2.1 Dosage and Administration

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Each vial of BAT contains a minimum potency for serotypes A, B, C, D, E, F, and G antitoxin [see Dosage Forms and Strengths (3 DOSAGE FORMS AND STRENGTHS

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For adult, pediatric, and infant patient groups, administer a dose of BAT according to Table 1. For details on pediatric dosing by body weight see Table 2.

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Administer all BAT doses after dilution 1:10 in normal saline by slow intravenous infusion according to the varying infusion rates in Table 1.

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Monitor vital signs throughout the infusion. If tolerated, the infusion rate can be increased incrementally up to the maximum infusion rate, and continued for the remainder of the administration. Decrease infusion rate if the patient develops discomfort or infusion-related adverse reactions.

Calculate pediatric BAT dose by body weight according to Table 2.

2.2 Preparation

1.

Bring vial to room temperature.

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If frozen, thaw vial by placing in a refrigerator at 36 to 46 °F (2 to 8 °C) until the contents are thawed for approximately 14 hours.

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Product can be thawed rapidly by placing at room temperature for one hour followed by a water bath at 98.6 °F (37°C) until thawed.

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Do not thaw this product in a microwave oven. Do not refreeze the vial.

2.

Inspect vial to ensure there is no damage to the seal or vial. If damaged, discard the vial.

3.

Do not shake the vial during preparation to avoid foaming.

4.

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 If a partial vial is required (for pediatric dosing), the entire content of the vial should be withdrawn to ensure accurate calculation of the dosage [Table 2].

5.

Visually inspect the product for particulate matter and discoloration prior to administration. Do not use if the solution is turbid, cloudy, or contains particles other than a few translucent-to-white proteinaceous particulates.

6.

Use an intravenous line with constant infusion pump. Use a 15-micron sterile, non-pyrogenic, low protein binding in-line filter.

7.

BAT vials are for single use only and contain no preservative. Once punctured, use the vial contents to prepare the infusion bag and administer as soon as possible.

8.

Discard any unused portion.

5.1 Hypersensitivity Reactions

Severe hypersensitivity reactions, including anaphylactic and anaphylactoid reactions may occur following BAT administration. Patients who have had previous therapy with an equine-derived antivenom/antitoxin, with a history of hypersensitivity to horses, asthma, or hay fever are at a greater risk for developing severe hypersensitivity reactions to BAT. Administer BAT in a setting with appropriate equipment, medication including epinephrine, and personnel trained in the management of hypersensitivity, anaphylaxis, and shock.

Monitor all patients for signs and symptoms of acute allergic reaction (e.g. urticaria, pruritus, erythema, angioedema, bronchospasm with wheezing or cough, stridor, laryngeal edema, hypotension, tachycardia) during and following the BAT infusion. In case of hypersensitivity reaction, discontinue BAT administration immediately and administer appropriate emergency care. Have immediately available medications such as epinephrine for emergency treatment of acute hypersensitivity reactions.

For patients at risk for hypersensitivity reaction, begin BAT administration at the lowest rate achievable (< 0.01 mL/min) and monitor.

5.2 Delayed Allergic Reactions (Serum Sickness)

Delayed allergic reactions (serum sickness e.g. fever, urticarial or maculopapular rash, myalgia, arthralgia, and lymphadenopathy) may occur following BAT administration, typically 10-21 days after infusion. Monitor patients for signs and symptoms of delayed allergic reaction.

If a delayed allergic reaction (serum sickness) is suspected, administer appropriate medical care.

5.3 Infusion Reactions

Chills, fever, headaches, nausea, and vomiting can be related to the rate of infusion. Arthralgia, myalgia and fatigue or vasovagal reactions may also develop. Carefully observe patients for the onset of these infusion reactions throughout the infusion period and immediately following an infusion.

Reduce the rate of infusion if the patient experiences infusion reactions and administer symptomatic therapy. If symptoms worsen, discontinue the infusion and administer appropriate medical care.

5.4 Interference with Blood Glucose Testing

The maltose contained in BAT can interfere with some types of blood glucose monitoring systems i.e. those based on glucose dehydrogenase pyrroloquinoline-quinone (GDH-PQQ) method. This can result in falsely elevated glucose readings and inappropriate administration of insulin, resulting in life-threatening hypoglycemia. Cases of true hypoglycemia may go untreated if the hypoglycemic state is masked by falsely elevated results [see Drug Interactions (7 DRUG INTERACTIONS)].

5.5 Transmissible Infectious Agents

Because BAT is made from equine plasma, it may carry the risk of transmitting infectious agents e.g. viruses. The equine plasma pools are screened for the presence of certain infectious agents and the manufacturing process for BAT includes measures to inactivate and remove certain viruses [see Description (11 DESCRIPTION)]. Despite these measures, such products can still potentially transmit disease. No cases of transmission of viral diseases have been associated with the use of BAT.

Report all infections thought by a physician to have been transmitted by BAT to Emergent BioSolutions Canada Inc. at 1-800-768-2304. Discuss the risks and benefits of this product with the patient or their legal guardian before administering it to the patient [see Patient Counseling Information (17 PATIENT COUNSELING INFORMATION)].

6.1 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.

6.2 Postmarketing Experience

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

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Anaphylactic shock

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Angioedema

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Urticaria

6.3 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. All subjects from the two clinical trials were tested for immunogenicity against BAT at baseline and at the end of the studies (Day 28) using a validated assay. Eleven subjects seroconverted during the course of the two trials. One subject from each clinical trial experienced a moderate allergic reaction during the administration of BAT. Both subjects were negative for anti-BAT antibodies at baseline and at the end of their respective studies. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to BAT with the incidence of antibodies to other products may be misleading.

Drug Laboratory Interactions: Blood Glucose Testing

BAT contains maltose which can interfere with certain types of blood glucose monitoring systems [see Warnings and Precautions (5.4 Interference with Blood Glucose Testing)]. 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.

8.1 Pregnancy

Risk Summary

There are no human or animal data to establish the presence or absence of BAT associated risk.

8.2 Lactation

Risk Summary

There are no data to assess the presence or absence of BAT in human milk, the effects on the breastfed child or the effects on milk production/excretion.

Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for BAT and any potential adverse effects on the breastfed child from BAT or from the underlying maternal condition.

8.4 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 [Table 2].

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.

8.5 Geriatric 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.

12.1 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.

12.2 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.

12.3 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 various PK parameters are summarized in Table 5.

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.

13.2 Animal Toxicology and/or Pharmacology

Toxicological 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 [Table 6].

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 [Table 7].

16.1 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.

16.2 Storage and Handling

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Store frozen at or below 5°F (≤ -15°C) until used.

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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.

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BAT vials are for single use only and contain no preservative. Discard any unused portion.

PATIENT INFORMATION

BAT® [Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G) – (Equine)]

What is botulism?

Botulism is a muscle-paralyzing disease caused by a toxin made by a bacterium called Clostridium botulinum.

Botulism can cause the following conditions:

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Double vision,

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Blurred vision,

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Drooping eyelids,

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Slurred speech,

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Difficulty swallowing,

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Dry mouth,

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Muscle weakness that spreads through the body,

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Difficulty breathing.

Botulism can also cause paralysis and death. After a person is exposed to the toxin, problems can start as early as three hours or as late as a few days. It can take weeks or months to get better. During that time, many people need special care in the hospital.

The effectiveness of BAT has been studied in animals with botulism.

What is BAT?

BAT is a botulism antitoxin made from the plasma of horses. It contains antibody fragments which can neutralize botulism toxins. BAT may make the illness from botulism less severe. Treatment with BAT will not reverse the paralysis, but may decrease the duration and extent of paralysis.

Who should use BAT?

Your doctor may give you BAT if they suspect that you have been exposed to botulism toxin. You should get the treatment as quickly as possible to stop the progression of the illness.

Unless the benefits outweigh the risks, you should not receive BAT if you have a known history of allergies to horses or horse blood products, asthma or hay fever (seasonal allergies).

How will you receive BAT?

BAT is given as an injection into your vein. Your doctor will determine the dose of BAT. The treatment may take several hours to administer. Your doctor will decide if you need more than one injection.

What are the possible or reasonably likely side effects of BAT?

The most common side effects of BAT are:

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Headache

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Fever

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Rash

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Hives

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Chills

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Nausea

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Swelling

Some people have a chilly feeling, difficulty breathing, and have a quick rise in body temperature within the first 20 to 60 minutes after getting BAT. This can be managed by your doctor.

BAT can cause allergic reactions. Tell your doctor or go to the emergency department right away if you have trouble breathing, swelling of your tongue or lips, or a very fast heart rate because this can be signs of a serious allergic reaction.

Tell your doctor if you get pains in your joints and back, fever, and a rash within one to three weeks after getting BAT. These can be signs of “serum sickness” and can last for a few weeks. Your doctor can give you medicine to help with serum sickness.

Talk to your doctor about any side effects that concern you. You can ask your doctor for additional prescribing information that is available to healthcare professionals.

What other information do you need to know about BAT?

BAT is made from horse plasma. The horses are carefully screened and the plasma is carefully cleaned, but there is a small risk that it may give you a virus. Talk to your doctor if you have any symptoms that concern you.

You may report side effects directly to Emergent BioSolutions Canada Inc. at 1-800-768-2304 or to the FDA’s MedWatch reporting system at 1-800-FDA-1088.

BAT® and any and all Emergent BioSolutions Inc. brand, product, service and feature names, logos and slogans are trademarks or registered trademarks of Emergent BioSolutions Inc. or its subsidiaries in the United States or other countries. All rights reserved.

Manufactured By:

Emergent BioSolutions Canada Inc.

155 Innovation Drive

Winnipeg, Manitoba

Canada, R3T 5Y3

US License No. 2084