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BIOTHRAX®
(Anthrax Vaccine Adsorbed) Intramuscular or Subcutaneous Injection

DESCRIPTION

BioThrax® (Anthrax Vaccine Adsorbed) is a sterile, milky-white suspension for intramuscular or subcutaneous injections 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 (PA) protein, released during the growth period and 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 final product is formulated to contain 25 mcg/mL benzethonium chloride and 100 mcg/mL formaldehyde, added as preservatives.

INDICATIONS

BioThrax is a vaccine indicated for the active immunization for the prevention of disease caused by Bacillus anthracis, in persons 18 through 65 years of age whose occupation or other activities place them at high risk of exposure.

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 have not been established.

DOSAGE AND ADMINISTRATION

For intramuscular or subcutaneous injection only.

Dose And Schedule

Administer BioThrax as a three-dose primary series of intramuscular injections of 0.5 mL each at 0, 1, and 6 months. Administer booster injections of 0.5 mL intramuscularly at 12 and 18 months after initiation of the series. For those who remain at risk, administer booster injections at 1-year intervals thereafter.

Individuals are not considered protected until they have completed the three-dose primary immunization series.

BioThrax may be administered by the subcutaneous route (for example, in persons who are at risk for hematoma formation following intramuscular injection). The schedule for BioThrax administered subcutaneously is 0, 2, 4 weeks, and 6 months with booster doses at 12 and 18 months, and at 1 year intervals thereafter.

Select a different injection site (e.g. alternating arms) for each sequential injection of this vaccine. Do not mix with any other product in the syringe.

The optimal schedule for catch up of missed or delayed booster doses is unknown. [See Clinical Studies]

Preparation For Administration

Shake the vial thoroughly to ensure that the suspension is homogeneous during withdrawal. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If either of these conditions exists, the vaccine should not be administered.

For intramuscular administration, use a 1- or 1½ -inch 23- or 25-gauge sterile needle and syringe.

BioThrax may be administered by the subcutaneous route using a 5/8-inch, 25- to 27-gauge sterile needle and syringe.

Use a separate sterile needle and syringe to withdraw a single dose for each patient.

HOW SUPPLIED

Dosage Forms And Strengths

BioThrax is a suspension for injection (0.5 mL dose) in 5 mL multidose vials. See DESCRIPTION for the complete listing of ingredients.

Storage And Handling

BioThrax is supplied in 5 mL multidose vials containing ten 0.5 mL doses.

NDC 64678-211-05 (vial), 64678-211-01 (carton)

Store at 2 °C to 8 °C (36 °F to 46 °F). Do not freeze. Do not use BioThrax after the expiration date printed on the label.

Manufactured by Emergent BioDefense Operations Lansing LLC, Lansing, MI 48906, US. Revised: May 2012

SIDE EFFECTS

The most common ( ≥ 10%) local (injection-site) adverse reactions observed in clinical studies were tenderness, pain, erythema, edema, and arm motion limitation. The most common ( ≥ 5%) systemic adverse reactions were muscle aches, headache, and fatigue.

Clinical Trials Experience

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

In an open-label safety study of 15,907 doses of BioThrax administered by the subcutaneous route to approximately 7,000 textile employees, laboratory workers and other at risk individuals, local and systemic reactions were monitored. Over the course of the 5-year study the following local adverse reactions were reported: 24 (0.15% of doses administered) severe local adverse 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), 150 (0.94% of doses administered) moderate local adverse reactions (edema or induration greater than 30 mm but less than 120 mm in diameter), and 1,373 (8.63% of doses administered) mild local adverse reactions (erythema only or induration measuring less than 30 mm in diameter). Four cases of systemic adverse reactions were reported during the 5-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.

In a randomized, double-blinded, placebo-controlled, and active-controlled multi-center clinical study, [NCT00119067] 1,564 healthy subjects were enrolled. The objective of this study was to evaluate the effect of (1) changing the route of vaccine administration from subcutaneous (SC) to intramuscular (IM), and (2) of reducing the number of doses on the safety and immunogenicity of BioThrax. The dosing schedules and routes studied are provided in Table 1. [See Clinical Studies]

Group A (8SC) (N=259) received BioThrax via the SC route of administration at Weeks 0, 2, 4, and Months 6, 12, 18 followed by 2 annual boosters (original U.S. licensed route/schedule). Group A served as the active control in this study.

Group B (8IM) (N=262) received BioThrax via the IM route of administration at Weeks 0, 2, 4, and Months 6, 12, 18 followed by 2 annual boosters.

Group C (COM) (N=782) received BioThrax via the IM route of administration at Weeks 0, 4 (no Week 2 dose), and Month 6 with various schedules thereafter. (Group C represents data from 3 randomized groups [Groups D, E, and F] combined for the analysis through Month 7 because the schedules are identical through the Month 6 dose.)

Group D (7IM) (N=256) received BioThrax via the IM route of administration at Weeks 0, 4 (no Week 2 dose), and Months 6, 12, 18 followed by 2 annual boosters.

Group E (5IM) (N=258) received BioThrax via the IM route of administration at Weeks 0, 4 (no Week 2 dose), and Months 6, 18 followed by 1 booster dose at Month 42 (2 year interval).

Group F (4IM) (N=268) received BioThrax via the IM route of administration at Weeks 0, 4 (no Week 2 dose), and Month 6 followed by 1 booster dose at Month 42 (3 year interval).

Table 1: Vaccination Schedules and Routes Evaluated

Group/Route	Weeks			Months
	0	2	4	6	12	18	30	42
Group A (8SC)*	V	V	V	V	V	V	V	V
Group B (8IM)	V	V	V	V	V	V	V	V
Group D (7IM)	V	S	V	V	V	V	V	V
Group E (5IM)	V	S	V	V	S	V	S	V
Group F (4IM)	V	S	V	V	S	S	S	V
Placebo^	S	S	S	S	S	S	S	S
SC: subcutaneous; IM: intramuscular; V: vaccine, S: saline. *Active Control. ^Subjects randomized to the control group were then re-randomized (1:1) to receive saline by the IM or SC route. The IM and SC placebo groups are combined in analyses.

Subjects were instructed to complete a 14-day post-vaccination diary card after the first 2 doses and a 28-day diary card after the subsequent doses to capture solicited and unsolicited adverse reactions. Adverse reaction data were also collected from in-clinic exams, which were performed prior to, and 15 to 60 minutes after each injection, at 1 to 3 days after each injection, and at 28 days after injections 3 through 8. The mean age, gender ratio, and race distribution were not significantly different across treatment groups among the vaccinated cohort (N=1563). The mean age was 39 years (range 18 to 62 years). Fifty-one percent of participants were female and 49% were male. Seventy-four percent were white, 21% were black and 5% were categorized as “other”.

Shown in Table 2 are the rates (percentage) of prospectively defined local and systemic solicited adverse reactions observed in the in-clinic exams for doses 1-4 as well as the rates (percentage) of local and systemic solicited adverse reactions observed in the in-clinic exams for doses 5-8.

Analysis of injection site (local) adverse reactions by study group was performed after each dose. It was observed that groups receiving BioThrax by the IM route had a statistically significantly lower incidence of any (one or more) local adverse reactions compared to the BioThrax SC route, by dose in the in-clinic data set, in almost all analyses. Injection site adverse reactions, including warmth, tenderness, itching, erythema, induration, edema, and nodule occurred at lower frequencies in participants given BioThrax by the IM route after each dose, in almost all comparisons. However, by dose, the incidence of arm motion limitation was usually higher in each BioThrax IM group compared to the 8SC group (excluding doses where IM groups received a placebo). The incidence of any moderate or severe local adverse reactions was consistently lower in BioThrax IM groups, compared to the 8SC group after each dose. Route of administration did not affect the occurrence of systemic adverse reactions, with the exception of muscle ache (increased incidence in the BioThrax IM groups after most doses). There was no clear pattern for differences in the incidence of any moderate or severe systemic adverse reactions for BioThrax IM groups compared to the 8SC group after each dose. The proportion of participants with severe local or systemic adverse reactions reported by adverse reaction category after each dose was very low (generally < 1%).

Overall, women had a higher incidence of any local adverse reaction than did men, by dose, within BioThrax groups, regardless of the route of administration. Overall, women also had a higher incidence of any systemic adverse reaction than men, within BioThrax groups, regardless of the route of administration. A brief pain or burning sensation, felt immediately after vaccine injection, and distinct from injection site pain, was reported by 45 - 97% of all study participants receiving BioThrax. Reporting frequency and event intensity varied with route of administration and vaccine dose. Up to 11% of subjects rated the brief pain or burning they experienced immediately after vaccine injection as 8 out of 10 or greater. Female participants generally experienced a higher pain scale rating than male participants.

Eight serious adverse events (SAEs) were reported with 6 subjects and determined to be possibly related to the administration of BioThrax: (1) a case of generalized allergic reaction, (2) a case of ANA positive autoimmune disorder manifesting as a moderate bilateral arthalgia of the metacarpophalangeal (MCP) joints, (3) a right shoulder supraspinatus tendon tear, (4) a case of bilateral pseudotumor cerebri with bilateral disc edema, (5) a case of generalized seizure and hospitalization for evaluation of hydrocephalus and endoscopic fluid ventriculostomy, (6) a case of bilateral ductal carcinoma of the breast. No SAEs were determined by the investigator to be probably or definitely related to administration of BioThrax. The percent of serious adverse events was similar between the BioThrax combined groups (193/1303 or 1.5%) and the placebo group (38/260 or 1.5%).

Out of a total of 51 pregnancies reported in this study, no distinct patterns of infant outcome were seen, with the majority of pregnancies uncomplicated and healthy term infants delivered. Of women who received vaccine within 90 days of the estimated date of conception (n = 14), 2 spontaneous abortions and a first trimester intra-utero fetal death were reported, along with one report of a healthy term infant with mild right clubbed foot abnormality.

Table 2: Adverse Reactions: In-Clinic Day 0 – 3, Solicited by Dose Number*

Number of Subjects (N)**	STUDY GROUP
	Group D BioThrax 7IM (BioThrax Doses 1, 3-8) Weeks-0-4-26† Months 12-18-30-42								Placebo‡ Control SC/IM (Doses 1-8) Weeks-0-2-4-26 Months 12-18-30-42								Group A BioThrax 8SC (BioThrax Doses 1-8) Weeks-0-2-4-26 Months 12-18-30-42
	256								260								259
	Dose								Dose								Dose
	1	2†	3	4	5	6	7	8	1	2	3	4	5	6	7	8	1	2	3	4	5	6	7	8
	%	%	%	%	%	%	%	%	%	%	%	%	%	%	%	%	%	%	%	%	%	%	%	%
Local Adverse Reactions
Presence of any local adverse reaction	60	23	68	68	69	77	76	73	22	22	19	27	25	29	25	18	81	89	80	84	81	84	84	92
Warmth	4	1	8	10	11	13	14	19	1	0	0	0	0	0	1	1	29	41	32	39	34	40	51	49
Tenderness	46	7	51	47	41	44	44	48	6	8	7	10	6	7	7	4	64	72	48	65	53	57	61	63
Itching	1	0	2	4	7	7	7	10	0	0	0	0	1	0	0	0	3	16	23	20	17	22	25	26
Pain	16	4	20	15	16	13	16	15	4	2	3	4	4	2	3	2	16	22	12	19	16	14	18	20
Arm motion limitation	14	1	15	11	10	10	15	9	1	0	2	1	1	1	1	0	8	12	5	11	10	5	8	5
Erythema	15	10	20	30	35	48	40	37	11	12	7	13	14	17	14	11	53	64	57	65	64	64	68	71
Induration	7	7	12	16	21	23	15	17	1	3	2	3	4	4	3	3	26	35	28	40	38	36	38	35
Edema	5	2	11	20	15	23	30	25	3	4	4	4	4	7	8	5	17	33	31	33	31	35	37	46
Nodule	3	0	4	5	8	9	6	5	0	2	0	1	2	0	2	0	39	42	36	26	26	23	21	27
Bruise	5	4	5	3	2	4	3	2	4	5	1	4	3	5	5	4	6	7	6	6	3	6	5	6
Presence of any moderate/severe local adverse reactions§	5	1	8	7	4	5	6	4	0	0	0	0	0	0	0	0	7	16	8	13	10	7	12	14
Presence of any large local adverse reaction|	0	0	0	2	2	4	2	2	0	0	0	0	0	0	0	0	0	1	4	2	1	2	2	4
Systemic Adverse Reactions
Presence of any systemic adverse reaction	18	12	24	19	15	19	10	9	10	10	13	11	13	8	13	4	16	20	18	21	18	14	20	17
Fatigue	9	4	12	10	9	11	4	6	5	4	7	7	8	5	10	3	9	12	8	12	12	10	10	13
Muscle ache	8	4	13	6	5	5	3	5	2	2	3	4	5	3	1	1	5	8	4	5	4	3	9	5
Headache	6	6	9	7	8	8	5	4	4	6	5	4	7	4	6	1	7	9	8	11	7	5	9	2
Fever ≥ 100.4°F	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0
Tender/painful axillary adenopathy	0	0	0	1	1	1	0	0	0	0	0	0	0	0	0	1	0	1	2	1	1	0	1	0
Presence of any moderate/severe systemic adverse reactions††	2	2	6	3	3	5	4	3	1	2	2	1	3	1	2	1	2	5	4	3	3	2	3	2
*Per-dose, statistical assessment performed on Intent-to-Treat population data. Evaluations performed at 15-60 minutes and 1-3 days following each injection and prior to the next scheduled injection. **N is the highest number per treatment arm (received at least one dose); denominator (N) varied with dose number due to attrition over time. †Subjects received saline (instead of BioThrax) for the Week 2 dose. Placebo dose data for 7IM group is in italics. ‡The two saline groups (SC and IM) were combined. § Moderate = causes discomfort and interferes with normal daily activities; Severe = incapacitating and completely prevents performing normal daily activities. This is based on the local AE categories of warmth, tenderness, itching, pain, and arm motion limitation. ¦Large = an occurrence of induration, erythema, edema, nodule, and bruise with a largest diameter greater than 120 mm. †† Moderate = causes discomfort and interferes with normal daily activities; Severe = incapacitating and completely prevents performing normal daily activities. This is based on the systemic AE categories of fatigue, muscle ache, headache, and fever.

Solicited and unsolicited adverse reactions observed from Day 0 through month 43 at a higher frequency (by at least 5%) in the BioThrax groups (IM and SC) as compared to the placebo (P) group were: headache (70.4% IM, 78.4% SC, 68.1% P); myalgia (72% IM, 76.1% SC, 50% P); and fatigue (70.1% IM, 76.8% SC, 60.8% P).

Postmarketing Experience

The following adverse events, not previously listed in Section 6.1, have been identified during post-approval use of BioThrax. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The reports included below are listed due to one or more of the following factors: (1) seriousness of the event, (2) number of reports, or (3) strength of causal relationship to the drug.

Blood and Lymphatic System Disorders

Lymphadenopathy

Gastrointestinal Disorders

Nausea

Immune System Disorders

Allergic reactions (including anaphylaxis, angioedema, rash, urticaria, pruritus, erythema multiforme, anaphylactoid reaction, and Stevens Johnson syndrome)

Nervous System Disorders

Paresthesia syncope, dizziness, tremor, ulnar nerve neuropathy

Musculoskeletal, Connective Tissue, and Bone Disorders

Arthralgia, arthropathy, myalgia, rhabdomyolysis, alopecia

General Disorders and Administration Site Conditions

Malaise, pain, cellulitis, flu-like symptoms

Psychiatric Disorders

Insomnia

Skin and Subcutaneous Disorders

Pruritis, rash, urticaria

Vascular Disorders

Flushing

Infrequent reports were also received of multisystem disorders defined as chronic symptoms involving at least two of the following three categories: fatigue, mood-cognition, and musculoskeletal system.

DRUG INTERACTIONS

Concomitant Administration With Other Vaccines

The safety and efficacy of concomitant administration of BioThrax with other licensed vaccines has not been evaluated.

BioThrax should not be mixed with any other vaccine in the same syringe or vial. If BioThrax is to be given at the same time as another injectable vaccine(s), the vaccine(s) should be administered at different injection sites.

Immunosuppressive Therapies

Immunosuppressive therapies, including chemotherapy, corticosteroids (used in high-doses longer than 2 weeks), and radiation therapy may reduce the response of BioThrax.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Hypersensitivity Reactions

Acute allergic reactions, including anaphylaxis, have occurred with BioThrax. Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of the vaccine. [See CONTRAINDICATIONS]

Latex

The stopper of the vial contains dry natural rubber and may cause allergic reactions to patients with a possible history of latex sensitivity.

Pregnancy

BioThrax can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. [See Pregnancy]

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. Results of a large observational study that examined the rate of birth defects among 37,140 infants born to U.S. military service women who received anthrax vaccine in pregnancy between 1998 and 2004 showed that birth defects were slightly more common in first trimester-exposed infants (odds ratio = 1.18, 95% confidence interval: 0.997, 1.41) when compared with infants of women vaccinated outside of the first trimester and compared to unvaccinated women.1 While the increased birth defect rates were not statistically significant when compared with infants born to women vaccinated outside of pregnancy, 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.

The effect of BioThrax on embryo-fetal and pre-weaning development was evaluated in a developmental toxicity study using pregnant rabbits. One group of rabbits was administered BioThrax twice prior to gestation and during the period of organogenesis (gestation day 7). A second group of rabbits was administered BioThrax twice prior to gestation and on gestation day 17. BioThrax was administered at 0.5 ml/rabbit/occasion, by intramuscular injection. No adverse effects on mating, fertility, pregnancy, parturition, lactation, embryo-fetal or pre-weaning development were observed. There were no vaccine-related fetal malformations or other evidence of teratogenesis noted in this study.

History Of Anthrax Disease

History of anthrax disease may increase the potential for severe local adverse reactions.

Altered Immunocompetence

If BioThrax is administered to immunocompromised persons, including those receiving immunosuppressive therapy, the immune response may be diminished.

Limitations Of Vaccine Effectiveness

Vaccination with BioThrax may not protect all individuals.

Patient Counseling Information

See FDA-approved patient labeling (PATIENT INFORMATION).

Advise women of the potential risk to the fetus. [See Use in Specific Populations]

Inform patients of the benefits and risks of immunization with BioThrax.

Instruct patients to report any serious adverse reaction to their health care provider.

Use In Specific Populations

Pregnancy

Pregnancy Category D. [See WARNINGS AND PRECAUTIONS]

Male Fertility

A retrospective study was performed at an in-vitro fertilization clinic to evaluate whether BioThrax may impact reproductive function in men. This study compared semen parameters, embryo quality, and pregnancy outcomes in 254 male clients who stated that they had received BioThrax, with those of 791 male clients who did not.2 Prior receipt of BioThrax did not influence semen parameters (including concentration, motility, and morphology), fertilization rate, embryo quality or clinical pregnancy rates.

Nursing Mothers

It is not known whether BioThrax is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when BioThrax is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established for BioThrax.

Geriatric Use

BioThrax has not been approved for use in patients greater than 65 years of age.

REFERENCES

1. Ryan, M.A.D., et al. 2008. Birth defects among infants born to women who received anthrax vaccine in pregnancy. Am J Epidemiol, 168:434-442.

2. Catherino, W., et al., 2005. The anthrax vaccine does not affect semen parameters, embryo quality, or pregnancy outcome in couples with a vaccinated male military service member. Fertility and Sterility, 83:480-483

OVERDOSE

No information provided.

CONTRAINDICATIONS

Do not administer BioThrax to individuals with a history of anaphylactic or anaphylactic-like reaction following a previous dose of BioThrax or any component of the vaccine. [See DESCRIPTION]

CLINICAL PHARMACOLOGY

Mechanism Of Action

Anthrax is a zoonotic disease caused by the Gram-positive, spore-forming bacterium Bacillus anthracis. Although an immune correlate of protection is unknown, BioThrax induces antibodies raised against PA, which may contribute to protection by neutralizing the activities of the cytotoxic lethal toxin and edema toxin of Bacillus anthracis.3 Bacillus anthracis proteins other than PA may be present in BioThrax, but their contribution to protection 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 and supplied by G. G. Wright and associates of the U.S. Army Chemical Corps, Fort Detrick, Frederick, MD, that consisted of an aluminum potassium sulfate-precipitated cell-free filtrate from an aerobic culture, was conducted from 1955-1959.4 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. The anthrax vaccine was administered subcutaneously at 0, 2, 4 weeks, 6, 12, 18 months. Prior to vaccination, the yearly average number of human anthrax cases (both cutaneous and inhalational) was 1.2 cases per 100 employees in these mills. During the trial, 26 cases of anthrax were reported across the four mills – 5 inhalation and 21 cutaneous.

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. The calculated efficacy of the vaccine to prevent all types of anthrax disease, regardless of the route of exposure or clinical manifestations, was 92.5% (lower 95% CI = 65%).

Between 1962 and 1974, the Centers for Disease Control and Prevention (CDC) collected surveillance data on the occurrence of anthrax disease in mill workers or those living near mills in the United States.5,6 In that time period, individuals received either BioThrax or the earlier protective antigen-based anthrax vaccine used in the field trial described above. Of the 27 reported cases of anthrax, 24 cases occurred in unvaccinated individuals. In vaccinated 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 at least three doses of the originally licensed six-dose series of anthrax vaccine.

Between 2002 and 2007, a prospective double-blinded, randomized, placebo-controlled and active-controlled study was conducted to evaluate the impact on safety and immunogenicity on changing the administration route from SC to IM, and reducing the number of doses [NCT00119067]. This study enrolled 1,564 healthy civilian men and women between the ages of 18 and 61. A total of 1,563 subjects received at least one dose (one subject withdrew consent prior to the first injection). Subjects were randomized to one of six groups. See Table 1.

Using an ELISA, IgG antibodies directed against anthrax protective antigen (PA) were measured at the Week 8 and Months 7, 13, 19, 31, and 43 time points. The three primary immunogenicity endpoints were: (1) Geometric Mean Concentration (GMC) (mcg/mL), (2) Geometric Mean Titer (GMT), and (3) percentage with 4-fold rise in anti-PA antibody titer from baseline.

The criteria for non-inferiority of comparisons based on ratios of GMCs and GMTs and differences in the rates of 4-fold rise in antibody titer were defined as follows:

Mean antibody concentration ratio: non-inferiority was achieved when the upper bound of the 95% confidence limit was < 1.5

Mean antibody titer ratio: non-inferiority was achieved when the upper bound of the 95% confidence limit was < 1.5

4-fold rise in antibody titer: non-inferiority was achieved when the upper bound of the 95% confidence limit was < 0.10

To compare the originally licensed 6-dose SC schedule (0, 2, 4 weeks and 6, 12, and 18 months) versus a 3-dose IM primary series (at 0, 1, and 6 months), non-inferiority analyses were performed for all three primary immunogenicity endpoints. This evaluation compared the immune response at Month 7 for Group C (COM, where COM is Combined, as described in 6.1) to Month 19 for Group A (TRT-8SC, where TRT is Treatment) and Group B (TRT-8IM). Non-inferiority was demonstrated for all analyses (See Table 3). These results support a 3 dose primary series of BioThrax administered IM at 0, 1 and 6 months, followed by booster doses at 12 and 18 months and at 1-year intervals thereafter to maintain protective immunity.

The Month 7 antibody levels of Group A (TRT-8SC) were non-inferior to Month 13 and 19 antibody levels after a 0, 2, 4 week and 6 month primary SC series followed by SC booster injections at 12 and 18 months (see Table 3). These results support a 4 dose SC primary series of BioThrax administered at weeks 0, 2, 4, and at 6 months followed by booster doses at 12 and 18 months after initiation of the series, and at 1-year intervals thereafter to maintain protective immunity.

Catch up Administration for Delayed or Missed Doses

In subjects who did not receive booster doses at 12, 18 and 30 months, PA antibody levels decline over time following the third dose of BioThrax administered intramuscularly at 6 months (Group F; 4IM; 0, 1, 6, and 42 months). In the absence of booster doses it is not known whether these individuals are adequately protected between 12 months and receipt of a booster dose at 42 months. One month following a dose of BioThrax at 42 months the immune response for Group F met the criteria for non-inferiority relative to Group A (8SC) for all three primary immunogenicity endpoints (see Table 3). The optimal schedule for further intramuscular booster doses among persons administered a single booster dose at 42 months following completion of a three-dose primary series at 0, 1, and 6 months is not known.

Table 3: Primary Immunogenicity Endpoints (According to Protocol†)

	Week 4	Week 8	Month 7	Month 13	Month 19	Month 31	Month 43
Anti-PA Specific IgG GMC, mcg/mL
	n GMC 95%CI	n GMC 95%CI	n GMC 95%CI	n GMC 95%CI	n GMC 95%CI	n GMC 95%CI	n GMC 95%CI
TRT-8SC	242	235	219	203	190	167	144
Group A	49.72	94.29	201.14	201.67	193.45	250.07	216.83
	(43.32, 57.06)	(82.08, 108.31)	(174.71, 231.56)	(174.77, 232.71)	(167.29, 223.69)	(215.38, 290.34)	(185.80, 253.05)
TRT-7IM*				203	192	169	139
Group D				229.86 (203.20, 260.02)	204.95 (180.82, 232.29)	263.13 (231.09, 299.61)	254.80 (222.03, 292.40)
TRT-5IM*	723	698	636	399	174	153	141
Group E	2.63 (2.39, 2.89)	46.39 (42.18, 51.01)	206.09 (187.14, 226.96)	28.64 (25.79, 31.81)	293.60 (258.30, 333.73)	33.68 (29.48, 38.48)	310.02 (270.49, 355.33)
TRT-4IM* Group F					193	179	157
					13.71 (12.11, 15.53)	7.80 (6.87, 8.86)	433.20 (379.58, 494.40)
Anti-PA Specific IgG GMT
	n	n	n	n	n	n	n
	GMT	GMT	GMT	GMT	GMT	GMT	GMT
	95% CI	95% CI	95% CI	95% CI	95% CI	95% CI	95% CI
TRT-8SC	242	235	219	203	190	167	144
Group A	565.16	1048.50	2211.94	2184.59	2080.89	2677.97	2282.36
	(492.57, 648.45)	(913.05, 1204.05)	(1921.78, 2545.90)	(1893.62, 2520.26)	(1799.87, 2405.79)	(2306.82, 3108.83)	(1955.79, 2663.45)
TRT-7IM*				203	192	169	139
Group D				2546.81 (2251.11, 2881.35)	2254.56 (1988.85, 2555.75)	2867.88 (2518.14, 3266.19)	2760.35 (2404.66, 3168.64)
TRT-5IM*	723	698	636	399	174	153	141
Group E	36.61	514.57	2257.09	296.08 (266.67, 328.74)	3167.26	348.89	3286.41
	(33.32, 40.23)	(468.08, 565.68)	(2050.12, 2484.94)		(2785.88, 3600.85)	(305.33, 398.66)	(2866.50, 3767.83)
TRT-4IM* Group F					193	179	157
					135.30 (119.44, 153.26)	79.63 (70.10, 90.44)	4683.79 (4102.99, 5346.80)
	Week 4	Week 8	Month 7	Month 13	Month 19	Month 31	Month 43
4-fold response
	n 4-fold response 95% CI	n 4-fold response 95% CI	n 4-fold response 95% CI	n 4-fold response 95% CI	n 4-fold response 95% CI	n 4-fold response 95% CI	n 4-fold response 95% CI
TRT-8SC Group A	242 80.99 (75.47, 85.73)	235 94.89 (91.25, 97.33)	219 98.63 (96.05, 99.72)	203 99.51 (97.29, 99.99)	190 98.95 (96.25, 99.87)	167 100.00 (97.82, 100.00)	144 100.00 (97.47, 100.00)
TRT-7IM* Group D	723	698	636	203	192	169	139
				100.00 (98.20, 100.00)	98.96 (96.29, 99.87)	100.00 (97.84, 100.00)	100.00 (97.38, 100.00)
TRT-5IM* Group E	4.15 (2.82, 5.87)	78.80 (75.57, 81.77)	97.80 (96.33, 98.79)	399	174 99.43 (96.84, 99.99)	153 63.40 (55.24, 71.03)	141 99.29 (96.11, 99.98)
TRT-4IM* Group F				60.40 (55.41, 65.23)	193 37.82 (30.96, 45.07)	179 22.35 (16.47, 29.16)	157 99.36 (96.50, 99.98)
CI: Confidence Interval; †According to Protocol (ATP): To be included in the ATP population at a particular timepoint, a participant must have: (a) received all injections up through that timepoint, (b) received these injections within the windows defined by protocol, (c) received the correct agent administered by the correct route according to subject's assigned study arm, (d) received the correct injection volume. A shot of 0.3 mL or greater is considered valid. *Groups TRT-7IM, -5IM, and -4IM combined as group TRT-COM (combined) through Month 7 of the study, GMC: geometric mean concentration. GMT: geometric mean titer. IM: Intramuscular; SC: Subcutaneous, TRT: treatment.

REFERENCES

3. Brachman, P.; Friedlander, A.; Grabenstein, J., 2008. Anthrax Vaccine. In: Vaccines, Fifth Edition, Plotkin, S.A.: Orenstein W.A. and Offit P.A. (eds.), 111-126

4. Brachman, P., et al., 1962. Field evaluation of a human anthrax vaccine. Amer. J. Public Health, 52:632-645.

5. Food and Drug Administration, 2005, Biological Products; Bacterial Vaccines and Toxoids; Implementation of Efficacy Review; Anthrax Vaccine Adsorbed; Final Order. FDA Federal Register 2005; 70(242): 75180-75198.

6. Food and Drug Administration. Biological Products; Bacterial vaccines and toxoids; Implementation of efficacy review. Federal Register (December 13, 1985), 50(240):51002-51117.

PATIENT INFORMATION

BioThrax®
(Anthrax Vaccine Adsorbed)

Please read this Patient Information summary carefully before you get this shot. This summary does not take the place of talking with your healthcare provider about BioThrax. If you have questions or would like more information, please talk with your healthcare provider.

What is the most important information I should know about BioThrax

• Only people with a high risk of getting the disease need to get the shots.
• BioThrax may not completely protect everyone who gets the shots.

What is BioThrax?

BioThrax is a vaccine to protect people 18 through 65 years of age from anthrax disease.

People can get anthrax from touching, eating, or breathing in anthrax germs. It is a serious disease and can be fatal.

Who should not get BioThrax?

You should not get BioThrax if you:

• Had a serious reaction after getting BioThrax before.

What should I tell my healthcare provider before getting BioThrax?

• If you may be pregnant, plan to get pregnant soon, or are nursing a baby
• About medicines that you take, including over-the-counter medicines and supplements.
• About immune problems you have, including steroid treatments and cancer treatments.
• About blood clotting problems or if you take “blood thinners.”
• If you are allergic to latex

How is BioThrax given?

BioThrax is given as a shot in your arm.

After getting the first shot, you should come back for the next shots on the schedule given to you by your health care provider. It is important that you get all your shots to get the best protection..

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

• Pain, tenderness, redness, bruising, or problems moving the arm in which you got the shot
• Muscle aches
• Headaches
• Fatigue
• Fainting

Tell your healthcare provider about any side effects that concern you. Your healthcare provider can give you a complete list of side effects available to healthcare professionals.

You may report side effects to FDA by calling 1-800-822-7967 or to the website www.vaers.hhs.gov. You may also report side effects directly to Emergent BioSolutions at 1-877-246-8472 or at [email protected]

What are the ingredients in BioThrax?

BioThrax contains aluminum hydroxide, benzothonium chloride and formaldehyde (as preservatives).

The vial stopper contains natural rubber latex.