Primograf 0.25 mmol/ml, solution for injection, prefilled syringe. 2 QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml solution for injection contains 181.43 mg gadoxetic acid, disodium (Gd-EOB-DTPA disodium), equivalent to 0.25 mmol Gd-EOB-DTPA disodium. For excipients, see section 6.1. 3 PHARMACEUTICAL FORM

Solution for injection, prefilled syringe: Clear, colourless to pale yellow liquid free from visible particles. 4 4.1 CLINICAL PARTICULARS Therapeutic indications

Primograf is indicated for the detection of focal liver lesions and provides information on the character of lesions in T1-weighted magnetic resonance imaging (MRI). This medicinal product is for diagnostic use only. 4.2 Posology and method of administration

Primograf is a ready-to-use aqueous solution to be administered undiluted as an intravenous bolus injection at a flow rate of about 2 ml/sec. After the injection of the contrast medium the intravenous cannula should be flushed using sterile 9 mg/ml (0.9 %) saline solution.

The recommended dose of Primograf is: Adults: 0.1 ml/kg body weight Primograf. For detailed imaging information refer to section 5.1. Newborns, infants, children and adolescents: Use is not recommended in newborns, infants, children and adolescents as no clinical experience is yet available for patients younger than 18 years. Patients aged 65 and older: No dosage adjustment is necessary. Patients with renal impairment: No dosage adjustment is necessary but caution is recommended in patients with severe renal impairment (see section 4.4 and section 5.2).

Hypersensitivity reactions can be more intense in patients on beta-blockers. Most of these reactions occur within half an hour after administration of contrast media.g. e. Diagnostic procedures that involve the use of contrast agents should be carried out under the direction of a physician with the prerequisite training and a thorough knowledge of the procedure to be performed.3). . The patient should refrain from eating for two hours prior to examination to reduce the risk of aspiration. Repeated use: No clinical information is available about repeated use of Primograf. However. Adequate measures for resuscitation should be made readily available prior to administration of contrast agents. as with other contrast media of this class. • Hypersensitivity Allergy-like reactions. are known to be rare events after administration of gadolinium-based MRI contrast media. 4.2). since experience with contrast media shows that the majority of undesirable effects occur within this time. delayed reactions may occur after hours to days in rare cases. Whenever possible.4 Special warnings and special precautions for use The usual safety precautions for MRI must be observed.Patients with hepatic impairment: No dosage adjustment is necessary. particularly in the presence of bronchial asthma. Caution should be exercised when Primograf is administered to patients with severe cardiovascular problems because only limited data are available so far. It cannot be excluded that Gd-EOB-DTPA may cause torsade de points arrhythmias in an individual patient (see section 5. the patient should be kept under observation for at least 30 minutes.3 Contraindications Hypersensitivity to the active substance or to any of the excipients. exclusion of cardiac pacemakers and ferromagnetic implants. Caution should be exercised in patients with severe renal impairment due to reduced elimination capacity of Gd-EOB-DTPA (see section 5. as nausea and vomiting are known possible adverse reactions. the contrast agent should be administered with the patient lying down. 4. It should be considered that patients on beta-blockers may be refractory to standard treatment of hypersensitivity reactions with beta-agonists. After the injection. including shock. Patients with a history of allergic/allergoid reactions or bronchial asthma might be at higher risk for severe reactions.

No further interactions with other medicinal products are known. Primograf should only be used in pregnant women after a clear benefit-to-risk analysis. Ferrocine complexation method) may result in false values for up to 24 hours after the examination with Primograf because of the free complexing agent contained in the contrast medium solution. In this case the expected benefit of an injection of Primograf might be limited.3).g. 4. Most of the undesirable effects were transient and of mild to moderate intensity. Animal studies have shown reproductive toxicity at repeated high doses (see section 5.If hypersensitivity reactions occur. anionic drugs primarily excreted into the bile (such as rifampicin) may compete with the hepatic contrast enhancement and the biliary excretion of Primograf.6 Pregnancy and lactation • Pregnancy There is no experience from the use of Gd-EOB-DPTA in pregnancy. • Lactation It is unknown whether Gd-EOB-DPTA is excreted in human breast milk.7 Effects on ability to drive and use machines On the basis of the pharmacodynamic profile.8 Undesirable effects During the clinical development phase the overall incidence of adverse reactions which were classified as related was below 5 %. But in general. It is recommended that breast-feeding be interrupted for 24 hours after administration of Primograf. • Interference with diagnostic tests Serum iron determination using complexometric methods (e. 4.3). Animal studies have shown excretion of Gd-EOB-DTPA in breast milk. • Interference from elevated bilirubin or ferritin levels in patients Elevated levels of bilirubin or ferritin can reduce the hepatic contrast effect of Primograf. . Animal studies demonstrated that compounds belonging to the class of rifamycins block the hepatic uptake of Primograf thus reducing the hepatic contrast effect. 4. • Local intolerance Intramuscular administration may cause local intolerance reactions including focal necrosis and should therefore be strictly avoided (see section5. The table below reports adverse reactions by body system. injection of the contrast medium must be discontinued immediately. Primograf is expected to exert no or negligible influence on the ability to drive or use machines.5 Interaction with other medicinal products and other forms of interaction No interaction studies have been conducted in man. 4.

In the event of excessive inadvertent overdose.3). a dose of 2. thoracic and mediastinal disorders Gastrointestinal disorders Skin and subcutaneous tissue disorders General disorders and administration site conditions Laboratory changes as elevated serum iron. the patient should be carefully observed including cardiac monitoring.No individual adverse reaction reached a frequency greater than 1/100. hyperglycemia. elevation of amylase. leucocytosis. increases in liver transaminases.9 Overdose No cases of overdose have been reported and no symptoms could be characterised. elevated inorganic phosphate. ECGs were regularly monitored during clinical studies and transient QT prolongation was observed in some patients without any associated adverse clinical events.0 ml/kg (500 micromol/kg) body weight was tested in clinical trials. more frequent occurrences of adverse events but no new undesirable effects were found in these patients. elevated bilirubin. decrease of hemoglobin. <1/100) headache dizziness paresthesia taste disturbance vasodilatation hypertension dyspnea vomiting nausea dry mouth rash pruritus maculopapular rash sweating increased rigors (chills) back pain pain asthenia injection site reaction injection site pain injection site edema Rare (>1/10 000. . elevated urine albumin. In this case induction of QT prolongations is possible (see section 5. elevated LDH were reported in clinical trials. Adverse reactions System Organ Class (MedDra) Nervous system disorders Uncommon (>1/1000. decrease of serum proteine. In a limited number of patients. 4. leucocyturia. hyponatremia. <1/1000) vertigo akathisia tremor parosmia bundle branch block palpitation Cardiac disorders Vascular disorders Respiratory. In very rare cases anaphylactoid reactions leading to shock may occur. hypokalemia.

s) Density at 37 oC (g/ml) pH 688 1. dynamic imaging during arterial. Imaging After bolus injection of Primograf.0881 7. The contrast-enhancing effect is mediated by the stable gadolinium complex. The physico-chemical characteristics of the ready-to-use solution of Primograf are as follows: Osmolality at 37 oC (mOsm/kg H2O) Viscosity at 37 oC (mPa . The diagnostic and technical efficacy results of the clinical studies show a minimal improvement at 20 minutes post injection over those at 10 minutes post injection. Additional clinical information is therefore needed to support a correct diagnosis. Hepatic excretion of Primograf results in enhancement of biliary structures. portovenous and equilibrium phases utilizes the different temporal enhancement pattern of different liver lesions as basis for the radiological lesion characterization.1 PHARMACOLOGICAL PROPERTIES Pharmacodynamic properties Pharmacotherapeutic group: paramagnetic contrast media. The differential enhancement/washout pattern of liver lesions contributes to the information from the dynamic phase. The enhancement of liver parenchyma during the hepatocyte phase assists in the identification of the number. the relaxivity (determined from the influence on the spin-lattice relaxation time of protons in plasma ) is about 8. visualization. hydrophilic compound with a lipophilic moiety due to the ethoxybenzyl group. thus improving lesion detection.7 l/mmol/sec at pH 7. hence.46).Primograf can be removed by hemodialysis. Well-differentiated hepatocellular carcinoma may contain functioning hepatocytes and can show some enhancement in the hepatocyte imaging phase. and delineation of liver lesions. EOB-DTPA forms a stable complex with the paramagnetic gadolinium ion with extremely high thermodynamic stability (log KGdl = –23. metastases. In T1-weighted scanning the gadolinium ion-induced shortening of the spin-lattice relaxation time of excited atomic nuclei leads to an increase in signal intensity and. The delayed (hepatocyte) phase can be investigated at 20 minutes post injection with an imaging window lasting at least 120 minutes. to an increase in the image contrast of certain tissues. 5 5. Lesions with no or minimal hepatocyte function (cysts.0 . segmental distribution. The paramagnetic efficacy. Gd-EOB-DTPA is a highly water-soluble. the majority of hepatocellular carcinoma) will not accumulate Primograf. Gd-EOB-DTPA. ATC code: V08 C A Primograf is a paramagnetic contrast agent for MRI. 39 °C at 0.19 1.47 T and displays only slight dependency on the strength of the magnetic field. The imaging window is reduced to 60 minutes in patients requiring hemodialysis and in patients with elevated bilirubin values (> 3 mg/dl).

3 Preclinical safety data Preclinical data reveal no special hazard for humans based on conventional studies of acute and subchronic toxicity and genotoxicity. whereas the renal clearance (Clr) corresponds to about 120 ml/min. However. no clinically relevant differences in hepatic signal enhancement were observed. • Characteristics in patients In patients with mild and moderate hepatic impairment . In patients with severe hepatic impairment.4 ml/kg (100 micromol/kg). representing approx.2 Pharmacokinetic properties • Distribution After intravenous administration the concentration time profile of Gd-EOB-DTPA was characterised by a bi-exponential decline. which represents 20 times the human dose. . In a rabbit embryotoxicity study. This indicates a possibility that Primograf might induce QT prolongation when overdosed.5 mmol/kg.0 mmol/kg of GdEOB-DTPA. especially in patients with abnormally high ( > 3 mg/dl) serum bilirubin levels.21 l/kg). about 30% of the Gd-EOB-DTPA dose was removed by hemodialysis. • Elimination Gd-EOB-DTPA is equally eliminated via the renal and hepatobiliary routes. 5. as well as decrease in hepatobiliary excretion have been observed in comparison to subjects with normal liver function. 80 fold the recommended human dose. The substance elicits only minor protein binding (less than 10%). Hemodialysis increased the clearance of Gd-EOB-DTPA (see section 4. In an average dialysis session of about 3-hour duration. an increased number of postimplantational losses and increased abortion rate were observed after repeated administration of 2. a slight to moderate increase in plasma concentration. No findings have been observed in safety pharmacology studies in other organ systems.5. The half–life of Gd-EOB-DTPA was approximately 1. A total serum clearance (Cltot) of about 250 ml/min was recorded.2). Gd-EOB-DTPA distributes in the extracellular space (distribution volume at steady state about 0. The pharmacokinetics was dose-linear up to the dose of 0. The compound does not pass the intact blood-brain barrier and diffuses through the placental barrier only to a small extent. plasma concentration and half-life is increased with pronounced decrease in hepatobiliary excretion and reduced hepatic signal enhancement. In telemetered conscious dogs a small and transient QT prolongation was observed at the highest dose tested of 0. In patients with end-stage renal failure the half-life is markedly prolonged and the AUC increased 6-fold. half-life and urinary excretion.0 hour.

Primograf should not be used in case of severe discoloration. • Package sizes: 1. 6. 5 and 10 x 5 ml (in 10 ml prefilled syringe) 1. It should be visually inspected before use. 6.5 ml (in 10 ml prefilled syringe) 1. a siliconized chlorobutyl elastomer plunger stopper. 6 6. 5 and 10 x 7. the occurrence of particulate matter or a defective container.4 Special precautions for storage Shelf life This medicinal product does not require any special storage precautions. 5 and 10 x 10 ml (in 10 ml prefilled syringe) Not all pack sizes may be marketed.1 PHARMACEUTICAL PARTICULARS List of excipients caloxetic acid.Local intolerance reactions were only observed after intramuscular administration of GdEOB-DTPA.5 Nature and contents of container 10 ml prefilled syringes consisting of a colourless siliconized PhEur type I glass barrel. and disposal • Inspection This medicinal product is a clear.2 Incompatibilities In the absence of compatibility studies. a polysulfone Luer Lock adapter and a polypropylene safety cap. No carcinogenicity studies were performed. a chlorobutyl elastomer rubber tip cap. • Shelf life after first opening of the container not applicable The product should be used immediately after opening.3 5 years.6 Instructions for use and handling. trisodium trometamol hydrochloric acid (for pH adjustment) sodium hydroxide (for pH adjustment) water for injections 6. . 6. this medicinal product must not be mixed with other medicinal products. colorless to pale yellow solution. 6.

• Handling The prefilled syringe must be taken from the pack and prepared for the injection immediately before the examination. • Disposal Any solution not used in one examination is to be discarded in accordance with local requirements. 7 MARKETING AUTHORISATION HOLDER Schering AG D-133 42 BERLIN Germany 8 18967 9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION MARKETING AUTHORISATION NUMBER(S) 2004-03-26 10 DATE OF REVISION OF THE TEXT 2004-10-04 .

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