ULTRAVIST Solution for injection Ref.[9475] Active ingredients: Iopromide

For all indications

Hypersensitivity reactions

Ultravist can be associated with anaphylactoid/hypersensitivity (see section 4.3) or other idiosyncratic reactions characterized by cardiovascular, respiratory and cutaneous manifestations. Allergy-like reactions ranging from mild to severe reactions including shock are possible (see section 4.8). Most of these reactions occur within 30 minutes of administration. However, delayed reactions (after hours to days) may occur.

The risk of hypersensitivity reactions is higher in case of:

• previous reaction to contrast media
• history of bronchial asthma or other allergic disorders.

Particularly careful risk/benefit judgement is required in patients with known hypersensitivity to Ultravist or any excipient of Ultravist, or with a previous hypersensitivity reaction to any other iodinated contrast medium due to an increased risk for hypersensitivity reactions (including severe reactions).

However, such reactions are irregular and unpredictable in nature.

Patients who experience such reactions while taking beta blockers may be resistant to treatment effects of beta agonists (see also section 4.5). In the event of a severe hypersensitivity reaction, patients with cardiovascular disease are more susceptible to serious or even fatal outcomes. Due to the possibility of severe hypersensitivity reactions after administration, post-procedure observation of the patient is recommended. Preparedness for institution of emergency measures is necessary for all patients.

In patients with an increased risk of acute allergy-like reactions, patients with a previous moderate or severe acute reaction, asthma or allergy requiring medical treatment, premedication with a corticosteroid regimen may be considered.

Thyroid dysfunction

Iodinated contrast media may induce hyperthyroidism and thyreotoxic crisis in patients with hyperthyroidism or goiter. Testing of thyroid function prior to Ultravist administration and/or preventative thyreostatic medication may be considered in patients with suspected hyperthyroidism.

In neonates, especially preterm infants, who have been exposed to Ultravist, either through the mother during pregnancy or in the neonatal period, it is recommended to monitor thyroid function, as an exposure to excess iodine may cause hypothyroidism, possibly requiring treatment.

CNS disorders

Patients with CNS disorders may be at increased risk to have neurological complications in relationship to Ultravist administration. Neurological complications are more frequent in cerebral angiography and related procedures. Caution should be exercised in situations in which there may be a reduced seizure threshold, such as a previous history of seizures and the use of certain concomitant medication.

Factors which increase blood-brain barrier permeability facilitate the passage of the contrast medium into cerebral tissue, possibly leading to CNS reactions.

Hydration

Adequate hydration must be assured before and after intravascular and intrathecal Ultravist administration in order to minimize the risk of contrast media-induced nephrotoxicity (see also subsection ‘Intravascular use’ – ‘Renal impairment’). This applies especially to patients with multiple myeloma, diabetes mellitus, polyuria, oliguria, hyperuricemia, as well as to newborns, infants, small children and elderly patients.

Anxiety Pronounced states of excitement, anxiety and pain may increase the risk of side effects or intensify contrast mediumrelated reactions. Care should be taken to minimize the state of anxiety in such patients.

Pretesting

Sensitivity testing using a small test dose of contrast medium is not recommended as it has no predictive value. Furthermore, sensitivity testing itself has occasionally led to serious and even fatal hypersensitivity reactions.

Intravascular use

Renal impairment

Contrast media-induced nephrotoxicity, presenting as a transient impairment of renal function, may occur after intravascular administration of Ultravist. Acute renal failure may occur in rare cases.

Risk factors include, e.g.:

pre-existing renal insufficiency,
dehydration,
diabetes mellitus,
multiple myeloma/paraproteinemia,
repetitive and/or large doses of Ultravist.

Adequate hydration must be ensured in all patients who receive Ultravist administration.

Patients on dialysis, if without residual renal function, may receive Ultravist for radiological procedures as iodinated contrast media are cleared by the dialysis process.

Cardiovascular disease

Patients with significant cardiac disease or severe coronary artery disease are at an increased risk of developing clinically relevant haemodynamic changes and arrhythmia. The intravascular injection of Ultravist may precipitate pulmonary oedema in patients with heart failure.

Pheochromocytoma

Patients with pheochromocytoma may be at an increased risk to develop a hypertensive crisis.

Myasthenia gravis

The administration of Ultravist may aggravate the symptoms of myasthenia gravis.

Thromboembolic events

A property of non-ionic contrast media is the low interference with normal physiological functions. As a consequence of this, non-ionic contrast media have less anticoagulant activity in vitro than ionic media.

Numerous factors in addition to the contrast medium, including length of procedure, number of injections, catheter and syringe material, underlying disease state and concomitant medication may contribute to the development of thromboembolic events. Therefore, when performing vascular catheterization procedures one should be aware of this and pay meticulous attention to the angiographic technique and flush the catheter frequently with physiological saline (if possible with the addition of heparin) and minimize the length of the procedure so as to minimize the risk of procedure-related thrombosis and embolism.

Biguanides (metformin): In patients with acute kidney failure or severe chronic kidney disease biguanide elimination can be reduced leading to accumulation and the development of lactic acidosis. As the application of Ultravist can lead to renal impairment or an aggravation of renal impairment, patients treated with metformin may be at an increased risk of developing lactic acidosis, especially those with prior renal impairment (see section 4.4 – subsection ‘Intravascular use’ – ‘Renal impairment’). Based on measurements of kidney function, the need for an interruption in the metformin administration should be considered.

Interleukin-2: Previous treatment (up to several weeks) with Interleukin-2 is associated with an increased risk for delayed reactions to Ultravist.

Radioisotopes: Diagnosis and treatment of thyroid disorders with thyrotropic radioisotopes may be impeded for up to several weeks after administration of Ultravist due to reduced radioisotope uptake.

The use of certain concomitant medication may reduce the seizure threshold, thus increasing the risk of a contrast medium related reaction (see also section ‘4.4 Special warnings and precautions for use’).

Caution must also be exercised in alcoholics because of the possibility of a reduced seizure threshold.

Pregnancy

Adequate and well-controlled studies in pregnant women have not been conducted. It has not been sufficiently demonstrated that non ionic contrast media are safe for use in pregnant patients. Since, wherever possible, radiation exposure should be avoided during pregnancy, the benefits of any X-ray examination – with or without contrast media – should be carefully weighed against the possible risk.

Animal studies do not indicate harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development following diagnostic application of iopromide in humans.

Lactation

Safety of Ultravist for nursed infants has not been investigated. Contrast media are poorly excreted in human breast milk. Harm to the nursed infant is not likely (see also section 4.4 – subsection ‘Thyroid dysfunction’).

No data available.

Summary of the safety profile

The overall safety profile of Ultravist is based on data obtained in pre-marketing studies in more than 3,900 patients and post-marketing studies in more than 74,000 patients, as well as data from spontaneous reporting and the literature. The most frequently observed adverse drug reactions (≥4%) in patients receiving Ultravist are headache, nausea and vasodilatation.

The most serious adverse drug reactions in patients receiving Ultravist are anaphylactoid shock, respiratory arrest, bronchospasm, laryngeal edema, pharyngeal edema, asthma, coma, cerebral infarction, stroke, brain edema, convulsion, arrhythmia, cardiac arrest, myocardial ischemia, myocardial infarction, cardiac failure, bradycardia, cyanosis, hypotension, shock, dyspnea, pulmonary edema, respiratory insufficiency and aspiration.

Tabulated list of adverse reactions

The adverse drug reactions observed with Ultravist are represented in the table below. They are classified according to System Organ Class (MedDRA version 13.0). The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.

Adverse drug reactions from clinical trials are classified according to their frequencies. Frequency groupings are defined according to the following convention:

common (≥1/100 to <1/10)
uncommon (≥1/1,000 to <1/100)
rare (≥1/10,000 to <1/1,000)

The adverse drug reactions identified only during post-marketing surveillance, and for which a frequency could not be estimated, are listed under ‘not known’.

Immune system disorders

Uncommon: Hypersensitivity/Anaphylactoid reactions (Anaphylactoid shock§*, Respiratory arrest§*, Bronchospasm*, Laryngeal*/Pharyngeal*/Face edema, Tongue edema§, Laryngeal/Pharyngeal spasm§, Asthma§*, Conjunctivitis§, Lacrimation§, Sneezing, Cough, Mucosal edema, Rhinitis§, Hoarseness§, Throat irritation§, Urticaria, Pruritus, Angioedema)

Endocrine disorders

Not Known: Thyrotoxic crisis, Thyroid disorder

Psychiatric disorders

Rare: Anxiety

Nervous system disorders

Common: Dizziness, Headache, Dysgeusia

Uncommon: Vasovagal reactions, Confused state, Restlessness, Paraesthesia/Hypoaesthesia, Somnolence

Not Known: Coma*, Cerebral ischaemia/infarction*, Stroke*, Brain edema^a*, Convulsion*, Transient cortical blindness^a, Loss of consciousness, Agitation, Amnesia, Tremor, Speech disorders, Paresis/Paralysis

Eye disorders

Common: Blurred/Disturbed vision

Ear and labyrinth disorders

Not Known: Hearing disorders

Cardiac disorders

Common: Chest pain/discomfort

Uncommon: Arrhythmia

Rare: Palpitations, Cardiac arrest*, Myocardial ischaemia*

Not Known: Myocardial infarction*, Cardiac failure*, Bradycardia*, Tachycardia, Cyanosis*

Vascular disorders

Common: Hypertension, Vasodilatation

Uncommon: Hypotension*

Not Known: Shock*, Thromboembolic events^a, Vasospasm^a

Respiratory thoracic and mediastinal disorders

Uncommon: Dyspnea*

Not Known: Pulmonary edema*, Respiratory insufficiency*, Aspiration*

Gastrointestinal disorders

Common: Vomiting, Nausea

Uncommon: Abdominal Pain

Not Known: Dysphagia, Salivary gland enlargement, Diarrhoea

Skin and subcutaneous tissue disorders

Not Known: Bullous conditions (e.g. StevensJohnson’s or Lyell syndrome), Rash, Erythema, Hyperhydrosis

Musculoskeletal, connective tissue and bone disorders

Not Known: Compartment syndrome in case of extravasationa)

Renal and urinary disorders

Not Known: Renal impairment^a, Acute renal failure^a

General disorders and administration site conditions

Common: Pain, Injection site reactions (various kinds e.g. pain, warmth§, edema§, inflammation§ and soft tissue injury§ in case of extravasation), Feeling hot

Uncommon: Edema

Not Known: Malaise, Chills, Pallor

Investigations

Not Known: Body temperature fluctuation

* life-threatening and/or fatal cases have been reported
^a intravascular use only
^§ identified only during post-marketing surveillance (frequency not known)

In addition to the adverse drug reactions (ADRs) listed above, the following ADRs have been reported with intrathecal use: Chemical meningitis and meningism at an unknown frequency.

In addition to the ADRs listed above, the following ADRs have been reported with use for ERCP: Elevation of pancreatic enzyme levels and pancreatitis at an unknown frequency. The majority of the reactions after myelography or use in body cavities occur some hours after the administration.

Description of selected adverse reactions

Based on experience with other non-ionic contrast media, the following undesirable effects may occur with intrathecal use in addition to the undesirable effects listed above:

Psychosis, neuralgia, paraplegia, aseptic meningitis, back pain, pain in extremities, micturition disorder, EEG Abnormal.

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. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

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