GAMIMUNE® N
Bayer
Immune Globulin (Human), I.V.
Passive Immunizing Agent
Action And Clinical Pharmacology: Primary Humoral Immunodeficiency: Gamimune N treated with solvent/detergent 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 is administered i.v., essentially 100% of the infused IgG antibodies are immediately available in the recipient’s circulation. Studies using a modified i.v. 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 IgG between the plasma and the extravascular space. A further decline of about 40% of the peak level found immediately post-infusion is to be expected during the first week. The in vivo half-life of Gamimune N equals or exceeds the 3-week half-life reported for IgG in the literature, but individual patient variation in half-life has been observed. 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, 5% treated with solvent/detergent and Gamimune N, 5% in 16 subjects demonstrated bioequivalence. 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 has been shown to be effective in some cases of idiopathic thrombocytopenic purpura (ITP) (see Indications) the mechanism of action has not been fully elucidated.
Allogeneic Bone Marrow Transplantation: Gamimune N has been shown to be effective in allogeneic bone marrow transplant patients ³20 years of age at increased risk for the following complications in the first 100 days post transplant: prevention of systemic and local infections, interstitial pneumonia of infectious and idiopathic etiologies and acute graft-versus-host disease (GVHD) (see Indications).
Administration of Gamimune N to allogeneic 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 in reducing the incidence of GVHD is presently unknown.
Pediatric HIV Infection: Children infected with human immunodeficiency virus (HIV) may display defects in both cellular and humoral immunity. As a result, children with AIDS have a markedly increased rate of serious, potentially life-threatening bacterial infections. The types of bacterial and viral infections observed in HIV-infected children are similar to those in children with primary hypogammaglobulinemia. The replacement of opsonic and neutralizing IgG antibodies has been shown to reduce a wide variety of infectious diseases in HIV-infected children.
General: The i.v. administration of solutions of maltose has been studied by several investigators. Healthy subjects tolerated the infusions well, and no adverse effects were observed at a rate of 0.25 g maltose/kg body weight/hour. In safety studies, infusions of 10% maltose administered at 0.27 to 0.62 g maltose/kg/h to normal subjects produced either mild side effects (e.g., headache) or no adverse reaction. Following i.v. administrations of maltose, maltose was detected in the peripheral blood; there was a dose-dependent excretion of maltose and glucose in the urine and a mild diuretic effect. These alterations were well tolerated without significant adverse effects. The highest recommended infusion rate, 0.06 mL/kg body weight/min (see Dosage), is equivalent to 0.36 g maltose/kg body weight/h.
The buffer capacity of Immune Globulin (Human), 5% is 16.5 mEq/L (approximately 0.3 mEq/g protein). A dose of 1 000 mg/kg body weight therefore represents an acid load of 0.33 mEq/kg body weight. The total buffering capacity of whole blood in a normal individual is 45 to 50 mEq/L of blood, or 3.6 mEq/kg body weight. Thus, the acid load delivered with a dose of 1 000 mg/kg of Gamimune N, 5% would be neutralized by the buffering capacity of whole blood alone, even if the dose were infused instantaneously. (An infusion usually lasts several hours.)
In Phase 1 human studies, no change in arterial blood pH measurements was detected following the i.v. administration of Gamimune N, 5% at a dose of 150 mg/kg body weight; following a dose of 400 mg/kg body weight in 37 patients, there were no clinically important differences in mean venous pH or bicarbonate measurements in patients who received Gamimune N, 5% compared with those who received a chemically modified i.v. immunoglobulin preparation with a pH of 6.8.
Glycine (aminoacetic acid) is a non-essential amino acid normally present in the body. Glycine is a major ingredient in amino acid solutions employed in i.v. alimentation. While toxic effects of glycine administration have been reported, the doses and rates of administration were 3 to 4-fold greater than those for Gamimune N, 10%.
The buffer capacity of Gamimune N, 10% is 35 mEq/L (approximately 0.35 mEq/g protein). A dose of 1 000 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 to 50 mEq/L of blood, or 3.6 mEq/kg body weight. Thus, the acid load delivered with a dose of 1 000 mg/kg of Gamimune N, 10% would be neutralized by the buffering capacity of whole blood alone, even if the dose were 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 i.v. 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.
In a similar, earlier Phase I study Gamimune N, 5% (in 10% maltose) was compared with a chemically modified 5% i.v. 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 the additional acid and/or protein load Gamimune N might present.
Indications And Clinical Uses: Primary Humoral Immunodeficiency: Gamimune N 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. It is especially useful when high levels or rapid elevation of circulating antibodies are desired or when i.m. 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 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 to 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 of 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 ³30 000/mm In the 12 children with acute ITP, there was an average increase in platelet count above baseline of 274 000/mm(range 33 000 to 529 000/mm.
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%, 5 of 6 (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 ³30 000 mmover baseline. The mean platelet count in children with ITP rose from 27 800/mmat baseline to 297 000/mm(range 50 000 to 455 000/mm and the mean platelet count in adults with ITP rose from 27 900/mmat baseline to 124 900/mm(range 11 000 to 341 000/mm. Two of 3 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 ³30 000/mmover baseline. This included 3 of 3 patients with ITP that were human immunodeficiency virus (HIV) antibody positive and 2 of 2 patients with ITP that were pregnant. The mean platelet count in chidren with ITP treated with Gamimune N, 5% 1 000 mg/kg body weight on 1 day or 2 consecutive days rose from 44 400/mmat baseline to 285 600/mm(range 89 000 to 473 000/mm and the mean platelet count in adults with ITP treated with the regimen rose from 23 400/mmat baseline to 173 100/mm(range 28 000 to 709 000/mm. 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/mmat baseline to 129 300/mm(range 51 000 to 242 000/mm 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% at doses of 400 to 1 000 mg/kg body weight, administered as a single maintenance dose, at intervals as indicated by the platelet count.
Allogeneic Bone Marrow Transplantation: Gamimune N could be considered for use in allogeneic bone marrow transplant (BMT) patients ³20 years of age to decrease the risk of septicemia and other infections, interstitial pneumonia of infectious or idiopathic etiologies and acute graft-versus-host disease (GVHD) in the first 100 days post-transplant.
Gamimune N is not indicated in allogeneic bone marrow transplant patients below 20 years of age.
In a controlled study of 369 evaluable bone marrow transplant patients (185 untreated and 184 treated with Gamimune N, 5% in doses of 500 mg/kg body weight on days -7 and -2 pretransplant then weekly through day 90 post-transplant), post-transplant complications were evaluated. Analysis of the study group as a whole and of those
In patients below age 20, there appeared to be no benefit from treatment with Gamimune N, either in reducing the incidence of infections or the incidence of acute GVHD.
Pediatric HIV Infection: Gamimune N, 5%, 400 mg/kg every 28 days, significantly decreases the frequency of serious and minor bacterial infections (laboratory-proven and clinically diagnosed) and the frequency of hospitalization, and increases the time free of serious infection in children with clinical or immunologic evidence of HIV disease with CD4+ counts of ³200 mm Gamimune N, 5% did not have any effect on mortality or on the frequency of opportunistic infection. To achieve optional efficacy the CD4+ counts should be determined prior to the onset of therapy. See Table I.
In a randomized, double-blind, placebo-controlled, multicenter study, 383 HIV-infected, nonhemophilic 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 to 136.8 months), 2) acquired HIV primarily through vertical transmission (91%), 3) a majority (82%) of CDC Class P-2 (symptomatic), and 4) had a median CD4+ count of 937 cells/mm(range 0 to 6 660 cells/mm. At the time of study entry, 14% (52 of 369) were receiving P. carinii pneumonia (PCP) prophylaxis. During the course of the study, 51% (189 of 369) received PCP prophylaxis and 44% (154 of 359) received zidovudine (ZDV).
The number of subjects who had at least 1 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 2-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 1 laboratory-proven infection (36 of 184 vs. 18 of 185, p=0.0081), and the number of subjects with at least 1 clinically diagnosed infection (71 of 184 vs. 45 of 185, p=0.0036). Efficacy in patients with CD4+ counts
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% 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% lower frequency of clinically diagnosed serious infections (24 vs. 37.5 infections per 100 patient years, p=0.003), a 40.6% reduction in total serious infections (laboratory proven and clinically diagnosed) (33.1 vs. 55.7 infections per 100 patients years, p=0.009), a 60% lower frequency of primary bacteremia (5.8 vs. 14.5 infections per 100 patient years, p=0.009), a 75.5% lower frequency of S. pneumoniae bacteremia (1.1 vs. 4.4 bacteremias per 100 patient years, p=0.026), a 54.3% lower frequency of clinically diagnosed pneumonias (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 average annual number of hospital days (6.9 vs. 10.5, p=0.030) than patients treated with placebo. In addition, Gamimune N, 5% treated patients 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 treated with placebo. At 24 months, the estimated probabilities of remaining infection-free for the Immune Globulin I.V. (Human) and placebo arms were 87.8% vs. 76% 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 all study groups, or on frequency of opportunistic infection, regardless of treatment group.
This study was not designed to evaluate possible interactions between Gamimune N, 5% and trimethoprim/sulfamethoxazole (TMP-SMZ) but a study by Spector et al did prospectively stratify patients receiving TMP-SMZ. However, the Bayer study stratified patients based on CD4+ counts 200/mmand no HIV defining infection. In actuality, these 2 different stratification schemes probably selected for nearly the same subgroups (namely less vs. more ill).
Contra-Indications: 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 since these patients may experience severe reactions to the IgA which may be present.
Manufacturers’ Warnings In Clinical States: Gamimune N should be administered i.v. only, since the i.m. and s.c. routes have not been evaluated.
Gamimune N 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 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 I.V. (Human) (IGIV) treatment. The syndrome usually begins within several hours to 2 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 studies are frequently positive with pleocytosis up to several thousand cells per cu.mm, 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.
Isolated reports have appeared of transient and reversible renal insufficiency following administration of Immune Globulin I.V. therapy. The mechanics involved are uncertain.
Drug Interactions: Antibodies in Gamimune N 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 administration.
Please see Dosage for other drug interactions.
Pregnancy: Animal reproduction studies have not been conducted with Gamimune N. It is not known whether Gamimune N can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Gamimune N should be given to a pregnant woman only if benefits outweigh risks.
Adverse Reactions: In a study of 37 patients with immunodeficiency syndromes receiving Gamimune N, 5% at 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 16 adult and adolescent subjects with primary immunodeficiency syndrome, comparing the side effects and bioequivalency of Gamimune N, 5% with those of Gamimune N, 5% treated with solvent/detergent. The incidence, nature and severity of reactions with Gamimune N, 5% treated with solvent/detergent were not different from those observed with Gamimune N, 5%.
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.
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%.
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 4 of 154 (2.6%) infusions, and all but one occurred at rates of infusions greater than 0.04 mL/kg body weight/minute. The symptoms reported included chest tightness, a sense of tachycardia (pulse was 84 beats/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 2 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, 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/min. In general, reactions reported with infusion of Gamimune N, 5% in these studies were reported as mild or moderate.
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 ³0.1 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 to 185 bone marrow transplant recipients at doses of 500 mg/kg (10 mL/kg) from day -7 and day -2 pretransplant then weekly through day 90 post-transplant, adverse reactions were noted in 12 (6.5%) of the 185 treated patients 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 9 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.
In a study with pediatric HIV infection patients, 376 patients, 187 treated with Gamimune N, 5% 400 mg/kg, and 189 treated with placebo [0.1% Albumin (Human)], were evaluated for safety. 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 symptom reported for both groups treated with placebo and Gamimune N, 5% with 30 of 105 (28.6%) reported symptoms and 19 of 78 (24.4%) reported symptoms, respectively. Irritability was the second most common reported, with 10 (9.5%) reports for the placebo group and 9 (11.5%) for the group treated with Gamimune N, 5%. A large number of diverse symptoms accounted for the remaining symptoms in both 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.
In the studies undertaken to date, other types of reactions have not been reported with Gamimune N. It may be, however, that adverse effects will be similar to those previously reported with i.v. and i.m. immunoglobulin administration. Potential reactions, therefore, may also include anxiety, flushing, wheezing, abdominal cramps, myalgias, arthralgia, and dizziness; rash has been reported rarely. Reactions to i.v. immunoglobulin tend to be related to the rate of infusion.
True anaphylactic reactions to Gamimune N may occur in recipients with documented prior histories of severe allergic reactions to i.m. immunoglobulin, but some patients may tolerate cautiously administered i.v. immunoglobulin without adverse effects. Very rarely an anaphylactoid reaction may occur in patients with no prior history of severe allergic reactions to either i.m. or i.v. immunoglobulin.
Dosage And Administration: General: For i.v. use only. Dosages for specific indications are indicated below, but in general, it is recommended that Gamimune N be infused by itself at a rate of 0.01 to 0.02 mL/kg body weight/min for 30 minutes; if well- tolerated, the rate may be gradually increased to a maximum of 0.08 mL/kg body weight/minute. Investigations indicate that Gamimune N 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 be given by a separate line, by itself, without mixing with other i.v. fluids or medications the patient might be receiving. Gamimune N should not be mixed with Immune Globulin I.V. (Human), from another manufacturer. Gamimune N is not compatible with saline. If dilution is required, Gamimune N, may be diluted with 5% dextrose in water (D5/W). No other drug interactions or compatibilities have been evaluated.
In patients with limited or compromised acid-base compensatory mechanisms and in patients in whom there is already an expanded fluid volume (e.g., during pregnancy), consideration should be given to the effect of the additional acid or protein load that i.v. Gamimune N might present.
Primary Humoral Immunodeficiency: The usual dosage of Gamimune N for prophylaxis in primary immunodeficiency syndromes is 100 to 200 mg/kg of body weight administered approximately once a month by i.v. 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 for 1 to 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 a level felt to be insufficient for the protection or normal function of the patient and/or the patient manifests clinically significant bleeding, Gamimune N 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 to 1 000 mg/kg of body weight given as a single infusion. Maintenance infusions may be administered intermittently as clinically indicated to maintain an adequate platelet count.
Allogeneic Bone Marrow Transplantation: Gamimune N should be administered in doses of 500 mg/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 post-transplant. Gamimune N may be administered by itself through a Hickman line while it is in place, and thereafter through a peripheral vein.
Pediatric HIV Infection: A reduction in the incidence of infections has been observed in children infected with the HIV virus whose CD4+ counts are ³200 mm Gamimune N, 5% should be administered at a dose of 400 mg/kg (8 mL/kg) body weight every 28 days.
Availability And Storage: Gamimune N, 5%: Immune Globulin I.V. (Human), 5% treated with solvent/detergent, is a sterile 4.5 to 5.5% solution of human protein in 9 to 11% maltose; it contains no preservatives. Each mL contains approximately 50 mg of protein, not less than 98% of which has the electrophoretic mobility of gamma globulin and approximately 100 mg maltose. Not less than 90% of the immunoglobulin 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 (approximately 0.3 mEq/g of protein). The calculated osmolality is 309 m0sm/kg of solvent (water) and the calculated osmolarity is 278 m0sm/L of solution.
Single use vials of 10, 20, 50, 100, 250 and 500 mL. The 10 mL vial contains 500 mg protein; the 20 mL vial contains 1 g protein; the 50 mL vial contains 2.5 g protein; the 100 mL vial contains 5 g protein; the 250 mL vial contains 12.5 g protein; the 500 mL vial contains 25 g protein.
Gamimune N, 10%: Immune Globulin I.V. (Human), 10% treated with solvent/detergent, is a sterile solution of human protein containing no preservative. Gamimune N, 10% consists of 9 to 11% protein in 0.16 to 0.24 M glycine. Each mL contains approximately 100 mg of protein, not less than 98% of which has the electrophoretic mobility of gamma globulin, and approximately 12 to 18 mg glycine. 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.
Single use vials of 10, 25, 50, 100 and 200 mL. The 10 mL vial contains 1g protein; the 25 mL vial contains 2.5 g protein; the 50 mL vial contains 5 g protein; the 100 mL vial contains 10 g protein; the 200 mL vial contains 20 g protein.
The products are 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 by diafiltration and ultrafiltration. The solution is adjusted to 0.3 to 0.4% tri-n-butyl phosphate (TNBP) and 0.2 to 0.3% sodium cholate. After addition of the solvent (TNBP) and the detergent (sodium cholate), the solution is heated at 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 has not been chemically modified other than in the adjustment of the pH of the solution to 4.0 to 4.5. Isotonicity is achieved by the addition of maltose, for Gamimune N, 5%, or glycine for Gamimune N, 10%. Gamimune N, 5% and 10% treated with solvent/detergent are then incubated in the final container (at the low pH of 4.25), for a minimum of 21 days at 20° C. The products are intended for i.v. administration.
The removal and inactivation of spiked model enveloped and non-enveloped viruses during the manufacturing process for Gamimune N, 5% and 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 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 the Effluent III steps and between the Effluent III and the Filtrate III steps. Significant reduction of enveloped viruses is achieved at the time of treatment of Filtrate III with TNBP/sodium cholate and also at the time of the low pH incubation in the final container.
Store between 2 and 8°C. Do not freeze. Do not use after expiration date.
GAMIMUNE® N Bayer Immune Globulin (Human), I.V. Passive Immunizing Agent
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