Botulism Antitoxin

Botulism Antitoxin
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alara Ece Dagsali, M.D.[2]

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Overview

Botulism Antitoxin is a {{{drugClass}}} that is FDA approved for the treatment of BAT [Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G) – (Equine)] is a mixture of immune globulin fragments indicated for the treatment of symptomatic botulism following documented or suspected exposure to botulinum neurotoxin serotypes A, B, C, D, E, F, or G in adults and pediatric patients.. Common adverse reactions include The most common adverse reactions observed in ≥ 5 % of healthy volunteers in clinical trials were headache, nausea, pruritus and urticaria. • The most common adverse reactions reported in ≥ 1% of patients in a clinical study were pyrexia, rash, chills, nausea and edema. • One serious adverse reaction of hemodynamic instability was observed in one patient in the clinical study..

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

BAT [Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G) – (Equine)] is a mixture of immune globulin fragments indicated for the treatment of symptomatic botulism following documented or suspected exposure to botulinum neurotoxin serotypes A, B, C, D, E, F, or G in adults and pediatric patients.

Each single-use vial contains a minimum potency of:

• 4,500 Units (U) for serotype A antitoxin, • 3,300 U for serotype B antitoxin, • 3,000 U for serotype C antitoxin, • 600 U for serotype D antitoxin, • 5,100 U for serotype E antitoxin, • 3,000 U for serotype F antitoxin, and • 600 U for serotype G antitoxin.

The effectiveness of BAT is based solely on efficacy studies conducted in animal models of botulism.

Off-Label Use and Dosage (Adult)

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

The effectiveness of BAT has not been established in pediatric patients. Limited pediatric safety data are available.

Fifteen pediatric subjects (age 10 days to 17 years; including 1 newborn, 3 infants and toddlers, 4 children and 7 adolescents) received BAT under the CDC expanded access clinical study. A 3-year old subject and an infant received two infant doses, and 13 pediatric subjects received one pediatric dose according to Salisbury Rule.

Two adverse reactions were reported in two pediatric subjects. One subject experienced an adverse reaction of pyrexia following infusion of BAT, while the other subject experienced a serious adverse reaction of hemodynamic instability characterized by tachycardia, bradycardia, and asystole during infusion of BAT.

Dosing in pediatric patients is based on Salisbury Rule.

Off-Label Use and Dosage (Pediatric)

Contraindications

None

Warnings

Hypersensitivity reactions including anaphylaxis. Prepare for monitoring and management of allergic reactions. • Delayed allergic reactions (serum sickness). Patient monitoring is recommended. • Infusion reactions. Monitor and slow or interrupt infusion and administer treatment based on the severity of the reaction. • Interference with non-glucose specific blood sugar testing systems. Use glucose-specific testing systems. • BAT is made from equine plasma and may contain infectious agents e.g. viruses

Adverse Reactions

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In a randomized, double-blind, parallel arm trial conducted to evaluate the safety of BAT in healthy subjects, and to establish the pharmacokinetic profile of the seven botulinum antitoxin serotypes contained in BAT following intravenous (IV) administration, 40 subjects were randomized to receive either one (n=20) or two vials (n=20) of BAT.

In a second parallel arm, randomized, double-blind pharmacodynamic trial, 26 healthy subjects were randomized to receive either BAT in saline (n=16) or placebo (0.9% saline; n=10).

The most common adverse reactions in all healthy subjects were headache (9%), pruritus (5%), nausea (5%), and urticaria (5%). Other adverse reactions reported in less than 4% of subjects included pyrexia and throat discomfort. All reported adverse reactions were considered mild or moderate. No serious adverse reactions were reported. Two moderate acute allergic reactions that required premature termination of the infusion and treatment were reported. Reactions were predefined as mild if the subject was aware but could tolerate. Moderate reactions were predefined as discomfort enough to interfere with normal daily activity.

A total of 231 subjects with suspected or confirmed botulism were exposed to BAT in an open-label observational expanded access clinical study sponsored by the Centers for Disease Control and Prevention (CDC).

The majority of adult (213/216) and pediatric (13/15) subjects received one dose of BAT. Three adult subjects were exposed to a second dose of BAT, and two pediatric subjects each received two infant doses (10% of the adult dose). The administration of a second dose varied from seven hours to one month after the first dose.

Safety data was actively collected from treating physicians by the CDC. However, no on-site safety monitoring was performed, and the CDC relied on follow-up information provided by the treating physicians to determine the reporting frequencies for adverse reactions. Of the 231 subjects receiving BAT, safety information was available for 228 subjects. Adverse reactions were reported in 10% of all subjects. The most common adverse reactions were pyrexia (4%), rash (2%), chills (1%), nausea (1%), and edema (1%). Other adverse reactions were reported in less than 1% of subjects. No subject experienced anaphylaxis. One subject experienced a serious adverse reaction of hemodynamic instability characterized by bradycardia, tachycardia, and asystole during BAT administration. One subject experienced mild serum sickness (< 1%) with myalgia, arthralgia, and dark urine twelve days after BAT administration.

Postmarketing Experience

The following hypersensitivity/allergic reactions have been reported in patients treated with BAT:

• Anaphylactic shock • Angioedema • Urticaria

Drug Interactions

BAT contains maltose which can interfere with certain types of blood glucose monitoring systems. Only test systems that are glucose-specific should be used in patients receiving BAT. This interference can result in falsely elevated glucose readings that can lead to untreated hypoglycemia or to inappropriate insulin administration, resulting in life-threatening hypoglycemia.

The product information of the blood glucose testing system, including that of the test strips, should be carefully reviewed to determine if the system is appropriate for use with maltose-containing parenteral systems. If any uncertainty exists, contact the manufacturer of the testing system to determine if the system is appropriate for use with maltose-containing parenteral products.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): There are no human or animal data to establish the presence or absence of BAT associated risk.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Botulism Antitoxin in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Botulism Antitoxin during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Botulism Antitoxin in women who are nursing.

Pediatric Use

The effectiveness of BAT has not been established in pediatric patients. Limited pediatric safety data are available.

Fifteen pediatric subjects (age 10 days to 17 years; including 1 newborn, 3 infants and toddlers, 4 children and 7 adolescents) received BAT under the CDC expanded access clinical study. A 3-year old subject and an infant received two infant doses, and 13 pediatric subjects received one pediatric dose according to Salisbury Rule.

Two adverse reactions were reported in two pediatric subjects. One subject experienced an adverse reaction of pyrexia following infusion of BAT, while the other subject experienced a serious adverse reaction of hemodynamic instability characterized by tachycardia, bradycardia, and asystole during infusion of BAT.

Dosing in pediatric patients is based on Salisbury Rule.

Geriatic Use

The safety, pharmacokinetics, and effectiveness of BAT have not been established in geriatric subjects.

Thirty-six geriatric subjects received BAT under the CDC expanded access clinical study. One geriatric subject experienced rash as an adverse reaction following infusion of BAT.

Gender

There is no FDA guidance on the use of Botulism Antitoxin with respect to specific gender populations.

Race

There is no FDA guidance on the use of Botulism Antitoxin with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Botulism Antitoxin in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Botulism Antitoxin in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Botulism Antitoxin in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Botulism Antitoxin in patients who are immunocompromised.

Administration and Monitoring

Administration

Each single-use vial contains a minimum potency of:

• 4,500 Units (U) for serotype A antitoxin, • 3,300 U for serotype B antitoxin, • 3,000 U for serotype C antitoxin, • 600 U for serotype D antitoxin, • 5,100 U for serotype E antitoxin, • 3,000 U for serotype F antitoxin, and • 600 U for serotype G antitoxin.

Monitoring

Prepare for monitoring and management of allergic reactions

IV Compatibility

Dilute 1:10 in 0.9% Sodium Chloride Injection, USP (saline) by adding BAT solution from the vial to the appropriate amount of saline in an IV bag. Do not use any other diluents. As the fill volume per vial varies by lot number (ranging from 10 to 26 milliliters per vial), 90 to 235 milliliters of saline will be required. Withdraw the entire contents of the vial to obtain the total volume in the vial. If a partial vial is required (for pediatric dosing), the entire content of the vial should be withdrawn to ensure accurate calculation of the dosage

Overdosage

There is limited information regarding Botulism Antitoxin overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

There is limited information regarding Botulism Antitoxin Pharmacology in the drug label.

Mechanism of Action

The mechanism of action of BAT is through passive immunization with equine polyclonal antibody fragments (primarily F(ab′)2 and Fab) against botulinum neurotoxin (BoNT) A, B, C, D, E, F, and G. In the circulation the polyclonal antibody fragments bind to free BoNT. This prevents the BoNT from interacting with ganglioside anchorage sites and protein receptors on the cholinergic nerve endings. In turn this prevents BoNT internalization into the target cells. The antibody/antigen complexes are then cleared from the circulation by the organs involved in processing immune complexes.

Experimental evidence concerning the amount of circulating antitoxin needed to counteract BoNT intoxication is not fully documented. The outcome of treatment depends, as it does with other comparable conditions, largely on the time interval elapsing after the onset of symptoms and antitoxin administration.

Structure

There is limited information regarding Botulism Antitoxin Structure in the drug label.

Pharmacodynamics

A proof-of-concept clinical dose-response trial was conducted using the extensor digitorum brevis (EDB) muscle of the foot as a model for measuring muscle paralysis after exposure to botulism toxin. In this model, BAT prevented subjects from experiencing a decrease in muscle function after exposure to botulinum neurotoxin (BoNT) serotypes A and B. Subjects treated with placebo (n=10) demonstrated a loss of greater than 50% EDB muscle function within 3 days of exposure to BoNT serotypes A and B. In the BAT arm of the trial (n=16), EDB muscle function was stable over time indicating that BAT was effective in preserving muscle function for up to 28 days following exposure to both BoNT serotype A and B.

Pharmacokinetics

The pharmacokinetics (PK) of the seven botulism antitoxin serotypes was determined in healthy human subjects following IV administration of either one (n=20) or two vials (n=20) of BAT.

The PK parameters varied based upon the antitoxin serotype measured. Antitoxin serotypes D and E had the shortest half-lives. While antitoxin serotype B and C had the longest half-lives. The AUC0-∞ and Cmax values increased in a dose proportional fashion as the BAT dose increased from one to two vials. In addition, mean clearance values appeared to be similar between both treatment groups for the seven antitoxin serotypes, suggesting dose linearity of BAT over the dose range studied.

Nonclinical Toxicology

oxicological studies were not conducted for BAT or its components.

The evaluation of new treatment options for botulism using controlled human trials is unethical and infeasible. Therefore the effectiveness of BAT for treatment of botulism is based on well controlled efficacy studies conducted in guinea pigs and rhesus macaques.

Guinea Pig

In a controlled therapeutic efficacy study, guinea pigs were intoxicated with various BoNT serotypes (A, B, C, D, E, F or G) at a dose of 1.5x guinea pig intramuscular lethal dose 50% units (GPIMLD50) via intramuscular injection into the right hind limb. The animals were then treated with either placebo control or 1x scaled human dose of BAT (weight/weight based on an average human body weight of 70 kilograms), after the onset of moderate clinical signs of botulism (right hind limb weakness, salivation, lacrimation, weak limbs and noticeable changes in breathing rate or pattern). Treatment with BAT resulted in a statistically significant improvement in the survival rate of animals across all of the serotypes tested Nonhuman Primate

In a controlled therapeutic efficacy study, rhesus macaques were intoxicated with BoNT serotype A delivered intravenously at a dose of 1.7x nonhuman primate intravenous lethal dose 50% (NHPLD50) units per kilogram of body weight. The animals were then treated with either placebo control or 1x scaled human dose of BAT (weight/weight based on an average human body weight of 70 kilograms), after the onset of clinical signs of botulism (ptosis, muscular weakness, or respiratory distress). Treatment with BAT resulted in a statistically significant improvement in the survival rate

Clinical Studies

The effectiveness of BAT is based on efficacy studies demonstrating a survival benefit in animal models of botulism [see Nonclinical Toxicology (13.2 ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY)]. The safety has been tested in healthy adults and patients with suspected botulism who were treated with BAT under an expanded access clinical study.

The pharmacokinetic, pharmacodynamic, and safety profiles of BAT have been evaluated in two clinical studies. In these clinical studies, BAT was shown to have an acceptable safety profile when one or two vials of BAT were administered intravenously to healthy subjects.

In a randomized, single-center, double-blind trial the pharmacokinetics and safety of BAT was evaluated in 40 healthy subjects receiving either one (n = 20) or two (n = 20) vials of BAT by IV infusion. Serum BAT levels were measured in the subjects using the Mouse Neutralization Assay (MNA) [see Clinical Pharmacology (12.3)].

In a randomized single center, double-blind trial the pharmacodynamics and safety of BAT was evaluated in 26 healthy subjects receiving either a single vial of BAT (n=16) or placebo (n=10) by IV infusion. The effects of BAT in preventing paralysis of the EDB foot muscle following administration of botulinum neurotoxin serotype A or B was determined [see Clinical Pharmacology (12.2)].

To provide additional support for the efficacy demonstrated in the animal models, a preliminary analysis of data from a Centers for Disease Control and Prevention (CDC) open-label, observational expanded access clinical study for the treatment of subjects with suspected or confirmed botulism with BAT was conducted. Across the 148 subjects treated with BAT in the period analyzed, 109 subjects had a final discharge diagnosis of suspected or confirmed botulism and were included in the analysis population. The median time from the onset of botulism symptoms to treatment with BAT was 3.6 days (range: 0.25 – 38 days). Early treatment (≤ 2 days after onset of symptoms) with BAT was associated with a shorter length of hospitalization, duration in intensive care unit (ICU) and duration of mechanical ventilation compared to later treatment and is consistent with the mechanism of action

How Supplied

BAT is supplied in either 20 milliliter or 50 milliliter glass vials seated with a butyl rubber stopper and an aluminum seal with a plastic flip-top cap, with a fill volume ranging from 10 to 26 milliliters per vial. Each vial, regardless of size or fill volume contains a minimum potency of > 4,500 U serotype A antitoxin, > 3,300 U serotype B antitoxin, > 3000 U serotype C antitoxin, > 600 U serotype D antitoxin, > 5,100 U serotype E antitoxin, > 3,000 U serotype F antitoxin, and > 600 U serotype G antitoxin.

BAT is not made with natural rubber latex.

NDC Number Product Description

60492-0075-2: A 50 milliliter single dose vial.

60492-0075-3: A 20 milliliter single dose vial.

60492-0075-4: A 50 milliliter single dose vial.

Storage

Store frozen at or below 5°F (≤ -15°C) until used. • Once thawed, Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G) – (Equine) may be stored at 2-8°C (36-46°F) for a maximum of 36 months or until 48 months from the date of manufacture, whichever comes first. Do not refreeze. • Once punctured, use the vial contents to prepare the infusion bag and administer as soon as possible. • BAT vials are for single use only and contain no preservative. Discard any unused portion.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

See FDA-approved patient labeling (Patient Information).

• Inform patients of the following: • BAT is prepared from equine plasma and may contain infectious agents such as viruses that can cause disease. • The risk that such products will transmit an infectious agent has been reduced by screening the horses for prior exposure to certain viruses, by testing for the presence of certain current viral infections, and by inactivating and/or removing certain viruses during manufacturing. • Despite these measures, such products can still potentially transmit disease. • There is also the possibility that unknown infectious agents may be present in such products. • Inform patients that persons who have received previous therapy with an equine-derived antivenom/antitoxin, have known allergies to horses, have asthma or get hay fever (seasonal allergies) may be at increased risk of hypersensitivity reactions and should only receive BAT if the benefits outweigh the risks. • Advise patients about the potential interference with non-glucose specific monitoring systems. • The maltose contained in BAT can interfere with some types of blood glucose monitoring systems. • Only testing systems that are glucose-specific should be used in patients receiving BAT. • This interference can result in falsely elevated glucose readings that can lead to untreated hypoglycemia or to inappropriate insulin administration, resulting in life-threatening hypoglycemia.

Precautions with Alcohol

Alcohol-Botulism Antitoxin interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

Brand Names

BAT

Look-Alike Drug Names

There is limited information regarding Botulism Antitoxin Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.