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Gammagard Liquid

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Gammagard Liquid

Gammagard Liquid

CLINICAL PHARMACOLOGY

Clinical Efficacy

Use of GAMMAGARD LIQUID (immune globulin intravenous (human) 10%) in patients with Primary Immunodeficiency is supported by the Phase 3 clinical study of subjects who were treated with 300 to 600 mg/kg every 21 to 28 days for 12 months. The 61 subjects in this study were between 6 to 72 years of age, 54% female and 46% male, and 93% Caucasian, 5% African-American, and 2% Asian. Three subjects were excluded from the per-protocol analysis due to non-study product related reasons. The primary efficacy endpoint was the annualized rate of specified acute serious bacterial infections, i.e., the mean number of specified acute serious bacterial infections per subject per year (see Table 2).

Table 2: Summary of Validated Acute Serious Bacterial Infections for the Per-Protocol Analysis

  Number of Events
Validated Infections a
  Bacteremia/Sepsis 0
  Bacterial Meningitis 0
  Osteomyelitis/Septic Arthritis 0
  Bacterial Pneumonia 0
  Visceral Abscess 0
Total 0
Hospitalizations Secondary to Infection 0
Mean Number of Validated Infections per Subject per Year 0
  p-value b p < 0.0001
  95% Confidence Interval b (0.000, 0.064)
a Serious acute bacterial infections were defined by FDA and met specific diagnostic requirements.
b The rate of validated infections was compared with a rate of 1 per subject per year, in accordance with recommendations by the FDA Blood Products Advisory Committee.10

The secondary efficacy endpoints in this study were the annualized rate of other specified validated bacterial infections (see Table 3), and the number of hospitalizations secondary to all validated infectious complications (see Table 2 and Table 3).

Table 3: Summary of Validated Other Bacterial Infections

  Number of Events
Validated Infections a
  Urinary Tract Infection 1
  Gastroenteritis 1
  Lower Respiratory Tract Infection:  
Tracheobronchitis, Bronchiolitis Without Evidence of Pneumonia
0
  Lower Respiratory Tract Infection:  
Other Infections (e.g., Lung Abscess, Empyema)
0
  Otitis Media 2
Total 4
Hospitalizations Secondary to Infection 0
Mean Number of Validated Infections per Subject per Year 0.07
  95% Confidence Interval (0.018, 0.168)
a Other bacterial infections that met specific diagnostic requirements.

In this study, there were no validated acute serious bacterial infections in any of the treated subjects. The annualized rate of acute serious bacterial infections was significantly less than (p < 0.0001) the rate of one infection per year, in accordance with recommendations by the FDA Blood Products Advisory Committee.10 Four of the 61 subjects reported a total of 4 other specified validated bacterial infections. None were serious or severe, none resulted in hospitalization, and all resolved completely. The rate of all clinically-defined but non-validated infections was 3.4 infections per patient per year. These consisted primarily of recurrent episodes of commonly observed infections in this patient population - sinusitis, bronchitis, nasopharyngitis, urinary tract infections, and upper respiratory infections.

Pharmacokinetics

The overall pharmacokinetic characteristics of Immune Globulin Intravenous (Human) [IGIV] products are well-described in the literature.11,12 Following infusion, IGIV products show a biphasic decay curve. The initial (a) phase is characterized by an immediate post-infusion peak in serum IgG and is followed by rapid decay due to equilibration between the plasma and extravascular fluid compartments. The second (p) phase is characterized by a slower and constant rate of decay The commonly cited "normal" half life of 18 to 25 days is based on studies in which tiny quantities of radiolabeled IgG are injected into healthy individuals.13,14 When radiolabeled IgG was injected into patients with hypogammaglobulinemia or agammaglobulinemia, highly variable half-lives ranging from 12 to 40 days were observed.13,14 In other radiolabeled studies, high serum concentrations of IgG, and hypermetabolism associated with fever and infection, have been seen to coincide with a shortened half-life of IgG.14,15,16,17

In contrast, however, pharmacokinetic studies in immunodeficient patients are based on the decline of IgG concentrations following infusions of large quantities of gammaglobulin. In such trials, investigators have reported uniformly prolonged half-lives of 26 - 35 days.16,18,19,20,21,22 Pharmacokinetic parameters for GAMMAGARD LIQUID (immune globulin intravenous (human) 10%) were determined from total IgG levels following the fourth infusion. A total of 61 subjects were enrolled and treated. Of these, 57 had sufficient pharmacokinetic data to be included in the dataset. Pharmacokinetic parameters are presented in Table 4.

Table 4: Summary of Pharmacokinetic Parameters in 57 Subjects

Parameter Median 95% Confidence Interval
Elimination Half-Life ( T ½ days) 35 (31, 42)
AUC0-21d (mg-days/dL) 29139 (27494, 30490)
Cmax (Peak, mg/dL) 2050 (1980, 2200)
Cmin (Trough, mg/dL) 1030 (939, 1110)
Incremental recovery (mg/dL)/(mg/kg) 2.3 (2.2, 2.6)
Abbreviations: AUC= area under the curve;
Cmax=maximum concentration;
Cmin= minimum concentration

Median IgG trough levels were maintained between 960-1120 mg/dL. These dosing regimens maintained serum trough IgG levels considerably above 450 mg/dL, which is consistent with levels considered to be effective in the treatment of patients with Primary Immunodeficiency.23,24 The elimination half-life of GAMMAGARD LIQUID (immune globulin intravenous (human) 10%) of 35 days was similar to the half-lives reported for other IGIV products.13,14,15,17,25,26

REFERENCES

11. Schiff RI. Intraveneous immunoglobulins for treatment of antibody deficiencies. In: Good RA, Lindenlaub E, eds. The Nature, Cellular, and Biochemical Basis and Management of Immunodeficiencies. Symposium Vernried, West Germany. 21-25 September. Stuttgart: F. K. Schattauer Verlag; 1986:523-541.

12. Morell A. Pharmacokinetics of intravenous immunoglobulin preparations. In: Lee ML, Strand V, eds. Intravenous Immunoglobulins in Clinical Practice. New York: M. Dekker, Inc.; 1997:1-18.

13. Morell A, Skvaril F. Structure and Biological Properties of Immunoglobulins and y-Globulin Preparations. II. Properties of y-Globulin Preparations, Schweizerishche Medizinische Wochenschrift 1980; 110:80-85.

14. Waldmann TA, Strober W. Metabolism of immunoglobulins. Prog Allergy. 1969;13:1-110.

15. Stiehm ER. Standard and special human immune serum globulins as therapeutic agents. Pediatrics. 1979;63:301-319.

16. Lee ML, Mankarious S, Ochs H, Fischer S, Wedgwood RJ. The pharmacokinetics of total IgG, IgG subclasses, and type specific antibodies in immunodeficient patients. Immunol Invest. 1991;20:193-198.

17. Buckley RH. Immunoglobulin replacement therapy: indications and contraindications for use and variable IgG levels achieved. In: Alving BM, Finlayson JS, eds. Immunoglobulins: characteristics and use of intravenous preparations. Washington, D.C.: US Department of Health and Human Services; 1979:3-8.

18. Mankarious S, Lee M, Fischer S, et al. The half-lives of IgG subclasses and specific antibodies in patients with primary immunodeficiency who are receiving intravenously administered immunoglobulin. J Lab Clin Med. 1988;112:634-640.

19. Pirofsky B. Safety and toxicity of a new serum immunoglobulin G intravenous preparation, IGIV pH 4.25. Rev Infect Dis. 1986;8 Suppl 4:S457-63.

20. Pirofsky B. Clinical use of a new pH 4.25 intravenous immunoglobulin preparation (Gamimune-N). J Infect. 1987;15 Suppl 1:29-37.

21. Schiff RI. Half-life and clearance of pH 6.8 and pH 4.25 immunoglobulin G intravenous preparations in patients with primary disorders of humoral immunity. Rev Infect Dis. 1986;8 Suppl 4:S449-56.

22. Schiff RI, Rudd C. Alterations in the half-life and clearance of IgG during therapy with intravenous gamma-globulin in 16 patients with severe primary humoral immunodeficiency. J Clin Immunol. 1986;6:256-264.

23. Eijkhout HW, Der Meer JW, Kallenberg CG, 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;135:165-174.

24. Roifman CM, Gelfand EW. Replacement therapy with high dose intravenous gamma-globulin improves chronic sinopulmonary disease in patients with hypogammaglobulinemia. Pediatr Infect Dis J. 1988;7:S92-S96.

25. Ballow M, Berger M, Bonilla FA, et al. Pharmacokinetics and tolerability of a new intravenous immunoglobulin preparation, IGIV-C, 10% (Gamunex, 10%). Vox Sang. 2003;84:202-210.

26. Ochs HD, Pinciaro PJ, The Octagam Study Group. Octagam((R)) 5%, an intravenous IgG product, is efficacious and well tolerated in subjects with primary immunodeficiency diseases. J Clin Immunol. 2004;24:309-314.

Last reviewed on RxList: 9/9/2008
This monograph has been modified to include the generic and brand name in many instances.

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