Raxibacumab

1 INDICATIONS AND USAGE Raxibacumab is indicated for the treatment of adult and pediatric patients with inhalational anthrax due to Bacillus anthracis in combination with appropriate antibacterial drugs, and for prophylaxis of inhalational anthrax when alternative therapies are not available or are not appropriate. ( 1.1 ) Limitations of Use: • The effectiveness of raxibacumab is based solely on efficacy studies in animal models of inhalational anthrax. ( 1.2 , 14.1 ) • There have been no studies of raxibacumab in the pediatric population. Dosing in pediatric patients was derived using an extrapolation approach. ( 1.2 , 8.4 ) • Raxibacumab does not cross the blood-brain barrier and does not prevent or treat meningitis. Raxibacumab should be used in combination with appropriate antibacterial drugs. ( 1.2 ) 1.1 Inhalational Anthrax Raxibacumab is indicated for the treatment of adult and pediatric patients with inhalational anthrax due to Bacillus anthracis in combination with appropriate antibacterial drugs. Raxibacumab is also indicated for prophylaxis of inhalational anthrax when alternative therapies are not available or are not appropriate. 1.2 Limitations of Use The effectiveness of raxibacumab is based solely on efficacy studies in animal models of inhalational anthrax. It is not ethical or feasible to conduct controlled clinical trials with intentional exposure of humans to anthrax [see Clinical Studies ( 14.1 )] . Safety and pharmacokinetics (PK) of raxibacumab have been studied in adult healthy volunteers. There have been no trials of safety or PK of raxibacumab in the pediatric population. An extrapolation approach was used to derive dosing regimens that are predicted to provide pediatric patients with exposure comparable to the observed exposure in adults [see Use in Specific Populations ( 8.4 )] . Raxibacumab binds to the protective antigen (PA) of B. anthracis ; it does not have direct antibacterial activity. Raxibacumab does not cross the blood-brain barrier and does not prevent or treat meningitis. Raxibacumab should be used in combination with appropriate antibacterial drugs.

2 DOSAGE AND ADMINISTRATION • Premedicate with diphenhydramine. ( 2.1 , 2.2 , 5.1 ) • Dilute and administer as an intravenous infusion over 2 hours and 15 minutes. ( 2.3 ) • - Adults: 40 mg/kg raxibacumab. ( 2.1 ) • - Pediatrics greater than 40 kg: 40 mg/kg raxibacumab. ( 2.2 ) • - Pediatrics greater than 10 kg to 40 kg: 60 mg/kg raxibacumab. ( 2.2 ) • - Pediatrics 10 kg or less: 80 mg/kg raxibacumab. ( 2.2 ) 2.1 Dose and Schedule for Adults Administer raxibacumab as a single dose of 40 mg/kg intravenously over 2 hours and 15 minutes after dilution in 0.9% Sodium Chloride Injection, USP (normal saline) to a final volume of 250 mL. Administer 25 to 50 mg diphenhydramine within 1 hour prior to the raxibacumab infusion to reduce the risk of occurrence and/or the severity of an infusion reaction. Diphenhydramine route of administration (oral or intravenous) should be based on the temporal proximity to the start of the raxibacumab infusion [see Warnings and Precautions ( 5.1 ) , Adverse Reactions ( 6.1 )] . 2.2 Dose and Schedule for Pediatric Patients The recommended dose for pediatric patients is based on weight as shown in Table 1 . Table 1. Recommended Pediatric Dose Pediatric Body Weight Pediatric Dose Greater than 40 kg 40 mg/kg Greater than 10 kg to 40 kg 60 mg/kg 10 kg or less 80 mg/kg Premedicate with diphenhydramine within 1 hour prior to the raxibacumab infusion to reduce the risk of occurrence and/or the severity of an infusion reaction. Diphenhydramine route of administration (oral or intravenous) should be based on the temporal proximity to the start of the raxibacumab infusion. Infuse raxibacumab over 2 hours and 15 minutes. No pediatric patients were studied during the development of raxibacumab. The dosing recommendations in Table 1 are derived from simulations designed to match the observed adult exposure to raxibacumab at a 40 mg/kg dose [see Use in Specific Populations ( 8.4 )] . 2.3 Preparation and Administration of Raxibacumab The recommended dose of raxibacumab is weight-based, given as an intravenous infusion after dilution in a compatible solution to a final volume of 250 mL in adults or to a volume indicated based on the child’s weight ( Table 2 ). Dilute raxibacumab using one of the following compatible solutions: • 0.9% Sodium Chloride Injection, USP • 0.45% Sodium Chloride Injection, USP Keep vials in their cartons prior to preparation of an infusion solution to protect raxibacumab from light. Raxibacumab vials contain no preservative. Table 2. Raxibacumab Dose, Diluents, Infusion Volumes, and Rates by Body Weight a For patients requiring maximal fluid restriction, dilution factors can be adjusted at the discretion of the physician to a maximal concentration of 32 mg/mL. Preparation Administration Body Weight Dose Total Infusion Volume a Type of Diluent Infusion Rate Infusion Rate First 20 Minutes Remaining Infusion Adults 40 mg/kg 250 mL 0.9% Sodium Chloride Injection 15 mL/hour 125 mL/hour Pediatric Patients (Younger than 18 Years) Less than 1 kg 80 mg/kg 7 mL 0.45% Sodium Chloride Injection or 0.9% Sodium Chloride Injection 0.5 mL/hour 3.5 mL/hour 1 kg to less than 2 kg 15 mL 1 mL/hour 7 mL/hour 2 kg to less than 3 kg 20 mL 1.2 mL/hour 10 mL/hour 3 kg to less than 5 kg 25 mL 1.5 mL/hour 12 mL/hour 5 kg to 10 kg 40 mL 3 mL/hour 20 mL/hour Greater than 10 kg to less than 15 kg 60 mg/kg 50 mL 0.9% Sodium Chloride Injection 6 mL/hour 25 mL/hour 15 kg to less than 30 kg 100 mL 6 mL/hour 50 mL/hour 30 kg to 40 kg 125 mL 15 mL/hour 62.5 mL/hour Greater than 40 kg 40 mg/kg 150 mL 15 mL/hour 75 mL/hour Preparation Follow the steps below to prepare the raxibacumab intravenous infusion solution. 1. Calculate the milligrams of raxibacumab injection by multiplying the recommended mg/kg dose in Table 2 by patient weight in kilograms. 2. Calculate the required volume in milliliters of raxibacumab injection needed for the dose by dividing the calculated dose in milligrams (Step 1) by the concentration, 50 mg/mL. Each single-use vial allows delivery of 34 mL raxibacumab. Based on the total infusion volume selected in Table 2 , prepare either a syringe or infusion bag as appropriate following the steps below. Syringe Preparation 1. Select an appropriate size syringe for the total volume of infusion to be administered, as described in Table 2 . 2. Using the selected syringe, withdraw the volume of raxibacumab as calculated in Step 2. 3. Withdraw an appropriate amount of compatible solution to prepare a total volume infusion syringe as specified in Table 2 . 4. Gently mix the solution. Do not shake. 5. Discard any unused portion remaining in the raxibacumab vial(s). 6. The prepared solution is stable for 8 hours stored at room temperature. Infusion Bag Preparation 1. Select appropriate size bag of compatible solution (see compatible solutions listed in Table 2 ); withdraw a volume of solution from the bag equal to the calculated volume in milliliters of raxibacumab in Step 2 above. Discard the solution that was withdrawn from the bag. 2. Withdraw the required volume of raxibacumab injection from the raxibacumab vial(s). 3. Transfer the required volume of raxibacumab injection to the selected infusion bag (Step 3). Gently invert the bag to mix the solution. Do not shake. 4. Discard any unused portion remaining in the raxibacumab vial(s). 5. The prepared solution is stable for 8 hours stored at room temperature. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard the solution if particulate matter is present or color is abnormal [see Description ( 11 )] . Administration • Administer raxibacumab in monitored settings appropriately equipped to manage hypersensitivity, anaphylaxis, and shock [see Warnings and Precautions ( 5.1 )] . • Administer the infusion solution as described in Table 2 . The rate of infusion may be slowed or interrupted if the patient develops any signs of adverse reactions, including infusion-associated symptoms.

4 CONTRAINDICATIONS None. None. ( 4 )

5 WARNINGS AND PRECAUTIONS Hypersensitivity and Anaphylaxis: ( Boxed Warning , 2.1 , 2.3 , 5.1 , 6.1 ) 5.1 Hypersensitivity and Anaphylaxis Hypersensitivity reactions including rash, urticaria, pruritus, chills, chest and throat tightness, lip and throat swelling, and hypotension were reported in 27 (4.5%) of 606 healthy subjects during or after the administration of raxibacumab in clinical trials. Two subjects experienced anaphylaxis during the raxibacumab infusion [see Adverse Reactions ( 6.1 )] . Some subjects with hypersensitivity or anaphylaxis required interruption or discontinuation of the raxibacumab infusion as well as additional appropriate treatment that included steroids, diphenhydramine, H2 blockers, and/or intravenous fluids [see Adverse Reactions ( 6.1 )] . Due to the risk of anaphylaxis, administer raxibacumab injection in monitored settings where appropriate equipment, medication (including epinephrine) and personnel trained to manage hypersensitivity, anaphylaxis, and shock are available. Monitor patients closely during the infusion and for a period of time after administration. If hypersensitivity reactions or anaphylaxis occur, interrupt or stop the raxibacumab infusion immediately and treat appropriately. Premedicate with diphenhydramine within 1 hour prior to administering raxibacumab to reduce the risk of occurrence and/or severity of a hypersensitivity reaction [see Dosage and Administration ( 2.1 ), Adverse Reactions ( 6.1 )] . Diphenhydramine premedication does not prevent anaphylaxis and may mask or delay the onset of symptoms of hypersensitivity.

7 DRUG INTERACTIONS 7.1 Ciprofloxacin Co-administration of 40 mg/kg raxibacumab intravenously with intravenous or oral ciprofloxacin in human subjects did not alter the PK of either ciprofloxacin or raxibacumab [see Clinical Pharmacology ( 12.3 )] . 7.2 Anthrax Vaccine Adsorbed (AVA) Co-administration of 40 mg/kg raxibacumab intravenously (Day 1) with a SC AVA regimen (Days 1, 15, and 29) did not affect the immunogenicity of AVA [see Clinical Pharmacology ( 12.3 )] .

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.

8.1 Pregnancy Risk Summary There are no data on the use of raxibacumab in pregnant women to inform on drug-associated risk. In pregnant rabbits, intravenous administration of raxibacumab was not associated with teratogenicity or other adverse developmental outcomes at 3 times the human maximum plasma concentrations at the maximum recommended adult dose (see Data) . All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background rate of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk: Limited data in the form of case reports of anthrax infection in pregnant women indicate that maternal infection is associated with a high risk of maternal, fetal, and neonatal deaths, particularly in the absence of treatment. Data Animal Data: A study was conducted in pregnant, healthy New Zealand White rabbits administered intravenous raxibacumab at dose levels of 40 or 120 mg/kg on Gestation Days 7 and 14. No teratogenicity or other adverse developmental outcomes were observed in pregnant rabbits at 3 times the human maximum plasma concentrations at the maximum recommended adult dose of 40 mg/kg. Maternal toxicity was observed at both doses (reduced body weight gain late in gestation, but no difference in mean total weight gain).