1196591 IND Posology Method of administration - The injection of may aggravate Cardiovascular disease Immediate reactions include one or more effects, which Adults symptoms of an existing asthma. In patients with In patients with severe cardiovascular disease Clariscan appear simultaneously or sequentially, which are most 1196591 The product is indicated for intravenous administration asthma unbalanced by the treatment, the decision should only be administered after careful benefit often cutaneous, respiratory and/or cardiovascular only. MRI of brain and spine to use gadoteric acid must be made after careful assessment because only limited data are available so far. reactions. Each sign may be a warning sign of a starting Infusion rate: 3-5 mL/min (higher infusion rates up to evaluation of the risk/benefit ratio. shock and go very rarely to death. The recommended dose is 0.1 mmol/kg BW, i.e. 0.2 mL/kg 120 mL/min, i.e. 2 mL/sec, may be used for angiographic BW. In patients with brain tumors, an additional dose of - As known from the use of iodinated contrast media, Patient preparation Isolated cases of nephrogenic systemic fibrosis (NSF) have GADOTERIC ACID procedures). Nausea and vomiting are known possible undesirable 0.2 mmol/kg BW, i.e. 0.4 mL/kg BW, may improve tumor hypersensitivity reactions can be aggravated in been reported with gadoteric acid, most of which were effects when using MRI contrast agents. The patient should TM characterisation and facilitate therapeutic decision Intravascular administration of contrast media should, patients on beta-blockers, and particularly in the in patients co-administered other -containing therefore refrain from eating for 2 hours prior to the making. if possible, be done with the patient lying down. After presence of bronchial asthma. These patients may be contrast agents (see Special warnings and precautions for the administration, the patient should be kept under refractory to standard treatment of hypersensitivity investigation. use). Whole body MRI (including lesions of the liver, observation for at least half an hour, since experience reactions with beta-agonists. The adverse reactions are listed in the table below by SOC 0.5 mmol/mL kidneys, pancreas, pelvis, lungs, heart, breast, and shows that the majority of undesirable effects occur within Interaction with other medicaments - Before any contrast medium is injected, the patient (System Organ Class) and by frequency with the following Solution for injection musculoskeletal system) this time. and other forms of interaction The recommended dose is 0.1 mmol/kg BW, i.e. 0.2 mL/kg should be questioned for a history of allergy No interactions with other medicinal products have been guidelines: very common (≥1/10), common (≥1/100 to Solution for injection in pre- lled syringe For single patient use only, any unused solution should be BW to provide diagnostically adequate contrast. (e.g. fish and seafood allergy, hay fever, hives), observed. Formal drug interaction studies have not been <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10 000 to discarded. For angiography: The recommended dose for intravenous sensitivity to contrast media and bronchial asthma as carried out. <1/1 000), very rare (<1/10 000), not known (cannot be Paediatric population (0-18 years). Depending on the the reported incidence of adverse reactions to contrast estimated from the available data). The data presented are Name of the proprietary medicinal product injection is 0.1 mmol/kg BW, i.e. 0.2 mL/kg BW to provide Beta-blockers, vasoactive substances, angiotensin- amount of Clariscan to be given to the child, it is preferable media is higher in patients with these conditions from clinical trials when available, or from an observational diagnostically adequate contrast. converting enzyme inhibitors, angiotensin receptor Clariscan 0.5 mmol/ mL solution for injection to use Clariscan vials with a single use syringe of a volume and premedication with antihistamines and/or study involving 82,103 patients. In exceptional circumstances (e.g. failure to gain antagonists: These medicinal products induce decreased Clariscan 0.5 mmol/ mL solution for injection in pre-filled adapted to this amount in order to have a better precision glucocorticoids may be considered. satisfactory images of an extensive vascular territory) efficacy of cardiovascular compensation mechanisms of syringe of the injected volume. System Organ Frequency : adverse reaction administration of a second consecutive injection of - During the examination, supervision by a physician blood pressure changes. The application of contrast media In neonates and infants the required dose should be Class Qualitative and quantitative composition 0.1 mmol/kg BW, i.e. 0.2 mL/kg BW may be justified. is necessary. If hypersensitivity reactions occur, may increase the incidence of hypersensitivity reactions However, if the use of 2 consecutive doses of Clariscan are administered by hand. administration of the contrast medium must be Immune system Uncommon: hypersensitivity, 1 mL solution for injection contains 279.3 mg gadoteric in patients taking beta-blockers (see Special warnings and anticipated prior to commencing angiography, the use of Image acquisition discontinued immediately and, if necessary, specific precautions for use). disorders anaphylactic reaction, anaphylactoid acid*(as gadoterate meglumine) equivalent to 0.5 mmol 0.05 mmol/kg BW (i.e. 0.1 mL/kg BW) for each dose may be Contrast enhanced MRI may be initiated immediately therapy instituted. A venous access should thus be kept reaction Active ingredient Content per mL of benefit, depending on the imaging equipment available. after administration of the agent. Optimal imaging: within during the entire examination. To permit immediate Fertility, and lactation Psychiatric Very rare: agitation, anxiety 45 minutes after injection. Optimal image sequence: emergency countermeasures, appropriate drugs (e.g. disorders Tetraxetan (DOTA) 202.46 mg Special populations T1-weighted adrenaline and antihistamines), an endotracheal tube Pregnancy and a respirator should be ready at hand. There are no data from the use of gadoteric acid in Nervous system Very common: paraesthesia, Gadolinium oxide 90.62 mg Impaired renal function pregnant women. Animal studies do not indicate direct disorders headache * Gadoteric acid: gadolinium complex with1,4,7,10 Clariscan should only be used in patients with severe renal Contraindications Impaired renal function or indirect harmful effects with respect to reproductive Rare: dysgeusia tetraazacyclododecane N,N’,N”,N’’’ tetraacetic acid impairment (GFR < 30 mL /min/1.73m2) and in patients in Hypersensitivity to gadoteric acid, to meglumine or to any Prior to administration of Clariscan it is recommended toxicity (see Preclinical safety data). Clariscan should not Very rare: coma, convulsion, syncope, (tetraxetan (DOTA)) the perioperative liver transplantation period after careful medicinal products containing gadolinium. that all patients are screened for renal dysfunction by be used during pregnancy unless the clinical condition of presyncope, dizziness, parosmia, risk/benefit assessment and if the diagnostic information obtaining laboratory tests. For the full list of excipients, see Pharmaceutical Special warnings and precautions for the woman requires use of gadoteric acid. tremor particulars is essential and not available with non-contrast enhanced There have been reports of nephrogenic systemic fibrosis Eye disorders Very rare: conjunctivitis, ocular MRI (see Special warnings and precautions for use). If it is use (NSF) associated with use of some gadolinium-containing Breastfeeding Pharmaceutical form necessary to use Clariscan the dose should not exceed Clariscan is administered strictly by intravenous injection Gadolinium containing contrast agents are excreted hyperaemia, vision blurred, contrast agents in patients with acute or chronic severe lacrimation increased, eyelid oedema Solution for injection. 0.1 mmol/kg body weight. only. In the event of extravasation local intolerance renal impairment (GFR < 30 mL/min/1.73m2). Patients into breast milk in very small amounts (see Preclinical Solution for injection in pre-filled syringe. More than one dose should not be used during a reactions may be observed, necessitating short term local undergoing liver transplantation are at particular high safety data). At clinical doses, no effects on the infant are Cardiac disorders Very rare: cardiac arrest, bradycardia, Clear, colourless to slightly yellow solution. scan. Because of the lack of information on repeated treatment. risk since the incidence of acute renal failure is high in anticipated due to the small amount excreted in milk and tachycardia, arrhythmia, palpitations administration, Clariscan injections should not be repeated poor absorption from the gut. Clariscan must not be administered by subarachnoid (or this group. As there is a possibility that NSF may occur Vascular disorders Very rare: hypotension, hypertension, Contrast medium 279.3 mg/mL unless the interval between injections is at least 7 days. Continuing or discontinuing breast feeding for a period of epidural) injections. with Clariscan, it should therefore only be used in patients vasodilatation, pallor concentration equivalent to 0.5 mmol/mL Elderly (aged 65 years and above) with severe renal impairment and in patients in the 24 hours after administration of Clariscan, should be at the -1 Appropriate facilities should be readily available for coping Osmolality at 37 °C 1350 mOsm.kg No dosage adjustment is considered necessary. Caution with any complication of the procedure, as well as for perioperative liver transplantation period after careful discretion of the doctor and lactating mother. Respiratory, Very rare: respiratory arrest, Viscosity at 20 °C 3.0 mPa.s should be exercised in elderly patients (see Special emergency treatment of severe reaction to the contrast risk/benefit assessment and if the diagnostic information thoracic and pulmonary oedema, bronchospasm, warnings and precautions for use). Fertility mediastinal laryngospasm, pharyngeal oedema, Viscosity at 37 °C 2.1 mPa.s agent itself (e.g. hypersensitivity, seizures). is essential and not available with non-contrast There are no clinical data available with regard to effects enhanced MRI. disorders dyspnoea, nasal congestion, sneezing, pH value 6.5 – 8.0 Impaired hepatic function The usual precaution for MRI examination should be taken, on fertility. The adult dose applies to these patients. Caution is cough, dry throat Clinical particulars such as exclusion of patients with pacemakers, vascular Haemodialysis shortly after Clariscan administration may recommended, especially in the case of perioperative liver clips, infusion pumps, nerve stimulators, cochlear implants, be useful at removing Clariscan from the body. There is Effects on ability to drive and use Gastrointestinal Common: nausea, vomiting Indications transplantation period (see above impaired renal function). or suspected intracorporeal metallic foreign bodies, no evidence to support the initiation of haemodialysis for machines disorders Very rare: diarrhoea, abdominal pain, Paediatric population (aged 0-18 years) particularly in the eye. prevention or treatment of NSF in patients not already salivary hypersecretion No studies on the effects on the ability to drive and use This medicinal product is for diagnostic use only. Encephalic and Spinal MRI, Whole body MRI: undergoing haemodialysis. Skin and Common: pruritus, erythema, rash machines have been performed. Ambulant patients while Clariscan is a indicated for enhancement of The recommended and maximum dose of Clariscan is Hypersensitivity subcutaneous Rare: urticaria, hyperhidrosis Elderly driving vehicles or operating machinery should take into the contrast in Magnetic Resonance Imaging for a better 0.1 mmol/kg body weight. More than one dose should not tissue disorders Very rare: eczema, angioedema - Hypersensitivity reactions can occur, including life- As the renal clearance of gadoteric acid may be impaired account that nausea may incidentally occur. visualization/delineation. be used during a scan. threatening (see Undesirable effects) Hypersensitivity in the elderly, it is particularly important to screen patients Not known: nephrogenic systemic Adult population and paediatric population Due to immature renal function in neonates up to 4 weeks reactions may be either allergic (described as aged 65 years and older for renal dysfunction. Undesirable effects fibrosis (0-18 years): of age and infants up to 1 year of age, Clariscan should anaphylactic reactions when serious) or non-allergic. Musculoskeletal Very rare: muscle contracture, - lesions of the brain, spine, and surrounding tissues only be used in these patients after careful consideration, They can be either immediate (less than 60 minutes), Paediatric population Side effects in association with the use of gadoteric acid Neonates and infants are usually mild to moderate in intensity and transient and connective muscular weakness, back pain - whole body MRI (see Posology and method of at a dose not exceeding or delayed (up to 7 days).Anaphylactic reactions can tissue disorders administration) 0.1 mmol/kg body weight. More than one dose should not occur immediately and can be fatal. Hypersensitivity Due to immature renal function in neonates up to 4 weeks in nature. A sensation of heat, cold and/or pain at the Use for whole body is not recommended in children less be used during a scan. Because of the lack of information reactions may be independent of the dose, may occur of age and infants up to 1 year of age, Clariscan should injection site is the most frequently observed reactions. General Common: feeling hot, feeling cold, than 6 months on repeated administration, Clariscan injections should after even the first dose of the product, and are often only be used in these patients after careful consideration. During clinical trials, headache and paresthesia were very disorders and injection site pain not be repeated unless the interval between injections is at In neonates and infants the required dose should be administration Very rare : malaise, thoracic pain, In adults only: unpredictable. commonly observed (>1/10), and nausea, vomiting and least 7 days. administered by hand. site conditions chest discomfort, fever, chills, face - lesions or stenoses of the non-coronary arteries - There is always a risk of hypersensitivity regardless of skin reactions such as erythematous rash and pruritus Use for whole body MRI is not recommended in children oedema, asthenia, injection site (MR Angiography). the dose injected. CNS disorders were commonly observed (>1/100 to <1/10). less than 6 months of age. discomfort, injection site reaction, - Patients who have already experienced a reaction Like with other gadolinium containing contrast agents Since post-marketing, the most commonly reported adverse injection site oedema, injection Angiography: Clariscan is not recommended for Posology and method of during previous administration of a gadolinium- special precaution is necessary in patients with a low reactions following administration of gadoteric acid are site extravasation, injection angiography in children under 18 years of age due to administration containing MRI contrast agent present an increased threshold for seizures. nausea, vomiting, pruritus and hypersensitivity reactions. site inflammation (in case of insufficient data on its efficacy and safety in this indication risk of experiencing another reaction on subsequent Precautionary measures should be taken, e.g. close In hypersensitivity reactions, the reactions most frequently This medicinal product should only be administered by extravasation), injection site necrosis (see Special warnings and precautions for use). administration of the same product, or possibly other monitoring. All equipment and drugs necessary to counter observed are skin reactions, which can be localized, trained healthcare professionals with technical expertise in (in case of extravasation), superficial products, and are therefore considered to be at high any convulsions, which may occur, must be made ready for extended or generalized. performing and interpreting gadolinium enhanced MRI. phlebitis risk. use beforehand. These reactions occur most often immediately (during the injection or within one hour after the start of injection) Investigations Very rare: decreased oxygen or sometimes delayed (one hour to several days after saturation injection), presenting as skin reactions in this case. Document: 1196591 IND Version: 0 The following adverse reactions were reported with other Biotransformation Polypropylene bottles of 50 mL (filled to 50 mL) and 100 mL intravenous contrast agents for MRI. It is therefore possible No metabolites were detected. (filled to 100 mL), closed with halobutyl rubber stopper that they also occur during examination with Clariscan Elimination held in place by a plastic screw cap with pull-off ring and tamper proof ring. Packed in outer box of 1 and 10 units. System Organ Adverse reaction Gadoteric acid is eliminated rapidly (89% after 6 h, 95% Class after 24 h) in unchanged form through the kidneys by Not all pack sizes may be marketed. glomerular filtration. Excretion via the feces is negligible. Blood and Haemolysis The elimination half-life amounts to about 1.6 hours in lymphatic system Instructions for use/handling patients with a normal renal function. disorders For single use. Psychiatric Confusion Special characteristics in patients with renal impairment The solution for injection should be inspected visually disorders In renally impaired patients, the elimination half-life prior to use. Only clear solutions free of visible particles was increased to approximately 5 hours for a creatinine Eye disorders Blindness transient, eye pain should be used. Vials and bottles: - Prepare a syringe with a clearance between 30 and 60 mL/min and approximately needle. For vials, remove the plastic disk. For polypropylene Ear and labyrinth Tinnitus, ear pain 14 hours for a creatinine clearance between 10 and bottles remove the plastic screw cap or top plastic lid disorders 30 mL/min. by pulling the top ring. After cleaning the stopper with Respiratory, Asthma a pad soaked in alcohol, puncture the stopper with the thoracic and Preclinical safety data needle. Withdraw the quantity of product required for the mediastinal examination and inject it intravenously. disorders Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, Pre-filled syringes: Inject intravenously the quantity of Gastrointestinal Dry mouth repeated dose toxicity, genotoxicity or toxicity to product required for the examination. disorders reproduction. Skin and Dermatitis bullous The remaining contrast medium in the vial/bottle, the Animal studies have shown negligible secretion (less than connecting lines and all disposable components in the subcutaneous 1% of the dose) of gadoteric acid in maternal milk. tissue disorders injector system must be discarded after the examination Renal and urinary Urinary incontinence, renal tubular Pharmaceutical Particulars The dose used should also be recorded. If electronic patient disorders necrosis, renal failure acute records are used, the name of the product, the batch Investigations Electrocardiogram PR prolongation, List of Excipients number and the dose should be entered into the patient record. blood iron increased, blood bilirubin Meglumine increased, serum ferritin increased, Tetraxetan (DOTA) Any unused medicinal product or waste material should be liver function test abnormal Water for injections disposed of in accordance with local requirements. Manufactured by: Adverse reaction in children Incompatibilities GE Healthcare AS Adverse events related to gadoteric acid are uncommon in In the absence of compatibility studies, this medicinal Nycoveien 1 children. The expectedness of these events is identical to product must not be mixed with other medicinal products. NO-0485 Oslo that of the events reported in adults. Norway Reporting of suspected adverse reactions: Shelf life Date of revision of the text Reporting suspected adverse reactions after authorisation 2 years February 2017 of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal Bottles product. Healthcare professionals are asked to report any Chemical and physical in-use stability has been Clariscan is a trademark of GE Healthcare. suspected adverse reactions via the national reporting demonstrated for 48 hours at room temperature. From a GE and GE Monogram are trademarks of the system. microbiological point of view, the product should be used General Electric Company. immediately. If not used immediately, in-use storage times Overdose and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at Clariscan can be removed by haemodialysis. However, 2 to 8° C, unless opening has taken place in controlled and there is no evidence that haemodialysis is suitable for validated aseptic conditions. prevention of nephrogenic systemic fibrosis (NSF). Pharmacological properties Special precautions for storage Vials/bottles: This medicinal product does not require any Pharmacodynamic Properties special storage conditions Pharmacotherapeutic group: paramagnetic contrast Pre-filled syringes: Do not freeze media for magnetic resonance imaging ATC code: V08 CA 02 Nature and contents of container This product has no specific pharmacodynamic activity. Clariscan is filled in the following containers: Gadoteric acid is a paramagnetic agent for Magnetic Vials Resonance Imaging (MRI). The contrast-enhancing effect Glass vials (type I, colourless) of 10 mL (filled to 5 or 10 mL) is mediated by gadoteric acid which is an ionic gadolinium and 20 mL (filled to 15 or 20 mL), closed with halobutyl complex composed out of Gadolinium oxide and 1,4,7,10 rubber stopper sealed with caps of aluminium with tetraazacyclododecane- N,N’,N’’,N’’’ tetraacetic acid (DOTA), coloured plastic top. Packed in outer box of 1 and 10 units. and present as meglumine salt. Pre-filled syringes Polymer syringe: Poly-cycloolefin, Crystal Clear Polymer Pharmacokinetic properties (CCP) syringe of 20 mL (filled to 10, 15, and 20 mL), label Distribution graduated per mL with tip cap and halobutyl plunger After intravenous injection, Clariscan is distributed in the stopper attached to a plunger rod. extracellular fluids of the body. The distribution volume Packed in outer box of 1 and 10 units. was approx. 18 L which is approximately equal to the Bottles volume of extra-cellular fluid. Gadoteric acid does not Glass bottles (type I, colourless) of 50 mL (filled to 50 mL) bind to proteins like serum albumin. Gadoteric acid is and 100 mL(filled to 100 mL), closed with halobutyl rubber poorly excreted in the milk and crosses slowly through the stopper sealed with caps of aluminium with coloured placenta barrier. plastic top. Packed in outer box of 1 and 10 units.

1196591 IND Document: 1196591 IND Version: 0