GAMMAPLEX Solution for infusion Ref.[27467] Active ingredients: Immunoglobulins, normal human, IV

Treatment of Primary Humoral Immunodeficiency

In the cross-over clinical trial assessing bioequivalence, safety and tolerability between GAMMAPLEX 10% and GAMMAPLEX 5% in PI, the pharmacokinetics (PK) of these products was assessed after administration to 30 adult subjects on 28-day (n=16) or 21-day (n=14) infusion cycles. Blood samples for PK analysis were obtained after at least five infusions.

The dose of GAMMAPLEX 10% ranged from 361-691 mg/kg for subjects on a 28-day cycle and from 254-794 mg/kg for those on a 21-day cycle. The doses of GAMMAPLEX 5% were similar to those of GAMMAPLEX 10% in this cross-over study. Table 6 compares the other PK variables parameters for GAMMAPLEX 10% and GAMMAPLEX 5% for both the 21-day and 28-day cycle regimens.

GAMMAPLEX 10% was pharmacokinetically equivalent to GAMMAPLEX 5% in adults.

PK outcomes after administration of GAMMAPLEX 10% were assessed in 13 pediatric subjects. Six subjects were on a 28-day regimen and 7 were on a 21-day regimen; doses for the PK assessments ranged from 400 to 745 mg/kg and 355 to 702 mg/kg respectively. Results are shown in Table 6 together with those from the adults in the study.

Table 6. Pharmacokinetic Parameters of GAMMAPLEX 10% compared with GAMMAPLEX 5% in Adults, and GAMMAPLEX 10% in Pediatric Subjects (corrected for baseline concentration):

C_max = maximum observed concentration
T_max = time at which C_max was apparent
^* Geometric mean
^† Median and range are presented for t_max
^‡ AUC_0-tau = area under the concentration versus time curve within a dosing interval, tau = dosing interval

14.1 Treatment of Primary Humoral Immunodeficiency

Pharmacokinetics, Safety and Tolerability study

A cross-over clinical trial assessed bioequivalence, safety and tolerability between GAMMAPLEX 10% and GAMMAPLEX 5% in PI after administration to 33 adult subjects on 28-day (n=19) or 21-day (n=14) infusion cycles, of whom 30 (90.9%) completed the PK component [see Pharmacokinetics (12.3)]. Thirty-two subjects completed the study of whom 12 were male and 20 were female. All adults were aged between 17 and 55 years. The mean doses of GAMMAPLEX 10% were 491.7 mg/kg for those on a 28-day cycle and 499.0 mg/kg for those on a 21-day cycle. For GAMMAPLEX 5%, the doses were similar: 473.5 and 502.1 mg/kg respectively. The maximum infusion rate was 0.08 mL/kg/min for each product and this rate was achieved by all adult subjects. In this study, PK bioequivalence was used as a surrogate marker for efficacy. Nevertheless, an ad hoc comparison was made between the products for the number of subjects reporting an infection while on each product. Comparing the number of subjects developing infections of any severity or type while on GAMMAPLEX 10% (22/32) with the period on GAMMAPLEX 5% (17/32) using the McNemar test provided an exact p value of 0.180, confirming the relevance of PK as a surrogate marker. No subject had an acute serious bacterial infection (SABI) during the study.

The pediatric population in the study comprised 15 subjects who received only GAMMAPLEX 10%, of whom 8 were on a 28-day cycle and 7 on a 21-day cycle. Of these, 13 completed the PK component (6 on a 28-day cycle and 7 on a 21-day cycle) [see Pharmacokinetics (12.3)]. There were two subjects in the 2-5 year age group, 7 in the 6-11 year age group and 6 in the 12-15 year age group. The mean dose across all infusions was 535.1 mg/kg. All pediatric subjects tolerated an infusion rate of 0.04 mL/kg/min and 8 subjects (53.3%) tolerated an infusion rate of 0.08 mL/kg/min for all infusions.

Overall, in the population receiving GAMMAPLEX 10%, the PK results (the surrogate for efficacy in this study) and the types and frequencies of adverse reactions were similar for the adult and pediatric populations.

14.2 Treatment of Chronic Immune Thrombocytopenic Purpura

The crossover bioequivalence study described in 14.1, above, did not include subjects with ITP. The results of the bioequivalence study comparing GAMMAPLEX 10% to GAMMAPLEX 5% in subjects with PI are supportive of the potential effectiveness of GAMMAPLEX 10% in the treatment of chronic ITP.

In a Phase 3 multicenter, open-label clinical trial to evaluate the efficacy and safety of GAMMAPLEX 5% in chronic ITP, of the 35 subjects enrolled from various ethnic groups, 9 were male and 26 were female. The age range was between 6 and 69 years. Subjects received intravenous infusions on two consecutive days (1 course) and then observed for a further 30 days. Individuals were given the option of a further two courses of treatment (if required), where only safety variables were assessed. Doses of GAMMAPLEX 5% ranged from 482 to 1149 mg/kg on Day 1 and Day 2. The median total dose per subject was 2035 mg/kg. Subjects received a total of 94 infusions (48 treatment courses).

All 35 subjects received at least one infusion of clinical trial drug, and all but one subject completed the first course of treatment.

The primary analysis was based on the platelet count achieved by Day 9 after the first course of treatment with GAMMAPLEX 5%, response being defined as a platelet count of 50 × 10⁹/L or greater. Response to treatment on or before Day 9 was achieved by 29 of 35 subjects (82.9%), and the one-sided 97.5% lower confidence limit of the response rate was 66.4%, which met the a priori success criterion that required it to be greater than 60%.

Efficacy analyses included the duration of response, and changes in the incidences of bleeding or hemorrhage. At Day 32, the median (+ SD) platelet count (24 + ⁹⁰ × 10⁹/L) was still higher than the baseline value, and 11 of 33 subjects (33.3%) continued to show response of platelet counts of 50 × 10⁹/L or greater. The median duration of platelet count response for the responders was 10 days.

Table 7. Median Platelet Count (Standard deviation) and Number and Percent of Subjects with a Platelet Count >50 × 10⁹/L during the clinical trial:

GAMMAPLEX 5% infusions given on Days 1 and 2.

There was an increase in platelet counts for the majority of subjects, and an overall reduction in the manifestations of bleeding after treatment compared to baseline (Day 1). Petechiae, hematomas and gastrointestinal, pulmonary and genitourinary bleeds were all either reduced or absent by Day 32.

There were no thromboembolic episodes reported in the clinical trial; and vital signs, biochemical, hematological and virology tests did not reveal any unexpected pathophysiology or toxicity.