IMMUNE GLOBULIN INTRAVENOUS (HUMAN) (Aventis Behring)
Immune Globulin Intravenous (Human), Gammar-P I.V., is a sterile, lyophilized preparation of intact, unmodified, immunoglobulin, primarily IgG, stabilized with Albumin (Human) and sucrose. The distribution of IgG subclasses is similar to that present in normal human plasma. It is prepared by cold alcohol fractionation of pooled plasma and is not chemically altered or enzymatically degraded.
The plasma used in the manufacture of this product has been tested and found negative for HBV, HCV, and HIV-1 by an investigational test procedure referred to as Nucleic Acid Testing (NAT) using Polymerase Chain Reaction (PCR) Technology. Investigational testing is being performed to determine the effectiveness of NAT to detect low levels of viral material. The significance of a negative result is unknown since the effectiveness of the test has not been established.
When reconstituted with the appropriate volume of Sterile Water for Injection, USP, Gammar-P I.V. contains 5% IgG, 3% Albumin (Human), 5% sucrose, and 0.5% sodium chloride. The pH of the solution has been adjusted to 6.8 Â± 0.4 with citric acid and/or sodium carbonate. Gammar-P I.V. contains no preservative. This product is intended for intravenous administration.
The heat treatment step employed in the manufacture of Immune Globulin Intravenous (Human), Gammar-P I.V., pasteurization at 60Â°C for 10 hours in aqueous solution form with stabilizers, has been validated in a series of in vitro experiments for its capacity to inactivate Human Immunodeficiency Virus (HIV) and the following model viruses: Sindbis, Vesicular Stomatitis (VSV), Bovine Viral Diarrhea Virus (BVDV), Vaccinia, Pseudorabies and Murine Encephalomyocarditis (EMC), a non-lipid enveloped model virus. HIV was reduced by 6.0 and 5.4 log 10 to an undetectable level after 0.5 hours of heating in two independent experiments. For each of the model viruses studied, two independent experiments were also conducted with the following results: Sindbis was reduced by 7.5 and 7.9 log 10 to an undetectable level after two hours of heating, VSV was reduced by 6.8 and 7.2 log 10 to an undetectable level after 0.5 hours of heating, BVDV, a model for hepatitis C virus, was reduced by 6.4 and 6.5 log 10 to an undetectable level after four hours of heating, Vaccinia was reduced by 5.6 and 5.6 log 10 to an undetectable level after two hours of heating, Pseudorabies was reduced by 4.9 and 3.6 log 10 to an undetectable level after six hours of heating and EMC, a non-lipid enveloped model virus, was reduced by 4.5 and 4.8 log 10 after ten hours of heating. 1
The viral reduction capacity of the purification procedures used in the manufacture of Immune Globulin Intravenous (Human), Gammar-P I.V., exclusive of heat treatment, was also studied in a series of in vitro experiments using HIV and three model viruses: Murine Encephalomyocarditis (EMC), a non-lipid enveloped virus; Bovine Viral Diarrhea Virus (BVDV), a model for hepatitis C virus; and Pseudorabies (PrV), a large DNA virus. HIV was reduced by at least 6.7 log 10 by the cold alcohol fractionation process used to isolate Cohn Fraction II from pooled plasma during the initial purification of Gammar-P I.V. Additionally, an alcohol purification step performed subsequent to heat treatment was found to have the following log 10 reduction capacities when challenged with HIV and the three model viruses in three replicate experiments each: HIV (3.4, 4.0, >4.6 log 10 ), EMC (3.4, 1.0, 1.5 log 10 ), BVDV (3.5, 3.6, 3.5 log 10 ), and PrV (>5.3, >5.5, >5.4 log 10 ). 1
The results of these validation studies document an HIV viral reduction capacity of >15.5 log 10 and a viral reduction capacity of >7.5 log 10 for Sinbis, >6.8 log 10 for VSV, >9.9 log 10 for BVDV, >5.6 log 10 for Vaccinia, >8.9 log 10 for PrV, and 5.5 log 10 for EMC.
These viral reduction data are summarized in Table 1 below.
The half-life of Immune Globulin Intravenous (Human), Gammar-P I.V., was evaluated in a double blind clinical study in which it was compared to Gammar I.V. The mean half-life of Gammar-P I.V. in nine patients was determined to be approximately 40 days and was not statistically different from the mean half-life of 34 days found for Gammar I.V. in seven patients. Furthermore, there do not appear to be any clinically relevant differences between children, adolescents, and adults with respect to the mean half-life of IgG. The half-life of IgG, however, can vary considerably from patient to patient. 1
Immune Globulin Intravenous (Human), Gammar-P I.V., is a native, non-chemically modified IgG fractionated from pooled human donor plasma. The distribution of IgG subclasses (IgG 1 , IgG 2 , IgG 3 , IgG 4 ) is similar to that present in Cohn Fraction II. Since the IgG concentrate is prepared from a large pool of at least 1000 donors, it represents the expected diversity of antibodies in that population. In a study of an unheated version of this product, Gammar I.V., it was found that Gammar I.V. provided a broad range of antibodies, capable of opsonization and neutralization of microbes and toxins, against bacterial and viral antigens for prevention or attenuation of infectious diseases. 2 In in vitro testing, Gammar-P I.V. has been shown to provide equivalent levels of a broad range of antibodies when compared to Gammar I.V. 1
Albumin (Human) and sucrose are added to the formulation in order to provide adequate stabilization of the IgG molecules and the reconstituted product. Because sucrose, when given intravenously, is excreted unchanged in the urine, Immune Globulin Intravenous (Human), Gammar-P I.V., may be given to diabetics without compensatory changes in insulin dosage regimen. 3 [SEE BOXED WARNING .]
Indications and Usage
Gammar-P I.V. is indicated for adults, children and adolescents with primary defective antibody synthesis such as agammaglobulinemia or hypogammaglobulinemia, who are at increased risk of infection. When high levels or rapid elevation of circulating gamma globulins are desired, intravenous administration is more desirable than intramuscular therapy. The safety and efficacy of Gammar-P I.V. in neonates and infants with primary defective antibody synthesis has not been established.
Gammar-P I.V. is contraindicated in individuals with a history of anaphylactic or severe systemic response to immune globulin intramuscular or intravenous preparations or in individuals with a history of allergic reactions to human albumin.
Immune Globulin Intravenous (Human), Gammar-P I.V., should not be given to persons with isolated immunoglobulin A (IgA) deficiency. Such persons have the potential for developing antibodies to IgA and could have anaphylactic reactions to subsequent administration of blood products that contain IgA. 4
Immune Globulin Intravenous (Human) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. 12 Patients predisposed to acute renal failure include patients with any degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs. Especially in such patients, IGIV products should be administered at the minimum concentration available and the minimum rate of infusion practicable. While these reports of renal dysfunction and acute renal failure have been associated with the use of many of the licensed IGIV products, those containing sucrose as a stabilizer accounted for a disproportionate share of the total number.
If anaphylactic or severe anaphylactoid reactions occur, discontinue infusion immediately. Epinephrine should be available for the treatment of any acute anaphylactoid reactions.
Patients with agammaglobulinemia or extreme hypogammaglobulinemia who have never received immunoglobulin substitution therapy before or who have not received immunoglobulin therapy within the preceding 8 weeks may be at risk of developing inflammatory reactions upon the infusion of human immunoglobulins. These reactions are manifested by a rise in temperature, chills, nausea and vomiting, and appear to be related to the rate of infusion.
Immune Globulin Intravenous (Human), Gammar-P I.V. 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 during manufacture (see DESCRIPTION section for viral reduction measures). The manufacturing procedure for Gammar-P I.V. includes processing steps designed to reduce further the risk of viral transmission. Stringent procedures utilized at plasma collection centers, plasma testing laboratories, and fractionation facilities are designed to reduce the risk of viral transmission. The primary viral reduction step of the Gammar-P I.V. manufacturing process is the heat treatment of the purified, stabilized aqueous solution at 60Â°C for 10 hours. In addition, the purification procedures used in the manufacture of Gammar-P I.V. also provide viral reduction capacity. Despite these measures, such products may still potentially contain human pathogenic agents, including those not yet known or identified. Thus, the risk of transmission of infectious agents cannot be totally eliminated. Any infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Aventis Behring at 800-504-5434. The physician should discuss the risks and benefits of this product with the patient.
Because Gammar-P I.V. is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent.
GENERAL -- Assure that patients are not volume depleted prior to the initiation of the infusion of IGIV.
Periodic monitoring of renal function tests and urine output is particularly important in patients judged to have a potential increased risk for developing acute renal failure. Renal function, including measurement of blood urea nitrogen (BUN)/serum creatinine, should be assessed prior to the initial infusion of Gammar-P I.V. and again at appropriate intervals thereafter. If renal function deteriorates, discontinuation of the product should be considered.
For patients judged to be at risk for developing renal dysfunction, it may be prudent to reduce the amount of product (and sucrose stabilizer) infused per unit time by infusing Gammar-P I.V. at a rate less than 3.0 mg IG/kg/min (0.06 mL/kg/min).
Epinephrine should be available for treatment of acute allergic reactions. See DOSAGE AND ADMINISTRATION section for product compatibility information.
INFORMATION FOR PATIENTS -- Patients should be instructed to immediately report symptoms of decreased urine output, sudden weight gain, fluid retention/edema, and/or shortness of breath (which may suggest kidney damage) to their physicians.
DRUG INTERACTIONS -- It is reported that antibodies in immune globulin preparations may interfere with the response to live viral vaccines such as measles, mumps and rubella. Immunizing physicians should be informed of recent therapy with Immune Globulin Intravenous (Human) so that appropriate precautions may be taken.
PREGNANCY CATEGORY C -- Animal reproduction studies have not been performed with Immune Globulin Intravenous (Human), Gammar-P I.V. It is also not known whether Immune Globulin Intravenous (Human), Gammar-P I.V., can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Gammar-P I.V. should be given to a pregnant woman only if clearly needed.
PEDIATRIC USE -- The safety and efficacy of Gammar-P I.V. has not been established in neonates and infants with primary defective antibody synthesis.
ASEPTIC MENINGITIS SYNDROME -- An aseptic meningitis syndrome (AMS) has been reported to occur infrequently in association with Immune Globulin Intravenous (Human) (IGIV) treatment. The syndrome usually begins within several hours to two days following IGIV treatment. It is characterized by symptoms and signs including severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, and nausea and vomiting. Cerebrospinal fluid (CSF) studies are frequently positive with pleocytosis up to several thousand cells per cubic millimeter, predominantly from the granulocytic series, and elevated protein levels up to several hundred mg/dL. Patients exhibiting such symptoms and signs should receive a thorough neurological examination, including CSF studies, to rule out other causes of meningitis. AMS may occur more frequently in association with high dose (2 g/kg) IGIV treatment. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae. 5-8
Increases in creatinine and blood urea nitrogen (BUN) have been observed as soon as one to two days following infusion. Progression to oliguria and anuria requiring dialysis has been observed, although some patients have improved spontaneously following cessation of treatment. 10 Types of severe renal adverse reactions that have been seen following IGIV therapy include: acute renal failure, acute tubular necrosis 11 , proximal tubular nephropathy, and osmotic nephrosis. 12, 13-15
Potential reactions for all Immune Globulin Intravenous (Human) products are often related to infusion rate and may include: nausea, vomiting, abdominal cramps, chills, pyrexia, chest tightness, palpitations, tachycardia, blood pressure changes, edema, flushing, diaphoresis, rash, erythema, pruritus, cyanosis, dizziness, headache, backache or other body aches, anxiety, wheezing (and other respiratory events), myalgia, shaking, fatigue, malaise and arthralgia, usually beginning within one hour of the start of the infusion.
A double blind study comparing Gammar I.V. and Gammar-P I.V. as replacement therapy was conducted in 19 patients (108 infusions) with primary defective antibody synthesis, such as common variable or X-linked hypogammaglobulinemia. The types of infusion related adverse reactions noted were similar in frequency and nature. For the ten patients receiving only Gammar-P I.V. (56 infusions), all of the infusion related adverse reactions were characterized as mild and of short duration. These included the following most frequent reactions: Chills 8.9% (5/56), Headache 5.4% (3/56), and Pain: Back/Neck 3.6% (2/56). The overall incidence of infusions associated with an adverse reaction was 16% (9/56 infusions) for Gammar-P I.V. which compared favorably to the overall incidence of infusions associated with an adverse reaction for Gammar I.V. (25%; 13/52 infusions). 1
True anaphylactic reactions may occur in patients with a history of prior systemic allergic reactions or seizure following administration of human immunoglobulin preparations. Very rarely an anaphylactoid reaction may occur in patients with no prior history of severe allergic reactions to human immunoglobulin preparations. Patients previously sensitized to certain antigens, including IgA, may be at risk of immediate anaphylactoid and hypersensitivity reactions. 4 Epinephrine should be available for the treatment of any acute anaphylactoid reaction. (See WARNINGS and CONTRAINDICATIONS .)
Infusion rates and clinical state should be monitored closely during infusion. If an adverse reaction occurs, the infusion rate should be reduced or the infusion stopped until the symptoms have subsided. (See DOSAGE AND ADMINISTRATION .)
Dosage and Administration
For treatment of primary defective antibody synthesis in adults, adolescents and children, Immune Globulin Intravenous (Human), Gammar-P I.V., is administered to restore the patient's circulating IgG level to near-normal levels. Starting doses of 200 mg/kg body weight every three to four weeks are recommended in children and adolescents. Slightly higher doses of 200 mg/kg to 400 mg/kg body weight given every three to four weeks are recommended in adults. The clinical management of adult, children and adolescent patients is optimized by adjusting doses to maintain desired IgG blood levels and clinical results.
PRODUCT COMPATIBILITY -- It is recommended that Immune Globulin Intravenous (Human), Gammar-P.I.V., be administered by a separate infusion line without admixture with other drugs or medications which the patient may be receiving. However, based upon compatibility studies, Gammar-P.I.V. may be infused sequentially into a primary i.v. line containing either 0.9% sodium chloride injection or 5% dextrose injection or flused with 0.9% sodium chloride injection or 5% dextrose injection. Do not mix Immune Globulin Intravenous (Human) products of differing formulations. If several doses of Immune Globulin Intravenous (Human), Gammar-P.I.V., are to be administered, several reconstituted vials of identical formulation and diluent may be pooled, using proper aseptic technique. As described under Reconstitution , below, do not shake or cause excessive foaming. Swirl gently to mix. Filtration is acceptable but not required; pore sizes of greater than or equal to 15 microns will be less likely to slow infusion.
|CAUTION:||Reconstitution instructions must be followed exactly. Please read the following instructions in their entirety before attempting to reconstitute product.|
- Bring both product vial and diluent vial to room temperature prior to reconstitution.
- Examine product vial to ensure no product powder or cake is wedged in the neck of the vial. If so, gently tap the vial to dislodge the product.
- Remove plastic flip-off caps from both vials.
- Treat rubber stoppers with antiseptic solution and allow to dry.
CAUTION: The double ended vented transfer spike (see diagram below), provided in the package is comprised of a white (diluent) end, which has a double orifice, and a green (product) end, which has a single orifice. Incorrect use of the transfer spike will result in loss of vacuum, and prevent transfer of diluent thereby preventing reconstitution of the product.
Â The transfer spike is sterile. Do not touch the exposed ends of the spike after removing the guards.
- Remove the guard from the white (diluent) end of the transfer spike. Insert the white end of the transfer spike into the center of the stopper of the upright diluent vial first.
- Remove the guard from the green (product) end of the transfer spike. Invert the diluent vial with the attached transfer spike and, using minimum force, insert the green end into the center of the stopper of the upright product vial. The flange of the transfer spike should rest on the surface of the stopper and the diluent will begin to transfer into the product vial.
- Allow the vacuum in the product vial to pull the diluent into the product vial.
- During diluent tranfer, wet the lyophilized cake completely by gently tilting the product vial. Do not allow the air inlet filter to face downward. Care should be taken not to lose the vacuum, as this will prolong reconstitution of the product.
- After diluent transfer is complete, the transfer spike will allow filtered air into the product vial through the air filter. Additional venting of the product vial after diluent transfer is complete, is not required. When diluent transfer is complete, withdraw and properly discard transfer spike and diluent bottle.
- Allow the product vial to remain undisturbed for 5 minutes after diluent addition. Do not touch or mix during this time.
- After 5 minutes, mix the product vial by gently swirling the vial without creating excessive foam. Never shake the product vial.
Note: A syrup-like layer may remain on the bottom of the vial following reconstitution. Swirl gently to disperse this layer until a homogenous solution is obtained.
- Examine solution. All unreconstituted product should dissolve with gentle swirling and the solution should be clear and ready to administer in 20 minutes or less.
- Product contains no preservative. Infusion must be initiated within 3 hours of reconstitution. If not used within this time frame, it should be properly disposed of and not administered.
- Reconstituted product does not need to be filtered. If a filter is used, it should be a 15 micron filter or larger.
- If several doses of Immune Globulin Intravenous (Human), Gammar-P.I.V., are to be pooled aseptically for administration, avoid excessive formation of foam in the pooliing container and gently swirl the pooling container to mix. DO NOT SHAKE THE POOLING CONTAINER.
|CAUTION:||When entering the product stopper with an IV set spike for administration, care should be taken to follow the path made by the transfer spike (see Reconstitution ).|
Immune Globulin Intravenous (Human), Gammar-P I.V., is to be administered by intravenous infusion. The infusion should begin at a rate of 0.01 mL/kg/min, increasing to 0.02 mL/kg/min after 15 to 30 minutes. Most patients tolerate a gradual incrase to 0.03-0.06 mL/kg/min. For the average 70 kg person this is equivalent to 2 to 4 mL/min. If adverse reactions develop, slowing the infusion rate will usually eliminate the reaction. Discard any unused solution.
For patients judged to be at increased risk for developing renal dysfunction, it may be prudent to reduce the amount of product (and sucrose stabilizer) infused per unit time by infusing Gammar-P I.V. at a rate less than 3.0 mg IG/kg/min (= 3.0 mg sucrose/kg/min) (0.06 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 selected 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. 9
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
Individual Vial Packages
Immune Globulin Intravenous (Human), Gammar-P I.V., is supplied in single dose vials, with diluent and sterile, vented transfer spike for reconstitution. The 10 g dosage form package also contains an administration set. The following dosage forms are available:
Immune Globulin Intravenous (Human), Gammar-P I.V., 5 g immune globulin/vial is supplied in a bulk pack (NDC 0053-7486-06) of six (6) single dose vials. Each single dose vial should be reconstituted with 100 mL Sterile Water for Injection, USP (not supplied).
When stored at temperatures not exceeding 25Â°C (77Â°F), Immune Globulin Intravenous (Human), Gammar-P I.V., is stable for the period indicated by the expiration date on its label. Avoid freezing which may damage container for the diluent.
- Data on File: Aventis Behring L.L.C.
- Steele RW, Augustine RA, Tannenbaum AS, Marmer DJ. Intravenous Immune Globulin for Hypogammaglobulinemia: A Comparison of Opsonizing Capacity in Recipient Sera. Clin. Immunol. Immunopathol. 1985; 34:275-283.
- Martindale. The Extra Pharmacopoeia 27th ed. Edited by Wade A. London: The Pharmaceutical Press. 1979: 65.
- Fudenberg HH. Sensitization to Immunoglobulins and Hazards of Gamma Globulin Therapy. Immunoglobulins, Biologic Aspects and Clinical Uses , 1970; 211-220. Edited by Merler E. National Academy of Sciences, Washington, D.C.
- Sekul EA, Cupler EJ, Dalakas, MC. Aseptic Meningitis Associated with High Dose Intravenous Immunoglobulin Therapy: Frequency and Risk Factors. Ann Int Med 1994; 121:4, 259-262.
- Kato E, Shindo S, Eto Y, et al. Administration of Immune Globulin Associated with Aseptic Meningitis. JAMA 1988; 259:3269-3271.
- Casteels-Van Daele M, Wijndale L, Hunnick K, Gillis P, Ziekenhuis V. Intravenous Immune Globulin and Acute Aseptic Meningitis. N Engl J Med 1990; 323:614-615.
- Scribner C, Kapit R, Phillips E, Rickels N. Aseptic Meningitis and Intravenous Immunoglobulin Therapy. Ann Int Med 1994; 121:305-306.
- Tan E, et al . Acute Renal Failure Resulting from Intravenous Immunoglobulin Therapy. Arch Neurol . 1993; 50(2): 137-139.
- Winward DB, Brophy MT: Acute renal failure after administration of intravenous immunoglobulin: review of the literature and case report. 1995; Pharmacotherapy 15:765-772.
- Phillips AO: Renal failure and intravenous immunoglobulin [letter; comment]. 1992; Clin Nephrol 36:83-86.
- Cayco AV, Perazella MA, Hayslett JP: Renal insufficiency after intravenous immune globulin therapy: A Report of Two Cases and an Analysis of the Literature. 1997; J Amer Soc Nephrology 8:1788-1793.
- Anderson W, Bethea W: Renal lesion following administration of hypertonic solutions of sucrose. 1940; JAMA 114:1983-1987.
- Lindberg H, Wald A: Renal changes following the administration of hypertonic solutions. 1939; Arch Intern Med 63:907-918.
- Rigdon RH, Cardwell ES: Renal lesions following the intravenous injection of hypertonic solution of sucrose: A clinical and experimental study. 1942; Arch Intern Med 69:670-690.
Polley MJ, Fischetti VA, Landaburu PH. Native Intravenous IgG Exhibits Greater Biological Activity than Modified IgG. From the XX Cong. Int. Soc. of Hematology ; 1984.
Revised July, 2001 Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â 12173-02
Kankakee, IL 60901 U.S.A.
U.S. License No. 1281