Ultravist 370

1. Name Of The Medicinal Product

Ultravist® 370

2. Qualitative And Quantitative Composition

1ml contains 769mg of iopromide (equivalent to 370mg iodine).

3. Pharmaceutical Form

Aqueous solution for injection.

4. Clinical Particulars

4.1 Therapeutic Indications

X-ray contrast medium for computerised tomography, digital subtraction angiography, intravenous urography, venography (phlebography), arteriography, arthrography, hysterosalpingography and fistulography.

4.2 Posology And Method Of Administration

• General information

Experience shows that contrast medium is tolerated better if it is warmed to body temperature.

Intravenous urography

Adults: The minimum dose is 0.8ml/kg body weight Ultravist 370, (1ml/kg Ultravist 300 or 1.3ml/kg Ultravist 240). These doses should provide adequate filling of the ureters. It may be necessary to increase the dose in individual cases.

Children: The poor concentrating ability of the immature nephron of infantile kidneys necessitates the use of relatively high doses of contrast medium, i.e. for Ultravist 300:

Neonates:	4.0 ml/kg body weight
Babies:	3.0 ml/kg body weight
Small children:	1.5 ml/kg body weight

Computerised tomography

Cranial CT: The following dosages are recommended for cranial CT:

Ultravist 240:	1.5-2.5ml/kg body weight
Ultravist 300:	1-2ml/kg body weight
Ultravist 370:	1-1.5ml/kg body weight

Whole-body CT: For whole-body computerised tomography, the doses of contrast medium and the rates of administration depend on the organs under investigation, the diagnostic problem and, in particular, the different scan and image-reconstruction times of the scanners in use.

Angiography: The dosage depends on the age, weight, cardiac output and general condition of the patient, the clinical problem, examination technique and the nature and volume of the vascular region to be investigated.

The following dosages may serve as a guide:

Cerebral angiography

Aortic arch angiography	50-80 ml Ultravist 300/inj.
Selective angiography	6-15 ml Ultravist 300/inj.
Retrograde carotid angiography	30-40 ml Ultravist 300/inj.
Thoracic aortography:	50-80 ml Ultravist 300/inj.
Abdominal aortography:	40-60 ml Ultravist 300/inj.
Bifemoral arteriography: Peripheral angiography:	40-60 ml Ultravist 300/inj.

Upper extremities:

Arteriography	8-12 ml Ultravist 300/inj.
Venography	50-60 ml Ultravist 240/inj. 15-30 ml Ultravist 300/inj.

Lower extremities:

Arteriography	20-30 ml Ultravist 300/inj.
Venography	50-80 ml Ultravist 240/inj. 30-60 ml Ultravist 300/inj.

Angiocardiography:

Cardiac-ventriculography	40-60 ml Ultravist 370/inj.
Coronary angiography:	5-8 ml Ultravist 370/inj.

Digital subtraction angiography (DSA): I.V. injection of 30-60 ml Ultravist 300 or 370 as a bolus (flow-rate: 8-12 ml/second into the cubital vein; 10-20 ml/second into the vena cava) is recommended for high-contrast demonstrations of the great vessels, of the pulmonary arteries and of the arteries of the neck, head, kidneys and extremities.

Intra-arterial digital subtraction angiography requires smaller volumes and lower iodine concentrations than the intravenous technique.

4.3 Contraindications

Uncontrolled thyrotoxicosis (see section 4.4).

4.4 Special Warnings And Precautions For Use

• Hypersensitivity reactions

As Ultravist can be associated with anaphylactoid/hypersensitivity or other idiosyncratic reactions with cardiovascular, respiratory and/or cutaneous effects, appropriate emergency drugs and equipment should be available for immediate use. It is also advisable to use a flexible indwelling cannula for intravenous contrast medium administration.

Due to an increased risk of hypersensitivity reactions, particularly careful risk/benefit judgment is required in patients:

- with known hypersensitivity to Ultravist or any excipient of Ultravist

- with a previous hypersensitivity reaction to any other iodinated contrast medium

- history of bronchial asthma or other allergic disorders.

If pre-medication is given, a corticosteroid regimen is recommended.

Allergy-like reactions range from mild to severe (including shock – see section 4.8). Most reactions occur within one hour of administration. However, as with other contrast agents, delayed reaction (after hours to days) may occur.

In order to minimise risk if a severe reaction should occur, patients:

- should lie down during Ultravist administration

- must be kept under close observation for 15 minutes following the last injection as the majority of severe reactions occur at this time

- should remain in the hospital environment (but not necessarily the radiology department) for one hour after the last injection, and should be advised to return to the radiology department immediately if any symptoms develop.

If the administration does not take place on the X-ray table, any patient with a labile circulation should be brought to the X-ray machine sitting or lying down.

If hypersensitivity reactions occur, administration of the contrast medium must be stopped at once and – if necessary – specific therapy instituted intravenously. Patients who experience hypersensitivity reactions while taking beta-blockers may be resistant to treatment effects of beta agonists (see section 4.5). In the event of a severe hypersensitivity reaction, patients with cardiovascular disease are more susceptible to serious or even fatal outcomes.

• Thyroid dysfunction

Particularly careful risk/benefit judgement is required in patients with known or suspected hyperthyroidism or goitre, as iodinated contrast media may induce hyperthyroidism and thyrotoxic crisis in these patients. Testing of thyroid function prior to Ultravist administration and/or preventive thyrostatic medication may be considered in patients with known or suspected hyperthyroidism.

• Cerebral arteriosclerosis, pulmonary emphysema or poor general health

For patients with cerebral arteriosclerosis, pulmonary emphysema or poor general health, the need for examination with X-ray contrast media merits careful consideration.

• Renal impairment

Contrast media-induced nephrotoxicity, presenting as a transient impairment of renal function, may occur after intravascular administration of iodinated contrast media.

Acute renal failure may occur in rare cases.

Risk factors include, for example:

- pre-existing renal insufficiency

- dehydration

- diabetes mellitus

- multiple myeloma / paraproteinaemia

- repetitive and / or large doses of iodinated contrast media.

• Hydration

Adequate hydration should be ensured in all patients who receive Ultravist administration. This applies especially to patients with multiple myeloma, diabetes mellitus, polyuria, oliguria or gout and in babies, small children and patients in a very poor state of health. Existing disturbances of the balance of water and electrolytes must be corrected before the administration of Ultravist.

• Cardiovascular disease

There is an increased risk of clinically relevant haemodynamic changes and arrhythmia in patients with significant cardiac disease or severe coronary artery disease. In the event of a severe hypersensitivity reaction, patients with cardiovascular disease are more susceptible to serious or even fatal outcomes.

• CNS disorders

Patients with seizure history or other CNS disorders may be at increased risk of seizures and neurological complications with administration of iodinated contrast media. Neurological complications are more frequent in cerebral angiography and related procedures.

• Thromboembolic events

Non-ionic contrast media have less anticoagulant activity in-vitro than ionic media. Meticulous attention should therefore be paid to angiographic technique. Non-ionic media should not be allowed to remain in contact with blood in a syringe, and intravascular catheters should be flushed frequently with physiological saline solution (if necessary with heparin added) to minimise the risk of clotting, which has rarely led to serious thromboembolic complications of the procedure.

• Phaeochromocytoma

Premedication with an alpha-blocker is recommended in patients with phaeochromocytoma because of the risk of blood pressure crises.

• Anxiety

Experience shows that pronounced states of excitement, anxiety and pain can be the cause of side effects or intensify contrast medium-related reactions. They can be counteracted by calm management of the patient and the use of suitable drugs.

• Myelography

Ultravist should not be used in myelography.

• Hysterosalpingography

Hysterosalpingography must not be carried out during pregnancy or in patients with acute inflammatory conditions in the pelvic cavity.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Biguanides (metformin): Diabetic nephropathy may predispose to renal impairment following intravascular contrast medium administration. This may precipitate lactic acidosis in patients who are taking biguanides. As a precaution, biguanides should be stopped 48 hours prior to the contrast medium examination and reinstated only after control of renal function has been regained.

Beta-blockers: Patients who experience hypersensitivity reactions while taking beta-blockers may be resistant to treatment effects of beta agonists (see section 4.4).

Interleukin: The prevalence of delayed reactions (e.g. fever, rash, flu-like symptoms, joint pain and pruritus) to contrast media is higher in patients who have received interleukin.

Radioisotopes: If iodine isotopes are to be administered for the diagnosis of thyroid disease, it should be borne in mind that after the administration of iodinated contrast media which are excreted via the kidneys, the capacity of the thyroid tissue to take up iodine will be reduced for 2 weeks and sometimes up to 6 weeks.

4.6 Pregnancy And Lactation

X-ray examinations should, if possible, be avoided during pregnancy. It has not yet been proved beyond question that Ultravist may be used without hesitation in pregnant patients. Therefore, an examination with a contrast medium during pregnancy should be carried out only if considered absolutely necessary by the physician.

It is not known whether Ultravist enters the breast milk.

4.7 Effects On Ability To Drive And Use Machines

There is no known effect on the ability to drive or operate machines. However, because of the risk of reactions, driving or operating machinery is not advisable for one hour after the last injection (see Section 4.4).

4.8 Undesirable Effects

Undesirable effects in association with the use of iodinated contrast media are usually mild to moderate and transient in nature. However, severe and life-threatening reactions as well as deaths have been reported. Nausea, headache, a sensation of pain and a general feeling of warmth are the most frequently recorded reactions.

System organ class	Common (	Uncommon (	Rare (< 1/1,000)
Immunological		Anaphylactoid reactions / hypersensitivity	Anaphylactoid shock (including fatal cases)
Endocrine			Alteration in thyroid function, thyrotoxic crisis
Nervous, Psychiatric		Dizziness, restlessness	Paraesthesia / hypoaesthesia, confusion, anxiety, agitation, amnesia, speech disorders, somnolence, unconciousness, coma, tremor, convulsion, paresis / paralysis, cerebral ischaemia / infarction, stroke. Transient cortical blindnessa
Eye		Blurred / disturbed vision	Conjunctivitis, lacrimation.
Ear			Hearing disorders.
Cardiac		Arrhythmia	Palpitations, chest pain / tightness, bradycardia, tachycardia, cardiac arrest, heart failure, myocardial ischaemia/infarction, cyanosis.
Vascular		Vasodilatation	Hypotension, hypertension, shock. Vasospasm,a thromboembolic eventsa
Respiratory		Sneezing, coughing	Rhinitis, dyspnoea, mucosal swelling, asthma, hoarseness, laryngeal / pharyngeal / tongue / face oedema, bronchospasm, laryngeal/pharyngeal spasm, pulmonary oedema, respiratory insufficiency, respiratory arrest.
Gastrointestinal	Nausea	Vomiting, taste disturbance	Throat irritation , dysphagia, swelling of salivary glands, abdominal pain, diarrhoea
Skin and subcutaneous tissue		Urticaria, pruritus, rash, erythema	Angioedema, mucocutaneous syndrome (e.g. Stevens-Johnson's or Lyell's syndrome)
Renal and urinary		Renal impairmenta	Acute renal failurea
General disorders and administration site conditions	Heat or pain sensations, headache	Malaise, chills, sweating, vasovagal reactions	Pallor, body temperature alterations, oedema Local pain, mild warmth and oedema, inflammation and tissue injury in case of extravasation

^a intravascular use only

Frequency estimates are based on data obtained in pre-marketing studies in more than 3900 patients and post-marketing studies in more than 74000 patients, as well as data from spontaneous reporting and literature. (Frequency estimations are based predominantly on intravascular use.).

4.9 Overdose

Symptoms may include fluid and electrolyte imbalance, renal failure, cardiovascular and pulmonary complications.

Monitor fluids, electrolytes and renal function. Treatment of overdose should be directed towards the support of vital functions.

Ultravist is dialysable.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Ultravist (iopromide) is a non-ionic contrast medium for intravascular radiological examinations and has only minimal pharmacological activity within the body.

The rate of protein binding is low and iopromide is a weak liberator of histamine. Cardiovascular and renal tolerance are good.

Ultravist has low osmolality.

The physico-chemical characteristics of the Ultravist range are listed below:

Iodine concentration (mg/ml)	150	240	300	370
Osmolality (osm/kg H2O) at 37 °C	0.33	0.48	0.59	0.77
Viscosity (mPa·s) at 20 °C at 37 °C	2.3 1.5	4.9 2.8	8.9 4.7	22.0 10.0
Density (g/ml) at 20 °C at 37 °C	1.164 1.158	1.263 1.255	1.328 1.322	1.409 1.399

5.2 Pharmacokinetic Properties

Following intravascular administration, iopromide is very rapidly distributed in the extracellular space. Plasma protein binding with a concentration of 1.2mg I/ml plasma is 0.9±0.2%. 5 minutes after intravenous bolus injection (within 1-5 min) of Ultravist 300, 28 ±6% of the dose was found in the total plasma volume, irrespective of the size of the dose. The contrast medium is first of all rapidly distributed, the half-life being 3 minutes, while the elimination half-life in patients with normal kidney function is approximately 2 hours, irrespective of the size of the dose. Under the doses recommended for diagnostic purposes, filtration of iopromide is exclusively glomerular. Renal excretion is approximately 18% of the dose within 30 minutes, approximately 60% within 3 hours and 92% within 24 hours. No metabolites were demonstrable in man following administration of the clinically relevant doses of iopromide.

5.3 Preclinical Safety Data

There are no pre-clinical safety data which could be of relevance to the prescriber and which are not already included in other relevant sections of the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium calcium edetate, trometamol,hydrochloric acid (diluted 10%), water for injection.

6.2 Incompatibilities

Some radiologists give an antihistamine or a corticosteroid prophylactically to patients with a history of allergy.

Because of possible precipitation, X-ray contrast media and prophylactic agents must not be injected as mixed solutions.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

Store below 30°C. Protect from light and X-rays.

6.5 Nature And Contents Of Container

Colourless glass infusion bottles of 50, 75, 100 and 200 ml. Colourless glass ampoules of 30 ml. Packs of 10 x 50 or 75 ml bottles and 1 x 100 or 200ml bottles.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Contrast media should be visually inspected prior to use and must not be used, if discoloured, nor in the presence of particulate matter (including crystals) or defective containers. As Ultravist is a highly concentrated solution, crystallization (milky-cloudy appearance and/or sediment at the bottom, or floating crystals) may occur very rarely.

The contrast medium solution should not be drawn up into the syringe of the infusion bottle attached to the infusion set until immediately before the examination.

Vials containing contrast medium are not intended for the withdrawal of multiple doses. The rubber stopper should never be pierced more than once.

Contrast medium solution not used in one examination session must be discarded.

7. Marketing Authorisation Holder

Bayer plc

Bayer House

Strawberry Hill

Newbury

Berkshire RG14 1JA

United Kingdom

Trading as Bayer plc, Bayer Schering Pharma

8. Marketing Authorisation Number(S)

PL 00010/0567

9. Date Of First Authorisation/Renewal Of The Authorisation

1 May 2008

10. Date Of Revision Of The Text

25 September 2009