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Gamimune N (Immune Globulin) - Indications and Dosage

 
 



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/mm3. In the 12 children with acute ITP, there was an average increase in platelet count above baseline of 274,000/mm3(range 33,000-529,000/mm3).

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/mm3 over baseline. The mean platelet count in children with ITP rose from 27,800/mm3 at baseline to 297,000/mm3(range 50,000-455,000/mm3) and the mean platelet count in adults with ITP rose from 27,900/mm3 at baseline to 124,900/mm3(range 11,000-341,000/mm3). 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/mm3 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/mm3 at baseline to 285,600/mm3(range 89,000-473,000/mm3) and the mean platelet count in adults with ITP treated with the regimen rose from 23,400/mm3 at baseline to 173,100/mm3(range 28,000-709,000/mm3). 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/mm3 at baseline to 129,300/mm3(range 51,000-242,000/mm3) 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/mm3(range 0-6660 cells/mm3). 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/mm3 versus >/= 200 cells/mm3) 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/mm3 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.

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/mm3 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/mm3.

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.

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