Omniscan

Solution for injection, for intravenous use.
The product is a clear, colourless to slightly yellow aqueous solution.
Qualitative and quantitative composition: See Table 1.

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OMNISCAN injection is a non-ionic linear paramagnetic gadolinium-based contrast agent (GBCA) with the following physicochemical properties: See Table 2.

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Total sodium content: 0.62 mg/mL.
Excipients/Inactive Ingredients: The following excipients are included: Caldiamide sodium, sodium hydroxide 1 M or hydrochloric acid 1 M, water for injections.

Pharmacology: Pharmacodynamics: The paramagnetic properties of OMNISCAN provides contrast enhancement during MRI.
There were no clinically significant deviations from pre-injection 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.
Pharmacokinetics: Distribution: 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.
Elimination: 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.
The elimination half-life of OMNISCAN is prolonged in patients with impaired renal function. No dose dependent kinetics have been observed after injection of 0.1 and 0.3 mmol/kg.
No metabolites have been detected. No protein binding has been observed.
Following GBCA administration, trace amounts of gadolinium is present for months or years in brain, bone, skin, and other organs.
Toxicology: Preclinical safety data: In vitro studies have demonstrated no or insignificant effects on mast cell histamine release, human serum complement activation factors, human erythrocyte cholinesterase activity, lysozyme activity, human erythrocyte fragility and morphology, and on tension in isolated bovine blood vessels. No evidence of antigenicity was seen in a dermal test in Guinea pigs. OMNISCAN had no effects on fertility or reproductive performance in rats or in teratology studies in rats and rabbits at doses that did not cause maternal toxicity.
Studies conducted in healthy rats injected repeatedly with GBCAs demonstrated progressive and persistent T1-weighted hyperintensity on MRI in the deep cerebellar nuclei (DCN) that was higher with linear than with macrocyclic agents. Signal enhancement in the globus pallidus (GP) could not be seen in the animals.
GBCA administered to pregnant mice (2 mmol/kg daily on gestational days 16 through 19) result in measurable gadolinium concentrations in the pups in bone, brain, kidney, liver, blood, muscle, and spleen at one-month postnatal age.
Quantitative results using mass spectrometry demonstrated that the total gadolinium concentrations were significantly higher following repeated administration of the linear GBCAs than following macrocyclic GBCAs. These studies reported no abnormal behavioural changes suggestive of neurological toxicity.

This medicinal product is for diagnostic use only.
GBCAs should be used only when diagnostic information is essential and not available with unenhanced magnetic resonance imaging (MRI).
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.

No special preparation of the patient is required. OMNISCAN should be drawn into the syringe immediately before use. 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.
For intravenous use. For both adults and children, the required dose should be administered as a single intravenous injection. For cardiac MRI, two injections for stress and rest perfusion examination are required. To ensure complete injection of the contrast medium, the intravenous line may be flushed with sodium chloride injection 0.9%.
Use the lowest effective dose. Calculate the dose based on the patient's body weight, and do not exceed the recommended dose per kilogram of body weight.
CNS: Dosage for adults and children: The recommended dosage is 0.1 mmol/kg body weight (equivalent to 0.2 mL/kg BW) 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, a dosage of 0.3 mmol/kg BW (equiv. to 0.6 mL/kg BW) can be administered up to 100 kg. Above 100 kg BW a total of 60 mL is usually sufficient. The dose of 0.3 mmol/kg BW can be administered as a bolus intravenous injection. In patients with equivocal scans after administration of the 0.1 mmol/kg BW injection, a second bolus injection of 0.2 mmol/kg BW (equiv. to 0.4 mL/kg BW) may be of additional diagnostic value when administered within 20 minutes of the first injection.
Whole body: Dosage for adults: The recommended dosage is usually 0.1 mmol/kg BW (equiv. to 0.2 mL/kg BW) or occasionally 0.3 mmol/kg BW (equiv to 0.6 mL/kg BW) up to 100 kg. Above 100 kg BW 20 mL resp. 60 mL is usually sufficient to provide diagnostically adequate contrast.
Dosage for children from 6 months of age: The recommended dosage is 0.1 mmol/kg BW (equiv. to 0.2 mL/kg BW).
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 b.w. (equiv. to 0.2 mL/kg b.w.). In cases of stenosis of abdominal and iliac arteries, a higher dosage of up to 0.3 mmol/kg b.w. (equiv. to 0.6 mL/kg b.w.) has been shown to provide additional diagnostic information.
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 contrast effect.
Mammography: Dosage for adults: The recommended dosage is 0.1-0.2 mmol/kg b.w. (equivalent to 0.2-0.4 mL/kg b.w.). Above 100 kg b.w. 20-40 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.
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.
If this medicinal product is intended to be used with an automatic application system, its suitability for the intended use has to be demonstrated by the manufacturer of the medical device.
Instructions for use of the medical device must be followed absolutely.

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. In patients with delayed elimination due to renal insufficiency and in patients who have received excessive doses, the contrast medium can be eliminated by haemodialysis.

Hypersensitivity to the active substance gadodiamide or to any of the excipients.
OMNISCAN is contraindicated in patients with severe renal impairment (GFR <30 mL/min/1.73 m²), and/or acute kidney injury and in neonates up to 4 weeks of age.

Risk Associated with Intrathecal Use and Nephrogenic Systemic Fibrosis: OMNISCAN must not be used intrathecally. Intrathecal administration of GBCAs can cause serious adverse reactions including death, coma, encephalopathy, and seizures.
Gadolinium-based contrast agents increase the risk for nephrogenic systemic fibrosis (NSF) in patients with: acute or chronic severe renal insufficiency (glomerular filtration rate <30 mL/min/1.73 m²), or acute renal insufficiency of any severity due to the hepato-renal syndrome or in the perioperative liver transplantation period.
In these patients, avoid use of gadolinium-based contrast agents unless the diagnostic information is essential and not available with non-contrast enhanced magnetic resonance imaging (MRI).
NSF may result in fatal or debilitating systemic fibrosis affecting the skin, muscle and internal organs. Screen all patients for renal dysfunction by obtaining a history and/or laboratory tests.
When administering a gadolinium-based contrast agent, do not exceed the recommended dose and allow a sufficient period of time for elimination of the agent from the body prior to any re-administration.

Hypersensitivity: 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.
Intrathecal administration: OMNISCAN must not be used intrathecally. Intrathecal administration of GBCAs can cause serious adverse reactions including death, coma, encephalopathy, and seizures.
Patients with renal impairment: 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 (gadodiamide) and other gadolinium-containing contrast agents in patients with chronic severe renal impairment and/or acute kidney injury.
OMNISCAN is contraindicated in these patients. The risk, if any, for the development of NSF among patients with moderate renal insufficiency is unknown.
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.
Gadolinium retention: Trace amounts of Gadolinium may be retained in the brain (particularly in the dentate nucleus and globus pallidus), and in other tissues for months to years after administration of GBCAs. Higher concentrations have been identified in human bone than in skin and brain. Nonclinical evidence suggests that the level of gadolinium retention is higher after repeat administration of linear than after repeat administration of macrocyclic agents.
Increased signal intensity on non-contrast T1 weighted images of the brain has been observed after multiple administrations of GBCAs even in patients with normal renal function. The clinical significance of gadolinium retention in brain is unknown.
There are rare reports of pathologic skin changes including gadolinium associated plaques in patients with normal renal function. Post marketing reports of adverse events involving multiple organ systems in patients with normal renal function have been received. A causal link to gadolinium retention has not been established. These events include fatigue, asthenia, pain syndromes, and heterogeneous clusters of symptoms in the neurological, cutaneous, and musculoskeletal systems.
While clinical consequences of gadolinium retention have not been established in patients with normal renal function, certain patients might be at higher risk. These include patients requiring multiple lifetime doses, pregnant and paediatric patients.
In order to minimize potential risks associated with gadolinium retention, it is recommended to use the lowest effective dose and to perform a careful benefit risk assessment before administering repeated doses.
Patients 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.
OMNISCAN interferes with serum calcium measurements with some colorimetric complexometric methods commonly used in hospitals. 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.
Effects on ability to drive and use machines: None known.
Use in Children: Neonates and infants: OMNISCAN is contraindicated in neonates up to 4 weeks of age. Due to immature renal function in infants up to 1 year of age, OMNISCAN should only be used in these patients after careful consideration.
Paediatric patients: Gadolinium is retained in paediatric brains similar in amount and distribution to adults. Developing paediatric brains may be more susceptible to the potential effects of gadolinium exposure.

Pregnancy: Adequate and well controlled studies in pregnant women have not been conducted.
GBCAs cross the placenta and result in foetal exposure and gadolinium retention. Human data on the association between GBCA and adverse foetal outcomes are limited and inconclusive. OMNISCAN should therefore only be used during pregnancy if the potential benefit justifies the potential risk to the foetus and the pregnant woman.
Breast-feeding: The degree of excretion into human milk is not known.
Available data in animals have shown excretion of gadodiamide in milk. A risk to the suckling child cannot be excluded.
Fertility: There are no clinical data available with regard to effects on fertility.

The following undesirable effects are recognised for OMNISCAN: Immune system disorders: Hypersensitivity, including anaphylactoid reactions, anaphylactic/anaphylactoid shock.
Psychiatric disorders: Anxiety.
Nervous system disorders: Taste alteration, headache, dizziness, convulsions, paraesthesia, tremor, somnolence, transient parosmia.
Eye disorders: Visual disturbance.
Cardiac disorders: Tachycardia.
Respiratory, thoracic and mediastinal disorders: Dyspnoea, coughing, bronchospasm, respiratory distress, throat irritation, sneezing.
Vascular disorders: Flushing.
Gastrointestinal disorders: Nausea, vomiting, diarrhea.
Skin and subcutaneous tissue disorders: Nephrogenic systemic fibrosis (NSF), pruritus, face oedema, angioedema, urticaria, rash, skin plaque*.
Musculoskeletal and connective tissue disorders: Arthralgia.
Renal and urinary system disorders: In patients with pre-existing severe renal insufficiency: Acute kidney injury, increase in blood creatinine.
General disorders and administration site conditions: Feeling hot, injection site pain, chest pain, fever, shivering.
* Cases of gadolinium associated skin plaques with demonstrated sclerotic bodies on histology have been reported with gadodiamide in patients who do not otherwise have symptoms or signs of nephrogenic systemic fibrosis.

None known.

Incompatibilities: OMNISCAN should not be directly mixed with other drugs. A separate syringe and needle should be used.
Instructions for use/handling: Vials are intended for one patient only. Any unused portions must be discarded.
Additional instructions for auto injector/pump: The 100 mL contrast medium bottle should only be used in connection with auto injectors/pumps approved for this volume. A single piercing procedure should be used. The line running from the auto injector/pump to the patient must be exchanged after each patient. Any unused portions of the contrast medium remaining in the bottle and all connecting tubes must be discarded at the end of the day. Instructions from the manufacturer of the auto injector/pump must be followed.

Store at temperatures not exceeding 25°C. Protect from light.

Radiographic & Diagnostic Agents

V08CA03 - gadodiamide ; Belongs to the class of paramagnetic agents used as magnetic resonance imaging contrast media.

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