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warnings and cautions
5 WARNINGS AND PRECAUTIONS Infusion reactions may occur. Premedicate with diphenhydramine. Slow or interrupt infusion and administer treatment based on severity of the reaction. ( 5.1 ) 5.1 Infusion Reactions Infusion-related reactions were reported during administration of raxibacumab in clinical trials including reports of rash, urticaria, and pruritus. If these reactions occur, slow or interrupt raxibacumab infusion and administer appropriate treatment based on severity of the reaction. Premedicate with diphenhydramine within 1 hour prior to administering raxibacumab to reduce the risk of occurrence and/or the severity of an infusion reaction [see Dosage and Administration ( 2.1 ), Adverse Reactions ( 6.1 )].
6 ADVERSE REACTIONS Common adverse reactions in healthy adult subjects (≥1.5%) were: rash, pain in extremity, pruritus, and somnolence. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 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. The safety of raxibacumab has been evaluated in 326 healthy subjects treated with a dose of 40 mg/kg in 3 clinical trials: a drug interaction trial with ciprofloxacin (Study 1), a repeat-dose trial of 20 subjects with the second raxibacumab dose administered ≥4 months after the first dose (Study 2), and a placebo-controlled trial evaluating single doses with a subset of subjects receiving 2 raxibacumab doses 14 days apart (Study 3). Raxibacumab was administered to 86 healthy subjects in Study 1. In Study 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. Adverse Reactions Leading to Discontinuation of Raxibacumab Infusion Four subjects (1.2%) had their infusion of raxibacumab discontinued for adverse reactions: 2 subjects (neither of whom received diphenhydramine premedication) due to urticaria (mild), and 1 subject each discontinued for clonus (mild) and dyspnea (moderate). Most Frequently Reported Adverse Reactions The most frequently reported adverse reactions were rash, pain in extremity, pruritus, and somnolence. Table 3. Adverse Reactions Reported in ≥1.5% of Healthy Adult Subjects Exposed to Raxibacumab 40 mg/kg Intravenously Preferred Term 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 clinical trials, 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 (Study 1). In the placebo-controlled raxibacumab study where all subjects received diphenhydramine (Study 3), the rate of rash was 2.5% in both placebo- and raxibacumab-treated subjects. 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 : Anemia, leukopenia, lymphadenopathy. • Cardiac Disorders : Palpitations. • Ear and Labyrinth : Vertigo. • General Disorders and Administration Site : Fatigue, infusion site pain, peripheral edema. • Investigations : Blood amylase increased, blood creatine phosphokinase increased, prothrombin time prolonged. • Musculoskeletal and Connective Tissue : Back pain, muscle spasms. • Nervous System : Syncope vasovagal. • Psychiatric : Insomnia. • Vascular : Flushing, hypertension. Immunogenicity The development of anti-raxibacumab antibodies was evaluated in all subjects receiving single and double doses of raxibacumab in Studies 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.