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Category Passive immunizing agent.

          Human Normal Immunoglobulin for Intravenous Administration (IGIV) is a liquid or freeze-dried preparation containing immunoglobulins from normal human subjects, mainly immunoglobulin G (IgG). Other proteins may be present. This monograph does not apply to products intentionally prepared to contain fragments or chemically modified IgG.

          IGIV is obtained from plasma complies with the requirements stated under Plasma for Fractionation, p. 193. No antibiotic is added to the plasma used.

Description The liquid IGIV is clear or slightly opalescent and colourless or pale yellow.

          The freeze-dried IGIV is a white or slightly yellow powder or solid friable mass. It is hygroscopic.

Stability Liquid IGIV should be discarded if it has been frozen. The reconstituted solution of freeze-dried IGIV should be used IGIV immediately or as stated on the label.

Strengths available Liquid or reconstituted preparation, 30 to 120 mg of protein per ml.

Dose Immunodeficiency: Intravenous infusion, 200 to 800 mg per kg of body weight once a month. Idiopathic thrombocytopenic purpura: Intravenous infusion, 400 mg per kg of body weight per day for 2 to 5 consecutive days or 1 g per kg of body weight per day 1 to 2 days. If the patient’s response is inadequate, up to 2 g per kg of body weight may be administered as a single maintenance dose every 2 weeks.

          Bacterial infection secondary to B-cell chronic lymphocytic leukemia: Intravenous infusion, 400 mg per kg of body weight per day for 4 days or 2 g per kg of body weight as a single dose.

          Prophylaxis of infection after bone marrow transplantation: Intravenous infusion, 500 mg per kg of body weight weekly.

          Kawasaki diaease: Intravenous infusion, 400 mg per kg of body weight per day for 4 days or 1 to 2 g per kg of body weight as a single dose.

          Bone marrow transplantation: Intravenous infusion, 500 mg per kg of body weight beginning on day 7 and day 2 pretransplantation (or at the time conditioning therapy for transplantation is begun), then weekly through 3 months posttransplantation.

Contra-indication It is contra-indicated in patients with immunoglobulin A deficiencies since anaphylaxis may occur.

Warning

          1. Backache, chills, flushing, headache, hypotension, myalgia, nausea or pyrexia usually begins within 1 hour of the start of the infusion of IGIV. Symptoms usually subside within 30 minutes.

          2. It may cause dyspnea, tachycardia, burning sensation in head, cyanosis, faintness, fatigue, wheezing, and renal dysfunction.

          3. Risk-benefit should be considered if it is to be used in cardiac function impairment patients and pregnant women.

          4. Caution should be exercised if it is to be used in patients with agammaglobulinemia or severe hypogammaglobulinemia.

Additional information Antibodies contained in IGIV may interfere with the body’s immune response to certain live virus vaccines, such as measles, mumps, and rubella including MMR which should be administered at least 14 days before or 3 months after treatment with IGIV. However, there appears to be no interference between IGIV and oral poliomyelitis vaccine (OPV), yellow fever vaccine, oral typhoid (strain Ty 21a) vaccine, or adsorbed diphtheria, pertussis (whole cell) and tetanus vaccine (DPT).

Expiration date When stored under the prescribed conditions, the expiration date is not later than 2 years from the date of manufacturing, or as indicated on the label.

Packaging and storage Liquid IGIV shall be kept in a sealed and colourless glass container, protected from light, and stored at a temperature of 2º to 8º; avoid freezing.

          Freeze-dried IGIV shall be kept in a tightly closed colourless glass container, protected from light, and stored at a temperature not exceeding 25º, unless otherwise specified by manufacturers.

Labelling Complies with the “General Information for Biological Products”, p. 177. In addition, the label on the container states (1) for the liquid IGIV, the volume of the preparation in container and the protein content expressed in grams per litre or for freeze-dried IGIV, the total amount of protein in the container; (2) the amount of immunoglobulin in the container; (3) the route of administration; (4) the distribution of subclasses of immunoglobulin G present in the preparation; (5) where applicable, the amount of albumin added as a stabilizer; (6) the maximum content of immunoglobulin A.

Before carrying out the identification and the tests (except those for constituted solution and water), immediately reconstitute the preparation to   be examined as stated on the label.

 

Identification Complies with the Identification described under Immunoglobulin, p. 209.

pH 4.0 to 7.4, when diluted with sufficient saline TS to produce a solution containing 1 per cent w/v of protein (Appendix 4.11).

Osmolality Not less than 240 mOsmol/kg (Appendix 4.35).

Total protein Not less than 3 per cent w/v of protein and not less than 90 per cent and not more than 110 per cent of the labelled quantity of protein stated on the label. Dilute the preparation to be examined with saline TS to obtain a solution containing about 15 mg of protein in 2 ml. To 2.0 ml of this solution in a roundbottomed centrifuge tube add 2 ml of a 7.5 per cent w/v solution of sodium molybdate and 2 ml of a mixture of 1 volume of nitrogen-free sulfuric acid and 30 volumes of water. Shake, centrifuge for 5 minutes, decant the supernatant liquid, and allow the inverted tube to drain on filter paper. Using the residue thus obtained, carry out the “Determination of Nitrogen” (Method II, Appendix 6.7).

Protein composition Carry out the test as described in the “Cellulose Acetate Electrophoresis” (Method II, Appendix 3.7) or other suitable electrophoresis methods, but applying an electric field such that the albumin band of normal human serum applied in a control strip migrates at least 30 mm. Prepare the following solutions. For solution (A), dilute the preparation being examined with saline TS to produce a solution containing 3 per cent w/v of protein. For solution (B), dilute Human Immunoglobulin for Electrophoresis RS with saline TS to produce a solution containing 3 per cent w/v of protein. In the strips prepared with solution (A) not more than 5 per cent of the protein is contained in bands other than the principal band. This limit is not applicable if albumin has been added to the preparation as a stabilizer; for such preparations, a test for protein composition is carried out during manufacture before addition of the stabilizer. The test is not valid unless the proportion of protein in the principal band in the strips prepared with solution (B) is within the limits stated in the leaflet supplied with Human Immunoglobulin for Electrophoresis RS.

Distribution of molecular size Carry out the test as described in the “High-pressure Liquid Chromatography” (Appendix 3.5).

          Mobile phase, Standard preparation, Test preparation, and Chromatographic system Proceed as directed in the test for distribution of molecular size described under Immunoglobulin, p. 210.

Anticomplementary activity (ACA) The consumption of complement is not more than 50 per cent (1 CH₅₀ per mg of immunoglobulin) (Appendix 15.1.11).

Prekallikrein activator (PKA) Not more than 35 IU per ml, calculated with reference to a solution containing 3 per cent w/v of immunoglobulin (Appendix 14.2.2).

Hemagglutinins, anti-A and anti-B Dilute the solution with saline TS to produce a solution containing about 3 per cent w/v of immunoglobulin. Carry out the test for hemagglutinins, anti-A and anti-B, using a suitable indirect method such as that described below. The 1 in 64 dilutions do not show agglutination.

          Prepare in duplicates serial dilutions of the preparation being examined in saline TS. To each dilution of one series add an equal volume of a 5 per cent v/v suspension of group A1 red blood cells previously washed three times with saline TS. To each dilution of the other series, add an equal volume of a 5 per cent v/v suspension of group B red blood cells previously washed three times with saline TS. Incubate the suspension at 37º for 30 minutes and then wash the cells three times with saline TS. Leave the cells in contact with a polyvalent anti-human globulin reagent for 30 minutes. Without centrifuging, examine each suspension for agglutination under a microscope.

Anti-D antibodies It complies with the “Test for Anti-D antibodies in Human Normal Immunoglobulin for Intravenous Administration” (Appendix 15.1.10).

Antibody to hepatitis B surface antigen Not less than 0.5 IU per g of immunoglobulin, determined by a suitable immunochemical method (Appendix 14.5).

Immunoglobulin A Not more than the maximum content stated on the label, determined by a suitable immunochemical method (Appendix 14.5).

Sterility Complies with the “Sterility Test” (Method II, Appendix 10.1).

Pyrogens or Bacterial endotoxins Complies with the “Pyrogen Test” (Appendix 8.2) or, preferably and where justified and authorized, with a validated in vitro test such as the “Test for Bacterial Endotoxins” (Appendix 8.5).

          For the pyrogen test, inject a volume equivalent to 0.5 g of immunoglobulin per kg of the rabbit’s weight, but not more than 10 ml per kg of the rabbit’s weight.

          Where the bacterial endotoxin test is used, it contains less than 0.5 Endotoxin Unit per ml for solutions with a protein content not more than 5 per cent, and less than 1.0 Endotoxin Unit per ml for solutions with a protein content more than 5 per cent but not more than 10 per cent.

Other requirements Freeze-dried IGIV complies with the following additional requirements.

          Solubility test Add the volume of the liquid stated on the label. The preparation dissolves completely within 30 minutes at 20º to 25º.

          Water Not more than 3.0 per cent w/w (Karl Fischer Method, Appendix 4.12).