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.

2.1 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.

• 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.

Preparation and Dilution in Bag for Infusion

1. Calculate the milligrams of ANTHIM injection needed by multiplying the recommended mg/kg dose in Table 2 by the patient weight in kilograms.
2. 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.
3. 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.
4. 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).
5. Transfer the required volume of ANTHIM injection to the selected infusion bag.
6. Gently invert the bag to mix the solution. Do not shake.
7. 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

1. Calculate the milligrams of ANTHIM injection needed by multiplying the recommended mg/kg dose in Table 2 by the patient weight in kilograms.
2. 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.
3. Select an appropriate size syringe for the total volume of infusion to be administered.
4. Using the selected syringe, withdraw the required volume of ANTHIM injection (calculated from step 2). Discard any unused portion remaining in the ANTHIM vial(s).
5. Withdraw an appropriate amount of 0.9% Sodium Chloride Injection, USP to prepare the total infusion volume specified in Table 2.
6. Gently mix the solution. Do not shake.
7. Once a diluted solution of ANTHIM has been prepared, administer immediately. Do not store solution in syringe. Discard unused 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.

5.1 Hypersensitivity and Anaphylaxis

Hypersensitivity reactions were the most common adverse reactions in the safety trials of ANTHIM, occurring in 34/320 healthy subjects (10.6%). Three (0.9%) cases of anaphylaxis occurred during or immediately after the infusion. In clinical trials, manifestations of anaphylaxis were rash/urticaria, cough, dyspnea, cyanosis, postural dizziness and chest discomfort. ANTHIM infusion was discontinued in 8 (2.5%) subjects due to hypersensitivity or anaphylaxis. The adverse reactions reported in these 8 subjects included urticaria, rash, cough, pruritus, dizziness, throat irritation, dysphonia, dyspnea and chest discomfort. The remaining subjects with hypersensitivity had predominantly skin-related symptoms such as pruritus and rash, and 6 subjects reported cough [see Adverse Reactions 6.1].

Due to the risk of anaphylaxis, ANTHIM should be administered in monitored settings by personnel trained and equipped to manage anaphylaxis. Patients should be monitored closely throughout the infusion period and for a period of time after administration [see Patient Counseling Information (17)]. If anaphylaxis or hypersensitivity reactions occur, stop the infusion immediately and treat appropriately.

Premedication with diphenhydramine is recommended prior to administration of ANTHIM [see Dosage and Administration (2.1) and Adverse Reactions (6.1)]. Diphenhydramine premedication does not prevent anaphylaxis, and may mask or delay onset of symptoms of hypersensitivity.

6.1 Clinical Trial 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.

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 significant 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.

7.1 Ciprofloxacin

Co-administration of 16 mg/kg ANTHIM intravenously with intravenous or oral ciprofloxacin in human subjects did not alter the PK of either ciprofloxacin or obiltoxaximab [see Clinical Pharmacology (12.3)].

8.1 Pregnancy

Risk Summary
There are no data on the use of ANTHIM in pregnant women to inform on drug-associated risk. There are adverse effects on maternal and fetal outcomes associated with anthrax in pregnancy (see Clinical Considerations). In pregnant rabbits, intravenous administration of obiltoxaximab during organogenesis was not associated with adverse developmental outcomes at up to 0.62 times the human systemic exposure at the maximum recommended adult dose (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

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 obiltoxaximab at dose levels of 16 or 32 mg/kg during organogenesis on Gestation Days 6, 10, 13 and 17. No maternal toxicity or adverse developmental outcomes were observed at the highest tested dose, 32 mg/kg. In those rabbits, mean maternal maximum plasma concentration (Cmax = 1180 mcg/mL) and mean maternal AUCinf (3220 mcg•day/mL) were approximately 3 times and 0.62 times the respective values for Cmax and AUC reported in clinical trial subjects at the maximum recommended adult dose of 16 mg/kg.

8.2 Lactation

Risk Summary
There is no information available on the presence of obiltoxaximab in human milk, the effects on the breastfed child, or the effects on milk production. Maternal IgG is known to be present in human milk. Therefore, the development and health benefits of breastfeeding should be considered along with the mother’s clinical need for ANTHIM and any potential adverse effects on the breastfed child from ANTHIM or from the underlying maternal condition.

8.4 Pediatric Use

As in adults, the effectiveness of ANTHIM in pediatric patients is based solely on efficacy studies in animal models of inhalational anthrax. As exposure of healthy children to ANTHIM is not ethical, a population PK approach was used to derive intravenous dosing regimens that are predicted to provide pediatric patients with exposure comparable to the observed exposure in adults receiving 16 mg/kg. The dose for pediatric patients is based on weight [see Dosage and Administration (2.2)].

There have been no studies of safety or PK of ANTHIM in the pediatric population.

8.5 Geriatric Use

Clinical studies of ANTHIM did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Of the 320 subjects in clinical studies of ANTHIM, 9.4% (30/320) were 65 years and over, while 2% (6/320) were 75 years and over. No alteration of dosing is needed for patients ≥65 years of age [see Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

Obiltoxaximab is a monoclonal antibody that binds the PA of B. anthracis[see Microbiology (12.4)].

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 Cmax and AUCinf 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 AUCinf 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 Cmax, AUCinf, 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 Cmax and greater AUCinf 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)].

12.4 Microbiology

Mechanism of Action
Obiltoxaximab is a monoclonal antibody that binds free PA with an affinity equilibrium dissociation constant (Kd) of 0.33 nM. Obiltoxaximab inhibits the binding of PA to its cellular receptors, preventing the intracellular entry of the anthrax lethal factor and edema factor, the enzymatic toxin components responsible for the pathogenic effects of anthrax toxin.

Activity In Vitro and In Vivo
Obiltoxaximab binds in vitro to PA from the Ames, Vollum, and Sterne strains of B. anthracis. Obiltoxaximab binds to an epitope on PA that is conserved across reported strains of B. anthracis.

In vitro studies in a cell-based assay, using murine macrophages, suggest that obiltoxaximab neutralizes the toxic effects of lethal toxin, a combination of PA + lethal factor.

In vivo efficacy studies in NZW rabbits and cynomolgus macaques challenged with the spores of the Ames strain of B. anthracis by the inhalational route, showed a dose-dependent increase in survival following treatment with ANTHIM. Exposure to B. anthracis spores resulted in increasing concentrations of PA in the serum of NZW rabbits and cynomolgus macaques. After treatment with ANTHIM there was a decrease in PA concentrations in a majority of surviving animals. PA concentrations in placebo animals increased until they died [see Clinical Studies (14)].

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity, genotoxicity, and fertility studies have not been conducted with obiltoxaximab.

13.2 Animal Toxicology and/or Pharmacology

Central nervous system (CNS) lesions (bacteria, inflammation, hemorrhage and occasionally necrosis) were seen in anthrax-infected non-surviving NZW rabbits and cynomolgus macaques administered IV obiltoxaximab (≥4 mg/kg) or control at the time of disease confirmation. Microscopic changes in the non-surviving animals that received obiltoxaximab were due to the presence of extravascular bacteria and not the effect of obiltoxaximab. No dose response relationship for brain histopathology was identified. No treatment-related brain lesions were shown in anthrax-infected surviving NZW rabbits (at day 28) or cynomolgus macaques (up to day 56) after a single administration of obiltoxaximab at doses up to 16 mg/kg and up to 32 mg/kg/dose, respectively. No obiltoxaximab-related neurobehavioral effects were observed in surviving anthrax-infected cynomolgus macaques following treatment with obiltoxaximab.