VENOFER

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

עדימ עדימ עדימ ל ןולעב )תוחיטב ל ןולעב )תוחיטב ל ןולעב )תוחיטב אפור אפור אפור

ןכדועמ( ןכדועמ( ןכדועמ(

.202.20

.202.20

.202.20

רשוא

–

11.11

_____________ ךיראת

1111111/11

__________

םושירה רפסמו תילגנאב רישכת םש

:

Venofer- 1003628277

םושירה לעב םש

________

טצכ

מ"עב

__________________

ה טורפל דעוימ הז ספוט לב תורמחה דב

תושקובמה תורמחהה

ןולעב קרפ

יחכונ טסקט

שדח טסקט

Posology and

administration

route

Monitor carefully patients for signs

symptoms

hypersensitivity

reactions during and following each

administration of Venofer.

Venofer

should

only

administered when staff trained to

evaluate and manage anaphylactic

reactions is immediately available,

environment

where

full

resuscitation

facilities

assured.

patient

should

observed for adverse effects for at

least

minutes

following

each

Venofer administration (see section

4.4).

Contraindication

Known

hypersensitivity

active

ingredient

any of the excipients

according

composition

Anaemia

caused

iron

deficiency

(e.g.

haemolytic anaemia,

megaloblastic

anaemia caused by

Vitamin

deficiency,

disturbances

erythropoesis,

hypoplasia

bone

marrow)

The use of Venofer is contraindicated in the

following conditions:

Hypersensitivity to the active

substance, to Venofer or any of its

excipients listed in section

"Excipients”

Known serious hypersensitivity to

other parenteral iron products

Evidence of iron overload or

hereditary disturbances in

utilisation of iron.

Iron

overload

(e.g.

haemochromatosis,

haemosiderosis)

Disturbances

utilisation

iron

(sidero-achrestic

anaemia,

thalassaemia,

lead

anaemia,

Porphyria

cutanea tarda)

First trimester of

pregnancy.

Special Warnings

and Precautions

for use

case

intravenous

injection being administered

quickly,

hypotonic

episodes

occur.

Paravenous leakage should

be avoided. If it does occur,

proceed

follows:

needle is still inserted, rinse

with

small

amount

sterile

0.9%

(m/V)

NaCl

solution. Cautiously apply a

heparin gel or ointment to

injection

site

massage

in!)

order

accelerate

elimination

and to avoid spreading of

the iron.

Potentially

fatal

hypersensitivity

reactions

with

circulatory

collapse,

loss of consciousness, drop

blood

pressure,

dyspnoea or

seizure

have

been reported with Venofer

treatment

rare

cases.

Hypersensitivity

reactions

with

fatal

outcome

have

been

reported

literature

during

treatment

with

iron

carbohydrate

complexes. For this reason

the infusion should only be

administrated at institutions

which have the facilities for

cardiopulmonary

resuscitation.

A drop in blood pressure is

commonly

observed

association

with

intravenous

administration

iron.

Therefore,

infusion

should

administered with caution.

Special care must be taken

administration

Venofer

patients

Parenterally

administered

iron

preparations can cause hypersensitivity

reactions

including

serious

potentially

fatal

anaphylactic/anaphylactoid

reactions.

Hypersensitivity

reactions

have

also

been

reported

after

previously

uneventful

doses

parenteral

iron

complexes

including

iron

sucrose.

However, in several studies performed

patients

history

hypersensitivity reaction to iron dextran

or ferric gluconate, Venofer was shown

to be well tolerated. For known serious

hypersensitivity to other parenteral iron

product see section 4.3.

The risk of hypersensitivity reactions is

enhanced

patients

with

known

allergies

including

drug

allergies,

including

patients

with

history

severe asthma, eczema or other atopic

allergy.

There

also

increased

risk

hypersensitivity reactions to parenteral

iron complexes in patients with immune

inflammatory

conditions

(e.g.

systemic

lupus

erythematosus,

rheumatoid arthritis).

Venofer

should only

be administered

when

staff

trained

evaluate

manage

anaphylactic

reactions

immediately

available,

environment

where

full

resuscitation

facilities can be assured. Each patient

should be observed for adverse effects

for at least 30 minutes following each

Venofer

injection.

hypersensitivity

reactions or signs of intolerance occur

during

administration,

treatment

must be stopped immediately. Facilities

for cardio respiratory resuscitation and

equipment

handling

acute

anaphylactic/anaphylactoid

reactions

should

available,

including

injectable

1:1000

adrenaline

solution.

Additional treatment with antihistamines

suffering

from

allergies,

asthma,

hepatic

impairment,

Osler-Rendu-

Weber

syndrome,

acute

exacerbation of rheumatoid

arthritis,

infectious

kidney

disorders

acute

phase,

uncontrolled

hyperparathyroidism,

decompensated cirrhosis of

the liver, epidemic hepatitis.

onset

undesirable

effects

patients

with

cardiovascular

disorders

intensify

associated

cardiovascular

complications.

Venofer

must

administered with caution in

patients

(adults

children)

with

sharply

elevated ferritin level due to

acute

chronic

infection,

since

parenteral

iron

have

unfavourable effect on the

course of a bacterial or viral

infection.

and/or corticosteroids should be given

as appropriate.

patients

with

liver

dysfunction,

parenteral

iron

should

only

administered

after

careful

risk/benefit

assessment.

Parenteral

iron

administration

should

avoided

patients with hepatic dysfunction where

iron overload is a precipitating factor, in

particular

Porphyria

Cutanea

Tarda

(PCT). Careful monitoring of iron status

is recommended to avoid iron overload.

Parenteral

iron

should

used

with

caution in the case of acute or chronic

infection. It is recommended that the

administration of Venofer is stopped in

patients with bacteraemia. In patients

with

chronic

infection,

risk/benefit

evaluation should be performed.

Paravenous leakage must be avoided

because

leakage

Venofer

injection

site

lead

pain,

inflammation,

tissue

necrosis

brown discoloration of the skin.

Fertility,

pregnancy and

Lactation

Caution

needed

when

administered

during

pregnancy.

Venofer

contraindicated

during

trimester of pregnancy (see

"Contraindications")

should only be used during

and 3

trimesters if the

indication is compelling.

Animal studies have shown

no direct or indirect toxicity

with an effect on pregnancy,

embryonic

development,

development

foetus

postnatal

development.

Data of a limited number of

exposed

pregnant

women

show no undesirable effects

on pregnancy or the health

foetus

neonate.

There is no experience from

epidemiological studies.

It is not yet known whether

iron

(III)

hydroxide

sucrose complex present in

Venofer

crosses

placenta, although minimal

passage

been

Pregnancy

There is no data from the use of iron

sucrose in pregnant women in the first

trimester.

Data

(303

pregnancy

outcomes) from the use of Venofer in

pregnant

women

second

third

trimester

showed

safety

concerns for the mother or newborn.

careful

risk/benefit

evaluation

required before use during pregnancy

and Venofer should not be used during

pregnancy

unless

clearly

necessary

(see section 4.4).

Iron deficiency anaemia occurring in the

first trimester of pregnancy can in many

cases

treated

with

oral

iron.

Treatment

with

Venofer

should

confined to second and third trimester if

the benefit is judged to outweigh the

potential risk for both the mother and

the fetus.

Animal studies do not indicate direct or

indirect harmful effects with respect to

reproductive toxicity (see section 5.3).

Breast-feeding

There

limited

information

excretion

iron

human

milk

following administration of intravenous

iron sucrose. In one clinical study, 10

demonstrated

iron

dextran.

However,

iron

bound

form

transferring does cross the

placental

barrier

and,

bound

lactofferin,

passed into breast milk.

clinical

study

shown that the intravenous

administration

iron is in form of Venofer

does not increase the iron

content

breast

milk.

Therefore,

Venofer

treatment

unlikely

represent

risk

breast-fed child.

healthy

breast-feeding

mothers

with

iron deficiency received 100 mg iron in

the form

iron

sucrose.

Four

days

after treatment, the iron content of the

breast milk had not increased and there

difference

from

control

group (n=5). It cannot be excluded that

newborns/infants may be exposed to

iron

derived

from

Venofer

mother's milk, therefore the risk/benefit

should be assessed.

Preclinical data do not indicate direct or

indirect harmful effects to the nursing

child. In lactating rats treated with

labelled iron sucrose, low secretion of

iron into the milk and transfer of iron

into the offspring was observed. Non

metabolised iron sucrose is unlikely to

pass into the mother's milk.

Fertility

effects

iron

sucrose

treatment

were observed on fertility and mating

performance in rates.

Undesirable

Effects

Immune system disorders

Hypersensitivity

Nervous system disorders

hypoaesthesia, somnolence,

anxiety, tremor

Vascular disorders

Flushing

Phlebitis

thrombophlebitis

Gastrointestinal disorders

constipation

Skin and subcutaneous tissue disorders

Urticaria, erythema

Musculoskeletal and connective tissue

disorders

arthralgia, pain in extremity

General disorders and administration site

conditions

Injection/infusion site reaction, Chills, pain

Investigations

alanine aminotransferase increased, aspartate

aminotransferase increased, Gamma-

glutamyltransferase increased, Serum ferritin

increased, blood lactate dehydrogenase

increased

ב"צמ נמוסמ ובש ,ןולעה תו

תורמחהה שקובמה תו והצ עקר לע

ב

ונמוס תורמחה רדגב םניאש םייוניש )ןולעב(

םוקימב םייוניש אלו יתוהמ ןכות קר ןמסל שי .הנוש עבצב .טסקטה

..........ךיראתב ינורטקלא ראודב רבעוה

1118811/82

......

The content of this leaflet was approved by the Ministry of Health in November 2016 and updated

according to the guidelines of the Ministry of Health in December 2019.

Summary of product characteristics

1.

Name of the medicinal product:

Venofer, solution for injection

2.

Qualitative and quantitative composition

One millilitre of solution contains 20 mg of iron as iron sucrose (iron(III)-hydroxide sucrose

complex).

Each 5 ml ampoule of Venofer contains 100 mg iron as iron sucrose (iron(III)-hydroxide

sucrose complex).

For the full list of excipients, see section 6.1.

3.

Pharmaceutical form

Solution for injection

Venofer is a dark brown, non-transparent, aqueous solution.

4.

Clinical particulars

4.1 Therapeutic indications

Venofer is indicated for the treatment of iron deficiency in the following indications:

Where there is a clinical need for a rapid iron supply,

In patients who cannot tolerate oral iron therapy or who are non-compliant,

In active inflammatory bowel disease where oral iron preparations are ineffective,

In chronic kidney disease when oral iron preparations are less effective.

The diagnosis of iron deficiency must be based on appropriate laboratory tests (e.g. Hb,

serum ferritin, TSAT, serum iron, etc.).

(Hb haemoglobin, TSAT transferrin saturation)

4.2 Posology and method of administration:

Monitor carefully patients for signs and symptoms of hypersensitivity reactions during and

following each administration of Venofer.

Venofer should only be administered when staff trained to evaluate and manage anaphylactic

reactions is immediately available, in an environment where full resuscitation facilities can be

assured. The patient should be observed for adverse effects for at least 30 minutes following

each Venofer administration (see section 4.4).

Posology

The cumulative dose of Venofer must be calculated for each patient individually and must not

be exceeded.

Calculation of dosage:

The total cumulative dose of Venofer, equivalent to the total iron deficit (mg), is determined

by the haemoglobin level (Hb) and body weight (BW). The dose of Venofer must be

individually calculated for each patient according to the total iron deficit calculated with the

following Ganzoni formula, for example:

Total iron deficit [mg] = BW [kg] x (target Hb - actual Hb) [g/dl] x 2.4* + storage iron

[mg]

Below 35 kg BW: Target Hb = 13 g/dl and storage iron = 15 mg/kg BW

35 kg BW and above: Target Hb = 15 g/dl and storage iron = 500 mg

* Factor 2.4 = 0.0034 (iron content of Hb = 0.34%) x 0.07 (blood volume = 7% of BW) x 1000

(conversion of [g] to [mg]) x 10

Total amount of Venofer (ml) to be administered according to body weight, actual Hb level

and target Hb level*:

Total amount of Venofer (20mg iron per ml) to be

administered:

Hb 6.0 g/dl

Hb 7.5 g/dl

Hb 9.0 g/dl

Hb 10.5 g/dl

30 kg

47.5 ml

42.5 ml

37.5 ml

32.5 ml

35 kg

62.5 ml

57.5 ml

50 ml

45 ml

40 kg

67.5 ml

60 ml

55 ml

47.5 ml

45 kg

75 ml

65 ml

57.5 ml

50 ml

50 kg

80 ml

70 ml

60 ml

52.5 ml

55 kg

85 ml

75 ml

65 ml

55 ml

60 kg

90 ml

80 ml

67.5 ml

57.5 ml

65 kg

95 ml

82.5 ml

72.5 ml

60 ml

70 kg

100 ml

87.5 ml

75 ml

62.5 ml

75 kg

105 ml

92.5 ml

80 ml

65 ml

80 kg

112.5 ml

97.5 ml

82.5 ml

67.5 ml

85 kg

117.5 ml

102.5 ml

85 ml

70 ml

90 kg

122.5 ml

107.5 ml

90 ml

72.5 ml

* Below 35 kg BW:

Target Hb = 13 g/dl

35 kg BW and above:

Target Hb = 15 g/dl

To convert Hb (mM) to Hb (g/dl), multiply the former by 1.6.

If the total necessary dose exceeds the maximum allowed single dose, then the

administration must be divided.

Posology

Adults

5-10 ml of of Venofer (100 – 200 mg iron) 1 to 3 times a week. For administration time and

dilution ration see “Method of administration”

Paediatric population

The use of Venofer has not been adequately studied in children and, therefore, Venofer is not

recommended for use in children.

Method of administration

Venofer must only be administered by the intravenous route. This may be by a slow

intravenous injection, by an intravenous drip infusion or directly into the venous line of the

dialysis machine.

Intravenous drip infusion

Venofer must only be diluted in sterile 0.9% m/V sodium chloride (NaCl) solution. Dilution

must take place immediately prior to infusion and the solution should be administered as

follows:

Venofer dose

(mg of iron)

Venofer dose

(ml of Venofer)

Maximum dilution volume

of sterile 0.9% m/V NaCl

solution

Minimum Infusion Time

50 mg

2.5 ml

50 ml

8 minutes

100 mg

5 ml

100 ml

15 minutes

200 mg

10 ml

200 ml

30 minutes

For stability reasons, dilutions to lower Venofer concentrations are not permissible.

Intravenous injection

Venofer may be administered by slow intravenous injection at a rate of 1 ml undiluted

solution per minute and not exceeding 10 ml Venofer (200 mg iron) per injection.

Injection into venous line of dialysis machine

Venofer may be administered during a haemodialysis session directly into the venous line of

the dialysis machine under the same conditions as for intravenous injection.

4.3 Contraindications

The use of Venofer is contraindicated in the following conditions:

Hypersensitivity to the active substance, to Venofer or any of its excipients listed in

section 6.1

Known serious hypersensitivity to other parenteral iron products

Anaemia not caused by iron deficiency

Evidence of iron overload or hereditary disturbances in utilization of iron.

4.4 Special warnings and precautions for use

Parenterally administered iron preparations can cause hypersensitivity reactions including

serious and potentially fatal anaphylactic/anaphylactoid reactions. Hypersensitivity reactions

have also been reported after previously uneventful doses of parenteral iron complexes

including iron sucrose. However, in several studies performed in patients who had a history of

a hypersensitivity reaction to iron dextran or ferric gluconate, Venofer was shown to be well

tolerated. For known serious hypersensitivity to other parenteral iron product see section 4.3.

The risk of hypersensitivity reactions is enhanced for patients with known allergies including

drug allergies, including patients with a history of severe asthma, eczema or other atopic

allergy.

There is also an increased risk of hypersensitivity reactions to parenteral iron complexes in

patients

with

immune

inflammatory

conditions

(e.g.

systemic

lupus

erythematosus,

rheumatoid arthritis).

Venofer should only be administered when staff trained to evaluate and manage anaphylactic

reactions is immediately available, in an environment where full resuscitation facilities can be

assured. Each patient should be observed for adverse effects for at least 30 minutes following

each Venofer injection. If hypersensitivity reactions or signs of intolerance occur during

administration, the treatment must be stopped immediately. Facilities for cardio respiratory

resuscitation and equipment for handling acute anaphylactic/anaphylactoid reactions should

be available, including an injectable 1:1000 adrenaline solution. Additional treatment with

antihistamines and/or corticosteroids should be given as appropriate.

In patients with liver dysfunction, parenteral iron should only be administered after careful

risk/benefit assessment. Parenteral iron administration should be avoided in patients with

hepatic dysfunction where iron overload is a precipitating factor, in particular Porphyria

Cutanea Tarda (PCT). Careful monitoring of iron status is recommended to avoid iron overload.

Parenteral iron should be used with caution in the case of acute or chronic infection. It is

recommended that the administration of Venofer is stopped in patients with bacteraemia. In

patients with chronic infection, a risk/benefit evaluation should be performed.

Paravenous leakage must be avoided because leakage of Venofer at the injection site can

lead to pain, inflammation and brown discoloration of the skin.

4.5 Interaction with other medicinal products and other forms of interaction

As with all parenteral iron preparations, Venofer should not be administered concomitantly with

oral iron preparations since the absorption of oral iron is reduced. Therefore, oral iron therapy

should be started at least 5 days after the last injection of Venofer.

4.6 Fertility, pregnancy and lactation

Pregnancy

There is no data from the use of iron sucrose in pregnant women in the first trimester. Data

(303 pregnancy outcomes) from the use of Venofer in pregnant women in the second and third

trimester showed no safety concerns for the mother or newborn.

A careful risk/benefit evaluation is required before use during pregnancy and Venofer should

not be used during pregnancy unless clearly necessary (see section 4.4).

Iron deficiency anaemia occurring in the first trimester of pregnancy can in many cases be

treated with oral iron. Treatment with Venofer should be confined to second and third trimester

if the benefit is judged to outweigh the potential risk for both the mother and the fetus.

Foetal bradycardia may occur following administration of parenteral irons. It is usually transient

and a consequence of a hypersensitivity reaction in the mother. The unborn baby should be

carefully monitored during intravenous administration of parenteral irons to pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive

toxicity (see section 5.3).

Breast-feeding

There is limited information on the excretion of iron in human milk following administration of

intravenous iron sucrose. In one clinical study, 10 healthy breast-feeding mothers with iron

deficiency received 100 mg iron in the form of iron sucrose. Four days after treatment, the iron

content of the breast milk had not increased and there was no difference from the control group

(n=5). It cannot be excluded that newborns/infants may be exposed to iron derived from

Venofer via the mother's milk, therefore the risk/benefit should be assessed.

Preclinical data do not indicate direct or indirect harmful effects to the nursing child. In lactating

rats treated with

Fe-labelled iron sucrose, low secretion of iron into the milk and transfer of

iron into the offspring was observed. Non metabolised iron sucrose is unlikely to pass into the

mother's milk.

Fertility

No effects of iron sucrose treatment were observed on fertility and mating performance in rats.

4.7 Effects on the ability to drive and use machines

case

symptoms

dizziness,

confusion

light

headedness

following

administration of Venofer, patients should not drive or use machinery until the symptoms have

ceased.

4.8 Undesirable effects

The most commonly reported adverse drug reaction in clinical trials with Venofer was

dysgeusia, which occurred with a rate of 4.5 events per 100 subjects. The most important

serious adverse drug reactions associated with Venofer are hypersensitivity reactions, which

occurred with a rate of 0.25 events per 100 subjects in clinical trials.

Anaphylactoid/anaphylactic

reactions

were

reported

only

post-marketing

setting

(estimated as rare); fatalities have been reported. See section 4.4.

The adverse drug reactions reported after the administration of Venofer in 4,064 subjects in

clinical trials as well as those reported from the post-marketing setting are presented in the

table below.

System Organ

Class

Common

(≥1/100,

<1/10)

Uncommon

(≥1/1,000, <1/100)

Rare

(≥1/10,000,

<1/1,000)

Frequency not

known

1)

Immune system

disorders

Hypersensitivity

Anaphylactoid/

anaphylactic

reactions,

angioedema

Nervous system

disorders

Dysgeusia,

Headache, dizziness,

paraesthesia,

hypoaesthesia

Syncope,

somnolence

Depressed level

consciousness,

confusional

state, loss of

System Organ

Class

Common

(≥1/100,

<1/10)

Uncommon

(≥1/1,000, <1/100)

Rare

(≥1/10,000,

<1/1,000)

Frequency not

known

1)

consciousness,

anxiety, tremor

Cardiac disorders

Palpitations

Bradycardia,

tachycardia

Vascular disorders

Hypotension,

hypertension

Flushing, phlebitis

Circulatory

collapse,

thrombophlebitis

Respiratory,

thoracic and

mediastinal

disorders

Dyspnoea

Bronchospasm

Renal and urinary

disorders

Chromaturia

Gastrointestinal

disorders

Nausea

Vomiting, abdominal

pain, diarrhoea,

constipation

Skin and

subcutaneous

tissue disorders

Pruritus, rash

Urticaria,

erythema

Musculoskeletal

and connective

tissue disorders

Muscle spasm, myalgia,

arthralgia, pain in

extremity, back pain

General disorders

and administration

site conditions

Injection/

infusion site

reaction

Chills, asthenia, fatigue,

oedema peripheral,

pain

Chest pain,

hyperdrosis,

pyrexia

Cold sweat,

malaise, pallor,

influenza like

illness

Investigations

Alanine

aminotransferase

increased, aspartate

aminotransferase

increased, gamma-

glutamyltransferase

increased, serum

ferritin

increased

Blood lactate

dehydrogenas

e increased

Spontaneous reports from the post-marketing setting; estimated as rare

The most frequently reported are: injection/infusion site pain, -extravasation, -irritation, -

reaction, -discolouration, -haematoma, -pruritus.

Onset may vary from a few hours to several days.

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

https://sideeffects.health.gov.il/

4.9 Overdose

Overdose can cause iron overload which may manifest itself as haemosiderosis. Overdose

should be treated, as deemed necessary by the treating physician, with an iron chelating

agent or according to standard medical practice.

5.

Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anti-anaemic preparation, iron, parenteral preparation, ATC

code: B03AC

Mechanism of action

Iron sucrose, the active ingredient of Venofer, is composed of a polynuclear iron(III)-

hydroxide core surrounded by a large number of non-covalently bound sucrose molecules.

The complex has a weight average molecular weight (Mw) of approximately 43 kDa. The

polynuclear iron core has a structure similar to that of the core of the physiological iron

storage protein ferritin. The complex is designed to provide, in a controlled manner, utilisable

iron for the iron transport and storage proteins in the body (i.e., transferrin and ferritin,

respectively).

Following intravenous administration, the polynuclear iron core from the complex is taken up

predominantly by the reticuloendothelial system in the liver, spleen, and bone marrow. In a

second step, the iron is used for the synthesis of Hb, myoglobin and other iron-containing

enzymes, or stored primarily in the liver in the form of ferritin.

Clinical efficacy and safety

Chronic kidney disease

Study LU98001 was a single arm study to investigate the efficacy and safety of 100 mg iron

as Venofer for up to 10 sessions over 3-4 weeks in haemodialysis patients with iron deficiency

anaemia (Hb >8 and <11.0 g/dl, TSAT <20%, and serum ferritin ≤300 μg/l) who were receiving

rHuEPO therapy. A Hb ≥11 g/dl was attained in 60/77 patients. The mean increase in serum

ferritin and TSAT was significant from baseline to the end of treatment (Day 24) as well as to

the 2 and 5 weeks follow-up visit.

Study 1VEN03027 was a randomised study comparing Venofer (1000 mg in divided doses

over 14 days) and oral ferrous sulphate (325 mg 3 times daily for 56 days) in non-dialysis

dependent chronic kidney disease patients (Hb≤11.0 g/dl, serum ferritin ≤300 μg/l, and TSAT

≤25%) with or without rHuEPO. A clinical response (defined as Hb increase ≥1.0 g/dl and

serum ferritin increase ≥160 μg/l) was more frequently observed in patients treated with

Venofer (31/79; 39.2%) compared to oral iron (1/82; 1.2%); p<0.0001.

Inflammatory Bowel Disease

A randomised, controlled study compared Venofer (single IV dose of 200 mg iron once per

week or every second week until the cumulative dose was reached) with oral iron (200 mg

twice daily for 20 weeks) in patients with inflammatory bowel disease and anaemia (Hb <11.5

g/dl). At the end of treatment, 66% of patients in the Venofer group had an increase in Hb ≥2.0

g/dl compared to 47% in the oral iron group (p=0.07).

Postpartum

A randomised, controlled trial in women with postpartum iron deficiency anaemia (Hb <9 g/dl

and serum ferritin <15 μg/l at 24–48 hours post-delivery) compared 2 × 200 mg iron given as

Venofer on Days 2 and 4 (n=22) and 200 mg of oral iron given as ferrous sulphate twice daily

for 6 weeks (n=21). The mean increase in Hb from baseline to Day 5 was 2.5 g/dl in the Venofer

group and 0.7 g/dl in the oral iron group (p<0.01).

Pregnancy

In a randomised, controlled study, women in their third trimester of pregnancy with iron

deficiency anaemia (Hb 8 to 10.5 g/dl and serum ferritin <13 μg/l) were randomised to Venofer

(individually calculated total dose of iron administered over 5 days) or oral iron polymaltose

complex (100 mg 3× daily until delivery). The increase in Hb from baseline was significantly

greater in the Venofer group compared to the oral iron group at Day 28 and at delivery (p<0.01).

5.2 Pharmacokinetic properties

Distribution

The ferrokinetics of iron sucrose labelled with

Fe and

Fe were assessed in 6 patients with

anaemia and chronic renal failure. In the first 6–8 hours,

Fe was taken up by the liver, spleen

and bone marrow. The radioactive uptake by the macrophage-rich spleen is considered to be

representative of the reticuloendothelial iron uptake.

Following intravenous injection of a single 100 mg iron dose of iron sucrose in healthy

volunteers, maximum total serum iron concentrations were attained 10 minutes after injection

and had an average concentration of 538 μmol/l. The volume of distribution of the central

compartment corresponded well to the volume of plasma (approximately 3 litres).

Biotransformation

Upon injection, sucrose largely dissociates and the polynuclear iron core is mainly taken up by

the reticuloendothelial system of the liver, spleen, and bone marrow. At 4 weeks after

administration, red cell iron utilization ranged from 59 to 97%.

Elimination

The iron sucrose complex has a weight average molecular weight (Mw) of approximately 43

kDa, which is sufficiently large to prevent renal elimination. Renal elimination of iron, occurring

in the first 4 hours after injection of a Venofer dose of 100 mg iron, corresponded to less than

5% of the dose. After 24 hours, the total serum iron concentration was reduced to the pre-dose

level. Renal elimination of sucrose was about 75% of the administered dose.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of

repeated dose toxicity, genotoxicity and toxicity to reproduction and development.

6.

Pharmaceutical particulars

6.1 List of excipients

Water for injection

Sodium hydroxide (for pH adjustment)

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those

mentioned in section 6.6. There is the potential for precipitation and/or interaction if mixed with

other solutions or medicinal products. The compatibility with containers other than glass,

polyethylene and PVC is not known.

6.3 Shelf life

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

Shelf life after first opening of the container

From a microbiological point of view, the product should be used immediately.

Shelf life after dilution with sterile 0.9% m/V sodium chloride (NaCl) solution

From a microbiological point of view, the product should be used immediately after dilution with

sterile 0.9% m/V sodium chloride solution.

6.4 Special precautions for storage

Prescribed storage conditions: 4 –25 °C. Do not freeze. Store in the original package in order

to protect from light.

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

6.5 Nature and contents of container

5 ml solution in one ampoule (type I glass) in pack sizes of 5.

6.6 Special precautions for disposal and other handling

Ampoules should be visually inspected for sediment and damage before use. Use only those

containing a sediment free and homogenous solution.

Venofer must not be mixed with other medicinal products except sterile 0.9% m/V sodium

chloride solution for dilution. For instructions on dilution of the product before administration,

see section 4.2.

The diluted solution must appear as brown and clear.

Each ampoule of Venofer is intended for single use only.

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

local requirements.

7.

Manufacturer:

Vifor (International), Rechenstrasse 37, St. Gallen, 9014, Switzerland

8.

License holder and importer:

CTS Ltd.

4 Haharash st.

Hod Hasharon 4524075

The content of this leaflet was approved by the Ministry of Health in November 2016 and

updated according to the guidelines of the Ministry of Health in December 2019.