Anthim

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 ].

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 ].

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 ].

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 ].

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.

Dosage for Adult Patients

• Pre-medicate with diphenhydramine prior to administering ANTHIM [see Warnings and Precautions ].
• Dilute the injection in 0.9% Sodium Chloride Injection, USP, before administering as an intravenous infusion [see Dosage and Administration ].
• 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 ].
• For adult patients weighing less than 40 kg, see Table 1 below.

Dosage for Pediatric Patients

• Pre-medicate with diphenhydramine prior to administering ANTHIM [see Warnings and Precautions ].
• Dilute the injection in 0.9% Sodium Chloride Injection, USP, before administering as an intravenous infusion [see Dosage and Administration ].
• 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 ].

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 ].

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.

Administration

• Administer ANTHIM in appropriately monitored settings which are equipped to manage anaphylaxis [see Warnings and Precautions ].
• Dilute ANTHIM injection [see Dosage and Administration ] 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 ].
• 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 ].
• Stop the infusion immediately and treat appropriately, if hypersensitivity or anaphylaxis occurs [see Warnings and Precautions ].
• Flush the line with 0.9% Sodium Chloride Injection, USP at the end of the intravenous infusion.

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.

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.

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 ].

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

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 ].