Bivigam

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Thrombotic Events

Thrombotic events may occur following treatment with IGIV products.4,5,6 Patients at risk 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/suspected hyperviscosity (see PATIENT INFORMATION).

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. For patients judged to be at risk of developing thrombotic events, administer BIVIGAM at the minimum rate of infusion practicable (see DOSAGE AND ADMINISTRATION).

Hypersensitivity

Severe hypersensitivity reactions may occur with IGIV products, including BIVIGAM. In case of hypersensitivity, discontinue BIVIGAM infusion immediately and institute appropriate treatment. Medications such as epinephrine should be available for immediate treatment of acute hypersensitivity reactions.

BIVIGAM contains trace amounts of IgA ( ≤ 200 micrograms per milliliter) (see DESCRIPTION). Patients with known antibodies to IgA may have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. BIVIGAM is contraindicated in IgA deficient patients with antibodies against IgA and a history of hypersensitivity reaction (see CONTRAINDICATIONS).

Acute Renal Dysfunction and Acute Renal Failure

Acute renal dysfunction/failure, osmotic nephrosis, and death1,2 may occur upon use of human IGIV products. Ensure that patients are not volume depleted before administering BIVIGAM. Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk of developing acute renal failure.2 Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of BIVIGAM and at appropriate intervals thereafter. If renal function deteriorates, consider discontinuing BIVIGAM (see PATIENT INFORMATION). In patients who are at risk of developing renal dysfunction, because of pre-existing renal insufficiency or predisposition to acute renal failure (such as diabetes mellitus, hypovolemia, overweight, use of concomitant nephrotoxic medicinal products or age of > 65 years), administer BIVIGAM at the minimum infusion rate practicable (see DOSAGE AND ADMINISTRATION).

Hyperproteinemia, Increased Serum Viscosity, and Hyponatremia

Hyperproteinemia, increased serum viscosity, and hyponatremia may occur in patients receiving IGIV therapy, including BIVIGAM. It is critical to clinically distinguish true hyponatremia from a pseudohyponatremia that is associated with or causally related to hyperproteinemia with concomitant decreased calculated serum osmolality or elevated osmolar gap, because treatment aimed at decreasing serum free water in patients with pseudohyponatremia may lead to volume depletion, a further increase in serum viscosity, and a possible predisposition to thrombotic events.3

Aseptic Meningitis Syndrome (AMS)

AMS may occur infrequently with IGIV treatments including BIVIGAM. AMS usually begins within several hours to 2 days following IGIV treatment. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae.7,8,9

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

AMS may occur more frequently in association with high doses (2 g/kg) and/or rapid infusion of IGIV.

Hemolysis

IGIV products, including BIVIGAM, may contain blood group antibodies that can act as hemolysins and induce in vivo coating of red blood cells (RBCs) with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, hemolysis.10,11,12 Delayed hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration,13 and acute hemolysis, consistent with intravascular hemolysis, has been reported.

Monitor patients for clinical signs and symptoms of hemolysis (see PATIENT INFORMATION). If these are present after BIVIGAM infusion, perform appropriate confirmatory laboratory testing. If transfusion is indicated for patients who develop hemolysis with clinically compromising anemia after receiving IGIV, perform adequate cross-matching to avoid exacerbating on-going hemolysis.

Transfusion-Related Acute Lung Injury (TRALI)

Noncardiogenic pulmonary edema may occur in patients following IGIV treatment14 including BIVIGAM. TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Symptoms typically appear within 1 to 6 hours following treatment.

Monitor patients for pulmonary adverse reactions. If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies in both the product and the patient's serum (see PATIENT INFORMATION).

TRALI may be managed using oxygen therapy with adequate ventilatory support.

Transmissible Infectious Agents

Because BIVIGAM is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent.

No cases of transmission of viral diseases or CJD have been associated with the use of BIVIGAM. All infections suspected by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Biotest Pharmaceuticals Corporation at 1-800-458-4244. Before prescribing BIVIGAM, the physician should discuss the risks and benefits of its use with the patient (see PATIENT INFORMATION).

Monitoring Laboratory Tests

  • Periodic monitoring of renal function and urine output is particularly 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 BIVIGAM and at appropriate intervals thereafter.
  • Because of the potentially increased risk of thrombosis with IGIV treatment, 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 BIVIGAM, perform appropriate laboratory testing for confirmation.
  • If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies in both the product and patient's serum.

Interference with Laboratory Tests

After infusion of immunoglobulin, the transitory rise of the various passively transferred antibodies in the patient's blood may yield positive serological testing results, with the potential for misleading interpretation. Passive transmission of antibodies to erythrocyte antigens (e.g., A, B, and D) may cause a positive direct or indirect antiglobulin (Coombs') test.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

No animal studies were conducted to evaluate the carcinogenic or mutagenic effects of BIVIGAM or its effects on fertility.

Animal Toxicology and/or Pharmacology

No animal studies were conducted to evaluate possible toxicity of BIVIGAM in animals.

BIVIGAM contains Polysorbate 80 at a concentration of up to 2.5 mg/mL. Intravenous administrations of Polysorbate 80 in multiple species have been linked with a decrease in blood pressure. In rats, single doses of Polysorbate 80 that were up to 25 times higher than the amount from 800 mg/kg BIVIGAM resulted in an increase of liver enzymes and total bilirubin.

Use In Specific Populations

Pregnancy

Pregnancy Category C

Animal reproduction studies have not been conducted with BIVIGAM. It is not known whether BIVIGAM can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. BIVIGAM should be given to pregnant women only if clearly needed.17,18

Nursing Mothers

Use of BIVIGAM in nursing mothers has not been evaluated. BIVIGAM should be given to nursing mothers only if clearly needed.

Pediatric Use

BIVIGAM was evaluated in 9 pediatric patients (4 children ages 6 – 11 years and 5 adolescents ages 12 – 16 years) with PI. This number of pediatric patients was too small for safety or efficacy. The safety and effectiveness of BIVIGAM has not been established in pediatric patients with PI who are under the age of 6 (see Clinical Studies).

Geriatric Use

BIVIGAM should be used with caution in patients age 65 and over who are judged to be at increased risk of developing renal insufficiency or thrombotic events (see BOXED WARNING, WARNINGS AND PRECAUTIONS). Do not exceed recommended doses and administer BIVIGAM at the minimum infusion rate practicable.

BIVIGAM was evaluated in 9 patients age 65 and older with PI. This number of geriatric patients is not being sufficient to determine whether they respond differently from younger patients (see Clinical Studies).

REFERENCES

1. Gupta N, Ahmed I, Nissel-Horowitz S, Patel D, Mehrotra B. Intravenous gammaglobulin-associated acute renal failure. Am J Hematol 2001; 66:151-152.

2. Cayco, A.V., M.A. Perazella, and J.P. Hayslett. Renal insufficiency after intravenous immune globulin therapy: a report of two cases and an analysis of the literature. J Am Soc Nephrol 1997; 8:1788-1794.

3. Steinberger BA, Ford SM, Coleman TA. Intravenous immune globulin therapy results in post-infusional hyperproteinemia, increased serum viscosity, and pseudohyponatremia. Am J Hematol 2003; 73:97-100.

4. Dalakas MC. High-dose intravenous immunoglobulin and serum viscosity: risk of precipitating thromboembolic events. Neurology 1994; 44:223-226.

5. Woodruff RK, Grigg AP, Firkin FC, Smith IL. Fatal thrombotic events during treatment of autoimmune thrombocytopenia with intravenous immunoglobulin in elderly patients. Lancet 1986; 2:217-18.

6. Wolberg AS, Kon RH, Monroe DM, Hoffman M. Coagulation factor XI is a contaminant in intravenous immunoglobulin preparations. Am J Hematol 2000; 65:30-34.

7. Casteels-Van Daele, M., et al. Intravenous immune globulin and acute aseptic meningitis [letter]. N Engl J Med 1990; 323:614-615.

8. Kato, E., et al. Administration of immune globulin associated with aseptic meningitis [letter]. Jama 1988; 259:3269-3271.

9. Scribner, C.L., et al. Aseptic meningitis and intravenous immunoglobulin therapy [editorial, comment]. Ann Intern Med 1994; 121:305-306.

10. Copelan EA, Stohm PL, Kennedy MS, Tutschka PJ. Hemolysis following intravenous immune globulin therapy. Transfusion 1986; 26:410-412.

11. Thomas MJ, Misbah SA, Chapel HM, Jones M, Elrington G, Newsom-Davis J. Hemolysis after high-dose intravenous Ig. Blood 1993; 15:3789.

12. Wilson JR, Bhoopalam N, Fisher M. Hemolytic anemia associated with intravenous immunoglobulin. Muscle & Nerve 1997; 20:1142-1145.

13. Kessary-Shoham H, Levy Y, Shoenfeld Y, Lorber M, Gershon H. In vivo administration of intravenous immunoglobulin (IVIg) can lead to enhanced erythrocyte sequestration. J Autoimmune 1999; 13:129-135.

14. Rizk A, Gorson KC, Kenney L, Weinstein R. Transfusion-related acute lung injury after the infusion of IVIG. Transfusion 2001; 41:264-268.

15. Siber GA, Werner BG, Halsey NA, et al. Interference of immune globulin with measles and rubella immunization. J Pediatr 1993; 122:204-211.

16. Salisbury D, Ramsay M, Noakes K, eds. Immunisation against infectious disease. The Stationery Office (TSO), London: UK Department of Health; 2009:426.

17. Hammarstrom L, Smith CIE. Placental transfer of intravenous immunoglobulin. Lancet 1986; 1:681.

18. Sidiropoulos D, Herrmann U, Morell A, von Muralt G, Barandun S. Transplacental passage of intravenous immunoglobulin in the last trimester of pregnancy. J Pediatr 1986; 109:505-508.

Last reviewed on RxList: 1/28/2013
This monograph has been modified to include the generic and brand name in many instances.

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