Introduction

Antitoxin; heptavalent preparation of equine immunoglobulin F(ab′)₂ and F(ab′)₂-related fragments capable of neutralizing botulinum neurotoxins A, B, C, D, E, F, and G. Other botulism antitoxin (equine) preparations containing antibody to fewer botulinum neurotoxins (e.g., bivalent botulinum antitoxin AB, monovalent botulinum antitoxin E) were previously available in the US and may be available elsewhere.

Uses for Botulism Antitoxin (Equine)

Treatment of Botulism

Treatment of symptomatic botulism following documented or suspected exposure to botulinum neurotoxin serotypes A, B, C, D, E, F, or G; designated an orphan drug by FDA for treatment of botulism.

Botulism is a potentially fatal neuroparalytic illness characterized by acute afebrile, symmetric, descending, flaccid paralysis. Caused by neurotoxin produced by Clostridium botulinum; certain strains of C. argentinense, C. baratii, and C. butyricum also can produce neurotoxin and cause botulism. C. botulinum spores are ubiquitous in the environment in soil and water sediments and can germinate into the vegetative bacteria that produce toxin. There are 7 known serotypes of botulinum toxin (A, B, C, D, E, F, G) and all cause similar disease; naturally occurring human botulism usually involves serotypes A, B, E, and F.

Foodborne botulism occurs following ingestion of food contaminated with botulinum toxin (e.g., improperly canned food); symptoms usually begin 12–48 hours (range: 2 hours to 10 days) after ingestion. Wound botulism occurs following contamination of wounds with C. botulinum spores from the environment that then germinate and produce botulinum toxin; time between wound contamination and onset of symptoms usually is 4–14 days. Infant botulism occurs when infants <1 year of age ingest C. botulinum spores that then germinate, colonize the GI tract, and produce botulinum toxin; time between exposure and onset of symptoms estimated to be 3–30 days. Intestinal botulism (child or adult) occurs following intestinal colonization with C. botulinum and subsequent production of botulinum toxin.

Botulism also could potentially occur from iatrogenic overdose or misinjection of commercially available botulinum toxin used therapeutically (e.g., abobotulinumtoxinA, incobotulinumtoxinA, onabotulinumtoxinA, rimabotulinumtoxinB) or from inhalation of aerosolized botulinum toxin (e.g., in the context of biologic warfare or bioterrorism). Symptoms of botulism may be evident within 12–72 hours following an inhalation exposure.

Botulism Antitoxin (Equine) Dosage and Administration

General

• Administer botulism antitoxin (equine) heptavalent as soon as possible after clinical diagnosis of botulism (ideally within 24 hours after onset of symptoms); use in conjunction with intensive supportive care (e.g., respiratory, fluid, and nutritional support).

• Do not delay treatment of botulism while waiting for confirmatory diagnostic testing (e.g., mouse bioassay, toxin assay and/or culture of wound, tissue, feces, or suspect food).

• Although prompt administration of the antitoxin can neutralize circulating botulinum toxin thereby preventing additional nerve damage and disease progression, it cannot reverse existing paralysis.

Intradermal Sensitivity Testing

• Consider skin sensitivity testing prior to administration of the antitoxin in patients at risk for severe hypersensitivity reactions, including those with a history of hypersensitivity to horses or equine blood products, other allergies (e.g., hay fever), or asthma. (See Sensitivity Reactions under Cautions.)

• Inject 0.02 mL of a 1:1000 dilution of botulism antitoxin (equine) heptavalent (prepared using 0.9% sodium chloride injection) into volar surface of patient’s forearm; this quantity should raise a small intradermal wheal. Inject 0.02 mL of histamine (positive control) and 0.02 mL of 0.9% sodium chloride injection (negative control) at different sites. Observe results after 15–20 minutes. Positive skin test reaction consists of urticarial wheal surrounded by zone of erythema ≥3 mm larger than negative control. If test is negative, inject 0.02 mL of a 1:100 dilution of botulism antitoxin equine. Histamine (positive) control must produce a positive skin test reaction for valid interpretation of antitoxin intradermal sensitivity test.

Restricted Distribution

• Approved by FDA for treatment of symptomatic botulism following documented or suspected exposure to botulinum neurotoxin serotypes A, B, C, D, E, F, or G, but available in US only from CDC. The antitoxin is stored at CDC quarantine stations located in major airports throughout US and can be delivered to any US location within hours. Also stored in US Strategic National Stockpile for emergency preparedness and response.

• To obtain botulism antitoxin (equine) heptavalent, clinicians should contact their state health department's 24-hour telephone number. State health departments should contact the CDC Emergency Operation Center at 770-488-7100 to arrange a telephone consultation and, if indicated, release of the antitoxin. If a response cannot be obtained through the state health department, clinicians should contact the CDC Emergency Operation Center directly.

Administration

IV Administration

Administer only by slow IV infusion.

Prior to administration, must be diluted in 0.9% sodium chloride. (See Dilution under Dosage and Administration.) Administer diluted antitoxin solution using a constant infusion pump; use of an inline filter is optional.

Monitor closely for signs and symptoms of acute sensitivity or infusion reactions during and immediately after completion of the IV infusion. (See Sensitivity Reactions and see Infusion Reactions under Cautions.)

Provided in single-use vials. May arrive from CDC either frozen or thawed. If frozen, thaw by placing vials in a refrigerator at 2–8°C for approximately 14 hours until contents are thawed. For more rapid thawing, place vials at room temperature for 1 hour, followed by immersion in a water bath at 37°C until thawed. Do not thaw in a microwave oven. Do not refreeze.

Dilution

Prior to dilution, thaw antitoxin (if necessary) and bring to room temperature.

Do not shake vial at any time since this may cause foaming.

Dilute 1:10 in 0.9% sodium chloride injection by withdrawing entire contents of the vial and adding it to appropriate amount of 0.9% sodium chloride in an IV bag. Appropriate amount of 0.9% sodium chloride injection varies from 90–200 mL since the antitoxin has a fill volume per vial that varies from approximately 10–22 mL depending on antitoxin lot number. To ensure accurate calculation of pediatric dosage when partial vial of antitoxin required, withdraw entire vial contents.

Inspect diluted antitoxin solution for particulate matter and discoloration; do not use if it is turbid, cloudy, or contains particulates.

Rate of Administration

Individualize IV infusion rate based on patient age and tolerance.

Monitor patient throughout the IV infusion. If tolerated, increase infusion rate incrementally up to maximum recommended infusion rate and continue until dose completely administered. If infusion not tolerated and adverse reactions occur, decrease infusion rate or discontinue infusion if necessary.

Infants <1 year of age: Initiate IV infusion at a rate of 0.01 mL/kg per minute for first 30 minutes; if tolerated, infusion rate can then be increased by 0.01 mL/kg per minute every 30 minutes up to a maximum infusion rate of 0.03 mL/kg per minute.

Children 1 through 16 years of age: Initiate IV infusion at a rate of 0.01 mL/kg per minute for first 30 minutes; if tolerated, infusion rate can then be increased by 0.01 mL/kg per minute every 30 minutes up to a maximum infusion rate of 0.03 mL/kg per minute. Do not exceed infusion rates recommended for adults.

Adults: Initiate IV infusion at a rate of 0.5 mL per minute for first 30 minutes; if tolerated, infusion rate can then be doubled every 30 minutes up to a maximum infusion rate of 2 mL per minute.

If used in patients at risk for hypersensitivity reactions (see Sensitivity Reactions under Cautions), initiate IV infusion using lowest rate achievable (i.e., <0.01 mL per minute) and closely monitor patient.

Dosage

Given as a single dose for treatment of symptomatic botulism following documented or suspected exposure to botulinum neurotoxin serotypes A, B, C, D, E, F, or G.

Each single-use vial (regardless of vial size or fill volume) contains at least 4500, 3300, 3000, 600, 5100, 3000, and 600 units of serotype A, B, C, D, E, F, and G antitoxin, respectively.

Pediatric Patients

Botulism

IV

Infants <1 year of age: 10% of recommended adult dose (i.e., one-tenth of a single-use vial), regardless of body weight. Dilute as recommended and give as a single IV infusion using age-appropriate infusion rate. (See Administration under Dosage and Administration.)

Children 1 through 16 years of age: 20–100% of recommended adult dose (i.e., 20–100% of a single-use vial) based on the Salisbury Rule, which takes into consideration weight differences between pediatric patients and adults. (See Table 1.) Dilute as recommended and give as a single IV infusion using age-appropriate infusion rate. (See Administration under Dosage and Administration.)

Based on the Salisbury Rule. Children weighing ≤30 kg: 2 × child's weight (kg). Children weighing >30 kg: child's weight (kg) + 30.

Minimum dosage is 20% of the recommended adult dosage.

Adults

Botulism

IV

Adults ≥17 years of age: 1 single-use vial. Dilute as recommended and give as a single IV infusion using age-appropriate infusion rate. (See Administration under Dosage and Administration.)

Prescribing Limits

Pediatric Patients

Botulism

IV

Infants <1 year of age: Maximum infusion rate 0.03 mL/kg per minute.

Children 1 through 16 years of age: Maximum dose is 1 single-use vial; minimum dose is 20% of single-use vial. Maximum infusion rate is 2 mL per minute.

Adults

Botulism

IV

Adults ≥17 years of age: Maximum dose is 1 single-use vial. Maximum infusion rate is 2 mL per minute.

Special Populations

No special population dosage recommendations.

Contraindications

• Manufacturer states none.

Warnings/Precautions

Sensitivity Reactions

Immediate Hypersensitivity or Anaphylaxis.

Severe hypersensitivity reactions (e.g., anaphylaxis, anaphylactoid reactions) may occur.

Risk of severe reactions may be increased in individuals with history of sensitivity to horses or equine blood products, other allergies (e.g., hay fever), or asthma. Consider skin sensitivity testing prior to administration of the antitoxin in such individuals to ascertain risk of allergic reactions. (See Intradermal Sensitivity Testing under Dosage and Administration.)

Administer in setting with appropriate equipment, medication (e.g., epinephrine), and personnel trained in management of hypersensitivity, anaphylaxis, and shock.

Closely monitor for signs and symptoms of acute allergic reactions (e.g., urticaria, pruritus, erythema, angioedema, bronchospasm with wheezing or cough, stridor, laryngeal edema, hypotension, tachycardia) during and after IV infusion of the antitoxin.

If hypersensitivity reaction occurs, immediately discontinue antitoxin infusion and initiate emergency medical care.

If used in patients at risk for hypersensitivity reactions, initiate the IV infusion using lowest rate achievable (i.e., <0.01 mL/minute) and closely monitor patient.

Delayed Hypersensitivity or Serum Sickness Reactions

Delayed hypersensitivity or serum sickness reactions reported. Usually manifest as fever, urticarial or maculopapular rash, myalgia, arthralgia, and lymphadenopathy and typically occur 10–21 days after IV infusion of the antitoxin.

Monitor for signs and symptoms of delayed allergic reactions or serum sickness. If such reactions suspected, administer appropriate medical care.

Infusion Reactions

Infusion-related reactions (e.g., chills, fever, difficulty breathing, headache, nausea, vomiting, arthralgia, myalgia, fatigue) reported within 20–60 minutes after IV infusion of the antitoxin. Arthralgia, myalgia, fatigue, and vasovagal reactions also reported.

Monitor patients during and immediately after IV infusion. If infusion-related reaction occurs, reduce infusion rate and administer symptomatic care. If reaction worsens, discontinue infusion and administer appropriate medical care.

Interference with Blood Glucose Testing

Parenteral preparations containing maltose, including the antitoxin, may cause falsely elevated results in blood glucose determinations that use glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ). May lead to inappropriate administration of insulin resulting in life-threatening hypoglycemia or may mask true hypoglycemic states.

Use only glucose-specific test methods not affected by maltose. Carefully review product information for the blood glucose testing system (including glucose test strips) to determine if appropriate. If any uncertainty exists, contact manufacturer of the glucose testing system to determine if the system will provide accurate blood glucose determinations in a patient treated with the antitoxin.

Risk of Transmissible Infectious Agents

Prepared from equine plasma; potentially may transmit infectious agents, including viruses. Screening of equine plasma and viral elimination/inactivation procedures included in manufacturing process reduce risk of transmission of viruses.

Report any suspected infections associated with administration of the antitoxin to the manufacturer at 800-768-2304.

Antibody Formation

Potential for immunogenicity. In healthy volunteers negative for anti-equine antibodies before receiving the antitoxin, 11 of 39 (28%) developed antibodies against the antitoxin. These were mainly IgG antibodies; IgE antibodies not detected in these individuals.

Specific Populations

Pregnancy

Category C.

Lactation

Not known whether distributed into milk. Use with caution in nursing women.

Pediatric Use

Labeled by FDA for use in pediatric patients. Efficacy not established in pediatric patients; only limited safety data regarding use in pediatric patients.

CDC and other experts state treatment of botulism in pediatric patients should be the same as that in adults. For treatment of infant botulism caused by serotypes A or B, consider that botulism immune globulin IV (BIG-IV) is available for use in those <1 year of age.

Fifteen pediatric patients ranging from 10 days to 17 years of age received the antitoxin in CDC expanded access study.

Geriatric Use

Efficacy and safety not established in geriatric patient; 36 patients ≥65 years of age received the antitoxin in CDC expanded access study.

Common Adverse Effects

Headache, nausea, pruritus, urticaria, fever, rash, chills, edema.

General

• Administer botulism antitoxin (equine) heptavalent as soon as possible after clinical diagnosis of botulism (ideally within 24 hours after onset of symptoms); use in conjunction with intensive supportive care (e.g., respiratory, fluid, and nutritional support).

• Do not delay treatment of botulism while waiting for confirmatory diagnostic testing (e.g., mouse bioassay, toxin assay and/or culture of wound, tissue, feces, or suspect food).

• Although prompt administration of the antitoxin can neutralize circulating botulinum toxin thereby preventing additional nerve damage and disease progression, it cannot reverse existing paralysis.

Intradermal Sensitivity Testing

• Consider skin sensitivity testing prior to administration of the antitoxin in patients at risk for severe hypersensitivity reactions, including those with a history of hypersensitivity to horses or equine blood products, other allergies (e.g., hay fever), or asthma. (See Sensitivity Reactions under Cautions.)

• Inject 0.02 mL of a 1:1000 dilution of botulism antitoxin (equine) heptavalent (prepared using 0.9% sodium chloride injection) into volar surface of patient’s forearm; this quantity should raise a small intradermal wheal. Inject 0.02 mL of histamine (positive control) and 0.02 mL of 0.9% sodium chloride injection (negative control) at different sites. Observe results after 15–20 minutes. Positive skin test reaction consists of urticarial wheal surrounded by zone of erythema ≥3 mm larger than negative control. If test is negative, inject 0.02 mL of a 1:100 dilution of botulism antitoxin equine. Histamine (positive) control must produce a positive skin test reaction for valid interpretation of antitoxin intradermal sensitivity test.

Restricted Distribution

• Approved by FDA for treatment of symptomatic botulism following documented or suspected exposure to botulinum neurotoxin serotypes A, B, C, D, E, F, or G, but available in US only from CDC. The antitoxin is stored at CDC quarantine stations located in major airports throughout US and can be delivered to any US location within hours. Also stored in US Strategic National Stockpile for emergency preparedness and response.

• To obtain botulism antitoxin (equine) heptavalent, clinicians should contact their state health department's 24-hour telephone number. State health departments should contact the CDC Emergency Operation Center at 770-488-7100 to arrange a telephone consultation and, if indicated, release of the antitoxin. If a response cannot be obtained through the state health department, clinicians should contact the CDC Emergency Operation Center directly.

Administration

IV Administration

Administer only by slow IV infusion.

Prior to administration, must be diluted in 0.9% sodium chloride. (See Dilution under Dosage and Administration.) Administer diluted antitoxin solution using a constant infusion pump; use of an inline filter is optional.

Monitor closely for signs and symptoms of acute sensitivity or infusion reactions during and immediately after completion of the IV infusion. (See Sensitivity Reactions and see Infusion Reactions under Cautions.)

Provided in single-use vials. May arrive from CDC either frozen or thawed. If frozen, thaw by placing vials in a refrigerator at 2–8°C for approximately 14 hours until contents are thawed. For more rapid thawing, place vials at room temperature for 1 hour, followed by immersion in a water bath at 37°C until thawed. Do not thaw in a microwave oven. Do not refreeze.

Dilution

Prior to dilution, thaw antitoxin (if necessary) and bring to room temperature.

Do not shake vial at any time since this may cause foaming.

Dilute 1:10 in 0.9% sodium chloride injection by withdrawing entire contents of the vial and adding it to appropriate amount of 0.9% sodium chloride in an IV bag. Appropriate amount of 0.9% sodium chloride injection varies from 90–200 mL since the antitoxin has a fill volume per vial that varies from approximately 10–22 mL depending on antitoxin lot number. To ensure accurate calculation of pediatric dosage when partial vial of antitoxin required, withdraw entire vial contents.

Inspect diluted antitoxin solution for particulate matter and discoloration; do not use if it is turbid, cloudy, or contains particulates.

Rate of Administration

Individualize IV infusion rate based on patient age and tolerance.

Monitor patient throughout the IV infusion. If tolerated, increase infusion rate incrementally up to maximum recommended infusion rate and continue until dose completely administered. If infusion not tolerated and adverse reactions occur, decrease infusion rate or discontinue infusion if necessary.

Infants <1 year of age: Initiate IV infusion at a rate of 0.01 mL/kg per minute for first 30 minutes; if tolerated, infusion rate can then be increased by 0.01 mL/kg per minute every 30 minutes up to a maximum infusion rate of 0.03 mL/kg per minute.

Children 1 through 16 years of age: Initiate IV infusion at a rate of 0.01 mL/kg per minute for first 30 minutes; if tolerated, infusion rate can then be increased by 0.01 mL/kg per minute every 30 minutes up to a maximum infusion rate of 0.03 mL/kg per minute. Do not exceed infusion rates recommended for adults.

Adults: Initiate IV infusion at a rate of 0.5 mL per minute for first 30 minutes; if tolerated, infusion rate can then be doubled every 30 minutes up to a maximum infusion rate of 2 mL per minute.

If used in patients at risk for hypersensitivity reactions (see Sensitivity Reactions under Cautions), initiate IV infusion using lowest rate achievable (i.e., <0.01 mL per minute) and closely monitor patient.

Dosage

Given as a single dose for treatment of symptomatic botulism following documented or suspected exposure to botulinum neurotoxin serotypes A, B, C, D, E, F, or G.

Each single-use vial (regardless of vial size or fill volume) contains at least 4500, 3300, 3000, 600, 5100, 3000, and 600 units of serotype A, B, C, D, E, F, and G antitoxin, respectively.

Pediatric Patients

Botulism

IV

Infants <1 year of age: 10% of recommended adult dose (i.e., one-tenth of a single-use vial), regardless of body weight. Dilute as recommended and give as a single IV infusion using age-appropriate infusion rate. (See Administration under Dosage and Administration.)

Children 1 through 16 years of age: 20–100% of recommended adult dose (i.e., 20–100% of a single-use vial) based on the Salisbury Rule, which takes into consideration weight differences between pediatric patients and adults. (See Table 1.) Dilute as recommended and give as a single IV infusion using age-appropriate infusion rate. (See Administration under Dosage and Administration.)

Based on the Salisbury Rule. Children weighing ≤30 kg: 2 × child's weight (kg). Children weighing >30 kg: child's weight (kg) + 30.

Minimum dosage is 20% of the recommended adult dosage.

Adults

Botulism

IV

Adults ≥17 years of age: 1 single-use vial. Dilute as recommended and give as a single IV infusion using age-appropriate infusion rate. (See Administration under Dosage and Administration.)

Prescribing Limits

Pediatric Patients

Botulism

IV

Infants <1 year of age: Maximum infusion rate 0.03 mL/kg per minute.

Children 1 through 16 years of age: Maximum dose is 1 single-use vial; minimum dose is 20% of single-use vial. Maximum infusion rate is 2 mL per minute.

Adults

Botulism

IV

Adults ≥17 years of age: Maximum dose is 1 single-use vial. Maximum infusion rate is 2 mL per minute.

Special Populations

No special population dosage recommendations.