Iveegam Immuno

IVEEGAM IMMUNO®

Baxter

Immune Globulin (Human), I.V.

Passive Immunizing Agent

Action And Clinical Pharmacology: Immune globulin for i.m. use is known to cause anaphylactoid reactions when given i.v. Osterreichisches Institut f¼r Haemoderivate has developed animal models which permit the testing of a preparation’s potential for causing anaphylactoid reactions.

The tests have shown that hypotensive, leukopenic, and bronchospastic substances are present in Cohn Fraction II, which is used for the preparation of Iveegam Immuno. Osterreichisches Institut für Haemoderivate has developed manufacturing processes which reduce these substances by 2 or 3 log steps. Assays are performed on each lot of the final product to guarantee that only traces of contaminants, if any, are present. Clinical experience has shown that lots meeting these criteria will minimize or exclude the occurrence of side effects in recipients.

The safety of Iveegam Immuno has been demonstrated in several preclinical and clinical studies.

The effectiveness of the manufacturing process of Iveegam Immuno to remove and/or inactivate virus was validated in in vitro spiking experiments using Human Immunodeficiency virus type I (HIV-1) as a target virus as well as the following model viruses: Pseudorabies virus (PRV, an enveloped DNA virus as a model for hepatitis B virus), Tick-Borne Encephalitis virus (TBEV, a small enveloped RNA virus as a model for HCV) and Equine Rhinovirus type-1 (ERV-1, a nonenveloped RNA virus as a model for hepatitis A virus). It was demonstrated that Immuno’s modified Cohn-fractionation process combined with hydrolase treatment and polyethylene glycol precipitation used in the manufacture of Iveegam Immuno is capable of providing an overall reduction factor of >19.7 for HIV-1, >20.7 for TBEV, >19.0 for PRV and >24.6 for ERV-1. (According to the Commission of European Communities, Note for Guidance: “Validation of Virus Removal and Inactivation Procedures” III/8115/89-EN.)

Sixteen lots of Iveegam Immuno were used in the treatment of 14 patients with idiopathic thrombocytopenia in both the U.S. and Italy. The patients were followed for HIV-1 antibody between 2 to 27 months after initial product administration. None of the patients tested positive for anti-HIV-1.

To evaluate the risk of hepatitis non-A/non-B virus transmission by Iveegam Immuno, 2 chimpanzees were treated with a total of 218 and 254 g respectively, of product from 2 lots of Iveegam Immuno on a chronic basis over 8 months. None of the 2 animals had signs indicative of non-A/non-B hepatitis virus infection.

These findings were corroborated in a clinical study conducted in Poland. In this study 21 lots were given to 6 patients who were tested for ALT levels at biweekly intervals and followed up for a total of 106 4-month periods. None of the patients had an increase in ALT levels exceeding 2.5 times the upper normal limit.

The safety and efficacy of Iveegam Immuno has been demonstrated in clinical studies both in the U.S. and Europe. In a study conducted by Rosen et al. at the Children’s Hospital Medical Center in Boston, Mass., from 1981 to 1983, 300 infusions were given to 16 patients with primary immunodeficiencies for an average time period of 14 months. Only 2 mild adverse reactions (0.7%) were observed. Patients accepted and tolerated the infusions well. The average dose applied per patient per month was 220 mg/kg. Using this dosage regime, a continuous increase of preinfusion serum IgG levels could be observed in 14 of the 16 patients. This increase continued after 6 months of therapy and levelled off after 1 year of treatment. The efficacy measured by increase of preinfusion serum immune globulin levels, and estimated on clinical grounds, was satisfactory and highly superior to the i.m. globulin regime. The ability to deliver larger doses with greater frequency has clearly been life-saving in 2 of the 16 patients.

Other studies conducted in Europe from the end of 1979 to mid 1983 in which a total of 1 956.37 g Iveegam Immuno were administered in 1 028 doses showed a rate of adverse reactions of less than 1%.

Indications And Clinical Uses: For replacement therapy in patients with primary and secondary antibody deficiency syndromes. The extent of impairment of antibody production may vary substantially and can involve all immune globulin classes, or only one immune globulin class, as well as IgG subclasses. Antibody deficiency syndromes with normal or elevated serum immune globulin levels have also been described. Patients with different forms of primary antibody deficiency are unduly susceptible to infections mainly with pyogenic microorganisms and may develop life-threatening bacterial infections or chronic lung diseases. Replacement therapy with Iveegam Immuno has been shown to be beneficial, and treatment should be started in patients with severe antibody deficiency syndromes even if no clinical symptoms or infections are apparent. Agammaglobulinemic patients might develop meningoencephalitis due to ECHO virus infection. This potentially fatal disease has been successfully treated with high dose immune globulin. I.V. immune globulin is preferable to the i.m. regime, because it allows for the delivery of high doses, the increase of serum IgG levels is fast, and infusions are not painful.

Replacement therapy is indicated in patients with hypo-and agammaglobulinemia, transient antibody deficiency syndrome in infancy, antibody deficiency with elevated IgM, antibody deficiency with normal IgM in combined IgG-IgA deficiency (see Precautions); isolated IgA deficiency with severe recurrent viral or bacterial infections (these patients often have additional IgG2 and IgG4 subclass deficiency) (see Precautions); IgG subclass deficiency, and patients with normal or elevated serum immune globulin levels who have been shown to be unable to produce antibodies.

Patients with combined immunodeficiency and severe combined immunodeficiency have in addition to a T-cell defect an impairment of antibody production as well, and may benefit from replacement therapy with Iveegam Immuno, even though this therapy will not correct the cellular immune defect.

Secondary antibody deficiencies may develop as consequence of protein loss, increased catabolism or decreased antibody production or a combination of these in the course of different underlying conditions and diseases. Patients with antibody deficiency syndromes, if unduly susceptible to infections, may benefit from treatment with Iveegam Immuno. These antibody deficiency syndromes may occur: in severe protein enteropathy; after major surgical intervention, e.g., gastrointestinal malignancies; in burn patients; in patients with malignancies; in patients with diseases of the hematopoietic and lymphoreticular system; after irradiation and/or cytostatic therapy.

Contra-Indications: Individuals who are known to have had an anaphylactic or severe systemic response to immune serum globulin (human). For individuals with selective IgA deficiencies, see Precautions.

Manufacturers’ Warnings In Clinical States: Iveegam Immuno should only be administered i.v. as the i.m. route has not yet been evaluated. This product is manufactured using components of human blood which may contain the causative agent of hepatitis and other viral diseases. Prescribed manufacturing procedures utilized in blood collection centres and the plasma testing laboratories are designed to reduce the risk of transmitting viral infection. However, the risk of the transmission of infective agents – also of hitherto unknown origin – cannot be totally excluded. Iveegam Immuno can, on occasion, cause a precipitous fall in blood pressure and the clinical picture of anaphylaxis even when the patient is not known to be sensitive to immune globulin preparations. These reactions are sometimes related to the rate of infusion. Accordingly, the infusion rate given under “Dosage” should be closely followed, at least until the physician has had sufficient experience with a given patient. The patient’s vital signs should be monitored continuously and careful observation made for any symptoms throughout the entire infusion. Epinephrine should be available for treatment of any acute anaphylactoid reaction.

Although moderate and severe anaphylactoid reactions have not been observed in any of the clinical studies with this product, their occurrence cannot be ruled out. Investigators using other immune globulin products for i.v. use have described true anaphylactic reactions following administration. These reactions have been attributed to the presence of immune globulin A in certain preparations, while high level circulating IgA antibodies have been demonstrated or assumed to be present in the patients.

Anaphylactic reactions have also been explained in certain instances by antigen-antibody interactions if patients had antigenemia and the respective antibodies were in the product.

If anaphylactic or anaphylactoid reactions occur, the injection or infusion is to be discontinued immediately. Antihistamines (H1-receptor and H2-receptor blockers) and/or steroids and/or sympathicomimetics, given i.v., have proven effective antidotes. It is advisable that these medications be available for the treatment of such reactions, should they occur.

The administration of high doses of Iveegam Immuno may cause temporary increase in serum glucose in diabetics.

Precautions: General: Patients with severe antibody deficiency syndromes may react more readily to the infusion of homologous immune globulin. Such patients can be treated with Iveegam Immuno.

Patients with IgA deficiency with severe recurrent viral or bacterial respiratory infections or with isolated IgA deficiency (and additional IgG2 and IgG4 deficiency), who may develop severe anaphylactic reactions after infusion of i.v. immune globulin, should receive the first infusion in the hospital under medical supervision.

Drug Interactions: Because antibodies in immune globulins may interfere with the immunogenic response to live virus vaccines, e.g., measles, mumps or rubella, vaccination should be postponed to 3 months after the last administration of immune globulin.

Pregnancy: Animal reproduction studies have not been carried out with this product. It is also not known whether Iveegam Immuno can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. The product should be given to a pregnant woman only if clearly needed.

Adverse Reactions: Iveegam Immuno is a specially purified preparation for i.v. administration. Although years of experience have shown the preparation to be particularly well tolerated, adverse reactions cannot be ruled out completely.

As with any i.v. immunoglobulin, untoward reactions (e.g., flushing of the face, rashes, itching, headache, chest tightness, anxiety, malaise, rise in temperature, chills, slight elevation of blood pressure, tachycardia, difficulty of breathing, backache) may occur. Severe reactions with sudden onset of dyspnea, nausea, vomiting, circulatory collapse, loss of consciousness and fever are more common in patients with antibody deficiencies.

In clinical studies with Iveegam Immuno the rate of adverse reactions was less than 1%. Only minor reactions occurred.

In many cases adverse reactions as listed above can be avoided by slowing of the infusion rate. If hypersensitivity reactions (e.g., flushing of the face, chest tightness, drop in blood pressure) occur, the infusion must be discontinued immediately. In the case of anaphylactic reactions or shock, therapy should follow the current guidelines of shock treatment.

I.V. dosages of antihistamines, steroids and/or sympathomimetics are effective treatment and should always be available.

After minor reactions have subsided, further treatment may be attempted using diluted solutions, lower doses, and/or shorter intervals (e.g., administer a lower dose in 2 infusions a day).

Dosage And Administration: Parenteral drug products should be inspected visually for particle matter and discoloration prior to administration whenever solution and container permit. Reconstituted vials found to contain product with either should not be used. In most cases a dosage of 200 mg/kg/month is sufficient for treatment. If required, the dosage may be increased up to 4-fold and/or intervals shortened.

In cases of hypo- or agammaglobulinemia the serum IgG levels should be monitored by measurements prior to each infusion until a preinfusion level of a minimum of 400 mg/100 mL is reached. With adequate doses given at regular intervals it can be expected that a steady increase of the preinfusion values will occur over a period of 6 to 12 months until a plateau of the preinfusion level is reached. If clinical results are not fully satisfactory with this preinfusion level of 400 mg/100 mL, attempts should be made to reach a preinfusion level of 600 mg/100 mL and more. Experience has shown that this may be achieved by increasing the dose to 500 to 600 mg/kg/month.

Reconstitution: Reconstitution with the Sterile Water for Injection provided in each pack results in a 5% solution. 1. Remove protective caps from the concentrate and solvent bottles and disinfect rubber stoppers of both bottles. 2. Remove protective covering from one end of the accompanying double-ended needle and insert the exposed needle through the diluent bottle stopper. 3. Remove protective cap from the other end of the double-ended needle. Do not touch exposed needle end! 4. Turn diluent bottle upside down and insert free end of the needle into the concentrate bottle stopper to half its length. Diluent will be drawn into the concentrate bottle by vacuum. 5. Disconnect the 2 bottles leaving the needle on the solvent bottle. Accelerate reconstitution by gently agitating or rotating the concentrate bottle. 6. Administer the solution directly using the accompanying infusion set with filter.

Reconstitution of the freeze-dried powder of Iveegam Immuno with the accompanying Sterile Water for Injection, yields a solution of the following composition: functionally intact monomeric IgG 50 mg/mL±5 mg/mL; total protein content 55 mg/mL±5 mg/mL; sodium chloride 3 mg/mL±1 mg/mL; stabilizer: glucose 50 mg/mL±5 mg/mL.

Iveegam Immuno must be administered i.v. immediately after reconstitution. The rate of administration should be generally 1 mL up to a maximum of 2mL/minute for the 5% solution.

If lower immune globulin concentrations are desired, the 5% solution of Iveegam Immuno can be diluted with isotonic saline or isotonic sugar solutions (glucose, levulose).

Availability And Storage: Iveegam Immuno is a sterile, freeze-dried concentrate of immune globulines G prepared from pooled human plasma. Plasma units are obtained from blood banks and from licensed plasmapheresis centers in the U.S. and Europe. The source material is subjected to a modified cold ethanol fractionation process according to COHN. From the immunoglobulin fraction thus obtained, Iveegam Immuno is manufactured in a multistep procedure.

The major manufacturing steps include: elimination of IgA by adsorption onto ion exchangers; inactivation and removal of viruses and substances causing adverse reactions by treatment with immobilized hydrolases; isolation of aggregate-free immunoglobulin G by fractionated precipitation with polyethylene glycol (PEG).

The individual steps of this manufacturing process also lead to the reduction and inactivation of potentially present viral contaminants. The treatment with immobilized hydrolases is an additional virus inactivation measure incorporated into the manufacture of Iveegam Immuno.

In the manufacture of Iveegam Immuno, the immune globulins remain unaltered in their native form, the biological half-life unimpaired and the Fc-function of the antibody molecule intact.

Single dose infusion vials of 5 000 mg of freeze-dried immune globulin (for i.v. use) accompanied by 100 mL vial of Sterile Water for Injection, 1 sterile double-ended needle and 1 infusion set with filter. Store at 2 to 8°C. Any vial that has been entered should be used promptly. Partially used vials should be discarded. Do not use after expiration date. Do not use if turbid. Avoid freezing, which may damage the diluent bottle.

IVEEGAM IMMUNO® Baxter Immune Globulin (Human), I.V. Passive Immunizing Agent

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