OCTAGAM 50 MG / ML SOLUTION FOR INFUSION - Summary of medicine characteristics

OCTAGAM

50 mg/ml solution for infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Human normal immunoglobulin (IVIg)

One ml contains :

Human normal immunoglobulin* * corresponding to the total protein content of which at least 95% is human Immunoglobulin G

50 mg

Distribution of IgG subclasses:

IgG1     ca. 60%

IgG2     ca. 32%

IgG3     ca. 7%

IgG4     ca. 1%

Maximum IgA content: 200 micrograms/ml

Each vial of 20 ml contains 1g of human normal immunoglobulin.

Each bottle of 50 ml contains 2.5g of human normal immunoglobulin.

Each bottle of 100 ml contains 5g of human normal immunoglobulin.

Each bottle of 200 ml contains 10g of human normal immunoglobulin.

Each bottle of 500 ml contains 25g of human normal immunoglobulin.

Produced from plasma of human donors.

For a full list of excipients, see section 6.1.

Solution for infusion.

The liquid preparation is clear to slightly opalescent and colourless to slightly yellow.

The pH of the liquid preparation is 5.1 – 6.0, the osmolality is > 240 mosmol/kg.

4.1 Therapeutic indications

Replacement therapy in adults, and children and adolescents (0–18 years) in:

Primary immunodeficiency syndromes with impaired antibody production (see Section 4.4).

Hypogammaglobu­linaemia and recurrent bacterial infections in patients with chronic lymphocytic leukaemia, in whom prophylactic antibiotics have failed.

Hypogammaglobu­linaemia and recurrent bacterial infections in plateau phase multiple myeloma patients who have failed to respond to pneumococcal immunisation.

Hypogammaglobu­linaemia in patients after allogeneic haematopoietic stem cell transplantation (HSCT).

Congenital AIDS with recurrent bacterial infections.

Immunomodulation in adults, and children and adolescents (0–18 years) in:

Primary immune thrombocytopenia (ITP), in patients at high risk of bleeding or prior to surgery to correct the platelet count.

Guillain Barré syndrome

Kawasaki disease

Chronic inflammatory demyelinating polyneuropathy (CIDP). Only limited experience is available of use of intravenous immunoglobulins in children with CIDP.

4.2 Posology and method of administration

Replacement therapy should be initiated and monitored under the supervision of a physician experienced in the treatment of immunodeficiency.

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 dose regimen should achieve a trough level of IgG (measured before the next infusion) of at least 5 – 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 given once followed by at least 0.2 g/kg every three to four weeks.

The dose required to achieve a trough level of 5 – 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 3 – 4 weeks.

Trough levels should be measured and assessed in conjunction with the incidence of infection. To reduce the rate of infection, it may be necessary to increase the dosage and aim for higher trough levels.

Hypogammaglobu­linaemia and recurrent bacterial infections in patients with chronic lymphocytic leukaemia, in whom prophylactic antibiotics have failed; hypogammaglobu­linaemia and recurrent bacterial infections in plateau phase multiple myeloma patients who have failed to respond to pneumococcal immunisation; congenital AIDS with recurrent bacterial infections:

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

Hypogammaglobu­linaemia in patients after allogeneic haematopoietic stem cell transplantation:

The recommended dose is 0.2–0.4 g/kg every three to four weeks. The trough levels should be maintained above 5g/l.

Primary immune thrombocytopenia:

There are two alternative treatment schedules:

0.8–1g/kg given on day one; this dose may be repeated once within 3 days

0.4 g/kg given daily for two to five days.

The treatment can be repeated if relapse occurs.

Guillain Barré syndrome:

0.4 g/kg/day over 5 days.

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.

Chronic inflammatory demyelinating polyneuropathy (CIDP):

2 g (40 ml)/kg BW as initial dose in divided doses over up to 5 consecutive days every 4 weeks.

The maintenance dose (dose and dosing interval) must be adapted to the individual clinical response. If there is no improvement within the first 3 months, the attempted therapy should be discontinued.

The dosage recommendations are summarised in the following table:

Paediatric population

The posology in children and adolescents (0–18 years) is not different to that of adults as the posology for each indication is given by body weight and adjusted to the clinical outcome of the above mentioned conditions.

There is only limited experience in the use of intravenous immunoglobulins in children with CIDP. Published data show that intravenous immunoglobulins are equally effective in children and adults with CIDP.

Method of administration

For intravenous use.

OCTAGAM 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.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients of OCTAGAM listed in Section 6.1 (see also Section 4.4).

Hypersensitivity to human immunoglobulins, especially in patients with antibodies against IgA.

4.4 Special warnings and precautions for use

This medicinal product contains 100 mg of maltose per ml as an excipient. The interference of maltose in blood glucose assays may result in falsely elevated glucose readings and, consequently, in the inappropriate administration of insulin, resulting in life threatening hypoglycaemia and death. Also, cases of true hypoglycaemia may go untreated if the hypoglycaemic state is masked by falsely elevated glucose readings (see Section 4.5). For acute renal failure see below.

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Precautions for use

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);

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 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.

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 (see 4.5).

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 adverse reaction.

Infusion reaction

Certain adverse reactions (e.g. headache, flushing, chills, myalgia, wheezing, tachycardia, lower back pain, nausea, and hypotension) may be related to the rate of infusion. The recommended infusion rate given under Section 4.2 must be closely followed. Patients must be closely monitored and carefully observed for any symptoms throughout the infusion period.

Adverse reactions may occur more frequently

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.

in patients with an untreated infection or underlying chronic inflammation

Hypersensitivity

Hypersensitivity reactions are rare.

Anaphylaxis can develop in patients

with undetectable IgA who have anti-IgA antibodies

who had tolerated previous treatment with human normal immunoglobulin

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

Thromboembolism

There is clinical evidence of an association between IVIg administration and thromboembolic events such as myocardial infarction, cerebral vascular accident (including 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 preexisting 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).

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

Acute renal failure

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, hypovolaemia, overweight, concomitant nephrotoxic medicinal products or age over 65.

Renal parameters should be assessed prior to infusion of IVIG, particularly in patients judged to have a potential increased risk for developing acute renal failure, and again at appropriate intervals. In patient at risk for acute renal failure, IVIg products should be administered at the minimum rate of infusion and dose practicable. In case of renal impairment, IVIg discontinuation should be considered.

While 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 that do not contain these excipients may be considered. OCTAGAM contains maltose (see excipients above).

Aseptic meningitis syndrome (AMS)

Aseptic meningitis syndrome has been reported to occur in association with IVIg treatment. The syndrome usually begins within several hours to 2 days following IVIg treatment.

Cerebrospinal fluid studies are frequently positive with pleocytosis up to several thousand cells per mm3, predominantly from the granulocytic series, and elevated protein levels up to several hundred mg/dl.

AMS may occur more frequently in association with high-dose (2 g/kg) IVIg treatment.

Patients exhibiting such signs and symptoms should receive a thorough neurological examination, including CSF studies, to rule out other causes of meningitis.

Discontinuation of IVIg treatment has resulted in remission of AMS within several days without sequelae.

Haemolytic anaemia

IVIg products can contain blood group antibodies which may act as haemolysins and induce in vivo coating of red blood cells with immunoglobulin, causing a positive direct antiglobulin reaction (Coombs’ test) and, rarely, haemolysis. Haemolytic anaemia can develop subsequent to IVIg therapy due to enhanced red blood cells (RBC) sequestration. IVIg recipients should be monitored for clinical signs and symptoms of haemolysis. (see section 4.8.)

Neutropenia/Le­ukopenia

A transient decrease in neutrophil count and/or episodes of neutropenia, sometimes severe, have been reported after treatment with IVIg. This typically occurs within hours or days after IVIg administration and resolves spontaneously within 7 to 14 days.

Transfusion related acute lung injury (TRALI)

In patients receiving IVIg, there have been some reports of acute non-cardiogenic pulmonary oedema [Transfusion Related Acute Lung Injury (TRALI)], therefore, this side effect cannot be totally excluded for Octagam even though no case has been observed so far for Octagam. TRALI is characterised by severe hypoxia, dyspnoea, tachypnoea, cyanosis, fever and hypotension. Symptoms of TRALI typically develop during or within 6 hours of a transfusion, often within 1–2 hours. Therefore, IVIg recipients must be monitored for and IVIg infusion must be immediately stopped in case of pulmonary adverse reactions. TRALI is a potentially life-threatening condition requiring immediate intensive-care-unit management.

Interference with serological testing

After the administration of immunoglobulin the transitory rise of the various passively transferred antibodies in the patient’s blood may result in misleading positive results in serological testing.

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

Transmissible agents

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.

Important information on some of the ingredients of OCTAGAM

This medicinal product contains 35 mg sodium per 100 ml, equivalent to 1.75% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

(Falsely) raised erythrocyte sedimentation rate

In patients who are receiving IVIG as a therapy, the erythrocyte sedimentation rate (ESR) may falsely be increased (noninflammato­ry rise).

Circulatory (volume) overload

Circulatory (volume) overload can occur when the volume of the infused IVIG (or any other blood or plasma-derived product) and other coincidental infusions cause acute hypervolaemia and acute pulmonary oedema.

Local injection site reactions:

Local reactions at the injection site have been identified which might include extravasation, infusion site erythema, infusion site pruritus, and similar symptoms.

Paediatric population

The listed warnings and precautions apply to both adults and children.

4.5 Interaction with other medicinal products and other forms of interaction

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.

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 (100 mg/ml) contained in OCTAGAM 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 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.

Paediatric population

There were no specific or additional interactions observed for the paediatric population.

4.6 Fertility, pregnancy and lactation

Pregnancy

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.. IVIg products have been shown to cross the placenta, increasingly during the third trimester. 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.

Breast-feeding

Immunoglobulins are excreted into the milk and may contribute to protecting the neonate from pathogens which have a mucosal portal of entry.

Fertility

Clinical experience with immunoglobulins suggests that no harmful effects on fertility are to be expected.

4.7 Effects on ability to drive and use machines

The ability to drive and operate machines may be impaired by some adverse reactions associated with OCTAGAM. Patients who experience adverse reactions during treatment should wait for these to resolve before driving or operating machines.

4.8 Undesirable effects

Summary of the safety profile

Adverse reactions caused by human normal immunoglobulins (in decreasing frequency) encompass (see also Section 4.4):

chills, headache, dizziness, fever, vomiting, allergic reactions, nausea, arthralgia, low blood pressure and moderate low back pain

reversible haemolytic reactions; especially in those patients with blood groups A, B, and AB and (rarely) haemolytic anaemia requiring transfusion.

(rarely) a sudden fall in blood pressure and, in isolated cases, anaphylactic shock, even when the patient has shown no hypersensitivity to previous administration.

(rarely) transient cutaneous reactions (including cutaneous lupus erythematosus -frequency unknown)

(very rarely) thromboembolic reactions such as myocardial infarction, stroke, pulmonary embolism, deep vein thrombosis

cases of reversible aseptic meningitis

cases of increased serum creatinine level and/or occurrence of acute renal failure

cases of Transfusion Related Acute Lung Injury (TRALI)

Tabulated list of adverse reactions

The table presented below is according to the MedDRA system organ classification (SOC and Preferred Term Level).

Frequencies have been evaluated according to the following convention: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data).

Within each adverse reaction, adverse reactions are presented in order of decreasing seriousness.

Frequency of adverse drug reactions in clinical studies with Octagam:

The following reactions have been reported from post-marketing experience with OCTAGAM.

Frequencies for post-marketing reported reactions cannot be estimated from the available data.

Description of selected adverse reactions

For description of selected adverse events, such as hypersensitivity reactions, thromboembolism, acute renal failure, aseptic meningitis syndrome and haemolytic anaemia, see Section 4.4.

Paediatric population

In clinical studies with OCTAGAM most adverse reactions observed in children were graded as mild and many of them responded to simple measurements such as reduction of the infusion rate or temporary discontinuation of the infusion. With respect to the type of adverse reaction, all were recognised for IVIG preparations. The most frequent adverse reaction observed in the paediatric population was headache.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.

United Kingdom

Yellow Card Scheme

Website : www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9 Overdose

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

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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 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 levels to the normal range.

The mechanism of action in indications other than replacement therapy is not fully elucidated.

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 postinfusion. Haematology parameters were assessed on Days 2 to 7, 14 and 21.

A total of 116 subjects were included in the analysis; 66 were subjects with chronic ITP, 49 were newly-diagnosed, and 1 subject was incorrectly enrolled in the study (had no ITP) and was therefore excluded from the efficacy analysis.

The overall response rate in the full analysis set was 80% (95% confidence interval: 73% to 87%). Clinical response rates were similar in the 2 cohorts: 82% in the chronic ITP cohort and 78% in the newly diagnosed cohort. In subjects with a response, the median time to platelet response was 2 days, with a range of 1 to 6 days.

The overall maximum infusion rate was 0.12 ml/kg/min. In the group of subjects in which a maximum infusion rate of 0.12 mL/kg/min was allowed (n=90), a median maximum infusion rate of 0.12 mL/kg/min (mean 0.10 mL/kg/min) was achieved. Overall, 55% of subjects experienced a drug-related adverse event, with a similar incidence in the chronic ITP and newly-diagnosed ITP cohort. All of the drug-related adverse events were mild or moderate in intensity, and all of them resolved. The most common adverse events were headache, increased heart rate (alterations in pulse rate of as little as > 10 beats/min were to be reported), and pyrexia. Drug-related infusional adverse events during or within 1 hour of infusions given at rates of < 0.08 ml/kg/min occurred in 32 of 116 subjects (28%), while only 6 of 54 subjects (11%) had such adverse events at a rate of 0.12 ml/kg/min (if adverse event onset was after the end of the infusion, the last rate applied was assigned to the adverse event). There was no case of haemolysis related to the study drug. Pre-treatment to alleviate infusion-related intolerability was not given except in 1 subject.

Chronic inflammatory demyelinating polyneuropathy (CIDP):

A retrospective study included data from 46 patients with chronic inflammatory demyelinating polyneuropathy (CIDP), who had been treated with Octagam 5%. The analysis of efficacy included 24 patients, with 11 untreated patients (group 1) and 13 patients who had received no immunoglobulins in the 12 weeks before the start of therapy with Octagam 5% (group 2). Group 3 contained 13 other patients who had been pretreated with immunoglobulins (immunoglobulins administered within 12 weeks before the start of administration of Octagam 5%). The treatment was regarded as effective if the ONLS (Overall Neuropathy Limitations Scale) was reduced by at least one point within 4 months of the start of treatment. In groups 1 and 2, the score was significantly reduced in 41.7% of the patients (p=0.02). Only 3 of the 13 patients (23.08%) in group 3 (pretreated with IVIg) exhibited an improvement in ONLS; 10 patients remained stable. No more marked improvement in the ONLS was to be expected for the patients pretreated with IVIg.

The mean age of the patients examined was 65 years, which is greater than in other CIDP studies. In patients older than 65 years, the response rate was lower than in younger patients. This is in accordance with published data.

Paediatric population

A prospective open-label phase III study was performed with OCTAGAM in 17 children/a­dolescent patients (median age 14.0 years, range 10.5 to 16.8) suffering from primary immunodeficiency disorders. Previously treated patients received 0.2 g/kg every 3 weeks for the 6 months study period. Naive patients received 0.4 g/kg every 3 weeks for the first 3 months, followed by 0.2 g/kg for the rest of the study period. Dosages had to be adjusted to maintain an IgG trough level of at least 4 g/L.

No. of days out of school: 11.2 days/pati­ent/year

No. of days with fever: 4.1 days/pati­ent/year

No. of days on antibiotics: 19.3 days/pati­ent/year

No. of days with infections: 29.1 days/pati­ent/year.

The severity of infections was assessed as mild. No severe infections leading to hospitalisation were observed.

5.2 Pharmacokinetic properties

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.

Paediatric population

A prospective open-label phase III study was performed with OCTAGAM in 17 children/a­dolescent patients (median age 14.0 years, range 10.5 to 16.8) suffering from primary immunodeficiency disorders. Patients were treated for a period of 6 months.

During the treatment period, the average Cmax in steady state was 11.1 ± 1.9 g/L; the average trough level was 6.2 ± 1.8 g/L. The mean terminal half-life of total IgG was 35.9 ± 10.8 days with a median of 34 days. The mean volume of distribution for the total IgG was 3.7 ± 1.4 L and the total body clearance was 0.07 ± 0.02 L/day.

5.3 Preclinical safety data

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.

6.1

Maltose

100 mg/ml ad 1ml

Water for injections

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

2 years

6.4 Special precautions for storage

Store below 25°C.

Do not freeze.

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

Do not use after expiry date.

6.5 Nature and contents of container

Not all pack sizes may be marketed.

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.

6.6 Special precautions for disposal

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.

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

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

7 MARKETING AUTHORISATION HOLDER

OCTAPHARMA LTD.

The Zenith Building

26 Spring Gardens

Manchester

M2 1AB

U.K.

8. MARKETING AUTHORISATION NUMBER

10673/0006

9 DATE OF FIRST AUTHORISATION/RE­NEWAL OF THE

Date of first authorisation: May 21st, 1997

Date of last renewal: May 21st, 2007