Update to section 4.8 to include HPRA reporting of suspected adverse reaction text

Update to section 4.8 to include HPRA reporting of suspected adverse reaction text

Section 4.2:
- Addition of heading 'Warning prior to use'

- Addition of the following statement under the heading 'Dosage for intravascular use'
    'Dosage should be adapted to age, weight, cardiac output, clinical question, examination technique and the nature and volume of the vascular region to be investigated'.

- Addition of the heading 'Newborns and infants' instead of 'Newborns (< 1 month) and infants (1 month - 2 months)

Section 4.5:
Addition of the following statement: 'Based on measurements of kidney function, the need for an interruption in the metformin administration should be considered'.

Section 4.7:
Addition of 'No data available' instead of 'Not known'

Section 10:
Date of revision of text: July 2013 instead of May 2013.

Section 4.2:
- Addition of heading 'Warning prior to use'

- Addition of the following statement under the heading 'Dosage for intravascular use'
    'Dosage should be adapted to age, weight, cardiac output, clinical question, examination technique and the nature and volume of the vascular region to be investigated'.

- Addition of the heading 'Newborns and infants' instead of 'Newborns (< 1 month) and infants (1 month - 2 months)

Section 4.5:
Addition of the following statement: 'Based on measurements of kidney function, the need for an interruption in the metformin administration should be considered'.

Section 4.7:
Addition of 'No data available' instead of 'Not known'

Section 10:
Date of revision of text: July 2013 instead of May 2013.

Red text = deleted text

Blue text = inserted text

 

Section 3. Pharmaceutical Form

……………………………

The physico-chemical properties of Ultravist at the concentrations listed below are:

Iodine concentration (mg/ml)	240	300	370
Osmolality (osm/kg H2O) at 37 °C Viscosity (mPa.s) at 20 °C at 37 °C	0.48 4.9 2.8	0.59 8.9 4.7	0.77 22.0 10.0
Density (g/ml) at 20 °C at 37 °C	1.263 1.255	1.328 1.322	1.409 1.399
pH-value	6.5-8.0	6.5-8.0	6.5-8.0

 

Section 4.1 Therapeutic indications

This medicinal product is for diagnostic use only.

For diagnostic use.

……………………………

 

Section 4.2 Posology and method of administration

General information

•Dietary suggestions

Normal diet may be maintained up to two hours prior to the examination. During the last two hours the patient should refrain from eating.

•Hydration

Adequate hydration must be assured before and after intravascular contrast medium administration. Disorders of water and electrolyte balance must be corrected. This applies especially to patients with multiple myeloma, diabetes mellitus, polyuria, oliguria, hyperuricemia, as well as to newborns, infants, small children and elderly patients.

•Newborns ( 1 month) and infants (1 month - 2 years)

Young infants (age < 1 year) and especially newborns are susceptible to electrolyte imbalance and haemodynamic alterations. Care should be taken regarding: the dose of contrast medium to be given, the technical performance of the radiological procedure and the patient status.

•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 countered by calm management of the patient and the use of suitable drugs.

•Warming prior to use

Contrast media which are warmed to body temperature before administration are better tolerated and can be injected more easily because of reduced viscosity.

For additional instructions see section 6.6.

•           Dosage regimen

•           Using an incubator, only the calculated number of bottles needed for the examination day should be warmed up to 37°C.

 

•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.

Dosage for intravascular use

Intravascular administration of contrast media should, if possible, be done with the patient lying down.

In patients suffering from marked renal or cardiovascular insufficiency and in patients in a poor general condition, the contrast medium dose must be kept as low as possible. In these patients it is advisable to monitor renal function in accordance with the clinical situation. for at least 3 days following the examination.

……………………………

Generally, doses of up to 1.5 g iodine per kg body weight are well tolerated.

Between separate injections the body should be given enough time for the influx of interstitial fluid to normalize the increased serum osmolality. If it is necessary in particular instances to exceed a total dose of 300 to 350 ml in the adult, additional water and possibly electrolytes should be given.

……………………………

•           Additional information on special populations

Newborns (< 1 month) and infants (1 month – 2 years)

Young infants (age <1 year) and especially newborns are susceptible to electrolyte imbalance and hemodynamic alterations. Care should be taken regarding the dose of contrast medium to be given, the technical performance of the radiological procedure and the patient status.

Elderly population (aged 65 years and above)

In a clinical study, no differences in pharmacokinetics of iopromide were observed between elderly (aged 65 years and above) and younger patients. Therefore, no specific recommendation for a dosage adjustment is given for elderly patients beside those described in subsection ‘Dosage regimen’. These general dose recommendations should not be exceeded, as the glomerular filtration rate might be physiologically slightly reduced in elderly subjects, thus increasing the risk of renal impairment aggravation by iodinated contrast agents.

Patients with hepatic impairment

Elimination of iopromide is not affected by impaired liver function as only about 2% of the dose is eliminated via feces and iopromide is not metabolized. No dosage adjustment is considered necessary in patients with hepatic impairment.

Patients with renal impairment

Since iopromide is excreted almost exclusively in an unchanged form via the kidneys, the elimination of iopromide is prolonged in patients with renal impairment. In order to reduce the risk of additional contrast media-induced renal impairment in patients with pre-existing renal impairment, the minimum possible dose should be used in these patients (see also sections 4.4 and 5.2).

Section 4.4 Special warnings and precautions for use

For all indications

The following warnings and precautions apply to any mode of administration, however, the risks mentioned are higher in intravascular administration.

Special Warnings

•           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).

Patients with hypersensitivity or a previous reaction to iodinated contrast media are at increased risk of having a severe reaction. 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 medium-related 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.

•The elderly

Underlying vascular pathology and neurological disorders often seen in the elderly constitute an increased risk of adverse reactions to iodinated contrast media.

•Very poor state of health

The need for examination merits particularly careful consideration in patients with a very poor general state of health.

Special Precautions

For all indications

•Hypersensitivity reactions

Ultravist can be associated with anaphylactoid/hypersensitivity 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 “Undesirable effects”). Most of these reactions occur within one hour of administration. However, delayed reactions (after hours to days) may occur.

The risk of hypersensitivity reactions is higher in the case of:

- previous reaction to contrast media

- history of bronchial asthma or other allergic disorders.

Patients who experience such reactions while taking beta blockers may be resistant to treatment effects of beta agonists (see also “Interactions with other medicaments and other forms of interaction”).

In the event of a severe hypersensitivity reaction, patients with cardiovascular disease are more susceptible to serious or even fatal outcomes.

Preparedness for institution of emergency measures is necessary for all patients.

If  hypersensitivity reactions occur (see section 4.8 “Undesirable effects”), administration of the contrast medium must be discontinued immediately and - if necessary - specific therapy instituted via a venous access. It is therefore advisable to use a flexible indwelling cannula for intravenous contrast medium administration. To permit immediate countermeasures to be taken in emergencies, appropriate drugs, an endotracheal tube and a respirator should be ready at hand.

If premedication is given, a corticosteroid regimen is recommended.

Intravascular use

• Renal impairment

……………………………

Adequate hydration should must be ensured in all patients who receive Ultravist administration. before contrast medium administration, preferably by maintaining intravascular infusion before and after the procedure and until the contrast medium has been cleared by the kidneys.

Avoiding additional strain on the kidneys in the form of nephrotoxic drugs, oral cholecystographic agents, arterial clamping, renal arterial angioplasty, major surgery etc. until the contrast medium has been cleared.

Postponing a new contrast medium examination until renal function returns to pre-examination levels.

Patients on dialysis, if without residual renal function, may receive contrast media 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 i Increased risk of clinically relevant haemodynamic changes and arrhythmia in patients with significant cardiac disease or severe coronary artery disease.

In patients with valvular disease and pulmonary hypertension contrast medium administration may lead to pronounced haemodynamic changes. Reactions involving ischemic ECG changes and major arrhythmia are more common in older patients and in those with pre-existing cardiac disease..

The intravascular injection of contrast media Ultravist may precipitate pulmonary oedema in patients with heart failure.

•CNS disorders

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

•           Pheochromocytoma

Patients with pheochromocytoma may be at an increased risk to develop a Risk of hypertensive crisis. Premedication with alpha-receptor blockers is recommended.

•Patients with autoimmune disorders

Cases of severe vasculitis or Stevens-Johnson like syndrome have been reported in patients with pre-existing autoimmune disorders.

•           Myasthenia gravis

The administration of iodinated contrast media Ultravist may aggravate the symptoms of myasthenia gravis.

•Alcoholism

Acute or chronic alcoholism may increase blood-brain barrier permeability. This facilitates the passage of the contrast medium into cerebral tissue, possibly leading to CNS reactions. Caution must also be exercised in alcoholics and drug addicts because of the possibility of a reduced seizure threshold.

 

•           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.

The use of plastic syringes in place of glass syringes has been reported to decrease but not eliminate the likelihood of in vitro clotting.

Caution is advised in patients with homocystinuria because of the risk of inducing thrombosis and embolism.

Use in other body cavities

The possibility of pregnancy must be excluded before performing hysterosalpingography. Inflammation of the bile ducts or salpinx may increase the risk of reactions following hysterosalpingography procedures.

Low osmolar water-soluble contrast media should be routinely used in gastrointestinal studies in newborns, infants and children because these patients are at particular risk for aspiration, intestinal occlusion or extraluminal leakage into the peritoneal cavity.

Section 4.5 Interaction with other medicaments and other forms of interaction

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’).

Transient renal impairment associated with intravascular use of Ultravist can lead to biguanide accumulation and the development of lactic acidosis in patients who are taking biguanides. As a precaution, biguanides should be stopped 48 hours before until at least 48 hours after contrast medium administration and reinstated only after baseline renal function has been regained.

Concomitant use of neuroleptics and antidepressants may reduce the seizure threshold, thus increasing the risk of a contrast medium related reaction.

Beta-blockers: Patients who experience hypersensitivity reactions while taking a beta-blocker may be resistant to treatment effects of beta agonists (see also “Special Precautions”).

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

•Interference with diagnostic tests

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.

Section 4.6 Pregnancy and lactation

Pregnancy

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

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

Section 4.7 Effects on ability to drive and use machines

No data available.Not Known.

Section 4.8 Undesirable effects

Summary of the safety profile

The overall safety profile of Ultravist is based on data obtained in pre-marketing studies in more than 3900 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’.

Table 1: Adverse drug reactions (ADRs) reported in clinical trials or during post marketing surveillance in patients treated with Ultravist 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, vomiting, a sensation of pain and a general feeling of warmth are the most frequently recorded reactions.

All indications:

System organ class	Common (> 1/100)	Uncommon (> 1/1,000, <1/100)	Rare (< 1/1,000)	Not Known
Immune system disorders Immunological		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) Anaphylactoid reactions / hypersensitivity	Anaphylactoid shock (including fatal cases)
Endocrine disorders			Alteration in thyroid function, thyrotoxic crisis	Thyrotoxic crisis, Thyroid disorder
Psychiatric disorders			Anxiety
Nervous, Psychiatric system disorders	Dizziness, Headache, Dysgeusia	Vasovagal reactions, Confused state, Restlessness, Paraesthesia / Hypoaesthesia, Somnolence Dizziness, restlessness	Paraesthesia / hypoaesthesia, confusion, anxiety, agitation, amnesia, speech disorders, somnolence, unconsciousness , coma, tremor, convulsion, paresis / paralysis, cerebral ischaemia / infarction, stroke Transient cortical blindnessa	Coma*), Cerebral ischaemia / infarction*), Stroke*), Brain edemaa) *), Convulsion*), Transient cortical blindnessa), Loss of consciousness , Agitation, Amnesia, Tremor, Speech disorders, Paresis / Paralysis
Eye disorders	Blurred / Disturbed vision	Blurred / disturbed vision	Conjunctivitis, lacrimation
Ear and labyrinth disorders			Hearing disorders	Hearing disorders
Cardiac disorders	Chest pain / discomfort	Arrhythmia	Palpitations, chest pain / tightness, bradycardia, tachycardia, Ccardiac arrest*), heart failure, Mmyocardial ischaemia*) / infarction cyanosis	Myocardial infarction*), Cardiac failure*), Bradycardia*), Tachycardia, Cyanosis*)
Vascular disorders	Hypertension Vasodilatation	Hypotension*) Vasodilatation	Hypotension, hypertension, shock Vasospasma, thromboembolic eventsa	Shock*), Thromboembolic eventsa) Vasospasma)
Respiratory thoracic and mediastinal disorders		Dyspnea*) Sneezing, coughing	Rhinitis, dyspnoea, mucosal swelling, asthma, hoarseness, laryngeal / pharyngeal / tongue / face oedema, bronchospasm, laryngeal / pharyngeal spasm, pulmonary oedema, respiratory insufficiency, respiratory arrest	Pulmonary edema*), Respiratory insufficiency*), Aspiration*)
Gastrointestinal disorders	Vomiting, Nausea	Abdominal PainVomiting, taste disturbance	Throat irritation, dysphagia, swelling of salivary glands, abdominal pain, diarrhoea	Dysphagia, Salivary gland enlargement, Diarrhoea
Skin and subcutaneous tissue disorders		Urticaria, pruritus, rash, erythema	Angioedema, mucocutaneous syndrome (e.g. Stevens- Johnson’s or Lyell syndrome)	Bullous conditions (e.g. Stevens- Johnson’s or Lyell syndrome), Rash, Erythema, Hyperhydrosis
Musculoskeletal, connective tissue and bone disorders				Compartment syndrome in case of extravasationa)
Renal and urinary disorders		Renal impairmenta	Acute renal failurea	Renal impairmenta) , Acute renal failurea)
General disorders and administration site conditions	Pain, Injection site reactions (various kinds e.g. pain, warmth§), edema§), inflammation§) and soft tissue injury§) in case of extravasation), Feeling hotHeat or pain sensations, headache	EdemaMalaise, chills, sweating, vasovagal reactions	Pallor, body temperature alterations, oedema Local pain, mild warmth and oedema, inflammation and tissue injury in case of extravasation	Malaise, Chills, Pallor
Investigations				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.

Frequency estimates are based on data obtained in pre-marketing studies in more

than 3900 patients and post-marketing studies in more than 74 000 patients, as well

as data from spontaneous reporting and the literature. (Frequency estimations are

based predominantly on intravascular use).

Section 4.9 Overdose

Results from acute toxicity studies in animals do not indicate a risk of acute intoxication following use of Ultravist.

 

·         Intravascular overdose

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

In case of inadvertent intravascular overdosage, it is recommended to mMonitor fluids, electrolytes, and renal function. Treatment of overdose should be directed towards the support of vital functions.

Ultravist is dialyzabledialyzable (see section ‘Pharmacokinetic properties’). In the event of accidental intravascular overdose in humans, the water and electrolyte losses must be compensated by infusion. Renal function needs monitoring for at least the next 3 days. If needed, haemodialysis can be used to eliminate the bulk of the contrast medium from the patient's system.

 

Section 5.1 Pharmacodynamic properties

 

Pharmacotherapeutic group: Watersoluble, nephrotropic, low osmolar X-ray contrast media ATC code: V08AB05

The contrast-giving substance in the Ultravist formulations is iopromide, a non-ionic water-soluble derivative of triiodinated isophthalic acid with a molecular weight of 791.12 in which the firmly bound iodine absorbs the X-rays.

 

Injection of iopromide opacifies those vessels or body cavities in the path of flow of the contrast agent, permitting radio-graphic visualization of the internal structures until significant dilution occurs.

Physico-chemical characteristics:

Iopromide, the contrast-giving substance of Ultravist, is a triiodinated, non ionic, water-soluble X-ray contrast medium with a molecular weight of 791.12. The physico-chemical characteristics of the injectable solutions of Ultravist at the concentrations listed below are:

                       

Iodine concentration (mg/ml)	240	300	370
Osmolality (osm/kg H2O) at 37 °C	0.48	0.59	0.77
Viscosity (mPa•s) at 20 °C at 37 °C	4.9 2.8	8.9 4.7	22.0 10.0
Density (g/ml) at 20 °C at 37 °C	1.263 1.255	1.328 1.322	1.409 1.399
pH-value	6.5-8.0	6.5-8.0	6.5-8.0

 

Section 5.2 Pharmacokinetic properties

•           General Information

Iopromide behaves in the organism like other highly hydrophilic biologically inert, renally excreted compounds (e.g. mannitol or inulin).

 

•           Absorption and dDistribution:

Following intravenousascular administration, plasma concentrations of iopromide declineUltravist is very rapidly due to distribution intodistributed in the extracellular space and subsequent elimination. The total distribution volume at steady state is about 16L corresponding roughly to the volume of the extracellular space.

 

Protein binding is negligible (about 1%). There is no indication that iopromide crosses the intact blood-brain-barrier. A small amount crossed the placental barrier in animal studies (≤0.3% of the dose were found in rabbit fetuses)

 

Following administration in the biliary and/or pancreatic duct during Endoscopic Retrograde Cholangiopancreaticography (ERCP), iodinated contrast agents are systemically absorbed and reach peak plasma concentrations between 1 and 4 h post administration. Maximum serum iodine levels following a mean dose of about 7.3 g iodine were about factor 40 lower compared to maximum serum levels reached after respective intravenous doses.

, the half-life being 3 minutes.

Plasma protein binding with a concentration of 1.2 mg I/ml plasma is 0.9 ± 0.2 %. It is unable to cross the intact blood-brain barrier but a small amount does cross the placental barrier (rabbit). Five 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.

 

•           Metabolism:

Iopromide is not metabolized.

No metabolites were demonstrable in man following administration of the clinically relevant doses of Ultravist.

 

•           Elimination:

The terminal elimination half-life in patients with normal kidney functionof iopromide is approximately 2 hours, irrespective of the dose. In the dose range tested, the mean total clearance of iopromide amounts to 106 ± 12 ml/min and is similar to the renal clearance of 102 ± 15 ml/min. Thus, excretion of iopromide is almost exclusively renal. Only about 2% of the dose administered is excreted via the fecal route within 3 days.

Approximately 60% of the dose is excreted within 3 hours after intravenous administration via urine. In the mean ≥ 93% of dose was recovered within 12 hours. Excretion is essentially complete within 24 hours.

Following administration into the biliary and/or the pancreatic duct for ERCP urinary iodine serum concentrations returned to pre-dose levels within 7 days.

 

•           Linearity/non-linearity

The pharmacokinetic parameters of iopromide in humans change dose proportionally (e.g. Cmax, AUC) or are dose independent (e.g. Vss, t1/2).

Under the doses recommended for diagnostic purposes, filtration of Ultravist is exclusively glomerular. Renal excretion is approximately 18 % of the dose within 30 minutes p. inj., approximately 60 % within 3 hours p. inj. and 92 % within 24 hours p. inj. The total clearance was 110 and 103 ml/min. at the lower dose levels (with 150 mg iodine/ml) and at the higher dose levels (with 370 mg iodine/ml), respectively.

•           Characteristics in special patient populations:

Elderly population (aged 65 years and above)

Middle-aged patients (49 - 64 years) and elderly patients (65 - 70 years), without significantly impaired renal function, had total plasma clearances between 74 and 114 ml/min (middle aged group, mean 102 ml/min) and between 72 and 110 ml/min (elderly group, mean 89 ml/min), which is only marginally lower than those in young healthy subjects (88 to 138 ml/min, mean 106 ml/min). The individual elimination half-lives were between 1.9 - 2.9 hours and 1.5 - 2.7 hours, respectively. Compared to the range of 1.4 to 2.1 h in young healthy volunteers, terminal half-lives are similar. The minor differences correspond to the physiologically reduced glomerular filtration rate with age.

 

Paediatric Population

Pharmacokinetics of iopromide have not been investigated in the pediatric population (see section 4.2).

 

Patients with renal impairment

In patients with impaired renal function, the plasma half-life of iopromide is prolonged according to the reduced glomerular filtration rate.

The plasma clearance was reduced to 49.4 ml/min/1.73 m2 (CV = 53%) in mildly and moderately impaired patients (80> CLCR >30 ml/min/1.73 m2) and to 18.1 ml/min/1.73 m2 (CV = 30%) in severely impaired patients not depending on dialysis (CLCR = 30 – 10 ml/min/1.73 m2).

 The mean terminal half-life is 6.1 hours (CV = 43%) in mildly and moderately impaired patients (80 ≥ CLCR > 30 ml/min/1.73 m2) and 11.6 hours (CV = 49%) in severely impaired patients not depending on dialysis (CLCR = 30 – 10 ml/min/1.73 m2).

The amount recovered in urine within 6 h post dose was 38% in mildly to moderately impaired patients and 26% in severely impaired patients, compared to more than 83% in healthy volunteers. Within 24 h post dose the recovery was 60% in mildly to moderately and 51% in severely impaired patients, compared to more than 95% in healthy volunteers.

Iopromide In end-stage renal failure patients, non-ionic contrast media can be eliminated by hemodialysis. Approximately 60% of the iopromide dose is removed during a 3 hour dialysis.

 

Patients with hepatic impairment

Elimination in patients with impaired liver function is not affected because only about 21.5 % of dose are excreted in faeces after 3 days.

 

Section 6.1 List of excipients

Sodium calcium edetate

Hydrochloric acid (for pH adjustment)

Trometamol Hydrochloric acid, dilute

Water for injection

Section 6.2 Incompatibilities

Contrast mediaUltravist must not be mixed with any other drugs medicinal products to avoid the risk of possible incompatibilities.

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

Section 6.6 Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product

……………………………

•           Visual IInspection

Ultravist is supplied ready to use as a clear, colourless to pale yellow solution.

……………………………

Section 10. Date of Revision of the Text

February 2009 May 2013

Red text = deleted text

Blue text = inserted text

 

Section 3. Pharmaceutical Form

……………………………

The physico-chemical properties of Ultravist at the concentrations listed below are:

Iodine concentration (mg/ml)	240	300	370
Osmolality (osm/kg H2O) at 37 °C Viscosity (mPa.s) at 20 °C at 37 °C	0.48 4.9 2.8	0.59 8.9 4.7	0.77 22.0 10.0
Density (g/ml) at 20 °C at 37 °C	1.263 1.255	1.328 1.322	1.409 1.399
pH-value	6.5-8.0	6.5-8.0	6.5-8.0

 

Section 4.1 Therapeutic indications

This medicinal product is for diagnostic use only.

For diagnostic use.

……………………………

 

Section 4.2 Posology and method of administration

General information

•Dietary suggestions

Normal diet may be maintained up to two hours prior to the examination. During the last two hours the patient should refrain from eating.

•Hydration

Adequate hydration must be assured before and after intravascular contrast medium administration. Disorders of water and electrolyte balance must be corrected. This applies especially to patients with multiple myeloma, diabetes mellitus, polyuria, oliguria, hyperuricemia, as well as to newborns, infants, small children and elderly patients.

•Newborns ( 1 month) and infants (1 month - 2 years)

Young infants (age < 1 year) and especially newborns are susceptible to electrolyte imbalance and haemodynamic alterations. Care should be taken regarding: the dose of contrast medium to be given, the technical performance of the radiological procedure and the patient status.

•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 countered by calm management of the patient and the use of suitable drugs.

•Warming prior to use

Contrast media which are warmed to body temperature before administration are better tolerated and can be injected more easily because of reduced viscosity.

For additional instructions see section 6.6.

•           Dosage regimen

•           Using an incubator, only the calculated number of bottles needed for the examination day should be warmed up to 37°C.

 

•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.

Dosage for intravascular use

Intravascular administration of contrast media should, if possible, be done with the patient lying down.

In patients suffering from marked renal or cardiovascular insufficiency and in patients in a poor general condition, the contrast medium dose must be kept as low as possible. In these patients it is advisable to monitor renal function in accordance with the clinical situation. for at least 3 days following the examination.

……………………………

Generally, doses of up to 1.5 g iodine per kg body weight are well tolerated.

Between separate injections the body should be given enough time for the influx of interstitial fluid to normalize the increased serum osmolality. If it is necessary in particular instances to exceed a total dose of 300 to 350 ml in the adult, additional water and possibly electrolytes should be given.

……………………………

•           Additional information on special populations

Newborns (< 1 month) and infants (1 month – 2 years)

Young infants (age <1 year) and especially newborns are susceptible to electrolyte imbalance and hemodynamic alterations. Care should be taken regarding the dose of contrast medium to be given, the technical performance of the radiological procedure and the patient status.

Elderly population (aged 65 years and above)

In a clinical study, no differences in pharmacokinetics of iopromide were observed between elderly (aged 65 years and above) and younger patients. Therefore, no specific recommendation for a dosage adjustment is given for elderly patients beside those described in subsection ‘Dosage regimen’. These general dose recommendations should not be exceeded, as the glomerular filtration rate might be physiologically slightly reduced in elderly subjects, thus increasing the risk of renal impairment aggravation by iodinated contrast agents.

Patients with hepatic impairment

Elimination of iopromide is not affected by impaired liver function as only about 2% of the dose is eliminated via feces and iopromide is not metabolized. No dosage adjustment is considered necessary in patients with hepatic impairment.

Patients with renal impairment

Since iopromide is excreted almost exclusively in an unchanged form via the kidneys, the elimination of iopromide is prolonged in patients with renal impairment. In order to reduce the risk of additional contrast media-induced renal impairment in patients with pre-existing renal impairment, the minimum possible dose should be used in these patients (see also sections 4.4 and 5.2).

Section 4.4 Special warnings and precautions for use

For all indications

The following warnings and precautions apply to any mode of administration, however, the risks mentioned are higher in intravascular administration.

Special Warnings

•           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).

Patients with hypersensitivity or a previous reaction to iodinated contrast media are at increased risk of having a severe reaction. 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 medium-related 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.

•The elderly

Underlying vascular pathology and neurological disorders often seen in the elderly constitute an increased risk of adverse reactions to iodinated contrast media.

•Very poor state of health

The need for examination merits particularly careful consideration in patients with a very poor general state of health.

Special Precautions

For all indications

•Hypersensitivity reactions

Ultravist can be associated with anaphylactoid/hypersensitivity 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 “Undesirable effects”). Most of these reactions occur within one hour of administration. However, delayed reactions (after hours to days) may occur.

The risk of hypersensitivity reactions is higher in the case of:

- previous reaction to contrast media

- history of bronchial asthma or other allergic disorders.

Patients who experience such reactions while taking beta blockers may be resistant to treatment effects of beta agonists (see also “Interactions with other medicaments and other forms of interaction”).

In the event of a severe hypersensitivity reaction, patients with cardiovascular disease are more susceptible to serious or even fatal outcomes.

Preparedness for institution of emergency measures is necessary for all patients.

If  hypersensitivity reactions occur (see section 4.8 “Undesirable effects”), administration of the contrast medium must be discontinued immediately and - if necessary - specific therapy instituted via a venous access. It is therefore advisable to use a flexible indwelling cannula for intravenous contrast medium administration. To permit immediate countermeasures to be taken in emergencies, appropriate drugs, an endotracheal tube and a respirator should be ready at hand.

If premedication is given, a corticosteroid regimen is recommended.

Intravascular use

• Renal impairment

……………………………

Adequate hydration should must be ensured in all patients who receive Ultravist administration. before contrast medium administration, preferably by maintaining intravascular infusion before and after the procedure and until the contrast medium has been cleared by the kidneys.

Avoiding additional strain on the kidneys in the form of nephrotoxic drugs, oral cholecystographic agents, arterial clamping, renal arterial angioplasty, major surgery etc. until the contrast medium has been cleared.

Postponing a new contrast medium examination until renal function returns to pre-examination levels.

Patients on dialysis, if without residual renal function, may receive contrast media 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 i Increased risk of clinically relevant haemodynamic changes and arrhythmia in patients with significant cardiac disease or severe coronary artery disease.

In patients with valvular disease and pulmonary hypertension contrast medium administration may lead to pronounced haemodynamic changes. Reactions involving ischemic ECG changes and major arrhythmia are more common in older patients and in those with pre-existing cardiac disease..

The intravascular injection of contrast media Ultravist may precipitate pulmonary oedema in patients with heart failure.

•CNS disorders

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

•           Pheochromocytoma

Patients with pheochromocytoma may be at an increased risk to develop a Risk of hypertensive crisis. Premedication with alpha-receptor blockers is recommended.

•Patients with autoimmune disorders

Cases of severe vasculitis or Stevens-Johnson like syndrome have been reported in patients with pre-existing autoimmune disorders.

•           Myasthenia gravis

The administration of iodinated contrast media Ultravist may aggravate the symptoms of myasthenia gravis.

•Alcoholism

Acute or chronic alcoholism may increase blood-brain barrier permeability. This facilitates the passage of the contrast medium into cerebral tissue, possibly leading to CNS reactions. Caution must also be exercised in alcoholics and drug addicts because of the possibility of a reduced seizure threshold.

 

•           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.

The use of plastic syringes in place of glass syringes has been reported to decrease but not eliminate the likelihood of in vitro clotting.

Caution is advised in patients with homocystinuria because of the risk of inducing thrombosis and embolism.

Use in other body cavities

The possibility of pregnancy must be excluded before performing hysterosalpingography. Inflammation of the bile ducts or salpinx may increase the risk of reactions following hysterosalpingography procedures.

Low osmolar water-soluble contrast media should be routinely used in gastrointestinal studies in newborns, infants and children because these patients are at particular risk for aspiration, intestinal occlusion or extraluminal leakage into the peritoneal cavity.

Section 4.5 Interaction with other medicaments and other forms of interaction

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’).

Transient renal impairment associated with intravascular use of Ultravist can lead to biguanide accumulation and the development of lactic acidosis in patients who are taking biguanides. As a precaution, biguanides should be stopped 48 hours before until at least 48 hours after contrast medium administration and reinstated only after baseline renal function has been regained.

Concomitant use of neuroleptics and antidepressants may reduce the seizure threshold, thus increasing the risk of a contrast medium related reaction.

Beta-blockers: Patients who experience hypersensitivity reactions while taking a beta-blocker may be resistant to treatment effects of beta agonists (see also “Special Precautions”).

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

•Interference with diagnostic tests

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.

Section 4.6 Pregnancy and lactation

Pregnancy

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

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

Section 4.7 Effects on ability to drive and use machines

No data available.Not Known.

Section 4.8 Undesirable effects

Summary of the safety profile

The overall safety profile of Ultravist is based on data obtained in pre-marketing studies in more than 3900 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’.

Table 1: Adverse drug reactions (ADRs) reported in clinical trials or during post marketing surveillance in patients treated with Ultravist 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, vomiting, a sensation of pain and a general feeling of warmth are the most frequently recorded reactions.

All indications:

System organ class	Common (> 1/100)	Uncommon (> 1/1,000, <1/100)	Rare (< 1/1,000)	Not Known
Immune system disorders Immunological		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) Anaphylactoid reactions / hypersensitivity	Anaphylactoid shock (including fatal cases)
Endocrine disorders			Alteration in thyroid function, thyrotoxic crisis	Thyrotoxic crisis, Thyroid disorder
Psychiatric disorders			Anxiety
Nervous, Psychiatric system disorders	Dizziness, Headache, Dysgeusia	Vasovagal reactions, Confused state, Restlessness, Paraesthesia / Hypoaesthesia, Somnolence Dizziness, restlessness	Paraesthesia / hypoaesthesia, confusion, anxiety, agitation, amnesia, speech disorders, somnolence, unconsciousness , coma, tremor, convulsion, paresis / paralysis, cerebral ischaemia / infarction, stroke Transient cortical blindnessa	Coma*), Cerebral ischaemia / infarction*), Stroke*), Brain edemaa) *), Convulsion*), Transient cortical blindnessa), Loss of consciousness , Agitation, Amnesia, Tremor, Speech disorders, Paresis / Paralysis
Eye disorders	Blurred / Disturbed vision	Blurred / disturbed vision	Conjunctivitis, lacrimation
Ear and labyrinth disorders			Hearing disorders	Hearing disorders
Cardiac disorders	Chest pain / discomfort	Arrhythmia	Palpitations, chest pain / tightness, bradycardia, tachycardia, Ccardiac arrest*), heart failure, Mmyocardial ischaemia*) / infarction cyanosis	Myocardial infarction*), Cardiac failure*), Bradycardia*), Tachycardia, Cyanosis*)
Vascular disorders	Hypertension Vasodilatation	Hypotension*) Vasodilatation	Hypotension, hypertension, shock Vasospasma, thromboembolic eventsa	Shock*), Thromboembolic eventsa) Vasospasma)
Respiratory thoracic and mediastinal disorders		Dyspnea*) Sneezing, coughing	Rhinitis, dyspnoea, mucosal swelling, asthma, hoarseness, laryngeal / pharyngeal / tongue / face oedema, bronchospasm, laryngeal / pharyngeal spasm, pulmonary oedema, respiratory insufficiency, respiratory arrest	Pulmonary edema*), Respiratory insufficiency*), Aspiration*)
Gastrointestinal disorders	Vomiting, Nausea	Abdominal PainVomiting, taste disturbance	Throat irritation, dysphagia, swelling of salivary glands, abdominal pain, diarrhoea	Dysphagia, Salivary gland enlargement, Diarrhoea
Skin and subcutaneous tissue disorders		Urticaria, pruritus, rash, erythema	Angioedema, mucocutaneous syndrome (e.g. Stevens- Johnson’s or Lyell syndrome)	Bullous conditions (e.g. Stevens- Johnson’s or Lyell syndrome), Rash, Erythema, Hyperhydrosis
Musculoskeletal, connective tissue and bone disorders				Compartment syndrome in case of extravasationa)
Renal and urinary disorders		Renal impairmenta	Acute renal failurea	Renal impairmenta) , Acute renal failurea)
General disorders and administration site conditions	Pain, Injection site reactions (various kinds e.g. pain, warmth§), edema§), inflammation§) and soft tissue injury§) in case of extravasation), Feeling hotHeat or pain sensations, headache	EdemaMalaise, chills, sweating, vasovagal reactions	Pallor, body temperature alterations, oedema Local pain, mild warmth and oedema, inflammation and tissue injury in case of extravasation	Malaise, Chills, Pallor
Investigations				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.

Frequency estimates are based on data obtained in pre-marketing studies in more

than 3900 patients and post-marketing studies in more than 74 000 patients, as well

as data from spontaneous reporting and the literature. (Frequency estimations are

based predominantly on intravascular use).

Section 4.9 Overdose

Results from acute toxicity studies in animals do not indicate a risk of acute intoxication following use of Ultravist.

 

·         Intravascular overdose

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

In case of inadvertent intravascular overdosage, it is recommended to mMonitor fluids, electrolytes, and renal function. Treatment of overdose should be directed towards the support of vital functions.

Ultravist is dialyzabledialyzable (see section ‘Pharmacokinetic properties’). In the event of accidental intravascular overdose in humans, the water and electrolyte losses must be compensated by infusion. Renal function needs monitoring for at least the next 3 days. If needed, haemodialysis can be used to eliminate the bulk of the contrast medium from the patient's system.

 

Section 5.1 Pharmacodynamic properties

 

Pharmacotherapeutic group: Watersoluble, nephrotropic, low osmolar X-ray contrast media ATC code: V08AB05

The contrast-giving substance in the Ultravist formulations is iopromide, a non-ionic water-soluble derivative of triiodinated isophthalic acid with a molecular weight of 791.12 in which the firmly bound iodine absorbs the X-rays.

 

Injection of iopromide opacifies those vessels or body cavities in the path of flow of the contrast agent, permitting radio-graphic visualization of the internal structures until significant dilution occurs.

Physico-chemical characteristics:

Iopromide, the contrast-giving substance of Ultravist, is a triiodinated, non ionic, water-soluble X-ray contrast medium with a molecular weight of 791.12. The physico-chemical characteristics of the injectable solutions of Ultravist at the concentrations listed below are:

                       

Iodine concentration (mg/ml)	240	300	370
Osmolality (osm/kg H2O) at 37 °C	0.48	0.59	0.77
Viscosity (mPa•s) at 20 °C at 37 °C	4.9 2.8	8.9 4.7	22.0 10.0
Density (g/ml) at 20 °C at 37 °C	1.263 1.255	1.328 1.322	1.409 1.399
pH-value	6.5-8.0	6.5-8.0	6.5-8.0

 

Section 5.2 Pharmacokinetic properties

•           General Information

Iopromide behaves in the organism like other highly hydrophilic biologically inert, renally excreted compounds (e.g. mannitol or inulin).

 

•           Absorption and dDistribution:

Following intravenousascular administration, plasma concentrations of iopromide declineUltravist is very rapidly due to distribution intodistributed in the extracellular space and subsequent elimination. The total distribution volume at steady state is about 16L corresponding roughly to the volume of the extracellular space.

 

Protein binding is negligible (about 1%). There is no indication that iopromide crosses the intact blood-brain-barrier. A small amount crossed the placental barrier in animal studies (≤0.3% of the dose were found in rabbit fetuses)

 

Following administration in the biliary and/or pancreatic duct during Endoscopic Retrograde Cholangiopancreaticography (ERCP), iodinated contrast agents are systemically absorbed and reach peak plasma concentrations between 1 and 4 h post administration. Maximum serum iodine levels following a mean dose of about 7.3 g iodine were about factor 40 lower compared to maximum serum levels reached after respective intravenous doses.

, the half-life being 3 minutes.

Plasma protein binding with a concentration of 1.2 mg I/ml plasma is 0.9 ± 0.2 %. It is unable to cross the intact blood-brain barrier but a small amount does cross the placental barrier (rabbit). Five 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.

 

•           Metabolism:

Iopromide is not metabolized.

No metabolites were demonstrable in man following administration of the clinically relevant doses of Ultravist.

 

•           Elimination:

The terminal elimination half-life in patients with normal kidney functionof iopromide is approximately 2 hours, irrespective of the dose. In the dose range tested, the mean total clearance of iopromide amounts to 106 ± 12 ml/min and is similar to the renal clearance of 102 ± 15 ml/min. Thus, excretion of iopromide is almost exclusively renal. Only about 2% of the dose administered is excreted via the fecal route within 3 days.

Approximately 60% of the dose is excreted within 3 hours after intravenous administration via urine. In the mean ≥ 93% of dose was recovered within 12 hours. Excretion is essentially complete within 24 hours.

Following administration into the biliary and/or the pancreatic duct for ERCP urinary iodine serum concentrations returned to pre-dose levels within 7 days.

 

•           Linearity/non-linearity

The pharmacokinetic parameters of iopromide in humans change dose proportionally (e.g. Cmax, AUC) or are dose independent (e.g. Vss, t1/2).

Under the doses recommended for diagnostic purposes, filtration of Ultravist is exclusively glomerular. Renal excretion is approximately 18 % of the dose within 30 minutes p. inj., approximately 60 % within 3 hours p. inj. and 92 % within 24 hours p. inj. The total clearance was 110 and 103 ml/min. at the lower dose levels (with 150 mg iodine/ml) and at the higher dose levels (with 370 mg iodine/ml), respectively.

•           Characteristics in special patient populations:

Elderly population (aged 65 years and above)

Middle-aged patients (49 - 64 years) and elderly patients (65 - 70 years), without significantly impaired renal function, had total plasma clearances between 74 and 114 ml/min (middle aged group, mean 102 ml/min) and between 72 and 110 ml/min (elderly group, mean 89 ml/min), which is only marginally lower than those in young healthy subjects (88 to 138 ml/min, mean 106 ml/min). The individual elimination half-lives were between 1.9 - 2.9 hours and 1.5 - 2.7 hours, respectively. Compared to the range of 1.4 to 2.1 h in young healthy volunteers, terminal half-lives are similar. The minor differences correspond to the physiologically reduced glomerular filtration rate with age.

 

Paediatric Population

Pharmacokinetics of iopromide have not been investigated in the pediatric population (see section 4.2).

 

Patients with renal impairment

In patients with impaired renal function, the plasma half-life of iopromide is prolonged according to the reduced glomerular filtration rate.

The plasma clearance was reduced to 49.4 ml/min/1.73 m2 (CV = 53%) in mildly and moderately impaired patients (80> CLCR >30 ml/min/1.73 m2) and to 18.1 ml/min/1.73 m2 (CV = 30%) in severely impaired patients not depending on dialysis (CLCR = 30 – 10 ml/min/1.73 m2).

 The mean terminal half-life is 6.1 hours (CV = 43%) in mildly and moderately impaired patients (80 ≥ CLCR > 30 ml/min/1.73 m2) and 11.6 hours (CV = 49%) in severely impaired patients not depending on dialysis (CLCR = 30 – 10 ml/min/1.73 m2).

The amount recovered in urine within 6 h post dose was 38% in mildly to moderately impaired patients and 26% in severely impaired patients, compared to more than 83% in healthy volunteers. Within 24 h post dose the recovery was 60% in mildly to moderately and 51% in severely impaired patients, compared to more than 95% in healthy volunteers.

Iopromide In end-stage renal failure patients, non-ionic contrast media can be eliminated by hemodialysis. Approximately 60% of the iopromide dose is removed during a 3 hour dialysis.

 

Patients with hepatic impairment

Elimination in patients with impaired liver function is not affected because only about 21.5 % of dose are excreted in faeces after 3 days.

 

Section 6.1 List of excipients

Sodium calcium edetate

Hydrochloric acid (for pH adjustment)

Trometamol Hydrochloric acid, dilute

Water for injection

Section 6.2 Incompatibilities

Contrast mediaUltravist must not be mixed with any other drugs medicinal products to avoid the risk of possible incompatibilities.

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

Section 6.6 Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product

……………………………

•           Visual IInspection

Ultravist is supplied ready to use as a clear, colourless to pale yellow solution.

……………………………

Section 10. Date of Revision of the Text

February 2009 May 2013

 

 

Section 7:   Marketing authorisation holder has been transferred to Bayer Limited for Ultravist 240 (50ml) and Ultravist 300 (50 ml, 75 ml, 100 ml, 150 ml and 200 ml).

 

HE Clissmann T/A Schering

72 Heather Road

Dublin 18

And   Bayer Limited The Atrium Blackthorn Road Dublin 18

 

8. Marketing Authorisation Numbers

Ultravist 240 (50 ml)	PA 1410/11/1
Ultravist 300 (20 ml)	PA 12/60/2
Ultravist 300 (50 ml, 75 ml, 100 ml, 150 ml and 200 ml)	PA 1410/11/3
Ultravist 370 (50 ml, 100 ml, 150 ml, 200 ml)	PA 12/60/5

Section 7:   Marketing authorisation holder has been transferred to Bayer Limited for Ultravist 240 (50ml) and Ultravist 300 (50 ml, 75 ml, 100 ml, 150 ml and 200 ml).

 

HE Clissmann T/A Schering

72 Heather Road

Dublin 18

And   Bayer Limited The Atrium Blackthorn Road Dublin 18

 

8. Marketing Authorisation Numbers

Ultravist 240 (50 ml)	PA 1410/11/1
Ultravist 300 (20 ml)	PA 12/60/2
Ultravist 300 (50 ml, 75 ml, 100 ml, 150 ml and 200 ml)	PA 1410/11/3
Ultravist 370 (50 ml, 100 ml, 150 ml, 200 ml)	PA 12/60/5

Section 6.2 Incompatibilities

The text was changed from

“This product should not be mixed with any other medicinal product.”

to

“Contrast media must not be mixed with any other drugs to avoid the risk of possible incompatibilities”

 

Section 6.6 Instructions for Use and handling: Bullet point, Inspection

The text was changed from;

“Ultravist is supplied ready to use as a clear, colourless to pale yellow solution. Contrast media should not be used in case of severe discolouration, the occurrence of particulate matter or defective container.”

to

“Ultravist is supplied ready to use as a clear, colourless to pale yellow solution. 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, crystallisation (milky-cloudy appearance and/or sediment at bottom or floating crystals) may occur very rarely.”

 

 

Section 10 Date of Revision of the Text:

The date was updated from “ November 2006 ” to “ May 2007”.

Section 6.2 Incompatibilities

The text was changed from

“This product should not be mixed with any other medicinal product.”

to

“Contrast media must not be mixed with any other drugs to avoid the risk of possible incompatibilities”

 

Section 6.6 Instructions for Use and handling: Bullet point, Inspection

The text was changed from;

“Ultravist is supplied ready to use as a clear, colourless to pale yellow solution. Contrast media should not be used in case of severe discolouration, the occurrence of particulate matter or defective container.”

to

“Ultravist is supplied ready to use as a clear, colourless to pale yellow solution. 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, crystallisation (milky-cloudy appearance and/or sediment at bottom or floating crystals) may occur very rarely.”

 

 

Section 10 Date of Revision of the Text:

The date was updated from “ November 2006 ” to “ May 2007”.

Main changes to the SPC include:

 

SECTION 2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Addition of the following information: The medicinal product contains 12.3 micrograms sodium per ml.

 

SECTION 4.2 POSOLOGY AND METHOD OF ADMINISTRATION

 

Section, General Information

Information in this section has been updated and is now laid out under the following headings:

• Dietary suggestions
• Hydration
• Newborns (< 1 month) and infants (1 month to 2 years)
• Anxiety
• Warming prior to use
• Pretesting

Section, Dosage for Intravascular Use

Addition of general information including the following:

-         information regarding use in patients with marked renal / cardiovascular insufficiency or in a poor general condition

-         dosage should be adapted to age, weight, cardiac output, clinical question, examination technique and the nature and volume of the vascular region to be investigated

-         dosages stated are recommendations only and based upon average adult weighing 70 kg.

 

Recommended dosages and information are provided for each of the approved indications. The following changes / additions have been made:

Intravenous DSA – no longer recommended for contrast demonstrations of the pulmonary arteries and arteries of the neck, head, kidneys and extremities.

Computerised Tomography – additional information regarding injection technique; use of Spiral CT.

Intravenous Urography – small change to recommended filming times for newborns, infants and patients.

 

Section, Dosage for Use in Body Cavities

New section for the SPC

 

SECTION 4.3 CONTRAINDICATIONS

Deletion of a contraindication: ‘Hysterosalpingography must not be performed during pregnancy or in the presence of acute inflammatory processes in the pelvic cavity.’

 

SECTION 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Information in this section has been updated and extended and is now laid out under the following headings:

 

Special Warnings

• Hypersensitivity reactions
• Thyroid dysfunction
• The elderly
• Very poor state of health

Special Precautions

            For all indications

·         Hypersensitivity reactions

 

Use in other body cavities

 

Intravascular Use

·         Renal impairment

·         Cardiovascular disease

·         CNS disorders

·         Pheochromocytoma

·         Patients with autoimmune disorders

·         Myasthenia gravis

·         Alcoholism

·         Thromboembolic events

 

SECTION 4.5 INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION

Addition of information regarding the interaction between Ultravist and neuroleptics / antidepressants.

 

Change to information provided regarding interactions with the following substances; biguanides, beta blockers and Interleukin-2.

 

SECTION 4.6 PREGANACY AND LACTATION

Updated information regarding use during pregnancy and lactation.

 

SECTION 4.7 ABILITY TO DRIVE AND USE MACHINERY

Text of this section has been revised to, ‘No data available’.

 

SECTION 4.8 UNDESIRABLE EFFECTS

Undesirable effects have been tabulated according to the System Organ Class affected and the frequency of occurrence.

In addition, the additonal possible undesirable effects have been included in the following categories:

Endocrine, Nervous / Psychiatric, Eye, Ear, Cardiac, Vascular, Respiratory, Gastrointestinal, Skin and Subcutaneous, General Disorders and Administration Site Conditions

 

SECTION 4.9 OVERDOSE

Revised and extended information provided regarding intravascular overdose of Ultravist.

 

SECTION 5.1 PHARMACODYNAMIC PROPERTIES

Addition of a table outlining the physicochemical properties of Ultravist solution.

 

SECTION 5.2 PHARMACOKINETIC PROPERTIES

Details of the Distribution, Metabolism, Elimination and Characteristics in Patients are described..

 

SECTION 5.3 PRECLINICAL SAFETY DATA

Updated in line with the most recently available information. Information is provided in relation to the following topics: Systemic toxicity, Local tolerance and contact-sensitizing potential, Genotoxic potential / tumorigenicity

 

SECTION 6.3 SHELF LIFE

Increased detail regarding in-use storage times.

 

SECTION 6.6 INSTRUCTIONS FOR USE, HANDLING AND DISPOSAL

Information presented in three sections

·         Inspection

·         Handling of vial / bottle presentations

·         Handling of large volume ( > 200 ml) presentations

Main changes to the SPC include:

 

SECTION 2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Addition of the following information: The medicinal product contains 12.3 micrograms sodium per ml.

 

SECTION 4.2 POSOLOGY AND METHOD OF ADMINISTRATION

 

Section, General Information

Information in this section has been updated and is now laid out under the following headings:

• Dietary suggestions
• Hydration
• Newborns (< 1 month) and infants (1 month to 2 years)
• Anxiety
• Warming prior to use
• Pretesting

Section, Dosage for Intravascular Use

Addition of general information including the following:

-         information regarding use in patients with marked renal / cardiovascular insufficiency or in a poor general condition

-         dosage should be adapted to age, weight, cardiac output, clinical question, examination technique and the nature and volume of the vascular region to be investigated

-         dosages stated are recommendations only and based upon average adult weighing 70 kg.

 

Recommended dosages and information are provided for each of the approved indications. The following changes / additions have been made:

Intravenous DSA – no longer recommended for contrast demonstrations of the pulmonary arteries and arteries of the neck, head, kidneys and extremities.

Computerised Tomography – additional information regarding injection technique; use of Spiral CT.

Intravenous Urography – small change to recommended filming times for newborns, infants and patients.

 

Section, Dosage for Use in Body Cavities

New section for the SPC

 

SECTION 4.3 CONTRAINDICATIONS

Deletion of a contraindication: ‘Hysterosalpingography must not be performed during pregnancy or in the presence of acute inflammatory processes in the pelvic cavity.’

 

SECTION 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Information in this section has been updated and extended and is now laid out under the following headings:

 

Special Warnings

• Hypersensitivity reactions
• Thyroid dysfunction
• The elderly
• Very poor state of health

Special Precautions

            For all indications

·         Hypersensitivity reactions

 

Use in other body cavities

 

Intravascular Use

·         Renal impairment

·         Cardiovascular disease

·         CNS disorders

·         Pheochromocytoma

·         Patients with autoimmune disorders

·         Myasthenia gravis

·         Alcoholism

·         Thromboembolic events

 

SECTION 4.5 INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION

Addition of information regarding the interaction between Ultravist and neuroleptics / antidepressants.

 

Change to information provided regarding interactions with the following substances; biguanides, beta blockers and Interleukin-2.

 

SECTION 4.6 PREGANACY AND LACTATION

Updated information regarding use during pregnancy and lactation.

 

SECTION 4.7 ABILITY TO DRIVE AND USE MACHINERY

Text of this section has been revised to, ‘No data available’.

 

SECTION 4.8 UNDESIRABLE EFFECTS

Undesirable effects have been tabulated according to the System Organ Class affected and the frequency of occurrence.

In addition, the additonal possible undesirable effects have been included in the following categories:

Endocrine, Nervous / Psychiatric, Eye, Ear, Cardiac, Vascular, Respiratory, Gastrointestinal, Skin and Subcutaneous, General Disorders and Administration Site Conditions

 

SECTION 4.9 OVERDOSE

Revised and extended information provided regarding intravascular overdose of Ultravist.

 

SECTION 5.1 PHARMACODYNAMIC PROPERTIES

Addition of a table outlining the physicochemical properties of Ultravist solution.

 

SECTION 5.2 PHARMACOKINETIC PROPERTIES

Details of the Distribution, Metabolism, Elimination and Characteristics in Patients are described..

 

SECTION 5.3 PRECLINICAL SAFETY DATA

Updated in line with the most recently available information. Information is provided in relation to the following topics: Systemic toxicity, Local tolerance and contact-sensitizing potential, Genotoxic potential / tumorigenicity

 

SECTION 6.3 SHELF LIFE

Increased detail regarding in-use storage times.

 

SECTION 6.6 INSTRUCTIONS FOR USE, HANDLING AND DISPOSAL

Information presented in three sections

·         Inspection

·         Handling of vial / bottle presentations

·         Handling of large volume ( > 200 ml) presentations