2.1 Preparation for Administration

Use a separate 1- or 1½ -inch 23- or 25-gauge sterile needle and syringe for each patient to avoid transmission of viral hepatitis and other infectious agents.

Shake the bottle thoroughly to ensure that the suspension is homogeneous during withdrawal. Inspect visually for particulate matter and discoloration prior to administration. If the product appears discolored or has visible particulate matter, DISCARD THE VIAL.

2.2 Dose and Schedule

Immunization consists of a series of 5 intramuscular doses administered at 0 and 4 weeks and 6, 12 and 18 months. Select a different injection site for each sequential injection of this vaccine. Do not mix with any other product in the syringe. Individuals should not be considered protected until they have received the full series of vaccinations. Do not inject BioThrax intravenously or intradermally.

Yearly booster injections of 0.5 mL intramuscularly are recommended for those who remain at risk.

When medically indicated, such as in persons with coagulation disorders or receiving medications that affect coagulation (e.g. warfarin), BioThrax may be administered by the subcutaneous route.

5.1 Latex

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

5.2 Hypersensitivity Reactions

Before administration, the patient’s medical immunization history should be reviewed for possible vaccine sensitivities and/or previous vaccination-related adverse reactions, to determine the existence of any contraindications to immunization. [See Contraindications section (4)] Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of the vaccine. [See Contraindications section (4)]

5.3 Pregnancy

Pregnancy Category D:
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.

BioThrax can cause fetal harm when administered to a pregnant woman. If this vaccine is used during pregnancy, or if the patient becomes pregnant during the immunization series, the patient should be apprised of the potential hazard to a fetus.

5.4 History of Anthrax Disease

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

5.5 Altered Immunocompetence

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

5.6 Limitations of Vaccine Effectiveness

Vaccination with BioThrax may not protect all individuals. The extent to which one is protected prior to completion of the full immunization schedule is unknown.

6.1 Clinical Trial 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.

Local and systemic reactions were monitored 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. Over the course of the 5-year study the following local reactions were reported: 24 (0.15% of doses administered) 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), 150 (0.94% of doses administered) moderate local 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 reactions (erythema only or induration measuring less than 30 mm in diameter). Four cases of systemic 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. The CDC sponsored a randomized, double-blind, placebo-controlled, multi-center clinical study [NCT00119067] in which 1,564 healthy volunteers were enrolled [See Clinical Studies section (14)]. The objective of this study was to evaluate the effect of (1) changing the route of vaccine administration from subcutaneous (SQ) to intramuscular (IM), and (2) of reducing the number of doses on the safety and immunogenicity of BioThrax. A planned analysis of the first 1,005 subjects compared four treatment groups over a period of seven months in which subjects received a total of either three (3) or four (4) doses of BioThrax. 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 events. Adverse reaction data were also collected from in-clinic exams, which were performed prior to, and 15 to 60 minutes post each injection, at 1 to 3 days after each injection, and at 28 days after injections 3 and 4. Demographic characteristics for each respective treatment group in the analysis are provided in Table 1.

Shown in Table 2 and Table 3, respectively, are the rates (percentage) of prospectively defined local and systemic solicited adverse reactions observed in the in-clinic exams.

The analysis of injection site (local) reactions demonstrated that administration of the vaccine by the IM route, as compared to the SQ route, resulted in a statistically significant reduction in reactogenicity (i.e. cutaneous adverse reactions). Injection site adverse reactions, including warmth, tenderness, itching, erythema, induration, edema, and nodule, consistently occurred at lower frequencies and for shorter duration in participants given BioThrax by the IM route. Route of administration did not statistically significantly influence the occurrence or duration of systemic adverse reactions, with the exception of muscle ache (increased occurrence only). Most local and systemic adverse reactions were mild or moderate in severity; the proportion of participants with severe adverse reactions reported was very low (< 1%). It was observed in this study that women receiving BioThrax reported significantly more injection-site adverse reactions than did men. This gender-related difference was seen regardless of the route of administration, but was more pronounced in those receiving the vaccine by the SQ route. Women also reported more systemic adverse reactions than men (in particular fatigue, muscle ache and headache), but these gender differences were not influenced by route of administration. A brief pain or burning sensation, felt immediately after vaccine injection, was reported by most study participants. The pain was rated on a visual analog scale as 0-10. It was described as significant (> 3) more often following SQ administration (41%) than IM administration (26%). Female participants generally experienced a higher pain scale rating than male participants.

Serious adverse reactions were infrequently reported during this study but two (2) important serious adverse reactions that were noted to be possibly related to BioThrax administration include: a case of anaphylaxis and a case of an ANA positive autoimmune disorder manifesting as a moderate bilateral arthralgia of the metacarpophalangeal (MCP) joints. The majority of serious adverse reactions reported were unrelated to vaccination. Out of a total of 44 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 approximately within the first trimester (n = 15), 2 reports of spontaneous abortion were reported, along with one report of a healthy term infant with mild right clubbed foot abnormality.

Table 4 shows adverse events (excluding injection site reactions) that occurred in ≥2% of participants through Study Month 7, and excluding those that occurred at a lower rate than those observed in the placebo group.

6.2 Post-marketing Experience

The following adverse events have been identified during postapproval 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

• Immune system disorders

    

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

• Nervous system disorders

    

  Headache, paresthesia syncope, tremor, ulnar nerve neuropathy

• Musculoskeletal, connective tissue and bone disorders

    

  Arthralgia, arthropathy, myalgia, rhabdomyolysis, alopecia

• General disorders and administration site conditions

    

  Injection site reactions (including pain, nodule, edema, induration, erythema, warmth, pruritus, cellulitis), fatigue, pyrexia, flu-like symptoms

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.

No fatalities have been determined to have been causally related to the administration of BioThrax.

7.1 Concomitant Administration with Other Vaccines

No prospective, controlled clinical studies to assess the concomitant administration of BioThrax with other vaccines have been performed. 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.

BioThrax should not be mixed with any other vaccine in the same syringe or vial.

7.2 Immunosuppressive Therapies

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

8.1 Pregnancy and Fertility

Pregnancy: Category D. See Warnings and Precautions section (5)

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.

8.3 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.

8.4 Pediatric Use

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

8.5 Geriatric Use

Clinical studies of BioThrax did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from subjects in the adult population under age 65. Sub-group analysis of study subjects < 30 years, 30 to < 40 years, 40 to < 50 years and > 50 years indicated that subjects in the > 50 years category had statistically insignificant but numerically lower immune responses than younger subjects.

12.1 Mechanism of Action

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 anthrax disease is contracted largely through the uptake of spores. Spores are markedly resistant to heat, cold, drought, UV light, and gamma radiation. Following germination at the site of infection, the bacilli can also enter the blood and lead to septicemia.

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.³Bacillus anthracis proteins other than PA may be present in BioThrax, but their contribution to protection has not been determined.

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.