4.1.1       Replacement therapy in:

·          Primary immunodeficiency syndromes such as:
- congenital agammaglobulinaemia and hypogammaglobulinaemia
- common variable immunodeficiency
- severe combined immunodeficiency
- Wiskott Aldrich syndrome

·          Myeloma or chronic lymphatic leukaemia with severe secondary hypogammaglobulinaemia and recurrent infections.

·          Children with congenital AIDS and recurrent infections.

4.1.2       Immunomodulation

·          Idiopathic thrombocytopenic purpura (ITP) in children or adults at high risk of bleeding or prior to surgery to correct the platelet count.

·          Guillain Barré syndrome

·          Kawasaki disease

4.1.3       Allogeneic bone marrow transplantation

4.2.1       Posology

The dose and dosage regimen is dependent on the indication.

In replacement therapy the dosage may need to be individualised for each patient dependent on the pharmacokinetic and clinical response.

The following dosage regimens are given as a guideline:

Replacement therapy in primary immunodeficiency syndromes

·          The dosage regimen should achieve a trough level of IgG (measured before the next infusion) of at least 4 – 6 g/l. Three to six months are required after the initiation of therapy for equilibration to occur. The recommended starting dose is 0.4 - 0.8 g/kg, followed by at least 0.2 g/kg every three weeks.

·          The dose required to achieve a trough level of 6 g/l is of the order of 0.2 - 0.8 g/kg/month.

·          The dosage interval when steady state has been reached, varies from 2 to 4 weeks.

·          Trough levels should be measured in order to adjust the dose and dosage interval.

Replacement therapy in myeloma or chronic lymphatic leukaemia with severe secondary hypogammaglobulinaemia and recurrent infections; replacement therapy in children with AIDS and recurrent infections:

·          The recommended dose is 0.2 - 0.4 g/kg every three to four weeks.

Idiopathic Thrombocytopenic Purpura:

·          For the treatment of an acute episode, 0.8 - 1 g/kg on day one, which may be repeated once within 3 days, or 0.4 g/kg daily for two to five days.

·          The treatment can be repeated if relapse occurs.

Guillain Barré syndrome:

·          0.4 g/kg/day for 3 to 7 days. Experience in children is limited.

Kawasaki disease:

·          1.6 - 2 g/kg should be administered in divided doses over two to five days or 2 g/kg as a single dose. Patients should receive concomitant treatment with acetylsalicylic acid.

Allogeneic Bone Marrow Transplantation:

·          Human normal immunoglobulin treatment can be used as part of the conditioning regimen and after the transplant. For the treatment of infections and prophylaxis of graft versus host disease, dosage is individually tailored.

·          The starting dose is normally 0.5 g/kg/week, starting seven days before transplantation and for up to 3 months after transplantation.

·          In the case of persistent lack of antibody production, dosage of 0.5 g/kg/month is recommended until antibody level returns to normal.

The dosage recommendations are summarised in the following table:

4.2.2       Method of administration

Octagam 10% should be infused intravenously at an initial rate of 0.01 mL/kg body weight per minute for 30 minutes. If well tolerated, the rate of administration may gradually be increased to a maximum of 0.12 mL/kg/ body weight per minute.

Certain severe adverse drug reactions may be related to the rate of infusion. The recommended infusion rate given under “4.2 Method of administration" must be closely followed. Patients must be closely monitored and carefully observed for any symptoms throughout the infusion period.

Certain adverse reactions may occur more frequently:

·          in case of high rate of infusion

·          in patients with hypo- or agammaglobulinaemia, with or without IgA deficiency

·          in patients who receive human normal immunoglobulin for the first time or, in rare cases, when the human normal immunoglobulin product is switched or when there has been a long interval since the previous infusion

True hypersensitivity reactions are rare. They can occur in very seldom cases of IgA deficiency with anti-IgA antibodies.

Rarely, human normal immunoglobulin can induce a fall in blood pressure with anaphylactic reaction, even in patients who had tolerated previous treatment with human normal immunoglobulin.

Potential complications can often be avoided by ensuring:

·          that patients are not sensitive to human normal immunoglobulin by initially injecting the product slowly (0.01 to 0.02 mL/kg body weight per minute);

·          that patients are carefully monitored for any symptoms throughout the infusion period; in particular, patients naive to human normal immunoglobulin, patients switched from an alternative IVIg product to Octagam 10% or when there has been a long interval since the previous infusion should be monitored during the first infusion and for the first hour after the first infusion, in order to detect potential adverse signs. All other patients should be observed for at least 20 minutes after administration.

There is clinical evidence of an association between IVIg administration and thromboembolic events such as myocardial infarction, stroke, pulmonary embolism and deep vein thromboses which is assumed to be related to a relative increase in blood viscosity through the high influx of immunoglobulin in at-risk patients. Caution should be exercised in prescribing and infusing IVIg in obese patients and in patients with pre-existing risk factors for thrombotic events (such as advanced age, hypertension, diabetes mellitus and a history of vascular disease or thrombotic episodes, patients with acquired or inherited thrombophilic disorders, patients with prolonged periods of immobilisation, severely hypovolemic patients, patients with diseases which increase blood viscosity).

Cases of acute renal failure have been reported in patients receiving IVIg therapy. In most cases, risk factors have been identified, such as pre-existing renal insufficiency, diabetes mellitus, hypovolemia, overweight, concomitant nephrotoxic medicinal products or age over 65.

In case of renal impairment, IVIg discontinuation should be considered. While these reports of renal dysfunction and acute renal failure have been associated with the use of many of the licensed IVIg products containing various excipients such as sucrose, glucose and maltose, those containing sucrose as a stabiliser accounted for a disproportionate share of the total number. In patients at risk, the use of IVIg products not containing such excipients may be considered.

In patients at risk for acute renal failure or thromboembolic adverse reactions, IVIg products should be administered at the minimum rate of infusion and dose practicable.

In all patients, IVIg administration requires:

·          adequate hydration prior to the infusion of IVIg

·          monitoring of urine output

·          monitoring of serum creatinine levels

·          avoidance of concomitant use of loop diuretics

In case of adverse reaction, either the rate of administration must be reduced or the infusion stopped. The treatment required depends on the nature and severity of the side effect.

In case of shock, standard medical treatment for shock should be implemented.

Some types of blood glucose testing systems may falsely interpret the maltose (90 mg/ml) contained in Octagam 10% as glucose. This may result in falsely elevated glucose readings and, consequently, in the inappropriate administration of insulin and cases of true hypoglycaemia may go untreated if the hypoglycaemic state is masked by falsely elevated glucose readings. For further details see Section 4.5.

Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.

The measures taken are considered effective for enveloped viruses such as HIV, HBV and HCV.

The measures taken may be of limited value against non-enveloped viruses such as HAV and parvovirus B19.

There is a reassuring clinical experience regarding the lack of hepatitis A or parvovirus B19 transmission with immunoglobulins and it is also assumed that the antibody content makes an important contribution to the viral safety.

It is strongly recommended that every time that Octagam 10% is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.

In order to infuse any product that may remain in the infusion tubing at the end of the infusion the tubing may be flushed with either 0.9% saline or 5% dextrose solution.

Live attenuated virus vaccines

Immunoglobulin administration may impair for a period of at least 6 weeks and up to 3 months the efficacy of live attenuated virus vaccines such as measles, rubella, mumps and varicella. After administration of this product, an interval of 3 months should elapse before vaccination with live attenuated virus vaccines. In the case of measles, this impairment may persist for up to 1 year. Therefore, patients receiving measles vaccine should have their antibody status checked.

Interference with serological testing

After injection of immunoglobulin the transitory rise of various passively transferred antibodies in the patients blood may result in misleading positive results in serological testing.

Passive transmission of antibodies to erythrocyte antigens, e.g. A, B or D may interfere with some serological tests for red cell allo-antibodies, for example the antiglobulin test (e.g. Coombs Test).

Blood Glucose Testing

Some types of blood glucose testing systems (for example, those based on the glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ) or glucose-dye-oxidoreductase methods) falsely interpret the maltose (90 mg/ml) contained in Octagam 10% as glucose. This may result in falsely elevated glucose readings during an infusion and for a period of about 15 hours after the end of the infusion and, consequently, in the inappropriate administration of insulin, resulting in life-threatening or even fatal hypoglycemia. Also, cases of true hypoglycemia may go untreated if the hypoglycemic state is masked by falsely elevated glucose readings. Accordingly, when administering Octagam 10% or other parenteral maltose- containing products, the measurement of blood glucose must be done with a glucose-specific method.

The product information of the blood glucose testing system, including that of the test strips, should be carefully reviewed to determine if the system is appropriate for use with maltose-containing parenteral products. If any uncertainty exists, contact the manufacturer of the testing system to determine if the system is appropriate for use with maltose- containing parenteral products.

The safety of this medicinal product for use in human pregnancy has not been established in controlled clinical trials and therefore should only be given with caution to pregnant women and breast-feeding mothers. Clinical experience with immunoglobulins suggests that no harmful effects on the course of pregnancy, or on the foetus and the neonate are to be expected. Immunoglobulins are excreted into the milk and may contribute to the transfer of protective antibodies to the neonate.

No effects on ability to drive and use machines have been observed.

In general, various allergic and hypersensitivity type of reactions and headache, chills, back pain, chest pain, fever, cutaneous reactions, vomiting, arthralgia, low blood pressure and nausea may occasionally occur. Reactions to intravenous immunoglobulins tend to be related to the dose and the rate of infusion.

The frequencies given in the following table are derived from clinical studies that were conducted with Octagam 5% (columns named "common" and "uncommon") and from postmarketing experience with Octagam 5% (column named "very rare"). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Cases of reversible aseptic meningitis, isolated cases of reversible haemolytic anaemia/haemolysis and rare cases of transient cutaneous reactions, have been observed with human normal immunoglobulin.

Increase in serum creatinine level and/or acute renal failure have been observed.

Very rarely: Thromboembolic reactions such as myocardial infarction, stroke, pulmonary embolism, deep vein thromboses.

Rarely human normal immunoglobulins may cause a sudden fall in blood pressure and, in isolated cases, anaphylactic shock, even when the patient has shown no hypersensitivity to previous administration.

Standard measures are taken to prevent infections resulting from the use of medicinal products prepared from human blood or plasma. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens. For safety with respect to transmissible agents, see 4.4.

Clinical experience in children is limited.

Overdose may lead to fluid overload and hyperviscosity, particularly in patients at risk, including elderly patients or patients with renal impairment.

Pharmacotherapeutic group: immune sera and immunoglobulins: immunoglobulins, normal human, for intravascular administration,

ATC-Code: J06B A02

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 prepared from pooled plasma from not fewer than 1000 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 level to the normal range.

The mechanism of action in indications other than replacement therapy is not fully elucidated, but includes immunomodulatory effects.

Clinical Studies

In a prospective, open-label, multicentre phase III trial, the efficacy and safety of Octagam 10% was studied in patients suffering from idiopathic (immune) thrombocytopenic purpura (ITP). Octagam 10% was infused on 2 consecutive days at a dose of 1 gram/kg/day, and patients were observed for a period of 21 days and at a follow-up visit on Day 63 post-infusion. Haematology parameters were assessed on Days 2 to 7, 14 and 21.

A total of 31 subjects were included in the analysis; 15 were subjects with chronic ITP, 15 were newly-diagnosed, and 1 subject was incorrectly enrolled in the study (had no ITP) and was therefore excluded from the efficacy analysis.

In total, 25 subjects (83%) showed a clinical response. A higher clinical response rate was seen in the newly-diagnosed cohort (93%) than in the chronic ITP cohort (73%). In subjects with a response, the median time to platelet response was 2 days, with a range of 1 to 5 days.

In 24 subjects (77%), Octagam 10% was given at the maximum allowed infusion rate of 0.06 mL/kg/min. Following a Protocol Amendment, 2 patients of the presented analysis received the product at a rate of 0.08 mL/kg/min which was uneventful in both cases. In the continuation of this on-going study, 22 subjects have been treated with the maximum allowed infusion rate of 0.12 mL/kg/min.

In 9 of 62 infusions (14.5%) treatment-related infusional AE were observed. The most common drug-related AE was headache, followed by tachycardia and pyrexia. There was no case of haemolysis related to the study drug. Pre-treatment to alleviate infusion-related intolerability was not given.

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 an average half life ranging from 26 to 41 days, as measured in immunodeficient patients. This half-life may vary from patient to patient, in particular in primary immunodeficiency. For Octagam 10%, no formal pharmacokinetic data in immunodeficient patients have been obtained.

IgG and IgG-complexes are broken down in cells of the reticuloendothelial system.

Immunoglobulins are normal constituents of the human body. Studies of repeated dose toxicity, genotoxicity, and toxicity to reproduction in animals are impracticable due to induction of and interference by developing antibodies to heterologous proteins. Since clinical experience provides no evidence for carcinogenic or mutagenic potential of immunoglobulins, no experimental studies in heterogolous species were performed.

Maltose          
Water for injections

This medicinal product must not be mixed with other medicinal products.

Store in a refrigerator (2°C – 8°C). Do not freeze.

Keep the container in the outer carton in order to protect from light.

The product may be removed from the refrigerator for a single period of up to 3 months (without exceeding the expiry date) and stored at a temperature below 25°C. At the end of this period, the product should not be refrigerated again and should be disposed of. The date at which the product was taken out of the refrigerator should be recorded on the outer carton.

20 ml of solution in a 30 ml vial (type II glass) with a stopper (bromobutyl rubber).

50 ml of solution in a 70 ml bottle (type II glass) with a stopper (bromobutyl rubber).

100 ml of solution in a 100 ml bottle (type II glass) with a stopper (bromobutyl rubber).

200 ml of solution in a 250 ml bottle (type II glass) with a stopper (bromobutyl rubber).

Not all pack sizes may be marketed.

The product should be brought to room or body temperature before use.

The solution should be clear to slightly opalescent and colourless to slightly yellow.

Do not use solutions that are cloudy or have deposits.

Any unused product or waste material should be disposed of in accordance with local requirements.

Due to the possibility of bacterial contamination, any remaining contents must be discarded.