an absolute efficacy of 89% in preventing pertussis in the German household contact study. Infanrix is the only DTaP proven by direct comparison to be more effective (84% protective efficacy) than a standard whole-cell DTP (36% protective efficacy; from Sanofi Pasteur).
Market:
Total worldwide sales of Infanrix and Pediarix were $1.183 billion in 2012 and $1.077 billion in 2011.
Total 1999 sales were $195 million. In Feb. 2001, GSK reported sales had increased 64% worldwide in 2000 to ~$320 million. In April 2002, Infanrix was reported to be the U.S. and worldwide leader in DTaP vaccine sales, then licensed in 69 countries. In July 2003, GSK reported that over 29 million doses had been distributed in the U.S. and over 43 million doses worldwide since product launch.
As reported by the National Immunization Program (NIP), Centers for Disease Control and Prevention (CDC; 7/2007), the Private Sector Cost/Dose (average cost) per dose is $13.25 for ten 1-dose vials, and $21.44 for a 5-pack of prefilled syringes. The CDC Cost/Dose, the cost negotiated by NIP, CDC, for bulk contract purchase for public-sector state and local immunization programs, is $13.25 for ten 1-dose vials and for 5-packs of prefilled syringes, with this supply contract ending March 31, 2008. These prices include the $2.25/dose ($.75/covered component vaccine) Federal Excise Tax charged by the manufacturer for the federal vaccine injury compensation program.
The 2005 Average Wholesale Price (AWP) is $126.38 for five single-dose vials, and $246.96 for 10 vials (Red Book, 2007; no changes since 2005). This include the $2.25/dose ($.75/covered component vaccine) federal excise tax charged by the manufacturer for the federal vaccine injury compensation program.
In 2001, four out of every five children in the U.S. received Infanrix through NIP/CDC’s Vaccines For Children (VFC) program. With an annual cohort of about 4 million new infants annually in the U.S., this indicates over 3 million infants/year received Infanrix.
Companies involvement:
Full monograph
433 DTaP Vaccine/GSK
Nomenclature:
DTaP Vaccine/GSK [BIO]
Infanrix [TR]
Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed [FDA]
DTaP vaccine [SY]
DTPa [CDC abbrev.]
NDC 58160-840-1 [NDC]
FDA Class: Biologic BLA
Year of approval (FDA) = 1997
Date of 1st FDA approval = 19970129
(in format YYYYMMDD)
Index Terms:
biopharmaceutical products
bovine materials used<!-- bovinesource -->
vaccines, bacterial
vaccines, combination
vaccines, toxoids (inactivated toxins)
bacterial culture <!-- bacterialculture -->
Bordetella pertussis
Clostridium tetani
Corynebacterium diphtheriae
2-phenoxyethanol
aluminum hydroxide
Diphtheria Toxoid
formaldehyde
pertactin (69 kDa protein)
Pertussis Vaccine Adsorbed, Acellular
sodium chloride
Sterile Water for Injection
Tetanus Toxoid
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
bovine source warning, BSE country
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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