Gamimune N, 10% solvent detergent treated

Description

Immune Globulin Intravenous (Human), 10% -- Gamimune N, 10% treated with solvent/detergent is a sterile solution of human protein containing no preservative. Gamimune N, 10% consists of 9%-11% protein in 0.16-0.24 M glycine. Not less than 98% of the protein 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. The measured buffer capacity is 35 mEq/L and the osmolality is 274 mOsmol/kg solvent.

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 glycine. Gamimune N, 10% 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, 10% 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.

Clinical Pharmacology

Primary Humoral Immunodeficiency

Gamimune N, 10% supplies a broad spectrum of opsonic and neutralizing IgG antibodies for the prevention or attenuation of a wide variety of infectious diseases. Since Gamimune N, 10% is administered intravenously, essentially 100% of the infused IgG antibodies are immediately available in the recipient's circulation. 2 Studies using a modified intravenous immunoglobulin at pH 6.8 have shown that approximately 30% of the infused IgG disappeared from the circulation in the first 24 hours, due primarily to equilibration of the IgG between the plasma and the extravascular space. 2-5 A further decline to about 40% of the peak level found immediately post-infusion is to be expected during the first week. 2-5 The in vivo half-life of Immune Globulin Intravenous (Human), 5%--Gamimune N, 5% equals or exceeds the 3-week half-life reported for IgG in the literature, but individual patient variation in half-life has been observed. 2 Thus, this variable as well as the amount of immune globulin administered per dose is important in determining the frequency of administration of the drug for each individual patient. A comparative study of Gamimune N, 10% with Gamimune N, 5% (in 10% maltose) in 18 subjects demonstrated equivalent post-infusion recovery for the two preparations. A comparative study of Gamimune N, 10% treated with solvent/detergent and Gamimune N, 10% in 17 subjects demonstrated bioequivalence.

Idiopathic Thrombocytopenic Purpura

While Gamimune N, 10% has been shown to be effective in some cases of idiopathic thrombocytopenic purpura (ITP) (see INDICATIONS AND USAGE ), the mechanism of action has not been fully elucidated.

Bone Marrow Transplantation

Clinical studies with Gamimune N, 5% have shown that it is effective in bone marrow transplant patients >/= 20 years of age in the first 100 days posttransplant for the following: prevention of systemic and local infections, interstitial pneumonia of infectious and idiopathic etiologies and acute graft-versus-host disease (AGVHD) 6 (see INDICATIONS AND USAGE ). Administration of Gamimune N, 5% to bone marrow transplant patients significantly increased IgG and IgG subclass levels while those seen in the control group fell below predicted levels. The mechanism of action of Gamimune N, 5% in reducing the incidence of AGVHD is presently unknown.

Pediatric HIV Infection

Children infected with human immunodeficiency virus (HIV) may display defects in both cellular and humoral immunity. 7-10 As a result, some children with HIV-1 infection experience serious, potentially life-threatening recurrent bacterial infections. 11-13 In one retrospective report, among 71 HIV-infected children observed over 3.5 years, 27 (37%) experienced serious documented bacterial infections. 12 The types of bacterial and viral infections observed in HIV-infected children are similar to those seen in children with primary hypogammaglobulinemia. 14 The replacement of opsonic and neutralizing IgG antibodies has been shown to reduce serious and minor bacterial infection in HIV-infected children. 15,16

In a randomized, double-blind, placebo-controlled, multicenter study performed between March 7, 1988 and January 15, 1991, the efficacy of Gamimune N, 5% in pediatric HIV disease to decrease the frequency of serious and minor bacterial infections and the frequency of hospitalization, and to increase the time free of serious bacterial infection was documented in children with clinical or immunologic evidence of HIV disease (see INDICATIONS AND USAGE ). The primary endpoint of this study was prospectively defined as a significant reduction in the proportion of subjects who develop at least one serious bacterial infection when compared to the control group of HIV-infected children who received placebo. Serious bacterial infections were defined as laboratory-proven and clinically diagnosed (i.e., radiologically proven acute pneumonia and sinusitis) infections. The Data Safety and Monitoring Board (DSMB) recommended early termination of the study based on data presented to them from an interim analysis in December 1990 which showed that treatment with Gamimune N, 5% increased the time free from serious infections in children with CD4 + counts >/= 200/mm 3 .

General

Glycine (aminoacetic acid) is a nonessential amino acid normally present in the body. 17 Glycine is a major ingredient in amino acid solutions employed in intravenous alimentation. 18 While toxic effects of glycine administration have been reported, 19 the doses and rates of administration were 3 - 4-fold greater than those for Gamimune N, 10%.

The buffer capacity of Gamimune N, 10% is 35.0 mEq/L (~0.35 mEq/g protein). A dose of 1000 mg/kg body weight therefore represents an acid load of 0.35 mEq/kg body weight. The total buffering capacity of whole blood in a normal individual is 45-50 mEq/L of blood, or 3.6 mEq/kg body weight. 20 Thus, the acid load delivered with a dose of 1000 mg/kg of Gamimune N, 10% would be neutralized by the buffering capacity of whole blood alone, even if the dose was infused instantaneously.

In Phase I human studies comparing Gamimune N, 10% with Gamimune N, 5% (in 10% maltose), venous blood measurements were taken following the intravenous administration of 400 mg/kg body weight in 18 patients. There were no clinically important changes in mean venous pH, bicarbonate, or base excess measurements in these patients receiving either preparation. 2

In a similar, earlier Phase I study Gamimune N, 5% (in 10% maltose) was compared with a chemically modified 5% intravenous immunoglobulin preparation with a pH of 6.8. No clinically important changes in mean venous pH and bicarbonate measurements were detected following infusions of either preparation at doses of 400 mg/kg body weight in 37 patients.

In patients with limited or compromised acid-base compensatory mechanisms, consideration should be given to the effect of the additional acid load Gamimune N, 10% might present.

Indications and Usage

Primary Humoral Immunodeficiency

Gamimune N, 10% is efficacious in the treatment of primary immunodeficiency states in which severe impairment of antibody forming capacity has been shown, such as: congenital agammaglobulinemias, common variable immunodeficiency, Wiskott-Aldrich syndrome, x-linked immunodeficiency with hyper IgM, and severe combined immunodeficiencies. 5,21-23 Gamimune N, 10% is especially useful when high levels or rapid elevation of circulating antibodies are desired or when intramuscular injections are contraindicated.

Idiopathic Thrombocytopenic Purpura (ITP)

In clinical situations in which a rapid rise in platelet count is needed to control bleeding or to allow a patient with ITP to undergo surgery, administration of Gamimune N, 10% should be considered. Studies with Gamimune N, 5% demonstrate that in patients in whom a response was achieved, the rise of platelets was generally rapid (within 1-5 days), transient (most often lasting from several days to several weeks) and were not considered curative. It is presently not possible to predict which patients with ITP will respond to therapy, although the increase in platelet counts in children seems to be better than that in adults. Childhood ITP may, however, respond spontaneously without treatment.

Gamimune N, 10% has been studied in 31 adult and pediatric subjects with ITP using a dosage of 1,000 mg/kg body weight on either 1 day or 2 consecutive days. Fourteen of 16 children (87.5%) and 9 of 10 adults with platelet follow-up (90%) responded to treatment with clinically significant platelet increments of >/= 30,000/mm 3 . In the 12 children with acute ITP, there was an average increase in platelet count above baseline of 274,000/mm 3 (range 33,000-529,000/mm 3 ).

Two different dosing regimens of Gamimune N, 5% have been studied in clinical investigations: a regimen consisting of 400 mg/kg body weight daily for 5 consecutive days, and a high dose treatment regimen consisting of 1,000 mg/kg body weight administered on either 1 day or 2 consecutive days (these studies are summarized below).

In clinical studies of Gamimune N, 5%, five of six (83.3%) children and 12 of 16 (75%) adults with acute or chronic ITP treated with 400 mg/kg body weight for 5 consecutive days demonstrated clinically significant platelet increments of >/= 30,000/mm 3 over baseline. The mean platelet count in children with ITP rose from 27,800/mm 3 at baseline to 297,000/mm 3 (range 50,000-455,000/mm 3 ) and the mean platelet count in adults with ITP rose from 27,900/mm 3 at baseline to 124,900/mm 3 (range 11,000-341,000/mm 3 ). Two of three children with acute ITP rapidly went into complete remission.

Thirteen of 14 children (92.9%) and 26 of 29 adults (89.7%) with acute or chronic ITP treated with Gamimune N, 5% 1,000 mg/kg body weight administered on either 1 day or 2 consecutive days responded to treatment with clinically significant platelet increments of >/= 30,000/mm 3 over baseline. This included three of three patients with ITP that were human immunodeficiency virus (HIV) antibody positive and two of two patients with ITP that were pregnant. The mean platelet count in children with ITP treated with Gamimune N, 5% 1,000 mg/kg body weight on 1 day or 2 consecutive days rose from 44,400/mm 3 at baseline to 285,600/mm 3 (range 89,000-473,000/mm 3 ) and the mean platelet count in adults with ITP treated with the regimen rose from 23,400/mm 3 at baseline to 173,100/mm 3 (range 28,000-709,000/mm 3 ). Two patients, one each with acute adult and chronic childhood ITP, entered complete remission with treatment.

Six of the 29 adult patients with ITP received Gamimune N, 5% 1,000 mg/kg on 1 day or 2 consecutive days to increase the platelet count prior to splenectomy. Mean platelet counts rose from 14,500/mm 3 at baseline to 129,300/mm 3 (range 51,000-242,000/mm 3 ) prior to surgery.

The duration of the platelet rise following treatment of ITP with either treatment regimen of Gamimune N, 5% was variable, ranging from several days to 12 months or more. Some ITP patients have demonstrated continuing responsiveness over many months to intermittent infusions of Gamimune N, 5% 400-1,000 mg/kg body weight, administered as a single maintenance dose, at intervals as indicated by the platelet count.

Bone Marrow Transplantation (BMT)

In clinical studies in bone marrow transplant patients >/= 20 years of age, Gamimune N, 5% decreased the risk of septicemia and other infections, interstitial pneumonia of infectious or idiopathic etiologies and acute graft-versus-host disease (AGVHD) in the first 100 days posttransplant. Gamimune N, 5% is not indicated in bone marrow transplant patients below 20 years of age. In a controlled study of 369 evaluable BMT patients (184 treated and 185 controls) who either did or did not receive Gamimune N, 5% in doses of 500 mg/kg body weight on days -7 and -2 pretransplant, then weekly through day 90 posttransplant, posttransplant complications were evaluated in the entire study group and in patients under age 20 and age 20 or older. For patients >/= 20 years of age (128 patients in the control group and 119 patients in the treated group), there was a statistically significant reduction in interstitial pneumonia from 21% in the control group to 9% in the treated group (p=0.0032) during the first 100 days posttransplant. Also significantly reduced in this age group were: overall septicemia from 53 infections in the 128 patient control group to 26 infections in the 119 patient treated group (relative risk control:treated [RR] 2.36, p=0.0025); gram-negative septicemia from 24 infections in the 128 patient control group to 9 infections in the 119 patient treated group (RR 2.53, p=0.015); gram-positive septicemia from 16 infections in the 128 patient control group to 8 infections in the 119 patient treated group (RR 2.73, p=0.046); and Grade II to IV AGVHD from an incidence of 58 of 110 in the control group to 38 of 108 in the treated group (p=0.0051).

The given p-values do not take into account multiple endpoints and subset analyses. Therefore, some of the p-values could occur by chance alone. There was no significant improvement in overall mortality in this study.

In patients below age 20, there appeared to be no benefit from treatment with Gamimune N, 5%, either in reducing the incidence of infections or the incidence of AGVHD.

Pediatric HIV Infection

Gamimune N, 5% 400 mg/kg every 28 days significantly decreased the frequency of serious and minor bacterial infections (laboratory-proven and clinically diagnosed) and the frequency of hospitalization, and increased the time free of serious bacterial infection. The effect of Gamimune N, 5% in preventing serious bacterial infections was especially apparent in preventing primary bacteremia (including Streptococcus pneumoniae bacteremia) and acute pneumonia.

In a randomized, double-blind, placebo-controlled, multicenter study, 394 HIV-infected, non-hemophilic, children less than 13 years of age were randomized. Of the children randomized, 369 were included in the efficacy analysis and 376 in the safety analysis. The study population had 1) a mean age of 40 months (range 2.4-136.8 months), 2) acquired HIV primarily through vertical transmission (91%), 3) a majority (87%) of CDC Class P-2 (symptomatic), and 4) had a median CD4 + count of 937 cells/mm 3 (range 0-6660 cells/mm 3 ). At the time of study entry, 14% (52 of 369) were receiving Pneumocystis carinii pneumonia (PCP) prophylaxis. During the course of the study, 51% (189 of 369) received PCP prophylaxis and 44% (164 of 369) received zidovudine (ZDV). Children with HIV-1 infection were initially stratified into two groups based upon CD4 + count (< 200 cells/mm 3 versus >/= 200 cells/mm 3 ) and CDC classification of pediatric HIV disease (history of opportunistic infections [P-2-D-1] and recurrent serious bacterial infections [P-2-D-2] versus others). Subjects received Gamimune N, 5% (400 mg/kg = 8 mL/kg) (n=185) or an equivalent volume of placebo (0.1% Albumin [Human]) (n=184) every 28 days. The mean follow-up for subjects receiving Gamimune N, 5% was 17.9 months and 17.8 months for patients on placebo.

The number of subjects who had at least one serious bacterial infection was 86 of 184 (47%) in the placebo group and 55 of 185 (30%) in the Gamimune N, 5% group (p=0.0009). All p-values reported are two-sided. Treatment with Gamimune N, 5% compared to placebo was also associated with a significant reduction in both the number of subjects with at least one laboratory-proven infection (36 of 184 vs. 18 of 185, p=0.0081), and the number of subjects with at least one clinically diagnosed infection (71 of 184 vs. 45 of 185, p=0.0036). Efficacy in patients with CD4+ counts < 200/mm 3 was not established, possibly because of the small number of subjects in this category.

The 2-year treatment period defined in the protocol was truncated for some patients by the DSMB based on data from the interim analysis. Rates of serious bacterial infections per 100 patient-years were computed and analyzed to take into account both the unequal duration of treatment and follow-up, as well as recurrent infections in individual subjects. Children treated with Gamimune N, 5% experienced a 50.5% lower frequency of laboratory-proven serious bacterial infection compared to the group treated with placebo (9.1 vs. 18.2 infections per 100 patient-years, p=0.031), a 36.0% lower frequency of clinically diagnosed serious infections (24.0 vs. 37.5 infections per 100 patient-years, p=0.013), a 40.6% reduction in total serious infections (laboratory-proven and clinically diagnosed) (33.1 vs. 55.7 infections per 100 patient-years, p=0.003), a 60% lower frequency of primary bacteremias (5.8 vs. 14.5 infections per 100 patient-years, p=0.009), a 75.6% lower frequency of Streptococcus pneumoniae bacteremia (1.1 vs. 4.5 bacteremias per 100 patient-years, p=0.026), a 54.3% lower frequency of clinically diagnosed pneumonia (12.7 vs. 27.8 infections per 100 patient-years, p=0.001), and a 22.5% lower frequency of minor bacterial infections (including otitis media, skin and soft tissue infections, and upper respiratory tract infections) (123.6 vs. 159.5 infections per 100 patient-years, p=0.033).

In addition to a reduced frequency of infection, children treated with Gamimune N, 5% had a 36.8% lower number of hospitalizations per 100 patient-years (72 vs. 114 per 100 patient-years, p=0.002) and a reduced number of hospital days (6.9 vs. 10.5 per patient-year, p=0.030) than patients treated with placebo. Patients treated with Gamimune N, 5% had a higher probability of remaining free of laboratory-proven infections (p=0.0093) and combined laboratory-proven and clinically diagnosed infections (p=0.0015) for 24 months than the group of children treated with placebo. At 24 months, the estimated probabilities of remaining infection-free for the Gamimune N, 5% and placebo arms were 87.8% vs. 76.1%, respectively, for laboratory-proven infections and 63.5% vs. 44.5%, respectively, for combined laboratory-proven and clinically diagnosed infections.

There was no effect of Gamimune N, 5% therapy on mortality, which was low in both treatment groups (17%), or on the frequency of opportunistic or viral infections during the period of study.

Since antibacterial prophylaxis could also account for the observed reduction in the rate of serious bacterial infections, further analysis was performed to evaluate the role of Pneumocystis carinii pneumonia (PCP) prophylaxis on the efficacy of Gamimune N, 5%. PCP prophylaxis consisted primarily (96%) of trimethoprim/sulfamethoxazole given 3 successive days each week. This antibiotic combination could be active against the bacteria commonly encountered in this patient population. In the subgroup of patients receiving PCP prophylaxis at study entry, treatment with Gamimune N, 5% was associated with 44.0 infections per 100 patient-years, whereas placebo recipients had 64.7 infections per 100 patient-years (p=0.047). In the subgroup of patients not receiving PCP prophylaxis at study entry, treatment with Gamimune N, 5% was associated with 22.1 infections per 100 patient-years, whereas placebo recipients had 44.9 infections per 100 patient-years on placebo (p=0.024). Thus, Gamimune N, 5% benefitted patients by reducing the rate of serious bacterial infections whether or not they were receiving PCP prophylactic treatment at study entry. However, it should be noted that the use of PCP prophylactic treatment in this study was not randomized and specific guidelines for its administration were not identified.

Contraindications

Gamimune N, 10% 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, 10% since these patients may experience severe reactions to the IgA which may be present. 22

Warnings

Immune Globulin Intravenous (Human) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis and death. 24 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. See PRECAUTIONS and DOSAGE AND ADMINISTRATION sections for important information intended to reduce the risk of acute renal failure.

Gamimune N, 10% 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.

Immune Globulin Intravenous (Human), 10% -- Gamimune N, 10% should be administered only intravenously as the intramuscular and subcutaneous routes have not been evaluated.

Immune Globulin Intravenous (Human), 5% -- Gamimune N, 5% has, on rare occasions, caused 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 for Gamimune N, 10% 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.

Precautions

General

Any vial that has been entered should be used promptly. Partially used vials should be discarded. Do not use if turbid. Solution which has been frozen should not be used.

An aseptic meningitis syndrome (AMS) has been reported to occur infrequently in association with Immune Globulin Intravenous (Human) treatment. The syndrome usually begins within several hours to two days following Immune Globulin Intravenous (Human) 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 mm 3 , 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) Immune Globulin Intravenous (Human) treatment. Discontinuation of Immune Globulin Intravenous (Human) treatment has resulted in remission of AMS within several days without sequelae. 25-28

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 Gamimune N, 10% 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 infused per unit time by infusing Gamimune N, 10% at a rate less than 8 mg IG/kg/min (0.08 mL/kg/min).

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

Antibodies in Gamimune N, 10% may interfere with the response to live viral vaccines such as measles, mumps and rubella. Therefore, use of such vaccines should be deferred until approximately 6 months after Gamimune N, 10% administration.

Please see DOSAGE AND ADMINISTRATION for other drug interactions.

Pregnancy Category C

Animal reproduction studies have not been conducted with Gamimune N, 10%. It is not known whether Gamimune N, 10% can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Gamimune N, 10% should be given to a pregnant woman only if clearly needed.

Adverse Reactions

General

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. 32 Types of severe renal adverse reactions that have been seen following IGIV therapy include: acute renal failure, acute tubular necrosis, 33 proximal tubular nephropathy, and osmotic nephrosis. 24, see also 34-36

In the studies undertaken to date, other types of reactions have not been reported with Gamimune N, 5% or Gamimune N, 10%. It may be, however, that adverse effects will be similar to those previously reported with intravenous and intramuscular immunoglobulin administration. Potential reactions, therefore, may also include anxiety, flushing, wheezing, abdominal cramps, myalgias, arthralgia, and dizziness; rash has been reported only rarely. Very rarely have there been cases reported of severe injection site reactions. Reactions to intravenous immunoglobulin tend to be related to the rate of infusion.

True anaphylactic reactions to Gamimune N, 10% may occur in recipients with documented prior histories of severe allergic reactions to intramuscular immunoglobulin, but some patients may tolerate cautiously administered intravenous immunoglobulin without adverse effects. 32 Very rarely an anaphylactoid reaction may occur in patients with no prior history of severe allergic reactions to either intramuscular or intravenous immunoglobulin. 2

Primary Humoral Immunodeficiency

A safety study has been conducted in 20 adult and pediatric subjects with primary immunodeficiency syndrome comparing side effects of Gamimune N, 5% with those of Gamimune N, 10%. The incidence, nature, or severity of reactions with Gamimune N, 10% were not different from those observed with Gamimune N, 5%, and were consistent with those observed in previous studies with Gamimune N, 5%. Symptoms related to the infusion of Gamimune N, 10% were observed in 9 (3.5%) of 255 infusions. These symptoms were all mild to moderate in severity and included chills, fever, headache and emesis.

In a study of 37 patients with immunodeficiency syndromes receiving Gamimune N, 5% in a monthly dose of 400 mg/kg body weight, reactions were seen in 5.2% of the infusions. Symptoms reported included malaise, a feeling of faintness, fever, chills, headache, nausea, vomiting, chest tightness, dyspnea and chest, back or hip pain. Mild erythema following infiltration of Gamimune N, 5% at the infusion site was reported in some cases.

A safety study has been conducted in 17 adult and adolescent subjects with primary immunodeficiency syndrome, comparing side effects and bioequivalency of Gamimune N, 10% with those of Gamimune N, 10% treated with solvent/detergent. The incidence, nature and severity of reactions with Gamimune N, 10% treated with solvent/detergent were not different from those observed with Gamimune N, 10%.

Idiopathic Thrombocytopenic Purpura

An investigation of Gamimune N, 10% in 31 adult and pediatric subjects with ITP encountered side effects in 17 of 119 (14.3%) infusions. The dosage in these studies was 1,000 mg/kg body weight for 1 day or 2 consecutive days. However, in the adult study, an induction dosage of 500 mg/kg body weight for 1 day or 2 consecutive days was associated with 17 of these infusions. Of those 17 infusions, three had adverse events. Overall, side effects included mild chest pain, mild and moderate emesis, moderate fever, mild or moderate headache (severe on one occasion) and a single incidence of hives, pruritus and rash. At least 17 of the 50 infusions in the pediatric study were given at rates of >/= 0.1 mL/kg body weight per minute as part of a rate escalation investigation. Maximum infusion rates obtained were not limited by or interrupted due to adverse effects.

In studies of Gamimune N, 5% administered at a dose of 400 mg/kg body weight in the treatment of adult and pediatric patients with ITP, systemic reactions were noted in only 4 of 154 (2.6%) infusions, and all but one occurred at rates of infusion greater than 0.04 mL/kg body weight per minute. The symptoms reported included chest tightness, a sense of tachycardia (pulse was 84 beats per minute), and a burning sensation in the head; these symptoms were all mild and transient.

In studies of Gamimune N, 5% administered at a dose of 1,000 mg/kg body weight either as a single dose or as two doses on consecutive days in the treatment of adult and pediatric patients with ITP, adverse reactions were noted in 25 of 251 (10%) infusions. Symptoms reported included headache, nausea, fever, chills, back pain, chest tightness, and shortness of breath. In children, the high dose regimen has been well-tolerated at the highest rates of infusion. In adults, however, the frequency of adverse reactions tended to increase with infusion rates in excess of 0.06 mL/kg body weight per minute. In general, reactions reported with infusion of Gamimune N, 5% in these studies were reported as mild or moderate, and responded to slowing of the infusion rate.

Bone Marrow Transplantation

In studies of Gamimune N, 5% administered to 185 bone marrow transplant recipients at doses of 500 mg/kg (10 mL/kg) body weight on day -7 and day -2 pretransplant, then weekly through day 90 posttransplant, adverse reactions were noted in 12 (6.5%) of the 185 patients that received Gamimune N, 5% and in 14 (0.6%) of 2,176 infusions. All reactions reported were rate-related and classified as mild. Chills were the most common symptom reported, occurring in nine patients. The other symptoms reported included headache, flushing, fever, pruritus and slight back discomfort. All reactions resolved satisfactorily, usually without treatment or decreasing the infusion rate.

Pediatric HIV Infection

Three hundred seventy-six (376) patients, 187 treated with Gamimune N, 5% and 189 treated with placebo (0.1% Albumin [Human]), were included in the safety analysis. Adverse reactions occurred during or within 24 hours of an infusion in 50 of 3,451 (1.4%) infusions of Gamimune N, 5% and 62 of 3,447 (1.8%) infusions of placebo. Fever was the most common adverse reaction and occurred in 30 of 105 (28.6%) patients receiving placebo and 19 of 78 (24.4%) patients treated with Gamimune N, 5%. Irritability was the second most common symptom reported, with 10 of 105 (9.5%) reports for the placebo group and 9 of 78 (11.5%) for the group treated with Gamimune N, 5%. A large number of diverse adverse reactions accounted for the remaining adverse reactions reported in both study groups. In general, the number of adverse events reported was comparable in both the placebo and Gamimune N, 5% treated groups. Three serious adverse reactions were reported. One patient experienced a hypersensitivity reaction and did not receive further Gamimune N, 5% treatment. A second patient developed tachycardia and was admitted to an intensive care unit, but later continued treatment with Gamimune N, 5%. A third patient had skin infiltration during infusion and developed a full thickness skin slough over the dorsum of the hand that required skin grafting.

Dosage and Administration

General

Dosages for specific indications are indicated below, but in general, it is recommended that Gamimune N, 10% be infused 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, 10% 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, 10% be given by a separate line, by itself, without mixing with other intravenous fluids or medications the patient might be receiving. Gamimune N, 10% should not be mixed with Immune Globulin Intravenous (Human) from another manufacturer. Gamimune N, 10% is not compatible with saline. If dilution is required, Gamimune N, 10% 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, 10% 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. 37

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, 10% for prophylaxis in primary immunodeficiency syndromes is 100-200 mg/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 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. Alternatively, studies in adults and children with Gamimune N, 5% and Gamimune N, 10% using a dose of 1,000 mg/kg body weight daily for 1 day or 2 consecutive days have also shown increases in platelet count. 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, 10% 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

A reduction in posttransplant complications has been observed in bone marrow transplant patients >/= 20 years of age receiving Gamimune N, 5%. An equivalent dosage of Gamimune N, 10% is recommended in doses of 500 mg/kg (5 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, 10% 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%. An equivalent dosage of Gamimune N, 10% is recommended in doses of 400 mg/kg (4 mL/kg) body weight every 28 days.

How Supplied

Gamimune N, 10% is supplied in the following sizes:

NDC Number
   Size    Grams Protein
0026-0648-12
 10 mL  1.0
0026-0648-15
 25 mL  2.5
0026-0648-20
 50 mL  5.0
0026-0648-71
100 mL 10.0
0026-0648-24
200 mL 20.0

STORAGE

Store at 2-8°C (36-46°F). Do not freeze. Do not use after expiration date.

CAUTION

Rx only

U.S. federal law prohibits dispensing without prescription.

References

  1. Tenold RA, inventor; Cutter Laboratories, assignee. Intravenously injectable immune serum globulin. U.S. Patent 4,396,608, Aug. 2, 1983.
  2. Data on file at Bayer Corporation.
  3. Pirofsky B, Campbell SM, Montanaro A: Individual patient variations in the kinetics of intravenous immunoglobulin administration. J Clin Immunol 2(2): 7S-14S, 1982.
  4. Pirofsky B: Intravenous immune globulin therapy in hypogammaglobulinemia. Amer J Med 76(3A):53-60, 1984.
  5. Pirofsky B, Anderson CJ, Bardana EJ Jr.: Therapeutic and detrimental effects of intravenous immunoglobulin therapy. In: Alving BM (ed.): Immunoglobulins: characteristics and uses of intravenous preparations. Washington, D.C., U.S. Government Printing Office, (1980), pp 15-22.
  6. Sullivan KM, Kopecky KJ, Jocom J, et al: Immunomodulatory and antimicrobial efficacy of intravenous immunoglobulin in bone marrow transplantation. N Engl J Med 323(11):705-12, 1990.
  7. Bernstein LJ, Ochs HD, Wedgwood RJ, et al; Defective humoral immunity in pediatric acquired immune deficiency syndrome. J Pediatr 107(3):352-7, 1985.
  8. Borkowsky W, Steele CJ, Grubman S, et al: Antibody responses to bacterial toxoids in children infected with human immunodeficiency virus. J Pediatr 110(4):563-6, 1987.
  9. Blanche S, Le Deist F, Fischer A, et al: Longitudinal study of 18 children with perinatal LAV/HTLV III infection: attempt at prognostic evaluation. J Pediatr 109(6):965-70, 1986.
  10. Pahwa S, Fikrig S, Menez R, et al: Pediatric acquired immunodeficiency syndrome demonstration of B-lymphocyte defects in vitro. Diagn Immunol 4(1):24-30, 1986.
  11. Bernstein LJ, Krieger BZ, Novick B, et al: Bacterial infections in the acquired immunodeficiency syndrome of children. Pediatr Infect Dis 4(5):472-5, 1985.
  12. Krasinski K, Borkowsky W, Bonk S, et al: Bacterial infections in human immunodeficiency virus-infected children. Pediatr Infect Dis J 7(5):323-8, 1988.
  13. Scott GB, Buck BE, Leterman JG, et al: Acquired immunodeficiency syndrome in infants. N Engl J Med 310(2):76-81, 1984.
  14. Mofenson LM, Willoughby A. Passive immunization. In: Pizzo PA, Wilfert CM, (eds.) Pediatric AIDS: the challenge of HIV infection in infants, children and adolescents. Baltimore: Williams & Wilkins (1991) pp 633-50.
  15. National Institute of Child Health and Human Development Intravenous Immunoglobulin Study Group. Intravenous immune globulin for the prevention of bacterial infections in children with symptomatic human immunodeficiency virus infection. N Engl J Med 325(2):73-80, 1991.
  16. Mofenson LM, Moye J Jr, Bethel J, et al: Prophylactic intravenous immunoglobulin in HIV-infected children with CD4 + counts of 0.20 × 10 9 /L or more. Effect on viral, opportunistic, and bacterial infections. JAMA 268(4):483-88, 1992.
  17. Glycine. In: Budavari S, O'Neil MJ, Smith A, et al, eds.: Merck Index . 11th ed. Rahway NJ, Merck & Co., 1989. p. 706.
  18. Wretlind, A: Complete intravenous nutrition: theoretical and experimental background. Nutr Metab 14(Suppl):1-57, 1972.
  19. Hahn RG, Stalberg HP, Gustafsson SA: Intravenous infusion of irrigating fluids containing glycine or mannitol with and without ethanol. J Urol 142(4):1102-1105, 1989.
  20. Guyton AC: Textbook of Medical Physiology. 5th ed. Philadelphia, W.B. Saunders, 1976, pp 499-500.
  21. Nolte MT, Pirofsky B, Gerritz GA, et al: Intravenous immunoglobulin therapy for antibody deficiency. Clin Exp Immunol 36: 237-43, 1979.
  22. Buckley RH: Immunoglobulin replacement therapy: indications and contraindications for use and variable IgG levels achieved. In: Alving BM (ed): Immunoglobulins: characteristics and uses of intravenous preparations. Washington, D.C., U.S. Government Printing Office, (1980), pp 3-8.
  23. Ochs HD: Intravenous immunoglobulin therapy of patients with primary immunodeficiency syndromes: efficacy and safety of a new modified immune globulin preparation. In: Alving BM (ed.): Immunoglobulins: characteristics and uses of intravenous preparations. Washington, D.C., U.S. Government Printing Office, (1980), pp 9-14.
  24. Cayco AV, Perazella MA, Hayslett JP: Renal insufficiency after intravenous immune globulin therapy: A Report of Two Cases and an Analysis of the Literature. J Amer Soc Nephrology 8:1788-1793, 1997.
  25. Sekul E, Cupler E, Dalakas M. Aseptic meningitis associated with high-dose intravenous immunoglobulin therapy: Frequency and risk factors. Ann Int Med 121:259-262, 1994.
  26. Kato E, Shindo S, Eto Y, et al: Administration of Immune Globulin Associated with Aseptic Meningitis. JAMA 259(22):3269-3270, 1988.
  27. Casteels-Van Daele M, Wijndaele L, Hunninck K, et al: Intravenous immune globulin and acute aseptic meningitis. N Engl J Med 323(9):614-615, 1990.
  28. Scribner C, Kapit R, Phillips E, et al: Aseptic meningitis and Intravenous immunoglobulin therapy. Ann Intern Med 121(4):305-306, 1994.
  29. Schiavotto C, Ruggeri M. Rodeghiero F. Adverse reactions after high-dose intravenous immunoglobulin: incidence in 83 patients treated for idiopathic thrombocytopenic purpura (ITP) and review of the literature. Haematologica 78(6:Suppl 2):35-40, 1993.
  30. Pasatiempo AM, Kroser JA, Rudnick M, et al: Acute renal failure after intravenous immunoglobulin therapy. J Rheumatol 21(2):347-9, 1994.
  31. Peerless AG, Stiehm ER: intravenous gammaglobulin for reaction to intramuscular preparation. [letter] Lancet 2(8347):461, 1983.
  32. Winward DB, Brophy MT: Acute renal failure after administration of intravenous immunoglobulin: review of the literature and case report. Pharmacotherapy 15:765-772, 1995.
  33. Phillips AO: Renal failure and intravenous immunoglobulin [letter; comment]. Clin Nephrol 36:83-86, 1992.
  34. Anderson W, Bethea W: Renal lesions following administration of hypertonic solutions of sucrose. JAMA 114:1983-1987, 1940.
  35. Lindberg H, Wald A: Renal changes following the administration of hypertonic solutions. Arch Intern Med 63:907-918, 1939.
  36. Ridgon RH, Cardwell ES: Renal lesions following the intravenous injection of hypertonic solution of sucrose: A clinical and experimental study. Arch Intern Med 69:670-690, 1942.
  37. Tan E, Hajinazarian M, Bay, et al. Acute renal failure resulting from intravenous immunoglobulin therapy. Arch Neurology 50:137-139, 1993.

Bayer Corporation

Pharmaceutical Division

Elkhart, IN 46515 USA                                            08692249

U.S. License No. 8                                (Rev. November 2001)

PRODUCT PHOTO(S):

NOTE: These photos can be used only for identification by shape, color, and imprint. They do not depict actual or relative size.

The product samples shown here have been supplied by the manufacturer. While every effort has been made to assure accurate reproduction, please remember that any visual identification should be considered preliminary. In cases of poisoning or suspected overdosage, the drug's identity should be verified by chemical analysis.
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