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Immune Globulin Intravenous (Human), 10% Liquid
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ACUTE RENAL DYSFUNCTION AND ACUTE RENAL FAILURE
Immune Globulin Intravenous (Human) (IGIV) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death.1 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. In such patients, IGIV products should be administered at 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. Privigen™ does not contain sucrose. (See DOSAGE AND ADMINISTRATION and WARNINGS and PRECAUTIONS for important information intended to reduce the risk of acute renal failure.)
Privigen™ (immune globulin intravenous) is a ready-to-use, sterile, 10% protein liquid preparation of polyvalent human immunoglobulin G (IgG) for intravenous administration. Privigen™ is prepared from large pools of human plasma by a combination of cold ethanol fractionation, octanoic acid fractionation, and anion exchange chromatography. The IgG proteins are not subjected to heating or to chemical or enzymatic modification. The Fc and Fab functions of the IgG molecule are retained. Fab functions tested include antigen binding capacities, and Fc functions tested include complement activation and Fc-receptor-mediated leukocyte activation (determined with complexed IgG). Privigen™ (immune globulin intravenous) does not activate the complement system or prekallikrein in an unspecific manner.
Privigen™ (immune globulin intravenous) has a purity of at least 98% IgG, consisting primarily of monomers. The balance consists of IgG dimers (≤ 12%), small amounts of fragments and polymers, and albumin. Privigen™ (immune globulin intravenous) contains ≤ 25 mcg/mL IgA. The IgG subclass distribution (approximate mean values) is IgG1, 67.8%; IgG2, 28.7%; IgG3, 2.3%; and IgG4, 1.2%. Privigen™ (immune globulin intravenous) has an osmolality of approximately 320 mOsmol/kg (range: 240 to 440) and a pH of 4.8 (range: 4.6 to 5.0).
Privigen™ (immune globulin intravenous) contains approximately 250 mmol/L (range: 210 to 290) of L-proline (a nonessential amino acid) as a stabilizer and trace amounts of sodium. Privigen™ (immune globulin intravenous) contains no carbohydrate stabilizers (e.g., sucrose, maltose) and no preservative.
All plasma units used in the manufacture of Privigen™ (immune globulin intravenous) are tested using FDA-licensed serological assays for hepatitis B surface antigen and antibodies to HCV and HIV-½ as well as FDA-licensed Nucleic Acid Testing (NAT) for HCV and HIV-1 and found to be nonreactive (negative). For HBV, an investigational NAT procedure is used and the plasma units found to be negative; however, the significance of a negative result has not been established.
The manufacturing process for Privigen™ (immune globulin intravenous) includes three steps to reduce the risk of virus transmission. Two of these are dedicated virus clearance steps: pH 4 incubation to inactivate enveloped viruses and virus filtration to remove, by size exclusion, both enveloped and non-enveloped viruses as small as approximately 20 nanometers. In addition, a depth filtration step contributes to the virus reduction capacity.
These steps have been independently validated in a series of in vitro experiments for their capacity to inactivate and/or remove both enveloped and non-enveloped viruses. Table 3 shows the virus clearance during the manufacturing process for Privigen™ (immune globulin intravenous) , expressed as the mean log10 reduction factor (LRF).
Table 3: Virus Inactivation/Removal in Privigen™ (immune globulin intravenous)
|Manufacturing step||Mean LRF|
|pH 4 incubation||≥ 5.4||≥ 5.9||4.6||≥ 7.8||nt||nt|
|Depth filtration||≥ 5.3||≥ 6.3||2.1||3.0||4.2||2.3|
|Virus filtration||≥ 5.3||nd||≥ 2.7||≥ 5.9||≥ 3.7||≥ 5.5|
|Overall reduction (log10 units)||≥ 16.0||≥ 12.2||≥ 9.4||≥ 16.7||≥ 7.9||≥ 7.8|
|HIV-1, human immunodeficiency virus type 1, a model for HIV-1 and HIV-2; PRV, pseudorabies virus, a nonspecific model for large enveloped DNA viruses (e.g., herpes virus); BVDV, bovine viral diarrhea virus, a model for hepatitis C virus; WNV, West Nile virus; EMCV, encephalomyocarditis virus, a model for hepatitis A virus; MVM, minute virus of mice, a model for a small highly resistant non-enveloped DNA virus (e.g., parvovirus); LRF, log10 reduction factor; nd, not determined; nt, not tested.|
The manufacturing process was also investigated for its capacity to decrease the infectivity of an experimental agent of TSE, considered a model for CJD and its variant vCJD.16 Several of the production steps have been shown to decrease TSE infectivity of an experimental model agent. TSE reduction steps include octanoic acid fractionation (≥ 6.4 log10), depth filtration (2.6 log10), and virus filtration (≥ 5.8 log10). These studies provide reasonable assurance that low levels of vCJD/CJD agent infectivity, if present in the starting material, would be removed.
1. Cayco AV, Perazella MA, Hayslett JP. Renal insufficiency after intravenous immune globulin therapy: a report of two cases and an analysis of the literature. J Am Soc Nephrol 1997;8:1788-1793.
16. Gregori L, Maring J-A, MacAuley C, Stühler A, Löwer J, Blümel J. Partitioning of TSE infectivity during ethanol fractionation of human plasma. Biologicals 2004;32:1-10.
Last reviewed on RxList: 8/27/2007
This monograph has been modified to include the generic and brand name in many instances.
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