Safety of intravenous equine F(ab')2: Insights following clinical trials involving 1534 recipients of scorpion antivenom

Leslie V Boyer, Janice Degan, Anne Michelle Ruha, Joanne Mallie, Emmanuelle Mangin, Alejandro Alagón

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Introduction The technology of antivenom production has gradually changed since the earliest production of antisera around the turn of the 20th century. Use of early antisera was associated with frequent acute adverse reactions and serum sickness. New F(ab')2 products, manufactured using pepsin degradation of immunoglobulin together with precipitation of unwanted protein and albumin serum fractions, should in concept cause fewer immune reactions in clinical use. Methods A linked set of five prospective clinical trials of an equine F(ab')2 antivenom, together with one historical control study, were completed during development of the product for a Biological License Application through the US FDA. Adverse events were recorded and categorized, with particular attention to the frequency of immune reactions. Results A total of 1534 patients ages 0.1-90.5 years received antivenom, in Arizona and in Mexico, for treatment of scorpion envenomation. Total dosing ranged from 1 to 5 vials except for one outlier who received 10 vials. Estimated protein exposure was 12-275 mg per patient (outlier, up to 550 mg). Three patients (0.2%) had acute reactions to antivenom infusion (one urticaria, one urticaria and dyspnea, and one panic attack). Eight (0.5%) had rashes suggestive of Type 3 immune reactions, although none had the full syndrome of serum sickness. Two women were treated for envenomation during the first trimester of pregnancy, one of whom subsequently experienced a spontaneous abortion. Conclusions Rates of immune reaction to this product were two orders of magnitude lower than the range (up to 75% for early and 81% for late reactions) historically reported with use of minimally refined whole immunoglobulin products against a variety of infections and envenomations. Lower protein dose, greater purity of the active component, lack of the immunogenic Fc portion of the immunoglobulin molecule, and slow intravenous infusion are likely to be the reason for this. Clinical implications of a safer product include that it can be employed in settings where antivenom was once considered too dangerous to use, such as primary care clinics and remote rural areas.

Original languageEnglish (US)
Pages (from-to)386-393
Number of pages8
JournalToxicon
Volume76
DOIs
StatePublished - Dec 15 2013

Fingerprint

Antivenins
Scorpions
Antigen-antibody reactions
Horses
Clinical Trials
Safety
Serum Sickness
Urticaria
Immunoglobulins
Immune Sera
Immunoglobulin Fc Fragments
Pepsin A
Panic Disorder
Spontaneous Abortion
First Pregnancy Trimester
Licensure
Mexico
Exanthema
Intravenous Infusions
Serum Albumin

Keywords

  • Adverse events
  • Antivenom
  • Safety
  • Scorpion

ASJC Scopus subject areas

  • Toxicology

Cite this

Safety of intravenous equine F(ab')2 : Insights following clinical trials involving 1534 recipients of scorpion antivenom. / Boyer, Leslie V; Degan, Janice; Ruha, Anne Michelle; Mallie, Joanne; Mangin, Emmanuelle; Alagón, Alejandro.

In: Toxicon, Vol. 76, 15.12.2013, p. 386-393.

Research output: Contribution to journalArticle

Boyer, Leslie V ; Degan, Janice ; Ruha, Anne Michelle ; Mallie, Joanne ; Mangin, Emmanuelle ; Alagón, Alejandro. / Safety of intravenous equine F(ab')2 : Insights following clinical trials involving 1534 recipients of scorpion antivenom. In: Toxicon. 2013 ; Vol. 76. pp. 386-393.
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abstract = "Introduction The technology of antivenom production has gradually changed since the earliest production of antisera around the turn of the 20th century. Use of early antisera was associated with frequent acute adverse reactions and serum sickness. New F(ab')2 products, manufactured using pepsin degradation of immunoglobulin together with precipitation of unwanted protein and albumin serum fractions, should in concept cause fewer immune reactions in clinical use. Methods A linked set of five prospective clinical trials of an equine F(ab')2 antivenom, together with one historical control study, were completed during development of the product for a Biological License Application through the US FDA. Adverse events were recorded and categorized, with particular attention to the frequency of immune reactions. Results A total of 1534 patients ages 0.1-90.5 years received antivenom, in Arizona and in Mexico, for treatment of scorpion envenomation. Total dosing ranged from 1 to 5 vials except for one outlier who received 10 vials. Estimated protein exposure was 12-275 mg per patient (outlier, up to 550 mg). Three patients (0.2{\%}) had acute reactions to antivenom infusion (one urticaria, one urticaria and dyspnea, and one panic attack). Eight (0.5{\%}) had rashes suggestive of Type 3 immune reactions, although none had the full syndrome of serum sickness. Two women were treated for envenomation during the first trimester of pregnancy, one of whom subsequently experienced a spontaneous abortion. Conclusions Rates of immune reaction to this product were two orders of magnitude lower than the range (up to 75{\%} for early and 81{\%} for late reactions) historically reported with use of minimally refined whole immunoglobulin products against a variety of infections and envenomations. Lower protein dose, greater purity of the active component, lack of the immunogenic Fc portion of the immunoglobulin molecule, and slow intravenous infusion are likely to be the reason for this. Clinical implications of a safer product include that it can be employed in settings where antivenom was once considered too dangerous to use, such as primary care clinics and remote rural areas.",
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AU - Mangin, Emmanuelle

AU - Alagón, Alejandro

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N2 - Introduction The technology of antivenom production has gradually changed since the earliest production of antisera around the turn of the 20th century. Use of early antisera was associated with frequent acute adverse reactions and serum sickness. New F(ab')2 products, manufactured using pepsin degradation of immunoglobulin together with precipitation of unwanted protein and albumin serum fractions, should in concept cause fewer immune reactions in clinical use. Methods A linked set of five prospective clinical trials of an equine F(ab')2 antivenom, together with one historical control study, were completed during development of the product for a Biological License Application through the US FDA. Adverse events were recorded and categorized, with particular attention to the frequency of immune reactions. Results A total of 1534 patients ages 0.1-90.5 years received antivenom, in Arizona and in Mexico, for treatment of scorpion envenomation. Total dosing ranged from 1 to 5 vials except for one outlier who received 10 vials. Estimated protein exposure was 12-275 mg per patient (outlier, up to 550 mg). Three patients (0.2%) had acute reactions to antivenom infusion (one urticaria, one urticaria and dyspnea, and one panic attack). Eight (0.5%) had rashes suggestive of Type 3 immune reactions, although none had the full syndrome of serum sickness. Two women were treated for envenomation during the first trimester of pregnancy, one of whom subsequently experienced a spontaneous abortion. Conclusions Rates of immune reaction to this product were two orders of magnitude lower than the range (up to 75% for early and 81% for late reactions) historically reported with use of minimally refined whole immunoglobulin products against a variety of infections and envenomations. Lower protein dose, greater purity of the active component, lack of the immunogenic Fc portion of the immunoglobulin molecule, and slow intravenous infusion are likely to be the reason for this. Clinical implications of a safer product include that it can be employed in settings where antivenom was once considered too dangerous to use, such as primary care clinics and remote rural areas.

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