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adverse reactions
6 ADVERSE REACTIONS Common adverse reactions in healthy adult subjects (≥1.5%) were injection site reaction, erythema and pain, headache, rash, pain in extremity, pruritus, and somnolence. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Emergent BioSolutions at 1-800-768-2304 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of raxibacumab has been studied only in healthy volunteers. It has not been studied in patients with inhalational anthrax. In the three pre-licensure clinical trials (Trials 1, 2, and 3), the safety of raxibacumab was evaluated in 326 healthy subjects treated with a dose of 40 mg/kg in 3 clinical trials: a drug interaction trial with ciprofloxacin (Trial 1), a repeat-dose trial of 20 subjects with the second raxibacumab dose administered ≥4 months after the first dose (Trial 2), and a placebo-controlled trial evaluating single doses with a subset of subjects receiving 2 raxibacumab doses 14 days apart (Trial 3). Raxibacumab was administered to 86 healthy subjects in Trial 1. In Trial 3, 240 healthy subjects received raxibacumab (217 received 1 dose and 23 received 2 doses) and 80 subjects received placebo. The overall safety of raxibacumab was evaluated as an integrated summary of these 3 clinical trials. Of 326 raxibacumab subjects, 283 received single doses, 23 received 2 doses 14 days apart, and 20 received 2 doses more than 4 months apart. The subjects were aged 18 to 88 years, 53% female, 74% white, 17% black/African American, 6% Asian, and 15% Hispanic. Trial 4 was a post-marketing trial in healthy subjects designed to evaluate the effect of a single 40 mg/kg infusion of raxibacumab on the immunogenicity of a concurrently administered 3-dose subcutaneous (SC) regimen of Anthrax Vaccine Adsorbed (AVA) [N=286] compared with an AVA-alone regimen [N=286]. In the combination arm, the first dose of AVA was administered immediately following the raxibacumab infusion (Day 1), while the second and third doses were administered on Days 15 and 29. The mean age of subjects was 36 years in both arms, 52% of subjects in the AVA arm and 50% in the AVA + raxibacumab arm were female, 75% and 77% in the two arms, respectively, were white, while 21% and 20%, respectively, were African American. Adverse Reactions Leading to Discontinuation or Interruption of Raxibacumab Infusion Four subjects (1.2%) in Trials 1, 2 and 3 had their infusion of raxibacumab discontinued for hypersensitivity and anaphylaxis: 2 subjects (neither of whom received diphenhydramine premedication) discontinued due to urticaria (mild), and 1 subject each discontinued for clonus (mild) and dyspnea (moderate). In Trial 4, six (2.1%) subjects required discontinuation of the raxibacumab infusion and 3 (1.0%) subjects required infusion interruption due to hypersensitivity or anaphylaxis [see Warnings and Precautions ( 5.1 )] . Most Frequently Reported Adverse Reactions Trials 1, 2, and -3 In Trials 1, 2, and 3, the most frequently reported adverse reactions were rash, pain in extremity, pruritus, and somnolence ( Table 3 ). Table 3. Adverse Reactions Reported in ≥1.5% of Healthy Adult Subjects Exposed to Raxibacumab 40 mg/kg Intravenously in Trials 1, 2, and 3 Adverse Reaction Placebo N = 80 (%) Single-Dose Raxibacumab N = 283 (%) Double-Dose Raxibacumab ≥4 Months Apart N = 20 (%) Double-Dose Raxibacumab 2 Weeks Apart N = 23 (%) Total Raxibacumab Subjects N = 326 (%) Rash/Rash erythematous/Rash papular 1 (1.3) 9 (3.2) 0 0 9 (2.8) Pain in extremity 1 (1.3) 7 (2.5) 0 0 7 (2.1) Pruritus 0 7 (2.5) 0 0 7 (2.1) Somnolence 0 4 (1.4) 0 1 (4.3) 5 (1.5) Rashes For all subjects exposed to raxibacumab in Trials 1, 2, and 3, the rate of rash was 2.8% (9/326) compared with 1.3% (1/80) of placebo subjects. Mild to moderate infusion-related rashes were reported in 22.2% (6/27) of subjects who did not receive diphenhydramine premedication compared with 3.3% (2/61) of subjects who were premedicated with diphenhydramine in the ciprofloxacin/raxibacumab combination trial (Trial 1). In the placebo-controlled raxibacumab trial where all subjects received diphenhydramine (Trial 3), the rate of rash was 2.5% in both placebo- and raxibacumab-treated subjects. Trial 4 Eleven (3.8%) of 286 subjects who received raxibacumab, all of whom received diphenhydramine premedication, experienced hypersensitivity manifesting as urticaria, pruritus, lip and throat swelling, chest and throat tightness, hypotension, and diffuse erythema; 2 (0.7%) of these subjects had anaphylaxis. Raxibacumab infusion was discontinued or interrupted in 9/11 subjects. Hypersensitivity reactions and anaphylaxis occurred during administration of raxibacumab prior to administration of the first dose of AVA [see Warnings and Precautions ( 5.1 )] . Common adverse reactions, other than hypersensitivity, occurring at a frequency of ≥1.5% in raxibacumab-exposed subjects are presented in Table 4 . Table 4. Adverse Reactions Other than Hypersensitivity Reported in ≥1.5% of Healthy Adult Subjects Exposed to Raxibacumab 40 mg/kg Intravenously in Trial 4 Adverse Reaction AVA + Raxibacumab Subjects N = 286 (%) AVA Subjects N = 286 (%) Injection site reaction 18 (6.3) 18 (6.3) Injection site erythema 13 (4.5) 11 (3.8) Headache 9 (3.1) 6 (2.1) Injection site pain 8 (2.8) 6 (2.1) Less Common Adverse Reactions Clinically significant adverse reactions that were reported in <1.5% of subjects exposed to raxibacumab and at rates higher than in placebo subjects are listed below: • Blood and Lymphatic System Disorders: Anemia, leukopenia, lymphadenopathy. • Cardiac Disorders: Palpitations. • Ear and Labyrinth Disorders: Vertigo. • General Disorders and Administration Site Conditions: Fatigue, infusion site pain, peripheral edema. • Investigations: Blood amylase increased, blood creatine phosphokinase increased, prothrombin time prolonged. • Musculoskeletal and Connective Tissue Disorders: Back pain, muscle spasms. • Nervous System Disorders: Syncope. • Psychiatric Disorders: Insomnia. • Vascular Disorders: Flushing, hypertension. Immunogenicity The development of anti-raxibacumab antibodies was evaluated in all subjects receiving single and double doses of raxibacumab in Trials 1, 2, and 3. Immunogenic responses against raxibacumab were not detected in any raxibacumab-treated human subjects following single or repeat doses of raxibacumab. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the immunogenicity assay. Additionally, the observed incidence of any antibody positivity in an assay is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to raxibacumab with the incidence of antibodies to other products may be misleading.