"The U.S. Food and Drug Administration today approved Octaplas, a pooled plasma (human) blood product for the replacement of clotting proteins (coagulation factors) in certain medical conditions where patients have insufficient levels. Clotting pr"...
Immune Globulin Intravenous (Human), 10%
10% Liquid Preparation
WARNING: ACUTE RENAL DYSFUNCTION AND ACUTE RENAL FAILURE
Immune Globulin Intravenous (Human) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis and death.  Patients predisposed to acute renal failure include patients with any degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs. Especially in such patients, IGIV products should be administered at the minimum concentration available and the minimum rate of infusion practicable. While these reports of renal dysfunction and acute renal failure have been associated with the use of many of the licensed IGIV products, those containing sucrose as a stabilizer accounted for a disproportionate share of the total number. GAMUNEX (immune globulin intravenous human 10%) does not contain sucrose. Glycine, a natural amino acid, is used as a stabilizer. (See DOSAGE AND ADMINISTRATION and WARNINGS and PRECAUTIONS for important information intended to reduce the risk of acute renal failure.)
Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified (GAMUNEX) is a ready-to-use sterile solution of human immune globulin protein for intravenous administration. GAMUNEX (immune globulin intravenous human 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. GAMUNEX (immune globulin intravenous human 10%) contains trace levels of fragments, IgA (average 0.046 mg/mL), and IgM. The distribution of IgG subclasses is similar to that found in normal serum. GAMUNEX (immune globulin intravenous human 10%) doses of 1 g/kg correspond to a glycine dose of 0.15 g/kg. While toxic effects of glycine administration have been reported , the doses and rates of administration were 3 – 4 fold greater than those for GAMUNEX (immune globulin intravenous human 10%) . In another study it was demonstrated that intravenous bolus doses of 0.44 g/kg glycine were not associated with serious adverse effects  Caprylate is a saturated medium-chain (C8) fatty acid of plant origin. Medium chain fatty acids are considered to be essentially non-toxic. Human subjects receiving medium chain fatty acids parenterally have tolerated doses of 3.0 to 9.0 g/kg/day for periods of several months without adverse effects . Residual caprylate concentrations in the final container are no more than 0.216 g/L (1.3 mmol/L).The measured buffer capacity is 35 mEq/L and the osmolality is 258 mOsmol/kg solvent, which is close to physiological osmolality (285-295 mOsmol/kg). The pH of GAMUNEX (immune globulin intravenous human 10%) is 4.0 – 4.5. GAMUNEX (immune globulin intravenous human 10%) contains no preservative and is latex-free.
GAMUNEX is made from large pools of human plasma by a combination of cold ethanol fractionation, caprylate precipitation and filtration, and anion-exchange chromatography. Isotonicity is achieved by the addition of glycine. GAMUNEX (immune globulin intravenous human 10%) is incubated in the final container (at the low pH of 4.0 – 4.3), for a minimum of 21 days at 23° to 27°C. The product is intended for intravenous administration.
The capacity of the manufacturing process to remove and/or inactivate enveloped and non-enveloped viruses has been validated by laboratory spiking studies on a scaled down process model, using the following enveloped and non-enveloped viruses: human immunodeficiency virus, type I (HIV-1) as the relevant virus for HIV-1 and HIV–2; bovine viral diarrhea virus (BVDV) as a model for hepatitis C virus; pseudorabies virus (PRV) as a model for large DNA viruses (e.g. herpes viruses); Reo virus type 3 (Reo) as a model for non-enveloped viruses and for its resistance to physical and chemical inactivation; hepatitis A virus (HAV) as relevant non-enveloped virus, and porcine parvovirus (PPV) as a model for human parvovirus B19.
Overall virus reduction was calculated only from steps that were mechanistically independent from each other and truly additive. In addition, each step was verified to provide robust virus reduction across the production range for key operating parameters.
Table 12: Log10 Virus Reduction
|Process Step||Log10 Virus Reduction|
|Enveloped Viruses||Non-enveloped Viruses|
|Caprylate Precipitation/Depth Filtration||C/Ia||C/I||2.7||≥ 3.5||≥ 3.6||4.0|
|Caprylate Incubation||≥ 4.5||≥ 4.6||≥ 4.5||NAb||NA||NA|
|Depth Filtrationd||CAPc||CAP||CAP||≥ 4.3||≥ 2.0||3.3|
|Column Chromatography||≥ 3.0||≥ 3.3||4.0||≥ 4.0||≥ 1.4||4.2|
|Low pH Incubation (21 days)||≥ 6.5||≥ 4.3||≥ 5.1||NA||NA||NA|
|Global Reduction||≥ 14.0||≥ 12.2||≥ 16.3||≥ 7.5||≥ 5.0||8.2|
|a C/I - Interference by caprylate precluded determination
of virus reduction for this step. Although removal of viruses is likely
to occur at the caprylate precipitation/depth filtration step, BVDV is
the only enveloped virus for which reduction is claimed. The presence
of caprylate prevents detection of other, less resistant enveloped viruses
and therefore their removal cannot be assessed.
b Not Applicable – This step has no effect on non-enveloped viruses.
c CAP - The presence of caprylate in the process at this step prevents detection of enveloped viruses, and their removal cannot be assessed.
d Some mechanistic overlap occurs between depth filtration and other steps. Therefore, Talecris Biotherapeutics, Inc. has chosen to exclude this step from the global virus reduction calculations.
Additionally, the manufacturing process was investigated for its capacity to decrease the infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE), considered as a model for the vCJD and CJD agents [38-42 ].
Several of the individual production steps in the GAMUNEX (immune globulin intravenous human 10%) manufacturing process have been shown to decrease TSE infectivity of that experimental model agent. TSE reduction steps include two depth filtrations (in sequence, a total of ≥ 6.6 logs). These studies provide reasonable assurance that low levels of CJD/vCJD agent infectivity, if present in the starting material, would be removed.
12. 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.
13. 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. 2000.
14. Traul, K.A., et al., Review of the toxicologic properties of medium-chain triglycerides. Food Chem Toxicol, 2000. 38(1): p. 79-98.
38. 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.
39. 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.
40. 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.
41. Cai K, Miller JL, Stenland, CJ, et al. Solvent-dependent precipitation of prion protein. Biochim Biophys Acta 2002. 1597(1):28-35.
42. 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.
Last reviewed on RxList: 10/2/2008
This monograph has been modified to include the generic and brand name in many instances.
Additional Gamunex Information
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