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.

2.1 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.

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.

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

3.

Select an appropriate size syringe for the total volume of infusion to be administered, as described in Table 2.

4.

Using the selected syringe, withdraw the volume of raxibacumab as calculated in Step 2.

5.

Withdraw an appropriate amount of compatible solution to prepare a total volume infusion syringe as specified in Table 2.

6.

Gently mix the solution. Do not shake.

7.

Discard any unused portion remaining in the raxibacumab vial(s).

8.

The prepared solution is stable for 8 hours stored at room temperature.

Infusion Bag Preparation

3.

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.

4.

Withdraw the required volume of raxibacumab injection from the raxibacumab vial(s).

5.

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.

6.

Discard any unused portion remaining in the raxibacumab vial(s).

7.

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.

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.

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).

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.

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.

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)].

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).

8.2 Lactation

Risk Summary

There is no information available on the presence of raxibacumab 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 developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for raxibacumab and any potential adverse effects on the breastfed child from raxibacumab or from the underlying maternal condition.

8.4 Pediatric Use

As in adults, the effectiveness of raxibacumab in pediatric patients is based solely on efficacy studies in animal models of inhalational anthrax. As exposure of healthy children to raxibacumab is not ethical, 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 receiving 40 mg/kg. The dose for pediatric patients is based on weight [see Dosage and Administration (2.2)].

Safety or PK of raxibacumab have not been studied in the pediatric population.

8.5 Geriatric Use

Clinical trials of raxibacumab did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Of the total number of subjects in clinical trials of raxibacumab, 6.4% (21/326) were 65 years and older, while 1.5% (5/326) were 75 years and older. However, no alteration of dosing is needed for patients aged 65 years and older [see Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

Raxibacumab is a monoclonal antibody that binds the protective antigen of B. anthracis [see Microbiology (12.4)].

12.3 Pharmacokinetics

The PK of raxibacumab is linear over the dose range of 1 to 40 mg/kg following single intravenous dosing in humans; raxibacumab was not tested at doses higher than 40 mg/kg in humans. Following single intravenous administration of raxibacumab 40 mg/kg in healthy male and female human subjects, the mean Cmax and AUCinf were 1,020.3 ± 140.6 mcg/mL and 15,845.8 ± 4,333.5 mcg•day/mL, respectively. Mean raxibacumab steady-state volume of distribution was greater than plasma volume, suggesting some tissue distribution. Clearance values were much smaller than the glomerular filtration rate indicating that there is virtually no renal clearance of raxibacumab.

Because the effectiveness of raxibacumab cannot be tested in humans, a comparison of raxibacumab 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 40 mg/kg intravenously as a single dose for the treatment of inhalational anthrax in humans. Humans achieve similar or greater systemic exposure (Cmax and AUCinf) to raxibacumab following a single 40 mg/kg intravenous dose compared with New Zealand White rabbits and cynomolgus macaques receiving the same dosage regimen.

Effects of Gender, Age, and Race

Raxibacumab PK was evaluated via a population PK analysis using serum samples from 322 healthy subjects who received a single 40 mg/kg intravenous dose across 3 clinical trials. Based on this analysis, gender (female versus male), race (non-white versus white), or age (elderly versus young) had no meaningful effects on the PK parameters for raxibacumab.

Raxibacumab PK has not been evaluated in children [see Dosage and Administration (2.2), Use in Specific Populations (8.4)].

Repeat Dosing

Although raxibacumab is intended for single-dose administration, the PK of raxibacumab following a second administration of 40 mg/kg given intravenously 14 days after the first 40 mg/kg intravenous dose was assessed in 23 healthy subjects (Trial 3). The mean raxibacumab concentration at 28 days after the second dose was approximately twice the mean raxibacumab concentration at 14 days following the first dose. In the human trial assessing the immunogenicity of raxibacumab (Trial 2), 20 healthy subjects who had initially received a single dose of raxibacumab 40 mg/kg intravenously received a second 40 mg/kg intravenous dose at ≥4 months following their first dose. No statistically significant differences in mean estimates of AUCinf, CL, or half-life of raxibacumab between the 2 doses administered ≥4 months apart were observed. The mean Cmax following the second dose was 15% lower than the Cmax following the first dose.

Ciprofloxacin Interaction Trial

In an open-label trial evaluating the effect of raxibacumab on ciprofloxacin PK in healthy adult male and female subjects (Trial 1), the administration of 40 mg/kg raxibacumab intravenously following ciprofloxacin intravenous infusion or ciprofloxacin oral tablet ingestion did not alter the PK of ciprofloxacin administered orally and/or intravenously. Likewise, ciprofloxacin did not alter the PK of raxibacumab [see Drug Interactions (7.1)].

Co-Administration with AVA Trial

The effect of a single 40 mg/kg infusion of raxibacumab on the immunogenicity of a three-dose regimen of AVA administered (SC) was assessed in an open-label randomized trial in healthy adult male and female subjects (Trial 4). The trial included two treatment arms. 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. In the AVA-alone arm, these SC AVA doses were administered on Days 1, 15 and 29. Overall immune response to AVA in the combination arm was found to be similar to the AVA-alone arm.

12.4 Microbiology

Mechanism of Action

Raxibacumab is a monoclonal antibody that binds free PA with an affinity equilibrium dissociation constant (Kd) of 2.78 ± 0.9 nM. Raxibacumab 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

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

In vivo studies in rats suggest that raxibacumab neutralizes the toxicity due to lethal toxin, as animals slowly infused with lethal toxin (a combination of PA + lethal factor) survived 7 days following administration. The median time to death in control rats was 16 hours. Similar observations were noted in animal efficacy studies in rabbits and monkeys challenged with B. anthracis spores by the inhalational route. PA was detected in animals following exposure to B. anthracis spores. PA levels rose and then fell to undetectable levels in animals that responded to treatment and survived, whereas levels continued to rise in animals that failed treatment and died or were euthanized because of poor clinical condition [see Clinical Studies (14.1)].

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

13.2 Animal Toxicology

Healthy cynomolgus macaques administered 3 intravenous doses or 3 SC doses of 40 mg/kg raxibacumab once every 12 days, or a single intramuscular dose (40 mg/kg) of raxibacumab, showed no adverse effects, including no effects up to 120 days post-dosing.

Studies with raxibacumab in rabbit, cynomolgus macaque, and human donor tissues showed no cross reactivity with brain.

Anthrax-infected rabbits and monkeys administered an intravenous injection of raxibacumab (40 mg/kg) at time of PA toxemia reproducibly showed greater severity of central nervous system (CNS) lesions (bacteria, inflammation, hemorrhage, and necrosis) in non-surviving animals compared with dead placebo-control animals, with no difference in mean time to death from spore challenge. The raxibacumab monoclonal antibody appears unable to penetrate the CNS until compromise of the blood-brain barrier (BBB) during the later stages of anthrax infection. The most severe brain lesions in rabbits were associated with bacteria and raxibacumab tissue binding in a similar pattern as endogenous IgG antibody that leaked across the compromised BBB. No dose/exposure-response relationship for brain histopathology was identified. Surviving rabbits and monkeys at the end of the 28-day studies showed no microscopic evidence of CNS lesions. CNS toxicity was not observed in healthy monkeys administered raxibacumab (40 mg/kg) or in GLP combination treatment studies with antibacterials in rabbits (levofloxacin) or in monkeys (ciprofloxacin) at any time.

14.1 Treatment of Inhalational Anthrax in Combination with Antibacterial Drug

The efficacy of raxibacumab administered with levofloxacin as treatment of animals with systemic anthrax disease (84 hours after spore challenge) was evaluated in New Zealand White rabbits (Study 1). The dose of levofloxacin was chosen to yield a comparable exposure to that achieved by the recommended doses in humans. Levofloxacin and raxibacumab PK in this study were unaffected by product co-administration. Forty-two percent of challenged animals survived to treatment. Treatment with antibacterial drug plus raxibacumab resulted in 82% survival compared with 65% survival in rabbits treated with antibacterial drug alone, P = 0.0874 (Table 5).

14.2 Post-Exposure Prophylaxis/Early Treatment of Inhalational Anthrax

Monkey Study 2 and rabbit Studies 3 and 4 evaluated treatment with raxibacumab alone at an earlier time point after exposure than rabbit Study 1. Treatment with raxibacumab alone resulted in a statistically significant dose-dependent improvement in survival relative to placebo when administered at the time of initial manifestations of anthrax disease in the rabbit and monkey infection models (Table 6). Raxibacumab at 40 mg/kg intravenous single dose was superior to placebo in the rabbit and monkey studies in the all-treated and the bacteremic animal analysis populations. All surviving animals developed toxin-neutralizing antibodies.

In other animal studies evaluating antibacterial drug alone and raxibacumab-antibacterial drug combination, the efficacy of an antibacterial drug alone (levofloxacin in rabbits and ciprofloxacin in monkeys) was very high (95% to 100%) when given at the initial manifestations of inhalational anthrax disease. The timing of treatment was similar to that reported for Studies 2, 3, and 4 above.

In another study, rabbits were exposed to 100 times LD50 B. anthracis spores and administered raxibacumab at a single dose of 40 mg/kg at the time of exposure, 12 hours, 24 hours, or 36 hours after exposure. Survival was 12/12 (100%) in animals treated at time of exposure or at 12 hours but decreased to 6/12 (50%) and 5/12 (42%) at 24 hours and 36 hours, respectively.

Efficacy Based on Animal Models

Inform patients that the efficacy of raxibacumab is based solely on efficacy studies demonstrating a survival benefit in animals and that the effectiveness of raxibacumab has not been tested in humans with anthrax. The safety of raxibacumab has been tested in healthy adults, but no safety data are available in children or pregnant women. Limited data are available in geriatric patients [see Use in Specific Populations (8.5)].

Hypersensitivity Reactions and Anaphylaxis

Inform patients that hypersensitivity reactions, including anaphylaxis, have occurred with the administration of raxibacumab. Inform patients of the signs and symptoms of hypersensitivity and anaphylaxis and instruct patients to seek immediate medical care if they experience such symptoms during or following administration of raxibacumab.

Prophylactic administration of diphenhydramine is recommended within 1 hour prior to administering raxibacumab to reduce the risk of occurrence and/or the severity of hypersensitivity reactions [see Warnings and Precautions (5.1)].

Manufactured by

Emergent Manufacturing Operations Baltimore LLC

Baltimore, MD 21224

U.S. License No. 2083

Emergent BioSolutions Inc.

Any and all Emergent BioSolutions Inc. brand, product, service and feature names, logos and slogans are trademarks or registered trademarks of Emergent BioSolutions Inc. or its subsidiaries in the United States or other countries. All rights reserved.