KIOVIG 100 MGML

Israel - English - Ministry of Health

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Active ingredient:
IMMUNOGLOBULIN NORMAL HUMAN
Available from:
TAKEDA ISRAEL LTD
ATC code:
J06BA02
Pharmaceutical form:
SOLUTION FOR INFUSION
Composition:
IMMUNOGLOBULIN NORMAL HUMAN 100 MG / 1 ML
Administration route:
I.V
Prescription type:
Required
Manufactured by:
BAXTER AG, AUSTRIA
Therapeutic group:
IMMUNOGLOBULINS, NORMAL HUMAN, FOR INTRAVASCULAR ADM.
Therapeutic area:
IMMUNOGLOBULINS, NORMAL HUMAN, FOR INTRAVASCULAR ADM.
Therapeutic indications:
IVIg can be used in all age ranges, unless otherwise specified below.Replacement therapy in:Primary immunodeficiency syndromes with impaired antibody production.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.Children and adolescents (age 0-18) with congenital AIDS and recurrent bacterial infections.Hypogammaglobulinaemia in patients after allogeneic haematopoietic stem cell transplantation (HSCT).ImmunomodulationPrimary immune thrombocytopenia (ITP), in patients at high risk of bleeding or prior to surgery to correct the platelet count.Guillain Barré syndrome.Kawasaki disease.
Authorization number:
146 45 33157 00
Authorization date:
2016-06-30

לע העדוה לע העדוה לע העדוה ( הרמחה ( הרמחה ( הרמחה

עדימ עדימ עדימ ןולעב )תוחיטב ןולעב )תוחיטב ןולעב )תוחיטב אפורל אפורל אפורל

יאמ ןכדועמ ,דבלב תורמחהה טורפל דעוימ הז ספוט

5102

ךיראת

2 Nov 2015

תילגנאב רישכת םש

Kiovig 100 mg/ ml Solution for Infusion

םושירה רפסמ

641-44-55643

םושירה לעב םש

Teva Medical Marketing Ltd

תורמחהה קובמה

ש

תו

ןולעב קרפ

יחכונ טסקט

שדח טסקט

Special

Warnings and

Special

Precautions for

Use

patients,

IVIg

administration requires:

adequate hydration prior

initiation

infusion of IVIg

monitoring

urine

output

monitoring

serum

creatinine levels

avoidance

concomitant use of loop

diuretics.

[…]

Thromboembolism

… Caution should be exercised

in prescribing and infusion of

IVIg in obese patients and in

patients with pre-existing risk

factors for thrombotic events

(such as a history of

atherosclerosis, multiple

cardiovascular risk factors,

advanced age, impaired cardiac

output, hypertension, diabetes

mellitus and a history of

vascular disease or thrombotic

episodes, patients with acquired

or inherited thrombophilic

disorders, hypercoagulable

disorders, patients with

prolonged periods of

immobilisation, severely

hypovolemic patients, patients

with diseases which increase

blood viscosity).

[…]

Acute renal failure

most

cases,

risk

factors

have

been

identified,

such

pre-existing renal insufficiency,

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

monitoring

signs

symptoms

thrombosis

assessment of blood vicosity in patients at

risk for hyperviscosity

avoidance

concomitant

loop

diuretics.

[…]

Thromboembolism

… Caution should be exercised in prescribing and

infusion of IVIg in obese patients and in patients

with pre-existing risk factors for thrombotic

events (such as a history of atherosclerosis,

multiple cardiovascular risk factors, advanced

age, impaired cardiac output, hypertension, use of

estrogens, diabetes mellitus and a history of

vascular disease or thrombotic episodes, patients

with acquired or inherited thrombophilic

disorders, hypercoagulable disorders, patients

with prolonged periods of immobilisation,

severely hypovolemic patients, patients with

diseases which increase blood viscosity, patients

with indwelling vascular catheters

and patients with high dose and rapid infusion).

[…]

Acute renal failure

... In most cases, risk factors have been identified,

such as pre-existing renal insufficiency, diabetes

mellitus, hypovolemia, overweight, concomitant

nephrotoxic

medicinal

products,

over 65,

sepsis, hyperviscosity or paraproteinemia.

[…]

Interference with serological testing

[…]

diabetes mellitus, hypovolemia,

overweight,

concomitant

nephrotoxic medicinal products,

over 65,

sepsis,

paraproteinemia.

Administration

KIOVIG

lead

false

positive

readings

assays

that

depend

detection

beta-D-glucans

diagnosis

fungal

infections.

This

persist

during

weeks following infusion of the product

Adverse events

Hypertension – Common

Dyspnea – Uncommon

Rash – Common

Pruritus, urticaria, erythematous

rash, pruritic rash – Common

infusion

related

reaction

Uncommon

Decreased appetite

Common

Hypertension - Very common

Dyspnea

Common

Dyspepsia

Common

Abdominal distension – Uncommon

Rash - Very common

Contusion

dermatitis

erythema

Common

Arthralgia

Common

Local reactions (e.g. infusion site

pain/swelling/reaction/pruritus

– Very common

Chills, edema

common

burning sensation – Uncommon

white blood cell count decreased, alanine

aminotransferase increased – Uncommon

cerebral vascular accident

- Not known

Kiovig_IL_ Jan2021

SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

KIOVIG 100 mg/ml

solution for infusion

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Human normal immunoglobulin (IVIg)

One ml contains:

Human normal immunoglobulin (IVIg)……………...100 mg*

*corresponding to human protein content, of which at least 98% is IgG

Each vial of 10 ml contains: 1 g of human normal immunoglobulin

Each vial of 25 ml contains: 2.5 g of human normal immunoglobulin

Each vial of 50 ml contains: 5 g of human normal immunoglobulin

Each vial of 100 ml contains: 10 g of human normal immunoglobulin

Each vial of 200 ml contains: 20 g of human normal immunoglobulin

Each vial of 300 ml contains: 30 g of human normal immunoglobulin

Distribution of IgG subclasses (approx. values):

IgG1

56.9%

IgG2

26.6%

IgG3

3.4%

IgG4

1.7%

The maximum IgA content is 140 micrograms/ml

Produced from the plasma of human donors.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Solution for infusion

The solution is clear or slightly opalescent and colourless or pale yellow.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

IVIg can be used in all age ranges, unless otherwise specified below.

Replacement therapy in:

Primary

immunodeficiency

syndromes

with

impaired

antibody production

(see

section 4.4).

Hypogammaglobulinaemia

recurrent

bacterial

infections

patients

with

chronic

lymphocytic leukaemia, in whom prophylactic antibiotics have failed.

Kiovig_IL_ Jan2021

Hypogammaglobulinaemia

recurrent

bacterial infections in plateau phase multiple

myeloma patients who have failed to respond to pneumococcal immunisation.

Hypogammaglobulinaemia

patients

after

allogeneic

haematopoietic

stem

cell

transplantation (HSCT).

Children

adolescents

(age

0-18)

with

congenital

AIDS

recurrent

bacterial

infections.

Immunomodulation:

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.

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 is dependent on the indication.

In replacement therapy the dose may need to be individualised for each patient dependent on

the pharmacokinetic and clinical response. The following dose 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 to 6 g/L. 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 given 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 dose 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 infection, it may be necessary to increase the dose

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

to pneumococcal immunisation; children and adolescents with congenital AIDS and 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 5 g/L.

Primary immune thrombocytopenia

There are two alternative treatment schedules:

0.8-1 g/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.

Kiovig_IL_ Jan2021

treatment

repeated

relapse occurs.

Guillain-Barré syndrome

0.4 g/kg/day over 5 days.

Kawasaki Disease

1.6-2 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.

The dose recommendations are summarised in the following table:

Indication

Dose

Frequency of injections

Replacement

therapy

primary

immunodeficiency

Replacement

therapy

secondary

immunodeficiency

Children and adolescents with AIDS

Hypogammaglobulinaemia (< 4 g/L) in

patients after allogeneic haematopoietic

stem cell transplantation

- 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

0.2 – 0.4 g/kg

every 3 – 4 weeks to obtain IgG

trough level of at least 5 – 6 g/l

every 3 – 4 weeks to obtain IgG

trough level of at least 5 – 6 g/L

every 3 – 4 weeks

every 3 – 4 weeks to obtain IgG

trough level above 5g/L

Immunomodulation:

Primary immune thrombocytopenia

Guillain-Barré syndrome

Kawasaki disease

0.8 – 1 g/kg

0.4 g/kg/d

0.4 g/kg/d

1.6 – 2 g/kg

2 g/kg

on day 1, possibly repeated once

within 3 days

for 2 – 5 days

for 5 days

in divided doses for 2 – 5 days in

association with acetylsalicylic acid

dose

association

with

acetylsalicylic acid

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.

Method of administration

For intravenous use.

Human normal immunoglobulin should be infused intravenously at an initial rate of 0.5 ml/kg

BW/hr for 30 minutes. If well tolerated

(see section 4.4), the rate of administration may

gradually be increased to a maximum of 6 ml/kg BW/hr. Clinical data obtained from a limited

number of patients also indicate that adult PID patients may tolerate an infusion rate of up to

8 ml/kg BW/hr. For further precautions for use see section 4.4.

Kiovig_IL_ Jan2021

dilution

prior

infusion

required, KIOVIG

diluted

with

glucose

solution to a final concentration of 50 mg/ml (5% immunoglobulin). For instructions on

dilution of the medicinal product before administration, see section 6.6.

Any infusion-related adverse events should be treated by lowering infusion rates or by

stopping the infusion.

4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Hypersensitivity to human immunoglobulins, especially in patients with antibodies against

IgA.

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

Infusion reaction

Certain

severe

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.

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

in patients with an untreated infection or underlying chronic inflammation.

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 (0.5 ml/kg BW/hr);

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 at the hospital 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

monitoring for signs and symptoms of thrombosis

assessment of blood viscosity in patients at risk for hyperviscosity

avoidance of concomitant use of loop diuretics

(see section 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.

If dilution of KIOVIG to lower concentrations is required for patients suffering from diabetes

mellitus, the use of 5% glucose solution for dilution may have to be reconsidered.

Hypersensitivity

Kiovig_IL_ Jan2021

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 infusion of IVIg in obese patients and in patients with

pre-existing risk factors for thrombotic events (such as a history of atherosclerosis, multiple

cardiovascular risk factors, advanced age, impaired cardiac output, hypertension, use of

estrogens, diabetes mellitus and a history of vascular disease or thrombotic episodes, patients

with acquired or inherited thrombophilic disorders, hypercoagulable disorders, patients with

prolonged periods of immobilisation, severely hypovolaemic patients, patients with diseases

which increase blood viscosity, patients with indwelling vascular catheters and patients with

high dose and rapid infusion).

Hyperproteinemia, increased serum viscosity and subsequent relative pseudohyponatremia

occur

patients

receiving

IVIg

therapy.

This

should

taken

into

account

physicians, since initiation of treatment for true hyponatremia (i.e. decreasing serum free

water) in these patients may lead to a further increase in serum viscosity and a possible

predisposition to thromboembolic events.

patients

risk

thromboembolic

adverse

reactions,

IVIg

products

should

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. These

include acute renal failure, acute tubular necrosis, proximal tubular nephropathy and osmotic

nephrosis.

most

cases,

risk

factors

have

been

identified,

such

pre-existing

renal

insufficiency,

diabetes

mellitus,

hypovolaemia,

overweight,

concomitant

nephrotoxic

medicinal products, age over 65, sepsis, hyperviscosity or paraproteinemia.

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 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. KIOVIG does not contain sucrose, maltose or glucose.

Transfusion Related Acute Lung Injury (TRALI)

In patients receiving IVIg (including KIOVIG), there have been reports of non-cardiogenic

pulmonary edema (Transfusion Related Acute Lung Injury, (TRALI)) .

Kiovig_IL_ Jan2021

TRALI is characterised by severe hypoxia, dyspnoea,

tachypnoea,

cyanosis,

fever

hypotension.

Symptoms

TRALI

typically

develop

during

within

hours

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 lifethreatening condition requiring immediate intensive-care-unit management.

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 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.

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.

From post-marketing data with KIOVIG no clear correlation of AMS to higher doses was

observed. Higher incidences of AMS were seen in women.

Haemolytic anaemia

IVIg products can contain blood group antibodies that 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 IVIgs. This typically occurs within hours or days after

IVIg administration and resolves spontaneously within 7 to 14 days.

Interference with serological testing

After infusion 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).

Administration of KIOVIG can lead to false positive readings in assays that depend on

detection of beta-D-glucans for diagnosis of fungal infections. This may persist during the

weeks following infusion of the product.

Transmissible agents

KIOVIG is made from human plasma. 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

plasma

Kiovig_IL_ Jan2021

administered, the possibility of transmitting infectious 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, and for the non-enveloped viruses HAV and parvovirus B19.

There is 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.

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.

Paediatric population

There are no paediatric specific risks with regard to any of the above adverse events.

Paediatric patients may be more susceptible to volume overload (see section 4.9).

4.5

Interactions with other medicinal products and other forms of interactions

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.

Dilution of KIOVIG with a 5% glucose solution may result in increased blood glucose levels.

Loop diuretics

Avoidance of concomitant use of loop diuretics.

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 it should only be given with caution to pregnant women

breast-feeding

mothers.

IVIg

products

have

been

shown

cross

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. No negative effects on the breastfed

newborn/infants are anticipated.

Fertility

Kiovig_IL_ Jan2021

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 KIOVIG. 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 such as chills, headache, dizziness, fever, vomiting, allergic reactions,

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

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

(including cutaneous lupus erythematosus - frequency unknown) 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, and deep vein thromboses.

Cases of Transfusion Related Acute Lung Injury (TRALI).

Tabulated list of adverse reactions

The tables presented below are according to the MedDRA system organ classification (SOC

and Preferred Term Level). Table 1 shows the adverse reactions from clinical trials and

Table 2 shows the post-marketing ARs.

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 available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing

seriousness.

Table 1

Frequency of Adverse Reactions (ADRs) in clinical studies with KIOVIG

MedDRA

System Organ Class

(SOC)

Adverse reaction

Frequency

Infections

infestations

Bronchitis, nasopharyngitis

Common

Chronic

sinusitis,

fungal

infection,

infection,

kidney infection, sinusitis, upper respiratory tract

infection,

urinary

tract

infection,

bacterial

urinary tract infection, meningitis aseptic

Uncommon

Blood

lymphatic

system disorders

Anaemia, lymphadenopathy

Common

Kiovig_IL_ Jan2021

Table 1

Frequency of Adverse Reactions (ADRs) in clinical studies with KIOVIG

MedDRA

System Organ Class

(SOC)

Adverse reaction

Frequency

Immune

system

disorders

Hypersensitivity, anaphylactic reaction

Uncommon

Endocrine disorders

Thyroid disorder

Uncommon

Metabolism

nutrition disorders

Decreased appetite

Common

Psychiatric disorders

Insomnia, anxiety

Common

Irritability

Uncommon

Nervous

system

disorders

Headache

Very common

Dizziness, migraine, paresthesia, hypoesthesia

Common

Amnesia,

dysarthria,

dysgeusia,

balance

disorder, tremor

Uncommon

Eye disorders

Conjunctivitis

Common

Eye pain, eye swelling

Uncommon

Ear and labyrinth

disorders

Vertigo, fluid in middle ear

Uncommon

Cardiac disorders

Tachycardia

Common

Vascular disorders

Hypertension

Very common

Flushing

Common

Peripheral coldness, phlebitis

Uncommon

Respiratory, thoracic

and mediastinal

disorders

Cough, rhinorrhoea, asthma, nasal congestion,

oropharyngeal pain, dyspnea

Common

Oropharyngeal swelling

Uncommon

Gastrointestinal

disorders

Nausea

Very common

Diarrhoea, vomiting, abdominal pain, dyspepsia

Common

Abdominal distension

Uncommon

Skin and subcutaneous

tissue disorders

Rash

Very common

Contusion,

pruritus,

urticaria,

dermatitis,

erythema

Common

Angioedema,

acute

urticaria,

cold

sweat,

photosensitivity

reaction,

night

sweats,

hyperhidrosis

Uncommon

Musculoskeletal and

connective tissue

disorders

Back pain, arthralgia, pain in extremity, myalgia,

muscle spasms, muscular weakness

Common

Muscle twitching

Uncommon

Renal and urinary

disorders

Proteinuria

Uncommon

General disorders and

administration site

Local

reactions

(e.g.

infusion

site

pain/swelling/reaction/pruritus), pyrexia, fatigue

Very common

Kiovig_IL_ Jan2021

Table 1

Frequency of Adverse Reactions (ADRs) in clinical studies with KIOVIG

MedDRA

System Organ Class

(SOC)

Adverse reaction

Frequency

Chills,

edema,

influenza-like

illness,

chest

discomfort, chest pain, asthenia, malaise, rigors

Common

Chest tightness, feeling hot, burning sensation,

swelling

Uncommon

Investigations

Blood

cholesterol

increased,

blood

creatinine

increased, blood urea increased, white blood cell

count decreased,

alanine

aminotransferase

increased, haematocrit decreased, red blood cell

count decreased, respiratory rate increased

Uncommon

Kiovig_IL_ Jan2021

Table 2

Post-Marketing Adverse Reactions (ARs)

MedDRA

System Organ Class

(SOC)

Adverse reaction

Frequency

Blood and lymphatic

system disorders

Haemolysis

Not known

Immune system

disorders

Anaphylactic shock

Not known

Nervous system

disorders

Transient ischemic attack, cerebral vascular

accident

Not known

Cardiac disorders

Myocardial infarction

Not known

Vascular disorders

Hypotension, deep vein thrombosis

Not known

Respiratory, thoracic

and mediastinal

disorders

Pulmonary embolism, pulmonary edema

Not known

Investigations

Coombs

direct

test

positive,

oxygen

saturation decreased

Not known

Injury, poisoning and

procedural

complications

Transfusion-related acute lung injury

Not known

Description of selected adverse reactions

Muscle

twitching

weakness

were

reported

only

in patients

with

Multifocal

Motor

Neuropathy (MMN).

Paediatric population

Frequency, type and severity of adverse reactions in children are the same as in adults.

Reporting of suspected adverse reactions

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

National Regulation by using an online form https://sideeffects.health.gov.il/

For safety with respect to transmissible agents, see section 4.4.

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 ).

Paediatric population

Smaller children below the age of 5 years may be particularly susceptible to volume overload.

Therefore, dosing should be carefully calculated for this population. In addition, children

with Kawasaki Disease are at especially high risk due to underlying cardiac compromise so

dose and rate of administration should be carefully controlled.

Kiovig_IL_ Jan2021

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

restore

abnormally

immunoglobulin G levels to the normal range.

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

but includes immunomodulatory effects.

Paediatric population

There are no theoretical or observed differences in the action of immunoglobulins in children

compared to adults.

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 to 5 days equilibrium is reached between the

intra- and extravascular compartments.

Pharmacokinetic parameters for KIOVIG were determined in the two clinical studies in PID

patients performed in Europe and the US. In these studies, a total of 83 subjects at least

2 years of age were treated with doses of 300 to 600 mg/kg body weight every 21 to 28 days

for 6 to 12 months. The median IgG half-life after administration of KIOVIG was 32.5 days.

This half-life may vary from patient to patient, in particular in primary immunodeficiency.

Pharmacokinetic

parameters

product

summarized

table

below.

parameters were analysed separately for three age groups, children (below 12 years, n=5),

adolescents (13 to 17 years, n=10), and adults (above 18 years of age, n=64). The values

obtained

studies

comparable

parameters

reported

other

human

immunoglobulins.

Summary of KIOVIG pharmacokinetic parameters

Parameter

Children

(12 years or below)

Adolescents

(13 to 17 years)

Adults

(18 years or above)

Median

95% CI*

Median

95% CI

Median

95% CI

Terminal half-life (days)

41.3

20.2 to 86.8

45.1

27.3 to 89.3

31.9

29.6 to 36.1

(mg/dl)/(mg/kg)

(trough level)

2.28

1.72 to 2.74

2.25

1.98 to 2.64

2.24

1.92 to 2.43

(mg/dl)/(mg/kg)

(peak level)

4.44

3.30 to 4.90

4.43

3.78 to 5.16

4.50

3.99 to 4.78

In-vivo

recovery (%)

87 to 137

75 to 121

96 to 114

Incremental

recovery

(mg/dl)/(mg/kg)

2.26

1.70 to 2.60

2.09

1.78 to 2.65

2.17

1.99 to 2.44

0-21d

(g·h/dl)

(area

under the curve)

1.49

1.34 to 1.81

1.67

1.45 to 2.19

1.62

1.50 to 1.78

*CI – Confidence Interval

Kiovig_IL_ Jan2021

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

5.3

Preclinical safety data

Immunoglobulins are normal constituents of the human body.

The safety of KIOVIG has been demonstrated in several non-clinical studies. Non-clinical

data reveal no special risk for humans based on conventional studies of safety pharmacology

and toxicity.

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

evidence

carcinogenic

potential

immunoglobulins, no experimental studies in heterogeneous species were performed.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Glycine

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

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

If dilution to lower concentrations is required, immediate use after dilution is recommended.

in-use

stability

KIOVIG

after

dilution

with

glucose

solution

final

concentration of 50 mg/ml (5%) immunoglobulin has been demonstrated for 21 days at 2°C to

8°C

well

28°C

30°C;

however,

these

studies

include

microbial

contamination and safety aspect.

6.4

Special precautions for storage

Store at room temperature, not more than 25°C.

Do not freeze.

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

For storage conditions after dilution of the medicinal product, see section 6.3.

6.5

Nature and contents of container

10, 25, 50, 100, 200 or 300 ml of solution in a vial (Type I glass) with a stopper (bromobutyl).

Pack size: 1 vial.

Not all presentations may be marketed.

6.6

Special precautions for disposal and other handling

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

Kiovig_IL_ Jan2021

If dilution is required, 5% glucose solution is recommended. For obtaining an immunoglobulin

solution of 50 mg/ml (5%), KIOVIG 100 mg/ml (10%) should be diluted with an equal volume

glucose

solution.

recommended

that

during

dilution

risk

microbial

contamination is minimised.

The product should be inspected visually for particulate matter and discolouration prior to

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

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

KIOVIG should only be administered intravenously. Other routes of administration have not

been evaluated.

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

local requirements.

7.

REGISTRATION NUMBER

146.45.33157.00

8.

MANUFACTURER

Baxter AG

Industriestrasse 67

A-1221 Vienna, Austria

9.

LICENSE HOLDER

Takeda Israel Ltd.,

25 Efal st., Petach Tikva 4951125

The leaflet was revised in Jan 2021.

Takeda Israel Ltd.

Efal st., P.O.B 4140, Petach-Tikva 4951125

Tel:+972-3-3733140 Fax (local) : + 972-3-3733150

ראוני

2021

אפור

/

ה

,

חקור

/

ת

דבכנ

/

ה

,

ןודנה

:

mL

mg/

100

Kiovig

אפורל ןולע ןוכדע

הדקט תרבח

שי עב לאר מ"

תשקבמ

עידוהל

ב ןוכדע לע ולע

אפורל לש

רישכתה

ןודנבש

רישכתה םושר

תהל לארשיב

האבה היוו

IVIg can be used in all age ranges, unless otherwise specified below.

Replacement therapy in:

Primary immunodeficiency syndromes with impaired antibody production.

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 whohave failed to respond to pneumococcal immunisation.

Children and adolescents (age 0-18) with congenital AIDS and recurrent bacterial infections.

Hypogammaglobulinaemia in patients after allogeneic haematopoietic stem cell

transplantation (HSCT).

Immunomodulation

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.

ביכרמ

ליעפ

Immunoglobulin Normal Human

יטרפ ןוכדעה

םיירקיעה

םניה

טסקט

ש

טמשוה

ןמוסמ

ב

םודא

,

טסקט

ש

ףסונ

ןמוסמ

טסקטכ

לוחכ

הווהמה טסקט

הרמחה

שגדומ

בוהצב

(

4.3

Contraindications

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

Infusion reaction

Certain

severe

adverse reactions

(e.g. headache, flushing, chills, myalgia, wheezing,

tachycardia, lower back pain, nausea, and hypotension)

may be related to the rate of

infusion.

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

in patients with an untreated infection or underlying chronic inflammation.

Precautions for use

Potential complications can often be avoided by ensuring that patients:

Takeda Israel Ltd.

Efal st., P.O.B 4140, Petach-Tikva 4951125

Tel:+972-3-3733140 Fax (local) : + 972-3-3733150

are not sensitive to human normal immunoglobulin by initially injecting the product

slowly (

0.5

0.01 ml/kg BW/minhr);

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

at the hospital

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.

Hypersensitivity

True h

H

ypersensitivity 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

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

patients

tolerated

previous

treatment

with

human

normal

immunoglobulin.

Acute renal failure

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.

Transfusion Related Acute Lung Injury (TRALI)

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 lifethreatening condition requiring immediate intensive-care-unit

management.

Aseptic meningitis syndrome (AMS)

Patients exhibiting such signs and symptoms should receive a thorough neurological

examination, including CSF studies, to rule out other causes of meningitis.

Takeda Israel Ltd.

Efal st., P.O.B 4140, Petach-Tikva 4951125

Tel:+972-3-3733140 Fax (local) : + 972-3-3733150

Neutropenia/Leukopenia

A transient decrease in neutrophil count and/or episodes of neutropenia, sometimes

severe, have been reported after treatment with IVIgs. This typically occurs within

hours or days after IVIg administration and resolves spontaneously within 7 to 14 days.

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.

It is strongly recommended that every time that KIOVIG 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.

4.5

Interactions with other medicinal products and other forms of interactions

Loop diuretics

Avoidance of concomitant use of loop diuretics.

4.6

Fertility, pregnancy and lactation

Breast-feeding

Immunoglobulins are excreted into the milk and may contribute to protecting the neonate

from pathogens which have a mucosal portal of entry.

No negative effects on the breastfed

newborn/infants are anticipated.

4.8

Undesirable effects

Summary of the safety profile

Adverse reactions such as chills, headache,

dizziness,

fever, vomiting, allergic reactions,

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

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

(including cutaneous lupus erythematosus - frequency unknown)

have been observed

with human normal immunoglobulin.

Cases of Transfusion Related Acute Lung Injury (TRALI).

Takeda Israel Ltd.

Efal st., P.O.B 4140, Petach-Tikva 4951125

Tel:+972-3-3733140 Fax (local) : + 972-3-3733150

לעה

כדועמה

חלשנ

.תואירבה דרשמ רתאבש תופורתה רגאמב םוסרפל

ומכ

ןכ

ןתינ

לבקל

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תועצמאב

היינפ

לעבל

םושירה

הדקט

לארשי

עב

"

חר

לעפא

חתפ

הווקת

לט

03‐3733140

הכרבב

ירס יל

תחקור

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הדקט

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