Gamunex-C

GAMUNEX®-C,
[Immune Globulin Injection (Human) 10% Caprylate/Chromatography Purified]

WARNING

ACUTE RENAL DYSFUNCTION AND ACUTE RENAL FAILURE

  • Renal dysfunction, acute renal failure, osmotic nephrosis, and death may occur with immune globulin intravenous (IGIV) products in predisposed patients. Patients predisposed to renal dysfunction include those with any degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs.
  • Renal dysfunction and acute renal failure occur more commonly in patients receiving IGIV products containing sucrose. [1] GAMUNEX-C does not contain sucrose.
  • For patients at risk of renal dysfunction or failure, administer GAMUNEX-C at the minimum concentration available and the minimum infusion rate practicable. (see WARNINGS AND PRECAUTIONS)

DRUG DESCRIPTION

GAMUNEX-C is a ready-to-use sterile solution of human immune globulin protein for intravenous and subcutaneous (PI indication only) administration. GAMUNEX-C 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-C 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-C 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-C. In another study it was demonstrated that intravenous bolus doses of 0.44 g/kg glycine were not associated with serious adverse effects. [20] 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. [21] 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-C is 4.0–4.5. GAMUNEX-C contains no preservative and is latex-free.

GAMUNEX-C 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-C is incubated in the final container (at the low pH of 4.0–4.3). The product is intended for intravenous administration and may be administered subcutaneously in treatment of PI.

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
HIV PRV BVDV Reo HAV PPV
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 ≥ .0 .3 ≥ .3. 3 4.0 ≥ 4.0 ≥ 1.4 4.2
Low pH Incubation ≥ 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, Grifols Therapeutics 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. [22-26]

Several of the individual production steps in the GAMUNEX-C 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.

REFERENCES

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(11): p. 1788-94.

20. 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.

21. Traul KA, et al. Review of the toxicologic properties of medium-chain triglycerides. Food Chem Toxicol, 2000. 38(1): p. 79-98. Secondary Endpoint p-valuea Randomized Withdrawal Period Time to Relapse p= 0.011

22. 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.

23. 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.

24. 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.

25. Cai K, Miller JL, Stenland CJ, et al. Solvent-dependent precipitation of prion protein. Biochim Biophys Acta 2002. 1597(1):28-35.

26. 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: 1/14/2013
This monograph has been modified to include the generic and brand name in many instances.

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