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CLINICAL PHARMACOLOGY Pharmacodynamic properties Pharmacotherapeutic group: Paramagnetic MRI contrast medium, ATC Code: V08C A05 Mangafodipir is a chelate containing the metal manganese - which has paramagnetic properties and is responsible for the contrast enhancement effect in MRI - and the ligand fodipir (dipyridoxyl diphosphate). Manganese is preferentially taken up by normal liver parenchyma and also in the pancreas so that contrast enhancement between abnormal and normal tissue can be expected. The effect of mangafodipir is to shorten the longitudinal relaxation time (T1) of targeted tissues during MRI, leading to an increase in signal intensity (brightness) of, for example, pancreas and liver parenchyma. Enhancement in both organs is near maximal for up to approx. 4 hours after the end of administration. Lesion-related enhancement of certain types of lesions, such as liver metastases and hepatocellular carcinomas, may be detectable for up to 24 hours. Clinical studies have demonstrated that mangafodipir facilitates the detection of liver lesions in patients with such lesions. TESLASCAN (mangafodipir) is isotonic with blood and normal body fluids. Pharmacokinetic properties Mangafodipir trisodium is metabolised (dephosphorylated) and manganese ions are released from the mangafodipir by exchange with plasma zinc (mainly) after intravenous administration. Manganese and the ligand (fodipir), which have different pharmacokinetics, are eliminated by different routes. The mean initial plasma half-life of manganese is 20 minutes or less, with significant uptake into the liver, pancreas, kidneys and spleen. The initial plasma half-life of ligand is about 50 minutes. The volume of distribution for manganese is between 0.5 and 1.5 l/kg, and for fodipir 0.17 to 0.45 l/kg. Following its metabolism, nearly all of the ligand (fodipir) is excreted in urine within 24 hours, with negligible amounts being eliminated via the faeces. About 15-20 % of the manganese is eliminated in the urine within the first 24 hours, most of the remainder is excreted in the faeces over the following 4 days. In whole human blood in vitro, the protein binding of manganese is approximately 27 % but binding of fodipir to protein is negligible. Preclinical safety data Non-clinical studies reveal no special hazard for humans based on conventional studies of genotoxicity, safety pharmacology and validating kinetics and metabolism. Relevant adverse effects from repeated dose toxicity studies were liver toxicity (cholangiohepatitis) observed at relatively low dosages in dogs, while sufficient margins of safety were determined in rats and monkeys. Mangafodipir is teratogenic in rats; it causes increased foetal skeletal abnormalities when given daily by intravenous injection to female rats at dosages slightly greater than clinical dosages. Embryo- and foetotoxicity has been observed in rabbits.

TESLASCAN 0.01 mmol/ml Solution for infusion (mangafodipir) SPC approved in Renewal in the Centralized procedure in EU DESCRIPTION Name Of The Medicinal Product TESLASCAN 0.01 mmol/ml solution for infusion (mangafodipir) . Qualitative And Quantitative Composition Each ml contains 7.57 mg of anhydrous mangafodipir trisodium, 0.01 mmol (10 μmol), equivalent to 6.91 mg of mangafodipir. 50 ml contains 378.5 mg of anhydrous mangafodipir trisodium, 0.50 mmol (500 μmol), equivalent to 345.5 mg of mangafodipir. Excipient: Sodium 0.16 mmol (3.6 mg)/ml equivalent to 126 mg per normal dose of 35 ml. For a full list of excipients, see the HOW SUPPLIED section. Pharmaceutical Form Solution for infusion A clear bright to dark yellow solution, TESLASCAN (mangafodipir) has the following physicochemical properties: pH 7.0-8.0. Osmolality (mosmol/kg H2O) at 37 °C 290 Viscosity (mPa.s) at 20 °C 1.0 Viscosity (mPa.s) at 37 °C 0.7 Density (g/ml) at 20 °C 1.01

INDICATIONS Therapeutic indications This medicinal product is for diagnostic use only. Contrast medium for diagnostic Magnetic Resonance Imaging (MRI) for the detection of lesions of the liver suspected to be due to metastatic disease or hepatocellular carcinomas. As an adjunct to MRI to aid in the investigation of focal pancreatic lesions. DOSAGE AND ADMINISTRATION Posology and method of administration The medicinal product is for single intravenous use only as repeated dosing has not been studied. It should be administered as an intravenous infusion at the rate of 2-3 ml/min for liver imaging and at a rate of 4-6 ml/min for imaging of the pancreas. Near maximal enhancement of the normal liver and pancreas parenchyma is generally observed 15-20 minutes from the start of administration and lasts for approximately 4 hours. At the clinical dose the contrast agent has no T2-effect, and pre- and post- T2-weighted images are equivalent. The clinical use of TESLASCAN (mangafodipir) has been investigated at field strengths from 0.5 to 2.0 Tesla. Dosage for adults The recommended dose is 0.5 ml/kg bodyweight (5 μmol/kg bodyweight). This corresponds to a dose of 35 ml for a 70 kg person. Above 100 kg body weight, 50 ml is usually sufficient to provide a diagnostically adequate contrast effect. Dosage for elderly 4 Pharmacokinetics in the elderly has not been investigated. However, clinical studies to date do not suggest that a dose adjustment is required. Children and adolescents Safety and efficacy in patients below the age of 18 have not been documented i.e. children (2-11 years) and adolescents (12-18 years). HOW SUPPLIED Pharmaceutical Particulars List of excipients Ascorbic acid Sodium chloride Sodium hydroxide and/or hydrochloric acid (pH adjustment) Water for injections. Incompatibilities This medicinal product must not be mixed with other medicinal products. A separate cannula should be used. Shelf life Unopened: 2 years. Once opened the product should be used immediately. Special precautions for storage Keep the vial in the outer carton in order to protect from light. The product should be used immediately after first opening (see above). Nature and contents of container 50 ml clear, colourless vials (type 1 glass). The containers are closed with rubber stoppers and sealed with aluminium caps with polypropylene lids. TESLASCAN (mangafodipir) is supplied in packs of 1 x 50 ml and 10 x 50 ml vials. Not all pack sizes may be marketed Special precautions for disposal and other handling TESLASCAN (mangafodipir) vials should be visually inspected for particulate matter and for the integrity of the container prior to use. Vials are intended for single use only; any unused portions must be discarded. The required volume to be given to the patient should be determined and any excess volume should be withdrawn from the vial before infusion. Connective tubing may be flushed with physiological saline (sodium chloride 9 mg/ml (0.9%)), to ensure complete administration of the contrast medium. Marketing Authorisation Holder: GE Healthcare AS Nycoveien 1-2 P.O. Box 4220 Nydalen NO-0401 OSLO, Norway Marketing Authorisation Numbers: EU/1/97/040/001 EU/1/97/040/002 Date Of First Authorisation/Renewal Of The Authorisation: Date of first authorisation: 22.05.1997 Date of latest renewal: 22.05.2007 Date Of Revision Of The Text: 22.05.2007

PATIENT INFORMATION No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

OVERDOSE Serious adverse events have not been reported in healthy subjects with dosages up to 5 times the normal clinical dose (maximum dose investigated). High doses of manganese can have negative inotropic and vasodilatory effects as well as effects on heart rhythm and conduction because of calcium antagonism. Treatment of an overdose should be symptomatic and directed towards the support of vital functions. There is no antidote to this contrast medium. Mangafodipir and its metabolites are dialysable whereas manganese is not dialysable because of protein binding (see also Pharmacokinetic properties under CLINICAL PHARMACOLOGY). CONTRAINDICATIONS Hypersensitivity to the active substance or to any of the excipients. Pregnancy and lactation. Phaeochromocytoma. Severely reduced liver function (Child - Pugh class C), especially severe obstructive hepatobiliary disease. Severely reduced renal function.

SIDE EFFECTS Undesirable Effects Most of the adverse reactions reported were transient and of mild intensity. Those most commonly reported were: feeling of warmth/flushing, headache and nausea. In clinical trials with Teslascan (mangafodipir) , adverse reactions have been reported with the following frequencies given in the table below (very common ≥ 1/10; common ( ≥ 1/100 to < 1/10); uncommon ( ≥ 1/1,000 to < 1/100); rare ( ≥ 1/10,000 to < 1/1,000); very rare < 1/10,000, not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. System Organ Class Adverse Reactions Frequency Immune system disorders Hypersensitivity reactions (such as skin reactions, rhinitis, pharyngitis) Anaphylactic/anaphylactoid reactions Uncommon Not known Nervous system disorders Headache Dizziness, paraesthesia, transient perverted sensation of taste Common Uncommon Eye disorders Visual disturbance Very rare Cardiac disorders Palpitation Uncommon Vascular disorders Hypertension Rare Gastrointestinal disorders Nausea Abdominal pain, diarrhoea, vomiting Flatulence Common Uncommon Very rare General disorders and administration site conditions Flushing, feeling hot Fever, injection site pain Chest pain Common Uncommon Very rare Mangafodipir can cause transient increases of bilirubin and liver transaminases and transient decreases in plasma zinc. The frequency of mild and moderate, non-serious adverse reactions, mainly transient warmth and flushing, is likely to increase when TESLASCAN (mangafodipir) is administered at the faster rate advised (4–6 ml/min). DRUG INTERACTIONS Interaction with other medicinal products and other forms of interaction No interaction studies have been performed.

WARNINGS Included as part of the PRECAUTIONS section PRECAUTIONS Special warnings and precautions for use Rarely, hypersensitivity reactions (urticaria and other possible allergic phenomena) or anaphylactoid reactions may occur. Familiarity with the practice and technique of resuscitation and treatment of anaphylaxis is essential. Appropriate medicinal products and instruments should be readily available. Care should be exercised in patients with severe cardiac disease and in patients with injuries of the blood brain barrier and severe cerebral disease. The fact that long term parenteral nutrition with manganese supplementation can cause manganese accumulation in the basal ganglia should be considered when administering TESLASCAN (mangafodipir) to patients on such treatment. This medicinal product contains 5.5 mmol (126 mg) sodium per normal dose of 35 ml. To be taken into consideration by patients on a controlled sodium diet. Pregnancy and lactation Pregnancy The safety of TESLASCAN (mangafodipir) in human pregnancy has not been established. TESLASCAN (mangafodipir) must not be used during pregnancy (see the CONTRAINDICATIONS section). Prior to administration of TESLASCAN (mangafodipir) to women of child bearing potential, pregnancy should be excluded. Pre-clinical studies in rats have established teratogenic effects when TESLASCAN (mangafodipir) was given repeatedly during major organogenesis. TESLASCAN (mangafodipir) causes foetotoxicity and embryotoxicity in rabbits. TESLASCAN (mangafodipir) is not teratogenic in rabbits. TESLASCAN (mangafodipir) has no effect on male or female fertility in rats. Lactation The degree of excretion into human breast milk is not known. Breast-feeding should be discontinued from the time of administration and should not be recommenced until 14 days after administration of TESLASCAN (mangafodipir) . Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed.