XENETIX 250

אפורל ןולעב )תוחיטב עדימ ( הרמחה לע העדוה :ךיראת

7.2013

:םושירה רפסמו תילגנאב רישכת םש

Xenetix 250 )105-07-28746-00(, Xenetix 300 )105-08-28747-00(, Xenetix 350 )105-09-28748-00(

:םושירה לעב םש

Promedico LTD

! דבלב תורמחהה טורפל דעוימ הז ספוט תושקובמה תורמחהה ןולעב קרפ יחכונ טסקט שדח טסקט

2. Qualitative and

Quantitative

Composition

Excipient with known effect: sodium (up to 3.5 mg per 100 mL).

4.3. Contraindications

Contra-indications

Xenetix is contraindicated in patients hypersensitive to the

product.

A history of sensitivity to iodine contraindicates the use of

Xenetix (see Warnings).

In the absence of specific studies, iobitridol is not indicated

for myelography.

4.3.

Contraindications

Hypersensitivity to iobitridol or any of the excipients.

History of a major immediate reaction or delayed skin reaction (see

Section 4.8) to a Xenetix injection.

Manifest thyrotoxicosis

4.4.

Special

warnings and special

precautions for use

Special warnings and precautions for use

Warnings

As in the case of all iodinated contrast agents, non-ionic

water soluble tri-iodinated products

may induce mild, severe or fatal intolerance reactions, often

of early onset but sometimes

delayed.

These reactions cannot be predicted but are more frequent

in patients with a history of allergy

(hives, asthma, hay-fever, eczema, various food and drug

allergies) or who have shown

particular sensitivity during a previous examination with an

iodinated contrast medium.

Risk-benefit should be considered when dehydration

exists, especially when associated with

pre-existing renal or hepatic disease, advanced vascular

disease, and diabetes mellitus, in

infants, young children and elderly patients.

Screening for these reactions by means of iodine reaction

tests or any other tests currently

available is not possible.

Precautions for use

During the examination, the following are required:

surveillance by a physician

maintenance of an intravenous access for

emergency treatment in the event of a reaction.

Caution is required in patients presenting with severe liver

or kidney failure.

Water intake need not be restricted. It is advisable to

maintain abundant urine output in subjects

with kidney failure, diabetes mellitus, myeloma or

hyperuricemia and in very young children

and atheromatous subjects.

Premedication is advisable for subjects at a high risk of

4.4.

Special warnings and special precautions for use

There is a risk of allergic reactions regardless of the route of

administration or the dose.

The risk of allergic reactions associated with products administered

locally for opacification of body cavities is not clear-cut:

Administration via certain specific routes (articular, biliary, intrathecal,

intra-uterine, etc.) results in varying degrees of systemic diffusion, i.e.

systemic effects may be observed.

Oral or rectal administration normally results in very limited systemic

diffusion. If the intestinal mucosa is normal, not more than 5% of the

administered dose is found in urine and the rest is eliminated in faeces.

Conversely, absorption is increased if the mucosa is damaged. In the

event of perforation, this absorption is rapid and total with diffusion into the

peritoneal cavity and the product is eliminated in urine. The occurrence of

dose-dependent systemic effects is therefore dependent on the status of

the intestinal mucosa.

However, the allergic immune mechanism is not dose-dependent and

immuno-allergic reactions may occur at any time, regardless of the

administration route.

Thus, in terms of the frequency and intensity of undesirable effects, there is a

difference between:

products administered via the vascular route and certain local routes, and

products administered via the GI tract which are only slightly absorbed

under normal conditions.

4.4.1. General particulars corresponding to all iodinated contrast agents

4.4.1.1 Warnings

In the absence of specific studies, myelography is not an indication for

Xenetix.

All iodinated contrast agents can cause minor or major reactions that can be

life-threatening. They may occur immediately (within 60 minutes) or be

reaction (allergy, history of poor

tolerance to iodinated products).

Given the risk involved, emergency resuscitation equipment

must be available, particularly

when the subject is concomitantly receiving ß-blockers (see

Drug interactions), since adrenaline

and plasma expansion have little effect in such cases.

delayed (up to 7 days). They are often unpredictable.

Because of the risk of major reactions, emergency resuscitation equipment

should be available for immediate use.

Several mechanisms have been evoked to explain the occurrence of these

reactions:

direct toxicity affecting the vascular endothelium and tissue proteins.

pharmacological

action

modifying

concentration

certain

endogenous factors (histamine, complement factors, inflammation

mediators), observed more frequently with hyperosmolar contrast media.

immediate IgE-mediated allergic reactions to the contrast agent Xenetix

(anaphylaxis)

allergic reactions due to a cellular-type mechanism (delayed cutaneous

reactions)

Patients who have already experienced a reaction during administration of an

iodinated contrast agent are at higher risk of experiencing another reaction

following administration of the same or possibly a different iodinated contrast

agent, and are thus considered to be at-risk patients.

Iodinated contrast agents and the thyroid (see also Section 4.4.1.2.5.)

Before administering an iodinated contrast agent, it is important to ensure that

the patient is not scheduled to undergo a scintigraphic examination or

laboratory tests related to the thyroid or to receive radioactive iodine for

therapeutic purposes.

Administration of contrast agents via any route disrupts hormone

concentrations and iodine uptake by the thyroid or by metastases of thyroid

cancer, until urine iodine levels have returned to normal.

Other warnings

Extravasation is an uncommon complication (0.04% to 0.9%) of intravenous

injections of contrast media. More frequent with the high osmolar products,

most of the injuries are minor, however severe injuries such as skin

ulceration, tissue necrosis, and compartment syndrome may occur with any

iodinated contrast medium. The risk and/or severity factors are patient-related

(poor or fragile vascular conditions), and technique-related (use of a power

injector, large volume). It is important to identify these factors, optimise the

injection site and technique accordingly, and monitor the injection prior to,

during and after the injection of Xenetix.

4.4.1.2. Precautions for use

4.4.1.2.1. Intolerance to iodinated contrast agents:

Prior to the examination:

identify at-risk patients by a precise screening of histories.

Corticosteroids and H1-type antihistamines have been suggested as

premedication in patients presenting with the highest risk for intolerance

reactions (history of intolerance to an iodinated contrast agent). However,

they do not prevent the occurrence of serious or fatal anaphylactic shock.

During the procedure, the following measures must be maintained:

medical surveillance

permanent venous access.

After the examination:

After administration of the contrast agent, the patient must be monitored

for at least 30 minutes, since most serious adverse reactions occur within

this time period.

The patient must be informed of the possibility of delayed reactions (for

up to seven days) (see Section 4.8. Undesirable effects)

4.4.1.2.2. Renal insufficiency

Iodinated contrast agents can induce a transient alteration in renal function or

worsen pre-existing renal insufficiency. Preventive measures include:

Identify at-risk patients, i.e. with dehydration or renal insufficiency,

diabetes,

severe heart failure,

monoclonal

gammapathy (multiple

myeloma, Waldenstrom's macroglobulinemia), a history of renal failure

after iodinated contrast agent administration, children under one year of

age and elderly subjects with atheroma.

Hydrate when necessary using a saline solution.

Avoid combinations with nephrotoxic medicines. If this cannot be avoided,

laboratory monitoring of renal function must be intensified. The medicines

concerned include aminoglycosides, organoplatinum compounds, high

doses of methotrexate, pentamidine, foscarnet and certain antiviral

agents [aciclovir, ganciclovir, valaciclovir, adefovir, cidofovir, tenofovir],

vancomycin, amphotericin B, immunosuppressants such as cyclosporine

or tacrolimus, ifosfamide.

Allow at least 48 hours between two radiological examinations with

injection of contrast agents, or postpone any new examination until renal

function returns to baseline.

Prevent lactic acidosis in diabetics treated with metformin, by monitoring

serum creatinine levels. Normal renal function: treatment with metformin

must be suspended before contrast agent injection and for at least 48

hours after or until normal renal function is restored. Abnormal renal

function: metformin is contraindicated. In case of emergency: if the

examination is mandatory, precautions must be taken, i.e. metformin

discontinuation, hydration, monitoring of renal function and checking for

signs of lactic acidosis.

Iodinated contrast agents can be used in haemodialysed patients as the

agents are removed by dialysis. Prior approval should be obtained from the

haemodialysis department.

4.4.1.2.3. Hepatic insufficiency

Particular attention is required when a patient presents with both hepatic and

renal insufficiency since, in this situation, the risk of contrast agent retention is

increased.

Care should be taken in case of renal or hepatic impairment, diabetes or in

patients with sickle cell disease.

Adequate hydration should be ensured in all patients before and after

contrast media administration and particularly in patients with renal

impairment or diabetes where it is important to maintain hydration to minimise

deterioration in renal function.

4.4.1.2.4. Asthma

Stabilisation of asthma is recommended before the injection of an iodinated

contrast agent.

Due to an increased risk of bronchospasm, special caution should be taken in

patients who suffered an asthmatic attack within eight days prior to the

examination.

4.4.1.2.5. Dysthyroidism

After iodinated contrast agent injection, particularly in patients with a goitre or

a history of dysthyroidism, there is a risk either of a flare-up of

hyperthyroidism or development of hypothyroidism. There is also a risk of

hypothyroidism in neonates who have received, or whose mother has

received, an iodinated contrast agent.

4.4.1.2.6. Cardiovascular diseases (see Section 4.8 Undesirable effects)

In patients with cardiovascular disease (such as early or patent heart failure,

coronaropathy, pulmonary hypertension, valvulopathy, cardiac arrhythmias),

the risk of cardiovascular reactions is increased after administration of an

iodinated contrast agent. Intravasal injection of the contrast medium may

cause pulmonary oedema in patients with manifest or incipient heart failure,

whereas administration in pulmonary hypertension and heart valve disorders

may result in marked changes in haemodynamics. The frequency and degree

of severity appear related to the severity of the cardiac disorders. In case of

severe and chronic hypertension, the risk of renal damage due to

administration of the contrast medium and also due to the catheterisation

itself may be increased. Careful weighing up of the risk-benefit ratio is

necessary in these patients.

4.4.1.2.7. Central nervous system disorders

The benefit-to-risk ratio must be evaluated for each case:

due to the risk of aggravation of neurological symptoms in patients with a

transient ischaemic attack, acute cerebral infarct, recent intracranial

haemorrhage, cerebral oedema, or idiopathic or secondary (tumour, scar)

epilepsy.

if the intra-arterial route is used in an alcoholic patient (acute or chronic

alcoholism) and other drug-addicted subject.

4.4.1.2.8. Phaeochromocytoma

Patients with phaeochromocytoma may develop a hypertensive crisis after

intravascular administration of a contrast agent, and must be monitored prior

to the examination.

4.4.1.2.9. Myasthenia.

Administration of a contrast agent may worsen the symptoms of myasthenia

gravis.

4.4.1.2.10. Intensification of side effects

Adverse reactions related to iodinated contrast agent administration may be

intensified in patients showing pronounced agitation, anxiety and pain.

Appropriate management such as sedation may be necessary.

4.4.1.2.11.

Excipients

This medicinal product contains sodium. It contains less than 1 mmol sodium

per 100 mL, i.e. essentially “sodium-free”.

4.5.

Interaction with

other medicinal

products

and

other forms of

interaction

Drug interactions and other forms of

interactions

Combinations requiring special precautions

Diuretics: In the event of dehydration induced by diuretics,

there is an increased risk of acute

kidney failure, in particular when high doses of iodinated

contrast media are administered.

The subject should be rehydrated before the iodinated

contrast medium is administered.

Metformin: Lactic acidosis was induced by functional kidney

failure related to radiological

investigation of a subject with diabetes mellitus.

Metformin treatment must be withdrawn 48 hours before the

examination and only reinstituted

2 days after the examination

Beta-adrenergic blocking agents: Concurrent intravascular

administration with beta-adrenergic

blocking agents may increase the risk of moderate to

severe anaphylactoid reaction; also

hypotensive effects may be exacerbated; discontinuation of

the beta-adrenergic blocking agent

may be advisable before administration of contrast media in

patients with other risk factors.

4.5.

Interaction with other medicinal products and other forms

of interaction

4.5.1. Medicinal products

+ Metformin in diabetics (see Section 4.4 Precautions for use — renal

insufficiency).

+ Radiopharmaceuticals (see Section 4.4 Warnings)

Iodinated contrast agents alter the uptake of radioactive iodine by the thyroid

for several weeks, which may on the one hand result in diminished uptake in

thyroid scintigraphy and on the other hand decrease the efficacy of iodine 131

treatment.

In patients scheduled to undergo renal scintigraphy with injection of a

radiopharmaceutical excreted by the renal tubules, it is preferable to carry out

this examination before injecting the iodinated contrast agent.

+ Beta blockers, vasoactive substances, angiotensin-converting enzyme

inhibitors, angiotensin receptor antagonists.

These medicinal products reduce the efficacy of the cardiovascular

compensation mechanisms that occur in haemodynamic disorders. The

physician must be aware of this before injecting the iodinated contrast agent

and appropriate intensive care equipment must be available.

+ Diuretics

Due to the risk of dehydration provoked by diuretics, rehydration with water

and electrolytes must be carried out prior to the examination in order to limit

the risk of acute renal failure.

+ Interleukin 2

The risk of developing a reaction to the contrast agents is increased if the

patient has recently been treated with interleukin 2 (intravenous route), i.e.

rash or, more rarely, hypotension, oliguria, or even renal failure.

4.5.2. Other forms of interaction

High concentrations of iodinated contrast agents in plasma and urine may

interfere with the in vitro determination of bilirubin, proteins and inorganic

substances (iron, copper, calcium and phosphate). It is recommended that

these determinations should not be carried out within 24 hours following the

examination.

4.6.

Pregnancy

and

lactation

Pregnancy and Lactation

Pregnancy

The safety of iobitridol administration to pregnant women

has not been demonstrated. Animal

studies have shown no evidence of teratogenic effects.

However, all exposure to X-rays should

be avoided during pregnancy. The decision of whether or

not to perform the examination

should be based on careful evaluation of the expected

benefit and potential risk.

Lactation

No clinical studies have been conducted on the secretion of

iobitridol in breast-milk. Animal

studies have shown excretion in breast-milk to be low (3%).

4.6.

Pregnancy and lactation

Embryotoxicity

Animal studies have not shown any teratogenic effects.

In the absence of any teratogenic effects in animal species, no malformative

effect is expected in humans. To date, substances causing malformations in

humans have always proved to be teratogenic in animals during studies

properly conducted in two species.

Foetotoxicity

The transient iodine overload following administration to the mother may

induce foetal dysthyroidism if the examination takes place after more than 14

weeks of amenorrhoea. However, in view of the reversibility of the effect and

expected benefit to the mother, the isolated administration of an iodinated

contrast agent is justifiable if the indication for the radiological examination in

a pregnant woman has been carefully evaluated.

Mutagenicity and fertility

The product was not found to be mutagenic under the test conditions used.

No data on reproductive function are available.

Lactation

Iodinated contrast agents are only excreted in breast milk in very small

amounts. Isolated administration to the mother consequently involves a minor

risk of adverse reactions in the infant. It is advisable to stop breastfeeding for

24 hours after administration of the iodinated contrast agent.

4.8.

Undesirable

Adverse reactions

Benign reactions may occur: feeling of hotness, very rarely

4.8.

Undesirable effects

effects

nausea, vomiting and redness of

the skin. These reactions are transient and devoid of clinical

consequences.

More serious manifestations are possible. Reactions may

occur as an isolated disorder or

combination of disorders: cutaneous, respiratory,

neurosensory, gastrointestinal and

cardiovascular disorders. The latter may consist of

cardiovascular collapse of variable severity.

Exceptionally, shock and/or circulatory

arrest may occur.

During clinical studies on 905 patients, 11% of patients experienced an

adverse reaction related to administration of Xenetix (apart from feeling of

warmth), the most common being pain, injection site pain, bad taste and

nausea.

Undesirable effects related to the use of Xenetix are generally mild to

moderate, and transient.

The adverse reactions most commonly reported during administration of

Xenetix since marketing are feeling of warmth, and pain and oedema at the

injection site.

The hypersensitivity reactions are usually immediate (during the injection or

over the hour following the start of the injection) or sometimes delayed (one

hour to several days after the injection), and then appear in the form of

adverse skin reactions.

Immediate reactions comprise one or several, successive or concomitant

effects, usually including skin reactions, respiratory and/or cardiovascular

disorders, which may be the first signs of shock, which can rarely be fatal.

Severe rhythm disorders including ventricular fibrillation have been very rarely

reported in heart disease patients, in as well as out of a context of

hypersensitivity (see Section 4.4 Precaution for use).

The adverse reactions are listed in the table below by SOC (System Organ

Class) and by frequency with the following guidelines: very common (

1/10),

common (

1/100 to <1/10), uncommon (

1/1000 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 presented are derived from the data of an

observational study on 352,255 patients.

System Organ Class

Frequency: adverse reaction

Immune system disorders

Rare: hypersensitivity

Very rare: anaphylactoid reaction,

anaphylactic reaction

Endocrine disorders

Very rare: thyroid disorder

Nervous system disorders

Rare: presyncope (vasovagal

reaction), tremor*, paresthesia*

Very rare: coma*, convulsions*,

confusion*, visual disorders*,

amnesia*, photophobia*, transient

blindness*, somnolence*, agitation*,

headache

Ear and labyrinth disorders

Rare: vertigo

Very rare: hearing impaired

Cardiac disorders

Rare: tachycardia

Very

rare:

cardiac

arrest,

myocardial

infarction

(more

frequent

after

intracoronary

injection),

arrhythmia,

ventricular

fibrillation, angina pectoris

Vascular disorders

Rare: hypotension

Very rare: circulatory collapse

Respiratory, thoracic and

mediastinal disorders

Rare: dyspnoea, cough, tightness in

the throat, sneezing

Very rare: respiratory arrest,

pulmonary oedema, bronchospasm,

laryngospasm, laryngeal oedema

Gastrointestinal disorders

Uncommon: nausea

Rare: vomiting

Very rare: abdominal pain

Skin and subcutaneous tissue

disorders

Rare: angioedema, urticaria (localised

or extensive), erythema, pruritus

Very rare: Acute Generalised

Exanthematous Pustulosis, Stevens-

Johnson syndrome, Lyell's syndrome,

eczema, maculopapulous exanthema

(all as delayed hypersensitivity

reactions)

Renal and urinary disorders

Very rare: acute renal failure, anuria

General disorders and

administration site conditions

Uncommon: feeling hot

Rare: facial oedema, malaise, chills,

injection site pain

Very rare: injection site necrosis

following extravasation, injection site

oedema, injection site inflammation

following extravasation

Investigations

Very rare: blood creatinine increased

*Examinations during which the iodinated contrast agent concentration in

arterial blood is high

The following adverse reactions were reported for other water-soluble

iodinated contrast agents:

System Organ Class

Frequency: adverse reaction

Nervous system disorders

Paralysis, paresis, hallucinations,

speech disorders

Gastrointestinal disorders

abdominal pain, diarrhoea, parotid gland

enlargement, salivary hypersecretion,

dysgeusia

Skin and subcutaneous tissue

disorders

Erythema multiforme

Vascular disorders

Thrombophlebitis

Investigations

Electroencephalogram abnormal, blood

amylase increased

Cardiovascular collapse of variable severity may occur immediately with no

warning signs, or may complicate the cardiovascular manifestations

mentioned in the above table.

Abdominal pain and diarrhoea, not reported for Xenetix, are linked mainly to

administration via the oral or rectal route.

Local pain and oedema may occur at the injection site without extravasation

of the injected product and are benign and transient.

During intra-arterial administration, the sensation of pain at the injection site

depends on the osmolality of the product injected.

Paediatric population

The expected nature of the undesirable effects connected with Xenetix is the

same as that of the effects reported in adults. Their frequency cannot be

estimated from the available data.

4.9.

Overdose

4.9.

Overdose

If a very high dose of contrast agent is administered, the water and electrolyte

loss must be compensated by suitable rehydration. Renal function must be

monitored for at least three days. Haemodialysis may be performed if

necessary.

SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

XENETIX 250, 300, 350 (250, 300, 350 mg Iodine/mL),

solution for injection

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Xenetix 250

Per 100 mL of solution:

Iobitridol .................................................................................................................................. 54.84 g

corresponding mass of iodine ....................................................................................................... 25 g

Iodine content per mL: 250 mg

Iodine quantity per 50 mL bottle: 12.5 g

Viscosity at 20 °C : 6 mPa.s

Iodine quantity per 100 mL bottle: 25 g

Viscosity at 37 °C : 4 mPa.s

Iodine quantity per 200 mL bottle: 50 g

Osmolality: 585 mOsm / kg H

Iodine quantity per 500 mL bottle: 125 g

Xenetix 300

Per 100 mL of solution:

Iobitridol .......................................................................................................... 65.81 g (658.1 mg/mL)

corresponding mass of iodine .................................................................................. 30 g (300 mg/mL)

Iodine content per mL: 300 mg

Iodine quantity per 20 mL bottle: 6 g

Viscosity at 20°C: 11 mPa.s

Iodine quantity per 50 mL bottle: 15 g

Viscosity at 37°C: 6 mPa.s

Iodine quantity per 60 mL bottle: 18 g

Osmolality: 695 mOsm/kg H

Iodine quantity per 75 mL bottle: 22.5 g

Iodine quantity per 100 mL bottle: 30 g

Iodine quantity per 150 mL bottle: 45 g

Iodine quantity per 200 mL bottle: 60 g

Iodine quantity per 500 mL bottle: 150 g

Xenetix 350

Per 100 mL of solution:

Iobitridol ......................................................................................................... 76.78 g (767.8 mg/mL)

corresponding mass of iodine .................................................................................. 35 g (350 mg/mL)

Iodine content per mL: 350 mg

Iodine quantity per 20 mL bottle: 7 g

Viscosity at 20°C: 21 mPa.s

Iodine quantity per 50 mL bottle: 17.5 g

Viscosity at 37°C: 10 mPa.s

Iodine quantity per 60 mL bottle: 21 g

Osmolality: 915 mOsm/kg H

Iodine quantity per 75 mL bottle: 26.25 g

Iodine quantity per 100 mL bottle: 35 g

Iodine quantity per 150 mL bottle: 52.5 g

Iodine quantity per 200 mL bottle: 70 g

Iodine quantity per 500 mL bottle: 175 g

Excipient with known effect: sodium (up to 3.5 mg per 100 mL).

For the full list of excipients, see Section 6.1.

3.

PHARMACEUTICAL FORM

Solution for injection

4.

CLINICAL PARTICULARS

4.1.

Therapeutic indications

This medicinal product is for diagnostic use only.

Xenetix 250

For adults and children undergoing:

phlebography

chest CT scan

intra-arterial digital subtraction angiography

Xenetix 300, Xenetix 350

For adults and children undergoing:

intravenous urography

brain or whole-body CT scan

intravenous digital subtraction angiography

arteriography

angiocardiography

4.2.

Posology and method of administration

The doses must be adapted to the examination and the regions to be opacified, as well

as to the body weight and renal function of the subject, especially in children.

Recommended mean dosages:

Xenetix 250

Indications

Mean dose

(mL/kg)

Total volume range

mL

Phlebography

150-220

Thoracic CT

95-170

Intra-arterial digital subtraction

angiography

75-360

Xenetix 300

Indications

Mean dose (mL/kg)

Total volume range

mL

Intravenous urography:

rapid i.v. injection

slow i.v. injection

1.2

1.6

50-100

100

CT-scan

Brain

Whole body

1.4

1.9

20-100

20-150

Intravenous digital

subtraction angiography

1.7

40-270

Arteriography

cerebral

lower limbs

2.8

42-210

85-300

Angiocardiography

1.1

70-125

Xenetix 350

Indications

Mean dose (mL/kg)

Total volume range

mL

Intravenous urography

50-100

CT-scan

brain

whole-body

1.0

1. 8

40-100

90-180

Intravenous digital

subtraction angiography

2.1

95-250

Arteriography

peripheral

lower limbs

abdominal

2.2

1.8

3.6

105-205

80-190

155-330

Angiocardiography

adults

children

4.6

65-270

10-130

4.3.

Contraindications

Hypersensitivity to iobitridol or any of the excipients.

History of a major immediate reaction or delayed skin reaction (see Section 4.8)

to a Xenetix injection.

history

sensitivity

iodine

contraindicates

Xenetix

(see

Warnings).

Manifest thyrotoxicosis

4.4.

Special warnings and special precautions for use

There is a risk of allergic reactions regardless of the route of administration or the

dose.

The risk of allergic reactions associated with products administered locally for

opacification of body cavities is not clear-cut:

a) Administration via certain specific routes (articular, biliary, intrathecal, intra-uterine,

etc.) results in varying degrees of systemic diffusion, i.e. systemic effects may be

observed.

b) Oral or rectal administration normally results in very limited systemic diffusion. If the

intestinal mucosa is normal, not more than 5% of the administered dose is found in

urine and the rest is eliminated in faeces. Conversely, absorption is increased if the

mucosa is damaged. In the event of perforation, this absorption is rapid and total with

diffusion into the peritoneal cavity and the product is eliminated in urine. The

occurrence of dose-dependent systemic effects is therefore dependent on the status

of the intestinal mucosa.

c) However, the allergic immune mechanism is not dose-dependent and immuno-

allergic reactions may occur at any time, regardless of the administration route.

Thus, in terms of the frequency and intensity of undesirable effects, there is a difference

between:

products administered via the vascular route and certain local routes, and

products administered via the GI tract which are only slightly absorbed under normal

conditions.

4.4.1. General particulars corresponding to all iodinated contrast agents

4.4.1.1 Warnings

In the absence of specific studies, myelography is not an indication for Xenetix.

All iodinated contrast agents can cause minor or major reactions that can be life-

threatening. They may occur immediately (within 60 minutes) or be delayed (up to 7

days). They are often unpredictable.

Because of the risk of major reactions, emergency resuscitation equipment should be

available for immediate use.

Several mechanisms have been evoked to explain the occurrence of these reactions:

direct toxicity affecting the vascular endothelium and tissue proteins.

pharmacological action modifying the concentration of certain endogenous factors

(histamine, complement factors, inflammation mediators), observed more frequently

with hyperosmolar contrast media.

immediate

IgE-mediated

allergic

reactions

contrast

agent

Xenetix

(anaphylaxis)

allergic reactions due to a cellular-type mechanism (delayed cutaneous reactions)

These reactions cannot be predicted but are more frequent in patients with a history of

allergy

(hives, asthma, hay-fever, eczema, various food and drug allergies).

Patients who have already experienced a reaction during administration of an iodinated

contrast

agent

higher

risk

experiencing

another

reaction

following

administration of the same or possibly a different iodinated contrast agent, and are thus

considered to be at-risk patients.

Iodinated contrast agents and the thyroid (see also Section 4.4.1.2.5.)

Before administering an iodinated contrast agent, it is important to ensure that the

patient is not scheduled to undergo a scintigraphic examination or laboratory tests

related to the thyroid or to receive radioactive iodine for therapeutic purposes.

Administration of contrast agents via any route disrupts hormone concentrations and

iodine uptake by the thyroid or by metastases of thyroid cancer, until urine iodine levels

have returned to normal.

Other warnings

Extravasation is an uncommon complication (0.04% to 0.9%) of intravenous injections of

contrast media. More frequent with the high osmolar products, most of the injuries are

minor,

however

severe

injuries

such

skin

ulceration,

tissue

necrosis,

compartment syndrome may occur with any iodinated contrast medium. The risk and/or

severity factors are patient-related (poor or fragile vascular conditions), and technique-

related (use of a power injector, large volume). It is important to identify these factors,

optimise the injection site and technique accordingly, and monitor the injection prior to,

during and after the injection of Xenetix.

4.4.1.2. Precautions for use

4.4.1.2.1. Intolerance to iodinated contrast agents:

Prior to the examination:

identify at-risk patients by a precise screening of histories.

Corticosteroids and H1-type antihistamines have been suggested as premedication in

patients presenting with the highest risk for intolerance reactions (history of intolerance

to an iodinated contrast agent). However, they do not prevent the occurrence of serious

or fatal anaphylactic shock. During the procedure, the following measures must be

maintained:

medical surveillance

permanent venous access.

After the examination:

After administration of the contrast agent, the patient must be monitored for at least

30 minutes, since most serious adverse reactions occur within this time period.

The patient must be informed of the possibility of delayed reactions (for up to seven

days) (see Section 4.8. Undesirable effects)

4.4.1.2.2. Renal insufficiency

Iodinated contrast agents can induce a transient alteration in renal function or worsen

pre-existing renal insufficiency. Preventive measures include:

Identify at-risk patients, i.e. with dehydration or renal insufficiency, diabetes, severe

heart

failure,

monoclonal

gammapathy

(multiple

myeloma,

Waldenstrom's

macroglobulinemia),

history

renal

failure

after

iodinated

contrast

agent

administration, children under one year of age and elderly subjects with atheroma.

Hydrate when necessary using a saline solution.

Avoid combinations with nephrotoxic medicines. If this cannot be avoided, laboratory

monitoring of renal function must be intensified. The medicines concerned include

aminoglycosides,

organoplatinum

compounds,

high

doses

methotrexate,

pentamidine, foscarnet and certain antiviral agents [aciclovir, ganciclovir, valaciclovir,

adefovir, cidofovir, tenofovir], vancomycin, amphotericin B, immunosuppressants

such as cyclosporine or tacrolimus, ifosfamide.

Allow at least 48 hours between two radiological examinations with injection of

contrast agents, or postpone any new examination until renal function returns to

baseline.

Prevent lactic acidosis in diabetics treated with metformin, by monitoring serum

creatinine

levels.

Normal

renal

function:

treatment

with

metformin

must

suspended before contrast agent injection and for at least 48 hours after or until

normal

renal

function

restored.

Abnormal

renal

function:

metformin

contraindicated. In case of emergency: if the examination is mandatory, precautions

must be taken, i.e. metformin discontinuation, hydration, monitoring of renal function

and checking for signs of lactic acidosis.

Iodinated contrast agents can be used in haemodialysed patients as the agents are

removed

dialysis.

Prior

approval

should

obtained

from

haemodialysis

department.

4.4.1.2.3. Hepatic insufficiency

Particular attention is required when a patient presents with both hepatic and renal

insufficiency since, in this situation, the risk of contrast agent retention is increased.

Care should be taken in case of renal or hepatic impairment, diabetes or in patients with

sickle cell disease.

Adequate hydration should be ensured in all patients before and after contrast media

administration and particularly in patients with renal impairment or diabetes where it is

important to maintain hydration to minimise deterioration in renal function.

4.4.1.2.4. Asthma

Stabilisation of asthma is recommended before the injection of an iodinated contrast

agent.

Due to an increased risk of bronchospasm, special caution should be taken in patients

who suffered an asthmatic attack within eight days prior to the examination.

4.4.1.2.5. Dysthyroidism

After iodinated contrast agent injection, particularly in patients with a goitre or a history of

dysthyroidism, there is a risk either of a flare-up of hyperthyroidism or development of

hypothyroidism. There is also a risk of hypothyroidism in neonates who have received,

or whose mother has received, an iodinated contrast agent.

4.4.1.2.6. Cardiovascular diseases (see Section 4.8 Undesirable effects)

patients

with

cardiovascular

disease

(such

early

patent

heart

failure,

coronaropathy, pulmonary hypertension, valvulopathy, cardiac arrhythmias), the risk of

cardiovascular reactions is increased after administration of an iodinated contrast agent.

Intravasal injection of the contrast medium may cause pulmonary oedema in patients

with

manifest

incipient

heart

failure,

whereas

administration

pulmonary

hypertension

heart

valve

disorders

result

marked

changes

haemodynamics. The frequency and degree of severity appear related to the severity of

the cardiac disorders. In case of severe and chronic hypertension, the risk of renal

damage due to administration of the contrast medium and also due to the catheterisation

itself may be increased. Careful weighing up of the risk-benefit ratio is necessary in

these patients.

4.4.1.2.7. Central nervous system disorders

The benefit-to-risk ratio must be evaluated for each case:

due to the risk of aggravation of neurological symptoms in patients with a transient

ischaemic attack, acute cerebral infarct, recent intracranial haemorrhage, cerebral

oedema, or idiopathic or secondary (tumour, scar) epilepsy.

if the intra-arterial route is used in an alcoholic patient (acute or chronic alcoholism)

and other drug-addicted subject.

4.4.1.2.8. Phaeochromocytoma

Patients with phaeochromocytoma may develop a hypertensive crisis after intravascular

administration of a contrast agent, and must be monitored prior to the examination.

4.4.1.2.9. Myasthenia.

Administration of a contrast agent may worsen the symptoms of myasthenia gravis.

4.4.1.2.10. Intensification of side effects

Adverse reactions related to iodinated contrast agent administration may be intensified

in patients showing pronounced agitation, anxiety and pain. Appropriate management

such as sedation may be necessary.

4.4.1.2.11. Excipients

This medicinal product contains sodium. It contains less than 1 mmol sodium per 100

mL, i.e. essentially “sodium-free”.

4.5.

Interaction with other medicinal products and other forms of interaction

4.5.1. Medicinal products

+ Metformin in diabetics (see Section 4.4 Precautions for use — renal insufficiency).

+ Radiopharmaceuticals (see Section 4.4 Warnings)

Iodinated contrast agents alter the uptake of radioactive iodine by the thyroid for several

weeks, which may on the one hand result in diminished uptake in thyroid scintigraphy

and on the other hand decrease the efficacy of iodine 131 treatment.

patients

scheduled

undergo

renal

scintigraphy

with

injection

radiopharmaceutical excreted by the renal tubules, it is preferable to carry out this

examination before injecting the iodinated contrast agent.

+ Beta blockers, vasoactive substances, angiotensin-converting enzyme inhibitors,

angiotensin receptor antagonists.

These medicinal products reduce the efficacy of the cardiovascular compensation

mechanisms that occur in haemodynamic disorders. The physician must be aware of

this

before

injecting

iodinated

contrast

agent

appropriate

intensive

care

equipment must be available.

+ Diuretics

Due to the risk of dehydration provoked by diuretics, rehydration with water and

electrolytes must be carried out prior to the examination in order to limit the risk of acute

renal failure.

+ Interleukin 2

The risk of developing a reaction to the contrast agents is increased if the patient has

recently been treated with interleukin 2 (intravenous route), i.e. rash or, more rarely,

hypotension, oliguria, or even renal failure.

4.5.2. Other forms of interaction

High concentrations of iodinated contrast agents in plasma and urine may interfere with

the in vitro determination of bilirubin, proteins and inorganic substances (iron, copper,

calcium and phosphate). It is recommended that these determinations should not be

carried out within 24 hours following the examination.

4.6.

Pregnancy and lactation

Embryotoxicity

Animal studies have not shown any teratogenic effects.

In the absence of any teratogenic effects in animal species, no malformative effect is

expected in humans. To date, substances causing malformations in humans have

always proved to be teratogenic in animals during studies properly conducted in two

species.

Foetotoxicity

The transient iodine overload following administration to the mother may induce foetal

dysthyroidism if the examination takes place after more than 14 weeks of amenorrhoea.

However, in view of the reversibility of the effect and expected benefit to the mother, the

isolated administration of an iodinated contrast agent is justifiable if the indication for the

radiological examination in a pregnant woman has been carefully evaluated.

Mutagenicity and fertility

The product was not found to be mutagenic under the test conditions used.

No data on reproductive function are available.

Lactation

Iodinated contrast agents are only excreted in breast milk in very small amounts.

Isolated administration to the mother consequently involves a minor risk of adverse

reactions

infant.

advisable

stop

breastfeeding

hours

after

administration of the iodinated contrast agent.

4.7.

Effects on ability to drive and use machines

Not applicable.

4.8.

Undesirable effects

During clinical studies on 905 patients, 11% of patients experienced an adverse reaction

related to administration of Xenetix (apart from feeling of warmth), the most common

being pain, injection site pain, bad taste and nausea.

Undesirable effects related to the use of Xenetix are generally mild to moderate, and

transient.

The adverse reactions most commonly reported during administration of Xenetix since

marketing are feeling of warmth, and pain and oedema at the injection site.

The hypersensitivity reactions are usually immediate (during the injection or over the

hour following the start of the injection) or sometimes delayed (one hour to several days

after the injection), and then appear in the form of adverse skin reactions.

Immediate reactions comprise one or several, successive or concomitant effects, usually

including skin reactions, respiratory and/or cardiovascular disorders, which may be the

first signs of shock, which can rarely be fatal.

Severe rhythm disorders including ventricular fibrillation have been very rarely reported

in heart disease patients, in as well as out of a context of hypersensitivity (see Section

4.4 Precaution for use).

The adverse reactions are listed in the table below by SOC (System Organ Class) and

by frequency with the following guidelines: very common (

1/10), common (

1/100 to

<1/10), uncommon (

1/1000 to <1/100), rare (

1/10 000 to <1/1 000), very rare (<1/10

000),

known

(cannot

estimated

from

available

data).

The frequencies

presented are derived from the data of an observational study on 352,255 patients.

System Organ Class

Frequency: adverse reaction

Immune system disorders

Rare: hypersensitivity

Very rare: anaphylactoid reaction, anaphylactic

reaction

Endocrine disorders

Very rare: thyroid disorder

Nervous system disorders

Rare: presyncope (vasovagal reaction), tremor*,

paresthesia*

Very rare: coma*, convulsions*, confusion*, visual

disorders*, amnesia*, photophobia*, transient

blindness*, somnolence*, agitation*, headache

Ear and labyrinth disorders

Rare: vertigo

Very rare: hearing impaired

Cardiac disorders

Rare: tachycardia

Very rare: cardiac arrest, myocardial infarction (more

frequent

after

intracoronary

injection),

arrhythmia,

ventricular fibrillation, angina pectoris

Vascular disorders

Rare: hypotension

Very rare: circulatory collapse

Respiratory, thoracic and

mediastinal disorders

Rare: dyspnoea, cough, tightness in the throat,

sneezing

Very rare: respiratory arrest, pulmonary oedema,

bronchospasm, laryngospasm, laryngeal oedema

Gastrointestinal disorders

Uncommon: nausea

Rare: vomiting

Very rare: abdominal pain

Skin and subcutaneous tissue

disorders

Rare: angioedema, urticaria (localised or extensive),

erythema, pruritus

Very rare: Acute Generalised Exanthematous

Pustulosis, Stevens-Johnson syndrome, Lyell's

syndrome, eczema, maculopapulous exanthema (all as

delayed hypersensitivity reactions)

Renal and urinary disorders

Very rare: acute renal failure, anuria

General disorders and

administration site conditions

Uncommon: feeling hot

Rare: facial oedema, malaise, chills, injection site pain

Very rare: injection site necrosis following

extravasation, injection site oedema, injection site

inflammation following extravasation

Investigations

Very rare: blood creatinine increased

*Examinations during which the iodinated contrast agent concentration in arterial blood

is high

The following adverse reactions were reported for other water-soluble iodinated contrast

agents:

System Organ Class

Frequency: adverse reaction

Nervous system disorders

Paralysis, paresis, hallucinations, speech disorders

Gastrointestinal disorders

abdominal

pain,

diarrhoea,

parotid

gland

enlargement, salivary hypersecretion, dysgeusia

Skin and subcutaneous tissue

disorders

Erythema multiforme

Vascular disorders

Thrombophlebitis

Investigations

Electroencephalogram abnormal, blood amylase

increased

Cardiovascular collapse of variable severity may occur immediately with no warning

signs, or may complicate the cardiovascular manifestations mentioned in the above

table.

Abdominal

pain

diarrhoea,

reported

Xenetix,

linked

mainly

administration via the oral or rectal route.

Local pain and oedema may occur at the injection site without extravasation of the

injected product and are benign and transient.

During intra-arterial administration, the sensation of pain at the injection site depends on

the osmolality of the product injected.

Paediatric population

The expected nature of the undesirable effects connected with Xenetix is the same as

that of the effects reported in adults. Their frequency cannot be estimated from the

available data.

4.9.

Overdose

If a very high dose of contrast agent is administered, the water and electrolyte loss must

be compensated by suitable rehydration. Renal function must be monitored for at least

three days. Haemodialysis may be performed if necessary.

5.

PHARMACOLOGICAL PROPERTIES

5.1.

Pharmacodynamic properties

IODINATED CONTRAST AGENT

(V: other) ATC code: V08AB11

Xenetix 250 is a urographic and angiographic water-soluble nonionic contrast agent with

an osmolality of 585 mOsm/kg.

Xenetix 300 is a urographic and angiographic water-soluble nonionic contrast agent with

an osmolality of 695 mOsm/kg.

Xenetix 350 is a urographic and angiographic water-soluble nonionic contrast agent with

an osmolality of 915 mOsm/kg.

5.2.

Pharmacokinetic properties

After intravascular injection, iobitridol is distributed in the intravascular system and

interstitial compartment. In humans, the elimination half-life is 1.8 h, the volume of

distribution is 200 mL/kg and the total clearance is 93 mL/min (mean values). Binding to

plasma proteins is negligible (< 2%). It is mainly eliminated via the kidneys (glomerular

filtration without tubular reabsorption or secretion) in unchanged form. The osmotic

diuresis induced by Xenetix is dependent on the osmolality and the volume injected.

In patients with renal insufficiency, elimination occurs mainly via the biliary route. The

substance can be dialysed.

5.3.

Preclinical safety data

Toxicological results for intravenous use show an absence of effects, or effects occurring

under conditions much more extreme than those recommended for clinical

use (dosage, repeated doses). Following the single administration of high doses (9 to 18

gI/kg), Xenetix caused transient signs of hypothermia, respiratory depression

and dose-dependent histological lesions that occurred in the target organs (liver, kidney)

included

hepatocellular

vacuolisation,

tubular

vacuolisation

dilation.

Following repeated administration of high doses (2.8 gI/kg) for 28 days in dogs, granular

vacuolar

degeneration

that

reversible

after

discontinuation

treatment

observed.

Local irritation could be observed in the event of extravasation.

Animal studies did not demonstrate any teratogenic effects.

6. PHARMACEUTICAL PARTICULARS

6.1. List of excipients

Sodium calcium edetate, trometamol, trometamol hydrochloride, sodium hydroxide or

hydrochloric acid, water for injection.

6.2. Incompatibilities

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

other medicinal products.

6.3. Shelf life

Three years.

6.4. Special precautions for storage

Store protected from light at a temperature of less than 30°C.

6.5. Nature and content of container

Xenetix 250

50 mL, 100 mL, 200 mL or 500 mL type II glass bottles with chlorobutyl rubber stoppers.

Xenetix 300, Xenetix 350

20 mL, 50 mL, 60 mL, 100 mL, 150 mL, 200 mL or 500 mL type II glass bottles with

chlorobutyl rubber stoppers.

Not all pack sizes may be marketed.

6.6. Instructions for disposal and handling

No special requirements

7.

MANUFACTURER

Guerbet, France.

8.

REGISTRATION HOLDER

Promedico Ltd. Hashiloach 6, POB 3340, Petach-Tikva.

The format of this leaflet has been defined by the MOH and its content has been

checked and approved – January 2014.