Gamunex-C

CLINICAL PHARMACOLOGY

Mechanism of Action

Treatment of Primary Humoral Immunodeficiency

GAMUNEX-C supplies a broad spectrum of opsonic and neutralizing IgG antibodies against bacteria, viral, parasitic, mycoplasma agents, and their toxins. The mechanism of action in PI has not been fully elucidated.

Treatment of Idiopathic Thrombocytopenic Purpura

The mechanism of action of high doses of immunoglobulins in the treatment of ITP has not been fully elucidated.

Treatment of Chronic Inflammatory Demyelinating Polyneuropathy

The precise mechanism of action in CIDP has not been fully elucidated.

Pharmacodynamics

Immunoglobulins are fractionated blood products made from pooled human plasma. Immunoglobulins are endogenous proteins produced by B lymphocyte cells. The main component of GAMUNEX-C is IgG ( ≥ 98%) with a sub-class distribution of IgG1, IgG2, IgG3 and IgG4 of approximately 62.8%, 29.7%, 4.8% and 2.7% respectively.

Pharmacokinetics

Intravenous Administration:

Two randomized pharmacokinetic crossover trials were carried out with GAMUNEX-C in 38 subjects with Primary Humoral Immunodeficiencies given 3 infusions 3 or 4 weeks apart of test product at a dose of 100-600 mg/kg body weight per infusion. One trial compared the pharmacokinetic characteristics of GAMUNEX-C to GAMIMUNE N, 10% and the other trial compared the pharmacokinetics of GAMUNEX-C (10% strength) with a 5% concentration of this product. The ratio of the geometric least square means for dose-normalized IgG peak levels of GAMUNEX-C and GAMIMUNE N, 10% was 0.996. The corresponding value for the dose-normalized area under the curve (AUC) of IgG levels was 0.990. The results of both PK parameters were within the pre-established limits of 0.080 and 1.25. Similar results were obtained in the comparison of GAMUNEX-C 10% to a 5% concentration of GAMUNEX-C.

The main pharmacokinetic parameters of GAMUNEX-C, measured as total IgG in study 100152 are displayed below:

Table 13: PK Parameters of GAMUNEX®-C and GAMIMUNE® N, 10%

  GAMUNEX®-C GAMIMUNE® N, 10%
N Mean SD Median N Mean SD Median
Cmax (mg/mL) 17 19.04 3.06 19.71 17 19.31 4.17 19.30
Cmax-norm (kg/mL) 17 0.047 0.007 0.046 17 0.047 0.008 0.047
AUC(0-tn)a (mg*hr/mL) 17 6746.48 1348.13 6949.47 17 6854.17 1425.08 7119.86
AUC(0-tn) norma (kg*hr/mL) 17 16.51 1.83 16.95 17 16.69 2.04 16.99
b (days) 16 35.74 8.69 33.09 16 34.27 9.28 31.88
a Partial AUC: defined as pre-dose concentration to the last concentration common across both treatment periods in the same patient.
b Only 15 subjects were valid for the analysis of T½.

The two pharmacokinetic trials with GAMUNEX-C show the IgG concentration/time curve follows a biphasic slope with a distribution phase of about 5 days characterized by a fall in serum IgG levels to about 65-75% of the peak levels achieved immediately post-infusion. This phase is followed by the elimination phase with a half-life of approximately 35 days. IgG trough levels were measured over nine months in the therapeutic equivalence trial. Mean trough levels were 7.8 ± 1.9 mg/mL for the GAMUNEX-C treatment group and 8.2 ± 2.0 mg/mL for the GAMIMUNE N, 10% control group.

Subcutaneous Administration
Treatment of Primary Humoral Immunodeficiency by the Subcutaneous (SC) Route

In a single sequence, open-label, crossover trial, the pharmacokinetics, safety, and tolerability of SC administered GAMUNEX-C in subjects with PI were evaluated. A total of 32 and 26 subjects received GAMUNEX-C as IV or SC for PK study, respectively. Subjects received GAMUNEX-C 200-600 mg/kg IV every 3-4 weeks for at least 3 months, at which time they entered the IV phase of the study. Subjects were crossed over to weekly SC infusions. The weekly SC dose was determined by multiplying the total IV dose by 1.37 and dividing the resultant new total dose by 3 or 4 depending on the previous IV interval. The PK endpoint parameter (AUC of total plasma IgG) following IV and SC administration is summarized below in Table 14. The lower bound of the 90% confidence interval for the geometric mean ratio of AUC (SC vs. IV) was 0.861, therefore, meeting the pre-specified non-inferiority margin between the two modes of administration.

Table 14: Summary of PK Endpoint of AUC

Route of Administration Statistics AUC0–ι,IV (mg*h/mL) AUC0–ι,SC (mg*h/mL) Adj. AUC0–ι,SC1 (mg*h/mL)
IV (n = 32) Mean 7640 NA NA
%CV 15.9
Range 5616-10400
SC (n = 26) Mean NA 1947 6858
%CV 20.4 18.1
Range 1300-2758 5169-10364
CV, coefficient of variation; NA, not applicable
1 Adj. AUC0-ι,SC: Adjusted steady-state area under the concentration vs. time curve following SC administration based on IV dosing schedule, calculated as AUC0-ι,SC multiplied by 3 or 4 for subjects on every-3-week or every-4-week IV dosing schedule, respectively.

The mean trough concentration ( mean Ctrough) of plasma total IgG following IV and SC administration are presented in Table 15.

Table 15: Mean Plasma Trough Concentrations of Total IgG (mg/mL) in Plasma

  IV Mean Ctrough SC Mean Ctrough
n 32 28
Mean (mg/mL) 9.58 11.4
%CV 22.3 20.4
Range 6.66-14.0 8.10-16.2

In contrast to plasma total IgG levels observed with monthly IV GAMUNEX-C treatment (rapid peaks followed by a slow decline), the plasma IgG levels in subjects receiving weekly SC GAMUNEX-C therapy were relatively stable (Figure 7).

Figure 7: Mean Steady-state Plasma Total IgG Concentration vs. Time Curves Following IV Administration or Weekly SC Administration

Mean Steady-state Plasma Total IgG Concentration vs. Time Curves - Illustration

Clinical Studies

Treatment of Primary Humoral Immunodeficiency by the Intravenous (IV) Route

In a randomized, double-blind, parallel group clinical trial with 172 subjects with primary humoral immunodeficiencies GAMUNEX-C was demonstrated to be at least as efficacious as GAMIMUNE N, 10% in the prevention of any infection, i.e., validated plus clinically defined, non-validated infections of any organ system, during a nine month treatment period. Twenty-six subjects were excluded from the Per Protocol analysis (2 due to non-compliance and 24 due to protocol violations). The analysis for efficacy was based on the annual rate of bacterial infections pneumonia, acute sinusitis and acute exacerbations of chronic sinusitis.

Table 16: Efficacy Results per Protocol Analysis

  GAMUNEX®-C (n=73) No. of subjects with at least one infection GAMIMUNE® N, 10% (n=73) No. of subjects with at least one infection Mean Difference (90% confidence interval) p-Value
Validated Infections 9 (12%) 17 (23%) -0.117 0.06
Acute Sinusitis 4 (5%) 10 (14%) (-0.220,-0.015)  
Exacerbation of Chronic Sinusitis 5 (7%) 6 (8%)    
Pneumonia 0 (0%) 2 (3%)    
Any Infection (Validated plus Clinically defined non-validated Infections) 56 (77%) 57 (78%) -0.020 (-0.135,0.096) 0.78

The annual rate of validated infections (Number of Infection/year/subject) was 0.18 in the group treated with GAMUNEX-C and 0.43 in the group treated with GAMIMUNE N, 10% (p=0.023). The annual rates for any infection (validated plus clinically-defined, non-validated infections of any organ system) were 2.88 and 3.38, respectively (p=0.300).

Treatment of Idiopathic Thrombocytopenic Purpura

A double-blind, randomized, parallel group clinical trial with 97 ITP subjects was carried out to prove the hypothesis that GAMUNEX-C was at least as effective as GAMIMUNE N, 10% in raising platelet counts from less than or equal to 20 x109/L to more than 50 x109/L within 7 days after treatment with 2 g/kg IGIV. Twenty-four percent of the subjects were less than or equal to 16 years of age.

GAMUNEX-C was demonstrated to be at least as effective as GAMIMUNE N, 10% in the treatment of adults and children with acute or chronic ITP.

Table 17: Platelet Response of Per Protocol Analysis

  GAMUNEX®-C
(n=39)
GAMIMUNE®
N, 10% (n=42)
Mean Difference (90% confidence interval)
By Day 7 35 (90%) 35 (83%) 0.075
(-0.037, 0.186)
By Day 23 35 (90%) 36 (86%) 0.051
(-0.058, 0.160)
Sustained for 7 days 29 (74%) 25 (60%) 0.164
(0.003, 0.330)

A trial was conducted to evaluate the clinical response to rapid infusion of GAMUNEX-C in patients with ITP. The study involved 28 chronic ITP subjects, wherein the subjects received 1 g/kg GAMUNEX-C on three occasions for treatment of relapses. The infusion rate was randomly assigned to 0.08, 0.11, or 0.14 mL/kg/min (8, 11 or 14 mg/kg/min). Pre-medication with corticosteroids to alleviate infusion-related intolerability was not permitted. Pretreatment with antihistamines, anti-pyretics and analgesics was permitted. The average dose was approximately 1 g/kg body weight at all three prescribed rates of infusion (0.08, 0.11 and 0.14 mL/kg/min). All patients were administered each of the three planned infusions except seven subjects. Based on 21 patients per treatment group, the a posteriori power to detect twice as many drug-related adverse events between groups was 23%. Of the seven subjects that did not complete the study, five did not require additional treatment, one withdrew because he refused to participate without concomitant medication (prednisone) and one experienced an adverse event (hives); however, this was at the lowest dose rate level (0.08 mL/kg/min).

Treatment of Chronic Inflammatory Demyelinating Polyneuropathy

A multi-center, randomized, double-blind, Placebo-controlled trial (The Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified CIDP Efficacy or ICE study) was conducted with GAMUNEX-C. [27] This study included two separately randomized periods to assess whether GAMUNEX-C was more effective than Placebo for the treatment of CIDP (assessed in the Efficacy Period for up to 24 weeks) and whether long-term administration of GAMUNEX-C could maintain long-term benefit (assessed in the 24 week Randomized Withdrawal Period).

In the Efficacy Period, there was a requirement for Rescue (crossover) to the alternate study drug if the subject did not improve and maintain this improvement until the end of the 24 week treatment period. Subjects entering the Rescue phase followed the same dosing and schedule as in the Efficacy period. Any subject who was rescued (crossed over) and did not improve and maintain this improvement was withdrawn from the study.

Subjects who completed 24 weeks treatment in the Efficacy period or Rescue phase and responded to therapy were eligible for entry into a double-blind Randomized Withdrawal Period. Eligible subjects were re-randomized to GAMUNEX-C or Placebo. Any subject who relapsed was withdrawn from the study.

The Efficacy Period and the Rescue treatment started with a loading dose of 2 g/kg body weight of GAMUNEX-C or equal volume of Placebo given over 2-4 consecutive days. All other infusions (including the first infusion of the Randomized Withdrawal Period) were given as maintenance doses of 1 g/kg bw (or equivalent volume of Placebo) every three weeks.

The Responder rates of the GAMUNEX-C and Placebo treatment groups was measured by the INCAT score. The INCAT (Inflammatory Neuropathy Cause and Treatment) scale is used to assess functional disability of both upper and lower extremities in demyelinating polyneuropathy. The INCAT scale has upper and lower extremity components (maximum of 5 points for upper (arm disability) and maximum of 5 points for lower (leg disability)) that add up to a maximum of 10-points (0 is normal and 10 is severely incapacitated). [28] At the start of the efficacy portion of the study, the INCAT scores were as follows: Upper Extremity mean was 2.2 ± 1.0, and median was 2.0 with a range of 0 to 5; Lower Extremity mean was 1.9 ± 0.9, and median was 2.0 with a range of 1 to 5; Total Overall Score mean was 4.2 ± 1.4, and median was 4.0 with a range of 2 to 9. A Responder was defined as a subject with at least 1-point improvement from baseline in the adjusted INCAT score that was maintained through 24 weeks.

More subjects with CIDP responded to GAMUNEX-C: 28 of 59 subjects (47.5%) responded to GAMUNEX-C compared with 13 of 58 subjects (22.4%) administered Placebo (25%difference; 95% CI 7%-43%; p=0.006). The study included both subjects who were IGIV naive and subjects who had previous IGIV experience. The outcome was influenced by the group of subjects who experienced prior therapy with IGIV, as shown by the outcomes table, below.

Time to relapse for the subset of 57 subjects who previously responded to GAMUNEX-C was evaluated: 31 were randomly reassigned to continue to receive GAMUNEX-C and 26 subjects were randomly reassigned to Placebo in the Randomized Withdrawal Period. Subjects who continued to receive GAMUNEX-C experienced a longer time to relapse versus subjects treated with Placebo (p=0.011). The probability of relapse was 13% with GAMUNEX-C versus 45% with Placebo (hazard ratio, 0.19; 95% confidence interval, 0.05, 0.70).

Table 18: Outcomes in Intent-to-Treat Population Efficacy Period

Efficacy Period GAMUNEX®-C Placebo p-valuea
Responder Non-Responder Responder Non-Responder
All Subjects 28/59 (47.5%) 31/59 (52.5%) 13/58 (22.4%) 45/58 (77.6%) 0.006
IGIV - Naive Subjects 17/39 (43.6%) 22/39 (56.4%) 13/46 (28.3%) 33/46 (71.7%) 0.174
IGIV - Experienced Subjects 11/20 (55.0%) 9/20 (45.0%) 0/12 (0%) 12/12 (100%) 0.002
a p-value based on Fisher's exact method

The following table shows outcomes for the Rescue Phase (which are supportive data):

Table 19: Outcomes in Rescue Phase

Rescue Phase GAMUNEX®-C Placebo p-valuea
Success Failure Success Failure
All Subjects 25/45 (55.6%) 20/45 (44.4%) 6/23 (26.1%) 17/23 (73.9%) 0.038
IGIV - Naive Subjects 19/33(57.6%) 14/33 (42.4%) 6/18 (33.3%) 12/18 (66.7%) 0.144
IGIV - Experienced Subjects 6/12 (50%) 6/12 (50%) 0/5 (0%) 5/5(100%) 0.102
a p-value based on Fisher's exact method

The following Kaplan-Meier curves show the outcomes for the Randomized Withdrawal Period:

Figure 8: Outcome for Randomized Withdrawal Period

Outcome for Randomized Withdrawal Period - Illustration

a p-value based on log-rank test

REFERENCES

27. Hughes RAC, Donofrio P, Bril V, et al. Intravenous immune globulin (10% caprylate/chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomized Placebo-controlled trial. Lancet Neurol 2008. 7:136-144.

28. Hughes R, Bensa S, Willison H, Van den BP, Comi G, Illa I, et al. Randomized controlled trial of intravenous immunoglobulin versus oral prednisolone in chronic inflammatory demyelinating polyradiculoneuropathy. Ann Neurol 2001 Aug;50(2):195-201.

Last reviewed on RxList: 1/14/2013
This monograph has been modified to include the generic and brand name in many instances.

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