Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Grifols Deutschland GmbH, Colmarer Straße 22, 60528 Frankfurt, Germany, Tel.: +49 69-660 593 100
Pharmacotherapeutic group: immune sera and immunoglobulins: immunoglobulins, normal human, for intravascular administration
ATC code: J06BA02
Human normal immunoglobulin contains mainly immunoglobulin G (IgG) with a broad spectrum of antibodies against infectious agents.
Human normal immunoglobulin contains the IgG antibodies present in the normal population. It is usually prepared from pooled plasma from not fewer than 1,000 donations. It has a distribution of immunoglobulin G subclasses closely proportional to that in native human plasma. Adequate doses of this medicinal product may restore abnormally low immunoglobulin G levels to the normal range. The mechanism of action in indications other than replacement therapy is not fully elucidated.
Gamunex 10% is adjusted to a weakly acidic pH. Since Gamunex 10% has a low buffering capacity, it is rapidly neutralised by the blood during the infusion. Even after administration of high doses of Gamunex 10%, no change in the pH of the blood was recorded. Osmolality is 258 mOsmol/kg solution and thus approximates to the normal range (285-295 mOsmol/kg).
The IVIG-C CIDP efficacy trial (ICE study), a double-blind, randomised, placebo-controlled study investigated the efficacy and safety of Gamunex 10% in the treatment of CIDP. A total of 117 CIDP patients were randomised to receive either Gamunex 10% or placebo every three weeks. Loading dose was 2 g/kg BW; maintenance dose was 1 g/kg BW.
Responder rates (determined by improvement in INCAT disability score and maintenance of ≥1 improvement over the 24 week efficacy period) were significantly higher in the Gamunex 10% group (54%), compared to the placebo group (21%, p=0.0002). Muscle strength as measured by the MRC score and grip strength, as well as sensation as measured by the ISS score improved significantly more in the Gamunex 10% group compared to placebo.
In view of the limited number of patients ≥ 65 years included in the study, a precise treatment effect could not be determined with regard to the INCAT score; for grip strength, a statistically significant treatment effect was shown in favour of Gamunex 10%.
Of the responders, less than half responded after the loading dose (by week 3), but most responded after the second dose (by week 6). Non-responders were crossed over to the alternative treatment, for again up to a maximum of 24 weeks of therapy.
All responders were re-randomised in an extension phase for another 6 months period of maintenance therapy with either Gamunex 10% or placebo. Of the former responders to Gamunex 10%, the actual relapse rate was significantly higher in the patients randomised to placebo (42%) than in those randomised to Gamunex 10% (13%, p=0.012).
The ICE study has shown short-term and long-term efficacy of Gamunex 10% in the treatment of CIDP. The results are summarised in the following table.
Primary endpoint and other results of the ICE study:
| Gamunex 10% | Placebo | p | |
|---|---|---|---|
| Responder rate during the efficacy period (primary endpoint) | 54% | 21% | 0.0002 |
| Probability of relapse in the extension period | 13% | 45% | 0.013 |
| Grip strength (kPA)1 (change from baseline) | |||
| Dominant hand | 13.2 | 1.5 | 0.0008 |
| Non-dominant hand | 13.3 | 4.3 | 0.005 |
| Muscle strength (MRC3 sum score)1 (change from baseline) | 3.3 | 0.2 | 0.001 |
| Sensibility (ISS4 score)2 (change from baseline) | -1.2 | 0.2 | 0.021 |
1 Improvement indicated by positive figure
2 Improvement indicated by negative figure
3 MRC: Medical Research Council
4 ISS: INCAT Sensory Sum Score
The study by Zinman et al. (2007) was a randomised, double-blind, placebo-controlled study in 51 patients to evaluate Gamunex 10% 2 g/kg given over the course of 2 days in myasthenia gravis (MG) exacerbations. The primary efficacy endpoint was the change from baseline in QMG score on Day 14. On Day 14, the mean change in QMG score was -2.54 (p=0.047). A clinically relevant effect on MG exacerbations was only observed in the exploratory subgroup of patients with moderate to severe MG at baseline (QMG score >10.5), with a mean change of -3.39 (p=0.010).
Additional support comes from a multicenter, prospective, open-label, non-controlled clinical trial, which also investigated the efficacy and safety of Gamunex 10% in the treatment of myasthenia gravis exacerbations. A total of 49 patients were enrolled into the clinical trial to receive a single, total dose of 2 g/kg of Gamunex 10% over 2 consecutive days (dose of 1 g/kg per day). There were no MuSK antibody positive patients who participated.
The primary efficacy endpoint was the change in Quantitative Myasthenia Gravis (QMG) score from baseline (day 0) to day 14. The mean changes in QMG score were -6.4 for the Evaluable and -6.7 for the Safety Population. Analysis of the secondary and exploratory efficacy endpoints results (assessed by QMG, MG-ADL, and MG Composite scores) supported the findings on the primary endpoint.
Human normal immunoglobulin is immediately and completely bioavailable in the recipient’s circulation after intravenous administration. It is distributed relatively rapidly between plasma and extravascular fluid, after approximately 3–5 days equilibrium is reached between the intra- and extravascular compartments.
Human normal immunoglobulin has a half-life of about 35 days as determined in patients with primary antibody deficiency syndrome and therefore exceeds that of 21 days described in the literature in healthy subjects. This half-life may vary from patient to patient, in particular in primary immunodeficiency.
IgG and IgG-complexes are broken down in cells of the reticuloendothelial system.
No differences of the pharmacokinetic properties are expected in the paediatric population.
Immunoglobulins are normal components of the human body. Because administration of immunoglobulins in animal studies may lead to the formation of antibodies, preclinical safety data are limited. In the acute and sub-acute animal studies that were performed, Gamunex 10% did not show special risks for humans.
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