Gamimune N, 5% solvent detergent treated

Immune Globulin Intravenous (Human), 5%--Gamimune N, 5% treated with solvent/detergent is a sterile 4.5%-5.5% solution of human protein in 9%-11% maltose; it contains no preservative. Each milliliter (mL) contains approximately 50 mg of protein, not less than 98% of which has the electrophoretic mobility of gamma globulin. Not less than 90% of the IgG is monomer. Also present are traces of IgA and of IgM. The distribution of IgG subclasses is similar to that found in normal serum. Gamimune N, 5% has a buffer capacity of 16.5 mEq/L of solution (~0.33 mEq/g of protein). The calculated osmolality is 309 milliosmoles per kilogram of solvent (water) and the calculated osmolarity is 278 milliosmoles per liter of solution.

The product is made by cold ethanol fractionation of large pools of human plasma. Part of the fractionation may be performed by another licensed manufacturer. The immunoglobulin is isolated from Cohn Effluent III after limited diafiltration and ultrafiltration. The solution is adjusted to 0.3% tri-n-butyl phosphate (TNBP) and 0.2% sodium cholate. After addition of the solvent (TNBP) and the detergent (sodium cholate), the solution is heated to 30°C and maintained at that temperature for not less than 6 hours. After the viral inactivation step, the reactants are removed by precipitation, filtration, and finally diafiltration and ultrafiltration. The protein is stabilized during the process by adjusting the pH of the solution to 4.0-4.5. 1 Isotonicity is achieved by the addition of maltose. Gamimune N, 5% treated with solvent/detergent is then incubated in the final container (at the low pH of 4.25), for a minimum of 21 days at 20°C. The product is intended for intravenous administration.

The removal and inactivation of spiked model enveloped and non-enveloped viruses during the manufacturing process for Gamimune N, 5% has been validated in laboratory studies. Human Immunodeficiency Virus, Type 1 (HIV-1) was chosen as the relevant virus for blood products; Bovine Viral Diarrhea Virus (BVDV) was chosen to model for Hepatitis C virus; Pseudorabies virus (PRV) was chosen to model for Hepatitis B and the Herpes viruses; and Reo virus type 3 (Reo) was chosen to model non-enveloped viruses and for its resistance to physical and chemical inactivation. Significant removal of model enveloped and non-enveloped viruses is seen between the Fraction II + IIIW and Effluent III steps and between the Effluent III and Filtrate III steps. Significant inactivation of enveloped viruses is achieved at the time of treatment of Filtrate III with TNBP/sodium cholate and also at the time of low pH incubation in the final container.

Gamimune N, 5% is contraindicated in individuals who are known to have had an anaphylactic or severe systemic response to Immune Globulin (Human). Individuals with selective IgA deficiencies who have known antibody against IgA (anti-IgA antibody) should not receive Gamimune N, 5% since these patients may experience severe reactions to the IgA which may be present. 23

Gamimune N, 5% is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses. Despite these measures, such products can still potentially transmit disease. There is also the possibility that unknown infectious agents may be present in such products. Individuals who receive infusions of blood or plasma products may develop signs and/or symptoms of some viral infections, particularly hepatitis C. ALL infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Bayer Corporation [1-800-288-8371].

The physician should discuss the risks and benefits of this product with the patient, before prescribing or administering it to the patient.

Gamimune N, 5% should be administered only intravenously as the intramuscular and subcutaneous routes have not been evaluated.

Gamimune N, 5% may, on rare occasions, cause a precipitous fall in blood pressure and a clinical picture of anaphylaxis, even when the patient is not known to be sensitive to immune globulin preparations. These reactions may be related to the rate of infusion. Accordingly, the infusion rate given under DOSAGE AND ADMINISTRATION 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 the treatment of an acute anaphylactic reaction.

General

Dosages for specific indications are indicated below, but in general, it is recommended that Gamimune N, 5% be administered by itself at a rate of 0.01 to 0.02 mL/kg body weight per minute for 30 minutes; if well-tolerated, the rate may be gradually increased to a maximum of 0.08 mL/kg body weight per minute. Investigations indicate that Gamimune N, 5% is well-tolerated and less likely to produce side effects when infused at the indicated rate. If side effects occur, the rate may be reduced, or the infusion interrupted until symptoms subside. The infusion may then be resumed at the rate which is comfortable for the patient. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

It is recommended that infusion of Gamimune N, 5% be given by a separate line, by itself, without mixing with other intravenous fluids or medications the patient might be receiving. Gamimune N, 5% should not be mixed with Immune Globulin Intravenous (Human) from another manufacturer. Gamimune N, 5% is not compatible with saline. If dilution is required, Gamimune N, 5% may be diluted with 5% dextrose in water (D5/W). No other drug interactions or compatibilities have been evaluated.

For patients judged to be at increased risk for developing renal dysfunction, it may be prudent to reduce the amount of product infused per unit time by infusing Gamimune N, 5% at a rate less than 8 mg IG/kg/min (0.08 mL/kg/min).

No prospective data are presently available to identify a maximum safe dose, concentration, and rate of infusion in patients determined to be at increased risk of acute renal failure. In the absence of prospective data, recommended doses should not be exceeded and the concentration and infusion rate should be the minimum level practicable. Reduction in dose, concentration, and/or rate of administration in patients at risk of acute renal failure has been proposed in the literature in order to reduce the risk of acute renal failure. 39

Only 18 gauge needles should be used to penetrate the stopper for dispensing product from 10 mL vial sizes; 16 gauge needles or dispensing pins should only be used with 20 mL vial sizes and larger. Needles or dispensing pins should only be inserted within the stopper area delineated by the raised ring. The stopper should be penetrated perpendicular to the plane of the stopper within the ring.

A number of factors beyond our control could reduce the efficacy of this product or even result in an ill effect following its use. These include improper storage and handling of the product after it leaves our hands, diagnosis, dosage, method of administration, and biological differences in individual patients. Because of these factors, it is important that this product be stored properly and that the directions be followed carefully during use.

Primary Humoral Immunodeficiency

The usual dosage of Gamimune N, 5% for prophylaxis in primary immunodeficiency syndromes is 100-200 mg/kg (2-4 mL/kg) of body weight administered approximately once a month by intravenous infusion. The dosage may be given more frequently or increased as high as 400 mg/kg (8 mL/kg) body weight, if the clinical response is inadequate, or the level of IgG achieved in the circulation is felt to be insufficient. The minimum level of IgG required for protection has not been determined.

Idiopathic Thrombocytopenic Purpura (ITP)

Induction:   An increase in platelet count has been observed in children and some adults with acute or chronic ITP receiving Gamimune N, 5% 400 mg/kg body weight daily for 5 days, or alternatively, 1,000 mg/kg body weight daily for 1 day or 2 consecutive days. In the latter treatment regimen, if an adequate increase in the platelet count is observed at 24 hours, the second dose of 1,000 mg/kg body weight may be withheld. The high dose regimen (1,000 mg/kg × 1-2 days) is not recommended for individuals with expanded fluid volumes or where fluid volume may be a concern. With both treatment regimens, a response usually occurs within several days and is maintained for a variable period of time. In general, a response is seen less often in adults than in children.

Maintenance:   In adults and children with ITP, if after induction therapy the platelet count falls to less than 30,000/mm 3 and/or the patient manifests clinically significant bleeding, Gamimune N, 5% 400 mg/kg body weight may be given as a single infusion. If an adequate response does not result, the dose can be increased to 800-1,000 mg/kg of body weight given as a single infusion. Maintenance infusions may be administered intermittently as clinically indicated to maintain a platelet count greater than 30,000/mm 3 .

Bone Marrow Transplantation

Gamimune N, 5% should be administered in doses of 500 mg/kg (10 mL/kg) body weight beginning on days -7 and -2 pretransplant (or at the time conditioning therapy for transplantation is begun), then weekly through day 90 posttransplant. Gamimune N, 5% should be administered by itself through a Hickman line while it is in place, and thereafter through a peripheral vein. Please see DOSAGE AND ADMINISTRATION for other drug interactions.

Pediatric HIV Infection

A reduction in bacterial infections has been observed in children infected with HIV-1 receiving Gamimune N, 5% 400 mg/kg (8 mL/kg) body weight every 28 days.

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2. Data on file at Bayer Corporation
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Bayer Corporation

Pharmaceutical Division

Elkhart, IN 46515 USA

U.S. License No. 8

08692443

(Rev. November 2001)

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