Influenza Virus Vaccine, Trivalent, Types A and B - Fluarix; Influsplit SSW; Alpharix
Status: marketed worldwide
Cross ref.: See the Influenza Virus Vaccines entry, and the entries for other influenza vaccines.
Organizations involved:
Sachsische Serumwerke – Manuf.: R&D; Tech.
GlaxoSmithKline plc – Intl. mark.; Parent
FFF Enterprises Inc. – USA mark.
Centers for Disease Control and Prevention (CDC) - Former
Cross ref.: Description: Fluarix is a conventional thimerosal-reduced, trivalent, inactivated, split-virion, influenza virus vaccine. Sodium deoxycholate is used to disintegrate, disrupt or split-up live whole virus cultured in pathogen-free chicken eggs. Further inactivation (assurance of killing all virus) is achieved using either formalin (formaldehyde in solution) or beta-propriolactone (a requirement for vaccines manufactured in Germany). Either before or after viral inactivation, monovalent culture fluid is concentrated by high-speed centrifugation and/or other methods. Unlike most other influenza vaccines, Fluarix contains no significant amounts of active influenza virus neuraminidase enzyme/antigen.
Each 0.5 mL dose of Fluarix contains 15 µg hemag-glutinin (HA) from each of the three influenza virus antigens, usually two type A antigens and one type B antigen, selected for that year’s flu season. Fluarix is packaged in prefilled 0.5 mL syringes.
Each 0.5 mL dose also contains octoxynol-10 (Triton X-100), ≤0.085 mg; alpha-tocopheryl hydrogen succinate (alpha-tocopheryl acid succinate; vitamin E succinate); ≤0.1 mg, and polysorbate 80 (Tween 80 from Union Carbide), ≤0.415 mg. The vaccine is formulated without preservatives. Thimerosal is used in the early stages of manufacture, but is removed by subsequent purification to <1.25 µg mercury per dose. Each dose may also contain residual amounts of hydrocortisone ≤0.0016 µg; gentamicin sulfate ≤0.15 µg; ovalbumin ≤1 µg; formaldehyde ≤50 mcg, and sodium deoxycholate ≤50 µg from the manufacturing process. This thimerosal-reduced formulation, i.e., manufactured without thimerosal added to the product as an antimicrobial preservative, became available with the 2002 Northern Hemisphere flu season.
Fluarix is supplied as a colorless to slightly opalescent suspension in prefilled single-dose prefilled Disposable TIP-LOK Syringes (packaged without needles; in packages of 10). Becton, Dickinson and Co. (BD) supplies these BD Hypak SCF prefillable syringes. The vaccine is stored at 2-8˚C (refrigerated). The dating period is 12 months from the date of manufacture of the filled final container vaccine when stored at 2-8˚C, but not beyond June 30th of the given influenza season. The 12-month shelf life is inclusive of the time that the product is held in filled final containers at 2-8˚C prior to packaging. The date of manufacture is defined as the date on which the trivalent vaccine is filled. Potency testing performed on the final filled containers must commence within 6 weeks after filling.
In April 2009, FDA approved a new thimerosal-free formulation in single-dose prefilled syringes.
Nomenclature: Influenza Vaccine/GSK Germany [BIO]; Fluarix [TR]; Influenza Virus Vaccine [FDA USAN]; Influenza vaccine (split virion, inactivated) [UK proper name]; Influsplit SSW [TR in Germany]; alpha-Rix [TR in some countries]; Alpharix [TR in some countries]; NDC 58160-871-99; NDC 58160-871-41; NDC 58160-871-51; NDC 58160-872-51 [NDC]
Companies.: The vaccine was originally developed and is manufactured by Sachsische Serumwerke (Dresden, Germany; in former East Germany), a subsidiary of GlaxoSmithKline plc (GSK). The vaccine has been marketed by GSK in Europe and most countries worldwide, except for the U.S. The vaccine is filled, labeled and packaged at GSK Biologics in a location redacted (censored) by FDA, but likely at facilities in Rixen-sart, Belgium.
In Dec. 2005, FFF Enterprises Inc. received a contract from GSK to be the exclusive U.S. distributor during the current 2006/7 flu season, and FFF helped launch Fluarix in the U.S. as a preferred distributor during the current 2005-2006 flu season.
GSK had decided in the early 1990s not to seek U.S. approval for Fluarix, then perceiving the U.S. market as overcrowded. In July 2005, GSK announced plans to double its Fluarix manufacturing capacity at its Dresden facility, investing ~$114 million. Manufacturing capacity is expected to 80 million doses a year by 2008.
Prior to its full approval, Fluarix was a U.S. backup vaccine, starting in 2004, in case of shortage, with the Centers for Disease Control and Prevention (CDC) purchasing and importing the vaccine and holding an IND allowing its use, if needed. CDC had purchased stocks and held them in reserve for the 2004/5 flu season.
Manufacture: As with other conventional trivalent influenza virus vaccines, each virus strain is cultured separately in embyronated chicken eggs. After harvesting the virus-containing fluids, each influenza virus is concentrated and purified by zonal centrifugation using a linear sucrose density gradient solution containing detergent (polysorbate 80) to disrupt the viruses. Following dilution, the vaccine is further purified by diafiltration. Each influenza virus solution is further inactivated by the consecutive effects of sodium deoxycholate and formaldehyde leading to the production of a “split virus.” Each split inactivated virus preparation is then suspended in sodium phosphate-buffered isotonic sodium chloride solution. The vaccine is formulated from the split inactivated virus solutions.
Fluarix is not manufactured with any substances of human origin, but manufacture includes exposure to bovine-derived materials. There is no evidence that any case of vCJD (new variant Creutzfeldt-Jakob disease; considered to be the human form of bovine spongiform encephalopathy (BSE) has resulted from the administration of this vaccine (or any other).
FDA class: Biologic BLA
Approvals: Date = 20050831; original BLA (STN: 125127/0)
Date = 20090401; BLA supplement; Indication = new thimerosal-free formulation in single-dose prefilled syringes and related changes in the labeling
Date = 20090920; BLA supplement; Indication = approval extended to use in children between three to 17 years (from 18 years and older)
Indications: [Full text of the "INDICATIONS AND USAGE” section of product insert/labeling, 10/21/2009]:
FLUARIX is indicated for active immunization for the prevention of disease caused by influenza virus subtypes A and type B contained in the vaccine. FLUARIX is approved for use in persons 3 years of age and older.
Status: Fluarix received its first approval in Germany in July 1991. Fluarix is licensed in 102 countries (nearly all countries worldwide; in Feb. 2006). Fluarix meets the WHO requirements for biological substances and influenza vaccines, and the European Pharmacopoeia requirements for influenza vaccines. Fluarix has also consistently exceeded EMEA/European Union criteria for immunogenicity required for annual registration. The new thimerosal-reduced formulation was launched in 2002.
As discussed in the Status section of the Influenza Vaccines entry, a shortage of influenza vaccine in the U.S. occurred leading up to and during the 2004/5 flu season. On Dec. 7, 2004, the Centers for Disease Control and Prevention (CDC) announced its intent to purchase, import and, if needed, distribute 4 million doses of Fluarix. CDC purchased and imported 1.2 million doses of Fluarix from GSK, after FDA approved an IND allowing its importation (and emergency use). Further, GSK agreed to manufacture and provide CDC with an additional 2.8 million doses (a total of 4 million doses), if needed, for use later in the flu season. See the Influenza Vaccine Products entry for further 2004/5 flu season supply information. Under CDC’s IND, patients receiving Fluarix had to sign an informed consent agreement acknowledging they are aware of the potential adverse effects associated with the investigational vaccine. However, none of the vaccine was ever used by CDC. GSK completed manufacturing capacity upgrades, FDA inspections of the facility were completed, and the vaccine was approved in time for the next, 2005/6 flu season.
On Oct. 20, 2009, Fluarix received FDA approval for pediatric use (in children ages 3-17), while the vaccine had previously only been approved for use in adults age 18 and over.
Trials: In Dec. 2004, the National Institutes of Allergy and Infectious Diseases (NIAID, NIH) began a double-blind, placebo-controlled, U.S. Phase III trial in ~1,000 healthy adults to evaluate the immunogenicity and safety of intramuscular Fluarix. This was the pivotal Phase III trial supporting the vaccine’s U.S. approval. Four out of every five participants in this trial received Fluarix, while the others received placebo.
For a review of clinical trials and experience with Fluarix, see “Ten Years of Experience With the Trivalent Split-Influenza Vaccine, Fluarix,” Clin Drug Invest 22(11):751-769, 2002; authored by GSK investigators.
Medical: As with other influenza vaccines, the dose is a single 0.5 mL injection in adults. Injections are administered intramuscularly, preferably in the region of the deltoid muscle.
In many countries, Fluarix has been and is approved for use in adults and children older than 3 months of age (6 months in the U.K). As with other comparable and similarly manufactured influenza vaccines, Fluarix is considered generally safe and immunogenic (effective) in its indicated age groups.
Market: Total 2004 sales of Fluarix were £79 million ($144 million). It was reported in Dec. 2004 that 126 million doses of Fluarix had cumulatively been distributed worldwide.
The 2007 Average Wholesale Price (AWP) is $78.75/five single-dose prefilled syringes (Red Book, 2007).
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 packages of 5 single-dose 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 $12.00 for packages of 5 single-dose prefilled syringe. These prices include the $0.75/dose ($.75/covered component vaccine) Federal Excise Tax charged by the manufacturer for the federal vaccine injury compensation program. Sanofi Pasteur’s contract with NIP, CDC, expires on Feb. 28, 2008.
In its March 22, 2006, price list, FFF Enterprises, a major biologics distributor, reported its price as .$107.40/5 mL box of 10 prefilled syringes.
Companies involvement:
Full monograph
476 Influenza Vaccine/GSK Germany
Nomenclature:
Influenza Vaccine/GSK Germany [BIO]
Fluarix [TR]
Influenza Virus Vaccine [FDA USAN]
Influenza vaccine (split virion, inactivated) [UK proper name]
Influsplit SSW [TR in Germany]
Alpahrix [TR in some countries]
alpha-Rix [TR in some countries]
NDC 58160-871-99; NDC 58160-871-41; NDC 58160-871-51; NDC 58160-872-51 [NDC]
FDA Class: BLA
Year of approval (FDA) = 2005
Date of 1st FDA approval = 20050831
(in format YYYYMMDD)
Index Terms:
biopharmaceutical products
bovine materials used<!-- bovinesource -->
bovine materials used<!-- bovinesource -->
chicken source materials
vaccines, subunit
vaccines, viral
chicken embryo (egg) culture
influenza virus
virus culture
alpha granules
beta-propiolactone (BPL; beta propiolactone)
beta-propiolactone (BPL; beta propiolactone)
formaldehyde
gentamicin (gentamycin)
hemagglutinin (HA) antigen, influenza A virus
hydrochloric acid (HCl)
influenza virus
Mab 1129, murine monoclonal antibody
octoxynol (Triton X-100)
osteoarthritis
polysorbate 80 (Tween 80)
porcine teeth
potassium phosphate
sodium chloride
sodium citrate
sodium phosphate, dibasic
sucrose
thimerosal (mercury derivative)
Tn5 (Pharmacia)
virus culture
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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