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Immunology Product Line
Liquid normal intravenous immunoglobulin (IVIG)
octagam® is a virus inactivated, liquid IVIG which can be stored at room temperature (2-25°C) up to 24 months.
Important Maltose Warning Letter, Oct 19, 2005
Viral safety
In total three validated manufacturing steps contribute to the viral safety of octagam®. Two independent steps are dedicated to inactivate virus.
The first of the dedicated virus inactivation steps in the manufacturing process is the Solvent Detergent (SD) treatment utilising 0.3% TNBP (Tri-N-Butylphosphate) and 1% Triton X-100 at 6°C for 4 hours. It inactivates lipid-enveloped viruses by destroying their lipid coat and the binding sites on the surface of the viruses. Kinetic studies on SD treatment using TNBP and Triton X-100 show that it is a very rapid and robust step, inactivating all enveloped viruses to below the limit of detection by the first meaningful sample point (1-3 minutes of treatment).
A second virus inactivation step, pH4 incubation (37°C for 24 hours) inactivates both enveloped and non-enveloped viruses.
According to the European CPMP (Committee for Proprietary Medicinal Products) and the World Health Organization (WHO) SD treatment and pH4 incubation are recommended virus inactivation steps.
Immune neutralisation in the plasma pool, removal by partititioning using Cohn-Oncley fractionation and storage in the liquid state also contribute to the viral safety of Octagam. All these measures have been validated for several transfusion relevant and model viruses.
In addition, the naturally occurring high antibody titres present in octagam®, contribute to viral safety, e.g. with regards to hepatitis A virus and parvovirus B19.
Tolerability
Certain stabilisers used in other IVIG preparations are associated with the risk of side effects, such as:
Sucrose: According to an FDA warning letter sucrose containing IVIGs are associated with a disproportionate share of cases of renal impairment and acute renal failure (ARF). Impaired renal function and ARF have been observed several times and were reported in 6.7% of patients in a retrospective analysis of infusions of IVIG preparations containing different amounts of sucrose (Levy 2000). In contrast, it has been shown that patients, who tolerated maltose containing IVIG well, developed ARF when switched to IVIG stabilised with sucrose (Rault Cantú Laidlaw 1999).
Sorbitol: In Germany, sorbitol containing IVIGs is contraindicated in patients with hereditary fructose intolerance and should not be given to neonates, young children, unconscious patients, and to patients, whose medical history is not known. Patients with hereditary fructose intolerance who receive sorbitol or fructose containing infusion solutions may develop an irreversible multiple organ failure (Locher 1987, Rey 1988).
Glucose: The glucose content has to be taken into account in patients with latent diabetes (transient glycosuria could appear), diabetes mellitus, or in patients on a low sugar diet. Close monitoring of blood sugar is necessary in these patients.
octagam® contains maltose, as an osmolarity regulator.
Certain blood glucose testing systems, such as those based on the GDH-PQQ method, falsely interpret maltose as glucose and give rise to (falsely) elevated blood sugar results. This has resulted in iatrogenic insulin overdose with subsequent severe adverse events. Please see the warning letter: Important Maltose Warning Letter, Oct 19, 2005
Pharmacovigilance
An extensive post-marketing observational study is considered to be the most appropriate way to gather information on the safety and tolerability of a biological product. Compared to clinical trials, more patients are enrolled, and a larger number of batches are studied, over a longer period of time. Such a study was initiated in Germany in 1995 and has been actively running ever since. This has allowed continuous assessment of both the safety and tolerability of octagam® under routine conditions.
No viral transmissions have ever been observed. This is consistent with the proven safety record of octagam®.
Adverse drug reactions have occurred in less than 0.4 % of infusions in the observational study, and in most cases have been judged as mild or moderate. Most frequently observed reactions are rigors, fever, headache, nausea and flushing (frequency 0.04 - 0.16 %).
Efficacy
octagam® typically contains ≥99.6% IgG molecules in a monomeric or dimeric structure. Less than 1% is polymeric IgG. Whereas IgG aggregates are associated with adverse events, only monomers and dimers appear to have meaningful therapeutic action. Dimers seem to play an important role in immunomodulatory properties of IVIG (Dalakas, Teeling 2001).
The IgG subclass distribution in octagam® is similar to that of human plasma. The broad spectrum of different mechanisms of the immune response is depending on a physiological distribution of subclasses. Preparations lacking a near physiological distribution may be compromised in affecting the specific functions of the missing subclass.
Chemical or enzymatical modifications of the IgG molecule, such as the use of beta-propiolactone, sulfitolysis or pepsin in the manufacturing process, may affect the Fc-portion of the molecule. A reduced Fc function is a marker for impaired opsonizing capacity and complement activation of the IgG molecule as well as for its capacity to bind to monocytes or macrophages. Thus, the therapeutic efficacy in substitution therapy and in immunomodulation may be affected. The IgG molecules in octagam® are neither chemically nor enzymatically treated. The Fc function of the IgG molecules in octagam® is close to 100%.
Convenience
octagam® is a liquid preparation. The reconstitution of lyophilised products may take 20 minutes or more. After reconstitution of a powder, the infusion must be given within a short period of time. If the patient feels too sick to receive his infusion or if he is unable to attend the scheduled infusion, the reconstituted product has to be discarded. Reconstitution of lyophilised products is recommended under sterile conditions (laminar flow) to avoid bacterial contamination.
octagam® can be stored at room temperature (2-25°C) for up to 24 months*. The risk of storage damage in the refrigerator is reduced and accidental freezing is avoided. In addition, whereas IVIGs, which have to be stored in the refrigerator, need to be warmed to at least room temperature before infusion to avoid side effects, octagam® is liquid and ready-to-use.
*octagam® labelling differs from country to country. Please review the local prescribing information for administration and storage recommendations.
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