OCTAGAM®

50 mg/ml solution for infusion

2.1 Active ingredients

Human normal immunoglobulin (IVIg)

2.2 Quantitative composition

1 ml solution contains:

Distribution of IgG subclasses:

For a full list of excipients, see section 6.1.

Solution for infusion.

4.1.1 Replacement therapy in:

• Primary immunodeficiency syndromes such as:

- congenital agammaglobulinaemia and hypogammaglobulinaemia

- common variable immunodeficiency

- severe combined immunodeficiencies

- Wiskott Aldrich syndrome.

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

• Children with congenital AIDS who have repeated bacterial 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 dependant on the indication.

In replacement therapy the dosage may need to be individualised for each patient dependant 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 4.0 - 6.0 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 6.0 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, 0.8-1.0 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:

• 1.6-2.0 g/kg should be administered in divided doses over two to five days or 2.0 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

Human normal immunoglobulin should be infused intravenously at an initial rate of 1 ml/kg/hour for 30 minutes, If well tolerated, the rate of administration may gradually be increased to a maximum of 5 ml/kg/hour.

Filtration of OCTAGAM is not required.

Hypersensitivity to any of the components of OCTAGAM.

Hypersensitivity to homologous immunoglobulins, especially in very rare cases of IgA deficiency, when the patient has antibodies against IgA.

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

The solution should be clear or slightly opalescent.

Do not use solutions that are cloudy or have deposits.

Certain severe adverse drug reactions may be related to the rate of infusion. The recommended infusion rate given under "4.2.2 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 the 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 (1 ml/kg/hour);

• 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 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, those containing sucrose as a stabiliser accounted for a disproportionate share of the total number. In patients at risk, the use of IVIg products that do not contain sucrose may be considered.

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

OCTAGAM contains maltose, a disaccharide sugar, which is derived from corn. Anaphylactoid / anaphylactic reactions have been reported in association with infusion of other maltose / corn starch related products. Patients known to have corn allergies should either avoid using OCTAGAM or be closely observed for signs and symptoms of acute hypersensitivity reactions.

In all patients, IVIg administration requires:

• adequate hydration prior to the initiation of 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.

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 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.

The infusion line may be flushed before and after administration of OCTAGAM with either normal saline or 5% dextrose in water.

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 the 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 (e.g. Coombs Test), reticulocyte count and haptoglobin .

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 contained in Octagam as glucose. This may result in falsely elevated glucose readings and, consequently, in the inappropriate administration of insulin, resulting in life-threatening hypoglycemia. Also, cases of true hypoglycemia may go untreated if the hypoglycemic state is masked by falsely elevated glucose readings. Accordingly, when administering Octagam 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 woman 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 minor allergic and hypersensitivity type of reactions and headache, chills, back pain, chest pain, fever, vomiting, cutaneous reactions, arthralgia, and nausea may occasionally occur. Reactions to intravenous immunoglobulins tend to be related to the dose and the rate of infusion.

Very rarely Octagam 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.

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 material from not fewer than 3500 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.

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 an equilibrium is reached between the intra- and extravascular compartments.

Human normal immunoglobulin has a half-life of about 40 days. 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.

Immunoglobulins are normal constituents of the human body. In animals, acute toxicity testing is of no relevance. Repeated dose toxicity testing and embryo-foetal toxicity studies are impracticable. Effects of the product on the immune system of the newborn have not been studied.

Virus inactivation by the SD method is carried out with TNBP and Octoxynol (Triton X-100). The maximum permitted amounts in the final product are 1 µg/ml TNBP and 5 µg/ml Octoxynol. In the doses in which Octagam is administered, these substances have been found to have no toxic effects in animal tests concerning acute and chronic toxicity, teratogenicity and embryotoxicity.

Since clinical experience provides no hint for tumorigenic or mutagenic effects of immunoglobulins, experimental studies, particularly in heterogolous species, are not considered necessary.

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

2 years at +2 °C to +25 °C.

The product should be stored and transported at +2°C to +25°C.

Do not freeze.

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

Do not use after expiry date.

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

Keep out of the reach of children.

The primary container is made of Ph. Eur. type II glass closed with bromobutyl rubber stopper.

Components used in the packaging of OCTAGAM are latex-free.

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

OCTAPHARMA LTD.

The Zenith Building

26 Spring Gardens

Manchester

M2 1AB

U.K.

10673/0006

Date of first authorisation: May 21^st, 1997

Date of last renewal: May 21^st, 2007

13/01/2009