AHFS Class:

• Antitoxins and Immune Globulins 80:04

Generic Name(s):

• Botulism Immune Globulin IV (Human)

Botulism immune globulin IV (BIG-IV) is a specific immune globulin (hyperimmune globulin).6,7 BIG-IV contains immunoglobulin G (IgG) prepared from plasma of adults immunized with pentavalent botulinum toxoid and is capable of neutralizing botulinum toxin types A and B.1

Infant Botulism

Botulism immune globulin IV (BIG-IV) is used for treatment of infant botulism caused by toxin types A or B in infants younger than 1 year of age.1 BIG-IV is designated an orphan drug by the US Food and Drug Administration (FDA) for this indication.2

Infant botulism occurs when young infants ingest spores of Clostridium botulinum that then germinate, colonize the GI tract, and produce botulinum toxin.5,7,9,10,12 Although honey has been identified as the source of C. botulinum spores in some cases of infant botulism,7,9,12 the spore source usually is unknown and may be environmental (e.g., soil or dust particles).7,12 The incubation period between spore ingestion and onset of infant botulism symptoms is estimated to be 3-30 days.7 In the US, the highest incidences of infant botulism have been reported in Delaware, Hawaii, Utah, California, and Pennsylvania.10,12 The majority of cases have occurred in infants 6 months of age or younger and almost all have been caused by C. botulinum toxin types A and B;3,4,5,7,12 disease caused by toxin type E from C. butyricum or toxin type F from C. baratii has been reported rarely.3,7,12 Botulinum toxins are neurotoxins that cause generalized weakness and loss of muscle tone.7,9,10,12 Constipation is a common initial symptom of infant botulism; other symptoms include feeding difficulties (impaired sucking and swallowing), weak or altered cry, diminished facial expression, ptosis, and neck and generalized weakness.7,9,10,12 Rarely, fatalities occur as the result of rapidly progressing muscle weakness, paralysis, and respiratory arrest.4,7

In the US, BIG-IV has become the standard of care for treatment of infant botulism in conjunction with supportive care measures, and should be administered as soon as possible after clinical diagnosis.3,4,7,10,12 (See Dosage and Administration.) There is some evidence that BIG-IV is more effective when administered during the first 72 hours of hospitalization than when given 4-7 days after admission.3,4 Anti-infectives are not effective and should not be used for treatment of infant botulism.7,9 Although botulinum antitoxin (equine) (available from the US Centers for Disease Control and Prevention [CDC]) may be used for treatment of foodborne and wound botulism, it is not used for treatment of infant botulism since it is associated with serious adverse effects (e.g., sensitivity reactions).5,7

Clinical Experience

There is evidence from clinical studies and postmarketing experience that BIG-IV is safe and effective for treatment of infant botulism and can reduce the duration of hospitalization and duration of supportive care measures (i.e., mechanical ventilation, tube feedings) if administered promptly after clinical diagnosis.1,4,10,11

In one placebo-controlled study in infants with laboratory-confirmed botulism, administration of BIG-IV within the first 3 days of hospital admission (59 patients) reduced the durations of hospital and intensive care unit stay, mechanical ventilation, and tube feeding compared with placebo (63 patients).1,4 In this study, the average duration of hospital stay was 2.6 or 5.7 weeks and the average duration of stay in the intensive care unit was 1.3 or 3.6 weeks in infants treated with BIG-IV or placebo, respectively.1 The average duration of mechanical ventilation was 0.7 weeks in BIG-IV-treated infants and 2.4 weeks in placebo-treated infants.1 Infants treated with BIG-IV required tube feedings for an average of 3.6 weeks compared with an average of 10 weeks in infants treated with placebo.1

General

Botulism immune globulin IV (BIG-IV) should be administered as soon as possible after a clinical diagnosis of infant botulism, and should not be delayed while waiting for confirmatory diagnostic testing (e.g., toxin assay and culture of stool or enema specimens).3,4,7,10,12

Patients should be adequately hydrated and renal function (e.g., BUN or serum creatinine) should be assessed prior to administration of BIG-IV.1 The patient's vital signs should be continuously monitored and the patient closely observed for infusion-related adverse effects while BIG-IV is being administered.1 (See Administration Precautions under Cautions: Warnings/Precautions.)

Because patients with infant botulism may excrete Clostridium botulinum and botulinum toxin in their feces for up to 3 months after symptom onset, meticulous handwashing should be practiced after diaper changes and soiled diapers should be properly disposed (e.g., bagged and autoclaved).9 Individuals with open cuts or wounds on their hands should wear gloves while handling soiled diapers.9 In addition, close contact between the infant and other infants or young children (e.g., sharing crib or toys) should be avoided during the time that the organism or toxin may be excreted.9

Administration

BIG-IV is administered only by IV infusion;1 other routes of administration have not been evaluated.1

IV infusions of BIG-IV should be given using an inline or syringe filter (pore size 18 µm), low-volume tubing, and a controlled-infusion device (e.g., IVAC^® pump or equivalent) to control flow rate.1

BIG-IV should be administered via a separate IV infusion line.1 If necessary, BIG-IV may be piggybacked into a preexisting line containing 0.9% sodium chloride injection or 2.5, 5, 10, or 20% dextrose injection (with or without sodium chloride), provided the dilution of BIG-IV with such fluids does not exceed 1:2.1

Admixtures with other drugs have not been evaluated.1

Reconstitution

Single-dose vials of lyophilized BIG-IV should be reconstituted by adding 2 mL of the sterile water for injection diluent provided by the manufacturer to provide a solution containing 50 mg of immunoglobulin per mL.1 After the diluent has been added to the powder, the vial should be gently swirled; to avoid foam formation, the vial should not be shaken.1 Complete dissolution may take 30 minutes.1 The manufacturer's information should be consulted for additional directions regarding reconstitution.1

The reconstituted solution should not be diluted.1

Following reconstitution, IV infusions of BIG-IV should be started within 2 hours and completed within 4 hours.1

BIG-IV does not contain a preservative;1 reconstituted BIG-IV solutions should be administered only if they are colorless, free of particulate matter, and not turbid.1

Rate of Administration

IV infusions of BIG-IV should be started at a rate of 25 mg/kg (0.5 mL/kg) per hour; if no adverse reactions have occurred after 15 minutes, the infusion rate can be increased to 50 mg/kg (1 mL/kg) per hour.1

The infusion rate should not exceed 50 mg/kg (1 mL/kg) per hour.1

If a relatively minor adverse effect (e.g., flushing) occurs, the infusion should be slowed or temporarily interrupted.1 If a more severe reaction (e.g., anaphylaxis, substantial decrease in blood pressure) occurs, the infusion should be discontinued and appropriate therapy (e.g., epinephrine) administered.1 (See Administration Precautions under Cautions: Warnings/Precautions.)

Dosage

Pediatric Patients

Infant Botulism

The recommended dosage of BIG-IV in infants younger than 1 year of age is 100 mg/kg (2 mL/kg) administered as a single IV infusion as soon as possible after a clinical diagnosis of infant botulism is made.1

Special Populations

The recommended dosage, concentration, and rate of IV infusion should not be exceeded, especially in patients with renal impairment or in those at increased risk of renal dysfunction.1 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Contraindications

History of severe reaction to any immune globulin preparation.1

Selective IgA deficiency.1

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Mild, transient, erythematous rash on the face or trunk occurred in 9-14% of infants receiving botulism immune globulin IV (BIG-IV) in clinical studies.1,4

Although acute or severe systemic allergic reactions (e.g., anaphylaxis, angioedema) were not reported in clinical studies evaluating BIG-IV, clinicians should consider that such reactions are possible.1

Anaphylaxis can occur in patients with no known sensitivity to immune globulin preparations.1 Reactions may also be related to the rate of infusion.1 (See Administration Precautions under Cautions: Warnings/Precautions.)

Epinephrine should be available to treat acute allergic symptoms.1

If anaphylaxis or hypotension occurs, the BIG-IV infusion should be immediately discontinued and appropriate treatment (e.g., epinephrine) initiated.1

IgA Deficiency

Individuals with IgA deficiency may develop antibodies to IgA, and anaphylaxis could occur following administration of BIG-IV or other blood products containing IgA.1 BIG-IV contains trace amounts of IgA.1

Renal Effects

Renal dysfunction, acute renal failure, osmotic nephrosis, and death have been reported in patients receiving immune globulin IV (IGIV).1 Increases in BUN and serum creatinine have been observed as soon as 1-2 days following IGIV treatment.1

Available data indicate that IGIV preparations stabilized with sucrose and administered at daily dosages of 400 mg/kg or greater are associated with a greater risk of developing IGIV-associated renal dysfunction.1 BIG-IV contains 5% sucrose as a stabilizer.1

BIG-IV should be administered at the minimum concentration available and the minimum IV infusion rate that is practicable, especially in patients predisposed to acute renal failure.1 Patients predisposed to acute renal failure include those who have any degree of preexisting renal insufficiency, diabetes mellitus, volume depletion, sepsis, or paraproteinemia and those who are receiving nephrotoxic drugs.1

Prior to administration of BIG-IV, patients should be adequately hydrated and renal function assessed (e.g., BUN or serum creatinine).1 Renal function and urine output should be monitored periodically; such monitoring is particularly important in patients at risk of acute renal failure.1

Administration Precautions

Adverse effects that appear to be related to the IV infusion rate (e.g., chills, muscle cramps, back pain, fever, nausea, vomiting, wheezing) have been reported with immune globulin preparations, including BIG-IV.1

The recommended IV infusion rate should not be exceeded.1 (See Dosage and Administration: Administration.)

If a relatively minor adverse effect (e.g., flushing) occurs, the infusion rate should be decreased immediately or the infusion temporarily interrupted.1 If anaphylaxis or substantial decrease in blood pressure occurs, the infusion should be discontinued and appropriate therapy (e.g., epinephrine) administered.1 (See Sensitivity Reactions under Cautions: Warnings/Precautions.)

Risk of Transmissible Infectious Agents in Plasma-derived Preparations

Because BIG-IV is prepared from pooled human plasma, it is a potential vehicle for transmission of human viruses and theoretically may carry the risk of transmitting the causative agent of Creutzfeldt-Jakob disease (CJD).1

Although donors are screened for certain viruses (e.g., human immunodeficiency virus [HIV], hepatitis B virus [HBV], hepatitis C virus [HCV]) and BIG-IV undergoes certain procedures (cold ethanol fractionation, nanofiltration, solvent/detergent viral inactivation) that reduce viral infectious potential, some unrecognized blood-borne infectious agents may not be inactivated and a risk for transmission of infectious agents still remains.1 BIG-IV should be administered only when a benefit is expected.1

Aseptic Meningitis Syndrome

Aseptic meningitis syndrome has been reported rarely in patients receiving IGIV, but was not reported in clinical trials of BIG-IV.1

Aseptic meningitis syndrome usually is evident within several hours to 2 days after administration of IGIV and is characterized by severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, and nausea and vomiting.1 The syndrome appears to occur more frequently in patients receiving high total doses of IGIV (e.g., 2 g/kg).1

Patients exhibiting signs and symptoms of aseptic meningitis syndrome should undergo a complete neurologic examination to rule out other causes of meningitis.1 CSF analysis frequently reveals pleocytosis (up to several thousand cells per mm³), predominantly from the granulocytic series, and protein concentrations up to several hundred mg/dL.1

When IGIV is discontinued, aseptic meningitis syndrome generally resolves within several days without sequelae.1

Hyperproteinemia, Hyponatremia, and Increased Serum Viscosity

Hyperproteinemia, hyponatremia, and increased serum viscosity have been reported in patients receiving IGIV,1 but have not been reported to date with BIG-IV.1

If hyponatremia occurs, it is critical to distinguish true hyponatremia from pseudohyponatremia caused by decreased calculated serum osmolality or elevated osmolar gap.1 Treatment aimed at decreasing serum free water in patients with pseudohyponatremia may lead to volume depletion, a further increase in serum viscosity, and increased risk of thromboembolic events.1

Thrombotic Events

Thrombotic events have been reported in patients receiving IGIV,1 but have not been reported to date with BIG-IV.1

Patients at risk of thrombotic events include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, coagulation disorders, prolonged periods of immobilization, and/or known or suspected hyperviscosity.1

Clinicians should consider baseline assessment of blood viscosity in patients at risk for hyperviscosity (e.g., those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols [triglycerides], monoclonal gammopathies).1

In patients judged to be at risk of developing thrombotic events, BIG-IV should be administered at the slowest IV infusion rate considered practicable.1

Hemolysis and Hemolytic Anemia

Immune globulin preparations may contain blood group antibodies that can act as hemolysins and induce in vivo coating of erythrocytes with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, hemolysis.1

Hemolytic anemia also can develop subsequent to immune globulin therapy due to enhanced erythrocyte sequestration.1

Patients receiving BIG-IV should be monitored for clinical signs and symptoms of hemolysis and, if necessary, appropriate confirmatory laboratory testing should be performed.1

Transfusion-related Acute Lung Injury

Transfusion-related acute lung injury (TRALI; noncardiogenic pulmonary edema) has been reported in patients receiving IGIV,1 but has not been reported to date with BIG-IV.1

TRALI typically occurs within 1-6 hours after IGIV infusion and is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever.1

Patients receiving BIG-IV should be monitored for adverse pulmonary reactions.1 If TRALI is suspected, appropriate tests should be performed to determine whether antineutrophil antibodies are present in the product or patient serum.1 TRALI should be managed using oxygen therapy with adequate ventilatory support.1

Improper Storage and Handling

Improper storage or handling of immune globulins may affect efficacy.6

BIG-IV that has been mishandled or has not been stored at the recommended temperature should not be administered.6 Lyophilized BIG-IV should be stored at 2-8°C and administered shortly after reconstitution.1 (See Reconstitution under Dosage and Administration: Administration.)

All immune globulins should be inspected upon delivery and monitored during storage to ensure that the appropriate temperature is maintained.6 If there are concerns about mishandling, the manufacturer or state or local health departments should be contacted for guidance on whether BIG-IV is usable.6

Specific Populations

Pregnancy

Safety and efficacy have not been evaluated in adults, including pregnant women.1

Pediatric Use

Safety and efficacy are established only in children younger than 1 year of age.1 Safety and efficacy have not been evaluated in older pediatric patients.1

Geriatric Use

Safety and efficacy have not been evaluated in adults, including geriatric adults.1

Renal Impairment

BIG-IV should be used with caution in patients with preexisting renal impairment and in patients judged to be at increased risk of developing renal impairment (e.g., those with diabetes mellitus, volume depletion, paraproteinemia, sepsis, or receiving nephrotoxic drugs).1

The recommended dosage, concentration, and IV infusion rate of BIG-IV should not be exceeded in patients with renal impairment or in those at increased risk of renal dysfunction.1 (See Dosage and Administration.)

Common Adverse Effects

Erythematous rash.1 (See Sensitivity Reactions under Cautions: Warnings/Precautions.)

Vaccines

Live Vaccines

Antibodies present in immune globulin preparations may interfere with immune responses to some live virus vaccines, including measles, mumps, and rubella virus vaccine live (MMR), varicella virus vaccine live, and fixed combination of MMR and varicella virus vaccine live (MMRV).1,6 The duration of possible interference between immune globulin preparations and live virus vaccines appears to depend on antibody concentrations in the immune globulin; there is evidence that certain immune globulin preparations can inhibit the immune response to measles virus vaccine live and rubella virus vaccine live for more than 3 months.6 Although specific information regarding the effect of immune globulin preparations on immune responses to mumps virus vaccine live and varicella virus vaccine live are not available, there is potential for similar interference since immune globulin preparations contain antibodies to these viruses.6

MMR and varicella vaccines should not be administered simultaneously with BIG-IV, and should be deferred until at least 3-5 months after BIG-IV.1,6,9 Revaccination with MMR and varicella vaccines may be necessary in infants who received these live virus vaccines less than 3-5 months after BIG-IV.1,6 In addition, revaccination is necessary if BIG-IV was administered less than 14 days after MMR or varicella vaccines, unless serologic testing is feasible and indicates that there was an adequate response to the vaccines.6

There is no evidence that immune globulin preparations interfere with immune responses to rotavirus vaccine live oral, influenza virus vaccine live intranasal, yellow fever virus vaccine live, typhoid vaccine live oral, or zoster vaccine live.6 When indicated, these vaccines can be administered simultaneously with or at any time before or after BIG-IV.6 However, because intestinal motility usually is profoundly slower in patients with infant botulism than in healthy infants, some clinicians recommend that administration of rotavirus vaccine live oral be deferred until 5 months after BIG-IV.9

Inactivated Vaccines and Toxoids

Immune globulin preparations are not expected to have a clinically important effect on immune responses to inactivated vaccines or toxoids; therefore, inactivated vaccines, recombinant vaccines, polysaccharide vaccines, and toxoids may be administered simultaneously (using different syringes and different injection sites) or at any interval before or after BIG-IV.6

Description

Botulism immune globulin IV (BIG-IV) is a lyophilized powder of immunoglobulin prepared from pooled plasma of adults who were immunized with pentavalent botulinum toxoid and selected for their high titers of neutralizing antibody against botulinum toxin types A and B.1

Following reconstitution with sterile water for injection provided by the manufacturer, each mL of BIG-IV contains approximately 40-60 mg of immunoglobulin, primarily immunoglobulin G (IgG) with trace amounts of immunoglobulin A (IgA) and immunoglobulin M (IgM), and 10 mg of albumin human, 50 mg of sucrose, and approximately 20 x 10^-3 mEq of sodium.1 Reconstituted BIG-IV contains antibody titers against botulinum toxin types A and B that are at least 15 and 2 international units (IUs, units), respectively;1 by definition, 1 unit neutralizes 10,000 intraperitoneal mouse LD₅₀ of these botulinum toxins.1 Titers of antibody against botulinum toxins C, D, and E in BIG-IV have not been determined.1 BIG-IV does not contain thimerosal or any other preservatives.1

Following IV administration, the specific antibodies contained in BIG-IV bind to and neutralize circulating botulinum toxin types A and B.1 In infants younger than 1 year of age, administration of a single dose of BIG-IV is expected to provide protective levels of antibodies sufficient to neutralize circulating levels of botulinum toxins A and B.1,4,9 The pharmacokinetics of BIG-IV have not fully elucidated.1 Data indicate that the mean elimination half-life of BIG-IV in infants is approximately 28 days.1,4

Advice to Patients

Advise patient's parent or legal guardian of the risks and benefits of botulism immune globulin IV (BIG-IV).1 Discuss the possibility of adverse reactions, including hypersensitivity reactions (e.g., anaphylaxis), renal failure, aseptic meningitis syndrome, hemolysis, thrombosis, and transfusion-related acute lung injury.1 (See Cautions.)

Advise patient's parent or guardian that BIG-IV is prepared from pooled human plasma.1 Although improved donor screening and viral-inactivating and purification procedures used in manufacture of plasma-derived preparations have reduced the risk of pathogen transmission, BIG-IV is a potential vehicle for transmission of infectious agents.1 Importance of reporting any concerning adverse effects.1

Advise patient's parent or guardian that BIG-IV may interfere with the immune response to certain live virus vaccines (e.g., MMR, varicella vaccines); importance of informing clinicians administering vaccines about recent use of BIG-IV.1,6 (See Live Vaccines under Drug Interactions: Vaccines.)

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

Importance of informing patient's parent or legal guardian of other important precautionary information.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug 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 cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. California Department of Public Health. BabyBIG^® (botulism immune globulin intravenous [human]) prescribing information. Richmond, CA; 2012 Jan.

2. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Rockville, MD. From FDA website. Accessed 2012 Mar 12. [Web]

3. Long SS. Infant botulism and treatment with BIG-IV (BabyBIG). Pediatr Infect Dis J . 2007; 26:261-2. [PubMed 17484226]

4. Arnon SS, Schechter R, Maslanka SE et al. Human botulism immune globulin for the treatment of infant botulism. N Engl J Med . 2006; 354:462-71. [PubMed 16452558]

5. Arnon SS. Creation and development of the public service orphan drug Human Botulism Immune Globulin. Pediatrics . 2007; 119:785-9. [PubMed 17403850]

6. National Center for Immunization and Respiratory Diseases. General recommendations on immunization -- recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep . 2011; 60:1-64.

7. American Academy of Pediatrics. Red Book: 2009 Report of the Committee on Infectious Diseases. 28th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009.

8. California Department of Public Health Services, Richmond CA: Personal Communication.

9. Infant Botulism Treatment and Prevention Program. Division of Communicable Disease Control, California Department of Health Services. From IBTPP website. Accessed 2012 Mar 26. [Web]

10. Underwood K, Rubin S, Deakers T et al. Infant botulism: a 30-year experience spanning the introduction of botulism immune globulin intravenous in the intensive care unit at Childrens Hospital Los Angeles. Pediatrics . 2007; 120:e1380-5. [PubMed 18055655]

11. Chalk C, Benstead TJ, Keezer M. Medical treatment for botulism. Cochrane Database Syst Rev . 2011; :CD008123. [PubMed 21412916]

12. Arnon SS. Infant botulism. In: Feigin RD, Cherry JD, Demmler-Harrison GJ et al. Feigin: Feigin and Cherry's Textbook of Pediatric Infectious Diseases, 6th ed. Philadelphia, PA: Saunders Elsevier; 2009.