BIOTHRAX Suspension for injection Ref.[9978] Active ingredients: Anthrax antigen

5.1 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 (4)].

5.2 Latex

The stopper of the vial contains natural rubber latex and may cause allergic reactions to patients with a possible history of latex sensitivity [See How Supplied/Storage and Handling (16)].

5.3 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. Weigh the potential benefits of vaccination against the potential risk to the fetus [See Use in Specific Populations (8.1)].

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 women¹. 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.

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 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.

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.

Pre-Exposure Prophylaxis

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, 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 (14)].

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:

SC: subcutaneous; IM: intramuscular; V: vaccine, S: saline
^a Active Control.
^b 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 for the first two injections, 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 (p ≤ 0.05) of any (one or more) local adverse reactions compared to the BioThrax SC route, by dose in the in-clinic data set, in 23 out of 24 analyses. (This excludes doses where IM groups received a placebo.) Individual injection site adverse reactions occurring at statistically significantly lower frequencies (p ≤ 0.05) in participants given BioThrax by the IM route included warmth (in all analyses), tenderness (in 19 out of 24 analyses), itching (in 22 out of 24 analyses), erythema (in all analyses), induration (in all analyses), edema (in 20 out of 24 analyses), and nodule (in all analyses). However, by dose, the incidences of arm motion limitation were comparable or higher in each BioThrax IM group compared to the 8SC group, with statistically significantly higher incidences (p ≤ 0.05) observed in 10 out of 24 analyses. The incidence of any moderate or severe local adverse reactions was 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 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 arthralgia 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 15%) and the placebo group (38/260 or 15%).

Fifty-one pregnancies were reported in this study, 33 of which occurred in women who received BioThrax as their last dose prior to conception and 18 in women who received placebo as their last dose prior to conception. Pregnancy outcomes where BioThrax was given within 30 days prior to conception (n=5) were 3 full-term live births (including 1 healthy term infant with a mild right clubbed foot abnormality), 1 spontaneous abortion, and 1 first trimester intra-utero fetal death. Pregnancy outcomes in the placebo group (n=5) were 4 full-term live births (including one with bilateral congenital hip dysplasia) and 1 elective abortion.

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

^a 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.
^b Subjects received saline (instead of BioThrax) for the Week 2 dose. Placebo dose data for 7IM group is in italics.
^c The two saline groups (SC and IM) were combined. |
^d N is the highest number per treatment arm (received at least one dose); denominator (N) varied with dose number due to attrition over time.
^e 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.
^f Large = an occurrence of induration, erythema, edema, nodule, and bruise with a largest diameter greater than 120 mm.
^g 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).

Post-Exposure Prophylaxis

A phase 3, open-label, uncontrolled, multi-center study evaluated the three-dose post-exposure prophylaxis BioThrax schedule (Week 0, 2, and 4) in 200 healthy adult subjects. The most common solicited adverse reactions reported 7 days after each vaccination comprised local reactions, including symptoms of lump, tenderness, and erythema. The most common solicited systemic reactions comprised fatigue, headache, and myalgia. Of the subjects that reported local and systemic solicited reactions, ≥ 98% required minimal or no treatment and resulted in little to no interference with subjects' daily activity. The most common (> 2.0%) unsolicited related adverse reactions reported following at least one dose up to 100 days after the third dose were: headache (4.0%), fatigue (3.5%), skin hyperpigmentation (3.5%), decreased joint range of motion (2.5%), myalgia (2.5%). No deaths were reported and neither of the two SAEs reported were considered to be related to vaccination. There were no pregnancies reported or subject withdrawals from the study due to adverse events.

The following adverse events have been reported spontaneously. Since 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.

7.1 Ciprofloxacin

Co-administration of 0.5 mL BioThrax SC with oral ciprofloxacin in human subjects did not alter the pharmacokinetics of ciprofloxacin or the immunogenicity of BioThrax as measured by the anthrax lethal toxin neutralization assay. [See Clinical Studies (14.3)]

7.2 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.

7.3 Immunosuppressive Therapies

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

Pregnancy Category D [See Warnings and Precautions (5.3)].

Healthcare practitioners are encouraged to register women who receive BioThrax during pregnancy in Emergent’s vaccination pregnancy registry by calling 1-619-553-9255.

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 not². Prior receipt of BioThrax did not influence semen parameters (including concentration, motility, and morphology), fertilization rate, embryo quality or clinical pregnancy rates.

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.

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

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