Gamunex immune globulin I.V., 10%

See PRECAUTIONS and DOSAGE AND ADMINISTRATION sections for important information intended to reduce the risk of acute renal failure.

Because this product is made from human blood, it may carry a risk of transmitting infectious agents, e.g. viruses, and, theoretically, the Creutzfeldt-Jakob (CJD) agent that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses. Despite these measures, such products can still potentially transmit disease. There is also the possibility that unknown infectious agents may be present in such products. Individuals who receive infusions of blood or plasma products may develop signs and/or symptoms of some viral infections.

ALL infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Talecris Biotherapeutics, Inc. [1-800-520-2807]. The physician should discuss the risks and benefits of this product with the patient, before prescribing or administering it to the patient.

GAMUNEX , Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified, should be administered only intravenously. On rare occasions, treatment with an immune globulin preparation may cause a precipitous fall in blood pressure and a clinical picture of anaphylaxis, even when the patient is not known to be sensitive to immune globulin preparations. Epinephrine and other appropriate supportive care should be available for the treatment of an acute anaphylactic reaction.

General

Any vial that has been entered should be used promptly. Partially used vials should be discarded. Visually inspect each bottle before use. Do not use if turbid. Solution that has been frozen should not be used.

An aseptic meningitis syndrome (AMS) has been reported to occur infrequently in association with Immune Globulin Intravenous (Human) treatment. The syndrome usually begins within several hours to two days following Immune Globulin Intravenous (Human) treatment. It is characterized by symptoms and signs including severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea and vomiting.

AMS may occur more frequently in association with high dose (2 g/kg) and/or rapid infusion of Immune Globulin Intravenous (Human) treatment. Discontinuation of Immune Globulin Intravenous (Human) treatment has resulted in remission of AMS within several days without sequelae 26-28 .

Assure that patients are not volume depleted prior to the initiation of the infusion of IGIV. Periodic monitoring of renal function and urine output is particularly important in patients judged to have a potential increased risk for developing acute renal failure. Renal function, including measurement of blood urea nitrogen (BUN)/serum creatinine, should be assessed prior to the initial infusion of GAMUNEX , Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified, and again at appropriate intervals thereafter. If renal function deteriorates, discontinuation of the product should be considered. For patients judged to be at risk for developing renal dysfunction and/or at risk of developing thrombotic events, it may be prudent to reduce the amount of product infused per unit time by infusing GAMUNEX at a rate less than 8 mg IG/kg/min (0.08 mL/kg/min).

Hemolysis

Immune Globulin Intravenous (Human)(IGIV) products can contain blood group antibodies which may act as hemolysins and induce in vivo coating of red blood cells with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, hemolysis. 29,30,31 Hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration. [See ADVERSE REACTIONS : Laboratory Abnormalities ]. IGIV recipients should be monitored for clinical signs and symptoms of hemolysis 32 [See PRECAUTIONS : Laboratory Tests ].

Transfusion-Related Acute Lung Injury (TRALI)

There have been reports of noncardiogenic pulmonary edema [Transfusion-Related Acute Lung Injury (TRALI)] in patients administered IGIV. 33 TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever and typically occurs within 1-6 hrs after transfusion. Patients with TRALI may be managed using oxygen therapy with adequate ventilatory support.

IGIV recipients should be monitored for pulmonary adverse reactions. If TRALI is suspected, appropriate tests should be performed for the presence of anti-neutrophil antibodies in both the product and patient serum [see PRECAUTIONS : Laboratory Tests ].

Thrombotic events

Thrombotic events have been reported in association with IGIV 34,35,36 (See ADVERSE REACTIONS ). Patients at risk may 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. The potential risks and benefits of IGIV should be weighed against those of alternative therapies for all patients for whom IGIV administration is being considered. Baseline assessment of blood viscosity should be considered in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies [See PRECAUTIONS : Laboratory Tests ].

Information for Patients

Patients should be instructed to immediately report symptoms of decreased urine output, sudden weight gain, fluid retention/edema, and/or shortness of breath (which may suggest kidney damage) to their physicians.

Laboratory Tests

If signs and/or symptoms of hemolysis are present after IGIV infusion, appropriate confirmatory laboratory testing should be done [see PRECAUTIONS : General ].

If TRALI is suspected, appropriate tests should be performed for the presence of anti-neutrophil antibodies in both the product and patient serum [see PRECAUTIONS ].

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

Drug Interactions

Antibodies in GAMUNEX may interfere with the response to live viral vaccines such as measles, mumps and rubella. Therefore, use of such vaccines should be deferred until approximately 6 months after GAMUNEX administration. Please see DOSAGE AND ADMINISTRATION for other drug interactions.

Pregnancy Category C

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

Dosage

General

For patients judged to be at increased risk for developing renal dysfunction and/or at risk of developing thrombotic events, it may be prudent to reduce the amount of product infused per unit time by infusing GAMUNEX , Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified, at a rate less than 8 mg/kg/min (0.08 mL/kg/min). No prospective data are presently available to identify a maximum safe dose, concentration, and rate of infusion in patients determined to be at increased risk of acute renal failure. In the absence of prospective data, recommended doses should not be exceeded and the concentration and infusion rate should be the minimum level practicable. Reduction in dose, concentration, and/or rate of administration in patients at risk of acute renal failure has been proposed in the literature in order to reduce the risk of acute renal failure 44 .

Primary Humoral Immunodeficiency (PI)

GAMUNEX doses between 300 and 600 mg/kg (3 and 6 mL/kg), which represented the dose range for 92% of the subjects in the therapeutic equivalence trial (100175), may be used for infection prophylaxis. The dose should be individualized taking into account dosing intervals (e.g. 3 or 4 weeks) and GAMUNEX dose (between 300 and 600 mg/kg). A target serum IgG trough level (i.e. prior to the next infusion) of at least 5 g/L has been proposed in the literature 22, 45 , however no randomized controlled trial data are available to validate this recommendation. In a clinical trial with 73 subjects with Primary Immune Deficiencies, treated for nine months with GAMUNEX , the relationship of validated infections and serum IgG levels at trough are shown in the table below:

Idiopathic Thrombocytopenic Purpura (ITP)

GAMUNEX may be administered at a total dose of 2 g/kg, divided in two doses of 1 g/kg (10 mL/kg) given on two consecutive days or into five doses of 0.4 g/kg (4 mL/kg) given on five consecutive days. If after administration of the first of two daily 1 g/kg (10 mL/kg) doses, an adequate increase in the platelet count is observed at 24 hours, the second dose of 1g/kg body weight may be withheld.

Forty-eight ITP subjects were treated with 2 g/kg GAMUNEX , divided in two 1 g/kg doses (10 mL/kg) given on two successive days. With this dose regimen 35/39 subjects (90%) responded with a platelet count from less than or equal to 20 × 10 9 /L to more than or equal to 50 × 10 9 /L within 7 days after treatment. 11

The high dose regimen (1 g/kg × 1-2 days) is not recommended for individuals with expanded fluid volumes or where fluid volume may be a concern.

Administration

GAMUNEX is not compatible with saline. If dilution is required, GAMUNEX may be diluted with 5% dextrose in water (D5/W). No other drug interactions or compatibilities have been evaluated.

It is recommended that GAMUNEX should initially be infused at a rate of 0.01 mL/kg per minute (1 mg/kg per minute) for the first 30 minutes. If well-tolerated, the rate may be gradually increased to a maximum of 0.08 mL/kg per minute (8 mg/kg per minute). If side effects occur, the rate may be reduced, or the infusion interrupted until symptoms subside. The infusion may then be resumed at the rate which is comfortable for the patient.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Only 18 gauge needles should be used to penetrate the stopper for dispensing product from 10mL vial sizes; 16 gauge needles or dispensing pins should only be used with 25 mL vial sizes and larger. Needles or dispensing pins should only be inserted within the stopper area delineated by the raised ring. The stopper should be penetrated perpendicular to the plane of the stopper within the ring.

Content of vials may be pooled under aseptic conditions into sterile infusion bags and infused within 8 hours after pooling.

It is recommended to infuse GAMUNEX using a separate line by itself, without mixing with other intravenous fluids or medications the patient might be receiving.

A number of factors could reduce the efficacy of this product or even result in an ill effect following its use. These include improper storage and handling of the product, diagnosis, dosage, method of administration, and biological differences in individual patients. Because of these factors, it is important that this product be stored properly and that the directions be followed carefully during use.

GAMUNEX , Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified, is supplied in the following sizes:

STORAGE

GAMUNEX , Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified, may be stored for 36 months at 2-8°C (36-46°F), AND product may be stored at temperatures not to exceed 25°C (77°F) for up to 6 months anytime during the 36 month shelf life, after which the product must be immediately used or discarded. Do not freeze. Do not use after expiration date.

Rx only

1. Kelleher J, F.G., Cyrus P, Schwartz L, A Randomized, Double-Blind, Multicenter, Parallel Group Trial Comparing the Safety and Efficacy of IGIV-Chromatography, 10% (Experimental) with IGIV-Solvent Detergent Treated, 10% (Control) in Patients with Primary Immune Deficiency (PID). 2000. Report on file.
2. Data on File.
3. Bayever E, M.F., Sundaresan P, Collins S, Randomized, Double-Blind, Multicenter, Repeat Dosing, Cross-Over Trial Comparing the Safety, Pharmacokinetics, and Clinical Outcomes of IGIV-Chromatography, 10% (Experimental) with IGIV-Solvent Detergent Treated, 10% (Control) in Patients with Primary Humoral Immune Deficiency (BAY-41-1000-100152). MMRR-1512/1, 1999.
4. Lathia C, E.B., Sundaresan PR, Schwartz L, A Randomized, Open-Label, Multicenter, Repeat Dosing, Cross-Over Trial Comparing the Safety, Pharmacokinetics, and Clinical Outcomes of IGIV-Chromatography, 5% with IGIV-Chromatography 10% in Patients with Primary Humoral Immune Deficiency (BAY-41-1000-100174) . 2000.
5. Blanchette, V.S., M.A. Kirby, and C. Turner, Role of intravenous immunoglobulin G in autoimmune hematologic disorders. Semin Hematol, 1992. 29 (3 Suppl 2): p. 72-82.
6. Lazarus, A.H., J. Freedman, and J.W. Semple, Intravenous immunoglobulin and anti-D in idiopathic thrombocytopenic purpura (ITP): mechanisms of action. Transfus Sci, 1998. 19 (3): p. 289-94.
7. Semple, J.W., A.H. Lazarus, and J. Freedman, The cellular immunology associated with autoimmune thrombocytopenic purpura: an update. Transfus Sci, 1998. 19 (3): p. 245-51.
8. Imbach, P.A., Harmful and beneficial antibodies in immune thrombocytopenic purpura. Clin Exp Immunol, 1994. 97 (Suppl 1): p. 25-30.
9. Bussel, J.B., Fc receptor blockade and immune thrombocytopenic purpura. Semin Hematol, 2000. 37 (3): p. 261-6.
10. Imbach, P., et al., Immunthrombocytopenic purpura as a model for pathogenesis and treatment of autoimmunity. Eur J Pediatr, 1995. 154 (9 Suppl 4): p. S60-4.
11. Cyrus P, F.G., Kelleher J, Schwartz L, A Randomized, Double-Blind, Multicenter, Parallel Group Trial Comparing the Safety, and Efficacy of IGIV-Chromatography, 10% (Experimental) with IGIV-Solvent Detergent Treated, 10% (Control) in Patients with Idiopathic (Immune) Thrombocytopenic Purpura (ITP), 2000. Report on file.
12. Wretlind, A., Complete intravenous nutrition. Theoretical and experimental background. Nutr Metab, 1972. 14 : p. Suppl:1-57.
13. Hahn, R.G., H.P. Stalberg, and S.A. Gustafsson, Intravenous infusion of irrigating fluids containing glycine or mannitol with and without ethanol. J Urol, 1989. 142 (4): p. 1102-5.
14. Tai VM, M.E., Lee-Brotherton V, Manley JJ, Nestmann ER, Daniels JM. Safety Evaluation of Intravenous Glycine in Formulation Development. in J Pharm Pharmaceut Sci ( www.ualberta.ca/-csps ). 2000.
15. Traul, K.A., et al., Review of the toxicologic properties of medium-chain triglycerides. Food Chem Toxicol, 2000. 38 (1): p. 79-98.
16. Guyton, A., Textbook of Medical Physiology. 5th Edition. 1976, Philadelphia: W.B. Saunders. 499-500.
17. Ammann, A.J., et al., Use of intravenous gamma-globulin in antibody immunodeficiency: results of a multicenter controlled trial. Clin Immunol Immunopathol, 1982. 22 (1): p. 60-7.
18. Buckley, R.H. and R.I. Schiff, The use of intravenous immune globulin in immunodeficiency diseases. N Engl J Med, 1991. 325 (2): p. 110-7.
19. Cunningham-Rundles, C. and C. Bodian, Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol, 1999. 92 (1): p. 34-48.
20. Nolte, M.T., et al., Intravenous immunoglobulin therapy for antibody deficiency. Clin Exp Immunol, 1979. 36 (2): p. 237-43.
21. Pruzanski, W., et al., Relationship of the dose of intravenous gammaglobulin to the prevention of infections in adults with common variable immunodeficiency. Inflammation, 1996. 20 (4): p. 353-9.
22. Roifman, C.M., H. Levison, and E.W. Gelfand, High-dose versus low-dose intravenous immunoglobulin in hypogammaglobulinaemia and chronic lung disease. Lancet, 1987. 1 (8541): p. 1075-7.
23. Sorensen, R.U. and S.H. Polmar, Efficacy and safety of high-dose intravenous immune globulin therapy for antibody deficiency syndromes. Am J Med, 1984. 76 (3A): p. 83-90.
24. Stephan, J.L., et al., Severe combined immunodeficiency: a retrospective single-center study of clinical presentation and outcome in 117 patients. J Pediatr, 1993. 123 (4): p. 564-72.
25. 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 (11): p. 1788-94.
26. Casteels-Van Daele, M., et al., Intravenous immune globulin and acute aseptic meningitis [letter]. N Engl J Med, 1990. 323 (9): p. 614-5.
27. Kato, E., et al., Administration of immune globulin associated with aseptic meningitis [letter]. Jama, 1988. 259 (22): p. 3269-71.
28. Scribner, C.L., et al., Aseptic meningitis and intravenous immunoglobulin therapy [editorial; comment]. Ann Intern Med, 1994. 121 (4): p. 305-6.
29. Copelan E.A., Stohm P.L., Kennedy M.S., Tutschka P.J. Hemolysis following intravenous immune globulin therapy. Transfusion 1986. 26 : 410-412.
30. Thomas M.J., Misbah S.A., Chapel H.M., Jones M., Elrington G., Newsom-Davis J. Hemolysis after high-dose intravenous Ig. Blood 1993. 15 :3789.
31. Wilson J.R., Bhoopalam N., Fisher M. Hemolytic anemia associated with intravenous immunoglobulin. Muscle & Nerve 1997. 20 :1142-1145.
32. Kessary-Shoham H., Levy Y., Shoenfeld Y., Lorber M., Gershon H. In vivo administration of intravenous immunoglobulin (IVIg) can lead to enhanced ecrythrocyte sequestration. J Autoimmune 1999. 13 :129-135.
33. Rizk A., Gorson K.C., Kenney L., Weinstein R. Transfusion-related acute lung injury after the infusion of IVIG. Transfusion 2001. 41 :264-268.
34. Dalakas M.C. High-dose intravenous Immunoglobulin and serum viscosity: risk of precipitating thromboembolic events. Neurology, 44 : 223-226.
35. Woodruff R.K., Grigg A.P., Firkin F.C., Smith I.L. Fatal thrombotic events during treatment of autoimmune thrombocytopenia with intravenous immunoglobulin in elderly patients. Lancet 1986. 2 :217-218.
36. Wolberg A.S., Kon R.H., Monroe D.M., Hjoffman M. Coagulation factor XI is a contaminant in intravenous immunoglobulin preparations. Am J Hematol 2000. 65 ,30-34.
37. Winward, D.B. and M.T. Brophy, Acute renal failure after administration of intravenous immunoglobulin: review of the literature and case report. Pharmacotherapy, 1995. 15 (6): p. 765-72.
38. Peerless, A.G. and E.R. Stiehm, Intravenous gammaglobulin for reaction to intramuscular preparation [letter]. Lancet, 1983. 2 (8347): p. 461.
39. Data on file.
40. Stangel, M.M., et al., Side effects of intravenous immunoglobulins in neurological autoimmune disorders A prospective study. J Neurol, 2003. 250 (7): p. 818-21.
41. Ebeling, F., et al., Tolerability and kinetics of a solvent-detergent-treated intravenous immunoglobulin preparation in hypogammaglobulinaemia patients. Vox Sang, 1995. 69 (2): p. 91-4.
42. Kelleher J., S.L., IGIV-C 10% Rapid Infusion Trial in Idiopathic (Immune) Thrombocytopenic Purpura (ITP), 2001 . Report on file.
43. George, J.N., et al., Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology [see comments]. Blood, 1996. 88 (1): p. 3-40.
44. Tan, E., et al., Acute renal failure resulting from intravenous immunoglobulin therapy. Arch Neurol, 1993. 50 (2): p. 137-9.
45. Eijkhout, H.W., et al., The effect of two different dosages of intravenous immunoglobulin on the incidence of recurrent infections in patients with primary hypogammaglobulinemia. A randomized, double-blind, multicenter crossover trial. Ann Intern Med, 2001. 135 (3): p. 165-74.
46. Pierce L.R., Jain N. Risks associated with the use of intravenous immunoglobulin. Trans Med Rev, 2003. 17 :241-251.
47. Stenland CJ, Lee DC, Brown P, et al. Partitioning of human and sheep forms of the pathogenic prion protein during the purification of therapeutic proteins from human plasma. Transfusion 2002. 42 (11):1497-500.
48. Lee DC, Stenland CJ, Miller, JL, et al. A direct relationship between the partitioning of the pathogenic prion protein and transmissible spongiform encephalopathy infectivity during the purification of plasma proteins. Transfusion 2001. 41 (4):449-55.
49. Lee DC, Stenland CJ, Hartwell, RC, et al. Monitoring plasma processing steps with a sensitive Western blot assay for the detection of the prion protein. J Virol Methods 2000. 84 (1):77-89.
50. Cai K, Miller JL, Stenland, CJ, et al. Solvent-dependent precipitation of prion protein. Biochim Biophys Acta 2002. 1597 (1):28-35.
51. Trejo SR, Hotta JA, Lebing W, et al. Evaluation of virus and prion reduction in a new intravenous immunoglobulin manufacturing process. Vox Sang 2003. 84 (3):176-87.

Talecris Biotherapeutics, Inc.

Research Triangle Park, NC 27709 USA

U.S. License No.1716 08936212 (Rev. July 2005)