August 24, 2016
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Privigen

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Privigen

Privigen®, Immune Globulin Intravenous
(Human), 10% Liquid




WARNING

THROMBOSIS, RENAL DYSFUNCTION AND ACUTE RENAL FAILURE

  • Thrombosis may occur with immune globulin products1-3, including Privigen. Risk factors may include: advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, and cardiovascular risk factors. Thrombosis may occur in the absence of known risk factors [see WARNINGS AND PRECAUTIONS, PATIENT INFORMATION].
  • 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.4 Privigen does not contain sucrose.
  • For patients at risk of thrombosis, renal dysfunction or failure, administer Privigen at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].

DRUG DESCRIPTION

Privigen is a ready-to-use, sterile, 10% protein liquid preparation of polyvalent human immunoglobulin G (IgG) for intravenous administration. Privigen 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 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 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 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 contains no carbohydrate stabilizers (e.g., sucrose, maltose) and no preservative.

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-receptormediated leukocyte activation (determined with complexed IgG). Privigen does not activate the complement system or prekallikrein in an unspecific manner.

All plasma units used in the manufacture of Privigen have been tested and approved for manufacture 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 HBV, HCV and HIV-1 and found to be nonreactive (negative). In addition, the plasma has been tested for B19 virus (B19V) DNA by NAT. Only plasma that passed virus screening is used for production, and the limit for B19V in the fractionation pool is set not to exceed 104 IU of B19V DNA per mL.

The manufacturing process for Privigen 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 nonenveloped 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 5 shows the virus clearance during the manufacturing process for Privigen, expressed as the mean log10 reduction factor (LRF).

Table 5: Virus Inactivation/Removal in Privigen*

  HIV-1 PRV BVDV WNV EMCV MVM
Virus property
Genome RNA DNA RNA RNA RNA DNA
Envelope Yes Yes Yes Yes No No
Size (nm) 80-100 120-200 50-70 50-70 25-30 18-24
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 ≥ 5 ≥ 5.1 ≥ 5.9 ≥ 5.4 ≥ 5.5
Overall reduction (log10 units) ≥ 16.0 ≥ 17.7 ≥ 11.8 ≥ 16.7 ≥ 9.6 ≥ 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; nt, not tested.
* The virus clearance of human parvovirus B19 was investigated experimentally at the pH 4 incubation step. The estimated LRF obtained was ≥ 5.3.

The manufacturing process was also investigated for its capacity to decrease the infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE), considered a model for CJD and its variant vCJD.18 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.

REFERENCES

1. Dalakas MC. High-dose intravenous immunoglobulin and serum viscosity: risk of precipitating thromboembolic events. Neurology 1994;44:223-226.

2. Woodruff RK, Grigg AP, Firkin FC, Smith IL. Fatal thrombotic events during treatment of autoimmune thrombocytopenia with intravenous immunoglobulin in elderly patients. Lancet 1986;2:217-218.

3. Wolberg AS, Kon RH, Monroe DM, Hoffman M. Coagulation factor XI is a contaminant in intravenous immunoglobulin preparations. Am J Hematol 2000;65:30-34.

18. 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.

What are the possible side effects of immune globulin?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have a serious side effect such as:

  • urinating less than usual or not at all;
  • drowsiness, confusion, mood changes, increased thirst, loss of appetite, nausea and vomiting;
  • swelling, weight gain, feeling short of breath;
  • wheezing, chest tightness;
  • feeling like you might pass out;
  • easy bruising, unusual bleeding (nose, mouth, vagina, or rectum),...

Read All Potential Side Effects and See Pictures of Privigen »

Last reviewed on RxList: 3/18/2016
This monograph has been modified to include the generic and brand name in many instances.

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


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