PRIMOVIST 0.25 mmol/ml Solution for injection

Important information, please read carefully!

Composition 1 ml of the MRI contrast agent Primovist contains 181.43 mg gadoxetic acid, disodium (Gd-EOB- DTPA) as active ingredient.

Pharmacological Properties

Pharmacodynamic properties

Pharmacotherapeutic group: paramagnetic contrast media, ATC code: V08 C A

Primovist is a paramagnetic contrast agent for magnetic resonance imaging. The contrast- enhancing effect is mediated by the stable gadolinium complex, Gd-EOB-DTPA). The paramagnetic efficacy, the relaxivity (determined from the influence on the spin-lattice relaxation time of protons in plasma) is about 8.7 L/mmol/sec at pH 7,39°C and at 0.47 T and displays only slight dependency on the strength of the magnetic field. 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, hence, to an increase of the image contrast of certain tissues.

EOB-DTPA forms a stable complex with the paramagnetic gadolinium ion with extremely high thermodynamic stability (log KGdl = -23.46). Gd-EOB-DTPA is a highly water-soluble, hydrophilic compound with lipophilic moiety due to the ethoxybenzyl group. The substance elicits only minor protein binding. Lesions with no or minimal hepatocyte function (cysts, metastases, the majority of hepatocellular carcinoma) will not accumulate Primovist. Well-differentiated hepatocellular carcinoma may contain functioning hepatocytes and can show enhancement in the hepatocyte imaging phase. Additional clinical information is therefore needed to support a correct diagnosis.

Imaging

After bolus injection of Primovist, dynamic imaging during arterial, portovenous and equilibrium phases utilises the different temporal enhancement pattern of different liver lesions as basis for the radiological lesion characterisation. The enhancement of liver parenchyma during the hepatocyte phase assists in the identification of the number, segmental distribution, visualisation, and delineation of liver lesions, thus improving lesion detection. The differential enhancement/washout pattern of liver lesions contributes to the information from the dynamic phase. The delayed (hepatocyte) phase can be investigated at 20 minutes post injection with an imaging window lasting at least 120 minutes. 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. The imaging window is reduced to 60 minutes in patients requiring haemodialysis and in patients with elevated bilirubin values > 3 mg/dl).

The physico-chemical characteristics of the ready-to-use solution of Primovist are listed below: Osmolality at 37°C (mOsm/kg H2O) 688 Viscosity at 37°C (mPa.s) 1.19 Density at 37°C (g/ml) 1.0881 pH 7.4

Pharmacokinetic properties

Distribution

After intravenous administration, the concentration time profile of Gd-EOB-DTPAwas characterised by a bi-exponential decline. Gd-EOB-DTPA ditributes in the extracellular space (distribution volume at steady state about 0,21 l/kg). Of this, the highest concentration was found in the kidneys and liver.

The compound does not pass the intact blood-brain barrier and diffuses through the placental barrier only to a small extent.

Elimination

In man, the half-life of Gd-EOB-DTPA in serum was found to be 1.0 ± 0.1 hour for the effective t1/2 and not significantly related to the administered doses. Terminal t1/2 was found to be 1.65 ± 0.23 hours or less. The pharmacokinetics observed were dose-linear up to 0.4 ml/kg (100 mmol/kg) body weight.

Gd-EOB-DTPA is completely eliminated in equal amounts via the renal and hepatobiliary routes.

Characteristics in patients

In patients with mild and moderate hepatic impairment, a slight to moderate increase in plasma concentration, half-life and urinary excretion, as well as decrease in hepatobiliary excretion have been observed in comparison to subjects with normal liver function. However, no clinically relevant differences in hepatic signal enhancement were observed. In patients with severe hepatic impairment, especially in patients with abnormally high (> 3 mg/dl) serum bilirubin levels, plasma concentrations and half-life are increased with pronounced decrease in hepatobiliary excretion and reduced hepatic signal enhancement.

In patients with end-stage renal failure the half-life is markedly prolonged and the AUC increased 6-fold. Haemodialysis increased the clearance of Gd-EOB-DTPA (see section 4.2.). In an average dialysis session of about 3-hour duration, about 30% of the Gd-EOB- DTPA dose was removed by haemodialysis.

Preclinical safety data In telemetered conscious dogs a small and transient QT prolongation was observed at the highest dose tested of 0,5 mmol/kg, which represents 20 times the human dose. At the high concentrations, Gd-EOB-DTPA blocked the HERG channel and prolonged the action potential duration in isolated guinea pig papillary muscles. This indicates a possibility that Primovist might induce QT prolongation when overdosed.

Preclinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity.

Systemic tolerance The result of the systemic tolerance studies following repeated daily intravenous administration showed no findings which oppose the diagnostic administration of Primovist to humans.

Genotoxic potential, tumorigenicity

Studies into genotoxic effects (gene-, chromosomal- and genome mutation tests) with Primovist in vivo and in vitro indicated no mutagenic potential. Studies for the evaluation of the tumorigenic potential of Primovist were not performed. This was not considered necessary since Primovist showed no genotoxic properties and no toxic effect on fast growing tissues. In addition, Primovist will usually be administered only once to an individual patient for diagnostic-purposes.

Reproduction toxicology

In a rabbit embryotoxicity study, an increased number of postimplantational losses and increased abortion rate were observed after repeated administration of 2.0 mmol/kg of Gd- EOB-DTPA, representing approximately 80 fold the recommended human dose.

Local tolerance and sensitizing potential Experimental local tolerance studies with Primovist indicated good local tolerability after intravascular [intravenous and intraarterial] and paravenous administration. However, intramuscular administration cause local intolerance reactions and should therefore be strictly avoided in humans (see Special warnings and special precautions for use).

Studies into antigenic and contact-sensitizing effects gave no indication of a sensitizing potential of Primovist.

Therapeutic indications

This medicinal product is for diagnostic use only.

Primovist is a gadolinium-based contrast agent for T1-weighted magnetic resonance imaging (MRI) of the liver.

In dynamic and delayed imaging, Primovist improves the detection of focal hepatic lesions (e.g.number, size, segmental distribution and visualization) and provides additional information regarding characterization and classification of focal liver lesions, thus increasing diagnostic confidence.

Dosage and method of administration

General Information The usual safety rules for magnetic resonance imaging must be observed, e.g. exclusion of cardiac pacemakers and ferromagnetic implants.

The patient should refrain from eating for two hours prior to examination to reduce the risk of aspiration, as nausea and vomiting are known possible adverse events of all contrast media. Whenever possible, the contrast agent should be administered with the patient lying down. After the injection, the patient should be kept under observation for at least 30 minutes, since experience with contrast media shows that the majority of undesirable effects occur within this time.

Dosage

Primovist is ready-to-use aqueous solution to be administered undiluted as an intravenous bolus injection at a flow rate of about 2 ml/sec through a large-bore needle or indwelling catheter (18- 20 gauge is recommended). After the injection of the contrast medium the intravenous cannula should be flushed using physiological saline solution.

The recommended dose of Primovist is :

Adults : 0.1 ml/kg body weight Primovist (equivalent to 25 mmol/kg body weight)

Newborns, infants, children and adolescents : No clinical experience is available for patients younger than 18 years. Therefore, use is not recommended in newborns, infants, children and adolescents.

Patients aged 65 and older: No dosage adjustment is necessary Patient with renal impairment: No dosage adjustment is necessary but caution is recommended in patients with severe renal impairment. Patients with hepatic impairment: No dosage adjustment is necessary Repeated use: No clinical information is available about repeated use of Primovist.

Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Special warnings and special precautions for use

Special Warnings Adequate measures for resuscitation should be made readily available prior to administration of contrast agents.

Hypersensitivity

Allergy-like hypersensitivity reactions ranging to severe reactions including shock are possible (see "Undesirable effects").

Patients with a history of allergic/allergoid reactions to any allergen as well as patients with bronchial asthma might be at higher risk for severe reactions. Most of these reactions occur within half an hour of administration. However, as with other contrast media of this class, in rare cases delayed reactions may occur (see Special Precautions).

Special Precautions

Hypersensitivity reactions

As with other intravenous contrast agents, Primovist can be associated with anaphylactoid/hypersensitivity or other idiosynchratic reactions characterized by cardiovascular, respiratory and cutaneous manifestations. As with other contrast enhanced diagnostic procedures, post-procedure observation of the patient is recommended.

- Risk of hypersensitivity reactions is higher in case of :

previous reaction of contrast media bronchial asthma or other allergic disorders

- Patients who experience such reactions while taking beta blockers may be resistant to treatment effects of beta agonists.

- Due to the possibility of severe hypersensitivity reactions after intravenous contrast administration, preparedness for institution of emergency measures is necessary

If hypersensitivity reactions occur, injection of the contrast medium must be discontinued immediately.

Cardiovascular disease

Caution should be exercised when Primovist is administered to patients with severe cardiovascular problems because only limited data are available so far.

Local intolerance

Intramuscular administration should be strictly avoided, because it may cause local intolerance reactions including focal necrosis (see Preclinical safety data)

Renal impairment: caution should be exercised in patients with severe renal impairment due to reduced elimination capacity of Gd-EOB-DTPA.

Gd-EOB-DTPA should not be used in patients with uncorrected hypokalemia Gd-EOB-DTPA should be used with special care in patients:

With known congenital long QT syndrome or a family history of congenital long QT syndrome With known previous arrhythmias when on drugs that prolong cardiac repolarisation Who are currently taking a drug that is known to prolong cardiac repolarisation e.g. a class III antiarrhythmic (e.g. amiodarone, sotalol)

Primovist may cause transtient QT-prolongation in individual patients.

Interaction with other medicaments and other forms of interaction Anionic drugs primarily excreted into the bile may compete with the hepatic contrast enhancement and the biliary excretion of Primovist, for example rifampicin. Animal studies demonstrated that compounds belonging to the class of rifamycins block the hepatic uptake of Gd-EOB-DTPA thus reducing the hepatic contrast effect. In this case the expected benefit of an injection of Primovist might be limited. No further interactions with other medicaments are known.

Interference from elevated bilirubin or ferritin levels in patients

Elevated levels of bilirubin or ferritin can reduce the hepatic contrast effect of Primovist

Interference with diagnostic tests Serum iron determination using complexometric methods (e.g. Ferrocine complexation method) may result in false values for up to 24 hours after the examination with Primovist because of the free complexing agent contained in the contrast medium solution.

Pregnancy and lactation

Pregnancy

There is no experience from the use of Gd-EOB-DTPA in pregnancy. Animal studies have shown reproductive toxicity at repeated high doses. Primovist should only used in pregnant woman after a clear benefit-to-risk estimation.

Lactation

It is unknown whether Gd-EOB-DTPA is excreted in human breast milk. Animal studies have shown excretion Gd-EOB-DTPA in breast milk. It is recommended that breast- feeding be interrupted for 24 hours after administration of Primovist.

Effects on ability to drive and use machines None known

Undesirable effects No individual adverse reaction reached a frequency greater that "uncommon".

Frequency of adverse reactions from pre-approval (Clinical trial) data:

Most of the undesirable effects were of mild to moderate intensity. Based on experience in more than 1400 patients, the following undesirable effects have been observed and classified by investigators as drug-related (possibly, probably, or definitely).

The table below reports adverse reactions by body system.

Adverse reactions Uncommon Rare System organ class (≥1/1,000,<1/100) (<1/1,000) headache

dizziness vertigo

Nervous system paresthesia akathisia disorders taste disturbance tremor

parosmia

bundle branch block Cardiac disorders palpitation vasodilatation Vascular disorders hypertension Respiratory, thoracic and mediastinal dyspnea disorders vomiting dry mouth Gastrointestinal disorders nausea increased salivation rash maculopapular rash Skin and subcutaneous tissue disorders pruritus sweating increased rigors (chills)

back pain

pain

General disorders and pain thorax administration site injection site pain conditions malaise

asthenia

injection site reaction

injection site edema

In very rare cases anaphylactoid reactions ranging to shock may occur.

Laboratory changes as elevated serum iron, elevated bilirubin, increases in liver transaminases, decrease of hemoglobin, elevation of amylase, leucocyturia, hyperglycemia, elevated urine albumin, hyponatremia, elevated inorganic phosphate, decrease of serum proteine, leucocystosis, hypokalemia, elevated LDH were reported in clinical trials. ECGs were regularly monitored during clinical studies and transient QT prolongation was observed in some patients without any associated adverse clinical events.

Overdose Based on the results of acute toxicity studies in animals, there is no risk of acute intoxication when using Primovist.

The maximum dose tested for use in MR imaging of 0.4 ml/kg (100 mmol/kg) body weight was well tolerated. In a limited number of patients, a dose of 2.0 ml/kg (500 mmol/kg) body weight was tested in clinical trials, more frequent occurrences of adverse events but no new undesirable effects were found in these patients.

In view of the low volume (max.10 ml) and the extremely low gastrointestinal absorption rate of Primovist, and based on acute toxicity data, intoxication due to inadvertent oral ingestion of the contrast medium is extremely improbable.

In the event of excessive inadvertenent overdose, the patient should be carefully observed including cardiac monitoring. In this case induction of QT prolongations is possible.

Treatment

In the event of excessive inadvertent overdosage in patients with substantially impaired renal and hepatic function, Primovist can be removed by hemodialysis.

Instructions for use/handling Inspection

Primovist is supplied ready to use as a clear, colorless to pale yellow solution. Contrast media should not be used in case of severe discoloration, the occurrence of particulate matter or a defective container.

Prefilled syringes

The prefilled syringe must be taken from the pack and prepared for the injection immediately before the examination. Any contrast medium not used in one examination is to be discarded.

Presentation Prefilled syringes

Shelf life 3 years

Do not store above 30° C

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Imported by: PT.Bayer Indonesia Jakarta-Indonesia

Manufactured by: Bayer Schering Pharma AG D-13342 Berlin Federal Republic of Germany