Clostridium botulinum toxin types A, B, and E immune globulin F(ab’)2 fragments, equine
Status: approved; controlled/gov’t dist.
Organizations involved:
Sanofi Pasteur Ltd. – Manuf.; R&D; Tech.
Sanofi Pasteur S.A. – Intl. mark.; Parent
Centers for Disease Control and Prevention (CDC) – USA mark.
Cross ref: See the entries for human botulinum toxin immune globulin (BabyBIG; #747); and for Antivenin Products (#706); and Botulinum Toxin Products (#600).
Description: Botulism Antitoxin is an aqueous formulation of equine (horse) immune globulin containing high titers of neutralizing antibody F(ab’)2 fragments with specificity for Clostridium botulinum toxin types A, B, and E, obtained from plasma from healthy horses vaccinated with botulinum toxin types A, B, and E. The plasma is pooled, defibrinated, enyzmatically digested with pepsin (despeciated to F(ab’)2 fragments), and fractionated with ammonium sulfate. It is then dialyzed and concentration is adjusted to about 20% immune globulin (protein). Botulism Antitoxin is composed of unmodified equine immune globulin, primarily immune globulin G (IgG), containing equine polyclonal botulinum toxin type A, B and E-neutralizing antibodies. Botulism Antitoxin is used for treatment of botulism (poisoning/toxicity due to botulinum toxin, e.g., from food poisoning; potentially from biological warfare/bioterrorism use of botulinum toxin type A, B or E).
Botulism Antitoxin is packaged as a solution in 10 mL single-dose vials. Each vial contains 7,500 International Units (IU; equivalent to 2,381 U.S. units) of antitoxin specific for C. botulinum type A antitoxin; 5,500 IU (1,839 U.S. units) of type B antitoxin; and 8,500 IU (8,500 U.S. units) of type E antitoxin. The vial generally contains 20% more than the labeled amount. Generally, the antitoxin is diluted 1:10 with 0.9% sodium chloride prior to intravenous administration. Botulism Antitoxin contains phenol, not exceeding 0.4%, used as a preservative. The product should be stored at 2-8˚C (refrigerated), with a shelf life of 60 months (5 years).
Potency is determined using a mouse protective potency assay, testing the antitoxin for neutralization of each type of botulinum toxin. The U.S. Pharmacopeia (USP) has established a standard for Botulism Antitoxin including this assay.
Nomenclature: Botulism Antitoxin/A,B,E [BIO]; Botulism Antitoxin [FDA USAN]; Clostridium botulinum toxin types A, B, and E immune globulin F(ab’)2 fragments, equine [SY]; botulinum toxin equine immune globulin [SY]; 11793-7510-01; 11793-7511-01 [NDC]
Biological.: Botulism Antitoxin is used for treatment of botulism due to poisoning with toxin expressed by Clostridium botulinum strain types A, B or E. The mechanism of action is antibody binding and neutralization of toxin circulating in the blood-stream. Botulism Antitoxin is not active against C. botulinum bacteria, i.e., does not affect infection with C. botulinum. Botulism Antitoxin generally halts progression of botulism due to toxin types A, B and E. Antibiotic treatment is generally used to treat active infections. Botulinum toxoid (vaccine) is useful to confer lasting immunity against botulism (but only a C. botulinum toxin A-based toxoid is commercially available).
The conditions in which C. botulinum spores germinate and produce toxin include absence of oxygen (i.e., the organism is anaerobic or microaerophilic), low acidity levels, and temperatures between 40-120˚F. These conditions may exist in improperly stored home-cooked or commercial foods, including improperly canned foods; in infant intestinal tracts, which have not yet developed the full range of beneficial intestinal bacteria; and from contamination of deep wounds with C. botulinum. The expressed toxin, whether it was ingested or formed in vivo from C. botulinum infection, causes poisoning (botulism).
History: Lederle Labs. was licensed by FDA to manufacture Botulism Antitoxin from Nov. 1941 to March 1981.
Companies.: Botulism Antitoxin was developed and is manufactured by Aventis Pasteur Ltd., now Sanofi Pasteur Ltd. (formerly Pasteur Merieux Connaught, Ltd. and Connaught Labs., Ltd.), FDA CBER est. no. 1280. Aventis Pasteur merged into Sanofi Aventis S.A. in late 2004.
This product is available to U.S. civilians needing it at no cost from the Centers for Disease Control and Prevention (CDC). The U.S. Department of Defense also, presumably, maintains stocks of Botulinum Antitoxin (for biological warfare/bioterrorism defense and research). This product is not part of the U.S biodefense stockpile. Presumably, the product is available in other countries for those needing it.
FDA class: Biologic PLA
CBER class: Antitoxins, Antivenins, Enzymes and Venoms
Approvals: Date = 19680816; first approval, PLA; Indication = prevention and treatment of botulism due to Clostridium botulinum strain types A, B and E
Date = 20000224; Indication = license revoked from Connaught Labs., Ltd. and reissued to Aventis Pasteur Ltd.
Indications: product insert/labeling not available
Medical: Botulism Antitoxin is used for treatment and prevention of food poisoning, infant botulism, and other natural cases of botulinum toxin poisoning. It is also useful for short-term preexposure prophylaxis and post-exposure prophylaxis of poisoning due to known or likely toxin exposure, e.g., potentially resulting from biological warfare use of botulinum toxin types A, B or E.
For prophylaxis, as soon as possible after known or presumed toxin ingestion (e.g., contaminated food), Botulism Antitoxin is administered intramuscularly at a dose varying from 20-100% of a full vial. Protective levels of antitoxin are assumed to be about 0.25 µg/mL. For treatment of botulism, as soon as possible, a large dose, in excess of the amount theoretically needed to neutralize circulating toxin, is administered as a 1:10 dilution (in 0.9% sodium chloride) by slow intravenous infusion. A full vial of Botulism Antitoxin is generally used, irrespective of patient age or weight. Additional doses may be required, depending on the persistence and magnitude of toxin ingested, severity of poisoning, etc., with additional doses administered 2-4 hours apart after the initial dose. Additional doses may also be administered by intramuscular injection, providing a depot for slow release of antitoxin.
Clinical studies have shown that administration of Botulism Antitoxin within 24 hours after onset of botulism from botulinum toxin A significantly reduces mortality and shortens the course of illness, while Botulism Antitoxin administered after 24 hours reduces mortality but not the length of illness. The in vivo half-life for Botulism Antitoxin is less than 15 days.
Botulism Antitoxin has various disadvantages, including its being injected intravenously and/or intramuscularly, rather than intravenously injected, and it has potential side effects (from equine components) including serum sickness and anaphylaxis. Efficacy is also uncertain and treatment is costly.
Disease: Generally, about 100 cases of botulism are reported annually in the U.S. About two-thirds are infant botulism, and 25-30% are classic food poisoning cases. From 1973-1998, there were a median of 24 cases of foodborne botulism, 3 cases of wound botulism, and 71 cases of infant botulism reported annually to CDC.
Most cases of types A and B food poisoning come from improperly preserved/prepared meat, canned low-acid, or alkaline foods. Most cases of type E result from seafood, fish and other marine animals. New methods for transmission of C. botulinum infection are emerging, e.g., wound botulism from crude heroin injection has increased in the past decade.
Market: Due to its limited use, the need for reporting and control of botulism outbreaks, and other factors (e.g., concern for potential toxin use for biological warfare/bioterrorism), Botulism Antitoxin is available to civilians in the U.S. only from the Drug Service, National Center for Infectious Diseases (NFID), Centers for Disease Control and Prevention (CDC) and the Division of Quarantine, NFID, CDC. Presumably, one or more components of the Department of Defense also have supplies for biological/chemical warfare defense.
The antitoxin is released by CDC only for suspected or actual cases of botulism poisoning. The product is stored at CDC quarantine stations located at major airports (international points-of-entry) throughout the U.S. to assure delivery anywhere in the country within hours. All suspected and actual cases of botulism poisoning must be reported to state or local health departments, and antitoxin is generally only provided to or through these organizations. This allows the CDC and health departments to detect and control botulism outbreaks as soon as possible.
Companies involvement:
Full monograph
912 Botulism antitoxin/A,B,E
Nomenclature:
Botulism Antitoxin/A,B,E [BIO]
Botulism Antitoxin [FDA USAN]
BAT [SY]
botulinum toxin equine immune globulin [SY]
Clostridium botulinum toxin types A, B, and E immune globulin F(ab')2 fragments, equine [SY]
NDC 11793-7510-01; 11793-7511-01 [NDC]
FDA Class: Biologic PLA
Year of approval (FDA) = 1968
Date of 1st FDA approval = 19680816
(in format YYYYMMDD)
Index Terms:
antibodies (see also immune globulins; monoclonal antibodies)
antitoxins
biopharmaceutical products
blood products
equine immune globulins <!-- immunoglobulins -->
equine materials used
botulinum toxins
Clostridium botulinum
equine plasma/serum
plasma proteins, immunoglobulin-depleted
ammonium sulfate
pepsin digestion
phenol
phenol
sodium chloride
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
conjugates
conjugates
EU200 Currently Approved in EU
UM100 Controlled/Gov't Distribution in US
US200 Currently Approved in US
EM160 Controlled/Gov't Distribution in EU
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