Diphtheria immune globulin F(ab’))2 fragments, equine
Status: approvals withdrawn; replacement available under IND
Organizations involved:
Instituto Butantan – Manuf.; R&D; Tech.
Centers for Disease Control and Prevention (CDC) – USA mark.
Pasteur Merieux Connaught S.A. – Former
Merrell-National Labs. – R&D; Tech.; Former
Cross ref.: See Antivenin Products (#906).
Description: Diphtheria Antitoxin is a concentrated aqueous solution of enzymatically-derived equine immune globulin G (IgG) F(ab’))2 fragments fractionated from immune globulin (containing antibodies) from horses vaccinated with diphtheria toxin and having high levels of diphtheria toxin-neutralizing polyclonal antibodies. Horses are vaccinated with diphtheria toxin (not inactivated toxoid), blood plasma is removed, the immune globulin fraction obtained, and the antibodies are digested by the enzyme pepsin to yield equine IgG F(ab’))2 fragments.
Diphtheria Antitoxin is used (now rarely) for treatment and prevention of Corynebacterium diphtheriae infection (diphtheria). The antibody fragments selectively bind and neutralize diphtheria toxin in the bloodstream. Prior to the advent of antibiotics, e.g., in the 1940s, this was among the main therapeutic options available for treatment of diphtheria.
Diphtheria Antitoxin from Connaught/Aventis Pasteur (now Sanofi Pasteur Inc.) was packaged in vials containing 20,000 units. Tricresol (0.4%) was used as a preservative. As described in 21 CFR 610.21, vials contained at least 500 units/mL.
Nomenclature: Diphtheria Antitoxin [BIO FDA]; Diphtheria Antitoxin USP (Purified, Concentrated Globulin - EQUINE) [FDA former, upon approval]; Diphtheria Antitoxin USP [USP]; DAT [SY]; diphtheria immune globulin F(ab’))2 fragments, equine [SY]
History: Behring and Kitasato first prepared diphtheria antitoxin in 1890. It was first administered by Ehrlich in 1891. Behring won the Nobel Prize in 1901 for diphtheria antitoxin and related research.
Companies previously licensed to manufacture Diphtheria Antitoxin: Bayer Corp. (Jan. 1914-June 1977); Lederle Labs. (March 1917-Oct. 1988); Massachusetts Public Health Biologic Labs. (March 1917-Oct. 1988); Merrell National Labs., Richardson-Merrell Inc. (Dec. 1927-Jan. 1978); Michigan Biologic Products Inst. (May 1926-May 1987); Parke-Davis div.,Warner-Lambert Co. (Nov. 1907-Nov. 1969); and SCLAVO SpA (May 1960-July 1990).
Mulford & Co., now Merck & Co., manufactured diphtheria antitoxin starting in 1894 (before drug regulation began in U.S.). FDA (CBER/FDA approvals database) has lost and no longer reports approvals for products from this predecessor of Merck’s vaccines division.
The now-famous Iditarod cross-country dog sled race in Alaska traces its origins to a 1920 effort to bring diphtheria antitoxin during a blizzard to Iditarod, Alaska, then experiencing a diphtheria epidemic.
Companies.: This Diphtheria Antitoxin was originally developed, manufactured and marketed in the U.S. by Merrell National Labs. (Swiftwater, PA), Richardson-Merrell Inc., CBER/FDA est. no. 0073, which became Connaught Labs., later Pasteur Merieux Connaught, later Aventis Pasteur, Inc., now Sanofi Pasteur Inc.
In May 1997, this product was replaced (in terms of availability in the U.S. under IND) by product manufactured by Pasteur Merieux Connaught S.A., now Sanofi Aventis S.A..
In May 2004, this product was replaced (in terms of marketing/availability in the U.S. under IND) by a similar equine diphtheria antitoxin manufactured by Instituto Butantan (Brazil). This product is stockpiled at each of the eight U.S. Public Health Service quarantine stations under the control of the Centers for Disease Control and Prevention (CDC). See the Status section for further information.
FDA class: Biologic PLA
CBER class: Antitoxins, Antivenins, Enzymes and Venoms
Approvals: Date = 19271212; first approval, granted to Merrell National Labs., Richardson-Merrell Inc.
Date = 19780103; licenses (PLA/ELA) revoked and granted (reissued) to new owner, Connaught Labs., Inc.
Date = 19970000; Investigational New Drug (IND) protocol for antitoxin manufactured by Pasteur Merieux S.A.
Date = 20040500; Investigational New Drug (IND) protocol for antitoxin manufactured by Instituto Butantan
Indications: = [from June 1981 product insert/labeling]:
For prevention or treatment of diphtheria. Diphtheria Antitoxin USP neutralizes toxin produced by Corynebacterium diphtheria.
Status: Diphtheria Antitoxin manufactured by Connaught/Aventis Pasteur in the U.S. was listed until recent years by FDA as an approved product, indicating that its license was voluntarily withdrawn, All existing supplies of this product expired on Jan. 6, 1997.
In May 1997 (MMWR, 5/2/1997), CDC reported that a comparable (equivalent) equine diphtheria antitoxin manufactured by Pasteur Merieux S.A. (Lyon, France; part of same company now Sanofi Pasteur S.A.) had become available through a CDC-sponsored Investigational New Drug (IND) protocol, with the product only available/released through CDC. This antitoxin was approved in European countries at the time.
In May 2004 (MMWR, 5/21/2004), CDC announced that no manufacturer had sought U.S. approval of a diphtheria antitoxin product since 1996, that production of the Pasteur Merieux S.A. (which had become Aventis Pasteur S.A., now Sanofi Pasteur S.A.) product ceased in 2002, and that remaining supplies at CDC expired on May 30, 2004. To ensure the continued availability of diphtheria antitoxin in the U.S., CDC has procured an equine DAT product from the Instituto Butantan, and is now making this available under an FDA-approved IND protocol, with the product only available/released by CDC (presumably, at no cost). Respiratory diphtheria is a reportable disease, so local/state public health authorities need to be notified of all cases.
Disease: Despite the availability of diphtheria vaccines and antibiotics highly effective against diphtheria, cases of respiratory diphtheria continue to occur sporadically in the U.S.. Respiratory diphtheria is caused by toxigenic Corynebacterium diphtheriae (also, rarely, by toxigenic C. ulcerans), and frequently manifests insidiously as a membranous nasopharyngitis or obstructive laryngotracheitis accompanied by a low-grade fever. Respiratory diphtheria most often affects unvaccinated or inadequately vaccinated persons, particularly those who travel to areas where diphtheria is endemic and those who come into close contact with travelers from such areas. Effective treatment of respiratory diphtheria may include early administration of an equine diphtheria antitoxin (in addition to antibiotics). Delay in antitoxin administration can lead to life-threatening respiratory obstruction, myocarditis, and other complications. To ensure quick access to antitoxin, CDC maintains a stock available for release to U.S. physicians.
Medical: Diphtheria Antitoxin was used for treatment and prophylaxis of diphtheria for much of the 20th century. As stated in the product insert/labeling (June 1981), “Any person with clinical symptoms of diphtheria should receive Diphtheria Antitoxin USP at once without waiting for bacteriologic confirmation of the diagnosis.” Antibiotics are now the preferred treatment for diphtheria. Skin sensitivity tests, to determine the patient’s reactions to equine blood proteins should be performed prior to administration (see Horse Serum Products, entry #903).
Dosages range from 20,000 to 80,000 units. Suggested dosage ranges after 48 hours of pharyngeal or laryngeal disease are 20,000 to 40,000 units; 40,000 to 60,000 units for naso-pharyngeal lesions; and 40,000 to 60,000 units for extensive disease of three or more days duration or for any patient with brawny swelling of the neck. Children and adults receive the same dosages. Antibiotics are often prescribed along with Diphtheria Antitoxin. It may be administered intramuscularly or intravenously all at once. Any delay after disease/exposure increases dosage requirements and decreases the beneficial effects. With the lower dosages used for prophylaxis, less than 10% of recipients develop serum sickness (reaction against non-human blood components). Incidence of serum sickness is higher with the higher dosages used for treatment.
Market: Now rarely used, replaced by antibiotics, the product is only available in the U.S. from the Centers for Disease Control and Prevention (CDC), which presumably provides it at no cost for those few cases needing the product.
Companies involvement:
Full monograph
916 Diphtheria Antitoxin
Nomenclature:
Diphtheria Antitoxin [BIO FDA]
Diphtheria Antitoxin USP (Purified, Concentrated Globulin - EQUINE) [FDA formerly, upon approval]
Diphtheria Antitoxin USP [USP]
DAT [SY]
diphtheria immune globulin F(ab')2 fragments, equine [SY]
FDA Class: Biologic IND
Year of approval (FDA) = 1997
Date of 1st FDA approval = 19970000
(in format YYYYMMDD)
Index Terms:
antibodies (see also immune globulins; monoclonal antibodies)
antitoxins
biopharmaceutical products
blood products
equine immune globulins <!-- immunoglobulins -->
equine materials used
immune globulins, equine <!-- immunoglobulins -->
Corynebacterium diphtheriae
equine plasma/serum
Mueller and Miller medium
plasma proteins, immunoglobulin-depleted
aluminum potassium sulfate (alum)
ammonium sulfate
diphtheria toxin-neutralizing antibody fragments
formaldehyde
pepsin digestion
tricresol
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
conjugates
FDA application withdrawn
implants
North American coral snake
EU011 Approved Formerly in EU/withdrawn
UM100 Controlled/Gov't Distribution in US
US011 Approved Formerly in US/withdrawn
EM999 Not Available/Not Marketed in EU
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