BAT: Package Insert and Label Information

BAT- equine botulinum neurotoxin a immune fab2, equine botulinum neurotoxin b immune fab2, equine botulinum neurotoxin c immune fab2, equine botulinum neurotoxin d immune fab2, equine botulinum neurotoxin e immune fab2, equine botulinum neurotoxin f immune fab2 and equine botulinum neurotoxin g immune fab2 liquid
Emergent BIoSolutions Canada Inc.

INDICATIONS AND USAGE

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.

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

2 DOSAGE AND ADMINISTRATION

BAT is for intravenous use only.

2.1 Dosage and Administration

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
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.
Administer all BAT doses after dilution 1:10 in normal saline by slow intravenous infusion according to the varying infusion rates in Table 1.
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.
Table 1BAT Dosing Guide and Intravenous Infusion Rate

Patient Group

Dose

Starting Infusion Rate

(first 30 minutes)

Incremental Infusion Rate if Tolerated

(every 30 minutes)

Maximum Infusion Rate

Adults

(≥ 17 years)

One vial

0.5 mL/min

Double the rate

2 mL/min

Pediatric

(1 year to < 17 years)

20 – 100% of adult dose

0.01 mL/kg/min

Do not exceed the adult rate.

0.01 mL/kg/min

0.03 mL/kg/min

Do not exceed the adult rate

Infants

(< 1 year)

10% of adult dose regardless of body weight

0.01 mL/kg/min

0.01 mL/kg/min

0.03 mL/kg/min

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

Table 2Pediatric Dosing Guide for BAT Based on Salisbury Rule (1 Year to < 17 Years)

Body Weight

(kg)

Percent of Adult Dose*

(%)

10-14

20**

15-19

30

20-24

40

25-29

50

30-34

60

35-39

65

40-44

70

45-49

75

50-54

80

≥ 55

100

* Dosing guide is based on the Salisbury Rule (1):

Body weight ≤ 30 kg: 2x weight (kg) = % adult dose to administer
Body weight > 30 kg: weight (kg) + 30 = % adult dose to administer

Do not exceed 1 vial dose regardless of body weight.

** Minimum pediatric dose is 20% of adult dose. See Table 1 for infant dose.

2.2 Preparation

1.
Bring vial to room temperature.
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.
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.
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 (approximately 10 to 22 milliliters per vial), 90 to 200 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.

3 DOSAGE FORMS AND STRENGTHS

BAT is a sterile solution of purified F(ab')2 plus F(ab')2 -related immune globulin fragments derived from equine plasma, containing antitoxin activity to botulinum neurotoxins A, B, C, D, E, F, and G.

Each single-use vial, regardless of size or fill volume, contains a minimum antitoxin potency of:

4,500 U serotype A antitoxin,
3,300 U serotype B antitoxin,
3,000 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.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

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 ADVERSE REACTIONS

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.

The following serious adverse reactions are discussed in detail in other sections of the labeling:

Hypersensitivity reactions [see Warnings and Precautions ( 5.1 Hypersensitivity Reactions)]
Delayed allergic reactions/serum sickness [see Warnings and Precautions ( 5.2 Delayed Allergic Reactions (Serum Sickness)]
Infusion reactions [See Warnings and Precautions ( 5.3 Infusion Reactions)]

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.

Table 3Summary of Adverse Drug Reactions (ADR) Reported in Subjects that Received BAT through the CDC Expanded Access Clinical Study
System Organ Class Preferred Term Overall
(N=228)
No. of Events No. of Subjects % of Subjects

ALL BODY SYSTEM

OVERALL

37

23

10.1

Cardiac disorders

Cardiac arrest

1

1

0.4

Bradycardia

1

1

0.4

Tachycardia

1

1

0.4

Gastrointestinal disorders

Vomiting

1

1

0.4

Nausea

2

2

0.9

General disorders and administration site conditions

Pyrexia

9

9

3.9

Chest discomfort

1

1

0.4

Edema

2

2

0.9

Chills

3

3

1.3

Feeling jittery

1

1

0.4

Immune system disorders

Serum Sickness

1

1

0.4

Investigations

Blood pressure increased

1

1

0.4

White blood cell count increased

1

1

0.4

Psychiatric disorders

Agitation

1

1

0.4

Anxiety

1

1

0.4

Renal and urinary disorders

Urinary retention

1

1

0.4

Respiratory, thoracic and mediastinal disorders

Bronchospasm

1

1

0.4

Skin and subcutaneous tissue disorders

Erythema

1

1

0.4

Hyperhidrosis

1

1

0.4

Rash

4

4

1.8

Vascular disorders

Hemodynamic instability

1

1

0.4

Hypotension

1

1

0.4

All adverse reactions were classified according to MedDRA Version 15.0 and are ranked according to medical significance within a given SOC.

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