OCTAGAM

ילוי

2019

ה/דבכנ ת/חקור ,הדבכנ ה/אפור

רישכתל אפורל ןולע ןוכדע : ןודנה

, solution for I.V. infusion

Octagam

היזופניאל הסימת ,םגאטקוא

ידירו ךות ןתמל

רישכתל אפורל ןולעב םינוכדע לע עידוהל תשקבמ מ"עב יעדמו יאופר רושכמ רבוד תרבח

Octagam

:רישכתב ליעפה רמוחה

Human normal immunoglobulin 50 mg/ml

:רישכתל תרשואמה היוותהה

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 bacterial infections

Immunomodulatory effect:

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

Allogeneic bone marrow transplantation

ןכדוע ילארשיה ןולעה לירפאב

2019

.הינטירבב רשואמה ןולע יפ לע

הרמחה הווהמה ןוכדע השענ םהב םיפיעס םיניוצמ וז העדוהב

שגדומ בוהצב

םינולעב .הרמחה םיווהמ םניאש םיפסונ םינוכדע םימייק

.תואירבה דרשמ ידי לע רשואש יפכ אפורל ןולעב ןייעל שי הפורתה לע אלמ עדימל ולעה

כדועמה

לשנ

םוסרפל

רגאמב

תופורתה

רתאבש

דרשמ לש טנרטניאה

:תואירבה

https://data.health.gov.il/drugs/index.html#/byDrug

ולעה תא לבקל ןתינ ספדומ ן :םושירה לעבל היינפ י"ע תולעמה ,מ"עב יעדמו יאופר רושכמ רבוד

.הילצרה

: ןופלט

09-9514545

ס הקבר ,בר דובכב םינול

הנוממ תחקור

:םיאבה םיפיעסב ושענ אפורל ןולעב םיירקיעה םינוכדעה

2. Qualitative and quantitative composition

[…]

Produced from plasma of human donors.

4.4 Special warnings and precautions for use

[…]

Certain adverse reactions may occur more frequently

in case of high rate of infusion

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.

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 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.

[…]

In all patients, IVIg administration requires:

[…]

avoidance of concomitant use of loop diuretics.

This medicinal product contains not more than 0.015 mmol (or 0.35 mg) sodium per ml. To be

taken into consideration by patients on a controlled sodium diet.

Hypersensitivity

[…]

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.

Thromboembolism

[…]

In patients at risk for thromboembolic adverse reactions, IVIg products should be

administered at the minimum rate of infusion and dose practicable.

[…]

Aseptic meningitis syndrome (AMS)

[...]

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

Haemolytic anaemia

[…]

The development of haemolysis is associated with the following risk factors: high IVIg doses

administered as a single dose or in divided doses over several days; blood groups other than

group O; underlying inflammatory disease. Haemolysis has only rarely been observed in

patients receiving substitution therapy for PID.

[…]

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.

[…]

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.

Transfusion-related acute lung injury (TRALI)

There have been reports of non-cardiogenic pulmonary oedema [Transfusion-Related Acute

Lung Injury (TRALI)] in patients treated with IVIG, therefore, this side effect cannot be totally

excluded for Octagam even though no case has been observed so far for Octagam. […]

(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.

[…]

4.5 Interaction with other medicinal products and other forms of interaction

[…]

Blood Glucose Testing

Some types of blood glucose testing systems […] 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 […] when

administering OCTAGAM or other parenteral maltose- containing products, the measurement

of blood glucose must be done with a glucose-specific method.

[…]

4.6 Fertility, pregnancy and lactation

Pregnancy

[…] IVIg products have been shown to cross the placenta, increasingly during the third

trimester.

[…]

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

.שדחמ ךרענ ולוכ ףיעסה

[…] Cases of reversible aseptic meningitis and rare cases of transient cutaneous reactions

have been observed with human normal immunoglobulin. Reversible haemolytic reactions

have been observed in patients, especially those with blood groups A, B, and AB. Rarely,

haemolytic anaemia requiring transfusion may develop after high dose IVIg treatment (see

also Section 4.4).

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.

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 Section 4.4.

Tabulated list of adverse reactions

[…]

MedDRA system organ

classification (SOC)

Adverse Reaction

(Preferred Term Level)

Frequency

Metabolic and nutritional

disorders

fluid overload

(pseudo)hyponatraemia

very rare

very rare

Psychiatric disorders

confusional state

agitation

anxiety

nervousness

very rare

very rare

very rare

very rare

Nervous system disorders

cerebrovascular accident

(see 4.4);

meningitis aseptic;

loss of consciousness;

speech disoder;

migraine;

headache

dizziness;

hypoaesthesia;

paraesthesia

photophobia;

tremor

very rare

very rare

very rare

very rare

very rare

common

very rare

very rare

very rare

very rare

very rare

Eye disorders

visual impairment

very rare

Cardiac disorders

myocardial infarction (see

4.4);

angina pectoris;

bradycardia;

tachycardia;

palpitations;

cyanosis

very rare

very rare

very rare

very rare

very rare

very rare

Vascular disorders

thrombosis (see 4.4);

circulatory collapse;

peripheral circulatory failure;

phlebitis;

hypotension;

hypertension

pallor

very rare

very rare

very rare

very rare

very rare

very rare

very rare

Respiratory, thoracic and

mediastinal disorders

respiratory failure;

pulmonary embolism (see

4.4);

pulmonary oedema;

bronchospasm;

hypoxia;

dyspnoea;

cough;

very rare

very rare

very rare

very rare

very rare

very rare

very rare

Skin and subcutaneous

tissue disorders

skin exfoliation;

urticaria;

rash;

rash erythematous;

dermatitis;

eczema;

pruritus;

alopecia

erythema;

very rare

very rare

very rare

very rare

very rare

uncommon

very rare

very rare

very rare

Musculoskeletal and

connective tissue disorders

arthralgia;

myalgia

pain in extremity

back pain;

neck pain;

muscle spasms;

muscular weakness;

musculoskeletal stiffness

very rare

very rare

very rare

uncommon

very rare

very rare

very rare

very rare

Renal and urinary disorders

renal failure acute (see 4.4)

renal pain

very rare

very rare

General disorders and

administration site conditions

chest pain;

chest discomfort;

oedema;

influenza like illness

fever;

chills;

hot flush;

flushing;

feeling cold;

feeling hot;

hyperhidrosis;

asthenia;

lethargy;

burning sensation;

injection site reaction;

fatigue;

malaise;

uncommon

very rare

very rare

very rare

common

uncommon

very rare

very rare

very rare

very rare

very rare

very rare

very rare

very rare

common

common

very rare

[…]

Description of selected adverse reactions

[…]

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.

[…]

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.

[…]

6.6 Special precautions for disposal and other handling

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

Do not use solutions that are cloudy or have deposits.

[…]

This leaflet format has been determined by the Ministry of Health and the content has been checked

and approved in

April 2019

SUMMARY OF THE PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT

OCTAGAM

50 mg/ml solution for infusion

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Human normal immunoglobulin (IVIg)

One ml contains :

Human normal immunoglobulin* 50 mg

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

Maximum IgA content: 200 micrograms/ml

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.

Produced from plasma of human donors.

For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM

Solution for infusion.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

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 bacterial infections

Immunomodulatory effect:

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

Allogeneic bone marrow transplantation

4.2

Posology and method of administration

Posology

The dose and dosage regimen is dependant on the indication.

replacement

therapy

dosage

need

individualised

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:

3/14

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

g/kg

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.

starting

dose

normally

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:

Indication

Dose

Frequency of injection

Replacement therapy in primary

immunodeficiency

Replacement therapy in

secondary immunodeficiency

Children with AIDS

-

Starting dose:

0.4 - 0.8 g/kg

-

Thereafter:

0.2 - 0.8 g/kg

0.2 - 0.4 g/kg

0.2 – 0.4 g/kg

every 2 - 4 weeks to obtain IgG

trough level of at least 4-6 g/l

every 3 - 4 weeks to obtain IgG

trough level of at least 4-6 g/l

every 3 - 4 weeks

Immunomodulation:

Idiopathic Thrombocytopenic

Purpura

0.8 – 1.0 g/kg

0.4 g/kg/day

on day 1, possibly repeated once

within 3 days

for 2-5 days

Guillain Barré syndrome

0.4 g/kg/day

for 3-7 days

Kawasaki syndrome

1.6 – 2.0 g/kg

in several doses for 2 - 5 days in

association with acetylsalicylic acid

2.0 g/kg

in one dose in association with

acetylsalicylic acid

Allogeneic bone marrow

transplantation:

-

treatment of infections and

prophylaxis of graft versus

host disease

0.5 g/kg

every week from day -7 up to 3

months after transplantation

-

Persistent lack of antibody

production

0.5 g/kg

every month until IgG levels return

to normal

4/14

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.

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

maltose

excipient.

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.

OCTAGAM

contains

maltose,

disaccharide

sugar,

which

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.

Certain

severe

adverse

drug

reactions

related

rate

infusion.

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.

Certain adverse reactions may occur more frequently

in case of high rate of infusion

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.

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 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

5/14

first infusion, in order to detect potential adverse signs. All other patients should be

observed for at least 20 minutes after administration.

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.

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

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.

This medicinal product contains not more than 0.015 mmol (or 0.35 mg) sodium per ml.

To be taken into consideration by patients on a controlled sodium diet.

Hypersensitivity

True hypersensitivity reactions are rare. They can occur in patients with anti-IgA

antibodies.

IVIg is not indicated in patients with selective IgA deficiency where the IgA deficiency is

the only abnormality of concern.

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.

Thromboembolism

There

clinical

evidence

association

between

IVIg

administration

thromboembolic

events

such

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

history

vascular

disease

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, hypovolemia, overweight, concomitant nephrotoxic medicinal products or age

over 65.

6/14

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 that do not contain these

excipients may be considered. OCTAGAM contains maltose (see excipients above).

In patient at risk for acute renal failure, IVIg products should be administered at the

minimum rate of infusion and dose practicable.

Aseptic meningitis syndrome (AMS)

Aseptic meningitis syndrome has been reported to occur in association with IVIg

treatment. Discontinuation of IVIg treatment has resulted in remission of AMS within

several days without sequelae. 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 mm

, 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.

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.

The development of haemolysis is associated with the following risk factors: high IVIg

doses administered as a single dose or in divided doses over several days; blood groups

other than group O; underlying inflammatory disease. Haemolysis has only rarely been

observed in patients receiving substitution therapy for PID. IVIg recipients should be

monitored for clinical signs and symptoms of haemolysis. (See section 4.8.)

Interference with serological testing

After injection 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.

7/14

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.

Transfusion-related acute lung injury (TRALI)

There have been reports of non-cardiogenic pulmonary oedema [Transfusion-Related

Acute Lung Injury (TRALI)] in patients treated with IVIG, 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 respiratory distress, pulmonary oedema,

hypoxaemia, normal left ventricular function, and fever and typically occurs within 1-6

hours after transfusion.

(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

There are no specific or additional warnings or precautions applicable for the paediatric

population.

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.

8/14

Blood Glucose Testing

Some types of blood glucose testing systems (for example, those based on the glucose

dehydrogenase

pyrroloquinolinequinone

(GDH-PQQ)

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

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

9/14

Adverse reactions such as chills, headache, dizziness, fever, vomiting, allergic reactions,

nausea, arthralgia, low blood pressure and moderate low back pain occur occasionally.

Reactions to intravenous immunoglobulins tend to be related to the dose and the rate of

infusion (see section 4.4).

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.

Cases of reversible aseptic meningitis and rare cases of transient cutaneous reactions have

been observed with human normal immunoglobulin. Reversible haemolytic reactions have

been observed in patients, especially those with blood groups A, B, and AB. Rarely,

haemolytic anaemia requiring transfusion may develop after high dose IVIg treatment (see

also Section 4.4).

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.

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 Section 4.4.

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).

The frequencies given in the following table are derived from clinical studies that were

conducted

with

Octagam

(Frequency

"common"

"uncommon")

from

postmarketing experience with Octagam (Frequency "very rare"). Within each frequency

grouping, undesirable effects are presented in order of decreasing seriousness.

MedDRA system organ

classification (SOC)

Adverse Reaction (Preferred

Term Level)

Frequency

Blood and lymphatic system

disorders

haemolytic anaemia,

leukopenia;

very rare

very rare

Immune system disorders (see

section 4.4)

anaphylactic shock;

hypersensitivity

anaphylactic reaction;

anaphylactoid reaction;

angioedema;

face oedema

very rare

common

very rare

very rare

very rare

very rare

Metabolic and nutritional disorders

fluid overload

(pseudo)hyponatraemia

very rare

very rare

Psychiatric disorders

confusional state

agitation

anxiety

very rare

very rare

very rare

10/14

nervousness

very rare

Nervous system disorders

cerebrovascular accident (see 4.4);

meningitis aseptic;

loss of consciousness;

speech disoder;

migraine;

headache

dizziness;

hypoaesthesia;

paraesthesia

photophobia;

tremor

very rare

very rare

very rare

very rare

very rare

common

very rare

very rare

very rare

very rare

very rare

Eye disorders

visual impairment

very rare

Cardiac disorders

myocardial infarction (see 4.4);

angina pectoris;

bradycardia;

tachycardia;

palpitations;

cyanosis

very rare

very rare

very rare

very rare

very rare

very rare

Vascular disorders

thrombosis (see 4.4);

circulatory collapse;

peripheral circulatory failure;

phlebitis;

hypotension;

hypertension

pallor

very rare

very rare

very rare

very rare

very rare

very rare

very rare

Respiratory, thoracic and mediastinal

disorders

respiratory failure;

pulmonary embolism (see 4.4);

pulmonary oedema;

bronchospasm;

hypoxia;

dyspnoea;

cough;

very rare

very rare

very rare

very rare

very rare

very rare

very rare

Gastrointestinal disorders

vomiting;

diarrhoea;

abdominal pain;

nausea

very rare

very rare

very rare

common

Skin and subcutaneous tissue

disorders

skin exfoliation;

urticaria;

rash;

rash erythematous;

dermatitis;

eczema;

pruritus;

alopecia

erythema;

very rare

very rare

very rare

very rare

very rare

uncommon

very rare

very rare

very rare

Musculoskeletal and connective

tissue disorders

arthralgia;

myalgia

pain in extremity

back pain;

neck pain;

muscle spasms;

muscular weakness;

musculoskeletal stiffness

very rare

very rare

very rare

uncommon

very rare

very rare

very rare

very rare

Renal and urinary disorders

renal failure acute (see 4.4)

renal pain

very rare

very rare

General disorders and administration

site conditions

chest pain;

chest discomfort;

oedema;

influenza like illness

fever;

chills;

uncommon

very rare

very rare

very rare

common

uncommon

11/14

hot flush;

flushing;

feeling cold;

feeling hot;

hyperhidrosis;

asthenia;

lethargy;

burning sensation;

injection site reaction;

fatigue;

malaise;

very rare

very rare

very rare

very rare

very rare

very rare

very rare

very rare

common

common

very rare

Investigations

hepatic enzyme increased;

blood glucose false positive (see 4.4)

very rare

very rare

Description of selected adverse reactions

For description of selected adverse events, 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.

Any suspected adverse events should be reported to the Ministry of Health according to the

National Regulation by using an online form

http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMed

ic@moh.gov.il

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: J06B A02

Human normal immunoglobulin contains mainly immunoglobulin G (IgG) with a broad

spectrum of antibodies against infectious agents.

12/14

Human

normal

immunoglobulin

contains

antibodies

present

normal

population.

prepared

from

pooled

material

from

fewer

than

1000

donations.

distribution of immunoglobulin G-subclasses closely proportional to that in native human

plasma.

Adequate

doses

this

medicinal

product

restore

abnormally

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.

Paediatric population

prospective

open-label

phase

study

performed

with

OCTAGAM

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.

severity

infections

assessed

mild.

severe

infections

leading

hospitalisation were observed.

5.2

Pharmacokinetic properties

Human

normal

immunoglobulin

immediately

completely

bioavailable

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

prospective

open-label

phase

study

performed

with

OCTAGAM

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 C

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.

13/14

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

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Maltose

Octoxynol

TNBP

Tri n-butyl phosphate

100 mg/ml

< 5 µg/ml

<1 µg/ml

Water for injections

ad 1ml

6.2

Incompatibilities

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

other medicinal products.

6.3

Shelf life

The expiry date of the product is indicated on the packaging materials

6.4

Special precautions for storage

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.

6.5

Nature and contents of container

Package size

Contents

Container

OCTAGAM 1 g

20 ml

30 ml infusion bottle

OCTAGAM 2.5 g

50 ml

70 ml infusion bottle

OCTAGAM 5 g

100 ml

100 ml infusion bottle

OCTAGAM 10 g

200 ml

250 ml infusion bottle

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.

14/14

6.6

Special precautions for disposal and other handling

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

Do not use solutions that are cloudy or have deposits.

possibility

bacterial

contamination,

remaining

contents

must

discarded.

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

requirements.

7

REGISTRATION HOLDER

Dover medical & Scientific Equipment Ltd.,

11 Hamaalot St.,

Herzliya 46583, Israel

8

REGISTRATION NUMBER

143 22 31778 00

9 MANUFACTURER

Octapharma Pharmazeutika Produktionsges.m.b.H.,

OBERLAAER ST. 235, A-1100 VIENNA,

Austria.