Pkg Insert - Anthrax Vaccine Adsorbed, ( BioThrax™ )

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Product Leaflet for Biothrax (aka: Anthrax Vaccine absorbed); revised

January 2002

http://www.fda.gov/cber/label/biopava0131022LB.pdf

Conversion of PDF file................to text

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ANTHRAX VACCINE ADSORBED (BIOTHRAX™)

DESCRIPTION

Anthrax Vaccine Adsorbed, (BioThrax™) is a sterile, milky-white suspension

(when mixed) made from cell-free filtrates of microaerophilic cultures of

an avirulent, nonencapsulated strain of Bacillus

anthracis. The production cultures are grown in a chemically defined

protein-free medium consisting

of a mixture of amino acids, vitamins, inorganic salts and sugars. The

final product, prepared from the sterile filtrate culture fluid contains

proteins, including the 83kDa protective antigen protein, released

during the growth period. The final product contains no dead or live

bacteria. The final product is

formulated to contain 1.2 mg/ mL aluminum, added as aluminum hydroxide in

0.85% sodium chloride.

The product is formulated to contain 25 mg/ mL benzethonium chloride and

100 mg/ mL formaldehyde, added as preservatives.

CLINICAL PHARMACOLOGY Epidemiology

Anthrax occurs globally and is most common in agricultural regions with

inadequate control programs for anthrax in livestock. Anthrax is a zoonotic

disease caused by the Gram-positive, spore-forming

bacterium Bacillus anthracis. The spore form of Bacillus anthracis is the

predominant phase of the

bacterium in the environment and it is largely through the upt ake of

spores that anthrax disease is contracted. Spore forms are markedly

resistant to heat, cold, pH, desiccation, chemicals and

irradiation. Following germination at the site of infection, the bacilli

can also enter the blood and lead

to septicemia. Antibiotics are effective against the germinated form of

Bacillus anthracis, but are not effective against the spore form of the

organism.

The disease occurs most commonly in wild and domestic animals, primarily

cattle, sheep, goats and other herbivores. In humans, anthrax disease can

result from contact with animal hides, leather or

hair products from contaminated animals, or from other exposures to

Bacillus anthracis spores. It

occurs in three forms depending upon the route of infection: cutaneous

anthrax, gastrointestinal anthrax and inhalation anthrax.

Cutaneous anthrax is the most commonly reported form in humans (> 95% of

all anthrax cases). It can occur when the bacterium enters a cut or

abrasion on the skin, such as when handling

contaminated meat, wool, hides, leather or hair products from infected

animals or other contaminated

materials. The symptoms of cutaneous anthrax begin with an itchy

reddish-brown papule on exposed skin surfaces and may appear approximately

1-12 days after contact. The lesion soon develops a

small vesicle. Secondary vesicles are sometimes seen. Later the vesicle

ruptures and leaves a

painless ulcer that typically develops a blackened eschar with surrounding

swollen tissue. There are often associated systemic symptoms such as

swollen glands, fever, myalgia, malaise, vomiting and

headache. The case fatality rate for cutaneous anthrax is estimated to be

20% without antibiotic

treatment.

Gastrointestinal anthrax usually begins 1-7 days after ingestion of meat

contaminated with anthrax

spores. There is acute inflammation of the intestinal tract with nausea,

loss of appetite, vomiting and fever followed by abdominal pain, vomiting

of blood and bloody diarrhea. There can also be

involvement of the pharynx with sore throat, dysphagia, fever, lesions at

the base of the tongue or

tonsils and regional lymphadenopathy. The case fatality rate is unknown but

estimated to be 25% to 60%.

Inhalation (pulmonary) anthrax has been reported to occur from 1-43 days

after exposure to aerosolized spores. 1 Studies in rhesus monkeys indicate

that a small number of inhaled spores may

remain viable for at least 100 days following exposure. 2 However,

information on how long spores

remain viable in the lungs of humans is unavailable and the incubation

period for inhalation anthrax is unknown. Initial symptoms are non-specific

and may include sore throat, mild fever, myalgia,

coughing and chest discomfort lasting up to a few days. The second stage

develops abruptly with

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findings such as sudden onset of fever, acute respiratory distress with

pulmonary edema and pleural effusion followed by cyanosis, shock and coma.

Meningitis is common. The fatality rate for inhalation

anthrax in the U. S. is estimated to be approximately 45% to 90%. From 1900

to October 2001, there were 18 identified cases of inhalation anthrax in

the U. S., the latest of which was reported in 1976,

with an 89% (16/ 18) mortality rate. Most of these exposures occurred in

industrial settings, i. e., textile

mills. 3 From October 4, 2001, to December 5, 2001, a total of 11 cases of

inhalation anthrax linked to intentional dissemination of Bacillus

anthracis spores were identified in the U. S. Five of these cases

were fatal. 4

Mechanism of Action

Virulence components of Bacillus anthracis include an antiphagocytic

polypeptide capsule and three proteins known as protective antigen (PA),

lethal factor (LF) and edema factor (EF). Individually these

proteins are not cytotoxic but the combination of PA with LF or EF results

in the formation of the

cytotoxic lethal toxin and edema toxin, respectively. Although an immune

correlate of protection is unknown, antibodies raised against PA may

contribute to protection by neutralizing the activities of

these toxins. 5 The contribution of Bacillus anthracis proteins other than

PA, that may be present in

BioThrax, to the protection against anthrax has not been determined.

CLINICAL STUDIES A controlled field study using an earlier version of a

protective antigen– based anthrax vaccine,

developed in the 1950's, that consisted of an aluminum potassium

sulfate-precipitated cell free filtrate

from an aerobic culture, was conducted from 1955-1959. This study included

1,249 workers [379 received anthrax vaccine, 414 received placebo, 116

received incomplete inoculations (with either

vaccine or placebo) and 340 were in the observational group (no treatment)]

in four mills in the

northeastern United States that processed imported animal hides. 6 During

the trial, 26 cases of anthrax were reported across the four mills -five

inhalation and 21 cutaneous. Prior to vaccination,

the yearly average number of human anthrax cases was 1.2 cases per 100

employees in these mills.

Of the five inhalation cases (four of which were fatal), two received

placebo and three were in the observational group. Of the 21 cutaneous

cases, 15 received placebo, three were in the observational

group, and three received anthrax vaccine. Of those three cases in the

vaccine group, one case

occurred just prior to administration of the scheduled third dose, one case

occurred 13 months after an individual received the third of the scheduled

6 doses (but no subsequent doses), and one case

occurred prior to receiving the scheduled fourth dose of vaccine. In a

comparison of anthrax cases

between the placebo and vaccine groups, including only those who were

completely vaccinated, the calculated vaccine efficacy level against all

reported cases of anthrax combined was 92.5% (lower

95% CI = 65%).

From 1962 to 1974, based on information reported to Centers for Disease

Control and Prevention (CDC), 27 cases of anthrax occurred in mill workers

or those living near mills in the United States. Of

those, 24 cases occurred in unvaccinated individuals, one case occurred

after the person had been given one dose of anthrax vaccine and two cases

occurred after individuals had been given two doses

of anthrax vaccine. No documented cases of anthrax were reported for

individuals who had received

the recommended six doses of anthrax vaccine. These individuals received

either an earlier version of a protective antigen-based anthrax vaccine or

BioThrax.

In an open-label safety study conducted by the CDC, BioThrax was

administered in 0.5 mL doses according to a 0, 2, 4 week initial dose

schedule followed by additional doses at 6, 12 and 18 months

to complete the 6 dose vaccination series. Annual boosters were

administered thereafter. In this

study, 15,907 doses of BioThrax were administered to approximately 7,000

textile employees, laboratory workers and other at risk individuals and the

incidence rates of local and systemic adverse

reactions were recorded. (See ADVERSE REACTIONS )

A randomized clinical study was conducted by the U. S. Army Medical

Research Institute of Infectious Diseases (USAMRIID) from 1996-1999 in 173

volunteers to evaluate changes to the vaccination

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schedule and route of vaccine administration. Of those, 28 were enrolled

into the study arm to receive the licensed schedule (initial injections at

0, 2 and 4 weeks followed by additional doses at 6, 12 and

18 months) and were subsequently monitored for the occurrence of local and

systemic adverse events. (See ADVERSE REACTIONS)

INDICATIONS AND USAGE BioThrax is indicated for the active immunization

against Bacillus anthracis of individuals between 18

and 65 years of age who come in contact with animal products such as hides,

hair or bones that come

from anthrax endemic areas, and that may be contaminated with Bacillus

anthracis spores. BioThrax is also indicated for individuals at high risk

of exposure to Bacillus anthracis spores such as

veterinarians, laboratory workers and others whose occupation may involve

handling potentially

infected animals or other contaminated materials.

Since the risk of anthrax infection in the general population is low,

routine immunization is not

recommended.

The safety and efficacy of BioThrax in a post-exposure setting has not been

established.

CONTRAINDICATIONS The use of BioThrax is contraindicated in subjects with a

history of anaphylactic or anaphylactic-like

reaction following a previous dose of BioThrax, or any of the vaccine

components.

WARNINGS Preliminary results of a recent unpublished retrospective study of

infants born to women in the U. S.

military service worldwide in 1998 and 1999 suggest that the vaccine may be

linked with an increase

in the number of birth defects when given during pregnancy (unpublished

data, Department of Defense). Although these data are unconfirmed, pregnant

women should not be vaccinated against

anthrax unless the potential benefits of vaccination have been determined

to outweigh the potential

risk to the fetus.

Animal reproduction studies have not been conducted with BioThrax.

PRECAUTIONS

Before administration, the patient's medical immunization history should be

reviewed for possible vaccine sensitivities and/ or previous

vaccination-related adverse events, in order to determine the

existence of any contraindications to immunization.

Pregnant women should not be vaccinated against anthrax unless the

potential benefits of vaccination clearly outweigh the potential risks to

the fetus.

BioThrax should not be administered to individuals with a history of

Guillain-Barré Syndrome (GBS) unless there is a clear benefit that

outweighs the potential risk of a recurrence.

History of anthrax disease may increase the potential for severe local

adverse reactions.

Patients with impaired immune responsiveness due to congenital or acquired

immunodeficiency, or immunosuppressive therapy may not be adequately

immunized following administration of BioThrax.

Vaccination during chemotherapy, high dose corticosteroid therapy of

greater than 2-week duration, or

radiation therapy may result in a suboptimal response. Deferral of

vaccination for 3 months after completion of such therapy may be

considered. 7

The administration of BioThrax to persons with concurrent moderate or

severe illness should be postponed until recovery. Vaccination is not

contraindicated in subjects with mild illnesses with or

without low-grade fever. 7

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This product should be administered with caution to patients with a

possible history of latex sensitivity

since the vial stopper contains dry natural rubber.

Epinephrine solution, 1: 1000, should always be available for immediate use

in case an anaphylactic

reaction should occur.

Pregnancy PREGNANCY CATEGORY D.

See Warnings.

Nursing Mothers

It is not known whether exposure of the mother to BioThrax poses a risk of

harm to the breast-feeding child. However, administration of non-live

vaccines (e. g., anthrax vaccine) during breast-feeding is not

medically contraindicated. 7

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use No data regarding the safety of BioThrax are available for

persons aged > 65 years.

ADVERSE REACTIONS

Pre Licensure Local Reactions-In an open-label safety study, 15,907 doses

of BioThrax were administered to

approximately 7,000 textile employees, laboratory workers and other at risk

individuals (See Clinical

Studies). Over the course of the 5-year study, there were 24 reports (0.15%

of doses administered) of severe local reactions (defined as edema or

induration measuring greater than 120 mm in diameter or

accompanied by marked limitation of arm motion or marked axillary node

tenderness). There were

150 reports (0.94% of doses administered) of moderate local reactions

(edema or induration greater than 30 mm but less than 120 mm in diameter)

and 1373 reports (8.63% of doses administered) of

mild local reactions (erythema only or induration measuring less than 30 mm

in diameter).

Systemic Reactions-In the same open label study, four cases of systemic

reactions were reported during a five-year reporting period (< 0.06% of

doses administered). These reactions, which were

reported to have been transient, included fever, chills, nausea and general

body aches.

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Post Licensure Recently (1996-1999), an assessment of safety was conducted

as part of a randomized clinical study

conducted by the U. S. Army Medical Research Institute of Infectious

Diseases (USAMRIID) (See Clinical Studies). A total of 28 volunteers were

enrolled to receive subcutaneous doses of BioThrax

according to the licensed schedule. Each volunteer was observed for

approximately 30 minutes after

administration of AVA and scheduled for follow-up evaluations at 1-3 days,

1 week and 1 month after vaccination. Four volunteers reported seven acute

adverse events within 30 minutes after the

subcutaneous administration of BioThrax. These included erythema (3),

headac he (2), fever (1) and

elevated temperature (1). Of these events, a single patient reported the

simultaneous occurrence of

headache, fever and elevated temperature (100.7°F).

Local Reactions-The most common local reactions reported after the first

dose (n= 28) in this study were tenderness (71%), erythema (43%),

subcutaneous nodule (36%), induration (21%), warmth

(11%) and local pruritus (7%). The most frequently reported local reactions

after the second dose

(n= 28) were tenderness (61%), subcutaneous nodule (39%), erythema (32%),

induration (18%), local pruritus (14%), warmth (11%) and arm motion

limitation (7%). After the third dose (n= 26), the most

frequently reported local reactions were tenderness (58%), warmth (19%),

local pruritis (19%),

erythema (12%), arm motion limitation (12%), induration (8%), edema (8%)

and subcutaneous nodule (4%). Local reactions were found to occur more

often in women. No abscess or necrosis was

observed at the injection site.

Systemic Reactions-All systemic adverse events reported in this study were

transient in nature. The systemic reactions most frequently reported after

the first dose (n= 28) were headache (7%),

respiratory difficulty (4%) and fever (4%). After the second dose (n= 28),

the most frequently reported systemic reactions were malaise (11%), myalgia

(7%), fever (7%), headache (4%), anorexia (4%) and

nausea or vomiting (4%). After the third dose (n= 26), the most frequently

reported systemic reactions

were headache (4%), malaise (4%), myalgia (4%) and fever (4%). There was

one report of delayed hypersensitivity reaction beginning with lesions 3

days after the first dose. The subject was reported

to have diffuse hives by day 17, 3 days after the second dose, and had

swollen hands, face and feet

by day 18 and discomfort swallowing. The subject did not receive any

subsequent scheduled doses.

Post Licensure Adverse Event Surveillance Data regarding potential adverse

events following anthrax vaccination are available from the Vaccine

Adverse Event Reporting System (VAERS). 8 The report of an adverse event to

VAERS is not proof

that a vaccine caused the event. Because of the limitations of spontaneous

reporting systems, determining causality for specific types of adverse

events, with the exception of injection-site

reactions, is often not possible using VAERS data alone. The following four

paragraphs describe

spontaneous reports of adverse events, without regard to causality.

From 1990 to October 2001, over 2 million doses of BioThrax have been

administered in the United

States. Through October 2001, VAERS received approximately 1850 spontaneous

reports of adverse events. The most frequently reported adverse events were

erythema, headache, arthralgia, fatigue,

fever, peripheral swelling, pruritus, nausea, injection site edema, pain/

tenderness and dizziness.

Approximately 6% of the reported events were listed as serious. Serious

adverse events include those that result in death, hospitalization,

permanent disability or are life-threatening. The serious

adverse events most frequently reported were in the following body system

categories: general disorders and administration site conditions, nervous

system disorders, skin and subcutaneous tissue

disorders, and musculoskeletal, connective tissue and bone disorders.

Anaphylaxis and/ or other

generalized hypersensitivity reactions, as well as serious local reactions,

were reported to occur occasionally following administration of BioThrax.

None of these hypersensitivity reactions have been

fatal.

Other infrequently reported serious adverse events that have occurred in

persons who have received BioThrax have included: cellulitis, cysts,

pemphigus vulgaris, endocarditis, sepsis, angioedema and

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other hypersensitivity reactions, asthma, aplastic anemia, neutropenia,

idiopathic thrombocytopenia purpura, lymphoma, leukemia, collagen vascular

disease, systemic lupus erythematosus, multiple

sclerosis, polyarteritis nodosa, inflammatory arthritis, transverse

myelitis, Guillain-Barré Syndrome, immune deficiency, seizure, mental

status changes, psychiatric disorders, tremors, cerebrovascular

accident (CVA), facial palsy, hearing and visual disorders, aseptic

meningitis, encephalitis,

myocarditis, cardiomyopathy, atrial fibrillation, syncope,

glomerulonephritis, renal failure, spontaneous abortion and liver abscess.

Infrequent reports were also received of multisystem disorders defined as

chronic symptoms involving at least two of the following three categories:

fatigue, mood-cognition,

musculoskeletal system.

Reports of fatalities included sudden cardiac arrest (2), myocardial

infarction with polyarteritis

nodosa (1), aplastic anemia (1), suicide (1) and central nervous system

(CNS) lymphoma (1).

Post Licensure Survey Studies In addition to the VAERS data, adverse events

following anthrax vaccination have been assessed in

survey studies conducted by the Department of Defense in the context of

their anthrax vaccination

program. These survey studies are subject to several methodological

limitations, e. g., sample size, the limited ability to detect adverse

events, observational bias, loss to follow-up, exemption of vaccine

recipients with previous adverse events and the absence of unvaccinated

control groups. Overall, the

most reported events were localized, minor and self-limited and included

muscle or joint aches, headache and fatigue. Across these studies, systemic

reactions were reported in 5-35% of vaccine

recipients and included reports of malaise, chills, rashes, headaches and

low-grade fever. Women

reported these symptoms more often than men.

Reporting Adverse Events

Adverse events following immunization with BioThrax should be reported to

the Medical Affairs Division of BioPort Corporation (517) 327-1675 during

regular working hours and (517) 327-7200

during off hours. Adverse events may also be reported to the U. S.

Department of Health and Human

Services (DHHS) Vaccine Adverse Event Reporting System. Report forms and

reporting requirement information can be obtained from VAERS through a toll

free number 1-800-822-7967.

DOSAGE AND ADMINISTRATION Dosage

Immunization consists of three subcutaneous injections, 0.5 mL each, given

2 weeks apart followed by three additional subcutaneous injections, 0.5 mL

each, given at 6, 12, and 18 months. Subsequent

booster injections of 0.5 mL of BioThrax at one-year intervals are

recommended.

Administration Use a separate 5/ 8-inch, 25-to 27-gauge sterile needle and

syringe for each patient to avoid

transmission of viral hepatitis and other infectious agents. Use a

different site for each sequential injection of this vaccine and do not mix

with any other product in the syringe.

1. Shake the bottle thoroughly to ensure that the suspension is homogeneous

during withdrawal

and visually inspect the product for particulate matter and discoloration.

If the product appears discolored or has visible particulate matter,

DISCARD THE VIAL.

2. Wipe the rubber stopper with an alcohol swab and allow to dry before

inserting the needle.

3. Clean the area to be injected with an alcohol swab or other suitable

antiseptic. 4. Holding the needle at a 45 o angle to the skin, inject the

vaccine subcutaneously.

5. DO NOT inject the product intravenously. Follow the usual precautions to

ensure that you

have not entered a vein before injecting the vaccine. 6. After injecting,

withdraw the needle and briefly and gently massage the injection site to

promote dispersal of the vaccine.

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HOW SUPPLIED/ STORAGE Anthrax Vaccine Adsorbed (BioThrax TM ) is supplied

in 5 mL multidose vials.

THIS PRODUCT IS TO BE STORED AT 2°C TO 8°C (36 TO 46°F). Do not freeze. Do

not use after the expiration date given on the package.

Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility

Animal studies have not been performed to ascertain whether BioThrax has

carcinogenic action, or any effect on fertility.

REFERENCES 1. Meselson, M., et al., 1994. The Sverdlosk anthrax outbreak of

1979. Science 266: 1201-8.

2. , D. W., Peacock, S., Belton, F. C., 1956. Observations on the

prophylaxis of experimental pulmonary anthrax in the monkey. J. Hygiene,

54: 28-36.

3. Brachman, P. S., 1980. Inhalation Anthrax. Ann. NY Acad. Science, 353:

83-93.

4. Update: Investigation of bioterrorism-related anthrax— Connecticut,

2001. MMWR. 2001; 50: 1077-9.

5. Brachman, P. S., & A. M. Friedlander. 1999. Anthrax. In Vaccines, Third

Edition, Plotkin &

Orenstein (eds.), pp. 629-637. 6. Brachman, P. S., et al., 1962. Field

Evaluation of a Human Anthrax Vaccine. Amer. J. Public

Health, 52: 632-645.

7. Centers for Disease Control and Prevention. General recommendations on

immunization recommendations of the Advisory Committee on Immunization

Practices (ACIP). MMWR. 1994;

Vol. 43 (No. RR-1).

8. Chen, R. T., et al., 1994. The Vaccine Adverse Event Reporting System

(VAERS). Vaccine 12( 6): 542-550.

Revision: January 31, 2002

Rx Only---Federal (U. S. A.) law prohibits dispensing without a prescription.

Manufactured by BIOPORT CORPORATION

Lansing, Michigan 48906

U. S. License No. 1260