Anthim

Anthim is a prescription medication used to treat inhalational anthrax. Anthim is also approved to prevent inhalational anthrax when alternative therapies are not available or not appropriate. Anthim belongs to a group of drugs called monoclonal antibodies. It works to neutralize the toxins produced by B. anthracis. 

Anthim is available as an injection and is administered by a healthcare provider. 

Common side effects of Anthim include headache, itching, and upper respiratory tract infections. 

Obiltoxaximab is a chimeric IgG1 kappa monoclonal antibody that binds the protective antigen (PA) component of Bacillus anthracis toxin.1

General

Obiltoxaximab is available in the following dosage form(s) and strength(s):

Injection: 600 mg/6 mL (100 mg/mL) solution in single-dose vial.1

Obiltoxaximab is stored in the US Strategic National Stockpile (SNS). FDA-approved vial and carton labeling and separate NDC numbers distinguish stockpile units of the drug from any units intended for commercial use.1 2

Dosage

It is essential that the manufacturer’s labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

• Premedicate with diphenhydramine.1

• Administer in a monitored setting equipped to manage anaphylaxis.1

• Dilute in 0.9% Sodium Chloride Injection, USP, as directed by the manufacturer and administer as an intravenous (IV) infusion over 1 hour and 30 minutes.1

• Adults:16 mg/kg.1

• Pediatric Patients Greater than 40 kg: 16 mg/kg.1

• Pediatric Patients Greater than 15 kg to 40 kg: 24 mg/kg.1

• Pediatric Patients Less than or equal to 15 kg: 32 mg/kg.1

Contraindications

None.1

Warnings/Precautions

Hypersensitivity and Anaphylaxis

Hypersensitivity reactions were the most common adverse reactions in the safety trials of obiltoxaximab, 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. Obiltoxaximab 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.1

Due to the risk of anaphylaxis, obiltoxaximab 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. If anaphylaxis or hypersensitivity reactions occur, stop the infusion immediately and treat appropriately.1

Premedication with diphenhydramine is recommended prior to administration of obiltoxaximab. Diphenhydramine premedication does not prevent anaphylaxis, and may mask or delay onset of symptoms of hypersensitivity.1

Specific Populations

Pregnancy Category B.

No adequate and well-controlled studies in pregnant women were conducted. Because animal reproduction studies are not always predictive of human response, obiltoxaximab should be used during pregnancy only if clearly needed.1

A single embryonic-fetal development study was conducted in pregnant, healthy New Zealand White (NZW) rabbits administered 4 intravenous doses of obiltoxaximab up to 32 mg/kg (2 times the human dose on a mg/kg basis) on gestation days 6, 10, 13, and 17. No evidence of harm to the pregnant dam or the fetuses due to obiltoxaximab was observed. Cumulative exposures in NZW rabbits (10,000 mcg•day/mL) at the NOAEL of 32 mg/kg/dose (n=4 doses) based on AUC0-15 days were approximately two-fold the human male and female combined mean AUC at the clinical intravenous dose of 16 mg/kg. Cmax values following a 32 mg/kg/dose were 1180 mcg•day/mL.1

Obiltoxaximab has not been evaluated in nursing women. Although human immunoglobulins are excreted in human milk, published data suggest that neonatal consumption of human milk does not result in substantial absorption of these maternal immunoglobulins into circulation. Inform a nursing woman that the effects of local gastrointestinal and systemic exposure to obiltoxaximab on nursing infant are unknown.1

As in adults, the effectiveness of obiltoxaximab in pediatric patients is based solely on efficacy studies in animal models of inhalational anthrax. As exposure of healthy children to obiltoxaximab 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.1

There have been no studies of safety or PK of obiltoxaximab in the pediatric population.1

Clinical studies of obiltoxaximab 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 obiltoxaximab, 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.1

Common Adverse Effects

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.1

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

In the U.S.

• Anthim

Available Dosage Forms:

• Solution

Pharmacologic Class: Monoclonal Antibody

Injection: 600 mg/6 mL (100 mg/mL) in a single-dose vial.

Anthim is a clear to opalescent, colorless to pale yellow to pale brownish-yellow solution and may contain few translucent-to-white proteinaceous particulates.

None.

Obiltoxaximab is a chimeric IgG1 kappa monoclonal antibody (mAb) that binds the PA component of B. anthracis toxin. It has an approximate molecular weight of 148 kDa.

Anthim injection is a sterile, preservative-free, clear to opalescent, colorless to pale yellow to pale brownish-yellow solution that may contain few translucent-to-white proteinaceous particulates. Anthim is supplied as 600 mg/6 mL in single-dose vials for intravenous infusion. Each mL contains 100 mg obiltoxaximab in L-histidine (6.2 mg), polysorbate 80 (0.1 mg), sorbitol (36 mg) with a pH of 5.5.

Mechanism of Action

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

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)].

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)].