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Gamimune N (Immune Globulin) - Description and Clinical Pharmacology



Immune Globulin Intravenous (Human), 10% -- Gamimune® N, 10% treated with solvent/detergent is a sterile solution of human protein containing no preservative. Gamimune N, 10% consists of 9%-11% protein in 0.16-0.24 M glycine. Not less than 98% of the protein has the electrophoretic mobility of gamma globulin. Not less than 90% of the IgG is monomer. Also present are traces of IgA and of IgM. The distribution of IgG subclasses is similar to that found in normal serum. The measured buffer capacity is 35 mEq/L and the osmolality is 274 mOsmol/kg solvent.

The product is made by cold ethanol fractionation of large pools of human plasma. Part of the fractionation may be performed by another licensed manufacturer. The immunoglobulin is isolated from Cohn Effluent III after limited diafiltration and ultrafiltration. The solution is adjusted to 0.3% tri-n-butyl phosphate (TNBP) and 0.2% sodium cholate. After addition of the solvent (TNBP) and the detergent (sodium cholate), the solution is heated to 30°C and maintained at that temperature for not less than 6 hours. After the viral inactivation step, the reactants are removed by precipitation, filtration, and finally diafiltration and ultrafiltration. The protein is stabilized during the process by adjusting the pH of the solution to 4.0-4.5. 1 Isotonicity is achieved by the addition of glycine. Gamimune N, 10% treated with solvent/detergent is then incubated in the final container (at the low pH of 4.25), for a minimum of 21 days at 20°C. The product is intended for intravenous administration.

The removal and inactivation of spiked model enveloped and non-enveloped viruses during the manufacturing process for Gamimune N, 10% has been validated in laboratory studies. Human Immunodeficiency Virus, Type 1 (HIV-1) was chosen as the relevant virus for blood products; Bovine Viral Diarrhea Virus (BVDV) was chosen to model for Hepatitis C virus; Pseudorabies virus (PRV) was chosen to model for Hepatitis B and the Herpes viruses; and Reo virus type 3 (Reo) was chosen to model non-enveloped viruses and for its resistance to physical and chemical inactivation. Significant removal of model enveloped and non-enveloped viruses is seen between the Fraction II + IIIW and Effluent III steps and between the Effluent III and Filtrate III steps. Significant inactivation of enveloped viruses is achieved at the time of treatment of Filtrate III with TNBP/sodium cholate and also at the time of low pH incubation in the final container.



Gamimune N, 10% supplies a broad spectrum of opsonic and neutralizing IgG antibodies for the prevention or attenuation of a wide variety of infectious diseases. Since Gamimune N, 10% is administered intravenously, essentially 100% of the infused IgG antibodies are immediately available in the recipient's circulation.2 Studies using a modified intravenous immunoglobulin at pH 6.8 have shown that approximately 30% of the infused IgG disappeared from the circulation in the first 24 hours, due primarily to equilibration of the IgG between the plasma and the extravascular space.2-5 A further decline to about 40% of the peak level found immediately post-infusion is to be expected during the first week. 2-5 The in vivo half-life of Immune Globulin Intravenous (Human), 5%--Gamimune® N, 5% equals or exceeds the 3-week half-life reported for IgG in the literature, but individual patient variation in half-life has been observed. 2 Thus, this variable as well as the amount of immune globulin administered per dose is important in determining the frequency of administration of the drug for each individual patient. A comparative study of Gamimune N, 10% with Gamimune N, 5% (in 10% maltose) in 18 subjects demonstrated equivalent post-infusion recovery for the two preparations. A comparative study of Gamimune N, 10% treated with solvent/detergent and Gamimune N, 10% in 17 subjects demonstrated bioequivalence.


While Gamimune N, 10% has been shown to be effective in some cases of idiopathic thrombocytopenic purpura (ITP) (see INDICATIONS AND USAGE), the mechanism of action has not been fully elucidated.


Clinical studies with Gamimune N, 5% have shown that it is effective in bone marrow transplant patients >/= 20 years of age in the first 100 days posttransplant for the following: prevention of systemic and local infections, interstitial pneumonia of infectious and idiopathic etiologies and acute graft-versus-host disease (AGVHD) 6(see INDICATIONS AND USAGE). Administration of Gamimune N, 5% to bone marrow transplant patients significantly increased IgG and IgG subclass levels while those seen in the control group fell below predicted levels. The mechanism of action of Gamimune N, 5% in reducing the incidence of AGVHD is presently unknown.


Children infected with human immunodeficiency virus (HIV) may display defects in both cellular and humoral immunity.7-10 As a result, some children with HIV-1 infection experience serious, potentially life-threatening recurrent bacterial infections. 11-13 In one retrospective report, among 71 HIV-infected children observed over 3.5 years, 27 (37%) experienced serious documented bacterial infections. 12 The types of bacterial and viral infections observed in HIV-infected children are similar to those seen in children with primary hypogammaglobulinemia.14 The replacement of opsonic and neutralizing IgG antibodies has been shown to reduce serious and minor bacterial infection in HIV-infected children. 15,16

In a randomized, double-blind, placebo-controlled, multicenter study performed between March 7, 1988 and January 15, 1991, the efficacy of Gamimune N, 5% in pediatric HIV disease to decrease the frequency of serious and minor bacterial infections and the frequency of hospitalization, and to increase the time free of serious bacterial infection was documented in children with clinical or immunologic evidence of HIV disease (see INDICATIONS AND USAGE). The primary endpoint of this study was prospectively defined as a significant reduction in the proportion of subjects who develop at least one serious bacterial infection when compared to the control group of HIV-infected children who received placebo. Serious bacterial infections were defined as laboratory-proven and clinically diagnosed (i.e., radiologically proven acute pneumonia and sinusitis) infections. The Data Safety and Monitoring Board (DSMB) recommended early termination of the study based on data presented to them from an interim analysis in December 1990 which showed that treatment with Gamimune N, 5% increased the time free from serious infections in children with CD4 + counts >/= 200/mm3.


Glycine (aminoacetic acid) is a nonessential amino acid normally present in the body.17 Glycine is a major ingredient in amino acid solutions employed in intravenous alimentation.18 While toxic effects of glycine administration have been reported, 19 the doses and rates of administration were 3 - 4-fold greater than those for Gamimune N, 10%.

The buffer capacity of Gamimune N, 10% is 35.0 mEq/L (~0.35 mEq/g protein). A dose of 1000 mg/kg body weight therefore represents an acid load of 0.35 mEq/kg body weight. The total buffering capacity of whole blood in a normal individual is 45-50 mEq/L of blood, or 3.6 mEq/kg body weight.20 Thus, the acid load delivered with a dose of 1000 mg/kg of Gamimune N, 10% would be neutralized by the buffering capacity of whole blood alone, even if the dose was infused instantaneously.

In Phase I human studies comparing Gamimune N, 10% with Gamimune N, 5% (in 10% maltose), venous blood measurements were taken following the intravenous administration of 400 mg/kg body weight in 18 patients. There were no clinically important changes in mean venous pH, bicarbonate, or base excess measurements in these patients receiving either preparation.2

In a similar, earlier Phase I study Gamimune N, 5% (in 10% maltose) was compared with a chemically modified 5% intravenous immunoglobulin preparation with a pH of 6.8. No clinically important changes in mean venous pH and bicarbonate measurements were detected following infusions of either preparation at doses of 400 mg/kg body weight in 37 patients.

In patients with limited or compromised acid-base compensatory mechanisms, consideration should be given to the effect of the additional acid load Gamimune N, 10% might present.

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