Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Omniscan 0.5 mmol/ml Solution for Injection

2 QUALITATIVE AND QUANTITATIVE COMPOSTION

Active ingredient	Content per ml	Function
GADODIAMIDE (GdDTPA-BMA)	287 mg equiv. 0.5 mmol	MRI-contrast agent

Omniscan injection is a non-ionic paramagnetic contrast medium with the following physicochemical properties:

Osmolality (mOsm/kg H₂O) at 37 °C    780

Viscosity (mPa*s) at 20 °C    2.8

Viscosity (mPa*s) at 37 °C    1.9

Density at 20 °C (kg/l)    1.15

Molar relaxivity

r1 (mM-1 • s-1)    at 20    MHz    and 37    °C    3.9

r1 (mM-1 • s-1)    at 10    MHz    and 37    °C    4.6

r2 (mM-1 • s-1)    at 10    MHz    and 37    °C    5.1

pH 6.0 - 7.0

Gadodiamide is freely soluble in water.

Excipient(s) with known effect:

Omniscan also contains sodium 0.62mg/ml

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Solution for injection, for intravenous use. The product is a clear, colourless to slightly yellow aqueous solution.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Contrast medium for cranial and spinal magnetic resonance imaging (MRI) and for general MRI of the body after intravenous administration.

The product provides contrast enhancement and facilitates visualisation of abnormal structures or lesions in various parts of the body including the CNS.

For cardiac MRI, the product is indicated for the evaluation of coronary artery disease (CAD) by myocardial perfusion imaging MRI (stress/rest and late enhancement examination) for the detection and localization of coronary artery disease (CAD) and differentiation between areas of ischaemia and infarction in subjects with known or suspected CAD.

4.2 Posology and method of administration

No special preparation of the patient is required. OMNISCAN should be drawn into the syringe immediately before use. Both the vial and the bottle are intended for one patient only. Contrast medium not used in one examination must be discarded. For both adults and children the required dose should be administered as a single intravenous injection. To ensure complete injection of the contrast medium, the intravenous line may be flushed with sodium chloride injection 0.9%.

CNS

Dosage for adults and children

The recommended dosage is 0.1 mmol/kg body weight (equivalent to 0.2 ml/kg b.w.) up to 100 kg. Above 100 kg body weight 20 ml is usually sufficient to provide diagnostically adequate contrast.

Adults only

When brain metastases are suspected in patients with equivocal scans after administration of the 0.1 mmol/kg b.w. injection, a second bolus injection of 0.2 mmol/kg b.w. (equiv. to 0.4 ml/kg b.w.) up to 100 kg b.w. may be of additional diagnostic value when administered within 20 minutes of the first injection. Above 100 kg b.w. a second bolus injection of 40 ml should be sufficient to provide diagnostically adequate contrast.

Whole body

Dosage for adults and children from 2 years of age

The recommended dosage is 0.1 mmol/kg b.w. (equiv. to 0.2 ml/kg b.w.) up to 100 kg. Above 100 kg b.w. 20 ml is usually sufficient to provide diagnostically adequate contrast. Omniscan has also been used in a limited number of children below 2 years of age.

CNS and Whole body only

Contrast-enhanced MRI should start shortly after administration of the contrast medium, depending on the pulse sequences used and the protocol for the examination. Optimal enhancement is observed within the first minutes after injection (time depending on type of lesion/tissue). Enhancement is generally lasting up to 45 minutes after contrast medium injection.

T1-weighted scanning sequences are particularly suitable for contrast-enhanced examinations with Omniscan. In the investigated range of field strengths, from 0.15 Tesla up to 1.5 Tesla, the relative image contrast was found to be independent of the applied field strength.

Angiography

Dosage for adults

The recommended dosage is 0.1 mmol/kg body weight (equivalent to 0.2 ml/kg b.w.). The efficacy and safety of Omniscan for use in angiography in children under the age of 18 years has not been established.

Imaging should be performed during the first pass of the contrast agent, during and immediately after injection, depending on the MR equipment used, to obtain optimal contrast effect.

Mammography

Dosage for adults

The recommended dosage is 0.1 - 0.2 mmol/kg body weight (equivalent to 0.2 - 0.4 ml/kg b.w.). Above 100 kg b.w. 20 ml - 40 ml is usually sufficient to provide diagnostically adequate contrast.

Coronary Artery Disease (CAD)

Dosage for adults

The recommended dosage for evaluation of cardiac perfusion is 0.15 mmol/kg b.w. (equiv. to 0.3 ml/kg b.w.) given as two separate doses of 0.075 mmol/kg b.w. (equiv. to 0.15 ml/kg b.w.) administered within an interval of >10 minutes; one at pharmacological stress followed by one at rest. For the intravenous bolus injection in cardiac MRI, the use of a suitable injector is recommended at a rate of up to 8 ml/sec. An adequate pharmacological stress agent should be administered via separate intravenous line. For the evaluation of late enhancement only, a total dose of 0.15 mmol/kg b.w. is recommended

The CAD indication has not been studied in children.

Special Populations

Renal impairment

Omniscan is contraindicated in patients with severe renal impairment (GFR < 30 ml/min/1.73m²) and/or acute kidney injury and in patients in the perioperative liver transplantation period (see section 4.3). Omniscan should only be used after careful risk/benefit evaluation in patients with moderate renal impairment (GFR 30-59 ml/min/1.73m²) at a dose not exceeding 0.1 mmol/kg body weight (see section 4.4). More than one dose should not be used during a scan. Because of the lack of information on repeated administration, Omniscan injections should not be repeated unless the interval between injections is at least 7 days.

Neonates up to 4 weeks of age and infants up to 1 year of age

Omniscan is contraindicated in neonates up to 4 weeks of age (see section 4.3).

Due to immature renal function in infants up to 1 year of age, Omniscan should only be used in these patients after careful consideration at a dose not exceeding 0.1 mmol/kg body weight. More than one dose should not be used during a scan. Because of the lack of information on repeated administration, Omniscan injections should not be repeated unless the interval between injections is at least 7 days.

Elderly (aged 65 years and above)

No dosage adjustment is considered necessary. Caution should be exercised in elderly patients (see section 4.4).

4.3 Contra-indications

Omniscan should not be used in patients known to have hypersensitivity to Omniscan or its constituents.

Omniscan is contraindicated in patients with severe renal impairment (GFR | <30ml/min/1.73m²) and/or acute kidney injury, in patients in the perioperative liver transplantation period and in neonates up to 4 weeks of age (see section 4.4).

4.4 Special warnings and precautions for use

The possibility of a reaction, including serious, life-threatening, fatal, anaphylactoid or cardiovascular reactions or other idiosyncratic reactions should always be considered, especially in those patients with a known clinical hypersensitivity or a history of asthma or other allergic respiratory disorders. A course of action should therefore be planned in advance, with necessary drugs and equipment available for immediate treatment should a serious reaction occur.

Transitory changes in serum iron (within the normal range in the majority of cases) have been observed in some patients after administration of Omniscan. The clinical significance of this, if any, is not known, but all patients in whom this effect was observed remained asymptomatic.

Omniscan interferes with serum calcium measurements with some colorimetric (complexometric) methods commonly used in hospitals. It may also interfere with determinations of other electrolytes (e.g. iron). Thus it is recommended not to use such methods for 12-24 hours after administration of Omniscan. If such measurements are necessary, the use of other methods is recommended.

Patients with impaired renal function

Prior to administration of Omniscan, all patients should be screened for renal dysfunction by obtaining laboratory tests.

There have been reports of nephrogenic systemic fibrosis (NSF) associated with use of Omniscan and some other gadolinium-containing contrast agents in patients with acute or chronic severe renal impairment (GFR < 30 ml/min/1.73m²) and/or acute kidney injury. Omniscan is contraindicated in these patients (see section 4.3).

Patients undergoing liver transplantation are at particular risk since the incidence of acute renal failure is high in this group. Therefore Omniscan must not be used in patients in the perioperative liver transplantation period and in neonates (see section 4.3).

The risk for development of NSF in patients with moderate renal impairment (GFR 30-59

ml/min/1.73 m²) is unknown therefore, Omniscan should be only used after careful risk-benefit evaluation in patients with moderate renal impairment.

The elimination half-life of Omniscan is prolonged in patients with impaired renal function. Because of the lack of information on repeated administration to these patients, Omniscan injections should not be repeated unless the interval between injections is at least 7 days

Haemodialysis shortly after Omniscan administration may be useful at removing Omniscan from the body. There is no evidence to support the initiation of haemodialysis for prevention or treatment of NSF in patients not already undergoing haemodialysis.

Patient with central nervous system disorders

In patients suffering from epilepsy or brain lesions the likelihood of convulsions during the examination may be increased. Precautions are necessary when examining these patients (e.g. monitoring of the patient) and the equipment and medicinal products needed for the rapid treatment of possible convulsions should be available.

Neonates and Infants

Omniscan is contraindicated in neonates up to 4 weeks of age (see section 4.3). Due to immature renal function in infants up to 1 year of age, Omniscan should only be used in these patients after careful consideration.

Elderly

As the renal clearance of gadodiamide may be impaired in the elderly, it is particularly important to screen patients aged 65 years and older for renal dysfunction.

This medicinal product contains: 0.62 mg/ml of sodium. This needs to be taken into consideration for patients on a controlled sodium diet.

Interactions with other medicinal products and other forms of interaction

None known.

4.6 Fertility, pregnancy and lactation Pregnancy

There are no data from the use of gadodiamide in pregnant women. Animal studies have shown reproductive toxicity at repeated high doses (see section 5.3).Omniscan should not be used during pregnancy unless the clinical condition of the woman requires use of gadodiamide.

Breastfeeding

It is unknown whether gadodiamide is excreted in human milk. Available data in animals have shown excretion of gadodiamide in milk (for details see section 5.3). A risk to the suckling child cannot be excluded. Breast-feeding should be discontinued for at least 24 hours after the administration of Omniscan.

4.7 Effects on ability to drive and use machines

None known.

4.8 Undesirable effects

Adverse reactions have been reported in approximately 6 % of the patients in clinical trials.

Most events have been transient and the majority of mild intensity. The most commonly reported spontaneous adverse effects after Omniscan are hypersensitivity reactions, nausea and vomiting. Cases of nephrogenic systemic fibrosis (NSF) have been reported with Omniscan (see section 4.4).

In clinical trials with Omniscan, adverse reactions have been reported with the frequencies given below (very common >1/10; common (>1/100, <1/10); uncommon (>1/1000, < 1/100); rare (>1/10,000, <1/1000). Reactions for which no frequency rate can be provided due to lack of clinical data, have been entered with “Not known”.

Immune system disorders

Uncommon:    Allergy-like skin and mucous membrane reactions, hypersensitivity

Not known:    Anaphylactic/anaphylactoid reactions*

Psychiatric disorders

Rare: Anxiety Nervous system disorders

Headache

Dizziness, paraesthesia, transient perverted sensation of taste Convulsions, tremor, somnolence, transient perverted sensation of smell

Eye disorders

Rare:    Visual disturbance

Cardiac disorders

Not known:    Tachycardia

Vascular disorders

Uncommon:    Flushing

Respiratory, thoracic and mediastinal disorders

Rare:    Dyspnoea, coughing

Not known:    Sneezing, throat irritation, bronchospasm,    respiratory distress

Gastrointestinal disorders

Common:    Nausea

Uncommon:    Vomiting, diarrhoea

Skin and subcutaneous disorders

Uncommon:    Pruritus

Rare:    Rash, urticaria, oedema including face    swelling    and angioneurotic

oedema

Not known: Nephrogenic systemic fibrosis (NSF)

Musculoskeletal and connective tissue disorders

Rare:    Arthralgia

Renal and urinary system disorders

Rare:    Acute renal failure

General disorders and administration site conditions

Common:    Transient sensation of warmth, coolness or local pressure in

connection with injection. Transient sensation of pain at the injection site

Rare:    Chest pain, fever, shivering

* Anaphylactic/anaphylactoid reactions which may occur irrespective of the dose given and the method of administration may be the first signs of an incipient shock.

Late adverse reactions can occur hours to days after administration of Omniscan.

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 the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard

4.9 Overdose

Clinical consequences of overdose have not been reported and acute symptoms of toxicity are unlikely in patients with a normal renal function. Treatment is symptomatic. There is no antidote for this contrast medium. Omniscan can be removed by haemodialysis. However there is no evidence that haemodialysis is suitable for prevention of nephrogenic systemic fibrosis (NSF).

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Paramagnetic contrast media.

ATC code: V08C A03

The paramagnetic properties of Omniscan provide contrast enhancement during MRI.

There were no clinically significant deviations from preinjection values in haemodynamic and blood and urine laboratory parameters following intravenous injection of gadodiamide in healthy volunteers. However, a minor transient change in serum iron levels 8 to 48 hours after gadodiamide injection was observed.

Omniscan does not cross the intact blood-brain barrier. Administration of Omniscan causes signal enhancement from areas where blood-brain barrier dysfunction has been induced by pathological processes, and may provide greater diagnostic yield than unenhanced MRI. Lack of enhancement needs not indicate absence of pathology since some types of low grade malignancies or inactive MS-plaques fail to enhance; it can be used for differential diagnosis between different pathologies.

5.2 Pharmacokinetic properties

Gadodiamide is rapidly distributed in the extracellular fluid. The volume of distribution is equivalent to that of extracellular water. The distribution half-life is approximately 4 minutes and the elimination half-life is approximately 70 minutes. In patients with impaired renal function (GFR<30ml/min) the elimination half-life will be prolonged to an extent inversely proportional to GFR.

Gadodiamide is excreted through the kidneys by glomerular filtration. In patients with normal renal function approximately 85 % of the administered dose is recovered in the urine by 4 hours and 95-98 % by 24 hours after intravenous injection. The renal and total clearance rates of gadodiamide are nearly identical, and are similar to that of substances excreted primarily by glomerular filtration.

No dose dependent kinetics has been observed after injection of 0.1 and 0.3 mmol/kg. No metabolites have been detected. No protein binding has been observed.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and local tolerance.

Toxicological studies have demonstrated a high acute tolerance of gadodiamide. The common finding after high single dose or repeated dose toxicology studies was proximal tubular vacuolation, which was reversible, and was not associated with altered renal function.

Gadodiamide had no effects on fertility, reproductive performance or peri- post-natal development in rats, or in teratology studies in rats and rabbits at doses not associated with paternal or maternal toxicity. In pregnant rabbits reduced fetal weights and skeletal anomalies were observed after repeated administration of doses of 0.5 mmol/kg/day and above (approximately 2 times the maximum human cumulative dose of 0.3 mmol/kg based on a mmol/kg comparison). The transfer of maternally administered gadodiamide into milk was small in lactating rats injected intravenously with gadodiamide.

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

The following excipients are included:

Caldiamide sodium, sodium hydroxide 1 M or hydrochloric acid 1 M, water for injections.

6.2    Incompatibilities

Omniscan should not be directly mixed with other drugs. A separate syringe and needle should be used.

6.3    Shelf life

3 years

6.4    Special precautions for storage

OMNISCAN in glass vials should be stored below 30°C and protected from light and freezing. The vial is intended for one patient only. Any unused portions must be discarded.

6.5 Nature and contents of container

The product is filled in injection vials with a fill volume of 5 ml, 10 ml, 15 and 20 ml. The vials are made of colourless highly resistant borosilicate glass (Ph.Eur. Type I) and are closed with latex free rubber stoppers, sealed with complete tear off capsules of aluminium with coloured plastic “flip-off tops.

The product is supplied as:    1 vial of 5 ml

10 vials of 5 ml 10 vials of 10 ml 10 vials of 15 ml 10 vials of 20 ml

6.6 Special precautions for disposal and other handling

The peel-off tracking label on the vials should be stuck onto the patient record to enable accurate recording of the gadolinium contrast agent used. The dose used should also be recorded. If electronic patient records are used, the name of the product, the batch number and the dose should be entered into the patient record.

7 MARKETING AUTHORISATION HOLDER

GE Healthcare AS Nycoveien 1-2

P.O. Box 4220 Nydalen NO-0401 OSLO,

NORWAY

8    MARKETING AUTHORISATION NUMBER

PL 00637/0015 in UK (Glass vials)

9    DATE OF THE FIRST AUTHORISATION OR RENEWAL

25 ^th September 1992 in UK / 30^th April 1999/10 June 2005

10 DATE OF REVISION OF THE TEXT

09/05/2016