OMNISCAN(tm)
Gadodiamide injection 287 mg/ml.
OMNISCAN is a clear, colourless to slightly yellow aqueous solution containing gadodiamide 287 mg/ml equivalent to 0.5 mmol/ml.
In magnetic resonance imaging, visualization of normal and pathological brain and spinal tissue depends, in part, on variations in the radiofrequency signal intensity. These variations occur due to: changes in proton density; alteration to spin-lattice or longitudinal relaxation time (T1); and variation of the spin-spin or transverse relaxation time (T2). OMNISCAN is a paramagnetic agent with unpaired electron spins, which generate a local magnetic field. As water protons move through this local magnetic field, the changes in magnetic field experienced by the protons reorient them with the main magnetic field more quickly than in the absence of a paramagnetic agent. Therefore, by increasing the relaxation rate OMNISCAN decreases both the T1 and T2, relaxation times in tissues where it is distributed. At clinical doses, the effect is primarily on the T1 relaxation time, and produces an increase in signal intensity. Gadodiamide does not cross the intact blood-brain barrier and therefore does not accumulate in normal brain, spinal cord, or in lesions that do not have an abnormal blood-brain barrier, such as cysts and mature postoperative scars. However, disruption of the blood-brain barrier or abnormal vascularity allows accumulation of gadodiamide in lesions such as neoplasms, abscesses and subacute infarcts. Use of OMNISCAN provided contrast enhancement or facilitated visualization of abnormal structures or lesions in 75% (266 of 353) of cases with abnormalities. In comparison with preinjection scans, OMNISCAN allowed visualization of more or smaller lesions in 16% (50/306) of the cases. In 29/96 of the cases OMNISCAN revealed lesions where no lesions were detected prior to OMNISCAN administration.
The pharmacokinetics of intravenously administered OMNISCAN in normal subjects conforms to an open, two compartment model with mean distribution and elimination half-lives (reported as mean + SD) of 3.7 + 2.7 minutes and 77.8 + 16 minutes, respectively. Gadodiamide is eliminated primarily in the urine with 95.4 + 5.5% (mean + SD) of the administered dose eliminated by 24 hours. There is no detectable biotransformation or decomposition of gadodiamide. The renal and plasma clearance rates of gadodiamide are nearly identical (1.7 and 1.8 mL/min/kg, respectively) and are similar to that of substances excreted primarily by glomerular filtration. In patients with impaired renal function (GFR 18-43 mL/min), the mean elimination half-life was 5.8 hours. Gadodiamide is cleared by routine haemodialysis, with 56% of the given dose eliminated during the first haemodialysis session and 72% during four sessions. Gadodiamide is also dialyzable by peritoneal dialysis with 76% of the given dose recovered over 22 days.
OMNISCAN is indicated as a contrast medium for cranial and spinal resonance imaging (MRI) and for general MRI of the body after intravenous administration. OMNISCAN provides contrast enhancement and facilitates visualisation of abnormal structures or lesions in various parts of the body including the CNS.
No special preparation of the patient is required. OMNISCAN should be drawn into the syringe immediately before use. The vial is intended for one patient only. Contrast medium not used in one examination must be discarded.
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. 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 5 ml sodium chloride injection 0.9%. Adults only. When brain metastases are suspected, a dosage of 0.3 mmol/kg b.w. (equivalent to 0.6 ml/kg b.w.) can be administered up to 100 kg. Above 100 kg b.w. a total of 60ml is usually sufficient. The dose of 0.3 mmol/kg b.w. can be administered as a bolus intravenous injection. 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. (equivalent to 0.4 ml/kg b.w.) may be of additional diagnostic value when administered within 20 minutes of the first injection.
Dosage for adults. The recommended dosage is usually 0.1mmol/kg b.w. (equivalent to 0.2 ml/kg b.w.) or occasionally 0.3 mmol/kg b.w. (equivalent to 0.6 ml/kg b.w.) up to 100 kg. Above 100 kg 20 ml or up to 60 ml is usually sufficient to provide diagnostically adequate contrast. Dosage for children. The recommended dosage is 0.1 mmol/kg b.w. (equivalent to 0.2 ml/kg b.w.) For patients with moderate renal impairment and in infants from 4 weeks to 1 year of age the dose should be restricted to the minimum recommended dose. 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. More than one dose should not be used during a scan. Because of the lack of information on repeated administration, injections should not be repeated unless the interval between injections is at least 7 days. 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%. 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 the type of lesion/tissue). Enhancement generally lasts 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.
OMNISCAN should not be used in patients known to have hypersensitivity to OMNISCAN or its constituents. OMNISCAN is also contraindicated in acute or chronic severe renal insufficiency (a glomerular filtration rate < 30mL/min/1.73m2); and in patients with acute renal insufficiency of any severity due to the hepato-renal syndrome or in the peri-operative liver transplantation period. OMNISCAN is also contraindicated in neonates up to 4 weeks of age.
The accepted safety considerations and procedures that are required for magnetic resonance imaging are applicable when OMNISCAN is used for contrast enhancement. Administration of contrast media should be performed by qualified personnel familiar with the procedure and an appropriate technique should be utilised. The possibility of a reaction, including serious, life-threatening, fatal, anaphylactoid or cardiovascular or other idiosyncratic reactions should always be considered, especially in those patients with 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.
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.
Impaired Renal Function (or Nephrogenic Systemic Fibrosis)
Nephrogenic Systemic Fibrosis (NSF) is a debilitating and sometimes fatal disease affecting the skin, muscle and internal organs. There have been reports of nephrogenic systemic fibrosis (NSF) associated with use of gadodiamide and some other gadolinium-containing contrast agents in patients with acute or chronic severe renal impairment (GFR <30ml/min/1.73 m2) and those who have or are undergoing liver transplantation. Therefore OMNISCAN must not be used in patients with severe renal impairment, in patients in the perioperative liver transplantation period and in neonates. Caution should be exercised in use and dose selection of OMNISCAN in patients with hepatorenal syndrome. All patients should be screened for renal dysfunction using laboratory testing prior to using OMNISCAN. Haemodialysis shortly after OMNISCAN administration in patients currently receiving haemodialysis 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. 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 that such methods not be used for 12-24 hours after administration of OMNISCAN. If such measurements are necessary, the use of other methods is recommended. Diagnostic procedures involving the use of contrast agents should be conducted under supervision of a physician with the prerequisite training and a thorough knowledge of the procedure to be performed. If OMNISCAN is drawn into a disposable syringe it should be used immediately. If non- disposable equipment is used, scrupulous care should be taken to prevent residual contamination with traces of cleansing agents. Data on the safety of repeated injections are not available. If the physician determines sequential or repeat examinations are required, a suitable time interval between administrations should be observed to allow for clearance of the drug from the body.
The results of three in vitro and one in vivo short-term genotoxicity assays were negative. No long-term studies have been performed to evaluate the carcinogenic potential of OMNISCAN. OMNISCAN had no effect on the fertility and general reproductive performance in rats or in teratology studies in rats and rabbits at doses that did not cause maternal toxicity.
Pregnancy category B3. No effects of OMNISCAN on reproductive performance were seen in rats at doses up to 1.0 mmol/kg. In rabbits, there is an increased incidence of litters with skeletal or visceral abnormalities at doses up to 0.5 and 1.0 mmol/kg. However, these effects are possibly attributable to maternal toxicity rather than a direct effect of the drug. There are no adequate and well-controlled studies of OMNISCAN in pregnant women. OMNISCAN should be used in pregnancy only if the potential benefit justifies the potential risk to the foetus.
It is not known whether OMNISCAN is excreted in human milk. Breast-feeding should be discontinued prior to administration and should not be recommenced until at least 24 hours after the administration of OMNISCAN.
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. The safety and effectiveness of OMNISCAN have been established for whole body magnetic resonance imaging in children from 6 months of age. The safety and effectiveness in infants and neonates have been established in the evaluation of lesions within the brain and spine. There is no experience with OMNISCAN in children below 6 months of age with severe hepatic or renal disease, or with premature infants below 4 weeks, or those with a post-conceptional age of less than 30 weeks.
As the renal clearance of OMNISCAN may be impaired in the elderly, it is particularly important to screen patients aged 65 years and older for renal dysfunction. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function.
None known
Discomfort with a general sensation of warmth, coolness or a sensation of local pressure or pain at the injection site were commonly (> 1% and < 10%) observed in clinical studies. Dizziness, nausea, headache and a perverted sense of taste or smell were reported less frequently, but also in > 1% of patients. Uncommon (> 0.1% and < 1%) reactions included vomiting, somnolence, paraesthesia or allergy-like symptoms such as urticaria, itching, irritation in the throat and bronchospasm. Anaphylactoid reactions have occurred. The majority of adverse reactions in clinical studies were of mild intensity. The following adverse reactions occurred in less than 1% of the patients, and were considered to be possibly related or of unknown relationship to OMNISCAN: Body as a whole: Body pain, fatigue, malaise, fever, anaphylactoid reaction Cardiovascular: Warmth, chest pain, hypotension (syncope), tachycardia, flushing Digestive: Melena, dyspepsia, vomiting, diarrhoea, abdominal pain Musculoskeletal: Arthralgia Nervous system: Anxiety, paraesthesia, tinnitus, somnolence, light headedness, trembling, ataxia, personality disorder, convulsions Respiratory system: Rhinitis, dyspnoea Skin and appendages: Urticaria, pruritus, flushing, rash Special senses: Visual disturbances Cases of nephrogenic systemic fibrosis (NSF) have been reported in patients with severe renal impairment. The causality is still under investigation. In patients with pre-existing severe renal insufficiency: acute kidney injury, an increase in blood creatinine has been reported. In very rare cases convulsions have been observed after the administration of OMNISCAN as is the case for other paramagnetic MR contrast media. However, a causal relationship seems to be questionable. Two cases of transient elevated liver enzymes have been reported. However, in both cases concomitant medication known to cause abnormal results for liver function tests was taken. A causal relationship to OMNISCAN could therefore not be established. Single cases of relapse of multiple sclerosis, encephalopathy, and hallucinations have been reported. Transient renal failure was observed in one patient who received an X-ray contrast medium for myelography 22 hours prior to the injection of OMNISCAN. The causality for the reaction has not been established.
Asymptomatic transitory increases in serum iron and bilirubin have been reported in patients receiving OMNISCAN.
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.
OMNISCAN should be stored at room temperature (below 30oC) and protected from light. The vial is intended for one patient only. Any unused portion must be discarded.
OMNISCAN should not be directly mixed with other drugs. A separate syringe and needle should be used.
Additional instructions for auto-injector/pump. The 100 ml contrast medium bottle should only be used in conjunction with auto injectors/pumps approved for this volume. A single piercing procedure should be used. The line running from this 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.
General Sale Medicine
Single dose glass vials of 5 ml, 10 ml, 15 ml, 20 ml and 100 ml. Single dose polypropylene vials of 10 ml, 15 ml, 20 ml, 40 ml and 50 ml. Pre-filled polypropylene or polycycloolefin syringes of 10 ml, 15 ml, and 20 ml. Not all presentations are marketed.
Pertinent physiochemical data for OMNISCAN are:
| Osmolarity (mOsm/kg water) | @ 37oC | 780 |
| Viscosity (cp) | @ 20oC | 2.8 |
| @ 37oC | 1.9 | |
| Density (g/cm 3 ) | @ 20oC | 1.15 |
OMNISCAN has an osmolarity 2.8 times that of plasma (285mOs/kg) at 37oC and is hypertonic under conditions of use.
The efficacy of gadodiamide in CNS and whole body imaging of adults and children aged over 6 months of age has been demonstrated in clinical trials.
CNS (Central Nervous System)-Children less than 6 months of age
A total of 7 clinical studies, including 363 patients, have been performed to document the use of gadodiamide injection in paediatric patients undergoing MRI examination of the CNS. Six of these clinical studies included both children and adolescents. The remaining study was designed specifically to demonstrate the safety and effectiveness of OMNISCAN for the enhancement of magnetic resonance images of intracranial and spinal lesions in infants and neonates less than 6 months of age. In this last study, 61 children below 6 months of age undergoing MRI were included in an open, non-randomised clinical trial conducted at three centres. Forty patients were recruited to receive gadodiamide injection at a dose of 0.1 mmol/kg in the OMNISCAN group (group A) and 21 patients requiring plain MRI examination without contrast were the control group (plain MRI - group B). No patients were withdrawn, however 2 of the children included were older than 6 months and their data excluded from all analyses. In group A, 16 patients were female and 23 male and in group B, 7 were female and 13 male. There were no relevant differences between the two groups regarding age, weight and height. Group A included 8 patients with mass lesions, 7 each with convulsive disorders and hydrocephalus, 6 with infections, 3 with congenital anomalies and 2 each with metabolic disease and hypoxia. Group B included 11 patients with congenital anomalies, 3 with hypoxia, 2 with vascular diseases, one each with convulsive disorders, hydrocephalus and metabolic disease and one with periventricular leukomalacia. In the comparison of pre- and post-contrast evaluation of the images neither the number of patients with lesions nor the number of lesions in each patient was found to be different. Both the on-site investigator and the independent reader found the quality of lesion delineation to be improved by the injection of contrast medium. There was a discrepancy between investigators in the evaluation of contrast enhancement in the pathological area of interest and was probably due to a different interpretation of the area of interest. In no case was a lesion obscured after administration of the contrast medium. For all patients, the post-contrast images contained at least as much diagnostic information as the pre-contrast images. No serious or significant adverse event occurred. Gadodiamide injection at a dose of 0.1 mmol/kg was shown to be safe, well tolerated and effective in MRI examination of children under 6 months.
OMNISCAN is a trademark of GE Healthcare. GE and the GE monogram are trademarks of General Electric Company.
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26 August 2013