This information is intended for use by health professionals

1. Name of the medicinal product

OCTAGAM 10%, solution for infusion

2. Qualitative and quantitative composition

Human normal immunoglobulin (IVIg)

One ml contains:

Human normal immunoglobulin (IVIg) 100 mg

(purity of at least 95% IgG)

Each vial of 20 ml contains 2g of human normal immunoglobulin.

Each bottle of 50 ml contains 5g of human normal immunoglobulin.

Each bottle l of 60 ml contains 6g of human normal immunoglobulin.

Each bottle of 100 ml contains 10g of human normal immunoglobulin.

Each bottle of 200 ml contains 20g of human normal immunoglobulin.

Distribution of IgG subclasses (approx. values):

IgG1

ca. 60%

IgG2

ca. 32%

IgG3

ca. 7%

IgG4

ca. 1%

The maximum IgA content is 400 micrograms/ml.

Produced from the plasma of human donors.

Excipient(s) with known effect

This medicinal product contains 69 mg sodium per 100 ml, equivalent to 3.45% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

For a full list of excipients, see section 6.1.

3. Pharmaceutical form

Solution for infusion

The liquid preparation is clear to slightly opalescent and colourless to slightly yellow. The pH of the liquid preparation is 4.5 – 5.0, the osmolality is ≥ 240 mosmol/kg.

4. Clinical particulars
4.1 Therapeutic indications

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

• Primary immunodeficiency syndromes (PID) with impaired antibody production

• Secondary immunodeficiencies (SID) in patients who suffer from severe or recurrent infections, ineffective antimicrobial treatment and either proven specific antibody failure (PSAF)* or serum IgG level of <4g/l.

*PSAF=failure to mount at least a 2-fold rise in IgG antibody titre to pneumococcal polysaccharide and polypeptide antigen vaccines

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 (in conjunction with acetylsalicylic acid; see 4.2)

• Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)

• Multifocal motor neuropathy (MMN)

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 dose regimen are dependent on the indication.

The dose may need to be individualised for each patient dependent on the clinical response. Dose based on bodyweight may require adjustment in underweight and overweight patients. In overweight patients dose should be based on the physiological standard bodyweight.

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 6 g/L or within the normal reference range for the population age. Three to six months are required after the initiation of therapy for equilibration (steady-state IgG levels) 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 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.

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

Secondary immunodeficiencies (as defined in 4.1.)

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

IgG trough levels should be measured and assessed in conjunction with the incidence of infection. Dose should be adjusted as necessary to achieve optimal protection against infections, an increase may be necessary in patients with persisting infection; a dose decrease can be considered when the patient remains infection free.

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 (possible repeat of dosing in case of relapse).

Kawasaki disease:

2.0 g/kg should be administered as a single dose. Patients should receive concomitant treatment with acetylsalicylic acid.

Chronic inflammatory demyelinating polyneuropathy (CIDP):

Starting dose: 2g/kg divided over 2-5 consecutive days.

Maintenance doses:

1 g/kg over 1-2 consecutive days every 3 weeks.

The treatment effect should be evaluated after each cycle; if no treatment effect is seen after 6 months, the treatment should be discontinued.

If the treatment is effective, long-term treatment should be subject to the physician's discretion based upon the patient response and maintenance response. The dosing and intervals may have to be adapted according to the individual course of the disease.

Multifocal Motor Neuropathy (MMN)

Starting dose: 2g/kg given over 2-5 consecutive days

Maintenance dose: 1 g/kg every 2 to 4 weeks or 2 g/kg every 4 to 8 weeks.

The treatment effect should be evaluated after each cycle; if no treatment effect is seen after 6 months, the treatment should be discontinued.

If the treatment is effective, long-term treatment should be subject to the physician's discretion based upon the patient's response and maintenance response. The dosing and intervals may have to be adapted according to the individual course of the disease.

The dosage recommendations are summarised in the following table:

Indication

Dose

Frequency of injections

Replacement therapy

Primary immunodeficiency syndromes

Starting dose:

0.4-0.8 g/kg

Maintenance dose:

0.2-0.8 g/kg

 

every 3 - 4 weeks

Secondary immunodeficiencies (as defined in 4.1.)

0.2–0.4 g/kg

every 3 - 4 weeks

Immunomodulation:

Primary immune thrombocytopenia

0.8 – 1.0 g/kg

or

0.4 g/kg/d

on day 1, possibly repeated once within 3 days

for 2-5 days

Guillain Barré syndrome

0.4 g/kg/d

for 5 days

Kawasaki disease

2 g/kg

in one dose in association with acetylsalicylic acid

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)

Starting dose:

2 g/kg

Maintenance dose:

1 g/kg

 

in divided doses over 2-5 days

 

every 3 weeks over 1-2 days

Multifocal Motor Neuropathy (MMN)

Starting dose:

2 g/kg

Maintenance dose:

1g/kg

or

2g/kg

 

over 2-5 consecutive days

 

every 2-4 weeks

or

every 4-8 weeks over 2-5 days

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.

Hepatic impairment

No evidence is available to require a dose adjustment.

Renal impairment

No dose adjustment unless clinically warranted, see section 4.4.

Elderly

No dose adjustment unless clinically warranted, see section 4.4.

Method of administration

For intravenous use.

Octagam 10% should be infused intravenously at an initial rate of 0.01 mL/kg body weight per minute for 30 minutes. See section 4.4. In case of adverse reaction, either the rate of administration must be reduced or the infusion stopped. If well tolerated, the rate of administration may gradually be increased to a maximum of 0.12 mL/kg body weight per minute.

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.

4.3 Contraindications

Hypersensitivity to the active substance (human immunoglobulins) or to any of the excipients (see Section 4.4 and 6.1).

Patients with selective IgA deficiency who developed antibodies to IgA, as administering an IgA-containing product can result in anaphylaxis.

4.4 Special warnings and precautions for use

This medicinal product contains 90 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 (0.01 to 0.02 mL/kg body weight per minute);

• 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 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).

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 patients 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 not containing such excipients may be considered. Octagam 10% 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 reports of non-cardiogenic pulmonary oedema [Transfusion-Related Acute Lung Injury (TRALI)], therefore, this side effect cannot be totally excluded for Octagam 10% even though no case has been observed so far for Octagam 10%. 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 10%

This medicinal product contains 69 mg sodium per 100 ml, equivalent to 3.45% 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 (non-inflammatory 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 both to adults and children.

4.5 Interaction with other medicinal products and other forms of interaction

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 medicinal 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.

Loop diuretics

Avoidance of concomitant use of loop diuretics

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.

Paediatric population

The listed interactions apply both to adults and children.

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 women 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 human milk. No negative effects on the breastfed newborns/infants are anticipated.

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

OCTAGAM 10% has no or negligible influence on the ability to drive and use machines. However, 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 thromboses

• 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 Organ Class, adverse reactions are presented in order of decreasing seriousness.

Frequency of adverse drug reactions in clinical studies with Octagam:

MedDRA System Organ Classification (SOC) according to the sequence:

Adverse Reaction

Frequency per patient

Frequency per infusion

Immune system disorders (see section 4.4)

hypersensitivity

very common

common

Nervous system disorders

headache

very common

common

Gastrointestinal disorders

nausea

common

uncommon

Skin and subcutaneous tissue disorders

eczema

common

uncommon

Musculoskeletal and connective tissue disorders

back pain

common

uncommon

General disorders and administration site conditions

fever;

fatigue;

injection site reaction

chills;

chest pain

common

common

common

common

uncommon

uncommon

uncommon

uncommon

uncommon

uncommon

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.

MedDRA System Organ Classification (SOC) according to the sequence:

Adverse Reaction (Preferred Term Level)

Frequency

Blood and lymphatic system disorders

haemolytic anaemia

leukopenia;

not known

not known

Immune system disorders (see section 4.4)

anaphylactic shock;

anaphylactic reaction;

anaphylactoid reaction;

angioedema;

face oedema

not known

not known

not known

not known

not known

Metabolic and nutritional disorders

fluid overload

(pseudo)hyponatraemia

not known

not known

Psychiatric disorders

confusional state

agitation

anxiety

nervousness

not known

not known

not known

not known

Nervous system disorders

cerebrovascular accident (see 4.4);

meningitis aseptic;

loss of consciousness;

speech disorder;

migraine;

dizziness;

hypoaesthesia;

paraesthesia

photophobia;

tremor

not known

not known

not known

not known

not known

not known

not known

not known

not known

not known

Eye disorders

visual impairment

not known

Cardiac disorders

myocardial infarction (see 4.4);

angina pectoris;

bradycardia;

tachycardia;

palpitations;

cyanosis

not known

not known

not known

not known

not known

not known

Vascular disorders

thrombosis (see 4.4);

circulatory collapse;

peripheral circulatory failure;

phlebitis;

hypotension;

hypertension;

pallor

not known

not known

not known

not known

not known

not known

not known

Respiratory, thoracic and mediastinal disorders

respiratory failure;

pulmonary embolism (see 4.4);

pulmonary oedema;

bronchospasm;

hypoxia;

dyspnoea;

cough

not known

not known

not known

not known

not known

not known

not known

Gastrointestinal disorders

vomiting;

diarrhoea;

abdominal pain

not known

not known

not known

Skin and subcutaneous tissue disorders

skin exfoliation;

urticaria;

rash;

rash erythematous;

dermatitis;

pruritus;

alopecia

erythema

not known

not known

not known

not known

not known

not known

not known

not known

Musculoskeletal and connective tissue disorders

arthralgia;

myalgia

pain in extremity

neck pain;

muscle spasms;

muscular weakness;

musculoskeletal stiffness

not known

not known

not known

not known

not known

not known

not known

Renal and urinary disorders

renal failure acute (see 4.4) ;

renal pain

not known

not known

General disorders and administration site conditions

oedema;

influenza like illness

hot flush;

flushing;

feeling cold;

feeling hot;

hyperhidrosis;

malaise

chest discomfort;

asthenia;

lethargy;

burning sensation;

not known

not known

not known

not known

not known

not known

not known

not known

not known

not known

not known

not known

Investigations

hepatic enzymes increased;

blood glucose false positive (see 4.4)

not known

not known

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 (see section 4.4).

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 naive 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 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.

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

No specific studies in the paediatric population were performed with Octagam 10%.

However, a prospective open-label phase III study was performed with Octagam 5% 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. The clinical efficacy was satisfying, as the number of days with infections or fever, and the number of days out of school were low, and the type and severity of infections was comparable to those observed in the normal population. No severe infections leading to hospitalisation were observed. It is also noteworthy that the number of infectious episodes was lower, when IgG plasma levels were maintained around 6 g/L than when the IgG plasma levels were around 4 g/L.

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 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.

Paediatric population

No specific studies in the paediatric population were performed with Octagam 10%.

However, a prospective open-label phase III study was performed with Octagam 5% 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 terminal half-life of total IgG was 36 ± 11 days with a median of 34 days. The 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 heterologous species were performed.

6. Pharmaceutical particulars
6.1 List of excipients

Maltose

Water for injections

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products, nor with any other IVIg products.

6.3 Shelf life

2 years

6.4 Special precautions for storage

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 9 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.

6.5 Nature and contents of container

Pack sizes:

2 g

in

20 ml

5 g

in

50 ml

6 g

in

60 ml

10 g

in

100 ml

20 g

in

200 ml

3 x 10 g

in

3 x 100 ml

3 x 20 g

in

3 x 200 ml

Not all pack sizes may be marketed.

20 ml of solution in a 30 ml vial.

50 ml of solution in a 70 ml bottle.

60 ml of solution in a 70 ml bottle.

100 ml of solution in a 100 ml bottle.

200 ml of solution in a 250 ml bottle.

The vials/bottles are made of type II glass closed with bromobutyl rubber stoppers.

6.6 Special precautions for disposal and other handling

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

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

Solutions that are cloudy or have deposits should be not used.

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.

7. Marketing authorisation holder

OCTAPHARMA Ltd

The Zenith Building

26 Spring Gardens

Manchester

M2 1AB

United Kingdom

8. Marketing authorisation number(s)

PL 10673/0028

9. Date of first authorisation/renewal of the authorisation

20/05/2018

10. Date of revision of the text

11/05/2019

LEGAL CATEGORY

For prescription only.