Immune Globulin Intravenous (Human) [IGIV] Gammagard S/D is a solvent/detergent treated, sterile, freeze-dried preparation of highly purified immunoglobulin G (IgG) derived from large pools of human plasma. The product is manufactured by the Cohn-Oncley cold ethanol fractionation process followed by ultrafiltration and ion exchange chromatography. Source material for fractionation may be obtained from another U.S. licensed manufacturer. The manufacturing process includes treatment with an organic solvent/detergent mixture, ^1,2 composed of tri-n-butyl phosphate, octoxynol 9 and polysorbate 80. ³ The Gammagard S/D IGIV manufacturing process provides a significant viral reduction in in vitro studies. ³ These studies, summarized in Table 1 , demonstrate virus clearance during Gammagard S/D manufacturing using infectious Human Immunodeficiency virus, Types 1 and 2 (HIV-1, HIV-2); Bovine Viral Diarrhea virus (BVD), a model virus for Hepatitis C virus; Sindbis virus (SIN), a model virus for lipid enveloped viruses; Pseudorabies virus (PRV), a model virus for lipid-enveloped DNA viruses such as Herpes; Vesicular stomatitis virus (VSV), a model virus for lipid-enveloped RNA viruses; and Encephalomyocarditis virus (EMC), a model virus for non-lipid enveloped viruses. ³ These reductions are achieved through a combination of process chemistry, partitioning and/or inactivation during cold ethanol fractionation and the solvent/detergent treatment. ³

When reconstituted with the total volume of diluent (Sterile Water for Injection, USP) supplied, this preparation contains approximately 50 mg of protein per mL (5%), of which at least 90% is gamma globulin. The product, reconstituted to 5%, contains a physiological concentration of sodium chloride (approximately 8.5 mg/mL) and has a pH of 6.8 ± 0.4. Stabilizing agents and additional components are present in the following maximum amounts for a 5% solution: 3 mg/mL Albumin (Human), 22.5 mg/mL glycine, 20 mg/mL glucose, 2 mg/mL polyethylene glycol (PEG), µg/mL tri-n-butyl phosphate, 1 µg/mL octoxynol 9, and 100 µg/mL polysorbate 80. If it is necessary to prepare a 10% (100 mg/mL) solution for infusion, half the volume of diluent should be added, as described in the Dosage and Administration section. In this case, the stabilizing agents and other components will be present at double the concentrations given for the 5% solution.

The manufacturing process for Gammagard S/D IGIV isolates IgG without additional chemical or enzymatic modification, and the Fc portion is maintained intact. Gammagard S/D IGIV contains all of the IgG antibody activities which are present in the donor population. On the average, the distribution of IgG sublcasses present in this product is similar to that in normal plasma. ³ Gammagard S/D IGIV contains only trace amounts of IgA (< 3.7 µg/mL in a 5% solution). IgM is also present in trace amounts.

Immune Globulin Intravenous (Human), Gammagard S/D IGIV contains no preservative.

Immune Globulin Intravenous (Human), Gammagard S/D, contains a broad spectrum of IgG antibodies against bacterial and viral agents that are capable of opsonization and neutralization of microbes and toxins. Peak levels of IgG are reached immediately after infusion of Gammagard S/D IGIV S/D. It has been shown that, after infusion, exogenous IgG is distributed relatively rapidly between plasma and extravascular fluid until approximately half is partitioned in the extravascular space. Therefore a rapid initial drop in serum IgG levels is to be expected. ⁴

As a class, IgG survives longer in vivo than other serum proteins. ^4,5 Studies show that the half-life of Gammagard S/D IGIV is approximately 37.7 ± 15 days. ³ Previous studies reported IgG half-life values of 21 to 25 days. ^4,5,6 The half-life of IgG can vary considerably from person to person, however. In particular, high concentrations of IgG and hypermetabolism associated with fever and infection have been seen to coincide with a shortened half-life of IgG. ^4-7

Primary Immunodeficiency Diseases

Gammagard S/D IGIV is indicated for the treatment of primary immunodeficient states, such as: congenital agammaglobulinemia, common variable immunodeficiency, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies. ^6,7 This indication was supported by a clinical trial of 17 patients with primary immunodeficiency who received a total of 341 infusions. Gammagard S/D IGIV is especially useful when high levels or rapid elevation of circulating IgG are desired or when intramuscular injections are contraindicated (e.g., small muscle mass).

B-cell Chronic Lymphocytic Leukemia (CLL)

Gammagard S/D IGIV is indicated for prevention of bacterial infections in patients with hypogammaglobulinemia and/or recurrent bacterial infections associated with B-cell Chronic Lymphocytic Leukemia (CLL). In a study of 81 patients, 41 of whom where treated with Immune Globulin Intravenous (Human), Gammagard S/D IGIV, bacterial infections were significantly reduced in the treatment group. ^8,9 In this study, the placebo group had approximately twice as many bacterial infections as the IGIV group. The median time to first bacterial infection for the IGIV group was greater than 365 days. By contrast, the time to first bacterial infection in the placebo group was 192 days. The number of viral and fungal infections, which were for the most part minor, was not statistically different between the two groups.

Idiopathic Thrombocytopenic Purpura (ITP)

When a rapid rise in platelet count is needed to prevent and/or to control bleeding in a patient with Idiopathic Thrombocytopenic Purpura, the administration of Gammagard S/D IGIV, should be considered.

The efficacy of Gammagard S/D IGIV has been demonstrated in a clinical study involving 16 patients. Of these 16 patients, 13 had chronic ITP (11 adults, 2 children), and three patients had acute ITP (one adult, two children). All 16 patients (100%) demonstrated a clinically significant rise in platelet count to a level greater than 40,000/mm ³ following the administration of Gammagard S/D IGIV. Ten of the 16 patients (62.5%) exhibited a significant rise to greater than 80,000 platelets/mm ³ . Of these ten patients, seven had chronic ITP (five adults, two children), and three patients had acute ITP (one adult, two children).

The rise in platelet count to greater than 40,000/mm ³ occurred after a single 1 g/kg infusion of Gammagard S/D IGIV in eight patients with chronic ITP (six adults, two children), and in two patients with acute ITP (one adult, one child). A similar response was observed after two 1 g/kg infusions in three adult patients with chronic ITP, and one child with acute ITP. The remaining two adult patients with chronic ITP received more than two 1 g/kg infusions before achieving a platelet count greater than 40,000/mm ³ . The rise in platelet count was generally rapid, occurring within five days. However, this rise was transient and not considered curative. Platelet count rises lasted two to three weeks, with a range of 12 days to six months. It should be noted that childhood ITP may resolve spontaneously without treatment.

Kawasaki Syndrome

Gammagard S/D IGIV is indicated for the prevention of coronary artery aneurysms associated with Kawasaki syndrome. The percentage incidence of coronary artery aneurysm in patients with Kawasaki syndrome receiving Gammagard S/D IGIV either at a single dose of 1 g/kg (n=22) or at a dose of 400 mg/kg for four consecutive days (n=22), beginning within seven days of onset of fever, was 3/44 (6.8%). This was significantly different (p=0.008) from a comparable group of patients that received aspirin only in previous trials and of whom 42/185 (22.7%) experienced coronary artery aneurysms. ^{19, 22, 23} All patients in the Gammagard S/D IGIV trial received concomitant aspirin therapy and none experienced hypersensitivity-type reactions (urticaria, bronchospasm or generalized anaphylaxis). ¹⁸

Several studies have documented the efficacy of intravenous gammaglobulin in reducing the incidence of coronary artery abnormalities resulted from Kawasaki syndrome. ^19-25

CONTRAINDICATIONS

None known.

Immune Globulin Intravenous (Human), Gammagard S/D, should only be administered intravenously. Other routes of administration have not been evaluated.

Immediate anaphylactic and hypersensitivity reactions are a remote possibility. Epinephrine should be available for treatment of any acute anaphylactoid reactions.

Gammagard S/D IGIV contains only trace amounts of IgA (< 3.7 µg/mL in a 5% solution). Nonetheless, it should be given with caution to patients with antibodies to IgA or selective IgA deficiencies. ^7,10

PRECAUTIONS

General

There is clinical evidence of a possible association between Immune Globulin Intravenous (Human) (IGIV) administration and thrombotic events. The exact cause of this is unknown; therefore, caution should be exercised in the prescribing and infusion of IGIV in patients with a history of cardiovascular disease or thrombotic episodes. ^12-17

As aseptic meningitis syndrome (AMS) has been reported to occur infrequently in association with Immune Globulin Intravenous (Human) (IGIV) treatment. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae. The syndrome usually begins within several hours to two days following IGIV treatment. It is characterized by symptoms and signs including 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 cu.mm., predominantly from the granulocytic series, and elevated protein levels up to several hundred mg/dL. Patients exhibiting such symptoms and signs should receive a thorough neurological examination, including CSF studies, to rule out other causes of meningitis. AMS may occur more frequently in association with high dose (2 g/kg) IGIV treatment.

Assure that patients are not volume depleted prior to the initiation of the infusion of IGIV.

Periodic monitoring of renal function tests 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 Gammagard S/D IGIV 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, it may be prudent to reduce the amount of product infused per unit time by infusing Gammagard S/D IGIV at a rate less than 13.3 mg IG/kg/min.

Certain components used in the packaging of this product contain natural rubber latex.

INFORMATION FOR PATIENTS

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

Drug Interactions

See Dosage and Administration Section.

Pregnancy Category C

Animal reproduction studies have not been conducted with Immune Globulin Intravenous (Human), Gammagard S/D IGIV. It is also not known whether Gammagard S/D IGIV can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Gammagard S/D IGIV should be given to a pregnant woman only if clearly needed.

ADVERSE REACTIONS

Increases in creatinine and blood urea nitogen (BUN) have been observed as soon as one to two days following infusion. Progression to oliguria and anuria requiring dialysis has been observed, although some patients have improved spontaneously following cessation of treatment. ²⁷

Types of severe renal adverse reactions that have been seen following IGIV therapy include:

• acute renal failure
• acute tubular necrosis ²⁸
• proximal tubular nephropathy
• osmotic nephrosis ^29-31

In general, reported adverse reactions to Gammagard S/D IGIV in patients with either congenital or acquired immunodeficiencies are similar in kind and frequency. Various minor reactions, such as headache, fatigue, chills, backache, leg cramps, lightheadedness, fever, urticaria, flushing, slight elevation of blood pressure, nausea and vomiting may occasionally occur. Slowing or stopping the infusion usually allows the symptoms to disappear promptly. Immediate anaphylactic and hypersensitivity reactions are a remote possibility. Epinephrine should be available for treatment of any acute anaphylactoid reaction (See ).

Primary Immunodeficiency Diseases

Twenty-one adverse reactions occurred in 341 infusions (6%), when using Gammagard S/D IGIV (5% solution). in a clinical trial of 17 patients with primary immunodeficiency. ¹¹ Of the 17 patients, 12 (71%) were adults, and 5 (29%) were children (16 years or younger).

In a cross-over study comparing Gammagard S/D IGIV and Gammard (5% solutions) conducted in a small number (n=10) of primary immunodeficient patients, no unusual or unexpected adverse reactions were observed in the Gammagard S/D IGIV group. The adverse reactions experienced in the Gammagard S/D IGIV group were similar in frequency and nature to those observed in the control group consisting of patients receiving Gammagard S/D IGIV.

Gammagard S/D IGIV reconstituted to a concentration of 10%, was administered intravenously at rates varying from 2-11 mL/kg/Hr. Systemic reactions occurred in 23 (10.5%) of 219 infusions. This compares with an adverse reaction incidence of 6% (only systemic reactions reported) for primary immunodeficient patients previously treated with a 5% solution at infusion rates varying between 2 and 8 mL/kg/Hr, as described above (also, see reference 11 ). Local pain or irritation was experienced during 35 (16%) of 219 infusions. Application of a warm compress to the infusion site alleviated local symptoms.

These local reactions tended to be associated with hand vein infusions and their incidence may be reduced by infusions via the antecubital vein.

B-cell Chronic Lymphocytic Leukemia (CLL)

In the study of patients with B-cell Chronic Lymphocytic Leukemia, the incidence of adverse reactions associated with Gammagard S/D IGIV infusions was approximately 1.3% while that associated with placebo (normal saline) infusions was 0.6%. ⁹

Idiopathic Thrombocytopenic Purpura (ITP)

During the clinical study of Gammagard S/D IGIV for the treatment of Idiopathic Thrombocytopenic Purpura, the only adverse reaction reported was headache which occurred in 12 of 16 patients (75%). Of these 12 patients, 11 had chronic ITP (9 adults, 2 children), and one child had acute ITP. Oral antihistamines and analgesics alleviated the symptoms and were used as pretreatment for those patients requiring additional IGIV therapy. The remaining four patients did not report any side effects and did not require pretreatment.

Kawasaki Syndrome

In a study of patients (n=51) with Kawasaki syndrome, no hypersensitivity type reactions (urticaria, bronchospasm or generalized anaphylaxis) were reported in patients receiving either a single 1 g/kg dose of IGIV. Gammagard S/D IGIV , or 400 mg/kg of IGIV, Gammagard S/D IGIV , for four consecutive days. 12 mild adverse reactions, including chills, flushing, cramping, headache, hypotension, nausea, rash, and wheezing, were reported with both dose regimens. These adverse reactions occurred in 7/51 (13.7%) patients and in association with 7/129 (5.4%) infusions. Of the 25 patients who received a single 1g/kg dose, four patients experienced adverse reactions for an incidence of 16%. Of the 26 patients who received 400 mg/kgday over four days, three experienced a single adverse reaction for an incidence of 11.5%. ³

DOSAGE AND ADMINISTRATION

Primary Immunodeficiency Diseases

For patients with primary immunodeficiencies, monthly doses of at least 100 mg/kg are recommended. Initially, patients may receive 200-400 mg/kg. As there are significant differences in the half-life of IgG among patients with primary immunodeficiencies, the frequency and amount of immunoglobulin therapy may vary from patient to patient. The proper amount can be determined by monitoring clinical response. The minimum serum concentration of IgG necessary for protection has not been established.

B-cell Chronic Lymphocytic Leukemia (CLL)

For patients with hypogammaglobulinemia and/or recurrent bacterial infrections due to B-cell Chronic Lymphocytic Leukemia, a dose of 400 mg/kg every three to four weeks is recommended.

Kawasaki Syndrome

For patients with Kawasaki syndrome, either a single 1 g/kg dose or a dose of 400 mg/kg for four consecutive days beginning within seven days of the onset of fever, administered concomitantly with appropriate aspirin therapy (80-100 mg/kg/day in four divided doses) is recommended.

Idiopathic Thrombocytopenic Purpura (ITP)

For patients with acute or chronic Idiopathic Thrombocytopenic Purpura, a dose of 1 g/kg is recommended. The need for additional doses can be determined by clinical response and platelet count. Up to three separate doses may be given on alternate days, if required.

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, the recommended doses should not be exceeded and the concentration and infusion rate selected 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. ³²

Reconstitution: Use Aseptic Technique

When reconstitution is performed aspetically outside of a sterile laminar air flow hood, administration should begin as soon as possible, but not more than two hours after reconstitution.

When reconstitution is performed aseptically in a sterile laminar air flow hood, the reconstituted product may be either maintained in the original glass container or pooled into Viaflex® bags and stored under constant refrigeration (2-8°C), for up to 24 hours. (The data and time of reconstitution/pooling should be recorded). If these conditions are not met, sterility of the reconstituted product cannot be maintained. Partially used vials should be discarded.

A.   5-Solution

1. Note: Reconstitute immediately before use.
2. If refrigerated, warm the Sterile Water for Injection, USP (diluent) and Immune Globulin Intravenous (Human), Gammagard S/D (dried concentrate), to room temperature.
3. Remove caps from concentrate and diluent bottles to expose central portion of rubber stoppers.
4. Cleanse stoppers with germicidal solution.
5. Remove protective covering from the spike at one end of the transfer device ( Figure 1 ).

1. Place the diluent bottle on a flat surface and, while holding the bottle to prevent slipping, insert the spike of the transfer device perpendicularly through the center of the bottle stopper.
2. Press down firmly so that the transfer device fits snugly against the diluent bottle ( Figure 2 ).

Caution: Failure to use center of stopper may result in dislodging the stopper.

1. Remove the protective convering from the other end of the transfer device. Hold diluent bottle to prevent slipping.
2. Hold concentrate bottle firmly and at an angle of approximately 45 degrees. Invert the diluent bottle with the transfer device at an angle complementary to the concentrate bottle (approximately 45 degrees) and firmly insert the transfer device into the concentrate bottle through the center of the rubber stopper ( Figure 3 ).

Note: Invert the diluent bottle with attached transfer device rapidly into the concentrate bottle in order to avoid loss of diluent.

Caution: Failure to use center of stopper may result in dislodging the stopper and loss of vacuum.

1. The diluent will flow into the concentrate bottle quickly. When diluent transfer is complete, remove empty diluent bottle and transfer device from concentrate bottle. Discard transfer device after single use.
2. Thoroughly wet the dried material by tilting or inverting and gently rotating the bottle ( Figure 4 ). Do not shake. Avoid foaming.

1. Repeat gentle rotation as long as undissolved product is observed.

B.  10% Solution

Follow steps 1-4 as previously described in A .

5. To prepare a 10% solution, reconstitute with the appropriate volume of diluent as indicated in Table 2 , which indicates the volume of diluent required for a 5% or 10% concentration. Using aseptic technique, draw required volume into a sterile hypodermic syringe and needle. Discard the filled syringe.

6. Using the residual diluent in the diluent vial, follow steps 5-12 as previously described in A .

Rate of Administration

It is recommended that initially a 5% solution be infused at a rate of 0.5 mL/kg/Hr. If infusion at this rate and concentration causes the patient no distress, the administration rate may be gradually increased to a maximum rate of 4 mL/kg/Hr. Patients who tolerate the 5% concentration at 4 mL/kg/Hr can be infused with the 10% concentration starting at 0.5 mL/kg/Hr. If no adverse effects occur, the rate can be increased gradually up to a maximum of 8 mL/kg/Hr.

For patients judged to be at risk for developing renal dysfunction, it may be prudent to reduce the amount of product infused per unit time by infusing Gammagard S/D IGIV at a rate less than 13.3 mg IG/kg/min. (<0.27 mL/kg/min. of 5% or <0.13 mL/kg/min. of 10%).

It is recommended that antecubital veins be used especially for 10% solutions, if possible. This may reduce the likelihood of the patient experiencing discomfort at the infusion site (see Adverse Reactions ).

A rate of administration which is too rapid may cause flushing and changes in pulse rate and blood pressure. Slowing or stopping the infusion usually allows the symptoms to disappear promptly.

Drug Interactions

Admixtures of Immune Globulin Intravenous (Human), Gammagard S/D , with other drugs and intravenous solutions have not been evaluated. It is recommended that Gammagard S/D IGIV , be administered separately from other drugs or medications which the patient may be receiving. The product should not be mixed with Immune Globulin Intravenous (Human) from other manufacturers.

Antibodies in immune globulin preparations may interfere with patient responses to live vaccines, such as those for measles, mumps, and rubella. The immunizing physician should be informed of recent therapy with Immune Globulin Intravenous (Human) so that appropriate precautions can be taken.

Administration

Gammagard S/D IGIV should be administered as soon after reconstitution as possible or as described in the Dosage and Administration section. The reconstituted material should be at room temperature during administration. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if particulate matter and/or discoloration is observed.

Follow directions for use which accompany the administration set provided. If another administration set is used, ensure that the set contains a similar filter.

How Supplied

Gammagard S/D IGIV is supplied in 0.5 g, 2.5 g, 5 g, or 10 g single use bottles. Each bottle of Gammagard S/D IGIV is furnished with a suitable volume of Sterile Water for Injection, USP, a transfer device and an administration set which contains an integral airway and a 15 micron filter.

Storage

Gammagard S/D IGIV , is to be stored at a temperature not to exceed 25°C (77°F). Freezing should be avoided to prevent the diluent bottle from breaking.

REFERENCES

1. Prince AM, Horowitz B, Brotman B: Sterilisation of hepatitis and HTLV-III viruses by exposure to tri-n-butyl phosphate and sodium cholate. Lancet 1 :706-710, 1986
2. Horowitz B, Wiebe ME, Lippin A, et al : Inactivation of viruses in labile blood derivatives: I. Disruption of lipid enveloped viruses by tri-n-butyl phosphate detergent combinations. Transfusion 25 :516-522, 1985
3. Unpublished data in the files of Baxter health-care Corporation
4. Waldmann TA, Storber W: Metabolism of immunoglobulins. Prog Allergy 13 :1-110, 1969
5. Morell A, Riesen W: Structure, function and catabolism of immuno globulins in Immunohemotherapy . Nydegger UE (ed), London, Academic Press, 1981, pp 17-26
6. Stiehm ER: Standard and special human immune serum globulins as therapeutic agents. Pediatrics 63 :301-319, 1979
7. Buckley RH: Immunoglobulin replacement therapy: and contraindications for use and variable IgG levels achieved in Immunoglobulins: Characteristics and Use of Intravenous Preparations . Alving BM, Finlayson JS (eds), Washington, DC, U.S. Department of Health and Human Services, 1979, pp 3-8.
8. Bunch C, Chapel HM, Rai K, et al: : Intravenous Immune Globulin reduces bacterial infections in Chronic Lymphocytic Leukemia: A controlled randomized clinical trial. Blood 70 Suppl 1 :753, 1987
9. Cooperative Group for the Study of Immunoglobulin in Chronic Lymphocytic Leukemia: Intravenous immunoglobulin for the prevention of infection in Chronic Lymphocytic Leukemia: A randomized, controlled clinical trial. N Eng J Med 319 :902-907, 1988
10. Burks AW, Sampson HA, Buckley RH: Anaphylactic reactions after gammaglobulin administration in patients with hypogammaglobulinemia: Detection of IgE antibodies to IgA. N Eng J Med 314 :560-564, 1986
11. Ochs HD, Lee ML, Fischer SH, et al : Efficacy of a New Intravenous Immunoglobulin Preparation in Primary Immunodeficient Patients. Clinical Therapeutics 9 :512-522, 1987
12. Reinhart WH, Berchtold PE: Effect of high-dose intravenous immunoglobulin therapy on blood rheology. Lancet 339 : 662-664, 1992
13. Dalakas MC: High-dose intravenous immunoglobulin and serum viscosity: Risk of precipitating thromboembolic events. Neurology 44 :223-226, 1994
14. Harkness K, Howell SJL, Davies-Jones GAB: Encephalopathy associated with intravenous immunoglobulin treatment for Guillain-Barre syndrome. Journal of Neurology 60 :586-598, 1996
15. Woodruff RK, Grigg AP, Firkin FC, Smith IL: Fatal thrombotic events during treatment of autoimmune thrombocytopenia with intravenous immunoglobulin in elderly patients. Lancet ii :217-218, 1986
16. Silbert PL, Knezevic WV, Bridge DT: Cerebral infarction complicating intravenous immunoglobulin therapy for polyneuritis cranialis. Neurology 42 :257-258, 1992
17. Duhem C, Dicato MA, Ries F: Side effects of intravenous immune globulins. Clin Exp Immunol 97: (Suppl 1) 70-83, 1994
18. Data in the files of Baxter Healthcare Corporation
19. Newburger J, Takahashi M, Burns JG, et al : The Treatment of Kawasaki Syndrome with Intravenous Gamma Globulin. New England Journal of Medicine 315 :341-347, 1986
20. Furusho K, Hroyuki N, Shinomiya K, et al : High Dose Intravenous Gammaglobulin for Kawasaki Disease. Lancet 2 :1055-1058, 1984
21. Engle MA, Fatica NS, Bussel JB, O'Laughlin JE, Snyder MS, Lesser ML: Clinical Trial of Single-Dose Intravenous Gammaglobulin in Acute Kawasaki Disease. AJDC143 :1300-1304, 1989
22. Furusho K, Sato K, Soeda T, et al : High Dose Intravenous Gammaglobulin for Kawasaki Disease [letter]. Lancet 2 :1359, 1983
23. Nagashima M, Matsushima M, Matsucka H, Ogawa A, Okumura N: High Dose Gammaglobulin Therapy for Kawasaki Disease. Journal of Pediatrics 110 :710-712, 1987
24. Isawa M, Sugiyama K, Kawase A, et al : Prevention of Coronary Artery Involvement in Kawasaki Disease by Early Intravenous High Dose Gammaglobulin. In: Doyle EF, Engle MA, Gersony WM, Rashkind EJ, Talner NS, eds. Pediatric Cardiology . New York: Springer-Verlag, 1986:1083-1085
25. Okuri M, Harada K, Yamaguchi H, et al : Intravenous Gammaglobulin Therapy in Kawasaki Disease: Trial of Low-Dose Gammaglobulin. In: Shulman ST, ed. Kawasaki Disease . New York: Alan R. Liss, 1987:433-439
26. Cayco AV, Perazella MA, Hayslett JP: Renal insufficiency after intravenous immune globulin therapy: A Report of Two Cases and an Analysis of the Literature. 1997; J Amer Soc Nephrology 8 : 1788-1793
27. Winward DB, Brophy MT: Acute renal failure after administration of intravenous immunoglobulin: review of the literature and case report. 1995; Pharmacotherapy 15 :765?
28. Phillips AO: Renal failure and intravenous immunoglobulin [letter, comment]. 1992; Clin Nephrol 36 :83-86
29. Anderson W, Bethea W: Renal lesions following administration of hypertonic solutions of sucrose. 1940; JAMA 114 :1983-1987
30. Lindberg H, Wald A: Renal changes following the administration of hypertonic solutions. 1939; Arch Intern Med 63 : 907-918
31. Rigdon RH, Cardwell ES: Renal lesions following the intravenous injection of hypertonic solution of sucrose: A clinical and experimental study. 1942; Arch Intern Med 69 :670-690
32. Tan E, Hajinazarian M, Bay, et al : Acute renal failure resulting from intravenous immunoglobulin therapy. 1993; Arch Neurology 50 :137-139

BIBLIOGRAPHY

Bussel JB, Kimberly RP, Inman RD, et al : Intravenous gammaglobulin treatment of chronic idiopathic thrombocytopenic purpura. Blood 62 :480-486, 1983

* Manufactured Under U.S. Patent No. 4,439,421.

Baxter Healthcare Corporation

Hyland Division

Glendale, CA 91203 USA

U.S. License No. 140 Revised May 1999

30-5K-03-120

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