Obiltoxaximab

1 INDICATIONS AND USAGE ANTHIM ® is a monoclonal antibody directed against the protective antigen of Bacillus anthracis . It is indicated in adult and pediatric patients for treatment of inhalational anthrax due to B. 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 ANTHIM should only be used for prophylaxis when its benefit for prevention of inhalational anthrax outweighs the risk of hypersensitivity and anaphylaxis. ( 1.2 , 5.1 ) The effectiveness of ANTHIM is based solely on efficacy studies in animal models of inhalational anthrax. ( 1.2 , 14 ) There have been no studies of the safety or pharmacokinetics (PK) of ANTHIM in the pediatric population. Dosing in pediatric patients was derived using a population PK approach. ( 1.2 , 8.4 ) ANTHIM does not have direct antibacterial activity. ANTHIM should be used in combination with appropriate antibacterial drugs. ( 1.2 ) ANTHIM is not expected to cross the blood-brain barrier and does not prevent or treat meningitis. ( 1.2 ) 1.1 Inhalational Anthrax ANTHIM is indicated in adult and pediatric patients for the treatment of inhalational anthrax due to Bacillus anthracis in combination with appropriate antibacterial drugs. ANTHIM is indicated for prophylaxis of inhalational anthrax due to B. anthracis when alternative therapies are not available or not appropriate [see Indications and Usage ( 1.2 )] . 1.2 Limitations of Use ANTHIM should only be used for prophylaxis when its benefit for prevention of inhalational anthrax outweighs the risk of hypersensitivity and anaphylaxis [see Warnings and Precautions ( 5.1 )] . The effectiveness of ANTHIM 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 )] . Safety and PK of ANTHIM have been studied in adult healthy volunteers. There have been no studies of safety or PK of ANTHIM in the pediatric population. A population PK approach was used to derive intravenous infusion 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 )] . ANTHIM binds to the protective antigen (PA) component of B. anthracis toxin; it does not have direct antibacterial activity. ANTHIM is not expected to cross the blood-brain barrier and does not prevent or treat meningitis. ANTHIM should be used in combination with appropriate antibacterial drugs.

2 DOSAGE AND ADMINISTRATION Pre-medicate with diphenhydramine. ( 2.1 , 5.1 ) Recommended Dosage of ANTHIM: Adult Patients: 16 mg/kg. ( 2.1 ) Pediatric Patients: ( 2.2 ) ➢ Greater than 40 kg: 16 mg/kg ➢ Greater than 15 kg to 40 kg: 24 mg/kg ➢ Less than or equal to 15 kg: 32 mg/kg Dilute the injection in 0.9% Sodium Chloride Injection, USP, before administering as an intravenous (IV) infusion over 1 hour and 30 minutes. ( 2.3 ) Administer ANTHIM in a monitored setting equipped to manage anaphylaxis. ( 2.4 , 5.1 ) See Full Prescribing Information for instructions on preparation, dilution and administration of ANTHIM injection. ( 2.3 , 2.4 ) 2.1 Dosage for Adult Patients Pre-medicate with diphenhydramine prior to administering ANTHIM [see Warnings and Precautions ( 5.1 )] . Dilute the injection in 0.9% Sodium Chloride Injection, USP, before administering as an intravenous infusion [see Dosage and Administration ( 2.3 )] . The recommended dosage of ANTHIM in adult patients is a single dose of 16 mg/kg administered intravenously over 90 minutes (1 hour and 30 minutes) [see Dosage and Administration ( 2.4 )] . For adult patients weighing less than 40 kg, see Table 1 below. 2.2 Dosage for Pediatric Patients Pre-medicate with diphenhydramine prior to administering ANTHIM [see Warnings and Precautions ( 5.1 )]. Dilute the injection in 0.9% Sodium Chloride Injection, USP, before administering as an intravenous infusion [see Dosage and Administration ( 2.3 )]. The recommended dose for pediatric patients is based on weight as shown in Table 1 below. Table 1. Recommended Pediatric Dose of ANTHIM (weight-based dosing) Body Weight Dose Greater than 40 kg 16 mg/kg Greater than 15 kg to 40 kg 24 mg/kg Less than or equal to 15 kg 32 mg/kg Administer the recommended dose of ANTHIM intravenously over 90 minutes (1 hour and 30 minutes) [see Dosage and Administration ( 2.4 )] . There have been no studies of the safety or PK of ANTHIM conducted in the pediatric population. The dosing recommendations in Table 1 are derived from simulations using a population PK approach designed to match the observed adult exposure to ANTHIM at a 16 mg/kg dose [see Use in Specific Populations ( 8.4 )] . 2.3 Preparation and Dilution for Administration Important Preparation Instructions Keep vials in their cartons prior to preparation of an infusion solution to protect ANTHIM from light. ANTHIM vials contain no preservative. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard the vial if the solution is discolored or contains extraneous particles other than a few translucent-to- white, proteinaceous particles [see Description ( 11 )] . Do not shake the vial. Table 2. ANTHIM Dose, Total Infusion Volume and Infusion Rate by Body Weight Body Weight (weight-based dosing) Total Infusion Volume Infusion Rate Greater than 40 kg or adult (16 mg/kg) Greater than 40 kg 250 mL 167 mL/hr Greater than 15 kg to 40 kg (24 mg/kg) 31 kg to 40 kg 250 mL 167 mL/hr 16 kg to 30 kg 100 mL 67 mL/hr 15 kg or less (32 mg/kg) 11 kg to 15 kg 100 mL 67 mL/hr 5 kg to 10 kg 50 mL 33.3 mL/hr 3.1 kg to 4.9 kg 25 mL 17 mL/hr 2.1 kg to 3 kg 20 mL 13.3 mL/hr 1.1 kg to 2 kg 15 mL 10 mL/hr 1 kg or less 7 mL 4.7 mL/hr Preparation and Dilution in Bag for Infusion Calculate the milligrams of ANTHIM injection needed by multiplying the recommended mg/kg dose in Table 2 by the patient weight in kilograms. Calculate the required volume in milliliters of ANTHIM injection and number of vials needed for the dose by dividing the calculated dose in milligrams (step 1) by the concentration, 100 mg/mL. Each single vial allows delivery of 6 mL of ANTHIM. Select an appropriate size bag of 0.9% Sodium Chloride Injection, USP. Withdraw a volume of solution from the bag equal to the calculated volume in milliliters of ANTHIM in step 2 above. Discard the solution that was withdrawn from the bag. Withdraw the required volume of ANTHIM injection (calculated from step 2) from the ANTHIM vial(s). Discard any unused portion remaining in the ANTHIM vial(s). Transfer the required volume of ANTHIM injection to the selected infusion bag. Gently invert the bag to mix the solution. Do not shake. The prepared solution is stable for 8 hours stored at room temperature 20°C to 25°C (68°F to 77°F) or 8 hours stored in the refrigerator at 2°C to 8°C (36°F to 46°F). Preparation and Dilution in Syringe for Infusion Calculate lunused product. 2.4 Administration Administer ANTHIM in appropriately monitored settings which are equipped to manage anaphylaxis [see Warnings and Precautions ( 5.1 )] . Dilute ANTHIM injection [see Dosage and Administration ( 2.3 )] before administering ANTHIM intravenously using the bag or syringe for infusion. After preparation of the bag or syringe for infusion administer the infusion solution using a 0.22 micron inline filter with the infusion rate described in Table 2 [see Dosage and Administration ( 2.3 )] . Administer diluted ANTHIM intravenous infusion over 1 hour and 30 minutes. Monitor patients closely for signs and symptoms of hypersensitivity throughout the infusion and for a period of time after administration [see Warnings and Precautions ( 5.1 )] . Stop the infusion immediately and treat appropriately, if hypersensitivity or anaphylaxis occurs [see Warnings and Precautions ( 5.1 )] . Flush the line with 0.9% Sodium Chloride Injection, USP at the end of the intravenous infusion.

6 ADVERSE REACTIONS The following clinically important adverse reactions are described elsewhere in the labeling: Hypersensitivity and Anaphylaxis [see Warnings and Precautions ( 5.1 )]. Most frequently reported adverse reactions in healthy adult subjects (≥1.5%) were headache, pruritus, infections of the upper respiratory tract, cough, vessel puncture site bruise, infusion site swelling, nasal congestion, infusion site pain, urticaria and pain in extremity. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Elusys Therapeutics, Inc. at 1-844-808-0222 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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of ANTHIM has been studied only in healthy volunteers. It has not been studied in patients with inhalational anthrax. The safety of ANTHIM was evaluated in 320 healthy subjects treated with one or more 16 mg/kg IV doses in three clinical studies. Study 1 was a placebo-controlled study evaluating a single dose of ANTHIM vs. placebo (210 subjects received ANTHIM, 70 received placebo). Study 2 was a repeat-dose study in which 70 subjects received the first dose, but 34 and 31 subjects received a second dose of ANTHIM in sequences A (2 weeks apart) and B (≥ 4 months apart), respectively. Study 3 was a drug interaction study of a single dose of ANTHIM with ciprofloxacin in 40 subjects (20 subjects received ANTHIM alone and 20 subjects received ANTHIM plus ciprofloxacin for 9 days). Subjects were 18 to 79 years of age, 54% were male, 70% Caucasian, 26% Black/African American, 2% American Indian/Alaska Native, 1% Asian and 10% Hispanic. Adverse Reactions Leading to Discontinuation of ANTHIM Infusion ANTHIM infusion was discontinued in 8/320 healthy subjects (2.5%) in clinical trials due to hypersensitivity reactions or anaphylaxis [see Warnings and Precautions ( 5.1 )] . Most Frequently Reported Adverse Reactions The most frequently reported adverse reactions were headache, pruritus, infections of the upper respiratory tract, cough, vessel puncture site bruise, infusion site swelling, urticaria, nasal congestion, infusion site pain, and pain in extremity. Table 3 shows the adverse reactions that occurred in ≥1.5% of healthy subjects receiving a single dose of ANTHIM (16 mg/kg IV) and more frequently than those receiving placebo. Table 3. Adverse Reactions Reported in ≥1.5% of Healthy Adult Subjects Exposed to a Single Dose of ANTHIM 16 mg/kg IV *Single-dose population: 210 subjects in study 1 plus 70 subjects in the first treatment period of study 2 plus 20 subjects in the ANTHIM alone treatment arm of study 3 Adverse Reactions Placebo N = 70 (%) Single Dose ANTHIM N = 300 * (%) Headache 4 (6%) 24 (8%) Pruritus 1 (1%) 11 (4%) Infections of the upper respiratory tract 2 (3%) 14 (5%) Cough 0 9 (3%) Vessel puncture site bruise 1 (1%) 8 (3%) Infusion site swelling 1 (1%) 8 (3%) Nasal congestion 1 (1%) 5 (2%) Infusion site pain 0 7 (2%) Urticaria 0 5 (2%) Pain in extremity 1 (1%) 5 (2%) Effect of Diphenhydramine on the Incidence of Adverse Reactions Overall in the single-dose population, subjects who received pre-medication with diphenhydramine were less likely to experience adverse reactions with administration of ANTHIM compared to those who did not (42% vs. 58% respectively). Specifically, the incidence of the following adverse reactions was lower in the subjects who received diphenhydramine prior to ANTHIM infusion compared to those who did not: headache (5% vs. 16%), cough (1% vs. 8%), rash (2% vs. 7%), pruritus (3% vs. 4%) throat irritation (0 vs. 3%), rhinorrhea (0 vs. 3%), and infusion site erythema (0% vs. 4%). Somnolence was only reported in subjects who were pretreated with diphenhydramine. Less Common Adverse Reactions Clinically important adverse reactions that were reported in <1.5% of subjects exposed to ANTHIM and at rates higher than in placebo subjects are listed below: General disorders and administration site conditions: chest discomfort/pain, fatigue, pyrexia, intravenous site discoloration Musculoskeletal and connective tissue disorders: myalgia, musculoskeletal pain Respiratory, thoracic and mediastinal disorders: oropharyngeal pain, sinus congestion, rhinorrhea, dysphonia, dyspnea Investigations: lymphocyte count decreased, neutrophil count decreased, white blood count decreased, increased creatine phosphokinase Cardiac disorders: palpitations, cyanosis Neurologic disorders: dizziness Gastrointestinal disorders: vomiting, dry mouth 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The development of anti-ANTHIM antibodies was evaluated in all subjects receiving single and double doses of ANTHIM in studies 1, 2 and 3. Eight subjects (2.5%) who received at least one dose of IV ANTHIM were positive for a treatment-emergent anti-therapeutic antibody (ATA) response. Quantitative titers were low ranging from 1:20 – 1:320. There was no evidence of altered PK or toxicity profile in subjects with ATA development. 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 incidence of antibodies to obiltoxaximab with the incidence of antibodies to other products may be misleading.

12.3 Pharmacokinetics The PK of obiltoxaximab are linear over the dose range of 4 mg/kg (0.25 times the lowest recommended dose) to 16 mg/kg following single IV administration in healthy subjects. Following single IV administration of ANTHIM 16 mg/kg in healthy, male and female human subjects, the mean C max and AUC inf were 400 ± 91.2 mcg/mL and 5170 ± 1360 mcg•day/mL, respectively. Repeat Dosing Although ANTHIM is intended for single dose administration, the PK of obiltoxaximab following a second dose administration of 16 mg/kg IV given 2 weeks or ≥ 4 months after the first 16 mg/kg IV dose was assessed in 65 healthy subjects (study 2). The obiltoxaximab AUC inf following two 16 mg/kg doses 2 weeks apart was approximately twice that after a single 16 mg/kg dose on Day 1 or Day 120. No significant differences in mean estimates of C max , AUC inf , CL, or half-life of obiltoxaximab between the 2 doses administered ≥4 months apart were observed. Distribution Mean obiltoxaximab steady-state volume of distribution was greater than plasma volume, suggesting some tissue distribution. Elimination Clearance values were much smaller than the glomerular filtration rate, indicating that there is virtually no renal clearance of obiltoxaximab. Because the effectiveness of ANTHIM cannot be evaluated in humans, a comparison of ANTHIM exposures achieved in healthy human subjects to those observed in animal models of inhalational anthrax in therapeutic efficacy studies is necessary to support the dosage regimen of 16 mg/kg IV as a single dose for the treatment of inhalational anthrax in humans. Based on observed and simulated data, humans achieve similar obiltoxaximab C max and greater AUC inf following a single 16 mg/kg IV dose compared to exposures achieved in NZW rabbits and cynomolgus macaques. Specific Populations Gender, Age, and Race ANTHIM PK were evaluated via a population PK analysis using serum samples from 303 healthy adult subjects who received a single IV dose across 3 clinical trials. Based on this analysis, gender (female versus male), race (non-Caucasian versus Caucasian), or age (elderly versus young) had no meaningful effects on the PK parameters for ANTHIM. Pediatric Population ANTHIM PK have not been evaluated in children [see Dosage and Administration ( 2.2 ) and Use in Specific Populations ( 8.4 )]. Drug Interaction Studies Ciprofloxacin In an open-label study evaluating the effect of ciprofloxacin on obiltoxaximab PK in healthy adult male and female subjects (study 3), the administration of 16 mg/kg ANTHIM IV infusion prior to ciprofloxacin IV infusion or ciprofloxacin oral tablets twice daily did not alter the PK of obiltoxaximab. Likewise, obiltoxaximab did not alter the PK of ciprofloxacin administered orally and/or intravenously [see Drug Interactions ( 7.1 )] .