2.1 Dose

The initial dose of ANTHRASIL for the treatment of inhalational anthrax in adults in combination with appropriate antimicrobial therapy is 420 units (seven vials). Data in animal models suggest that administration of higher doses may result in improved survival [See 13.2 Animal Toxicology and/or Pharmacology]. An initial dose of 840 units (14 vials) may be considered, depending on the clinical status of the patient.

Depending on the severity of symptoms and the response to treatment, consider an initial dose of 840 units (14 vials) and repeat dosing especially in patients experiencing substantial hemorrhage as reflected in large transfusion requirements, patients with significant compartmental fluid losses such as from large volume and/or repeated therapeutic thoracentesis and/or abdominal paracentesis, and in patients whose own immune response may be impaired/delayed. Take the magnitude of ongoing blood and fluid losses and the clinical status of the patient into account in determining the time interval between doses when repeat doses are administered. Repeated dosing and single doses greater than 840 units in humans have not been studied. Without substantially delaying therapy, give consideration to performing therapeutic thoracentesis and/or abdominal paracentesis as indicated prior to or concurrently with administration of ANTHRASIL.

2.2 Preparation and Administration

Each vial of ANTHRASIL has a minimum potency of ≥60 units per vial [See 3 DOSAGE FORMS AND STRENGTHS].

1.

Bring ANTHRASIL vials to room temperature.

•

Thaw frozen vials rapidly for immediate use by placing at room temperature for one hour followed by a water bath at 37°C (98.6°F) until thawed.

•

Alternatively, thaw vials by placing the required number of vials in a refrigerator at 2 to 8°C (36 to 46°F) until the vials are thawed (approximately 14 hours).

•

Do not thaw in a microwave oven. Do not refreeze vials.

•

Bring thawed vials to room temperature by letting sit on a bench for a few minutes prior to infusion.

2.

Inspect vials to ensure the product is fully thawed and free from discoloration and particulate matter. The solution should be clear or slightly opalescent. Do not use solutions that are cloudy, turbid or have particulates.

3.

Inspect vials to ensure there is no damage to the seal or vial. If damaged, do not use and contact the manufacturer.

4.

Gently swirl upright vials by hand to ensure uniformity. Do not shake the vial during preparation to avoid foaming.

5.

Follow the steps below to prepare the ANTHRASIL infusion bag:

•

Remove the protective caps from the product vials.

•

Wipe the exposed central portion of the rubber stopper with an isopropyl alcohol swab.

•

Withdraw the vial contents of ANTHRASIL into a syringe, aseptically transfer into an appropriately sized intravenous bag and label with the volume to be infused.

•

No further dilution is required.

•

Once punctured, use the vial contents to prepare the infusion bag and administer as soon as possible. ANTHRASIL contains no preservative.

6.

Administer in an intravenous line with constant infusion pump. Use of an in-line filter is optional.

7.

If adverse reactions occur, such as flushing, headache, nausea, changes in pulse rate or blood pressure, slow the rate of infusion or temporarily stop the infusion.

ANTHRASIL vials are for single use only. Discard any unused portion.

5.1 Hypersensitivity Reactions

Hypersensitivity reactions may occur with ANTHRASIL.

Administer ANTHRASIL in a setting where appropriate equipment, medication (including epinephrine) and personnel trained in the management of hypersensitivity, anaphylaxis and shock are available.

Monitor all patients for signs and symptoms of acute allergic reactions (e.g. urticaria, pruritus, erythema, angioedema, bronchospasm with wheezing or cough, stridor, laryngeal edema, hypotension, tachycardia) during and following the ANTHRASIL infusion. In case of severe hypersensitivity reactions, discontinue the administration of ANTHRASIL immediately and administer appropriate emergency care.

ANTHRASIL contains trace amounts of IgA (less than or equal to 40 mcg per mL). Patients with known antibodies to IgA may have greater risk of developing severe hypersensitivity and anaphylactic reactions. ANTHRASIL is contraindicated in patients with antibodies against IgA and a history of hypersensitivity reaction [See 4 CONTRAINDICATIONS].

5.2 Interference with Blood Glucose Testing

ANTHRASIL contains maltose. Maltose has been shown to give falsely high blood glucose levels in certain types of blood glucose testing systems (for example, by systems based on glucose dehydrogenase pyrroloquinolinequinone (GDH‑PQQ) or glucose‑dye-oxidoreductase methods). Due to the potential for falsely elevated glucose readings (or falsely normal glucose readings when hypoglycemia is present), only use testing systems that are glucose‑specific to test or monitor blood glucose levels in patients receiving ANTHRASIL.

Review the product information of the blood glucose testing system, including that of the test strips, to determine if the system is appropriate for use with maltose-containing parenteral products. If any uncertainty exists, contact the manufacturer of the testing system to determine if the system is appropriate for use with maltose-containing parenteral products.

5.3 Thrombosis

Thrombosis may occur following treatment with immune globulin products, including ANTHRASIL [See BOXED WARNING]. Risk factors include cardiovascular risk factors, advanced age, impaired cardiac output, hypercoagulable disorders, prolonged periods of immobilization, history of arterial or venous thrombosis, estrogen use, indwelling central vascular catheters, and/or known or suspected hyperviscosity. Thrombosis may occur in the absence of known risk factors. Weigh the potential risks and benefits of ANTHRASIL against those of alternative therapies for all patients for whom ANTHRASIL administration is being considered.

Because of the potentially increased risk of thrombosis, consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies.

In patients with risk factors where the benefits of ANTHRASIL administration out-weigh the potential risks of thrombosis, administer ANTHRASIL at the minimum rate of infusion practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis.

5.4 Acute Renal Dysfunction/Failure

Acute renal dysfunction, acute renal failure, osmotic nephropathy, acute tubular necrosis, proximal tubular nephropathy, and death may occur upon use of immune globulin intravenous products, including ANTHRASIL. Use ANTHRASIL with caution in patients with any degree of pre-existing renal insufficiency and in patients at risk of developing renal insufficiency (including, but not limited to those with diabetes mellitus, age greater than 65 years, volume depletion, paraproteinemia, sepsis, and patients receiving known nephrotoxic drugs), administering at the minimum rate of infusion practicable. Ensure that patients are not volume depleted before ANTHRASIL infusion. Do not exceed the recommended infusion rate, and follow the infusion schedule closely. Periodic monitoring of renal function and urine output is important in patients judged to be at increased risk of developing acute renal failure. Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of ANTHRASIL and at appropriate intervals thereafter. If renal function deteriorates, consider discontinuing ANTHRASIL.

Most cases of renal insufficiency following administration of immune globulin products have occurred in patients receiving total doses containing 400 mg per kg of sucrose or greater. ANTHRASIL does not contain sucrose.

5.5 Infusion Rate Precautions

Adverse reactions (such as chills, fever, headache, nausea and vomiting) may be related to the rate of infusion. Follow closely the recommended infusion rate given under 2.1 Dose. Closely monitor and carefully observe patients and their vital signs for any symptoms throughout the infusion period and immediately following an infusion.

5.6 Hemolysis

Hemolytic anemia and hemolysis may develop subsequent to ANTHRASIL administration. ANTHRASIL may contain blood group antibodies that may act as hemolysins and induce in vivo coating of red blood cells with immune globulin, causing a positive direct antiglobulin reaction and hemolysis. Acute hemolysis, including intravascular hemolysis, has been reported following immune globulin administration and delayed hemolytic anemia can develop due to enhanced red blood cell sequestration. Severe hemolysis may lead to renal dysfunction/failure.

The following risk factors may be associated with the development of hemolysis: high doses (e.g., >2 g per kg), given either as a single administration or divided over several days, and non-O blood group (1). Other individual patient factors, such as an underlying inflammatory state (as may be reflected by, for example, elevated C-reactive protein or erythrocyte sedimentation rate), have been hypothesized to increase the risk of hemolysis (2), but their role is uncertain.

Monitor ANTHRASIL recipients for clinical signs and symptoms of hemolysis. Consider appropriate laboratory testing in higher risk patients, including measurement of hemoglobin or hematocrit prior to infusion and within approximately 36 to 96 hours and again approximately seven to 10 days post infusion. If signs and/or symptoms of hemolysis or a significant drop in hemoglobin or hematocrit have been observed after infusion, perform additional confirmatory laboratory testing.

5.7 Aseptic Meningitis Symptom (AMS)

AMS may occur in association with administration of immune globulin products, including ANTHRASIL. AMS usually is associated with high total doses (>2 g per kg) and begins within several hours to two days following treatment. Discontinuation of treatment has resulted in remission of AMS within several days without sequelae.

AMS is characterized by the following symptoms and signs: severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, and nausea and vomiting. Cerebrospinal fluid (CSF) studies are frequently positive with pleocytosis up to several thousand cells per cubic millimeter, predominately from the granulocytic series, and with elevated protein levels up to several hundred mg per dL, but negative culture results. Conduct a detailed neurological examination in patients exhibiting such symptoms and signs, including CSF studies, to rule out other causes of meningitis (particularly anthrax meningitis).

5.8 Monitoring: Laboratory Tests

•

Consider periodic monitoring of renal function and urine output in patients judged to be at increased risk of developing acute renal failure. Assess renal function, including measurement of BUN and serum creatinine, before the initial infusion of ANTHRASIL and at appropriate intervals thereafter.

•

Because of the potentially increased risk of thrombosis, consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies.

•

If signs and/or symptoms of hemolysis are present after an infusion of ANTHRASIL, perform appropriate laboratory testing for confirmation.

If TRALI is suspected, perform appropriate tests for the presence of anti-HLA and anti-neutrophil antibodies in the product. TRALI may be managed using oxygen therapy with adequate ventilator support.

5.9 Interference with Laboratory Tests

ANTHRASIL contains maltose, which can be misinterpreted as glucose by certain types of blood glucose testing systems (for example, those based on the GDH-PQQ or glucose-dye-oxidoreductase methods). Due to the potential for falsely elevated glucose readings, use only testing systems that are glucose-specific to test or monitor blood glucose levels in patients receiving ANTHRASIL [See BOXED WARNING and 5.2 Interference with Blood Glucose Testing].

Antibodies present in ANTHRASIL may interfere with some serological tests. After administration of immune globulins like ANTHRASIL, a transitory increase of passively transferred antibodies in the patient’s blood may result in positive results in serological testing (e.g. Coombs’ test) [See 5.6 Hemolysis].

Urinalysis after ANTHRASIL administration may result in elevated glucose [See 6.1 Clinical Trials Experience]. As this is a known transient effect, testing should be repeated to determine if further action is warranted.

5.10 Transfusion-related Acute Lung Injury (TRALI)

Noncardiogenic pulmonary edema may occur in patients receiving immune globulin products, including ANTHRASIL. TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever and typically occurs within one to six hours after transfusion.

Monitor recipients for pulmonary adverse reactions. If TRALI is suspected, perform tests for the presence of anti-HLA and anti-neutrophil antibodies in the product.

5.11 Transmission of Infectious Agents from Human Plasma

Because ANTHRASIL is made from human plasma, it may carry a risk of transmitting blood-borne infectious agents, e.g., viruses, the variant Creutzfeld-Jakob disease (vCJD) agent, and, theoretically, the Creutzfeld-Jakob disease (CJD) agent. No cases of transmission of viral diseases, vCJD or CJD have been associated with the use of ANTHRASIL.

All infections thought to have been possibly transmitted by this product should be reported by the physician or other health care provider to Emergent BioSolutions Canada Inc. at 1-800-768-2304.

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.

In a double blind, randomized, placebo-controlled study designed to assess the safety and pharmacokinetics of three doses of ANTHRASIL after a single intravenous infusion in healthy volunteers, 72 healthy adult subjects were randomized to receive a dose of 210, 420 or 840 units of ANTHRASIL by Toxin Neutralization Assay (TNA) (N=18/dosing group) or an equal volume of saline placebo (N=6/dosing group). A total of 54 healthy volunteers received one of the three ANTHRASIL doses while 18 healthy volunteers received a saline placebo.

A second stage of the study, designed only for additional safety assessment, was a randomized, open-label study in 20 healthy adult volunteers. Subjects were randomized to receive a dose of 840 units by TNA from one of two additional product lots (10 subjects per lot). There was no placebo group.

There were no serious adverse reactions reported in any of the AIGIV or saline placebo control groups in these studies. Non-serious adverse events and adverse reactions were more frequent in the active AIGIV dosage groups that in the subjects administered placebo.

Headache and back pain rates occurred in a dose-dependent fashion. Back pain was observed with 840 unit doses in five out of 74 subjects (6.8%).

Dose-related elevations in urine glucose were also noted transiently following infusion [See 5.9 Interference with Laboratory Testing].

Infusion of ANTHRASIL was stopped for four subjects due to adverse reactions. One subject was withdrawn due to chest discomfort, flushing, tachycardia and throat tightness.

Patient Experience

Nineteen adult patients with severe systemic anthrax have been dosed with single 420 unit doses of ANTHRASIL and antimicrobial therapy through expanded access use with the Centers for Disease Control and Prevention (CDC): three patients with inhalational anthrax, 15 patients with anthrax due to injection of anthrax-contaminated heroin and one patient with gastrointestinal anthrax.

A total of 16 serious adverse reactions that began within 72 hours of infusion were reported for eight out of 19 patients (42%) as follows: acute respiratory distress syndrome (n=2), pulmonary edema, pleural effusion, acute renal insufficiency/failure (n=4), coagulopathy, cardiac arrest/death (not otherwise specified, n=2), hypotension, ascites, metabolic acidosis, hyperkalemia, and edema/perhipheral edema.

Six deaths were reported including one patient with inhalational anthrax. The cause of death in three of these six expired patients, including the patient who expired with inhalational anthrax, was consistent with progression of anthrax disease or co-morbidities and the cause of death in the remaining three patients was not determined or available.

7.1 Ciprofloxacin and Levofloxacin

Based on animal studies, ANTHRASIL did not interfere with antibiotic therapy. Concomitant administration of ANTHRASIL with levofloxacin or ciprofloxacin in exposed rabbits and cynomolgus macaques, respectively, did not affect the efficacy of antibacterial therapy.

7.2 Live, Attenuated Vaccines

Immune globulin administration may impair the efficacy of live attenuated vaccines such as measles, rubella, mumps and varicella. Defer vaccination with live virus vaccines until approximately three months after administration of ANTHRASIL. Revaccinate people who received ANTHRASIL shortly after live virus vaccination three months after the administration of ANTHRASIL.

8.1 Pregnancy

Risk Summary

There are no human data to establish the presence or absence of ANTHRASIL associated risk.

8.2 Lactation

Risk Summary

There are no data to assess the presence or absence of ANTHRASIL in human milk, the effects on the breastfed child or the effects on milk production/excretion.

8.4 Pediatric Use

Safety and effectiveness of ANTHRASIL in the pediatric population (≤16 yrs of age) have not been studied. Allometric scaling was used to derive dosing regimens to provide pediatric patients with exposure comparable to the observed exposure in adults receiving 420 units and 840 units. The dose for pediatric patients is based on body weight.

8.5 Geriatric Use

Safety and effectiveness of ANTHRASIL in the geriatric population (>65 yrs of age) have not been studied.

8.6 Renal Insufficiency

Use ANTHRASIL with caution in patients with any degree of pre-existing renal insufficiency and in patients at risk of developing renal insufficiency (including, but not limited to those with diabetes mellitus, age greater than 65 years, volume depletion, paraproteinemia, sepsis, and patients receiving known nephrotoxic drugs), administering at the minimum rate of infusion practicable. Ensure that patients are not volume depleted before ANTHRASIL infusion. Do not exceed the recommended infusion rate, and follow the infusion schedule closely.

8.7 Use in Obese Populations

Safety and effectiveness of ANTHRASIL in the obese population have not been studied.

12.1 Mechanism of Action

The polyclonal immune globulin G in ANTHRASIL is a passive immunizing agent that neutralizes anthrax toxin. ANTHRASIL binds to protective antigen (PA) to prevent PA mediated cellular entry of anthrax edema factor and lethal factor. ANTHRASIL is administered in combination with appropriate antibiotic therapy as the product itself is not known to have direct antibacterial activity against anthrax bacteria, which otherwise may continue to grow and product anthrax toxins.

12.3 Pharmacokinetics

The mean TNA activities for three doses of ANTHRASIL (210, 420 and 840 units TNA) in the clinical trial in healthy volunteers [See 14 CLINICAL STUDIES] are plotted on a semi-log scale in Figure 1. The pharmacokinetics of ANTHRASIL after intravenous infusion of the three dose levels were characterized; the peak levels of ANTHRASIL were reached immediately after infusion and then declined over the duration of study (84 days). The mean TNA activity remained above the lower limit of quantitation (5 milliunits per mL) over the entire 84-day post-dose period for the three doses studied.

Figure 1 Mean TNA Activities for Three Doses of ANTHRASIL

A summary of the mean pharmacokinetic results for the TNA data collected in the healthy volunteer study is presented in Table 3.

In comparison to healthy subjects, patients with inhalational anthrax are expected to initially have greater clearance of anti-PA antibodies and lower AUC from ANTHRASIL administration due to the presence of PA antigen.

Mean PK results (TNA data) were evaluated by sex and revealed no sex-related differences over the dose range studied. Systemic exposure of ANTHRASIL increased in a dose-proportional manner over the dose range studied. ANTHRASIL has a serum elimination half-life of 24 to 28 days in healthy humans.

Inhalational anthrax patients, concomitantly treated with antibiotics and a single 420 unit TNA dose of ANTHRASIL, exhibited increases in serum and pleural anti-PA levels; these levels remained at >50% of the peak anti-PA levels over the next five days. The peak serum anti-PA levels in these patients following ANTHRASIL administration (132 to 160 mcg/mL, mean 145 mcg/mL) overlapped with those obtained with the 420 unit dose in healthy volunteers (135 to 250 mcg/mL, mean 190 mcg/mL, median 192 mcg/mL), although mean levels were approximately 25% lower in the inhalational anthrax patients. In the three inhalational anthrax patients, serum and pleural levels of lethal factor declined after initiation of antibiotics and further decreased over the period of five days following ANTHRASIL administration; however, due at least in part to ANTHRASIL targeting the PA component of lethal toxin, plasma and pleural fluid lethal factor levels remained detectable when measured two to five days following ANTHRASIL administration.

Because the effectiveness of ANTHRASIL cannot ethically be tested in placebo-controlled trials in humans, a comparison of ANTHRASIL exposures achieved in healthy human subjects to those observed in animal models of inhalational anthrax in therapeutic efficacy studies was necessary to support the dosage regimen. A dose of 420 units has a similar exposure to the efficacious dose of 15 U/kg administered to New Zealand white rabbits and cynomolgus macaques. In cynomolgus macaques treated with ANTHRASIL monotherapy, a higher dose of 30 U/kg, with a similar exposure to a human dose of 840 units, may result in improved survival [See 13.2 Animal Toxicology and/or Pharmacology]. As a result, the initial dosing regimen is given as a range of 420 to 840 units, and the recommended regimen includes the potential for repeat dosing.

13.2 Animal Toxicology and/or Pharmacology

Anthrax infected New Zealand white rabbits and cynomolgus macaques administered an intravenous injection of ANTHRASIL (15 units TNA per kg) that did not survive their infection showed an increase in the severity and/or incidence of central nervous system lesions (bacteria, hemorrhage and necrosis) as compared to immune globulin (“placebo”) treated animals who also did not survive the infection. The mean time to death between non-surviving ANTHRASIL and placebo treated animals was comparable. Surviving rabbits had no evidence of central nervous system lesions at the end of the study. No surviving cynomolgus macaques in monotherapeutic studies were tested for central nervous system lesions.

Safety and Pharmacokinetics of ANTHRASIL in Healthy Volunteers

In a double blind, randomized, placebo-controlled study designed to assess the safety and pharmacokinetics of three doses of ANTHRASIL after a single intravenous infusion in healthy volunteers, a total of 72 healthy adult subjects were randomized to receive a dose of 210, 420 or 840 units of ANTHRASIL by TNA (N=18/dosing group) or an equal volume of saline placebo (N=6/dosing group).

A second stage of this study, designed only for additional safety assessment, was a randomized, open-label study in 20 healthy adult volunteers. Subjects were randomized to receive a dose of 840 units by TNA from one of two additional product lots (10 subjects per lot). There was no placebo group [See 6 ADVERSE REACTIONS and 12.3 Pharmacokinetics].

Patient Experience

Nineteen adult patients have been treated with ANTHRASIL under expanded access use, including three patients with inhalational anthrax, one patient with gastrointestinal anthrax and 15 patients with injectional anthrax due to injection of anthrax-contaminated heroin. Patients were receiving antimicrobial therapy before, during and after ANTHRASIL administration.

In patients with inhalational anthrax, two out of three patients treated with ANTHRASIL plus antimicrobial therapy survived and one died from progression of anthrax disease, systemic candidiasis and multiorgan failure. Among the 15 patients with injectional anthrax treated with ANTHRASIL plus antibiotics, 10 survived and five died (two from progression of anthrax disease; the cause of death was not determined or available for three patients). The single patient with gastrointestinal anthrax treated with ANTHRASIL survived. Therapy for these systemic anthrax cases included aggressive supportive measures including mechanical ventilation and pulmonary/abdominal fluid drainage.

In the three inhalational patients, the ANTHRASIL dose of 420 units by TNA resulted in increased anti-PA levels (correlating with increased TNA activity); these levels remained stable up to seven to 20 days post-administration, probably reflecting the rising antibody production by the patient at the same time that the exogenously-administered antibody was being cleared.

In some injectional anthrax cases, complicated by hemorrhage and pleural and/or peritoneal fluid losses from thoracentesis and/or paracentesis, serum anti-PA antibody levels fell as much as approximately 90% from their post-ANTHRASIL peak levels by 24 hours following ANTHRASIL administration. In the gastrointestinal anthrax patient, serum anti-PA levels were observed prior to ANTHRASIL infusion with further increases in anti-PA levels post-administration and maintenance of anti-PA above pre-administration levels for 11 days was observed.

16.1 How Supplied

NDC 60492-0249-1 for single vial

NDC 60492-0249-2 for shelf carton containing seven vials

ANTHRASIL is supplied as a 50 mL single dose vial seated with a butyl rubber stopper and an aluminum seal with a plastic flip-top cap. Each vial, regardless of fill volume, contains ≥60 units. It is packaged in a shelf carton with seven vials and a package insert.

ANTHRASIL does not contain natural rubber latex.

16.2 Storage and Handling

Store frozen at or below ≤-15°C (≤5°F) until required for use. Do not use after expiration date.

Once punctured, use the vial contents to prepare the infusion bag and infuse as soon as possible. ANTHRASIL contains no preservative.

Do not refreeze, reuse or save ANTHRASIL for future use.

Discard any partially used vials.