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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

MultiHance 529 mg/ml solution for injection in pre-filled syringe

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml of solution for injection contains: gadobenic acid 334 mg (0.5M) as the dimeglumine salt.

[Gadobenate dimeglumine 529 mg = gadobenic acid 334 mg + meglumine 195 mg].

5 ml of solution for injection contain: gadobenic acid 1670 mg (2.5 mmol) as dimeglumine salt. [gadobenate dimeglumine 2645 mg = gadobenic acid 1670 mg + meglumine 975 mg]

10 ml of solution for injection contain: gadobenic acid 3340 mg (5 mmol) as dimeglumine salt. [gadobenate dimeglumine 5290 mg = gadobenic acid 3340 mg + meglumine 1950 mg]

15 ml of solution for injection contain: gadobenic acid 5010 mg (7.5 mmol) as dimeglumine salt. [gadobenate dimeglumine 7935= gadobenic acid 5010 mg + meglumine 2925 mg]

20 ml of solution for injection contain: gadobenic acid 6680 mg (10 mmol) as dimeglumine salt. [gadobenate dimeglumine 10580 mg = gadobenic acid 6680 mg + meglumine 3900 mg]

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Solution for injection in a pre-filled syringe.

Clear, colourless to slightly yellow, aqueous solution. Osmolality at 37°C: 1.97 osmol/kg Viscosity at 37°C: 5.3 mPa.s pH: 6.9-7.3

CLINICAL PARTICULARS

4.1 Therapeutic indications

This medicinal product is for diagnostic use only.

MultiHance is a paramagnetic contrast agent for use in diagnostic magnetic resonance imaging (MRI) indicated for :

•    MRI of the liver for the detection of focal liver lesions in patients with known or suspected primary liver cancer (eg. hepatocellular carcinoma) or metastatic disease.

•    MRI of the brain and spine where it improves the detection of lesions and provides diagnostic information additional to that obtained with unenhanced MRI.

•    MRI of the breast, for the detection of malignant lesions in patients where breast cancer is known or suspected on the basis of previous mammography or ultrasound results.

4.2 Posology and method of administration

Posology

MRI of the liver: the recommended dose of MultiHance injection in adult patients is 0.05 mmol/kg body weight. This corresponds to 0.1 mL/kg of the 0.5 M solution.

MRI of the brain and spine : the recommended dose of MultiHance injection in adult and in paediatric patients greater than 2 years of age is 0.1 mmol/kg body weight. This corresponds to 0.2 mL/kg of the 0.5 M solution.

MRA: the recommended dose of MultiHance injection in adult patients is 0.1 mmol/kg body weight. This corresponds to 0.2 mL/kg of the 0.5 M solution. MRI of the breast: the recommended dose of MultiHance in adult patients is 0.1 mmol/kg body weight. This corresponds to 0.2 mL/kg of the 0.5 M solution.

Method of administration

MultiHance should be drawn up into the syringe immediately before use and should not be diluted. Any unused product should be discarded and not be used for other MRI examinations.

To minimise the potential risks of soft tissue extravasation of MultiHance, it is important to ensure that the i.v. needle or cannula is correctly inserted into a vein.

The product should be administered intravenously either as a bolus or slow injection (10 mL/min.), see table for post-contrast imaging acquisition.

The injection should be followed by a flush of sodium chloride 9 mg/ml (0.9%) solution for injection.

Post-contrast imaging acquisition:

Liver	Dynamic imagine:	Immediately following bolus injection.
	Delayed imaging:	between 40 and 120 minutes following the injection, depending on the individual imaging needs.
Brain and Spine	up to 60 minutes after the administration.
MRA	immediately after the administration, with scan delay calculated on the basis of test bolus or automatic bolus detection technique. If an automatic contrast detection pulse sequence is not used for bolus timing, then a test bolus injection <2 mL of the agent should be used to calculate the appropriate scan delay.
Breast	Tl-weighted, dynamic acquisition immediately following bolus injection and then repeated at 2, 4, 6 and 8 minutes.

Special Populations

Impaired renal function

Use of MultiHance should be avoided in patients with severe renal impairment (GFR < 30 ml/min/1.73m²) and in patients in the perioperative liver transplantation period unless the diagnostic information is essential and not available with non-contrast enhanced MRI (see information on renal impairment in section 4.4).

If use of MultiHance cannot be avoided, the dose should not exceed 0.1 mmol/kg body weight when used for MR of the brain and spine, MR-angiography or breast MRI and should not exceed 0.05 mmol/kg body weight when used for MR of the liver. More than one dose should not be used during a scan. Because of the lack of information on repeated administration, MultiHance injections should not be repeated unless the interval between injections is at least 7 days.

Elderly (aged 65 years and above)

No dosage adjustment is considered necessary. Caution should be exercised in elderly patients (see section 4.4).

Paediatric population

No dosage adjustment is considered necessary.

Use for MRI of the brain and spine is not recommended in children less than 2 years of age.

Use for MRI of the liver, MRI of the breast or MRA is not recommended in children less than 18 years of age.

4.3 Contraindications

MultiHance is contra-indicated in:

•    patients with hypersensitivity to the active substance or to any of the excipients listed in section 6.1

•    patients with a history of allergic or adverse reactions to other gadolinium chelates.

4.4 Special warnings and precautions for use

The use of diagnostic contrast media, such as MultiHance, should be restricted to hospitals or clinics staffed for intensive care emergencies and where cardiopulmonary resuscitation equipment is readily available.

Patients should be kept under close supervision for 15 minutes following the injection as the majority of severe reactions occur at this time. The patient should remain in the hospital environment for one hour after the time of injection.

The accepted general safety procedures for Magnetic Resonance Imaging, in particular the exclusion of ferromagnetic objects, for example cardiac pacemakers or aneurysm clips, are also applicable when MultiHance is used.

Caution is advised in patients with cardiovascular disease.

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.

Hypersensitivity reactions

As with other gadolinium chelates, the possibility of a reaction, including serious, life-threatening, or fatal anaphylactic and anaphylactoid reactions involving one or more body systems, mostly respiratory, cardiovascular and/or mucocutaneous systems, should always be considered, especially in patients with a history of asthma or other allergic disorders.

Prior to MultiHance administration, ensure the availability of trained personnel and medications to treat hypersensitivity reactions.

Insignificant quantities of benzyl alcohol (<0.2%) may be released by gadobenate dimeglumine during storage. Nonetheless, MultiHance should not be used in patients with a history of sensitivity to benzyl alcohol.

As with other gadolinium-chelates, a contrast-enhanced MRI should not be performed within 7 hours of a MultiHance-enhanced MRI examination to allow for clearance of MultiHance from the body.

Extravasation of MultiHance might lead to injection site reactions (see section 4.8 Undesirable Effects). Exercise caution to avoid local extravasation during intravenous administration of MultiHance. If extravasation occurs, evaluate and treat as necessary if local reactions develop.

Impaired renal function

Prior to administration of MultiHance, it is recommended that all patients are screened for renal dysfunction by obtaining laboratory tests.

There have been reports of nephrogenic systemic fibrosis (NSF) associated with use of some gadolinium containing contrast agents in patients with acute or chronic severe renal impairment (GFR<30ml/min/1.73m²).

Patients undergoing liver transplantation are at particular risk since the incidence of acute renal failure is high in this group. As there is a possibility that NSF may occur with MultiHance, it should therefore be avoided in patients with severe renal impairment and in patients in the perioperative liver transplantation period unless the diagnostic information is essential and not available with non-contrast enhanced MRI.

Haemodialysis shortly after MultiHance administration may be useful at removing MultiHance 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.

Elderly

As the renal clearance of gadobenate dimeglumine may be impaired in the elderly, it is particularly important to screen patients aged 65 years and older for renal dysfunction.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed during the clinical development of MultiHance. However no drug interactions were reported during the clinical development programme.

4.6 Fertility, Pregnancy and lactation Pregnancy

There are no data from the use of gadobenate dimeglumine in pregnant women. Animal studies have shown reproductive toxicity at repeated high doses (see section 5.3). MultiHance should not be used during pregnancy unless the clinical condition of the woman requires use of gadobenate dimeglumine.

Lactation

Gadolinium containing contrast agents are excreted into breast milk in very small amounts (see section 5.3). At clinical doses, no effects on the infant are anticipated due to the small amount excreted into milk and poor absorption from the gut. Continuing or discontinuing breast feeding for a period of 24

hours after administration of MultiHance should be at the discretion of the doctor and lactating mother.

4.7 Effects on ability to drive and use machines

MultiHance has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

The following adverse events were seen during the clinical development of MultiHance among 2637 adult subjects. There were no adverse reactions with a frequency greater than 2%.

System organ classes	Common (>1/100, <1/10)	Uncommon (>1/1,000, <1/100)	Rare (1/10,000, <1/1,000)
Infections and infestations		Nasopharyngitis
Nervous system disorders	Headache	Paraesthesia, dizziness, syncope, parosmia	Hyperaesthesia, tremor, intracranial hypertension, hemiplegia, convulsion
Eye disorders			Conjunctivitis
Ear and labyrinth disorders			Tinnitus
Cardiac disorders		Tachycardia, atrial fibrillation, first-degree atrioventricular block, ventricular extrasystoles, sinus bradycardia,	Arrhythmia, myocardial ischaemia, prolonged PR interval
Vascular disorders		Hypertension, hypotension
Respiratory, thoracic and mediastinal disorders		Rhinitis,	Dyspnoea N.O.S., laryngospasm, wheezing, pulmonary congestion, pulmonary oedema
Gastrointestinal disorders	Nausea	Dry mouth, taste perversion, diarrhoea, vomiting, dyspepsia, salivation, abdominal pain	Constipation, faecal incontinence, necrotising pancreatitis

Skin & subcutaneous tissue disorders		Pruritus, rash, face oedema, urticaria, sweating
Musculoskeletal, connective tissue and bone disorders		Back pain, myalgia
Renal and urinary disorders			Urinary incontinence, urinary urgency
General disorders and administration site conditions	Injection Site Reaction, feeling hot	Asthenia, fever, chills, chest pain, pain, injection site pain, injection site extravasation	injection site inflammation
Investigations		Abnormal laboratory tests, abnormal ECG, prolonged QT

Laboratory abnormalities cited above include hypochromic anaemia, leukocytosis, leukopenia, basophilia, hypoproteinaemia, hypocalcaemia, hyperkalaemia, hyperglycaemia or hypoglycaemia, albuminuria, glycosuria, haematuria, hyperlipidaemia, hyperbilirubinaemia, serum iron increased, and increases in serum transaminases, alkaline phosphatase, lactic dehydrogenase, and in serum creatinine and were reported in equal or less than 0.4% of patients following the administration of MultiHance. However these findings were mostly seen in patients with evidence of pre-existing impairment of hepatic function or pre-existing metabolic disease.

The majority of these events were non-serious, transient and spontaneously resolved without residual effects. There was no evidence of any correlation with age, gender or dose administered.

Paediatric population

In paediatric patients enrolled in clinical trials the most commonly reported adverse reactions included vomiting (1.4%), pyrexia (0.9%) and hyperhydrosis (0.9%). The frequency and nature of adverse reactions was similar to that in adults.

In marketed use, adverse reactions were reported in fewer than 0.1 % of patients.

Most commonly reported were: nausea, vomiting, signs and symptoms of hypersensitivity reactions including angioedema, laryngeal spasm and rash. More severe reactions including anaphylactoid reactions and anaphylactic shock may have fatal outcome.

Injection site reactions due to extravasation of the contrast medium leading to local pain or burning sensations, swelling, blistering and, in rare cases when localised swelling is severe, necrosis have been reported.

Localised thrombophlebitis has also been rarely reported.

Isolated cases of nephrogenic systemic fibrosis (NSF) have been reported with MultiHance in patients co-administered other gadolinium-containing contrast agents (see Section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme -Website: www.mhra.gov.uk/yellowcard.

4.9 Overdose

There have been no cases of overdose reported. Therefore, the signs and symptoms of overdosage have not been characterised. Doses up to 0.4 mmol/kg were administered to healthy volunteers, without any serious adverse events. However, doses exceeding the specific approved dosage are not recommended. In the event of overdosage, the patient should be carefully monitored and treated symptomatically.

MultiHance can be removed by haemodialysis. However there is no evidence that haemodialysis is suitable for prevention of nephrogenic systemic fibrosis (NSF) dialysable.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: paramagnetic contrast media, ATC code V08CA08

Mechanism of action and pharmacodynamic effects

The gadolinium chelate, gadobenate dimeglumine, shortens longitudinal (T1), and, to a lesser extent, transversal (T2) relaxation times of tissue water protons.

The relaxivities of gadobenate dimeglumine in aqueous solution are ri = 4.39 and r₂ = 5.56 mM"¹s"¹ at 20 MHz.

Gadobenate dimeglumine experiences a strong increase in relaxivity on going from aqueous solution to solutions containing serum proteins, r1 and r2 values were 9.7 and 12.5 respectively in human plasma.

Clinical efficacy and safety

In liver imaging, MultiHance may detect lesions not visualised in pre-contrast enhanced MRI examination of patients with known or suspected hepatocellular cancer or metastatic disease. The nature of the lesions visualised after contrast enhancement with MultiHance has not been verified by pathological anatomical investigation. Furthermore, where the effect on patient management was assessed, the visualisation of post-contrast-enhanced lesions was not always associated with a change in the patient management.

In the liver MultiHance provides strong and persistent signal intensity enhancement of normal parenchyma on T1-weighted imaging. The signal intensity enhancement persists at high level for at least two hours after the administration of doses of either 0.05 or 0.10 mmol/kg. Contrast between focal liver lesions and normal parenchyma is observed almost immediately after bolus injection (up to 2-3 minutes) on T1-weighted dynamic imaging. Contrast tends to decrease at later time points because of non-specific lesion enhancement. However, progressive washout of MultiHance from the lesions and persistent signal intensity enhancement of normal parenchyma are considered to result in enhanced lesion detection and a lower detection threshold for lesion site between 40 and 120 minutes after MultiHance administration.

Data from pivotal Phase II and Phase III studies in patients with liver cancer indicate that, compared with other reference imaging modalities (e.g. intraoperative ultrasonography, computed tomographic angio-portography, CTAP, or computed tomography following intra-arterial injection of iodized oil), with MultiHance enhanced MRI scans there was a mean sensitivity of 95% and a mean specificity of 80% for detection of liver cancer or metastasis in patients with a high suspicion of these conditions.

In MRI of the brain and spine, MultiHance enhances normal tissues lacking a blood-brain barrier, extra axial tumours and regions in which the blood-brain-barrier has broken down. In the pivotal phase III clinical trials conducted in adults for this indication, designed as parallel-group comparisons, off-site readers reported an improvement in level of diagnostic information in 32-69% of images with MultiHance, and 35-69% of images with the active comparator.

In two studies designed as intra-individual, crossover comparisons of 0.1 mmol/kg body weight MultiHance vs 0.1 mmol/kg body weight of two active comparators (gadopentetate dimeglumine or gadodiamide), conducted in patients with known or suspected brain or spine disease undergoing MRI of the central nervous system (CNS), MultiHance provided significantly (p<0.001) higher increase in lesion signal intensity, contrast-to-noise ratio, and lesion-to-brain ratio, as well as significantly (p<0.001) better visualisation of CNS lesions in images obtained with 1.5 Tesla scanners as tabulated below.

	(Study MH-109) (n=151)		(Study MH-130) (n=113)
Definition of extent of CNS Disease	25% to 30%	<0.001	24% to 25%	<0.001
Visualisation of Lesion Internal Morphology	29% to 34%	<0.001	28% to 32%	<0.001
Delineation of Borders of Intra- and Extra-axial Lesions	37% to 44%	<0.001	35% to 44%	<0.001
Lesion Contrast Enhancement	50% to 66%	<0.001	58% to 67%	<0.001
Global Diagnostic Preference	50% to 68%	<0.001	56% to 68%	<0.001

In the trials MH-109 and MH-130, the impact of improved visualization of CNS lesions with MultiHance versus gadodiamide or gadopentetate dimeglumine on diagnostic thinking and patient management was not studied.

In MR A, MultiHance improves image quality by increasing blood signal to noise ratio as a result of blood T1 shortening, reduces motion artifacts by shortening scan times and eliminates flow artifacts. In the phase III clinical trials in MRA of arteries extending from the supra-aortic territory to the pedal circulation, off-site readers reported an improvement in diagnostic accuracy ranging from 8% to 28% for the detection of clinically significant steno-occlusive disease (i.e. stenosis of >51% or >60% depending on the vascular territory) with MultiHance-enhanced images compared to time of flight (TOF) MRA, on the basis of conventional angiographic findings.

In MRI of female breast, MultiHance increases the contrast between neoplastic breast tissues and adjacent normal tissues, thus improving the conspicuity of breast tumors .

The pivotal, Phase III trial was an intra-individual, crossover comparison of 0.1 mmol/kg body weight MultiHance vs 0.1 mmol/kg body weight of an active, established comparator agent (gadopentate dimeglumine) in MRI of patients with suspected or known breast cancer on the basis of previous ultrasound or mammography. The images were read off-site by three blinded readers with no affiliation to any of the study centres.

The sensitivity for the detection of benign and malignant lesions ranged from 91.7%-94.4% for MultiHance and 79.9%to 83.3% for the comparator (p<0.0003 for all readers).

The results for specificity in the detection of benign and malignant lesions were not statistically significant and ranged from 59.7%-66.7% for MultiHance and 30.6%-58.3% for the comparator (p<0.157 for all readers). Statistically significant improvements were observed for both sensitivity and specificity in the region level analysis.

5.2 Pharmacokinetic properties

Modelling of the human pharmacokinetics was well described using a biexponential decay model. The apparent distribution and elimination halftimes range from 0.085 to 0.117 h and from 1.17 to 1.68 respectively. The apparent total volume of distribution, ranging from 0.170 to 0.248 L/kg body weight, indicates that the compound is distributed in plasma and in the extracellular space.

Gadobenate ion is rapidly cleared from plasma and is eliminated mainly in urine and to a lesser extent in bile. Total plasma clearance, ranging from 0.098 to 0.133 L/h kg body weight, and renal clearance, ranging from 0.082 to 0.104 L/h kg body weight, indicate that the compound is predominantly eliminated by glomerular filtration. Plasma concentration and area under the curve (AUC) values show statistically significant linear dependence on the administered dose. Gadobenate ion is excreted unchanged in urine in amounts corresponding to 78%-94% of the injected dose within 24 hours. Between 2% and 4% of the dose is recovered in the faeces.

Gadobenate ion does not cross the intact blood-brain barrier and, therefore, does not accumulate in normal brain or in lesions that have a normal blood-brain barrier. However, disruption of the blood-brain barrier or abnormal vascularity allows gadobenate ion penetration into the lesion.

Population pharmacokinetic analysis was performed on systemic drug concentration-time data from 80 subjects (40 adult healthy volunteers and 40 paediatric patients) aged 2 to 47 years following intravenous administration of gadobenate dimeglumine. The kinetics of gadolinium down to the age of 2 years could be described by a two compartment model with standard allometric coefficients and a covariate effect of creatinine clearance (reflecting glomerular filtration rate) on gadolinium clearance. The pharmacokinetic parameter values (referenced to adult body weight) were consistent with previously reported values for MultiHance and consistent with the physiology presumed to underlie MultiHance distribution and elimination: distribution into extracellular fluid (approximately 15 L in an adult, or 0.21 L/kg) and elimination by glomerular filtration (approximately 130 mL plasma per minute in an adult, or 7.8 L/h and 0.11 L/h/kg). Clearance and volume of distribution decreased progressively for younger subjects due to their smaller body size. This effect could largely be accounted for by normalising pharmacokinetic parameters for body weight. Based on this analysis, weight based dosing for MultiHance in paediatric patients gives similar systemic exposure (AUC) and maximum concentration (Cmax) to those reported for adults, and confirms that no dose adjustment is necessary for the paediatric population over the proposed age range (2 years and above).

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential.

Indeed, preclinical effects were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.

Animal experiments revealed a poor local tolerance of MultiHance, especially in case of accidental paravenous application where severe local reaction, such as necrosis and eschars, could be observed.

Local tolerance in case of accidental intra-arterial application has not been investigated, so that it is particularly important to ensure that the i.v. needle or cannula is correctly inserted into a vein (see section 4.2).

Pregnancy and lactation

In animal studies no untoward effects on the embryonic or foetal development were exerted by daily intravenous administration of gadobenate dimeglumine in rats. Also, no adverse effects on physical and behavioural development were observed in the offspring of rats. However, after repeated daily dosing in rabbit, isolated cases of skeletal variations and two cases of visceral malformations were reported.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Water for injections.

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

3 years

From a microbiological point of view, the product should be used immediately after opening.

6.4 Special precautions for storage

Do not freeze.

6.5 Nature and contents of container

-    10, 15 and 20 mL solution filled into a single dose transparent plastic (cyclic polyolefin) syringe with chlorobutyl rubber plunger and tip cap.

-    Kit with administration devices : 15 and 20 mL pre-filled syringe, 20 mL syringe (polypropylene), connector with 3-way stopcock (polycarbonate), spike (ABS/polypropylene), 20 G secured catheter.

-    Kit with administration devices : 15 and 20 mL pre-filled syringe, syringe for magnetic resonance automatic injector ((115 mL syringe (polyethelene terephthalate/polycarbonate), connector

(PVC/polycarbonate/polypropylene/silicone), spike (ABS)), 20 G secured catheter.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

For single use only.

Before use, examine the product to assure that the container and closure have not been damaged, the solution is not discoloured and no particulate matter is present.

The peel-off tracking label on the syringes should be stuck onto the patient records to enable accurate recording of the gadolinium contrast agent used. The dose used should also be recorded. If electronic patient records are used, the name of the product, the batch number and the dose should be entered into the patient record.

Any unused product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Bracco Imaging SpA

via Egidio Folli 50 -20134 Milan

Italy

8    MARKETING AUTHORISATION NUMBER(S)

PL 12032/0010

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

21/07/2012

DATE OF REVISION OF THE TEXT

13/05/2015