MultiHance is a clear, colourless aqueous solution containing gadobenic acid 334 mg/ml (0.5M) as the dimeglumine salt.

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Pharmacotherapeutic group, ATC code V08CA Dimeglumine gadobenate is an octadentatate chelate of gadolinium salified with meglumine. As a paramagnetic contrast agent, it shortens longitudinal (T1), and, to a lesser extent, transversal (T2) relaxation times of tissue water protons. The relaxivities of dimeglumine gadobenate in aqueous solution (r1= 4.39 and r2= 5.56 mM-1s-1 at 20 MHz) are only slightly higher than those of other paramagnetic contrast agents already in clinical use. However, unlike other contrast agents, dimeglumine gadobenate experiences strong increase in relaxivity on going from aqueous solution to solutions containing serum proteins. Particularly r1 and r2 amount to 9.7 and 12.5 (20 MHz) respectively in human plasma. Dimeglumine gadobenate, is the only gadolinium chelate which combines:

Early temporal differences in enhancement between normal and diseased liver can be detected with compact bolus injection of the contrast medium and rapid imaging technique ("dynamic MRI") to improve liver-lesion characterisation. Different from all the other gadolinium chelates, the liver enhancement produced by dimeglumine gadobenate does not start to decrease in a few minutes, but remains steady for hours. The enhancement of signal intensity in the normal liver parenchyma is much more persistent and long lasting than in lesions, so that the differential contrast between normal parenchyma and lesions results is significantly enhanced on images acquired 40-120 minutes after MultiHance administration. The lesion-to-liver contrast enhancement provided by MultiHance facilitates visualisation and identification of individual lesions in the liver parenchyma. After rapid intravascular distribution, the gadobenic ion rapidly diffuses into the extracellular-fluid space. Due to its high hydrophilicity, the gadobenic ion does not pass the intact blood-brain barrier, so that, similarly to other gadolinium chelates, the agent can be applied in the detection and delineation of neoplasms, infections, inflammation or vascular abnormalities in the CNS, marking areas of abnormal vascularity or of impaired or absent blood-brain barrier.

Pharmacokinetics

Human pharmacokinetics of gadobenic ion, the MRI contrast effective anion in dimeglumine gadobenate, was described using a biexponential decay model. The apparent distribution and elimination half-lives ranges of means are from 0.084 to 0.36 h and from 1.17 to 1.68 h respectively. The apparent total volume of distribution, ranging from 0.170 to 0.248 L/kg body weight (bw), indicates that the compound is distributed in plasma and in the extracellular space. Gadobenate ion is rapidly cleared from plasma and is eliminated mainly through urinary route and in less extent through biliary route. Total plasma clearance, ranging from 0.098 to 0.133 L/h kg bw, and renal clearance, ranging from 0.082 to 0.104 L/h kg bw, 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. The compound does not bind measurably to plasma proteins, as assessed by equilibrium dialysis. 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.

MultiHance is cleared from the body mainly by glomerular filtration and to a minor degree by hepatobiliary excretion. The pharmacokinetics of an intravenous bolus of 0.2 mmol/kg of dimeglumine gadobenate (0.5M) was evaluated in a double-blind, placebo-controlled, parallel-group study in 20 patients administered MultiHance and in 12 patients administered placebo. They were patients with moderate (creatinine clearance >30 ml/min and 60 ml/min) and with severe renal impairment (creatinine clearance 10 ml/min and 30 ml/min). The pharmacokinetic terminal half-life of MultiHance increased as the degree of renal impairment increased (6.1 and 9.5 hr for moderate and severe renal impairment respectively, as compared to 1-2 hours in healthy volunteers). However, no differences were noted in the total recovery of gadolinium in urine or the rate and type of adverse events reported compared with healthy volunteers, and no deterioration in renal function was observed following the administration of MultiHance. Dose adjustments in patients with renal impairment are not recommended. In cases of end-stage renal disease, consideration should be given to removing MultiHance by haemodialysis. Approximately 72% of the dose is recovered by haemodialysis over a 4-hour period.

Dosage and Administration

The recommended dose of MultiHance in adult patients is 0.05 mmol/kg body weight. This corresponds to 0.1 mL/kg of the 0.5 M solution. The product should be administered intravenously either as a bolus or as an infusion (10 mL/min. ). Post-contrast imaging can be performed immediately following the bolus (dynamic MRI). Delayed, liver-specific imaging can be performed between 40 and 120 minutes following the injection, depending on the individual imaging needs.

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. In patients with known or suspected metastatic disease to the central nervous system, a second injection of 0.1 mmol/kg provides a significant increase in lesion-to-normal parenchyma contrast enhancement, which improves lesion detectability. The product should be administered intravenously either as a bolus or as an infusion (10 mL/min. ). In MRI of the CNS, imaging can be started up to 60 minutes after the administration.

The product should be administered intravenously as a bolus injection, either manually or using an automatic injector system. 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. MultiHance should be drawn up into the syringe immediately before use and should not be diluted. Contains no antimicrobial agent. Product is for single use in one patient only. Discard any residue.

MultiHance should be drawn up into the syringe immediately before use and should not be diluted. The injection should be followed by a saline flush of at least 5 mL. Contains no antimicrobial agent. Product is for single use in one patient only. Discard any residue. 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. Parenteral products should be inspected visually for particulate matter and discoloration prior to administration. Do not use the solution if it is discolored or particulate matter is present. Concurrent medications or Parenteral Nutrition should not be physically mixed with contrast agents and should not be administered in the same intravenous line because of the potential of chemical incompatibility.

Contraindications

MultiHance is contra-indicated in patients with hypersensitivity to any of the ingredients. MultiHance should not be used in patients with a history of allergic or adverse reactions to other gadolinium chelates.

Warnings and Precautions

Nephrogenic Systemic Fibrosis (NSF)

Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the medicines. Avoid use of GBCAs among these patients unless the diagnostic information is essential and not available with non-contrast enhanced MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR <30 mL/min/1.73m2) as well as patients with acute kidney injury of any severity due to the hepato-renal syndrome or in the peri-operative liver transplantation period. As there is a possibility that NSF may occur with MultiHance it should only be used in these patients after careful consideration. NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Screen patients for acute kidney injury and other conditions that may reduce renal function. Features of acute kidney injury consist of rapid (over hours to days) and usually reversible decrease in kidney function, commonly in the setting of surgery, severe infection, injury or medicine induced kidney toxicity. Serum creatinine levels and estimated GFR may not reliably assess renal function in the setting of acute kidney injury. For patients at risk for chronically reduced renal function (e.g., age >60 years, diabetes mellitus or chronic hypertension), estimate the GFR through laboratory testing. Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a GBCA and the degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administered to a patient. For patients at highest risk for NSF, do not exceed the recommended MultiHance dose and allow a sufficient period of time for elimination of the medicine prior to re-administration. For patients receiving haemodialysis, physicians may consider the prompt initiation of haemodialysis following the administration of a GBCA in order to enhance the contrast agent's elimination. The usefulness of haemodialysis in the prevention of NSF is unknown.

Hypersensitivity Reactions

Anaphylactoid reactions or shock have been observed with MultiHance as well as other related products. Therefore patients should be kept under close observation. Appropriate facilities should be available for coping with any complication of the procedure, as well as for the emergency treatment of severe reactions to the contrast itself. The accepted safety considerations and procedures that are required for Magnetic Resonance Imaging in particular the exclusion of ferromagnetic objects, for example cardiac pace-makers or aneurysm clips, are also applicable when MultiHance is used for contrast enhancement. Data on the safety of repeated injections of MultiHance are not available. If the physician determines sequential or repeat examinations are required, an interval of at least 7 hours between administrations should be observed to allow for clearance of the medicine from the body. Caution is advised in patients with cardiovascular disease. Small quantities of benzyl alcohol (<0.2%) may be released by dimeglumine gadobenate during storage. Thus MultiHance should not be used in patients with a history of sensitivity to benzyl alcohol.

Carcinogenicity, mutagenicity and impairment of fertility

Long term animal carcinogenicity studies were not conducted with dimeglumine gadobenate. Dimeglumine gadobenate did not induce gene mutations in Salmonella typhimurium, E. coli or Saccharomyces cerevisiae, nor chromosomal aberrations in Chinese Hamster lung cells, human lymphocytes or human epithelial cells in vitro. Dimeglumine gadobenate did not induce micronuclei in bone marrow cells in rats in vivo. Intravenous administration of dimeglumine gadobenate did not affect reproduction or fertility in male and female rats at doses up to 1.5 mmol/kg/day (1.4x the maximum clinical dose, adjusted for body surface area). Long-term animal carcinogenicity studies were not conducted with dimeglumine gadobenate. Dimeglumine gadobenate did not induce gene mutation in Salmonella typhimurium, E. coli or mouse lymphoma cells, or chromosomal aberrations in CHO cells in vitro or in bone marrow cells in mice in vivo.

Use in pregnancy

In studies in rats and rabbits, no untoward effects on embryonic or foetal development were exerted by daily intravenous administration of dimeglumine gadobenate in rats up to 2 mmol/kg/day or in rabbits at doses up to 1.5mmol/kg/day. However, an increase in abortions and decreased foetal bodyweights were noted in rabbits at doses of 2 mmol/kg/day (3.3x the maximum clinical dose, adjusted for body surface area). The safety and efficacy of MultiHance have not been established in pregnant women and, therefore, MultiHance should not be used during pregnancy unless the clinical condition of the woman requires use of gadobenate dimeglumine.

Use in lactation

It is not known to what extent MultiHance is excreted in human milk, however a study with radiolabelled dimeglumine gadobenate in lactating rats showed that small amounts of radioactivity were transferred via milk to neonates. Although the clinical significance of this observation is unknown, breast-feeding should be discontinued prior to the administration of MultiHance and should not be recommended until at least 24 hours after the administration of MultiHance.

Use in children

The safety and efficacy of MultiHance have not been established in patients under 18 years old. Therefore, use of MultiHance in this patient group cannot be recommended.

Effect on ability to drive or operate machinery

On the basis of the pharmacokinetic and pharmacodynamic profiles, no or negligible influence is expected with the use of MultiHance on the ability to drive or use machines.

Adverse Effects

The following adverse events were seen during the clinical development of MultiHance among 4144 adult subjects during clinical trials are shown in the table below. There were no adverse reactions with a frequency greater than 1.4%:

Adult subjects

System organ classes	Common (>=1/100, <1/10) (>=1% to <10%)	Uncommon (>1/1,000, <1/100) (>=0.1% to <1%)	Rare (>1/10,000, <1/1,000) (>=0.01 to <0.1)
Blood and lymphatic system disorders		Basophilia	Leukopenia
Metabolism and nutrition disorders		Hypocalcaemia	Hyperkalaemia Hyperglycaemia Hypoglycaemia Hyperlipidaemia
Immune system disorders			Anaphylactic reaction
Infections and infestations		Nasopharyngitis
Nervous system disorders	Headache	Paraesthesia, Dizziness, Syncope, Parosmia Hypoaesthesia Taste perversion	Convulsions, Hyperaesthesia, Tremor, intracranial, hypertension, hemiplegia, parosmia
Eye disorders			Conjunctivitis
Eye and labyrinth disorders			Tinnitus,
Cardiac disorders		Tachycardia, Atrial fibrillation, First-degree atriovascular block, Ventricular extrasystoles, Sinus bradycardia Atrioventricular block first degree	Arrhythmia, Myocardial ischaemia Prolonged PR interval
Vascular disorders	Hypertension	Vasodilatation, 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, abdominal pain	Constipation, Faecal incontinence, Necrotising Pancreatitis Hypoaesthesia oral
Skin & subcutaneous tissue disorders		Rash including erythematous rash, macular, maculopapular and popular rash, localised oedema, pruritus, urticaria, sweating	Face oedema
Musculoskeletal and connective tissue disorders		Back pain, Myalgia	Muscle spasms
Renal and urinary disorders		Proteinuria Glycosuria Haematuria	Urinary incontinence, Urinary urgency Pollakiuria
System organ classes	Common (>=1/100, <1/10) (>=1% to <10%)	Uncommon (>1/1,000, <1/100) (>=0.1% to <1%)	Rare (>1/10,000, <1/1,000) (>=0.01 to <0.1)
General disorders and administration site conditions	Injection site reaction, including injection site pain, inflammation, burning, warmth, coldness, discomfort, erythema, paraesthesia pruritis	Asthenia, Feeling Hot, Fever, Chills, Chest Pain, Injection site pain, Injection site extravasation	Injection site inflammation, Malaise
Investigations		Abnormal laboratory tests including haemoglobin decreased, blood bilirubin increased, blood iron increased, increases in serum transaminases, gamma- glutamyltransferase, lactic dehydrogenase and creatinine	Electrocardiogram abnormalities including: Electrocardiogram QT prolonged; electrocardiogram T wave inversion, and electrocardiogram PR prolongation, laboratory test abnormal including blood albumin decreased, and alkaline phosphatase increased

Also reported were single individual serious incidents of laryngospasms within an anaphylactic reaction, pancreatitis necrotising, pulmonary oedema, intracranial pressure increased, and hemiplegia. 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. Laboratory abnormalities, such as hypochromic anaemia, leukocytosis, leukopenia, basophilia, hypoproteinaemia, hypocalcaemia, hyperkalaemia, hyperglycaemia, hypoglycaemia, albuminuria, glucosuria, haematuria, hyperlipidaemia, hyperbilirubinaemia, increase in total iron and increases in serum transaminases, alkaline phosphatase, lactic dehydrogenase, and in serum creatinine and serum iron 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..

Post Marketing Data

In marketed use, adverse reactions were reported in less than 0.1% of patients. Most commonly reported were: nausea, vomiting. Injection site reactions due to extravasation of the contrast medium leading to local pain or burning sensations, swelling and blistering have been reported. Isolated cases of NSF have been reported with MultiHance in patients co-administered other gadolinium containing contrast agents. None of the occurrences was related to age, gender or dose administered.

System Organ Class	Rare(>=1/10,000, <1/1,000)	Very rare (<1/10,000)
Immune System Disorders		Anaphylactic reaction, anaphylactoid reaction, hypersensitivity reactions, anaphylactic shock
Psychiatric disorders		Anxiety
Nervous system disorder		Dizziness, syncope, loss of conciousness
Eye disorders		Conjunctivitis
Cardiac disorders		Cyanosis, cardiac arrest
Vascular disorders		Hypotension, flushing, hypertension
Respiratory, thoracic and mediastinal disorders		Cough, laryngeal oedema, dyspnoea, laryngospasm, bronchospasm, wheezing, hypoxia, respiratory failure
Gastrointestinal disorders	Nausea, vomiting	Abnormal pain, oedema mouth
Skin and subcutaneous tissue disorders		Urticaria, rash, pruritis, face oedema, angioneurotic oedema
General disorders and administration site conditions		Feeling hot and cold, injection site extravasation, injection site reaction, injection site burning, injection site swelling, injection site vesicles
Investigations		Pulse pressure decreased

Interactions

Interaction studies with other medicinal products were not carried out during the clinical development of MultiHance. However no interactions with other medications were reported during the clinical development program.

Overdose

Symptoms

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. MultiHance can be removed by haemodialysis.

Treatment

In the event of overdosage, the patient should be carefully monitored and treated symptomatically. MultiHance has been shown to be dialysable.

Pharmaceutical Precautions

List of excipients

Incompatibilities

Shelf life

Special precautions for storage

Instruction for use/handling

MultiHance should be drawn up into the syringe immediately before use and should not be diluted. 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. Any unused product should be discarded. Not all pack sizes may be marketed.

Medicine Classification

Package quantities

MultiHance is available in 5 mL, 10 mL, 15 mL and 20 mL colourless type I glass vials with elastomeric closures, aluminium sealing crimps and polypropylene caps.

Further Information

Osmolality (mOsmol/kg water) @ 37oC: 1970 Viscosity (cP) @ 37oC: 5.3 Density @ 20oC: 1.220g/mL MultiHance has an osmolality 6.9 times that of plasma (285 mOsm/kg water) and is hypertonic under conditions of use.

Clinical trials

MultiHance was evaluated in three multicentre, randomised, blinded-read clinical trials in 424 adult patients who underwent hepatic MRI for evaluation of known or suspected focal liver disease. The first study was an open-label, multicentre, blinded-read trial in a total of 216 adults referred for MRI for diagnosis or follow-up of suspected or known liver lesions. Of the 214 patients who received MultiHance, 86 patients received a bolus injection of the recommended MultiHance dose of 0.05 mmol/kg, had MRI scans performed before and within 10 minutes of receiving the injection, and had available histology data. The sets of images were evaluated blindly as predose unenhanced MR images alone and paired predose unenhanced plus postdose contrast-enhanced MRIs. The results of contrast- enhanced MRI scans were compared to non-contrast scans. A total of 107 lesions were histologically characterized in these 86 patients. As shown in Table 1, enhancement of images with MultiHance significantly improved the accuracy to classify the nature of the lesions (benign or malignant) and to specifically characterize the type of the lesions.

The other two studies were double-blind, multicentre, parallel-group, blinded-read trials in a total of 210 adults with known or suspected focal liver lesions. Patients had to be referred for either intraoperative ultrasound (IOUS) for surgical resection of a malignancy or computed-tomographic arterial portography (CTAP); in one study, patients could also have been referred for chemoembolization of a liver tumor and required lipiodol computed tomography (L-CT). Of the 210 patients who received MultiHance, 105 patients received a single intravenous infusion of MultiHance 0.05 mmol/kg at a rate of 10 mL/min. MRI scans were performed before receiving MultiHance and at 40 to 120 minutes after receiving MultiHance. The results of contrast-enhanced MRI scans were compared to non-contrast scans and to the results of the gold-standard procedures (for a subgroup of patients). The combination of predose and postdose image sets detected more lesions (see Table 2) compared to predose image sets alone. Generally, greater concordance in the number of lesions detected with the gold-standard procedures was also seen with the combined predose and postdose image sets than with the predose image sets alone.

MultiHance was studied in three multicentre blinded-read clinical trials in a total of 560 adults who underwent MRI of the CNS for evaluation of known or suspected lesions of the brain or spine. Two of these studies were double-blind, multicentre, parallel-group, blinded-read trials to demonstrate the non-inferiority of MultiHance compared with an approved gadolinium contrast agent in a total of 410 adults who were highly suspected of having a lesion(s) of the CNS (brain or spine) based on nuclear medicine imaging, contrast-enhanced computed tomography (CECT), computed tomography (CT), contrast-enhanced magnetic resonance imaging (CEMRI), magnetic resonance imaging (MRI), or angiography. Patients were randomised to one of three dosing regimens, which consisted of two bolus injections within 15 minutes of MultiHance (0.05 + 0.1 mmol/kg or 0.1 + 0.1 mmol/kg) or an approved gadolinium contrast agent (0.1 + 0.2 mmol/kg). MultiHance was administered to 276 adults, and an approved gadolinium contrast agent was administered to 134 patients. MRI scans were performed predose and within 5 minutes after each injection. The sets of images were evaluated blindly as predose unenhanced MR images alone and paired predose unenhanced plus postdose contrast- enhanced MRIs for each injection. Image sets were rated on a 3-point scale (limited, adequate, excellent) for the level of diagnostic information provided. The results of contrast-enhanced MRI scans were compared to an approved gadolinium contrast agent and to non-contrast scans. MultiHance was considered non-inferior to the comparator if the upper limit of the confidence interval for between group differences did not exceed 20%. Analyses between image sets were based on increases in the level of diagnostic information and changes in numbers of lesions. When read in combination with the predose unenhanced images, MultiHance-enhanced images provided statistically significant improvement in the level of diagnostic information (LDI) over predose images alone. The proportions of patients with an increase in the level of diagnostic information (LDI) were comparable following administration of a single injection of MultiHance 0.1 mmol/kg and an approved gadolinium contrast agent 0.1 mmol/kg. Table 3 shows the proportion of the 136 patients who were evaluated for efficacy following the first dose of MultiHance 0.1 mmol/kg and had an increase in the level of diagnostic information from predose images to paired first-postdose images. In addition, the number of lesions visualized with predose and paired postdose images is displayed.

The third study was a double-blind, multicentre, parallel-group trial in a total of 150 adults who had proven malignancy outside the CNS and intraaxial metastatic disease to the CNS already diagnosed by CEMRI or CECT. Patients were randomised to one of two dosing regimens, which consisted of three bolus injections (0.05 + 0.05 + mmol/kg or 0.1 + 0.1 + 0.1 mmol/kg) of MultiHance. The injections were administered in 10-minute intervals. MRI scans were performed predose and after each injection. The sets of images were evaluated blindly as predose unenhanced MR images alone, postdose contrast-enhanced images alone, and paired predose unenhanced plus postdose contrast-enhanced MRIs for each injection. The results of contrast-enhanced MRI scans following single and cumulative injections were compared between dosing regimens. Analyses between dosing regimens were based on quantitative measures of lesion-to background ratio and lesion signal enhancement, and qualitative measures (i.e., changes in numbers of lesions). The mean change from predose MRI in lesion-to-background ratio as well of the percent of enhancement of lesion signal intensity increased significantly (p < 0.001) with dosing up to the second dose of both regimens (cumulative doses of 0.1 and 0.2 mmol/kg, respectively). Increases in lesion counts, as well as improvement in lesion conspicuity, delineation of lesion borders, and reviewer confidence in detection or exclusion of lesions were also reported. However, a cumulative dose of 0.2 mmol/kg provided an increase in lesion counts comparable to a cumulative dose of 0.3 mmol/kg.

The MultiHance MRA Clinical Program was conducted in Europe, North America, and Latin America and consisted of:

The 3 Phase II dose response studies were designed as prospective, randomised, double-blind, within-patient comparisons of MultiHance-enhanced MRA vs. unenhanced MRA and as parallel group comparisons of different doses of MultiHance. They were aimed at establishing the most appropriate dose of MultiHance in terms of improved technical performance of MultiHance-enhanced MRA over unenhanced MRA. One dose- response study was designed as retrospective, blinded comparison of different doses of MultiHance in terms of level of improvement of diagnostic performance over unenhanced MRA on the basis of Digital Subtraction Angiography findings. The 4 Phase III confirmatory and supportive trials were designed as prospective, open label, within-patient comparisons of MultiHance-enhanced MRA vs. unenhanced MRA on the basis of Digital Subtraction Angiography (DSA) as the gold standard. They were aimed at establishing the improved technical and diagnostic performance of MultiHance- enhanced MRA over unenhanced MRA. No head-to head comparison with currently available MRA contrast agents was carried out in the dose-response program or in Phase III, since no agent had a European-wide approval for MRA during development of MultiHance in MRA. A total of 1467 subjects were studied in the MultiHance MRA Clinical Program. The list of the studies in the MultiHance MRA Clinical Program, together with the vascular territory investigated, the number of subjects, and the doses tested is given in Table 4 below. The MultiHance MRA Clinical Program was performed investigating different vascular territories of the body, which are representative of different flow rates (high flow, low flow), different vessel sizes, different types of flow (laminar flow, turbulent flow), as well as flow to an organ.

Tables 5 and 6 provide an overview of the results of Phase III clinical trials :

The study results in Table 5 show that MultiHance is an effective contrast agent for CE- MRA of the peripheral vessels when compared to unenhanced MRA, as demonstrated by: Significant increases in the overall diagnostic performance of MRA in the detection of clinically significant (>=51%) steno-occlusive disease of the peripheral arteries (iliofemoral vessels- the primary territory) in all components, i.e., sensitivity, specificity, and accuracy when compared to DSA as the absolute standard; these increases were always statistically significant (p<0.001) across all readers both off-site and on-site.

The results of this study aimed at the intra-subject comparison of CE-MRA and UE-MRA in the abdominal arterial territory with DSA at the absolute standard indicated that MultiHance is an effective contrast agent for MRA of the abdominal vessels when compared to unenhanced TOF MRA as demonstrated by significant increases in the overall diagnostic performance of MRA in the detection of clinically significant (>=51%) steno-occlusive disease of the abdominal arteries in all components, i.e. sensitivity, specificity and accuracy when compared to DSA as the absolute standard; these increases were statistically significant (p<0.001) for all readers. The administration of MultiHance to subjects with known or suspected renal artery disease undergoing MRA of the abdominal vessels was safe and very well tolerated based on the results of monitoring of adverse events, vital signs, ECG parameters, and clinical laboratory investigations.

Name and Address

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TABLE 1: ACCURACY (MALIGNANT/BENIGN) AND CORRECTLY CLASSIFIED LESIONS (SPECIFIC) IN A CLINICAL STUDY OF PATIENTS WITH KNOWN OR SUSPECTED LESIONS OF THE LIVER
	MULTIHANCE 0.05 mmol/kg (N = 107 LESIONS)
Image Set	Accuracy (Nature)	p-value * (Nature)	Classified Correctly (Specific)	p-value * (Specific)
Reviewer 1	74.8%	-----	48.6%	-----
Predose
Predose + Dynamic	90.7%	<0.01	75.7%	<0.01
Reviewer 2	82.2% - 61.7%	-----	90.7%	-----
Predose -
Predose + Dynamic		0.02	70.1%	0.06
* p-value based on exact McNemar test comparing accuracy and correctly classified lesions for each of the postdose image sets with predose.

TABLE 2: NUMBER OF LESIONS DETECTED (% INCREASE) FOLLOWING DELAYED IMAGING IN TWO CLINICAL STUDIES OF PATIENTS WITH KNOWN OR SUSPECTED FOCAL LIVER LESIONS
	MultiHance 0.05 mmol/kg
	Study A 1		Study B 2
	Number of Lesions (% increase from predose)
Reviewer	Predose	Predose + Postdose	Predose	Predose + Postdose
Predose + Postdose image set includes all available images at all timepoints. 1 Number of patients evaluated ranges from 39 to 41. 2 Number of patients evaluated ranges from 50 to 52.
1	48	58 (21%)	61	87 (43%)
2	56	63 (13%)	69	82 (19%)
3	45	51 (13%)	70	85 (21%)

TABLE 3: IMAGE RESULTS AFTER UNENHANCED AND MULTIHANCE-ENHANCED MRI IN TWO CLINICAL STUDIES OF PATIENTS WITH KNOWN OR SUSPECTED LESIONS OF THE CNS
	MultiHance		Comparator
	Reviewer 1	Reviewer 2	Reviewer 1	Reviewer 2
Level of diagnostic information based on a 3-point scale: Limited: Unable to make diagnosis, or a differential diagnosis of >3 possibilities, or both malignant and benign possibilities. Adequate: Diagnosis <= 3 possibilities with high confidence or definite with moderate confidence. Excellent: Definitive diagnosis with high confidence or no further testing required. # One-sided 97.23% confidence interval for comparator % - MultiHance %, corresponding to Dunnett's procedure. MultiHance and comparator are non-inferior if upper limit does not exceed +20%. * p<0.001 based on two-sided within-group comparison using Binomial Test comparing equality of increases and decreases from predose.
Study A
Outcome Measure/Image Set	(N = 65)	(N = 65)	(N = 66)	(N = 68)
% Patients With Increase in Level of	40% *	69% *	35% *	69% *
Diagnostic Information
Predose + Post-0.1 mmol/kg
Dose Difference (Comparator -	5.2%	0.1%	----	----
MultiHance)
Confidence Interval #	[-100%,	[-100%, 5.2%]	----	----
	11.0%]
Number of Lesions (% change)	168	187	144	181
Predose
Predose + Post-0.1 mmol/kg Dose	183 (9%)	227 (21%)	139 (-3%)	190 (5%)
Study B
Outcome Measure/Image Set	(N = 66)	(N = 68)	(N = 65)	(N = 65)
% Patients With Increase in Level of	32% *	53% *	45% *	51% *
Diagnostic Information
Predose + Post-0.1 mmol/kg Dose
Difference (Comparator - MultiHance)	12.8%	-2.2%	----	----
Confidence Interval#	[-100%, 9.1%]	[-100%,	----	----
		14.4%]
Number of Lesions (% change)	110	131	100	177
Predose
Predose + Post-0.1 mmol/kg Dose	131 (19%)	149 (14%)	135 (35%)	189 (7%)

Table 4: Categories of MRA Studies Included in the Evaluation of Efficacy and Safety
				Number of Subjects a
Type of Study	Study Number (Territory)	Dose (mmol/kg)	Flow Area	MH	MG	Total
Phase I Studies in Healthy Volunteers	B19036/037 (abdomen) b	0.0125, 0.05, 0.2	High	10	-	10
	B19036/040 (abdomen) c	0.1	High	10	10	10
	BBG605 (run-off) c	0.1	High	21	21	21
	Subtotal			40	31	41
Phase II Studies in Patients	B19036/042 (carotid) d	0.025, 0.05, 0.1, 0.2	High/Turbulent	163	--	163
	B19036/943 (renal/abdomen) d	0.025, 0.05, 0.1, 0.2	High/Organ	94	--	94
	B19036/044 (pelvic) d	0.025, 0.05, 0.1, 0.2	High/Turbulent	136	--	136
	MH-118 (carotid, abdominal/renal, pelvic) e	0.025, 0.05, 0.1, 0.2	Turbulent, High/Organ	[84]	--	[84]
	B19036/052 (renal) c	0.1MH, 0.2 MG.	High/Organ	38	38	41
	Subtotal			431	38	434
Phase III Studies in Patients	43,779-11 (abdominal) confirmatory f	0.1	High/Organ	293	--	293
	MH-103 (peripheral) confirmatory f	0.1	High/Turbulent	287	--	287
	B19036/supra-aortic) confirmatory f	0.1	High/Turbulent	248	--	248
	MH-104 (foot) supportive f	0.1	Low/Turbulent	164	--	164
	Subtotal			992	--	992
TOTAL	12 Studies			1463	69	1467
MH=MULTIHANCE; MG = MAGNEVIST
The number of subjects who received MULTIHANCE and/or MAGNEVIST may not add up to the total since some subjects may have received one or both of the agents in crossover trials. ascending-dose crossover trial; c crossover design with comparator; d parallel-group dose-finding trial; parallel-group dose-finding trial [read of images from Studies B19036/042, e B190936/043, B19036/044] f intra-individual comparison controlled trial. Table data derived from Individual Clinical Trial Reports.

Table 5: Agreement of MRA with DSA for Clinically Significant Stenosis (>=51%) - Sensitivity, Specificity and Accuracy- Peripheral (Illiofemoral) Arteries, Intent-to Treat Population, Phase III Study MH-103
	Reader 1		Reader 2		Reader 3		On-site
	UE- MRA	CE/ MRA	UE- MRA	CE/ MRA	UE- MRA	CE/ MRA	UE- MRA	CE/ MRA
True Positive (TP)	314	527	590	786	389	657	359	552
True Negative (TN)	2273	2809	2096	2619	2504	2763	1853	2719
Phase Positive (FP)	589	138	724	301	313	177	1266	409
False Negative (FN)	631	449	350	185	537	318	541	344
Sensitivity TP/(TP+FN)	33.2%	54.0% *	62.8%	80.9% *	42.0%	67.4% *	39.9%	61.6% *
95% CI		(50.9,		(78.5,		(64.4,		(58.4,
		57.1)		83.4)		70.3)		64.8)
Difference	20.6		17.7		24.9		21.6
95% CI of Difference	(17.0, 24.2)		(14.4, 21.0)		(21.2, 28.5)		(18.1, 25.1)
P value	<0.001		<0.001		<0.001		<0.001
Specificity TN (TN+FP)	79.4%	95.3% *	74.3%	89.7% *	88.9%	94.0% *	59.4%	86.9% *
95% CI		(94.6,		(88.6,		(93.1,		(85.7,
		96.1)		90.8)		94.8)		88.1)
Difference	15.8		15.2		5.0		27.4
95% CI of Difference	(14.1, 17.4)		(13.3, 17.1)		(3.6, 6.4)		(25.4, 29.3)
P value	<0.001		<0.001		<0.001		<0.001
Accuracy(TP+TN)/	68.0%	85.0% *	71.4%	87.5% *	77.3%	87.4% *	55.0%	81.3% *
(TP+TN+FP+FN)		(83.9,		(86.5,		(86.3,		(80.1,
95% CI		86.2)		88.5)		88.4)		82.5)
Difference	17.0		15.9		9.9		26.1
95% CI of Difference	(15.5, 18.5)		(14.2, 17.5)		(8.5, 11.3)		(24.4, 27.8)
P value	<0.001		<0.001		<0.001		<0.001
Intent-to-treat population consisted of those subjects who had undergone all predose and postdose MRA examinations and DSA. A total of 272 patients and 4003 vessels were evacuated with 983 diseased segments and 58 technically inadequate segments in off-site DSA assessment. *Statistically significant change CE-MRA - UE-MRA (p<0.001 based on McNemar's test). Test data derived from Clinical Trial Report, End-of-Text Table 8.2.1.

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