1. SUMMARY STATEMENT OF THE PROPOSAL FOR INCLUSION4 … · interventional radiology techniques, in cardiology and in oncology or for the treatment of vascular malformations, for example

WHO list of essential medicines

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CONTENTS

1. SUMMARY STATEMENT OF THE PROPOSAL FOR INCLUSION.......................................4

2. NAME OF THE FOCAL POINT IN WHO SUBMITTING OR SUPPORTING THEAPPLICATION .................................................................................................................................. 12

3. NAME OF THE ORGANIZATION(S) CONSULTED AND/OR SUPPORTING THEAPPLICATION .................................................................................................................................. 12

4. INTERNATIONAL NON-PROPRIETARY NAME (INN, GENERIC NAME) ..................... 13

5. FORMULATION PROPOSED FOR INCLUSION, INCLUDING ADULT AND PEDIATRIC.............................................................................................................................................................. 13

5.1. Chemical characteristics .......................................................................................................................... 13

5.2 The formulation proposed for inclusion ................................................................................................... 13

5.3 Stability of the formulation ...................................................................................................................... 13

6. INTERNATIONAL AVAILABILITY – SOURCES, MANUFACTURERS AND TRADENAMES................................................................................................................................................ 13

6.1 Sources and Manufacturers...................................................................................................................... 13

6.2 History of the product .............................................................................................................................. 14

6.3 International availability and production capacity ................................................................................... 14

7. WHETHER LISTING IS REQUESTED AS AN INDIVIDUAL MEDICINE OR AS ANEXAMPLE OF A THERAPEUTIC GROUP. .................................................................................. 14

8. INFORMATION SUPPORTING THE PUBLIC HEALTH RELEVANCE(EPIDEMIOLOGICAL INFORMATION ON DISEASE BURDEN, ASSESSMENT OFCURRENT USE, TARGET POPULATION).................................................................................. 15

9. TREATMENT DETAILS (DOSAGE REGIMEN, DURATION; REFERENCE TO EXISTINGWHO AND OTHER CLINICAL GUIDELINES; NEED FOR SPECIAL DIAGNOSTICS,TREATMENT OR MONITORING FACILITIES AND SKILLS)................................................ 15

9.1 Dosage regimen........................................................................................................................................ 15Brain and spinal cord MRI ................................................................................................................................ 15MRI of other organs and angiography.............................................................................................................. 15


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9.2 Duration ................................................................................................................................................... 16

9.3. Clinical guideline for the use of Gadolinium-based Contrast Agents........................................................ 169.3.1 American College of Radiology guideline........................................................................................... 169.3.2 Royal College of Radiology guideline ................................................................................................. 179.3.3 European Society of Urogenital Radiology (ESUR) guideline ............................................................. 17

9.4 Treatment Facilities and Skills .................................................................................................................. 17

10. SUMMARY OF COMPARATIVE EFFECTIVENESS IN A VARIETY OF CLINICALSETTING ............................................................................................................................................ 18

10.1 Efficacy studies in CNS imaging............................................................................................................... 1810.1.1 Gadoterate meglumine in CNS imaging in clinical studies at single dose. ............................................ 2010.1.2 Gadoterate meglumine in CNS imaging in non-randomized studies at single dose ............................. 2010.1.3 Gadoterate meglumine in CNS imaging in non-randomized studies at higher dose ............................ 2310.1.4 Gadoterate meglumine in CNS imaging in non-randomized studies in a pediatric population ............ 24

10.2 Efficacy studies in whole body imaging................................................................................................... 2510.2.1 Hepatic and pancreatic imaging ........................................................................................................... 2610.2.2 Musculoskeletal imaging ....................................................................................................................... 2710.2.3 Female pelvis imaging ........................................................................................................................... 2910.2.4 Renal imaging ........................................................................................................................................ 3010.2.5 Cardiac imaging ..................................................................................................................................... 3210.2.6 Breast imaging....................................................................................................................................... 3510.2.7 Pulmonary and chest imaging ............................................................................................................... 3610.2.8 Pediatric imaging ................................................................................................................................... 36

10.3 Efficacy studies in MR angiography ........................................................................................................ 3810.3.1 Randomized studies in MRA.................................................................................................................. 3910.3.2 Non-Randomized studies in MRA.......................................................................................................... 4010.3.3 Well established use in MRA – Analysis of the literature...................................................................... 42

10.4 Efficacy conclusions ................................................................................................................................ 45

11. SUMMARY OF COMPARATIVE EVIDENCE ON SAFETY ................................................ 53

11.1 Overall exposure .................................................................................................................................... 5311.1.1 Adult population.................................................................................................................................... 5311.1.2 Paediatric population ............................................................................................................................ 54

11.2 Safety finding from clinical studies and post-marketing experience ....................................................... 5611.2.1 Safety findings from Guerbet sponsored trials and from published trials ............................................ 5611.2.2 Safety findings from Guerbet observational post-marketing studies ................................................... 5811.2.3 Safety findings from post-marketing pharmacovigilance (cut-off 2014) .............................................. 6011.2.4 Occurrence of Nephrogenic Systemic Fibrosis (NSF) ............................................................................ 6111.2.5 Deaths and other serious adverse events ............................................................................................. 63

11.3 Gadoterate meglumine safety profile in special groups and situations................................................... 6611.3.1 Patients with renal impairment............................................................................................................. 6611.3.2 Patients with cardiovascular risk........................................................................................................... 6711.3.3 Children below 2 years old .................................................................................................................... 6811.3.4 Use in pregnancy ................................................................................................................................... 70

11.4 Gadoterate meglumine safety: laboratory tests, and vital signs ............................................................. 7011.4.1 Laboratory evaluations.......................................................................................................................... 70


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11.4.2 Vital signs............................................................................................................................................... 71

11.5 Gadoterate meglumine comparative safety data ................................................................................... 7111.5.1 Clinical studies with gadoterate meglumine conducted by Guerbet (n=50)......................................... 7111.5.2 Gadoterate meglumine published trials................................................................................................ 72

12. SUMMARY OF AVAILABLE DATA ON COMPARATIVE COST AND COST-EFFECTIVENESS WITHIN THE PHARMACOLOGICAL CLASS OR THERAPEUTICGROUP................................................................................................................................................ 75

13. SUMMARY OF REGULATORY STATUS OF THE MEDICINE (IN VARIOUSCOUNTRIES)..................................................................................................................................... 76

14. AVAILABILITY OF PHARMACOPOEIAL STANDARDS .................................................. 77

15. PROPOSED TEXT THAT COULD BE INCLUDED IN A REVISED WHO MODELFORMULARY .................................................................................................................................... 77

ANNEX 1: SUMMARY OF PRODUCT CHARACTERISTICS (FRANCE) ............................... 79


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1. Summary statement of the proposal for inclusion.

Executive summary

Medical imaging has undergone a major revolution over the last 20 years and is now a

key element of health care management. It can be used for the diagnosis of diseases

such as breast cancer by mammography, for example, or to confirm or rule out a

proposed diagnosis. Medical imaging also contributes to patient management with

interventional radiology techniques, in cardiology and in oncology or for the treatment

of vascular malformations, for example. Several techniques are available: conventional

radiology, computed tomography (CT), sonography and magnetic resonance imaging

(MRI). This last, noninvasive technique became available during the 1980s and has

gradually occupied a very important place for the examination of soft tissues such as the

brain, spinal cord, digestive tract, muscles and tendons, but also heart and vessels.

Under a high magnetic field and an appropriate radiofrequency pulse, water protons are

able to emit a specific signal related to the characteristics of each tissue. Contrast agents

are used in about 40% of MRI examinations and improve the quality of the information

obtained. Like iodinated contrast agents used in CT, MRI contrast agents must be used

for a number of diagnostic tests to increase contrast between normal tissues and

pathological structures, to speed up image acquisitions and also to provide additional

functional information on the tissues and organs under evaluation.

In this setting, it is important to include a contrast agent that can be used for MRI in the

list of WHO essential drugs, as is already the case for iodinated contrast agents. Several

types of MRI contrast agents are available which all decrease proton spin relaxation

times. They are either paramagnetic or super-paramagnetic. The most popular agents are

paramagnetic molecules including a gadolinium ion, similar to calcium size, but with 7

single electrons which induce striking magnetic properties. The basic principal is to use

an atom with a high magnetic moment, as such atoms have several single electrons

which interfere with the nuclear magnetic moment of protons, which constitutes the

basis of the MRI signal. However, the free gadolinium ion is toxic and its release in the

body depends on the stability of the chelates that are associated with the gadolinium ion

in the pharmaceutical product used for injection. It is therefore essential to choose an

appropriate gadolinium chelate, which is as stable as possible to simultaneously ensure

sufficient efficacy and, even more importantly, an excellent short-term and long-term

safety profile for patients receiving the product for a noninvasive procedure.

Gadolinium complexes (GCs). Place of gadoterate meglumine

In all paramagnetic gadolinium-based agents for intravascular administration, the

gadolinium ion is bound to a ligand in the form of a chelate to minimize its toxicity.

Gadolinium is a heavy metal, which, in its free form, is very toxic and may cause liver

necrosis, hematological changes etc. A human being would not survive a dose of 0.1


5

mmol kg-1 of free gadolinium injected into the circulation. Nine gadolinium-based

contrast agents are currently commercially available in various countries (Table 1).

Gadolinium-based agents are classified by the chemical structure of the ligand to which

the gadolinium is bound. The ligands are either linear or cyclic, and may be ionic, with

a charge in solution, or non-ionic (Table 1).

Complexation of these chelates obeys the mass action law. The stability of a metal

chelate refers to an equilibrium between the metal (M), its ligand (L) and the complex

(ML), according to the equation:

[M] + [L] [ML] (Equation 1)

The stability behavior of Gadolinium complexes (GCs) has been investigated in

numerous studies (Laurent 2001; Laurent 2006; Frenzel 2008; Port 2008). The stability

of GC is commonly described by two concepts:

a) thermodynamic stability, which describes the strength of the bond between Gd

and its ligand (expressed in terms of Log Ktherm or Log Kcond), where:

Ktherm = [ML] / [M] * [L] (Equation 2)

and Kcond = Ktherm * [L] / LT (Equation 3)

where LT is the total concentration of the uncomplexed ligand, i.e. { L +[ HL] + [H2L]

+ ...} where [HL], [H2L] are the protonated forms of the free ligand species.

b) kinetic stability, which refers to the rate at which dissociation of the GC occurs

(characterized by the dissociation half-life (T1/2) at acidic pH) (Port et al., 2008).

Basically, three classes of GCs can be distinguished according to this approach: (1)

macrocyclic chelates characterized by high kinetic stability (gadobutrol, gadoteridol and

gadoterate), with the highest stability being reached with the ionic and macrocyclic

GC gadoterate [Port 2008]); (2) ionic linear chelates (gadobenate, gadopentetate,

gadofosveset) for which a moderate kinetic inertia leads to significant dissociation; and

(c) nonionic linear chelates (gadodiamide and gadoversetamide), which exhibit poor

kinetic stability and the highest extent of dissociation. Table 1 summarizes the

physicochemical profiles of all of the currently marketed GCs.

Extracellular GC are not metabolized and are excreted unchanged by the kidneys by

passive glomerular filtration (excretion half-life in healthy adult patients is ~1.5 hours)

(Idée 2009a).

Gadoterate is the most stable of all gadolinium chelates currently available on the

market.


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Table 1 : General characteristics of currently marketed gadolinium chelates used for magnetic resonance imaging (Port 2008)

GC

Generic Name Gadopentetatedimeglumine

Gadoxeticacid,

disodium salt

Gadobenatedimeglumine

Gadofosveset,trisodium salt

Gadodiamide Gadoversetamide Gadoteridol Gadobutrol Gadoteratemeglumine

Trade Name Magnevist Primovist®

Eovist®MultiHance Ablavar®

VasovistOmniscan OptiMARK ProHance Gadovist Dotarem

Magnescope

Company Bayer Healthcare BayerHealthcare

Bracco Imaging Lantheus MedicalImaging

Bayer Healthcare

GE-Healthcare Covidien BraccoImaging

BayerHealthcare

Guerbet

Chemical Structure Open-chain Open-chain Open-chain Open-chain Open-chain Open-chain Macrocyclic Macrocyclic Macrocyclic

Charge Di-ionic Di-ionic Di-ionic Tri-ionic Nonionic Nonionic Nonionic Nonionic Ionic

Concentration of the marketedsolution (M)

0.5 0.25 0.5 0.25 0.5 0.5 0.5 1.0 0.5

Formulation of the marketedsolution

Free DTPA(1 mmol/l)

Ca-EOB-DTPA(trisodium

salt)1.5 mmol/l

No added ligand Fosveset(0.325 mmol/l)

Ca-DTPA-BMA(caldiamide)

(Na+ salt)(25 mmol/l)

Ca-DTPA-BMEA(Na+ salt)

(50 mmol/l)

[Ca-HP-DO3A]2

(Ca2+ salt)0.5 mmol/l

Ca-BT-DO3A(Na+ salt)

1.0 mmol/l

No added ligand

log Ktherm 22.1 23.5 22.6 22.06 16.9 16.6 23.8 21.8 25.6

log Kcond 17.7 18.7 18.4 18.9 14.9 15.0 17.1 14.7 19.3

Kinetic Stability Low Medium Medium Medium Low Low High High High


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Safety and risk of NSF (Nephrogenic Systemic Fibrosis)

Up until the 2000s, gadolinium complexes were all considered to be equally effective and safe.

However, Nephrogenic Systemic Fibrosis (NSF), first recognized in 1997 and described in 2000, was

associated, in 2006, with the administration of gadolinium contrast agents to patients with renal failure.

NSF is a rare, serious and life-threatening syndrome involving fibrosis of the skin, joints and internal

organs. In December 2007, The Scientific Advisory Group (SAG) for Diagnostics of the CHMP

(Committee for Medicinal Products for Human Use) agreed with PhVWP that the risk of developing

NSF depends on the type of gadolinium chelates used, and advised that these agents should be

categorized into three groups:

• High risk: gadoversetamide (OptiMARK), gadodiamide (Omniscan) and gadopentetic acid

(Magnevist, Magnegita, and Gado-MRT-Ratiopharm);

• Medium risk: gadofosveset (Vasovist), gadoxetic acid (Primovist) and gadobenic acid

(MultiHance);

• Low risk: gadoteric acid (Dotarem), gadoteridol (ProHance) and gadobutrol (Gadovist).

In November 2008 a referral procedure was initiated to allow the CHMP to carry out an assessment of

the risk of NSF for the authorized gadolinium chelates and recommend measures that could be taken to

reduce this risk. The final CHMP opinion was issued in November 2009, and was ratified by an

European Commission decision in July 2010. The conclusions confirmed the classification of the

active substances into the three categories of risk, and the CHMP issued recommendations for different

labelling of the various agents according to their risk classification (Table 2). At present, gadoterate

meglumine is a product that has never induced any “pure form” of NSF worldwide, although more that

43 million patients have received this product for an MRI examination. Considering the importance of

this disease and the risk of misuse of European and USA guidelines, it is highly recommended to use

the most stable of all available agents on the market, regardless of the patient’s renal function. In

addition, the European Society of Urogenital Radiology (ESUR) has issued recommendations

according to this risk classification for various types of patients (Table 3).


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Table 2 : Revised contraindications and precautions for use of gadolinium-containing contrast agents (CHMP 2010)

*In the low and medium risk categories of NSF, DOTAREM provides the largest range of indications for newborns and infants ranging from 0 to 2 years old, for whole body MRI and MRI of the brain, spinal cord and vertebral column

Risk class LOW RISK:Dotarem, ProHance, Gadovist

MEDIUM RISK:Primovist, Vasovist,MultiHance, Eovist, Ablavar

HIGH RISK:Omniscan, Optimark, Magnevist

Pregnancy Not recommended, unless the benefit/risk balance is considered to be favorable

Lactation Continuation or suspension for 24h according to the mother’s decision(in consultation with the physician)

Discontinuation for at least 24h

Renal insufficiency (RI),liver transplantation,dialysis

Precaution in severe renal insufficiency (RI) and livertransplant recipients: minimum diagnostic dose and aminimum of 7 days between 2 doses

To be avoided in patients withsevere RI and liver transplantrecipientsIf used, minimum diagnostic doseand minimum of 7 days between 2doses

Contraindication in severe RI and liver transplant recipientsPrecaution in patients with moderate RI, depending on thebenefit/risk balance, minimum diagnostic dose and minimum of7 days between 2 doses

No evidence supporting the use of hemodialysis to prevent or treat NSF in non-dialyzed patients,may be useful in dialyzed patients

Paediatric population Precaution in neonates, minimum diagnostic dose and minimum of 7 days between 2 doses* Contra-indication in neonate < 4 weeks

Precaution in children < 1 year, minimum diagnostic dose and minimum of 7 days between 2 doses

Elderly patients Important to screen patients > 65 years for renal dysfunction

Screening of renal function Laboratory test recommended to screen patients for renal dysfunction Mandatory laboratory test to screen all patients for renaldysfunction


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Table 3: Contra-indications and precautions for use of gadolinium-containing contrast agents (ESUR)

Pregnancy Can be used to give essential diagnostic information Contra-indication in pregnant women

Lactation Continuation or suspension 24h according to mother’s decision

(in consultation with the physician)

Discontinuation at least 24h

Renal insufficiency (RI),

hepatic transplantation,

dialysis

Should be used with caution in patients with Chronic Kidney Disease (CDK) 4 and

5 (GFR<30mL/min), including patients on dialysis, with at least 7 days between 2

administrations.

Contra-indication in patients with CDK 4 and 5 (GFR<30mL/min) and with acute

renal insufficiency.

Should be used with caution in patients with CDK 3 (GFR 30-60 mL/min),

depending on benefit/risk balance, minimum diagnostic dose and minimum of

7 days between 2 doses.

No evidence supporting the use of hemodialysis to prevent or treat NSF in non-dialyzed patients,

but may be useful in dialyzed patients.

Paediatric population Precaution in neonates, minimum diagnostic dose and minimum of 7 days between

2 doses

Contra-indication in neonates < 4 weeks

Precaution in children < 1 year, minimum diagnostic dose and minimum of 7 days between 2 doses

Patients with NSF GBCA (gadolinium-based contrast agents) should only be used if the indication is

vital

Contra-indication in patients with NSF

Screening of renal function Laboratory testing of renal function (eGFR) is not mandatory but renal function

assessment by questionnaire should be used if serum creatinine is not measured.

Mandatory laboratory test to screen all patients for renal dysfunction

All patients Use the smallest amount of contrast medium necessary for a diagnostic result. Should never be administrated at doses higher than 0.1mmol/kg per examination

Always record the name and dose of the contrast agent used in the patient’s records.


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Rationale for the proposed formulation and available presentations

Gadoterate meglumine is supplied in the form of a solution for injection at a

concentration of 0.5 M in 5 to 100 ml vials, to be adapted to the various indications and

to the usual practice of radiologists in various countries. As the usual dosage is 0.1

mmol/kg BW (or 0.2 ml/kg BW), 60 and 100 ml vials are used to perform several

consecutive examinations without the need to prepare a new dose of product for the next

patient, in order to improve productivity (number of MRI examinations per day). With

this type of use, only the injection catheters are changed between two patients. The 15

and 20 ml vials are designed for single use for an adult patient according to body

weight. The 5 and 10 ml vials are better adapted to pediatric examinations. Some agents

on the market are not approved for children and infants. All countries have approved the

use of gadoterate meglumine for children older than 2 years of age and a majority of

countries have also approved the use of gadoterate meglumine for infants (less than 2

years old), especially in Europe.

In some countries, prefilled syringes are also marketed, mainly for manual injections,

which are performed according to different modalities from one region to another

according to the radiologists’ habits. A very diluted form, specific for intra-articular

injections for bone and joint diseases is also available in a few countries, in 20 ml vials

or prefilled syringes.

Proof of efficacy and safety

Gadoterate meglumine is a solution administered by intravenous injection and intended

for diagnostic Magnetic Resonance Imaging (MRI) examinations. Its efficacy as a

contrast agent has been extensively evaluated during both pre-clinical and clinical

development (see section 10).

The clinical value of gadoterate meglimine as a contrast agent in MRI has been

documented in various clinical trials and published studies. These specific studies tested

gadoterate meglimine in various situations, such as CNS imaging, hepatic and

pancreatic imaging, renal imaging, etc.

MRA with gadoterate meglumine appears to be an effective technique and could be

proposed as a first-line investigation (renal arteries, pulmonary arteries or coronary

arteries) or as a second-line investigation after Doppler ultrasound (aorta, lower limbs,

supra-aortic vessels). In these indications, the imaging efficacy and general safety of

gadoterate meglimine have been unambiguously documented in well-designed clinical

trials.

Furthermore, gadoterate meglumine has been evaluated in numerous additional trials

that have been published in peer-reviewed medical journals. Although these studies

were not conducted under the responsibility of Guerbet, they provide supportive data

confirming the usefulness and safety of this paramagnetic contrast agent.


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The efficacy data obtained with gadoterate meglumine from multiple studies shows that

gadoterate meglumine can be efficiently used in three types of examinations, namely: (i)

MR imaging for intracranial and spinal cord diseases, (ii) whole body MR imaging and

(iii) magnetic resonance angiography. Gadoterate meglumine use was associated with

improved diagnostic efficacy when compared to unenhanced images, and with a non-

inferior diagnostic ability when compared to competitors. Together with its reduced

potential to induce adverse reactions compared to other Gd-based contrast agents (see

section 11), these data support the inclusion of gadoterate meglumine in the WHO List

of Essential Medicines.

Justification for the cost of the product

The cost of gadoterate meglumine can vary from one country to another according to

local public and private market organization. In any event, the cost of the product is

very limited compared to the cost of the MRI examination, including the fact that only

40% of MRI examinations need to be performed with the use of gadolinium-based

contrast agents.

A generic of gadoterate meglumine is available on some markets at similar prices to that

of the original product Dotarem®.

Quality

Each active ingredient manufacturer is declared to be GMP compliant by local

authorities. Guerbet’s chemical sites for production of DOTA (either internal or

subcontracted by Guerbet), one of the active ingredients of the product, were inspected

by the FDA in 2013. Several pharmaceutical production manufacture vials of

Gadoterate meglumine, in France and Brazil. One of these sites has been FDA

approved, and the other sites manufacture vials for other parts of the world and are

GMP compliant. Gadoterate meglumine (marketed under the trade names of Dotarem®

or Magnescope®) has been approved in nearly all countries worldwide, including

Japan, USA, Europe, Korea, China, India…

Bibliography

Port M, Idée JM, Medina C, Robic C, Sabatou M, Corot C. Efficiency, thermodynamic andkinetic stability of marketed gadolinium chelates and their possible clinical consequences: acritical review. Biometals. 2008 Aug;21(4):469-90.

Port M, Idee JM, Medina C, Dencausse A, Corot C. Stability of gadolinium chelates and theirbiological consequences: new data and some comments. Br J Radiol. 2008 Mar;81(963):258-9.

Laurent S, Elst LV, Copoix F, Muller RN. Stability of MRI paramagnetic contrast media: aproton relaxometric protocol for transmetallation assessment. Invest Radiol. 2001Feb;36(2):115-22.


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Laurent S, Elst LV, Muller RN. Comparative study of the physicochemical properties of sixclinical low molecular weight gadolinium contrast agents. Contrast Media Mol Imaging. 2006May-Jun;1(3):128-37.

Frenzel T, Lengsfeld P, Schirmer H, Hütter J, Weinmann HJ. Stability of gadolinium-basedmagnetic resonance imaging contrast agents in human serum at 37 degrees C. Invest Radiol.2008 Dec;43(12):817-28.

2. Name of the focal point in WHO submitting or supporting the

Application

Not relevant.

3. Name of the organization(s) consulted and/or supporting the

Application

Not relevant.


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4. International Non-proprietary name (INN, generic name)

Gadoterate meglumine

5. Formulation proposed for inclusion, including adult and

pediatric

5.1. Chemical characteristics

DOTA is an ionic macrocyclic chelate, the only one marketed in the form of gadolinium

chelate, meglumine salt (or methylglucamine).

5.2 The formulation proposed for inclusion

The formulation proposed for inclusion is 5 to 20 ml vials, which correspond to the

conventional uses of gadoterate meglumine in adults and children.

5.3 Stability of the formulation

Gadoterate meglumine in solution for injection in vials from Guerbet is formulated and

packaged to guarantee the stability of the finished product for a period of 3 years even

under tropical conditions (climatic areas IVa and IVb). Vials are made of type I or type

II glass depending on the country of commercialization. The manufacturer recommends

that the drug be stored below 30°C in the original package.

6. International availability – Sources, manufacturers and trade

names.

6.1 Sources and Manufacturers

Gadoterate meglumine is formed extemporaneously at the time of manufacture of the

finished product by complexation of DOTA and Gadolinium oxide. DOTA is mainly

manufactured by Simafex in France in its Marans facility, with back-up organized in

Finland.

The finished product in vials is mainly manufactured by Guerbet in France in its

Aulnay-sous-bois facility, with back-up organized in France and Brazil.


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Main manufacturing sites:

Active ingredient Finished product

SIMAFEX

16, Avenue des Fours à Chaux

17230 MARANS

FRANCE

GUERBET

BP 57400

95943 Roissy CdG cedex

FRANCE

Located at:

16-24 rue Jean Chaptal

93600 Aulnay-sous-Bois

FRANCE

All sites are certified as GMP compliant by local authorities.

6.2 History of the product

Gadoterate meglumine was approved for the first time in France in 1989 and has been

progressively approved in other countries (see section 13) since that date. The product is

consequently available in most countries worldwide.

6.3 International availability and production capacity

To support the chemical development and industrial manufacture of gadoterate

meglumine, Guerbet has chosen to invest in its manufacturing plant, SIMAFEX, located

in Marans (France) for capacities of more than 30 tons of DOTA a year. In addition and

as a back-up to SIMAFEX, DOTA is also produced in Finland.

The finished product in vials is mainly manufactured by GUERBET (France), with

back-up organized in Brazil and in France.

Gadoterate meglumine is commercialized in worldwide (on five continents) under the

name of Dotarem®, except in Japan where is it commercialized under the name of

Magnescope (prefilled syringes only).

7. Whether listing is requested as an individual medicine or as an

example of a therapeutic group.

Listing is requested as an individual medicine. Although several agents are present on

the market, we consider gadoterate meglumine (Dotarem®) to be a unique product for

two reasons:


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1°) It is the only ionic macrocyclic gadolinium chelate and is consequently considered

as the most stable of all gadolinium contrast agents.

2°) No case of NSF has ever been reported with the use of gadoterate meglumine alone.

8. Information supporting the public health relevance

(epidemiological information on disease burden, assessment of

current use, target population).

MRI procedures are mainly performed for central nervous system diseases (50%) and

cardiovascular diseases (17%). MRI is used for the diagnosis and treatment of diseases

responsible for more than 25 million deaths per year. Cancer is the leading indication

for MRI examinations, accounting for 27% of all examinations. About 40% of MRI

examinations are performed with injection of contrast agents such as gadoterate

meglumine.

9. Treatment details (dosage regimen, duration; reference to

existing WHO and other clinical guidelines; need for special

diagnostics, treatment or monitoring facilities and skills).

9.1 Dosage regimen

Gadoterate meglumine (Dotarem®) is for diagnostic use only. Doses can vary depending

on the examinations performed.

Brain and spinal cord MRI

The recommended dose in neurological examinations is 0.1 mmol/kg, but in some

circumstances it can vary from 0.1 to 0.3 mmol/kg BW, corresponding to 0.2 to 0.6

ml/kg BW. After administration of 0.1 mmol/kg BW to patients with brain tumors, an

additional dose of 0.2 mmol/kg BW may improve tumor characterization and facilitate

therapeutic decision-making.

MRI of other organs and angiography

The recommended dose for intravenous injection is 0.1 mmol/kg (i.e. 0.2 ml/kg) to

provide diagnostically adequate contrast.


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Angiography: In exceptional circumstances (e.g. failure to obtain satisfactory images of

an extensive vascular territory) administration of a second consecutive injection of

0.1 mmol/kg BW, equivalent to 0.2 ml/kg BW, may be justified. However, if the use of

2 consecutive doses of gadoterate meglumine is expected prior to commencing

angiography, the use of 0.05 mmol/kg BW, equivalent to 0.1 ml/kg BW, for each dose

may be of benefit, depending on the imaging equipment available.

9.2 Duration

Gadoterate meglumine is indicated for intravenous bolus administration only (single

administration). The duration of the injection procedure ranges from 5 seconds to 30

seconds depending on the injection rate. The recommended injection rate is 2 ml/sec for

usual procedures.

Intravascular administration of contrast media should, if possible, be performed with the

patient lying down. After administration, the patient should be kept under observation

for at least half an hour, since experience shows that the majority of adverse effects

occur within this timeframe.

Injection of gadoterate meglumine can be performed by using a manual single-use

(sterile) syringe or an automatic injection system.

The total duration of an MRI examination also depends on the technique used.

Compared to unenhanced-MRI, the contrast enhancement obtained with the use of

gadoterate meglumine allows the examination time to be halved because unenhanced

MRI requires the acquisition of both T1- and T2-weighted images, whereas contrast-

enhanced MRI only requires the acquisition of T1-weighted images.

For magnetic resonance angiography, the total examination time with gadoterate

meglumine is three times shorter than that of Digital Subtraction Angiography, and

systematically shorter than TOF (Time-Of-Flight) magnetic resonance imaging.

9.3. Clinical guideline for the use of Gadolinium-based Contrast Agents

Three clinical guidelines have been issued concerning the use of iodinated and

gadolinium contrast agents. They all focus on safety of use, particularly the prevention

and treatment of adverse reactions associated with the use of these agents.

9.3.1 American College of Radiology guideline

This manual was developed by the ACR Committee on Drugs and Contrast Media of

the ACR Commission on Quality and Safety as a guide for radiologists to enhance the

safe and effective use of contrast agents. Suggestions for patient screening,

premedication, recognition of adverse reactions, and emergency treatment of such


17

reactions are emphasized. Its major purpose is to provide useful information regarding

contrast agents used in daily practice.

This guideline offers radiologists a consensus of scientific evidence and clinical

experience concerning the use of contrast agents in general and of GBCAs in particular.

9.3.2 Royal College of Radiology guideline

As for the ACR guidelines, the Royal College of Radiology guidelines focus on the safe

and efficient use of both iodinated and gadolinium contrast agents. This guideline

provides a listing of vulnerable groups of patients susceptible to experience adverse

reactions to gadolinium agents. It also details the procedures to minimize the risk and to

treat adverse effects.

9.3.3 European Society of Urogenital Radiology (ESUR) guideline

The European Society of Urogenital Radiology established its Contrast Media Safety

Committee in 1994. It consists of 14 expert members in the field of contrast media

research. There is currently one member from each of the four pharmaceutical

companies producing contrast agents (Bracco, Italy; GE Healthcare Diagnostics, USA;

Guerbet, France; Schering, Germany). Unlike the previous two guidelines, the ESUR

guidelines emphasize the occurrence of adverse reactions according to body systems

such as renal, vascular or pulmonary adverse reactions.

Conclusion: the latest versions of all three guidelines have integrated the differential

ability of GBCAs to induce Nephrogenic Systemic Fibrosis (NSF) and indicate that, due

to their increased kinetic stability, macrocyclic ionic GBCAs, such as gadoterate

meglumine, present a lower risk of inducing NSF in renally impaired patients.

9.4 Treatment Facilities and Skills

The use of GBCAs such as gadoterate meglumine requires at least a MRI scanner and a

syringe for injection. Scanners yielding high magnetic fields (3T or 7T) have the

advantage of producing images with higher resolutions. An automated injection system

can also be used to control the GBCA injection rate.

In the case of allergic reactions (i.e. hypersensitivity), administration of the contrast

agent must be discontinued immediately and specific therapy must be instituted, if

necessary. A venous access should therefore be maintained during the entire

examination in case hypersensitivity reactions occur. This venous access allows

immediate emergency countermeasures, such as the delivery of appropriate drugs to

counteract hypersensitivity (e.g. epinephrine and antihistamines). In addition, an

endotracheal tube and a respirator should be at hand in the event of hypoventilation due

to hypersensitivity-induced bronchospasm.


18

10. Summary of comparative effectiveness in a variety of clinical

setting

Several clinical trials and post-marketing studies sponsored by Guerbet as well as

various scientific articles published between 1989 and 2007 support the efficacy of

gadoterate meglumine as a contrast agent in a variety of indications. The trials included:

double-blind, comparative, randomized, trials comparing gadoterate meglumine with

Gd-DTPA (Magnevist®); single-blind, randomized, comparative trials using X-ray

angiography as gold standard; open, randomized, comparative trial comparing

gadoterate meglumine with a control group and open, non-randomized trials for various

imaging procedures.

10.1 Efficacy studies in CNS imaging

The table below presents a selection of randomized clinical trials assessing efficacy of

gadoterate meglumine for CNS imaging.

Table 4 : Overview of selected randomized clinical studies with MRI for CNS imaging

Study reference Study

Design

Imaging No of

cases

No of gadoterate

meglumine cases

DGD-3-17 R, DB, U,

C

CNS 20 10

DGD-3-31 R, DB, M,

C

CNS 299 149

Baleriaux et al.,

1993

R, DB, M,

C

CNS 58 30

Oudkerk et al.,

1995

R, DB, M,

C

CNS 1038 518

Total 707

C: Comparative; U: Unicentric; O: Open; M: Multicentric; DB: Double-Blind; R: Randomized, SB: Single Blind

As far as neoplasms are concerned, gadolinium-enhanced T1-weighted images are

preferred for the diagnosis of all types of intracranial tumors (Oudkerk et al., 1995;

Baleriaux et al., 1993). They have been shown to be more sensitive than double-dose

contrast-enhanced CT in detecting metastasis. MRI is also superior to CT in the

detection of associated features of the tumor: oedema, cysts, necrosis, etc.


19

These advantages of gadolinium-enhanced imaging have been documented for

gadoterate meglumine in various randomized and non-randomized clinical trials either

conducted by the sponsor or independently published in the medical literature.

Table 5 : Overview of selected non-randomized clinical studies with MRI for CNS imaging


Design

Imaging No of evaluable

cases

No of gadoterate meglumine

cases

DGD-3-7 NR, O, U, C CNS 56 56

DGD-3-11 NR, O, U, C CNS 19 19

DGD-3-4 NR, O, U, C CNS 20 20

DGD-3-8 NR, O, U, C CNS 54 54

DGD-3-1 NR, O, U, C CNS 10 10

DGD-3-12 NR, O, U, C CNS 50 50

DGD-3-14 NR, O, U, C CNS 55 55

DGD-3-23 NR, O, U, C CNS 50 50

DGD-3-5 NR, O, U, C CNS 10 10

DGD-3-3 NR, O, U, C CNS 30 30

DGD-3-21 NR, O, U, C CNS 50 50

DGD-3-9 NR, O, U, C CNS 22 22

DGD-3-20 NR, O, U, C CNS 48 48

DGD-3-34 NR, O, U, C CNS 45 45

DGD-3-33 NR, O, U, C CNS 62 65

DGD-44-050 R, B, M, C CNS 245 245

DGD-44-051 NR, O, M, C CNS 151 149

Neiss et al., 1991 NR, O, U CNS 4169 1991

2969


20

10.1.1 Gadoterate meglumine in CNS imaging in clinical studies at single dose.

Two adequate and well-controlled phase 3 studies were conducted to demonstrate the

efficacy of gadoterate meglumine at a single dose in CNS imaging (DGD-44-050 and

DGD-44-051).

DGD-44-050 – SENTIO study

Title of the study: Safety and efficacy evaluation of gadoterate meglumine in magnetic

resonance imaging (MRI) in patients with central nervous system (CNS) lesions

(SENTIO Study DGD-44-050).

In this multicenter, randomized, double-blind, fixed sequence (unenhanced MRI

followed by either Dotarem- or Magnevist-enhanced MRI), patients were randomly

assigned to receive gadoterate meglumine or Magnevist in a 2 to 1 ratio. Pediatric

patients were assigned to the gadoterate meglumine group only. This study

demonstrated the superiority of gadoterate meglumine-enhanced MRI as compared to

unenhanced MRI in terms of CNS lesion visualization (border delineation, internal

morphology and degree of contrast enhancement). The validity of gadoterate

meglumine efficacy as a contrast agent was validated against the approved contrast

agent Magnevist and had a better safety profile, notably with fewer injection site

conditions. The use of gadoterate meglumine in pediatric population appears effective

and safe.

DGD-44-051

Title of the study: Evaluation of MRI with gadoterate meglumine in the diagnosis or

follow-up assessment of cerebral or spinal tumors. Re-reading of MRI images

This study was aimed at demonstrating the superiority of gadoterate meglumine-

enhanced MRI as compared to unenhanced MRI in terms of lesion visualization in

patients presenting or suspected of having cerebral or spinal tumors. As for the SENTIO

study “paired” (contrasted and uncontrasted) images were shown to be superior to “Pre

(uncontrasted)” images, thus confirming the superiority of gadoterate meglumine-

enhanced over unenhanced images. This superiority was statistically significant (all p <

0.001) for all 3 readers.

10.1.2 Gadoterate meglumine in CNS imaging in non-randomized studies at singledose

In non-randomized studies at single dose, gadoterate meglumine has been evaluated in a

series of 13 open, comparative, clinical trials that involved a total population of 474

patients (471 evaluable patients) who benefited from MRI procedures for the diagnosis


21

of various suspected cerebral lesions. All patients were treated with a single dose

administration: gadoterate meglumine IV bolus 0.2 mL/kg (0.1 mmol/kg) and the

studies followed a similar protocol as described below.

In one study (DGD-3-20), patients were investigated for neuro-ophtalmological or ENT

diseases (Ear, nose and throat). In the remaining studies, brain and spinal cord

explorations were performed. In this latter case, 426 lesions were imaged that were

mostly extra- and intra-axial brain lesions.

Table 6 : Type of imaged lesions in the CNS MRI studies with gadoterate meglumine

Type of imaging No of lesions (%)

Brain imaging Intraaxial 131 31%

Extraaxial 168 39%

Spinal cord imaging Intraaxial 81 19%

Extraaxial 46 11%

Total 426

In the course of the same exploration, MRI without contrast medium was performed and

then followed by the post-injection procedure.

Investigators scored the interest of the Gd-enhanced MRI in terms of diagnostic

contribution (4-point scale from no diagnostic to excellent diagnostic contribution).

Additionally, a possible change in diagnosis after gadoterate meglumine injection was

noted as were the therapeutic implications of this change.

The main results are summarized hereafter.


22

Table 7 : Non-randomized studies in CNS and spinal cord imaging at single dose

Study reference Studydesign

Inclusion diagnostic Total No ofpatients

Diagnosticcontribution

Changein

diagnostic

Modificationof therapeuticmanagement

Good ExcellentDGD-3-7 U, O, NR, C Neurological MRI for various reasons 56+ 40% 40% 51% 45%

DGD-3-11 U, O, NR, C Neurological MRI for various reasons 19 37% 47% 68% 47%


DGD-3-8 U, O, NR, C Neurological MRI for various reasons 54 91% - 89% * 94%** 96%




DGD-3-23 U, O, NR, C Neurological MRI for various reasons 50 70% - 97% **** 15% 29%




DGD-3-21 U, O, NR, C Neurological MRI for various reasons 50 69% - 95% *** 78% 74%

DGD-3-20 U, O, NR, C MRI for neuro-opthalmic or ENT diseases. 48a 35% - 79% # 44% °60% °°

6% °77% °°

U: Unicentric; O: Open; NR: Not Randomized; C: Comparativea 49 patients included+ 3 protocol deviations: patients evaluated for bone and soft tissues imaging* MRI with gadoterate meglumine (T1-weighted) superior to preliminary CT scan in 91% of cases and to MRI (T2-weighted) in 89% ofcases.** Correction of initial plain MRI based diagnosis in 94% of cases and detection of new small lesions in 37% of cases.*** 95% in 22 cases in comparison with CT, 80% improvement in comparison with the same sequence without gadoterate meglumine and78% in comparison with T2-weighted spin echo sequence. Lesion-healthy tissue delineation improved in 69% of cases.****70% improvement of the diagnostic contribution in comparison with plain MRI, T1- and T2-weighted sequences. Better delineation of

lesion limits in 97% of cases in comparison with the same T1 sequence without gadoterate meglumine.# MRI with gadoterate meglumine (T1-weighted) was considered superior to CT in 79% of cases and to plain MRI in 35% of cases.°Neuro-ophtalmic diseases °°ENT lesions

There was improved diagnostic efficacy in comparison to CT and the results

demonstrated better visualisation and change in therapeutic management. The use of

gadoterate meglumine proved to be essential in the search for acoustic neuroma.

Gadoterate meglumine superiority was demonstrated mainly for extra-axial intracranial

tumours, including pituitary adenomas, with a better characterisation of active or

inactive, cystic and solid components. Cystic, solid, oedematous and necrotic

components of the lesions were also more clearly defined. Gadoterate meglumine also

made the search for recurrent tumours more reliable.

The diagnostic efficacy of gadoterate meglumine was demonstrated mainly for the

etiological diagnosis and staging of intra-axial lesions (astrocytomas, ependymomas,


23

lymphomas, ischaemia) and for the diagnosis, staging or search for recurrences of intra-

medullary lesions (angiomas, ependymomas, astracytomas, ischaemia).

Additionally, a large post-marketing study was carried out in in 61 radiologic

institutions in Germany (Herborn et al., 2007). Image quality and diagnostic value of

gadoterate meglumine-enhanced MR imaging scans were evaluated by radiologists

through the use of standardized questionnaires. Out of 24,308 patients, the contrast-

enhanced MRI study was performed for neurological purposes in 13,668 patients and

most patients (98%) received a single injection of 0.1 mmol/kg gadoterate meglumine.

For the entire study cohort, the examination allowed a diagnosis to be established in

>99% of cases and image quality was rated as “excellent” or “good” in 97.5% of all

cases.

10.1.3 Gadoterate meglumine in CNS imaging in non-randomized studies at higherdose

While gadolinium complexes are usually used at a dose of 0.1 mmol/kg, numerous

studies have documented the interest of injecting higher than the standard dose

(Haustein et al., 1993; Runge et al., 1992; Yuh et al., 1995; Mathews et al., 1994). This

approach has been shown in various settings to improve diagnostic contribution and to

allow detection of small tumors (less than 10 mm in size) or of recent metastases.

Furthermore, a quantitative correlation between tumor/normal tissue contrast and dose

injected was demonstrated (Haustein et al., 1993; Kuhn et al., 1994; Vogl et al., 1994;

Wolansky et al., 1994; Svaland et al., 1994; Yue, 1993; Filippi et al., 1998).

Accordingly, a triple gadoterate meglumine dose has been evaluated in two clinical

studies sponsored by Guerbet (DGD-3-34 and. DGD-3-33).

The first trial, DGD-3-34, was mainly a safety study aimed at verifying the safety of a

gadoterate meglumine triple dose administration. Nevertheless, this study highlighted

the diagnostic interest of this procedure. The second study (DGD-3-33) was planned to

demonstrate superior diagnostic efficacy of the 0.3 mmol/kg cumulative dose in

comparison to the standard dose in the detection of brain metastases. In this multicenter

study, 65 patients (62 evaluable patients, 41 males, 21 females, mean age 58 (SD) 12

years) were evaluated by MRI after injection of a 0.1 mmol/kg dose in an antecubital

vein. Within 20 to 30 min after the first dose, a second dose of 0.2 mmol/kg was

injected and MRI immediately repeated in the same conditions. The main efficacy

criterion was the number of visualized metastases with the second MRI compared to the

0.1 mmol/kg injection. Schematically this study demonstrated that a triple gadoterate

meglumine dose significantly increased the number of definitively established

metastatic lesions and improved lesion delineation in more than 80% of the

explorations.


24

10.1.4 Gadoterate meglumine in CNS imaging in non-randomized studies in apediatric population

Three clinical trials and one post-marketing study were conducted with gadoterate

meglumine in CNS imaging in children.

Three non-randomized trials were conducted by Guerbet (DGD-3-16; DGD-3-15; DGD-3-

29). The age of this population ranged from 8 to 18 years. These studies used MR for

imaging purposes of various neurological lesions. Overall, the observed results were

similar to those already described with adult patients. Gadoterate meglumine enhanced-

MRI has allowed better visualization of lesions with a more accurate delineation of the

lesion/normal tissue or lesion/oedema borders. Furthermore, blood supply was more

easily imaged. This better visualization modified the planned therapeutic approach in

15% to 34% of cases.

Table 8 : Non-randomized clinical trials in the pediatric population


Design

Imaging No of evaluable

cases


cases

DGD-3-16 NR, O, U, C Paediatric 20 20DGD-3-15 NR, O, U, C Paediatric 29 29DGD-3-29 NR, O, U, C Paediatric 50 53Herve-Somma et al., 1992 NR, O, U, C Paediatric 24 24Bonnerot et al., 1994 NR, O, U, C Paediatric 9 9Ducou Le Pointe et al., 1994 NR, O, U, C Paediatric 21 21

Total 156

C: Comparative; U: Unicentric; M: Multicentric; O: Open; NR: Not Randomized; R: Randomized; DB: double-blinded

Finally, the post-marketing study by Briand et al., (1992) was a continuation of the

study by Neiss et al., (1991). These open, comparative, trials followed a relatively

similar protocol. Children (0 to 17 years old) having already undergone MRI without

injection of a contrast medium were eligible after obtaining the written consent to

participate from both parents. Gadoterate meglumine was used as a slow intravenous

injection into a peripheral vein at a dose of 0.1 mmol/kg of a 0.5 m/L solution, i.e. 0.2

mL/kg at an injection rate of 3 mL/min. The images were acquired a few minutes after

injection. Prior to gadoterate meglumine injection, a score on a 3-point scale (1=less

good, 2=identical, 3=better) was assigned to the T2-weighted MRI, relative to the T1-

weighted MRI. After injection, the T1-weighted MRI was compared in the same way

(score on a 3-point scale) with the pre-injection T1-weighted MRI and with the pre-

injection T2-weighted MRI. The post-injection diagnosis was rated as worse, identical

to, better than, or complementary to the pre-injection diagnosis. Both studies showed

that diagnosis and therapeutic strategies could vary following gadoterate meglumine

enhancement.

The post-marketing study SECURE (DGD-55-001) included over 35,000 patients

undergoing gadoterate meglumine-enhanced MRI for various indications. The pediatric


25

population amounted to over 1500 patients. Although the image quality in pediatric

patients appeared to be slightly compromised when compared to adults, 99.6% of

pediatric patients had received a diagnosis as compared to 99% of adult patients,

suggesting that the lesser quality of images did not impact the physician ability to

establish a diagnosis.

Table 9 : Overview of post-marketing studies

Study reference StudyDesign

Imaging Conducted by thesponsor

No of gadoterate megluminecases

Neiss et al., 1991 NR, O, U CNS Yes, Post-marketing 4,169Briand et al., 1992 NR, O, U Paediatric Yes, Post-marketing 402

Ishiguchi et al.,2010

NR, O, M Various Yes, Post-marketing 3,444

Herborn et al., 2007 NR, O, M Various Yes, Post-marketing 24,308

Maurer et al., 2012 NR, O, M Various Yes, Post-marketing 104,033

DGD-55-001* NR, O, M Various Yes, Post-marketing 35,499

Total 171,855

C: Comparative; U: Unicentric; M: Multicentric; O: Open; NR: Not Randomized; R: Randomized; DB: double-blinded; * Studyreport and article in preparation.

Conclusion – Gadoterate meglumine in CNS MRI

The advantages of gadolinium-enhanced imaging have been documented for gadoterate

meglumine in various clinical trials conducted by Guerbet or independently published in

medical peer-reviewed journals.

The previously presented studies showed that gadoterate meglumine is particularly

useful for the assessment of extracerebral tumors (meningiomas, neuromas, pituitary

tumors) and for a more precise topographic assessment of intracerebral tumors (gliomas,

ependymomas, metastases) and their staging. Gadoterate meglumine also increases the

sensitivity of MRI for the detection of metastases. A fact clearly confirmed in the triple

gadoterate meglumine dose study.

Regarding other brain diseases, the injection of gadoterate meglumine in patients with

cerebral vascular accidents or lesions related multiple sclerosis was followed to by a

high-intensity signal indicating rupture of the bloods brain barrier that accompanies this

type of lesion in their acute phase.

10.2 Efficacy studies in whole body imaging

Gadoterate meglumine was first registered for whole body in 1996. Gadoterate

meglumine has been approved in most European countries in this indication and has

been extensively used for at least a decade. Furthermore, taking into account both

Guerbet sponsored trials and relevant published trials, 855 patients suffering from


26

different diseases (excluding CNS and arterial diseases) have been submitted to

gadoterate meglumine-enhanced MRI.

Two studies deserve to be highlighted, due to the large number of patients they involved

in two of the most common injected MRI procedures, i.e. pelvis and osteo-articular

region.

Thurnher (1992) performed a large study on female pelvic masses, in which 97 patients

with a total of 124 surgically proved lesions were recruited. This study compared

gadoterate meglumine-enhanced MRI (at a dose of 0.1 mmol/kg) to unenhanced MRI,

using histology as gold standard (obtained through surgery for all patients). The authors

concluded that gadoterate meglumine-enhanced MRI, complemented unenhanced MRI,

by providing important information for surgical planning and definition of adequate

therapeutic strategies.

Drapé (1993) performed a musculoskeletal imaging study on 53 patients. This study

compared gadoterate meglumine-enhanced MRI (at a dose of 0.1 mmol/kg) to

unenhanced MRI, using arthroscopy in 14 patients and arthrography in the other

patients, as a gold standard. The diagnostic contribution of gadoterate meglumine-

enhanced MRI was assessed as better than that of unenhanced MRI for menisci,

whatever the level of effusion.

Another important study (Soyer et al., 1996) included 50 patients presenting with liver

lesions and compared gadoterate meglumine-enhanced MRI (at a dose of 0.1 mmol/kg)

to unenhanced MRI. Gadoterate meglumine-enhanced MRI enabled all tumors (100%)

to be well defined and confidently depicted. Contrast-to-Noise values, morphological

patterns and hemodynamics were assessed as being helpful in differentiating between

hemangiomas and other tumors, as well as between benign and malignant tumors. A

peripheral rim of enhancement on delayed gadoterate meglumine-enhanced MRI was

described as being specific for malignancy.

10.2.1 Hepatic and pancreatic imaging

In liver tumor MR imaging, 3 non-randomized trials were conducted by Guerbet. In

total 93 patients were enrolled and the underlying lesions were liver metastases in 56%

of cases. In all trials gadoterate meglumine enhanced-imaging was compared with CT

and T2-weighted MRI without contrast agent. Single 0.1 mmol/kg and double

gadoterate meglumine doses were evaluated.

Table 10 : Overview of selected non-randomized clinical trial with gadoterate meglumine-enhanced MRIfor hepatic and pancreatic imaging

Study reference Study Design Imaging No of evaluable

cases


cases

DGD-3-22 NR, O, U, C Hepatic, Pancreatic 24 24DGD-3-13 NR, O, U, C Hepatic, Pancreatic 30 30Cuenod et al., 1991 NR, O, U, C Hepatic, Pancreatic 39 39Soyer et al., 1994 NR, O, U, C Hepatic, Pancreatic 12 12


27

Von Hagspiel et al., 1994 NR, O, U, C Hepatic, Pancreatic 55 55Soyer et al., 1996 NR, O, U, C Hepatic, Pancreatic 50 50

Total 210


The objective of the trial by Soyer et al., (1994) was to determine MRI features of

hepatic metastases from pancreatic neuroendocrine tumors and to assess their

enhancement characteristics on dynamic sequences. In this study it was documented that

hepatic metastases from pancreatic neuroendocrine tumors exhibited a large spectrum of

MR features with early gadoterate meglumine enhancement on dynamic gradient-

recalled echo, thus allowing a precise localization of metastasis.

The second study by Von Hagspiel et al., (1994) concerned the detection of suspected

neoplasm of the liver and/or pancreas by using spin-echo and gradient echo MR

sequences. Von Hagspiel et al., (1994) showed that, in the presence of pancreatic

neoplasms, T1-weighted gradient echo sequences after administration of gadoterate

meglumine ensured better image quality and yielded more diagnostic information.

10.2.2 Musculoskeletal imaging

MRI is also widely used in musculoskeletal imaging to assist in the diagnosis of joint

injuries, soft-tissue tumors, and other musculoskeletal abnormalities. In the knee, MRI

has a reported sensitivity of 75% to 100% for the identification of meniscal tears, as

indicated by increased signal intensity in the fibro-cartilaginous meniscus that extends

to an articular surface. MRI has largely supplanted arthrography (Edelman et al., 1993).

Meniscal degeneration not seen by arthroscopy is detected as an increased intra-

meniscal signal. Concerning accuracy in detecting recurrent meniscal tears after

previous resection or repair, prospective surveys have shown that conventional imaging

had a sensitivity of 57.9%, specificity of 80%, and overall accuracy of 62.5% and

intravenous contrast improved the sensitivity to 90.9%, specificity to 100%, and overall

accuracy to 93.8% whereas intra-articular contrast had a sensitivity of 91.7%, specificity

of 100%, and an overall accuracy of 92.9% (Vives et al., 2003).

Table 11 : Overview of gadoterate meglumine studies in musculoskeletal imaging

Sudy reference Study Design Imaging No of evaluable

cases


cases

DGD-3-2 NR, O, U, C Musculoskeletal 20 20Hodler et al., 1990 NR, O, U, C Musculoskeletal 42 42Vande Berg et al., 1992 NR, O, U, C Musculoskeletal 15 15Chastanet et al., 1993 NR, O, U, C Musculoskeletal 8 8Drape et al., 1993 NR, O, U, C Musculoskeletal 53 53Daenen et al., 1994 NR, O, U, C Musculoskeletal 16 16

Total 154

C: Comparative; U: Unicentric; M: Multicentric; O: Open; NR: Not Randomized; R: Randomized

In arthritis, after IV injection, gadolinium is taken up by inflamed synovium and Gd-

enhanced MR scans may be useful in detecting acute synovitis in patients with

rheumatoid arthritis (Bjorkengren et al., 1990). Furthermore, in small joints, the long-


28

term follow-up of rheumatoid synovial proliferation in the hand using IV contrast

enhanced MRI is feasible and may provide additional information regarding disease

activity (Jevtic et al., 1997). MRI, because of its exquisite soft tissue contrast, has

dramatically improved the ability to preoperatively stage primary osseous and soft

tissue neoplasms. This technique has also enabled monitoring of the effects of

chemotherapy and screening for recurrence of neoplasms (Kransdorf et al., 1996).

Concerning infections, MRI examinations using intravenous contrast are becoming the

preferred modality to study complicated extremity infections (Towers et al., 1997).

One non-randomized study conducted by Guerbet (DGD-3-2) studied the interest of

gadoterate meglumine enhanced-MRI in 20 patients with primary musculoskeletal

tumors. Additionally, 5 published trials have reported various experiences with

gadoterate meglumine for musculoskeletal indications after IV injection. A pilot trial by

Hodler et al., (1990) evaluated gadoterate meglumine-enhanced imaging in 42 cases of

musculoskeletal pathology. The other publications evaluated the interest of delayed

sequences to demonstrate synovial fluid enhancement (Daenen et al., 1994), the passage

of gadolinium into synovial fluids (Drapé et al., 1993), the interest of fat-suppressed

MRI in avascular imaging of femoral head and its correlation with histology (Vande

Berg et al., 1992) or the value of Gd-enhanced MRI in the staging of pigmented

villonodular synovitis (Chastanet et al., 1993).

In the Guerbet trial (DGD-3-2), 5 to 20 minutes after iv injection of a 0.1 mmol/kg dose,

T1-weighted spin-echo sequences were compared to MRI without contrast agent (T1-

and T2-weighted sequences). The use of gadolinium in MRI of soft tissue tumor

improved the diagnosis contribution in 17 patients out of 20 with a proposed change in

therapeutic management in 15% of cases. Gadoterate meglumine injection made it

possible to distinguish active parts of lesion, intra-tumoral necrosis or sequel cavities

that do not take up contrast medium.

Regarding the knee, the study by Drapé et al., (1993) evaluated the intra-articular

passage of gadoterate meglumine after IV injection. No immediate passage was

observed and the maximum enhancement was obtained at 30 min post-injection and

remained stable for up to 60 minutes. Joint mobilization appeared to be a major factor

influencing contrast agent passage. This technique obviates the need for intra-articular

injection. Overall, diagnostic contribution was shown to be better for menisci whose

contrast was increased and in which lesional filling could be obtained despite lack of

effusion. The trial by Daenen et al., (1994) confirmed that delayed sequence after

gadoterate meglumine IV injection allows visualization of synovial fluid in the knee

after 30 minutes. This technique could be useful for visualizing post-operative intra-

articular lesions.

Regarding the hip, the trial by Vande Berg et al., (1992) demonstrated that enhanced

areas detected on post-contrast MRI were a common finding in osteonecrotic femoral

heads. These areas were observed in the peri-lesional marrow space, the interface and


29

within the presumed necrotic areas. Enhanced areas corresponded to reactive changes of

repair tissues.

Finally, the study by Chastanet et al., (1993), which focused on MR imaging of

pigmented villonodular synovitis (PVNS) of the knee and hip, showed that gadoterate

meglumine allowed differentiating, joint effusion from the PVNS lesions which are of

similar signal intensity on the long TR/long TE sequences.

10.2.3 Female pelvis imaging

For visualization of female pelvic masses, MRI has also been shown to have a high

degree of diagnostic specificity for certain types of ovarian masses such as dermoid

cysts.

Two published studies are available with gadoterate meglumine in MR imaging of

pelvis masses in female patients. The study by Thurnher et al., (1992) included 97

successive women with a total of 124 pelvic masses. Patients were scheduled for

surgery and were selected for MRI on the basis of showing a suspected pelvic mass on

sonography or having a biopsy proven cervical or endometrial tumor. A reader not

aware of patient’s history and past imaging analyzed MR images before surgery.

Unenhanced T1- and T2-weighted images were compared with gadoterate meglumine-

enhanced T1-weighted images.

Thirty-two patients were enrolled in the study with cervical cancers. Gadolinium-

enhanced MRI was shown to be a valuable method for the detection of this disease,

particularly when plain T2 images were equivocal. These improved images provided

essential additional information. Examination times were significantly reduced since

only T1 sequences (both pre- and post-contrast) are required when a contrast agent is

administered. In cervical cancer, the administration of gadoterate meglumine was a

useful tool to help therapeutic decision-making (surgery or radiotherapy). Gadoterate

meglumine led to better definition of intra-tumoral architecture facilitating tumor

detection and localization, particularly when adnexic masses were concerned.

Table 12 : Overview of gadoterate megluminestudies in female pelvis imaging


cases


cases

Ghossain et al., 1991 NR, O, U, C Female pelvis 40 8Thurnher et al., 1992 NR, O, U, C Female pelvis 97 97

Total 105


In the trial by Ghossain et al., (1991), 8 patients with ovarian tumors diagnosed at

pathological examination were evaluated by MRI after gadoterate meglumine injection.

T1-weighted images were obtained immediately before and after IV administration of

the contrast agent. CT and MRI were compared for the detection of pelvic tumors and

masses. Both methods were comparable. MRI with gadoterate meglumine was

particularly valuable for the detection of endocystic vegetations and nodules.


30

10.2.4 Renal imaging

MRI can help characterize renal masses if the results of other imaging methods are

indeterminate (Levy et al., 1994). It may also be useful for staging renal-cell carcinoma,

particularly if the results of CT are equivocal or iodinated contrast material cannot be

given. Delineation from the surrounding renal parenchyma is successful with the aid of

dynamic examinations after intravenous administration of gadolinium. Although

enhancement properties of renal and para-renal lesions may be different, the

characteristic signal intensity changes in functioning kidneys allow an accurate

diagnosis. Furthermore, using dynamic MR studies, semi-quantitative evaluation of

renal excretory function is possible. Finally, contrast enhanced MRI and MRA permit a

comprehensive assessment of renal transplants without inducing nephrotoxicity (Hanna

et al., 1991; Helenon et al., 1992).

At least 6 published non-randomized studies and one randomized trial conducted by

Guerbet have highlighted the various interests of gadoterate meglumine in renal MR

imaging. Two trials had the objective to evaluate the detection of perfusion defects to

help diagnose renal transplant rejection (Hanna et al., 1991; Helenon et al., 1992).

Table 13 : Overview of gadoterate meglumine studies in renal imaging


cases


cases

Brichaux et al., 1991 NR, O, U, C Kidney 26 26Hanna et al., 1991 NR, O, U, C Kidney 8 8Helenon et al., 1992 NR, O, U, C Kidney 21 21Laissy et al., 1994 NR, O, U, C Kidney 7 7Levy et al., 1994 NR, O, U, C Kidney 11 11Grenier et al., 1996 NR, O, U, C Kidney 15 15

Total 88


10.2.4.1 Randomized studies in renal imaging

One randomized, open, prospective trial has been conducted in France by Guerbet in

20 patients with various underlying renal diseases (Bellin et al., 1992). Subjects were

non-dialyzed in-patients presenting a glomerular filtration rate 60 mL/min. They were

randomly allocated to renal MRI imaging with gadoterate meglumine (single 0.1

mmol/kg IV dose; n=10) after baseline examination or without contrast agent (n=10).

Imaging diagnostic quality and laboratory tests were the main evaluation criteria of this

trial. The diagnostic quality of MRI was considered as good or excellent in 7 patients

out of 10 in the gadoterate meglumine group and in 3 out of 10 in the control group. In

the gadoterate meglumine group, and compared with baseline MRI examination without

contrast agent, the consequences of gadoterate meglumine use was a modified diagnosis

in 3 patients and a modification in the therapeutic strategy.


31

10.2.4.2 Non-randomized studies in renal imaging

Allograft rejection.

The trial by Hanna et al., (1991) included 62 consecutive MR examinations performed

on 59 transplanted patients. A spin-echo sequence was used in all cases. Eight other

patients were studied using the spin-echo technique after injection of gadoterate

meglumine. Out of 8 patients explored with contrast medium, 6 had normal uptake and

signal appearance in their allograft kidneys. In 2 patients with severe acute rejection,

there were multiple zones without enhancement, which proved to be areas of necrosis.

Gadoterate meglumine use seemed promising in the detection of these perfusion defects.

In the study by Helenon et al., (1992), 21 recipients of renal transplantation suspected of

allograft necrosis were explored. The results of Hanna et al., (1991) were confirmed by

Helenon et al., (1992), gadoterate meglumine-enhanced MRI demonstrated various

patterns of allograft necrosis. Unlike color Doppler US, contrast-enhanced MRI

precisely depicted areas of infarction and even smaller defects of perfusion. In addition,

dynamic MR studies provided some information about transplant perfusion and

parenchymal function.

A third study by Brichaux et al., (1991) on transplanted patients assessed the diagnostic

contribution and the image quality of a 2D FLASH sequence pre and post contrast, in

the evaluation of the vascularization of allografts and the detection of arterial stenoses,

when compared to Color Doppler and/or angiography. Gadoterate meglumine improved

image quality in 30% of the cases when compared to unenhanced MRI. It increased the

rate of true negatives when compared to Color Doppler by ruling out 3 false positives

among the 19 true negatives.

Renal cysts

The study by Levy et al., (1994) assessed the magnetic resonance imaging

characteristics of

13 benign complex renal cysts using T1 and T2-weighted images and contrast-enhanced

images. The results were compared to CT and ultrasonographic findings in all cases and

correlated with histopathologic data in 12 cases. The results suggested that MRI could

be useful in the diagnosis of benign complex cyst of the kidney presenting as

indeterminate cystic lesion on other modalities. In this case MRI provides argument in

favour of atypical benign cyst when it identifies the hydric nature of their content and

lack of signal increase after gadoterate meglumine injection was demonstrated.

Renal perfusion anomalies


32

The trial by Laissy et al., (1994) evaluated the functional value of TurboFLASH MRI in

the assessment of dynamic contrast enhancement and renal perfusion anomalies. This

study was conducted in 7 prospectively included patients. All of them were originally

examined for renovascular lesions. For dynamic acquisitions, a heavily T1-weighted

gradient-echo sequence in the Turbofast low angle shot technique was used. After

gadoterate meglumine injection, imaging was repeated every 20 seconds during the first

2 min and then every 30 s up to

6-10 min post-injection. The study demonstrated the feasibility of dynamic MRI to

evaluate renal function. Global renograms of MRI correlated with 99mTc-MAG3-renal

scintigraphy (r=0.82, p<0.001) with similar curve shape and time to peak. Relative renal

function evaluations were also strongly correlated. These results showed a high

accuracy of MRI for a whole evaluation of glomerular filtration per patient but also per

kidney. The areas under the enhancement phase of renograms were also well assessed.

In the trial by Grenier et al., (1996), preliminary evaluation of the feasibility of

captopril-sensitized, dynamic MR imaging of the kidney in a series of patients with a

high suspicion of renovascular hypertension was performed. Results were compared

with captopril scintigraphy data. Fifteen hypertensive patients were studied with

sequential gadolinium-enhanced MR imaging after oral administration of 50 mg of

captopril. Symmetry of onset and evolution of tubular phases between the two kidneys

were analyzed, and medullary signal intensity time curves were drawn for each kidney.

When asymmetry between kidneys was noted, the same dynamic study was repeated 24

hr later, without captopril sensitization. All patients also underwent renal scintigraphy

after administration of captopril to compare captopril-induced changes in both

techniques. MR imaging showed that four patients had impairment of glomerular

filtration: studies without captopril were symmetric or slightly asymmetric, but

administration of captopril induced severe functional impairment on the side of stenosis

characterized by a delayed tubular phase with late corticomedullary decrease of signal

intensity in the first two patients and absence of tubular phase in the other two.

Therefore, renal hypertension could be diagnosed by contrast-enhanced dynamic

imaging using the captopril functional test.

10.2.5 Cardiac imaging

Five non-randomized published trials (not conducted by Guerbet) have been selected for

highlighting the use of gadoterate meglumine in MR imaging of heart disease. One trial

concerned detection of myocardial perfusion abnormalities, 3 the visualization of

myocardial infarction and the last one the analysis of cardiac allograft rejection features.

Table 14 : Overview of gadoterate meglumine studies in cardiac imaging


cases


cases

Richoz et al., 1990 NR, O, U, C Cardiac 15 15


33

Jau et al.,1991 NR, O, U, C Cardiac 10 10Loubeyre et al., 1992 NR, O, U, C Cardiac 12 12Mousseaux et al., 1993 NR, O, U, C Cardiac 39 39Eichenberger et al., 1994 NR, O, U, C Cardiac 8 8

Total 84


10.2.5.1 Detection of ischemic regions.

The feasibility study by Eichenberger et al., (1994) was conducted in 8 patients with a

novel approach to determine whether myocardial ischemia can be assessed with MR

imaging and dynamic first-pass bolus tracking enhanced with gadoterate meglumine.

All patients were suffering from ischemic heart disease and stable angina. Three

tomographic planes were acquired before and after pharmacological stress with

dipyridamole, with use of the bolus-tracking series at rest as a reference. The change in

myocardial rate of enhancement was compared with the results obtained with other

techniques such as thallium scintigraphy and coronary angiography. The MR imaging

measure of myocardial perfusion showed good agreement with the standard methods

allowing correct detection of ischemic regions in 6 out of 8 patients compared with

findings of either coronary angiography or thallium scintigraphy Detection of ischemic

regions with MR imaging showed a sensitivity, specificity, and diagnostic accuracy of

65%, 76%, and 74%, respectively. Ultrafast MR imaging with gadoterate meglumine

can, therefore, be used to detect regions of myocardial ischemia.

10.2.5.2 Myocardial infarction.

In the trial by Jau et al., (1991) 10 patients with acute myocardial infarction were

studied. The time interval between the onset of symptoms and MRI was 8 to 12 days.

MRI was performed with the multiple spin technique. A series of tomographic sections

was recorded immediately after intravenous injection of 0.4 mmol/kg of gadoterate

meglumine. Recent myocardial infarction with parenchymal edema gave an enhanced

transmural signal: only 3 patients had a sufficiently contrasted image on the 1st spin

echo. After gadoterate meglumine, 7 patients had significantly increased contrast on this

echo. An excellent contrast between infarcted and healthy myocardium was obtained in

9 of the 10 patients, enabling precise evaluation of infarct size, which is of great

prognostic and therapeutic value.


34

In the trial by Richoz et al., (1990) 15 patients were studied 4 to 8 days after myocardial

infarction by using ECG gated MR (1.5 Tesla magnet) before and after administration

of 0.2 mmol/kg gadoterate meglumine. The diagnosis in each patient was confirmed by

electrocardiographic criteria, elevated levels of fractionated creatine kinase (CK)

isoenzyme, thallium scintigraphy, ventriculography and coronarography. Furthermore

each patient benefited from a thrombolysis performed within the first 4 hours after

symptom onset. T1-weighted, spin-echo images were obtained before and immediately

after injection of gadoterate meglumineand were repeated 15 min later. The site of

infarction was visualized in 10 patients as an area of high signal intensity after the

injection of gadoterate meglumine. Contrast between normal and infarcted myocardium

was the greatest 15 min after injection.

In the trial by Loubeyre et al., (1992), 12 patients with extensive acute Q-wave

myocardial infarction were evaluated within 7 to 21 days after the ischemic event. MRI

was performed with a 1.5 Tesla magnet device. A T1-weighted contrast TurboFLASH

was used. Ultrafast images were all ECG-gated enabling successive images to be

acquired during diastole. The potential of first pass gadoterate meglumine enhanced MR

imaging to assess occlusive and re-perfused infarctions and to predict coronary stenosis

greater than 90% was shown.

Allograft rejection

Mousseaux et al., (1993) explored the potential role of MRI in detecting cardiac

allograft rejection in transplant recipients using Gd- DOTA for contrast enhancement. 7

normal healthy volunteers and 39 patients separated into three groups according to

histological findings were examined. MR images were obtained at 1.5 Tesla. An ECG-

gated series of slices was acquired throughout all systole and protodiastole. For all

patients and healthy volunteers,

3 successive series were performed, one before and 2 after gadoterate meglumine

injection with no change in scanning parameters and patient position. The results

demonstrated that quantitative myocardial enhancement (ME), expressed as the ratio of

maximum signal intensity after intravenous gadoterate meglumine injection to signal

intensity before injection, was significantly lower for patients without histological

rejection (n=14) when compared with patients with grade 1 histological rejection (n=18)

and with patients with grade 2 or 3 rejection (n=7). Myocardial enhancement was not

significantly different in patients with grade 1 histological rejection compared with

patients with grade 2 or 3 rejection. Because predominant focal areas of ME were

observed in all patients, regional ME seemed a better measurement than mean ME to

distinguish focal histological changes when the rejection process is beginning.

However, software improvement appeared to be necessary to more quantify and map

high ME to establish the exact relationship between the extent of edema and the severity

of rejection.


35

10.2.6 Breast imaging

One non-randomized trial (DGD-3-32) was conducted by Guerbet for the evaluation of

early diagnosis of breast cancer by contrast enhancement MR imaging. 80 patients were

evaluated by 4 centers. All patients had benefited from a mammography within the

preceding month demonstrating the existence of a lesion of dubious malignant

appearance without confirmative biopsy. In all cases, tumorectomy was planned shortly

after MRI exploration. MR image acquisitions were performed with 0.5 to 1.5 Tesla

magnet according to center equipments. T1-weighted spin-echo sequences were used in

3 centres and gradient echo sequences in one center. Image analysis was performed in

each center by an experienced radiologist unaware of the histological results. In the

diagnosis of early malignant breast tumor, the Gd-enhanced MRI examination

demonstrated that when correlated with histological findings, a sensitivity ranging from

90% to 93% when the lesion or the patient is considered as the statistical unit. In the

same conditions, specificity ranged from 59% to 61%. Regarding the number of

detected lesions, it was possible through MRI to detect a supplementary lesion or to

better delineate the tumor in 11 patients.

Table 15 : Overview of gadoterate meglumine studies in breast imaging


cases


cases

Gilles et al.,1993 NR, O, M, C Breast 26 26Ha Dao et al.,1993 NR, O, U, C Breast 35 35DGD-3-32 NR, O, U, C Breast 80 80

Total 141


Two additional non-randomized studies (not conducted by Guerbet) have been

published. In the trial by Gilles et al., (1993) local relapse was suspected in 26 women

treated conservatively for breast cancer. All women underwent routine magnetic

resonance imaging and a dynamic MR subtraction study after injection of gadoterate

meglumine. Twelve women had no local relapse. Surgical biopsy enabled confirmation

of recurrence in 14 patients. The dynamic study was performed by using a T1-weighted

spin-echo sequence with fat saturation. Routine MR imaging did not allow

differentiation of recurrence from glandular or scar tissue. Except for one case of fat

necrosis, patients without local relapse showed no contrast enhancement 1 minute 34

seconds after injection. At dynamic MR imaging, all recurrences showed contrast

enhancement 1 minute 34 seconds after injection. Nodular enhancement (n=11) was

found in invasive carcinoma, whereas linear enhancement was seen in intraductal

carcinoma (n=3). Subtraction of precontrast from postcontrast images always allowed

better visualization of contrast enhancement. Contrast-enhanced subtraction dynamic

MR imaging was proved to be accurate in diagnosis of local relapses of breast cancer.

The study by Ha Dao et al., (1993) assessed the value of magnetic resonance imaging of

the breast in the differentiation of late post-irradiation fibrosis from recurrent


36

carcinoma. Thirty-five women with a history of breast carcinoma treated conservatively

with radiation therapy underwent MRI. Nine patients had recurrent tumors confirmed at

biopsy and surgery. Twenty-six patients had a localized fibrotic mass confirmed at

biopsy and/or during long-term clinical and radiological follow-up. In all cases, a

localized hypointense area was present on plain spin-echo T1-weighted images.

Dynamic Gd-enhanced T1-weighted imaging was performed to study the hemokinetic

of the suspected lesions. In all recurrent tumors, dynamic gadolinium-enhanced T1-

weighted images demonstrated early increased signal intensity of the lesion within 3

minutes after bolus injection. The signal intensity over time in localized fibrosis differed

from that in tumor recurrence, with no substantial enhancement on post- contrast T1-

weighted images. Short inversion time inversion recovery and spin- echo T2-weighted

images were not useful in the differential diagnosis of recurrent tumor versus radiation

fibrosis.

Overall, MR imaging with gadoterate meglumine in the field of breast disease is

gradually becoming routine practice. This technique obviates certain biopsies and, as an

adjunct to mammography, allows a precise diagnosis to be reached in cases where

mammography has failed to provide conclusive data.

10.2.7 Pulmonary and chest imaging

One non-randomized study (not conducted by Guerbet) has been published (Laissy et

al., 1994). This trial evaluated 9 patients with biopsy-proven lung carcinoma and who

had previously undergone CT and exhibited ipsilateral enlarged MLNs (Mediastinal

Lymph Nodes). MR studies included spin-echo, electrocardiographically gated axial

and coronal sequences and transaxial gradient-echo breath-hold sequences, which were

performed after administration of a bolus of gadoterate meglumine (bolus injection of

0.1 mmol/kg). The enhancement curves were established on the basis of mean signal

intensities from regions of interest at the level of tumor and the enlarged MLN. MR

images were compared with pathologic specimens obtained at surgical resection.

Metastatic MLNs exhibited their peak enhancement at 60-80 seconds, with a slow

decrease until 6 minutes. Granulomatous and anthracotic lymph nodes displayed a slight

enhancement, with no peak within 6 minutes. Dynamic contrast-enhanced MR images

may provide informative data about the nature of enlarged MLNs in the preoperative

assessment of lung carcinoma, an imaging interest which merits further evaluation.

10.2.8 Pediatric imaging

Three non-randomized studies have been published with gadoterate meglumine in MR

imaging of various paediatric musculoskeletal diseases: juvenile rheumatoid arthritis


37

(Herve-Somma et al., 1992), Legg-Perthes-Calve syndrome (Ducou le Pointe et al.,

1994) and in the management of painful osseous crisis in children with sickle cell

disease (Bonnerot et al., 1994). The mean age of this population ranged from 8 to 18

years.

Additionally, one post-marketing survey has been conducted in France on a paediatric

population (Briand et al., 1992, Neiss et al., 1991). 402 patients were involved in this

open and not controlled survey. 81% of these children were 15-years old or less and

6.5% were 2-years old or less. CNS exploration accounted for 82.4% of the

examinations and bone and soft tissue imaging for 11.4%. The mean gadoterate

meglumine injected dose was 0.22 mL/kg (range: 0.10 to 0.78 mL/kg). A single benign

and transient adverse event was reported (papule at the injection site). Overall,

diagnostic evaluation was considered to be improved post-contrast in 85% of the

neuroradiological examinations and in 95% of the musculoskeletal explorations.

Conclusion – Gadoterate meglumine in whole body MRI

The results obtained for breast tumours imaging demonstrate the potential value of

gadoterate meglumine-enhanced MRI for patients with equivocal mammographic

findings. In particular, it contributes to detect tumours unseen on mammography, and

could therefore play a part in pre-tumorectomy workups, to detect additional foci.

The diagnostic efficacy of gadoterate meglumine enhanced-MR in liver imaging

appears to be comparable or even slightly superior to that of CT. These data suggest that

dynamic gadoterate meglumine-enhanced MR imaging provides useful information to

differentiate between benign and malignant hepatic tumors, and to distinguish

hemangiomas from other tumors.

Moreover, gadoterate meglumine injection in musculo-skeletal diseases allowed

distinguishing active parts of lesion from intra-tumoral necrosis or sequel cavities that

did not take up contrast medium.

Regarding, female pelvic masses, gadoterate meglumine-enhanced MRI, as a supportive

and complementary sequence to unenhanced MRI, provides useful information for

assisting surgical planning and definition of therapeutic strategy.

In renal imaging gadoterate meglumine allowed better detection of cysts or of localized

lesions and the identification of their nature. Renal hypertension can be diagnosed by

contrast-enhanced dynamic imaging using the captopril functional test. Results showed

a high accuracy of MRI for a whole evaluation of glomerular filtration per patient but

also per kidney. Unlike Doppler US, contrast-enhanced MRI precisely depicts areas of

infarction and even smaller defects of perfusion. In addition, dynamic MR studies

provided some information about transplant perfusion and parenchymal function.


38

In non-vascular chest imaging gadoterate meglumine provide information about the

nature of enlarged MLNs in the preoperative assessment of lung carcinoma. While in

myocardial ischemia, serial MRI tomography with gadoterate meglumine enabled

precise evaluation of infarct size, which is of great prognostic and therapeutic value.

10.3 Efficacy studies in MR angiography

Guerbet has carried out five controlled clinical trials in this indication including 2

single-blind randomized trials (DGD-3-37; DGD-3-39) and 3 open, non-randomized trials

(DGD-3-36; DGD-3-38; DGD-44-038) in pulmonary embolism, arterial stenosis of the lower

limbs, renal artery stenosis, carotid artery stenosis, coronary artery stenosis, and non-

coronary stenosis, respectively. In these 5 trials, the main efficacy criterion was the

determination of sensitivity, specificity and the predictive values of the new technique

in comparison with the selected gold standard, i.e. X-ray angiography or DSA.

In all but one study (DGD-44-038) images were analysed by two independent off-site

investigators, and confirmed the high sensitivity and specificity of a contrast-enhanced

MRA compared to DSA.

In addition, a Medline search identified 16 European clinical trials supporting the use of

gadoterate meglumine for MRA.

Table 16 : Overview of the selected randomized and non-randomized clinical studies in MRA

Study reference Study Design Imaging No of gadoterate meglumine cases**

Laissy et al., 1998 R, SB, M, C MRA 40DGD-3-37 R, SB, U, C MRA 35Brichaux et al., 1991* NR, O, U, C MRA 24Revel et al., 1993 NR, O, U, C MRA 26Loubeyre et al., 1994 NR, O, U, C MRA 23Laissy et al., 1995 MRA 28Laissy et al., 1995 MRA 20Perrier et al., 1998 MRA 23Laissy et al., 1998 MRA 20DGD-3-36 NR, O, M, C MRA 41DGD-3-38 NR, O, M, C MRA 40Randoux et al., 2001 MRA 22Nchimi et al., 2002 MRA 49Cottier et al., 2003 MRA 58Randoux et al., 2003 MRA 33Wyttenbach et al., 2003 MRA 56Loewe et al., 2003 MRA 39Loewe et al., 2004 MRA 28Lapeyre et al., 2005 MRA 31Gauvrit et al., 2006 MRA 54Feydy et al., 2006 MRA 30DGD-44-38 NR, O, M, C MRA 100Vogt et al., 2007 MRA 9DGD-44-42 NR, O, U, C MRA 92DGD-44-48 NR, O, M, C MRA 222DGD-44-49 NR, O, M, C MRA 211DGD-44-45 R, DB, M, C MRA 93

Total 829C: Comparative; U: Unicentric; M: Multicentric; O: Open; NR: Not Randomized; R: Randomized; DB: double-blinded This was the same study as for renal imaging (Table 13).


39

** In these studies all patients were treated with gadoterate meglumine

10.3.1 Randomized studies in MRA

10.3.1.1 Lower limb arteries (DGD-3-39)

This multicentre single-blind comparative and randomized (two doses) clinical trial with

2 parallel groups, aimed at evaluating the diagnostic efficacy of gadoterate meglumine-

enhanced MRA compared to X-ray angiography used as the gold standard. Twenty

patients received doses of 0.1 mmol/kg while 20 other patients received 0.05 mmol/kg.

Since the presence of arterial lesions (stenoses or segmental thromboses) is not always

correlated with clinical features of arterial insufficiency - as the collateral circulation

may be sufficiently developed - an assessment as complete as possible in case of arterial

insufficiency is necessary, in order to plan treatment. Exhaustive detection of all lesions

is actually difficult, especially in distal leg arteries, which explains the poor sensitivity

during segment-by-segment analysis (41%). Since MRA is a diagnostic evaluation and

not a screening technique, per-segment specificity is the most important parameter. In

this study the specificity by segment was 89% with the higher gadoterate meglumine

dose, when compared to 84% for the lower dose. Regarding the evaluation of collateral

arteries, MRA with gadolinium was considered to provide good or excellent results in

73.9% of the cases.

10.3.1.2 Pulmonary arteries (DGD-3-37)

This single-centre comparative randomised clinical trial was aimed at assessing the

efficacy of gadoterate meglumine-MRA for the diagnosis of pulmonary embolism. The

study objective was to exclude or confirm pulmonary embolism, thus the results by

patient were the most relevant to confirm or refute the diagnosis. Accordingly, the

sensitivity and the specificity of the MRA with gadoterate meglumine were respectively

71.4% and 100% with no difference between the two tested gadoterate meglumine

doses.

The comparison between MRA and CT angiography was not the subject of this study.

However, MRA presents the advantage of being potentially more extensive than CT, as

it is possible to simultaneously evaluate pulmonary perfusion, with one injection of the

same contrast agent, and without any ionizing radiations.


40

10.3.2 Non-Randomized studies in MRA

10.3.2.1 Renal arteries (DGD-3-36)

The results of gadoterate meglumine-enhanced MRA in the DGD-3-36 study were very

satisfactory as the specificity was 86.3% for the on-site reading (and 90.2% for the

centralized reading).

These results of gadoterate meglumine-enhanced MRA are concordant with those

published in the literature, which report specificity ranging from 89% to 98% and

sensitivity ranging from 93% to 100%. Quantification of the stenosis was more precise

with contrast-enhanced MRA, which presented a better concordance with conventional

angiography. This superiority over unenhanced MRA is due to the use of the contrast

agent, which opacifies the arterial lumen while, in the flow method, quantification is

based on the signal loss effect, related to turbulence, but which is actually a

multifactorial phenomenon. However, contrast-enhanced MRA does tend to slightly

overestimate the degree of stenosis, which is less dangerous than when underestimated.

Contribution to the visualization of renal arteries and aorta was better with gadoterate

meglumine MRA than with TOF MRA concerning stenosis grading, distality

visualisation, detection of accessory renal arteries, aortic lesions visualization, S/N and

C/N ratio. Total duration of the MRA examination was 3 times shorter than DSA.

Moreover when compared to DSA, a major advantage of gadoterate meglumineMRA is

the lack of patient exposuire to ionizing radiation.

10.3.2.2 Carotid arteries (DGD-3-38)

This multicentre study assessed the efficacy of Dotarem-MRA to diagnose carotid

artery stenosis in comparison to unenhanced MRA (TOF). The results yielded were very

satisfactory. The sensitivity of contrast-enhanced MRA was 93.5% for the centralized

readings, with a specificity 89.6%, which corresponded to the expected values. These

performances are very similar to those of unenhanced MRA, with gave a sensitivity and

specificity of 93.5% and 84.4%, respectively. These good performances of unenhanced

MRA are also due to the easier visualization of these superficial vessels with surface

coils (without respiratory movement artefacts).

The difference between the two methods, observed in this study, concerned an

estimation of the degree of stenosis. Overestimation is frequently observed in MRA and

occurred more frequently with unenhanced sequences (1% of stenosis on contrast-

enhanced MRA was evaluated as 0.86% by angiography, while 1% of stenosis on

unenhanced MRA was evaluated as 0.51% on angiography). This difference has clinical

implications as it influences the surgical indication.


41

The technique that will eventually replace conventional arteriography must be able to

cover the entire territory of the supra-aortic vessels. This is now possible with contrast-

enhanced MRA with the use of appropriate surface coils.

10.3.2.3 Non-coronary arteries (DGD-44-038)

The study objective was to assess diagnostic accuracy of gadoterate meglumine-MRA

over unenhanced MRA for the diagnosis of non-coronary arterial disease. Subjects with

suspected arterial disease entered in this trial.

The percentage of diagnosis agreement at the subject level (primary efficacy criterion),

each segment score for the TOF and gadoterate meglumine-enhanced MRA evaluations

was compared to the corresponding segment score from the X-ray angiogram.

A total of 100 subjects had been enrolled in the study. The arterial areas targeted were

renal (33%), aorto-iliac (31%), calf (3%), carotid (12%), femoral (15%) and popliteal

(6%).

The study showed that the degree of agreement in assessing non-coronary arterial

lesion(s) as compared to the gold standard, X-ray angiography was significantly higher

in gadoterate meglumine-enhanced MRA than in TOF-MRA (respectively 86% versus

79.5%, p=0.02), taking conventional X-ray angiography as the gold standard.

Considering technical failures excluded, there was a statistically significant difference

in sensitivity between gadoterate meglumine (77.8%) and TOF (58.3%) at segment

level, largely in favor of gadoterate meglumine enhanced procedure (= 19.4%, p=

0.0391 Mc Nemar’s test).

The X-ray angiography procedure, even if more invasive, obtained the best image

quality. Nevertheless, when compared to unenhanced images gadoterate meglumine

enhancement improved image quality, and shortened examination time while allowing

for a more reliable interpretation and hence a more precise diagnosis.

10.3.2.4 Renal and pancreatic arteries (Brichaux et al., 1991)

In this trial, 24 patients with renal and 2 patients with pancreatic transplants were

studied for evaluation of allografts arteries 10 days to 6 months after transplantation. 19

patients with normal renal function were evaluated as a routine follow-up and 7

suspected of renal stenosis were submitted to color Doppler flow examination. In 20

patients the 2D FLASH sequence before and after gadoterate meglumine (rapid drip-

infusion of 0.1 mmol/kg) were compared and classified by 2 observers. Gadoterate

meglumine injection improved image quality in 6/20 cases (30%), reduced it in 1 case

and allowed elimination of 3 false-positives among the 19 cases without suspected

stenosis.


42

10.3.2.5 Pulmonary arteries (Loubeyre et al., 1994)

In this study, 23 consecutive patients with suspected pulmonary embolism were

included. All patients have had intra-arterial DSA, which showed emboli in 12 patients

(13 proximal and six peripheral emboli). MR angiography was done within 24 hours

after digital subtraction angiography. MR angiograms were interpreted by two observers

who had no knowledge of the findings on digital subtraction angiography. A diagnosis

of pulmonary emboli was made when MR angiograms showed a constant intra-luminal

filling defect or an abrupt vascular cut-off.

All thrombi in the proximal branches of the pulmonary arteries were visualized on MR

angiograms whereas none of the thrombi in the distal part of the pulmonary arteries

were visible. These results suggested that gadoterate meglumine-enhanced MR

angiography was an accurate method for detecting emboli in the proximal portions of

the pulmonary arteries but was of limited value in detecting peripheral emboli.

10.3.2.6 Aorta and pulmonary arteries (Revel et al., 1993)

In this trial, gadoterate meglumine was evaluated for studying great thoracic vessels,

using high-speed MR imaging combined with intravenous rapid bolus injection of a

paramagnetic contrast media. Two groups of patients were studied: 16 patients after

having surgery for type A aortic dissection and 10 patients presenting pulmonary

embolism documented by selective pulmonary angiography.

In this study the information acquired on the aorta and pulmonary arteries obtained by

contrast-enhanced MR tomo-angiography appeared complementary to that obtained

with other vascular MRI procedures.

10.3.3 Well established use in MRA – Analysis of the literature

Since 1992 gadoterate meglumine has been extensively used in MRA in all kind of

arteries and diseases for more than 10 years in Europe.

A search in literature, using Medline identified 50 European clinical trials regarding

gadoterate meglumine-enhanced MRA. Among these 50 clinical trials, a total of 16

trials bring significant and valuable results for a diagnostic performance analysis. These

16 trials were all published in high quality peer-reviewed journals, and their results are

summarized in the following table.


43

Table 17: Gadoterate meglumine clinical trials publications (1994 to date)Studyreference

indication Arterialterritory

Country Dose Nb ofpatients

Statunit

sensitivity Specificity

N % N %

Laissy etal.,1995

Detection ofrenal arterystenoses inpatients withabdominalaorticaneurysms

Aortoiliofemoral

France 0.2ml/kg

20 lesion 5 100 35 97

Perrier etal.,1998*

Detection ofstenoses inilio femoralarteries(reader 1)

Aortoiliofemoral

France 0.2ml/kg**

23 segment

77 98 200 82

Perrier etal.,1998*

(reader 2) Aortoiliofemoral

France 0.2ml/kg**

23 segment

78 98 198 82

Nchimi etal.,2002

Detection ofstenoses inaorta andfemoralarteries

Aortoiliofemoral

Belgium 17 ml 49 segment

138 94 437 96

Randouxet al., 2001

Detection ofcarotid arterystenoses

Head &neck

France 20 ml 22 segment

18 93 26 100

Cottier etal.,2003

Depiction ofremnantaneurysm intreatedintracranialaneurysms

Head &neck

France 0.2ml/kg

58 lesion 36 83 35 100

Gauvrit etal., 2006

Detection ofresidualnidus orvenousdrainage intreatedcerebralarteriovenousmalformations

Head &neck

France 10 ml 54 lesion 32 81 22 100

Loubeyreet al., 1994

Diagnosis ofpulmonaryembolism

Thorax France 0.2ml/kg

23 segment

12 70 MD

100

Laissy etal.,1995

Diagnosis ofpulmonaryembolism

Thorax France 0.2ml/kg

28 patient 12 88 16 85

Randouxet al.,2003*

Detection ofostialstenoses inaortic arch(vertebralarteries)

Thorax France 20 ml 33 segment

10 100 137 85

Randouxet al.,2003*

(otherarteries)

Thorax France 20 ml 33 segment

11 100 55 98

Loewe etal.,2004

Detection ofstenoses inaortic archvessels

Thorax Switzerland

25 ml** 28 segment

27 93 162 99

Laissy etal.,

Detection ofsignificant

Periph France 0.2ml/kg

20 segment

113 100 413 97


44

1998 stenoses inlower limbs

Wyttenbach et al.,2003*

Detection ofstenosis andocclusion inperipheralarteries(reader 1)

Periph Switzerland

34 ml 56 segment

167 96 610 93

Wyttenbach et al.,2003*

(reader 2) Periph Switzerland

34 ml 56 segment

167 96 614 85

Loewe etal.,2003*

Detection ofstenoses inbypass graftsof peripheralarteries

Periph Switzerland

40 ml** 39 segment

17 82 30 98

Loewe etal.,2003*

Detection ofstenoses innativeperipheralarteries

Periph Switzerland

40 ml** 39 segment

60 78 878 96

Lapeyre etal., 2005*

Detection ofstenoses inlimbischemia indiabetes(reader 1)


31 segment

335 95 285 98


Detection ofocclusions inlimbischemia indiabetes(reader 1)


31 segment

335 95 285 98


Detection ofstenoses inlimbischemia indiabetes(reader 2)


31 segment

335 96 285 98


Detection ofocclusions inlimbischemia indiabetes(reader 2)


31 segment

335 90 285 99

Feydy etal.,2006

Detection oftumorinvasion inlower limbsarteries


30 patient 11 82 20 85

Vogt et al.,2007*

Detection ofperipheralarterialdisease (allsegments)

Periph Germany 0.2ml/kg

9 segment

43 100 129 89

Vogt et al.,2007*

Detection ofperipheralarterialdisease (infrapoplitealsegments)

Periph Germany 0.2ml/kg

9 segment

MD

100 MD

86

Nielsen etal., 2010

Detection ofperipheralarterialdisease

Periph Denmark 0.3mmol/kg

26 segment

13 73 13 94

Attenberge Detection of Periph Germany 0.07 31 segmen 31 86 31 76


45

r et al.,2010

peripheralarterialdisease

mmol/kg

t

Shah et al.,2012

Detection ofnon-coronaryartery disease

Periph Korea 0.1mmol/kg

162 segment

162 93.3

162 89.7

Lee et al.,2014

Detection ofsupra-aorticarterialstenosis

HeadandNeck

Korea 0.1mmol/kg

30 segment

30 88.2

30 99.3

*One publication, 2 to 4 lines, one line per artery-type or per lesion-type or per reader**Patients received equally Gadoterate meglumineor another non-specific gadolinium based contrast agentMD: missing data

Conclusion – Gadoterate meglumine and MRA

Gadoterate meglumine-contrast MRA can detect with a good accuracy arterial lesions or

stenosis whatever the artery location, the artery size, or the concerned disease. This

overview is also supported by the well-established use of gadoterate meglumine in

whole-body MRA in Europe for more than 15 years. The literature shows for the

majority of the arterial territories and the indications studied, that gadoterate

meglumine-enhanced MRA is clinically useful and achieves a good and satisfactory

diagnostic performance, with sensitivity and specificity ranging from 80% to 100%.

Magnetic resonance angiography with gadoterate meglumine is an effective technique

that could be proposed as a first-line or as a second-line investigation after Doppler US.

10.4 Efficacy conclusions

Gadoterate meglumine is a solution administered by intravenous route and intended for

diagnostic examinations carried out by Magnetic Resonance Imaging (MRI). Its

efficacy as a contrast agent have been evaluated extensively both during pre-clinical and

clinical development.

The clinical interest of gadoterate meglumine as a contrast agent in MRI has been

documented in various clinical trials and published studies. These specific studies tested

gadoterate meglumine in various situations, such as CNS imaging, hepatic and

pancreatic imaging, renal imaging, etc.

MRA with gadoterate meglumine appears to be an effective technique and could be

proposed as a first-line investigation (renal arteries, pulmonary arteries or coronary

arteries) or as a second-line investigation after Doppler ultrasound (aorta, lower limbs,

supra-aortic vessels). In these indications, the imaging efficacy and general safety of

gadoterate meglumine have been unambiguously documented in well-designed clinical

trials.


46

Furthermore, gadoterate meglumine has been evaluated in numerous additional trials

that were published in peer-reviewed medical journals. Whereas these studies were not

conducted under the responsibility of Guerbet, they provide supportive data confirming

the usefulness and the safety of this paramagnetic contrast agent.

General conclusion:

The efficacy data obtained with gadoterate meglumine from multiple studies shows that

gadoterate meglumine can be efficiently used in three types of examinations, namely: (i)

MR imaging for intracranial and spinal cord diseases, (ii) whole body MR imaging and

(iii) magnetic resonance angiography. Gadoterate meglumine use was associated with

an improved diagnostic efficacy when compared to unenhanced images, and with a non-

inferior diagnostic ability when compared to competitors. Together with its reduced

potential to induce adverse reaction when compared to other Gd-based contrast media

(see section 11), these data support the inclusion of gadoterate meglumine in the WHO

List of Essential Medicines.

Table 18 : List of Guerbet sponsored clinical studies (Stinson BA, Clinical Review, NDA 204,781 SD 1Dotarem Gadoterate Meglumine. FDA Reference ID: 3258714)

Study referencenumber

Study title

DGD-3-1 G449-06 Magnetic resonance irnaging.Renal Safety/Diagnostic efficacy. Phase IIClinical Trial.

DGD-3-2 G449.06 Magnetic Resonance Imaging hematological safety / diagnostic efficacy.DGD-3-3 G449.06 in magnetic resonance imaging. Hematological safety / diagnostic efficacy.

Phase II Clinical Trial.DGD-3-4 G449.06 Magnetic Resonance Imaging renal and hepatic safety / diagnostic efficacy.DGD-3-5 G449-06 Magnetic Resonance Imaging Laboratory safety/ Diagnostic efficacy. Phase II

clinical trial.DGD-3-6 Study of the excretion of G449-06 (an NMR enhancing substance) in blood, urine and

faeces in healthy male volunteersDGD-3-7 G449.06 Magnetic Resonance Imaging. General safety and Diagnostic efficacy. Phase II

clinical trialDGD-3-8 G449.06 Magnetic Resonance Imaging. General safety and Diagnostic efficacy. Simple

open Phase III clinical trial.DGD-3-9 G449.06 Magnetic Resonance Imaging Renal and hepatic safety / Diagnostic efficacy

Phase II clinical trial.DGD-3-11 G449.06 Magnetic Resonance Imaging - Cerebral safety Coagulation/Diagnostic

efficacy.DGD-3-12 G449-06 - Magnetic Resonance Imaging - General Safety/Diagnostic Efficacy Phase II

clinical trial.DGD-3-12 G449-06 in Hepatic Imaging by Magnetic Resonance General Safety/ Diagnostic

Efficacy - Phase III Clinical Study.DGD-3-14 G449-06 Magnetic resonance imaging General safety / Diagnostic efficacy Phase III

clinical trial.DGD-3-15 G449-06 Magnetic Resonance Imaging Simple open phase II trial in pediatrics.DGD-3-16 G449-06 - Magnetic resonance imaging Phase II open-label trial in paediatricsDGD-3-17 G449-06 versus Gadolinium-DTPA. Magnetic resonance imaging Comparative,

randomised, double-blind study. Clinical phase II study. Diagnostic efficacy/ Clinical andlaboratory safety.

DGD-3-20 G449-06 Magnetic Resonance Imaging General safety/Diagnostic efficacy open Phase IIIclinical trial.

DGD-3-21 G449-06 in Neurological Magnetic Resonance Imaging General safety/Diagnostic


47

Study referencenumber

Study title

efficacy Phase III clinical trial.DGD-3-23 G449-06 in Neurological Magnetic Resonance Imaging General safety/Diagnostic

efficacy Phase III clinical trial.DGD-3-28 Pharmacokinetic study of Dotarem® (gadoteric acid) in chronic renal failure patients.DGD-3-29 Evaluation of the efficacy and safety of Dotarem® (gadolinium DOTA) in MRI of the

central nervous system in children. Open-label phase IV clinical trial. 50 patients.DGD-3-31 Comparative randomised double-blind trial of Dotarem versus Magnevist in central

nervous system MRI phase III-IV trial. Laboratoire Guerbet.DGD-3-32 Evaluation of the diagnostic efficacy of Dotarem® in the early diagnosis of breast

carcinoma.DGD-3-33 Evaluation of the diagnostic efficacy and cllnlcal safety of triple-dose Dotarem® in

comparison to the standard dose for the detection of brain metastasesDGD-3-34 Evaluation of the safety and diagnostic efficacy of triple-dose Dotarem® in the detection

of brain tumours.DGD-3-36 Diagnosis of renal artery stenosis by contrast-enhanced MR angiography: efficacy of

Dotarem® at 0.1 mmol/kg.DGD-3-37 Diagnosis of pulmonary embolism by contrast-enhanced MR angiography: efficacy of

two doses of Dotarem®.DGD-3-38 Diagnosis of carotid artery stenosis by contrast-enhanced MR angiography: Efficacy of

Dotarem® at 0.1 mmol/kg.DGD-3-39 Diagnosis of lower limb arterial stenosis by contrast-enhanced MR angiography: efficacy

of two doses of Dotarem®.

DGD-3-44 Evaluation of MRI with Dotarem® in the diagnosis or follow-up assessment of cerebral orspinal tumors.

DGD-3-50 Evaluation of MRI with DOtarem® in the characterization of abdominal and pelviclesions.

DGD-44-038 Evaluation of Dotarem®-enhanced MRA compared to time-of- flight MRA in thediagnosis of clinically significant non-coronary arterial disease.

DGD-44-039 Gd-DOTA (Dotarem®) : evaluation of the electrocardiographic safety in patients PhaseIIb clinical trial.

DGD-44-042 Evaluation of Dotarem®-enhanced MRA compared to time-of-flight MRA in thediagnosis of clinically significant non-coronary arterial disease.

DGD-44-044 Renal safety evaluation after Dotarem®-enhanced MRI compared with non-enhancedMRI in patients at high risk of developing contrast medium induced nephropathy(RESCUE study).

DGD-44-045 Efficacy evaluation of Dotarem®-enhanced MRA compared to Gadovist®-enhanced MRAin the diagnosis of clinically significant abdominal or lower limb arterial diseases.

DGD-44-050 Safety and efficacy evaluation of Dotarem® in magnetic resonance imaging (MRI) inpatients with central nervous system (CNS) lesions (SENTIO study).

DGD-44-051 Evaluation of MRI with Dotarem® in the diagnosis or follow-up assessment of cerebral orspinal tumors. Re-reading of MRI images.

DGD-55-001 SECURE: Observational Study on the Safety and the Efficacy of DOTAREM.

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53

11. Summary of comparative evidence on safety

The clinical safety data for gadoterate meglumine presented hereafter are derived from

three sources, namely, (i) clinical trials conducted by Guerbet (see section 11.2.1)

including pharmacokinetic trials, CNS and other total body imaging trials, pediatric

studies, and MRA evaluations, in which 2813 patients have received various doses of

gadoterate meglumine for various imaging purposes; (ii) post-marketing studies

concerning over 137,000 patients (see section 11.2.2); and (iii) post-marketing

pharmacovigilance data compiling safety information relative to the use of over 41

million doses of gadoterate meglumine since first obtaining marketing authorization in

1989 (see section 11.2.3).

The extensive use of gadoterate meglumine notably since the recognition in 2006 of the

link between NSF and gadolinium-based contrast agents (GBCAs) has allowed for a

thorough analysis of its safety profile.

11.1 Overall exposure

11.1.1 Adult population

As a diagnostic agent, gadoterate meglumine is administered most of the time at the

usual dose of 0.1 mmol/kg in a single IV injection. However, in angiographic

indications gadoterate meglumine is intended to be used at doses of up to 0.3 mmol/kg;

administered at 0.1 mmol/kg (0.2 mL/kg) as a bolus at a rate of 1 to 2 mL/sec followed

by a second injection of 0.2 mmol/kg (0.4 mL/kg) 20 minutes later. This gadoterate

meglumine cumulative dose of 0.3 mmol/kg was chosen because it corresponded to the

highest dose used in clinical practice.

In the various clinical trials conducted by Guerbet a total of 2813 patients received

gadoterate meglumine and the overall extent of exposure at doses of 0.05 mmol/kg, 0.1

mmol/kg and ≥0.2 mmol/kg of gadoterate meglumine is shown in the following table.

Table 19 : Number of adverse events (AE) reported in gadoterate meglumine clinical studiesconducted by Guerbet

Total nb

of

patients*

Patients

with

at least

one AE

%

of patients

PK, CNS (0.1 mmol/kg) and total body imaging (0.1 to

0.2 mmol/kg)

871 76 8.7%

Pediatric population (0.05 to 0.1 mmol/kg) 99 1 1.0%

CNS high dose studies (0.2 or 0.1 + 0.2 mmol/kg) 110 3 2.7%

MR angiography studies (2 0.05, 0.1 and 2 0.1

mmol/kg)

156 1 0.6%

Total 2813 81 6.6%

* Patients who received Gd-DOTA; PK: pharmacokinetics studies


54

Two studies in liver/pancreas imaging (DGD-3-9; DGD-3-13) investigated a dose of 0.2

mmol/kg gadoterate meglumine in 31 patients and no serious adverse events were

recorded. Also, two studies (DGD-3-39; DGD-3-37) investigated a dose of 0.2 mmol/kg

gadoterate meglumine in MRA imaging in 40 patients and only 1 patient reported a mild

to moderate allergic-like non-serious AE.

Two clinical trials were carried out in order to demonstrate the efficacy of a "triple

dose" compared to the standard dose in patients with suspected or confirmed brain

lesions (DGD-3-33 and DGD-3-34). The results of these studies show no significant

imbalance in terms of incidence between the adverse events reported after the standard

dose and those reported after the triple dose.

As shown in Table 21, besides 2813 patients receiving gadoterate meglumine in clinical

studies, over 147,000 patients received gadoterate meglumine in the post marketing

studies (PMS), and based on global sales and marketing data (as of December 2013), it

is estimated that over 41 million administrations of gadoterate meglumine have been

given since it was first launched in France in 1989.

11.1.2 Paediatric population

The calculation of the estimated number of children below 2 years of age injected with

gadoterate meglumine between 2005 and 2012 is described hereafter. This period has

been chosen since the sales within that time period represent 80% of the total sales from

the first marketing authorization. This was consecutive to the recognition in 2005/2006

of the link between NSF and gadolinium-based contrast agents (GBCAs) and a marked

increase in sales specifically in at risk-populations, such as the very old or the very

young patient.

Based on the data from the CCAM (Classification Commune des Actes Médicaux or

Common Classification of Medical Procedures), 3,320 MR examinations with GBCAs

injection were performed in children below 2 years of age in France in 2011. According

to the GERS (economic interest group made up of the pharmaceutical companies

operating in France) using data collected from wholesale distributors and

pharmaceutical companies, gadoterate meglumine reached a market share of 85% in

France from hospital sector in 2011.

Therefore, it is estimated that 2,822 (3,320 x 0.85) MR examinations were performed

with gadoterate meglumine in children below 2 years of age in France in 2011.

According to the Guerbet database from January to December 2011, the total number of

MR examinations performed with gadoterate meglumine (based on 16.8

mL/examination) in France was 1,047,500, of which 0.27% (2,822/1,047,500)

concerned children below 2 years of age.


55

On the basis of the percentage of gadoterate meglumine exposure (0.27%) for children

below 2 years of age in France in 2011, the following table summarized the estimated

gadoterate meglumine exposure for pediatric population (0-2 years of age) in the

countries where gadoterate meglumine is approved for use (see table Table 20 below).

Table 20 : Estimated number of children below 2 years of age injected with gadoterate megluminebetween 2005 and 2012

Country Total number

of

gadoterate

meglumine

sold (Liters)

Total number of

MR

examinations

with gadoterate

meglumine

Estimated number of

Children below 2 years

of age

injected with gadoterate

meglumine

FRANCE 98,371 5,855,416 15,809

AUSTRIA 6,307 375,416 1,013

BELGIUM 18,636 1,109,285 2,995

GERMANY 86,147 5,127,797 13,845

ITALY 25,031 1,489,940 4,022

NETHERLANDS 12,768 760,000 2,052

PORTUGAL 2,433 144,821 391

SWITZERLAND 14,459 860,654 2,323

TURKEY 11,939 710,654 1,918

SOUTH KOREA 7,164 426,428 1,151

TAIWAN 3,226 192,023 518

MEXICO 1,816 108,095 291

BRAZIL 32,959 1,961,845 5,296

Total 321,256 19,122,374 51,624

In conclusion, according to this calculation and data collected from main countries in

Europe, from South Korea, Turkey, Taiwan, Mexico, and Brazil, the estimated number

of children below 2 years of age injected with gadoterate meglumine between 2005 and

2012 was around 51,000.


56

11.2 Safety finding from clinical studies and post-marketing experience

Preclinical data has highlighted the very large safety margin of gadoterate megluminewithout identifying any particular target organ at risk and no teratogenic, immunotoxic ormutagenic potential nor effects on fertility were observed. The good safety profile wasconfirmed in clinical trials, post-marketing studies and pharmacovigilance.

11.2.1 Safety findings from Guerbet sponsored trials and from published trials

As of January 1st 2014, 50 clinical studies have been conducted by Guerbet, accounting

for a total of 2813 patients injected with gadoterate meglumine. Most patients who

received gadoterate meglumine were male (1532 patients [54.5%]) and among those

whose race was recorded, most were Caucasian (1181 patients [74.4%]), followed by

Asian (11.9%), Black (4.0%) and others (9.6%). The mean age of patients who

received gadoterate meglumine was 53 years and their mean weight was 69.1 kg.

Most patients treated with gadoterate meglumine (90.4%) did not experience AEs.

Among the 263 patients (9.3%) treated with gadoterate meglumine who did experience

AEs, 111 patients (4.6%) had 363 AEs that were considered to be related to treatment.

Most of the AEs in gadoterate meglumine-treated patients were of mild severity

(71.1%) or moderate (16.3%) in intensity. A total of 7 AEs (1.9%) were pre-existing

conditions.

Of total 363 drug related AEs in gadoterate meglumine-treated group, 32 AEs (8.8%)

were severe, 29 (8.0%) were SAEs, and 11 AEs led to death (3.0%). The most common

related AEs in gadoterate meglumine-treated patients were nausea (0.6%), headache

(0.5%), and injection site pain (0.4%); all others related AEs occurred in < 0.2% of

patients.

For gadoterate meglumine-related AEs, the median time to onset was 5 minutes and

median duration was 15 minutes.

Most patients (94.1%) did not receive treatment for their AEs and for most AEs,

recovery occurred without treatment (263 AEs [72.5%]). Among gadoterate

meglumine-treated patients, 17 (6.5%) received treatment for AEs. For 3 AEs (0.8%),

recovery occurred with sequelae, 44 AEs were not recovered or ongoing (12.1%), and

for 11 AEs from 8 patients, the outcome was death (3.0%), 7 patients were from study

DGD-3-44 and the other one was from study DGD-3-50. None of the deaths were

considered to be related to gadoterate meglumine.


57

A total of 23 patients treated with gadoterate meglumine (0.8%) experienced 29 SAEs,

2 of which were considered to be possibly related to treatment (one was moderate

hypersensitivity and the other was mild renal failure).

The adverse reactions observed in the clinical trials are characteristic of the

pharmacological class of gadolinium contrast agents and are cited in several recent

review articles in the scientific literature about their good safety profile among various

commercially available contrast media, including gadoterate meglumine (Bruder et al.,

2011, Reimer et al., 2004; Kirchin et al., 2003; Runge et al., 2000).


58

11.2.2 Safety findings from Guerbet observational post-marketing studies

As shown in Table 21, more than 147,000 patients have been evaluated for gadoterate

meglumine safety in 6 observational post-marketing studies.

Table 21: Overview of post-marketing studies conducted by Guerbet

Author Study Design Imaging No of gadoterate meglumine

patients

Neiss et al., 1991 NR, O, S CNS 4169

Briand et al., 1992 NR, O, S Various (including CNS) 402

Herborn et al., 2007 NR, O, M Various 24,308

Ishiguchi et al., 2010

Emond et al., 2011

Maurer et al., 2012

SECURE study (DGD-55-001)

NR, O, M

NR, O, S

NR, O, M

NR, O, M

Various (including CNS)




3444

104

104,033

35,499

TOTAL 147,651

S: Single center; M: Multicentric, O: Open; NR: Not Randomized

In the PMS by Neiss et al., (1991), a total of 15 patients (0.84%) experienced at least

one adverse event. The majority of the 43 AEs observed were considered as

mild/moderate intensity. The most frequent AEs reported were vomiting, nausea and

headache.

In the PMS by Briand et al., (1992), no adverse events were reported in the children

aged below 15 years. One 16-year-old adolescent developed a papule on the inside of

the thigh 10 minutes after the injection, but this did not require discontinuation of

treatment.

In the PMS study by Herborn et al., (2007), from a total of 24,308 patients adverse

events were noted in only 0.4% of the examinations and were mostly rated as minor,

such as feeling of warmth or taste alteration. There was one serious adverse event, albeit

with complete recovery.

In the PMS by Ishiguchi et al., (2010), a total of 40 adverse reactions were recorded in

32 patients, giving an overall incidence of adverse reactions of 0.93%. Gastrointestinal

disorders were the most commonly reported adverse reactions (0.49%). Most adverse

reactions reported were of mild intensity and no serious adverse reactions were

reported.

In the PMS by Emond et al., (2011), no adverse event was reported.

In the PMS by Maurer et al., (2012), adverse events occurred after injection of

gadoterate meglumine in 328 out of 104,033 patients (0.3%). Adverse events were

predominantly mild to moderate and uncommon to very rare.


59

The causal relationship was reported in 228 patients. A relationship with gadoterate

meglumine was excluded in 2 out of 228 patients (0.9%). In 69 patients (30.3%), the

relationship was certain, in 93 patients (40.8%) probable, in 48 patients (21.1%)

possible and in 16 patients (7.0%) unlikely.

The patient’s outcome was mentioned in 224 patients: 217 of the 224 patients (96.9%)

recovered after the examination, 2 patients (0.9%) had not yet recovered and the

outcome was unknown in 5 patients (2.2%). In the patients who had not yet recovered

after the examination, the adverse events pruritus, pustular rash and urticaria were

observed.

The number of patients with at least one serious adverse event was 11 (0.01%). The

causal relationship with gadoterate meglumine was rated as possible in 7 patients and

doubtful in 3 patients, and not reported in one patient. Ten patients recovered after

treatment of the adverse event while the outcome was unknown in one patient.

In the PMS SECURE (DGD-55-001) comprising 35,499 patients, a total of 70 AEs

were recorded in 44 patients (0.12%). Urticaria and nausea were the most frequent AEs

accounting respectively for 12.9% and 10.0% of all AEs. Among 1630 pediatric

patients, only one patient (0.06%) aged 2 experienced mild vomiting which was deemed

doubtfully related to Dotarem®.

In post-marketing studies adverse events have been very rarely reported (<0.01%) and

are described below:

Table 22 : Adverse events reported in the post-marketing studies

System Organ Class Adverse event

Skin and subcutaneous tissue

disorders

Eczema, erythema, urticaria, pruritus and rash

Musculoskeletal, connective tissue

and bone disorders

Muscle cramps, muscle weakness

Nervous System disorders Dizziness, generalized convulsions, tremor,

fatigue and somnolence.

Psychiatry: Anxiety, confusion, insomnia, somnolence

Gastro-Intestinal disorders Abdominal pain

Respiratory, thoracic and

mediastinal disorders

Laryngitis, laryngismus, rhinitis, respiratory

disorders

General disorders & administration

sites conditions

Chest pain, back pain, malaise, fever, sweating

increased, coldness, pallor and syncope.

In conclusion, the results of these 6 observational PMS did not reveal any untoward or

unexpected findings concerning the safety of gadoterate meglumine. The low incidence

of adverse reactions (<1%) reported during these PMS showed that gadoterate

meglumine was very well tolerated.


60

11.2.3 Safety findings from post-marketing pharmacovigilance (cut-off 2014)

Concerning the use of gadoterate meglumine, a total of 5819 adverse reactions were

reported to Guerbet in 2694 cases from about 41,742,857 million patients exposed in the

post-marketing setting for all gadoterate meglumine dosages since first marketing

authorization obtained in 1989. The total number of patients exposed was estimated

from the volume of gadoterate meglumine sold. This corresponds to an incidence of

about 6 cases for 100,000 patients exposed and 14 adverse reactions for 100,000

patients.

In terms of seriousness, 859 serious cases were reported; the incidence of serious cases

is estimated to be about 2.1 serious cases for 100,000 patients exposed.

The most frequently affected body systems were:

Skin and Subcutaneous Tissue disorders (28.0%) with 1630 adverse drugreactions (ADRs)

Gastrointestinal disorders (18.9%) with 1103 adverse drug reactions Respiratory thoracic and mediastinal disorders (12.3%) with 718 adverse drug

reactions General disorders and administration site conditions (11.7%) with 678 adverse

drug reactions Nervous system disorders (6.9%) with 402 adverse drug reactions Immune disorders (5.2%) with 300 adverse drug reactions

ADRs recorded during the post-marketing experience are presented below accordingtheir System Body Class.

Skin System Organ Class: the most frequently reported reaction was urticaria (451

ADRs). Most of the remaining cases concern non-serious rashes.

Gastrointestinal System Organ Class: the most frequently reported reactions were

nausea (358 ADRs) and vomiting (252 ADRs). The majority of these cases were non

serious.

Respiratory System Organ Class: the most frequently reported reactions were

dyspnea (175 ADRs) and cough (131 ADRs) which occurred in the context of

hypersensitivity reactions.

General disorders and administration site conditions: the most frequently reported

reactions were feeling hot (74 ADRs) and malaise (69 ADRs).


61

Nervous System Organ Class: the most frequently reported reactions were headache

(58 ADRs), paraesthesia (56 ADRs), and dizziness (56 ADRs). The majority of these

cases were non serious.

Immune System Organ Class: hypersensitivity/anaphylactoid reactions, consisting

primarily of cutaneous, respiratory, and cardiovascular symptoms, have been reported

with gadoterate meglumine and are recognized to occur in association with all

gadolinium-based contrast agents (GBCAs), including rare instances of life threatening

or fatal shock.

In total, the post-marketing experience of over 20 years of global marketing is

consistent with the known safety profile of gadoterate meglumine as obtained during

clinical trials. Also this analysis confirms the absence of nephrotoxicity for gadoterate

meglumine based on the low number of renal adverse drug reactions.

The benefit of contrast-enhanced imaging exceeds the risk in the greatest majority of

patients in which imaging is indicated.

11.2.4 Occurrence of Nephrogenic Systemic Fibrosis (NSF)

Nephrogenic systemic fibrosis (NSF), is a rare, but serious, condition associated with

the use of GBCAs. Symptoms of NSF include scaling, hardening and tightening of the

skin; red or dark patches on the skin; and stiffness. NSF can also cause fibrosis of

internal organs which may lead to death. There is no effective treatment for NSF. NSF

has not been reported in patients with normal kidney function. Patients at greatest risk

for developing NSF after receiving GBCAs are those with impaired elimination of the

drug, including patients with acute kidney injury (AKI) or chronic, severe kidney

disease (with a glomerular filtration rate or GFR < 30 mL/min/1.73m2). Higher than

recommended doses or repeat doses of GBCAs also appear to increase the risk for NSF.

No un-confounded case of NSF or NSF-like symptoms have been received and/ or

reported for gadoterate meglumine in which the available clinical and histological

information is consistent with NSF according to the criteria of Cowper et al., (2007).

This is consistent with nonclinical studies suggesting that gadoterate meglumine, due to

its macrocyclic structure, exhibits the highest kinetic stability among all GBCAs and is

thus expected to have a very low propensity to release free Gd3+.

Since the start of gadoterate meglumine commercialization in 1989 over 41 milliondoses were used. A cumulative review of pharmacovigilance data from March 8, 1989to February 2013 identified 16 cases of NSF. A summary of these 16 cases is presentedin Figure 1.

Figure 1: NSF cases reported for patients having received gadoterate meglumine

More than 41 million doses sold


62

*Non qualifiable = unspecified agent received in addition to gadoterate meglumine

The causality of gadoterate meglumine was deemed doubtful in all reported cases of

NSF.

In December 2007, the EMA issued a classification of GBCAs according to their risk to

induce NSF. The opinion adopted was that the potential of a GBCA to induce NSF was

due to an increased ability to release Gd3+ ions from the chelate. Since gadoterate

meglumine has not only a macrocyclic chelate but is also charged it exhibits the highest

stability among GBCAs and hence displays the lowest risk of inducing NSF.

– Low risk: Macrocyclic chelates including gadoterate meglumine (Dotarem®),gadoteridol (ProHance®) and gadobutrol (Gadovist®).

– Medium risk: Linear ionic chelates including gadofosveset trisodium(Vasovist®), gadoxetic acid disodium (Primovist®) and gadobenate dimeglumine(Mutihance).

– High risk:a) Linear non-ionic chelates including gadoversetamide (OptiMARK®) and

Gadodiamide (Omniscan®).

b) The linear ionic chelate gadopentetate dimeglumine (Magnevist®,

Magnegita®, Marktiv®).

In september 2010 the U.S. Food and Drug Administration (FDA) issued new warnings

for using gadolinium-based contrast agents in patients with kidney dysfunction. The

FDA required changes in the drug label for gadolinium-based contrast agents (GBCAs)

to minimize the risk of nephrogenic systemic fibrosis (NSF).

16 reported cases of NSF

11 unconfirmed or doubtful cases of NSF

Due to missing information the Girardi

score cannot be applied and/or the

differential diagnoses cannot be ruled out

1

Single-

agent

9

Multiple-

agent

1 Non

qualifiable

case*

0 Single-

agent case5

Multiple-

agent

0 Non

qualifiable

case*

5 confirmed or very likely cases of NSF

Confirmed or consistent diagnosis (Girardi

score), information sufficient to rule out

the differential diagnoses


63

The revised labeling enhanced the safe use of GBCAs, by recommending that

healthcare professionals:

- Not use three of the GBCA drugs: Magnevist®, Omniscan®, and Optimark®, in

patients with acute kidney injury (AKI) or with chronic, severe kidney disease.

These three GBCA drugs are contraindicated in these patients. This is due to the

lower kinetic stability of these GBCAs and hence a highest propensity to release

free Gd3+ ions.

- Screen patients prior to administration of a GBCA to identify those with AKI or

chronic, severe, kidney disease. These patients appear to be at highest risk for

NSF.

- Use the clinical history to screen patients for features of AKI or risk factors for

chronically reduced kidney function.

Features of AKI consist of rapid (over hours to days) and usually reversible

decrease in kidney function, commonly in the setting of surgery, severe

infection, injury, or drug-induced kidney toxicity. Serum creatinine levels

and estimated GFR may not reliably assess kidney function in the setting of

AKI.

For patients at risk for chronically reduced kidney function (such as

patients over age 60 years, patients with high blood pressure, or patients

with diabetes), estimate the kidney function (GFR) through laboratory

testing.

- Avoid use of GBCAs in patients suspected or known to have impaired drug

elimination unless the need for the diagnostic information is essential and not

available with non-contrasted MRI or other alternative imaging modalities.

- Monitor for signs and symptoms of NSF after a GBCA is administered to a patient

suspected or known to have impaired elimination of the drug.

- Do not repeat administration of any GBCA during a single imaging session.

11.2.5 Deaths and other serious adverse events

During all clinical trials, 8 deaths have been reported but none of them were considered

to be related to gadoterate meglumine by both the company and the investigator (Table

23).

There were 7 deaths in the phase III trial DGD-3-44 for the evaluation of MRI with

gadoterate meglumine in the diagnosis or follow-up assessment of cerebral or spinal

tumors, involving 151 patients. One death occurred in the phase III trial DGD-3-50 for the

evaluation of MRI with gadoterate meglumine in the characterization of abdominal and

pelvic lesions, a study involving 110 patients.


64

Table 23: Summary of all deaths reported with gadoterate meglumine

Patient

Country

Clinicaltrial

Reaction Description Outcome Relationship

gadoterate

meglumine

05001

France

DGD- 3-

50

Cardiac failure Death due to adverse event No

06001

France

DGD-3-

44

Heart failure Death due to adverse event No

06005

France

DGD-3-

44

Pulmonary embolism Death due to adverse event No

02012

France

DGD-3-

44

Thrombophlebitis

Cerebral haemorrhage

Death due to adverse event No

08005

France

DGD-3-

44

Intracranial pressure increased Adverse event may have contributed to the death No

10001

France

DGD-3-

44

Post-operative haemorrhage,

Vasospasm

Adverse event may have contributed to the death No

01017

France

DGD-3-

44

Cerebral ischaemia Death due to adverse event No

03029

France

DGD-3-

44

Condition aggravated,

Metastases neoplasm

Death due to adverse event No

In addition to these 8 deaths reported in clinical trials, 3 other have been reported in the

SECURE study DGD-55-001(post-marketing study conducted by Guerbet). These 3 cases

(candida sepsis, heart failure, multi-organ failure) were not related to gadoterate

meglumine by the company and by the investigator.

Otherwise, the analysis of pharmacovigilance data (1989-2013) shows a total of 29 fatal

cases reported since the first product marketing. The cumulative incidence of fatal cases

corresponds to 0.07 cases per 100,000 patients.

In 12 fatal cases, death was most likely related to anaphylaxis. Notably however,

anaphylactic shock was clearly indicated as a reaction in only four of these cases. In

nine out of these 12 cases, cardio-respiratory reactions were the main causes leading to

death, predominantly cardiac arrhythmias, within the context of anaphylaxis. It was not

possible to elucidate to what extent cardiac arrhythmias may occur independently from

immediate hypersensitivity reactions. Hypothetically, cardiac arrhythmia may be the

most obvious and most severe manifestations of hypersensitivity reactions prompting it

to be more frequently designated as the cause of fatal outcomes instead of anaphylaxis.

Serious adverse events

In clinical studies, a total of 23 patients out of 2813 patients exposed to gadoterate

meglumine (0.8%) were known to have experienced SAEs. Among these patients 8 died

but none of the SAEs or the deaths were related to gadoterate meglumine (see above).


65

Two SAEs were considered to be possibly related to treatment (moderate

hypersensitivity and mild renal failure).

Other serious adverse events were spontaneously reported to Guerbet during a post-

marketing safety study (Maurer et al., 2012). Serious adverse events were observed in

11 of 104,033 patients (0.01%). A total of 31 symptoms all together were observed in

the 11 patients. The causal relationship with gadoterate meglumine was rated as

possible in 7 patients and doubtful in 3 patients. The causal relationship was not

reported in one patient; 10 patients recovered after treatment of the adverse events; the

outcome was unknown in one patient.

Pharmacovigilance data gathered since 1989 has evidenced the occurrence of 2379

serious adverse reactions experienced by 859 patients out of an estimated patient

exposure of over 41 million patients. This corresponds to an incidence of 2.1 cases for

100.000 patients.

General conclusion for safety data from clinical trials and post-marketing

experience:

Clinical trials:

• The clinical safety profile of gadoterate meglumine has been well

characterized during a large clinical development program (50 clinical studies

including 2813 adults and pediatric patients who received gadoterate

meglumine).

• The most frequently reported related AE were nausea, headache and injection

site pain.

• 29 SAEs (including fatalities) were observed in 23 (0.8%) patients treated

with gadoterate meglumine. Among SAEs in gadoterate meglumine-treated

patients, 2 were considered to be possibly related to treatment (moderate

hypersensitivity and mild increase in serum creatinine) and none of them were

fatal.

Observational Post-marketing studies: Six post-marketing observational

studies with more than 147,000 patients provided reassuring additional safety

data for both adult and pediatric populations.

Pharmacovigilance database: Accumulated post-marketing safety data, based

on approximately 41 million doses, demonstrate a well-characterized safety

profile consistent with the AEs observed in clinical studies. Most reactions

were reported in the system organ classes of Skin and subcutaneous tissue

disorders (28.0%), Gastrointestinal disorders (18.9%) and Respiratory, thoracic

and mediastinal disorders (12.3%).

No cases of NSF or NSF-like symptoms have been observed in clinical studies. No

single-agent/un-confounded cases of NSF were reported for gadoterate meglumine in


66

the post-marketing experience, according to an assessment based on available clinical

and histological information (Girardi et al., 2011).

11.3 Gadoterate meglumine safety profile in special groups and situations

Subgroup analysis of safety was done according to patient demographics in order to

determine risk populations. Treatment related AEs were evaluated by subgroups of age,

gender, race, dose, cardiac function, renal function, hepatic function, diabetes, allergic

history and for potential safety differences. No particular subgroup appeared to be at an

increased risk of adverse effects of drug treatment. Furthermore, adverse event data

across all studies showed that gadoterate meglumine did not display toxicity to hepatic,

renal, or cardiovascular systems.

11.3.1 Patients with renal impairment

A potential increased risk of toxicity is expected in patients with impaired renal function

due to the prolonged elimination of the substance. However results from both animal

and human studies indicate that gadoteric acid can be removed via dialysis.

In the pharmacokinetic study DGD-3-28, the general clinical and biological safety of

gadoterate meglumine was assessed as good in the 8 evaluated renal failure subjects.

In the trial by Bellin et al., 1992, clinical and biological tolerance of gadoterate

meglumine was studied in patients with chronic renal failure (glomerular filtration rate

60 mL/min). Twenty patients were randomized into two groups. In the control group,

spin-echo T1-and T2-weighted images of the kidneys were obtained without injection of

gadoterate meglumine and in the DOTA-group, patients received 0.1 mmol/kg of

gadoterate meglumine. Clinical data, serum creatinine, and laboratory parameters were

estimated before, 24 and 48 hr after MRI. No adverse reaction was reported after

injection of gadoterate meglumine. Mean serum creatinine and glomerular filtration rate

remained unchanged in both groups. For five patients in the control group and three

patients in the DOTA-group the serum creatinine levels increased more than 10% and

less than 25% respectively. No evidence of nephrotoxicity was observed with gadoterate

meglumine in patients with chronic renal failure.

Two published studies not sponsored by Guerbet (Hanna et al., 1991, Helenon et al.,

1992) showed that contrast enhanced MRI and MRA with gadoterate meglumine

permitted a comprehensive assessment of renal transplants without inducing

nephrotoxicity. Furthermore, other published studies also observed no deterioration in

renal function and no pain during injection with gadoterate meglumine (Brillet et al.,

2003; Geoffroy et al., 2001).


67

However as a precautionary measure, gadoterate meglumine is contra-indicated for

severe renally impaired patients and caution is required in patients with mild to

moderate renal insufficiency.

Two recent Guerbet sponsored studies conducted in renally impaired patients are

summarised below:

RESCUE study (DGD-44-044)

This open label, multicentre, non-randomized comparative trial was aimed at assessing

in renal insufficient patients, the frequency of contrast-induced nephropathy after

gadoterate meglumine-enhanced MRI, in comparison with the frequency of nephropathy

observed after unenhanced MRI. The primary endpoint was the percentage of patients

presenting nephrotoxicity as evidenced by a significant increase in creatinine level

relative to baseline (at least 25%) at 72±24h after injection. Only one single case of

nephrotoxicity was observed with gadoterate meglumine in this study, out of 75 patients

injected with gadoterate meglumine. This study showed that gadoterate meglumine-

enhanced MRI is not inferior to unenhanced-MRI in terms of nephrotoxicity and that its

safety profile in this patient population is good.

Dialysability study (DGD-44-054)

In order to estimate whether gadoterate meglumine can be effectively removed by

hemodialysis, a monocentric, non-comparative, non-randomized, open-label clinical

trial was carried out with 10 patients with end-stage renal failure requiring

haemodialysis. This study showed that gadoterate meglumine can be effectively

removed from blood by hemodialysis and that its use is therefore safe and well-

tolerated.

11.3.2 Patients with cardiovascular risk

Gadoterate meglumine is intended to be used in doses up to 0.3 mmol/kg in

angiographic indications, i.e. in a population with a high risk for cardiovascular events.

In pre-clinical studies performed in vitro (Purkinje fibres) and in vivo (several studies on

normal and sensitized animals), there was no signal of any potential of gadoterate

meglumine to induce QT/QTc prolongation even at high doses/concentrations (far

above the maximum human dose or human plasma Cmax).

The ECG safety of gadoterate meglumine has been evaluated in 18 patients during two

controlled clinical trials performed by Guerbet (DGD-3-6; DGD-3-28). No abnormality

was found. Also, a Japanese pharmacokinetic study (Matsuyama et al., 1994) evaluated

the electrocardiographic safety of gadoterate meglumine in 20 healthy volunteers at

doses 0.05 to 0.3 mmol/kg (5 subjects per dose) and no abnormality was reported.


68

In addition, the pharmacokinetic study DGD-44-039 involved 40 patients suffering from a

cardiac disease. Patients received a triple dose of gadoterate meglumine and 11 ECGs

were performed for each patient for each period. The tolerance and safety of gadoterate

meglumine was confirmed, as there was no clinically significant abnormality in the

laboratory safety and vital sign results. Thirty three out of 40 included patients

presented no treatment emergent adverse event. All adverse events were mild to

moderate in intensity and resolved during the study. Also, the ECG parameter analyses

showed that gadoterate meglumine had no effect on QT or QTc interval or other ECG

parameters after bolus intravenous administration of the highest therapeutic cumulative

dose of 0.3 mmol/kg to patients.

11.3.3 Children below 2 years old

Three non-randomized trials were conducted by Guerbet in CNS imaging indication

(DGD-3-16, DGD-3-15, DGD-3-29), involving 99 children who received gadoterate

meglumine.

Among them, 7 children were below 2 years and one adverse event was reported in a

female child (1.8 year-old). This child was pre-medicated with sodium hydroxybutyrate

and received 2 mL of gadoterate meglumine at 1 mL/min. This child experienced a brief

episode of mild vomiting 20 minutes after Gadoterate meglumine injection. The event

was considered as not related to gadoterate meglumine by the reporter.

In addition to the 3 clinical trials, a total of 6 post-marketing studies (Maurer et al.,

2012; Emond et al., 2011; Ishiguchi e al., 2010; Briand et al., 1992; Neiss et al., 1991;

and SECURE DGD-55-001) provide safety results on a population of 234 children below

2 years and are summarized below (Table 24).

Table 24: Demography and safety results in patients below 2 years old.

PMS Gender Mean age

(years or

months)

Type of examination Children

with risk

factors

Mean

injected

volume*

Patients

with at

least one

adverse

event

German PMS

(Maurer et

al., 2012)

2 males

7 females

1 unknown

8.7±3.2 monthsNeurological =6

Musculoskeletal =30 4.2 ±1.6ml 0

Japanese

PMS

(Ishiguchi et

al., 2010)

2 females Child#1: 0.1 y.

Child#2: 1.8 y.

Child#1= neurological

Child#2: chest0

Child#1=

1mL

Child#1=2mL

0

French PMS

(Emond

2011)

Male: 58

(55.8%)

Female: 45

(43.3%)

8.1 ±5.2

months

(range: 3 days-

18 months)

Primary diagnosis=

50.8%

Evaluation of the

extension of a known

condition= 31.7%

0

Median: 2

mL

(range: 0.6 –

4 mL)

0


69

1 unknown Postoperative control=

11.1%

Follow-up= 6.3%

SECURE

(DGD-55-

001)

Male: 44

(51.2%)

Female: 42

(48.8%)

0.8 ±0.4 years

(range: 0-1.9)

CNS: 70 (84.1%)

Whole-body: 6 (7.0%)

Muskulosqueletal: 7

(8.1%)

Angiography: 1 (1.2%)

Others: 2 (2.3%)

Impaired

renal

function

(creatinine

clearance <

60 ml/min):

2 (2.3%)

3.8

(range: 0.6-

25)

0

French PMS

(Briand et

al., 1992)

26 children

(6.5% of 402

were below 2

years)

Not availableCNS in most cases Not

available

Mean dose=

0.22 ml/kg0

French PMS

(Neiss et al.,

1991)

6 (5 females

and 1 male)

Range: 1 to 1.5

yearsCNS

Not

available1.6 to 3 ml 0

Total number

of patients < 2 years234

When considering children below 2 years of age, the 3 clinical trials and all PMS

including more than 230 children reported no related adverse event.

Otherwise, when analyzing the pharmacovigilance data up to December, 31st, 2013,

there were 8 reports in pediatric population ≤ 2 years (1 girl and 7 boys) which

corresponds to 10 adverse drug reactions.

Two cases were serious and 6 were non-serious. There were no fatal outcomes.

Out of 10 adverse drug reactions, the most frequent reactions were associated with SOC

Injury, poisoning and procedural complications (4/10) which include medication errors

and overdose, followed by General disorders and administration site conditions (3/10).

The majority of cases were associated with various medication errors. The most

frequently reported terms were Overdose and Accidental overdose (3 cases), but no

associated adverse events were reported in these cases. This is followed by

Extravasation (2 cases).

The only serious event which is not associated with medication errors describes Heart

rate decrease followed by spontaneous recovery.

The analysis of the pharmacovigilance data shows that the reactions observed in patients

≤ 2 years are most frequently due to medication errors such as overdose or

extravasation. Attention is required in the vulnerable population, but no particularly

different pattern of adverse reaction or a safety concern has been identified. Reactions

most frequently reported in the older age groups, such as hypersensitivity/anaphylactic

reactions have not been reported.


70

In conclusion, the 3 clinical studies and the 6 prospective post-marketing observational

studies that included a total of 241 pediatric patients less than 2 years of age provided a

good level of efficacy and safety, consistent with those found for adult patients and

pediatric patients older than 2 years of age. Gadoterate meglumine has therefore a very

good overall safety profile in children below 2 years.

11.3.4 Use in pregnancy

Animal studies showed no teratogenic effects. Furthermore, during the post-marketing

surveillance of gadoterate meglumine, some pregnancies have been followed and they

did not show any teratogenic effect of the product. Nevertheless these data are limited in

number and no clinical study has been conducted with pregnant women. Therefore

gadoterate meglumine should only be administered during pregnancy if strictly

necessary.

Experimental data show that only small quantities of gadoterate meglumine are secreted

in breast milk (<1%) but no clinical data are available on the patient. Consequently it is

advisable to interrupt breastfeeding temporarily for several days following the

administration of gadoterate meglumine.

In the post-marketing pharmacovigilance setting, there were 140 reports of drug

exposure during pregnancy cumulatively. Based on available information, pregnancy

cumulative experience did not provide any signal. The cases accumulated during the

reporting period did not provide relevant information to modify the benefit risk-balance.

General conclusions for safety in special groups:

No dose adjustment is required for any special groups of patients. In patients with

cardiovascular risks, gadoterate meglumine does not induce any modification of ECGs

nor does it extend QT/QTc intervals. In children safety data does no differ from the

adult population, and the use of gadoterate meglumine during pregnancy did not

evidence a particular risk for the fetus or the mother.

11.4 Gadoterate meglumine safety: laboratory tests, and vital signs

11.4.1 Laboratory evaluations

Clinical laboratory evaluations were available in 21 trials (973 patients), including 4

pharmacokinetic studies (90 patients) and a study with children (29 patients), involving

a total of 1092 patients. Subject evaluations included clinical chemistry, hematology,

and urinalysis, which were performed on the patients usually at the pre- and post-

treatment periods (at various time points post injection, up to 30 days depending on the

study).

In general, laboratory data showed no remarkable variations in the mean values of

single blood and urine parameters over the course of the study. Most individual


71

fluctuations remained within the normal range and were not associated with other

simultaneous changes in laboratory parameters. Baseline characteristics and

demographic analysis showed no effect of gadoterate meglumine on the subgroups that

were analyzed. No substantial changes were noted in the pediatric population from

baseline to follow up.

11.4.2 Vital signs

Vital signs were assessed in the 2 pivotal studies and in 15 other supportive studies on a

total number of 1547 patients. No clinically significant effects were observed for vital

signs (blood pressure, heart rate, respiratory rate) following gadoterate meglumine

injection. There were no clinically relevant trends or unexpected fluctuations in vital

sign measurement (heart rate, blood pressure) among gadoterate meglumine treated

patients.

The ECG safety of gadoterate meglumine has been evaluated in 18 patients during two

controlled clinical trials sponsored by Guerbet (study DGD-3-6: 6 patients; study DGD-

3-28: 12 patients) as described in section 11.3.2. No abnormality was found. Also, the

Japanese pharmacokinetic study (Matsuyama et al., 1994) evaluated the

electrocardiographic safety of gadoterate meglumine in 20 healthy volunteers at doses

0.05 to 0.3 mmol/kg (5 patients per dose) and no abnormality was reported.

Conclusions for lab tests/vital signs parameters:

Hematology and biochemistry evaluations from 21 studies showed no remarkable

changes from baseline after injection of gadoterate meglumine. Concerning vital signs,

the mean values showed minimal fluctuations from pre-procedure at each time point

post injection. These changes observed in vital sign parameters were attributed to

underlying conditions or procedure-related stress, which is commonly expected with

this type of MRI examination.

11.5 Gadoterate meglumine comparative safety data

11.5.1 Clinical studies with gadoterate meglumine conducted by Guerbet (n=50)

In clinical studies sponsored by Guerbet, among the 2822 patients injected with

gadoterate meglumine, only 271 patients (9.6%) experienced AEs. 113 patients (4.0%)

had 153 AEs that were considered to be related to treatment. By comparison, among

372 patients receiving a comparator (Magnevist®/Gadovist®), 51 patients (13.7%)

experienced AEs, with 36 patients (9.7%) having related AEs. Thus the rate of patients

with AEs deemed related to Comparators (9.7%) was twice the rate of gadoterate

meglumine (4.0%).


72

The most common related AEs in gadoterate meglumine-treated patients were nausea

(0.6%), headache (0.4%), and injection site pain (0.4%). By contrast, the most common

related AEs in patients treated with a comparator were headache (4.3%), injection site

pain (1.3%), and nausea (1.1%). Although the most common related AEs were similar

for gadoterate meglumine and its comparators, their respective frequency was at least

twice superior in the comparator group.

Twelve severe AEs in 11 patients (0.1%) were related to gadoterate meglumine,

including headache (in 3 patients), nausea (in 2 patients) and injection site pain (1

patient). By contrast, 7 patients (1.9%) treated with Magnevist®/Gadovist® had severe

related AEs, including headache, nausea, abdominal pain, wheezing, and feeling hot.

The clinical studies conducted by Guerbet evidenced a major advantage of gadoterate

meglumine when compared to comparators concerning the time of onset and duration of

treatment-related AEs. For gadoterate meglumine-related AEs, the median time of onset

was 5 minutes and median duration was 15 minutes. By comparison, in patients treated

with Magnevist®or Gadovist® the median time to onset for related AEs was 2 minutes

and median duration was 4 hours. This corresponds to an onset of related AEs 7-fold

faster and a duration of related AEs 16-fold longer for Magnevist®/other Gd-treated

patients when compared to gadoterate meglumine-treated patients.

In the double-blind randomized trial by Brugières et al. (1994) on 299 patients (DGD-3-

31), gadoterate meglumine was compared to Magnevist®. Adverse reactions concerned

17.3% of patients in the gadoterate meglumine group and 19.3% of those in the

Magnevist group (difference not statistically significant). The adverse reactions most

often involved headache, nausea and local reactions. In the case of headache in

particular, it is sometimes difficult to draw distinction between the role played by

underlying pathology and that of the contrast medium or investigation conditions

(patient confined for a varying period of time in a noisy area). Nonetheless, adverse

reactions were minor in all cases and that they most often abated without treatment. In

this study the rates of adverse reactions were higher than expected due to the use of

three safety questionnaires that promoted over-reporting of adverse reactions.

11.5.2 Gadoterate meglumine published trials

The comparison of the respective safety profile of gadoterate meglumine, Magnevist®

and Omniscan® has been performed in 3 published randomized, double-blind trials

(Oudkerk et al., 1995; Nielsen et al., 2010; Attenberger et al., 2010).

Nielsen YW, Eiberg JP, Løgager VB, Just S, Schroeder TV, Thomsen HS. Whole-bodymagnetic resonance angiography with additional steady-state acquisition of the infrageniculararteries in patients with peripheral arterial disease. Cardiovasc Intervent Radiol. 2010Jun;33(3):484-91

OudkerkThe results of these 3 trials showed that gadolinium chelates are safe agents

and that their safety profiles are similar.


73

General conclusions

The current paradigm stipulates that GBCAs adverse reactions are at least partially due

to a competition between Ca2+ ions and Gd3+ ions – released from the chelate - which

share similar properties such as its radius. Dissociated gadolinium ions have the ability

to interfere with calcium ions thus prompting the possible occurrence of adverse

reaction – among which NSF which can occur in renally impaired patients. Gadoterate

meglumine superiority in terms of safety is due to its unique chemical structure: a

macrocyclic and ionic gadolinium complex, making it the most stable known GBCA. Its

improved safety profile, when compared to non-ionic linear chelates, results from its

highest kinetic and thermodynamic stability among all GBCAs. These parameters have

been identified as critical to reducing the risk of disassociated gadolinium in vivo and in

vitro. Such particular chemical structure and the safety benefits associate with it support

the inclusion of gadoterate meglumine in the WHO list of essential medicines.

References on safety

Attenberger UI, Haneder S, Morelli JN, Diehl SJ, Schoenberg SO, Michaely HJ.Peripheral arterial occlusive disease: evaluation of a high spatial and temporalresolution 3-T MR protocol with a low total dose of gadolinium versus conventionalangiography. Radiology. 2010 Dec;257(3):879-87.

Baleriaux D, Matos C, De Greef D. Gadodiamide injection as a contrast medium forMRI of the central nervous system: a comparison with gadolinium-DOTA.Neuroradiology 1993; 35(7): 490-494.

Beaudouin E, Kanny G, Blanloeil Y, Guilloux L, Renaudin JM, Moneret-Vautrin DA.Anaphylactic shock induced by gadoterate meglumine (Dotarem). Eur Ann Allergy ClinImmunol 2003; 35(10): 382-5.

Bellin MF, Deray G, Assogba U, et al. Dotarem: evaluation of its renal tolerance inpatients with chronic renal failure. Magn Reson Med 1992; 10: 115-118.

Briand Y, Neiss AC, Vitry A. Efficacy and safety of the macrocyclic complexGadoterate megluminein children: results of a multi-centre study. 29th congress of theEuropean Society of Pediatric Radiology 1992, Budapest: R12.

Brillet PY, Vayssairat M, Tassart M, Deux JF, Bazot M, Allaire E, Boudghene F.Gadolinium-enhanced MR angiography as first-line preoperative imaging in high-riskpatients with lower limb ischemia. J Vasc Interv Radiol. 2003 Sep;14 (9 Pt 1):1139-45.

Bruder O, Schneider S, Detlev Nothnagel D. Acute adverse reactions to gadolinium-based contrast agents in CMR. Multicenter experience with 17,767 patients from theEuroCMR registry. JACC: cardiovascular imaging 2011; 4(11): 1171-1176.

Brugieres P, Gaston A, Degryse HR, et al. Randomised double blind trial of the safetyand efficacy of two gadolinium complexes (Gd-DTPA and Dotarem). Neuroradiology


74

1994; 36(1): 27-30.

Chanalet S, Masson B, Boyer L, et al. Etudes comparatives de la tolérance dugadodiamide, du gadopentetate de diméglumine et du gadotérate de méglumine au coursd'un examen IRM du système nerveux central. J Radiol 1995; 76(7): 417-421.

Cowper SE. Nephrogenic Systemic Fibrosis: a review and exploration of the role ofgadolinium. Advances in Dermatology 2007; 23: 131-154.

Cuenod CA, Bellin MF, Bousquet JC, Duron A, Auberton E, Mazoyer BM, Khayat D,Opolon P, Grellet J. MRI of liver tumors using gadolinium-DOTA: prospective studycomparing spin-echo long TR-te sequence and CT. Magn Reson Imaging.1991;9(2):235-45.

De Ridder F, De Maeseneer M, Stadnik T, Luypaert R, Osteaux M. Severe adversereactions with contrast agents for magnetic resonance: clinical experience in 30,000 MRexaminations. JBR-BTR. 2001; 84(4): 150-62.

Emond S., Brunelle F. Gd-DOTA administration at MRI in children younger than 18months of age: immediate adverse reactions. Pediatr Radiol 2011; 41(11): 1401-1406.

Geoffroy O, Tassart M, Le Blanche AF, Khalil A, Duédal V, Rossert J, Bigot JM,Boudghène FP. Upper extremity digital subtraction venography with gadoteratemeglumine before fistula creation for hemodialysis. Kidney Int 2001; 59(4): 1491-7.

Girardi M, Kay J, Elston DM, Leboit PE, Abu-Alfa A, Cowper SE. Nephrogenic systemicfibrosis: clinicopathological definition and workup recommendations. J Am AcadDermatol. 2011 Dec;65(6):1095-1106.e7.

Hanna S, Helenon O, Legendre C, et al. MR imaging of renal transplant rejection. ActaRadiol 1991; 32(1): 42-46.

Helenon O, Attlan E, Legendre C, et al. Gd-DOTA-enhanced MR imaging and colorDoppler US of renal allograft necrosis. Radiographics 1992; 12(1): 21-33.

Herborn CU, Honold E, Wolf M, et al. Clinical safety and diagnostic value of thegadolinium chelate gadoterate meglumine (Gd-DOTA). Investigative Radiology 2007; 42(1): 58-62.

Ishiguchi T., Takahashi S. Safety of gadoterate meglumine (Gd-DOTA) as a contrastagent for magnetic resonance imaging results of a post-marketing surveillance study inJapan. Drugs R&D 2010; 10 (3): 133-145.

Jung JW, Kang HR, Kim MH, et al. Immediate Hypersensitivity Reaction toGadolinium-based MR Contrast Media. Radiology 2012; 264 (2): 414-422.

Kirchin MA, Runge VM. Contrast agents for magnetic resonance imaging: safety update.Top Magn Reson Imaging 2003; 14(5): 426-35.

Laissy JP, Debray MP, Menegazzo D, et al. Prospective evaluation of peripheral arterial


75

occlusive disease by 2D MR subtraction angiography. JMRI 1998; 8: 1060-1065.

Li A, Wong CS, Wong MK, et al. Acute adverse reactions to magnetic resonancecontrast media – gadolinium chelates. BJR 2006; 79, 368-371.

Matsuyama M, Ota Y, Nezu H, et al. Phase I clinical trial of the MRI contrast agent EK-5504 (Gd-DOTA) (translation from japanese). Shinryo to shin'yaku 1994; 31(3): 513-521.

Maurer M, Heine O, Wolf M, et al. Tolerability and diagnostic value of gadoteric acidin the general population and in patients with risk factors: Results in more than 84,000patients. Eur J Radiol 2012; 81(5): 885-890.

Neiss AC, Le Mignon MM, Vitry A, et al. Efficacité et tolérance du DOTA-Gd lorsd'une enquête multricentique européenne. Rev Im Med 1991; 3: 383-387.

Nielsen YW, Eiberg JP, Løgager VB, Just S, Schroeder TV, Thomsen HS. Whole-bodymagnetic resonance angiography with additional steady-state acquisition of theinfragenicular arteries in patients with peripheral arterial disease. Cardiovasc InterventRadiol. 2010 Jun;33(3):484-91

Oudkerk M, Sijens PE, Van Beek EJ, et al. Safety and efficacy of Gadoteratemeglumine (Gd-DOTA) versus Magnevist(Gd-DTPA) in magnetic resonance imagingof the central nervous system. Invest Radiol 1995; 30(2): 75-78.

Reimer P, Vosshenrich R. Contrast agents in MRT. Substance, effects, pharmacologyand validity. Radiologe 2004; 44(3): 273-83.

Runge VM. Safety of approved MR contrast media for intravenous injection. J MagnReson Imaging 2000; 12(2): 205-13. Review.

12. Summary of available data on comparative cost and cost-

effectiveness within the pharmacological class or therapeutic

groupNo data are available for diagnostic agents.


76

13. Summary of regulatory status of the medicine (in various

countries)

The registration file of gadoterate meglumine (Dotarem®) was first submitted and

registered in France on 08/03/1989.

Following this initial registration, several countries have subsequently granted local

Marketing Authorization.

Gadoterate meglumine is registered in 82 countries all over the world under the brand

name of gadoterate meglumine (excepted in Japan where it is registered under the name

of Magnescope®).

The indications approved in all countries are magnetic resonance imaging for: brain and

spinal cord diseases, diseases of the vertebral column, and other whole body diseases

(including angiography), except in Australia where the angiography indication has not

been approved, and in the USA where only the indication for MRI in brain, spine and

associated tissues is approved.

Africa

Gadoterate meglumine is registered in 8 countries: Algeria, Cameroon, Cote d’Ivoire,

Egypt, Morocco, Senegal, South Africa, and Tunisia.

Asia

Gadoterate meglumine is registered in 13 countries: China, Hong Kong, India,

Indonesia, Japan, Malaysia, Nepal, Philippines, Singapore, South Korea, Taiwan,

Thailand, and Vietnam.

Europe

Gadoterate meglumine is registered in 35 countries: Austria, Belgium, Bosnia and

Herzegovina, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland,

France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg,

Macedonia, Montenegro, The Netherlands, Norway, Poland, Portugal, Romania,

Russian Federation, Serbia, Slovakia, Slovenia, Switzerland, and Turkey.

Latin America

Gadoterate meglumine is registered in 15 countries: Argentina, Bolivia, Chile,

Colombia, Costa Rica, Ecuador, El Salvador, Guatemala, Mexico, Panama, Paraguay,

Peru, Uruguay, and Venezuela.

Middle East


77

Gadoterate meglumine is registered in 8 countries: Iran, Iraq, Israel, Jordan, Kuwait,

Lebanon, Saudi Arabia, and United Arab Emirates.

North America

Gadoterate meglumine is registered in 1 country: the United States of America.

Oceania

Gadoterate meglumine is registered in 2 countries: Australia, New Zealand.

14. Availability of pharmacopoeial standards

Gadoterate meglumine is not included in any pharmacopoeia.

15. Proposed text that could be included in a revised WHO Model

Formulary

Gadoterate meglumine

Solution for injection: 5, 10, 15, 20 ml vial

Uses: Magnetic resonance imaging for brain and spinal cord diseases, diseases of thevertebral column, and other whole body diseases (including angiography).

Contraindications: Hypersensitivity to gadoteric acid, meglumine or any medicinalproducts containing gadolinium.

Precautions: usual precautionary measures for MRI examination; hypersensitivity;impaired renal function (Appendix 1); impaired hepatic function (perioperative livertransplantation period); the elderly (screen for renal dysfunction); neonates and infants(immature renal function – same precaution as for impaired renal function – seeAppendix 1); CNS disorders (precaution in patients with a low seizure threshold);pregnancy (Appendix 2) and breastfeeding (Appendix 3).

Dose:

Brain and spinal cord MRI: 0.1 to 0.3 mmol/kg BW; in patients with brain tumor, anadditional dose of 0.2 mmol/kg BW after administration of 0.1 mmol/kg BW mayimprove tumor characterization and facilitate therapeutic decision-making.

MRI of other organs and Angiography: 0.1 mmol/kg. In angiography, a second injectionof 0.1 mmol/kg may be justified; if anticipated, use of 0.05 mmol/kg for each dose maybe of benefit, depending on the imaging equipment available.

Pediatric population: 0.1 mmol/kg for all indications except angiography.

Adverse effects: Most adverse effects are contributive signs and symptoms ofhypersensitivity and anaphylactic reactions. Very common: paresthesia, headache;nausea, vomiting, pruritus, erythema, rash, feeling hot, feeling cold, injection site pain.Uncommon: hypersensitivity, anaphylactic reaction, anaphylactoid reaction. Rare:dysgeusia, urticaria, hyperhidrosis. Very rare: agitation, anxiety, coma, convulsion,


78

syncope, presyncope, dizziness, parosmia, tremor, conjunctivitis, ocular hyperemia,vision blurred, lacrimation increased, eyelid edema, cardiac arrest, bradycardia,tachycardia, arrhythmia, palpitations, hypotension, hypertension, vasodilatation, pallor,respiratory arrest, pulmonary edema, bronchospasm, laryngospasm, pharyngeal edema,dyspnea, nasal congestion, sneezing, cough, dry throat, diarrhoea, abdominal pain,salivary hypersecretion, eczema, angioedema, muscle contracture, muscular weakness,back pain, malaise, thoracic pain, chest discomfort, fever, chills, face edema, asthenia,injection site discomfort, injection site reaction, injection site edema, injection siteextravasation, injection site inflammation (in case of extravasation), injection sitenecrosis (in case of extravasation), superficial phlebitis, decreased oxygen saturation.

Nephrogenic Systemic Fibrosis (NSF) has been associated with Gadolinium Based

Contrast Agents in patients with acute or chronic severe renal impairment (GFR < 30

ml/min/1.73m2). To date, no confirmed NSF has been associated with Gadoteric acid

single use.

Appendix 1: renal impairment: see Summary of product characteristics (annex 1).

Appendix 2: pregnancy: see Summary of product characteristics (annex 1).

Appendix 3: breastfeeding: see Summary of product characteristics (annex 1).


79

Annex 1: Summary of product characteristics (France)

1. NAME OF THE MEDICINAL PRODUCT

Dotarem 0.5 mmol/mL, solution for injection in prefilled syringes

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Per 100 mL of solution:

Gadoteric acid* ........................................................................................................27.932 g

corresponding to DOTA.................................................................................20.246 g

corresponding to gadolinium oxide .................................................................9.062 g

* Gadoteric acid: complex gadolinium of 1, 4, 7, 10 tetraazacyclododecane-N,N’,N’’,N’’’ tetraaceticacid.

Contrast agent concentration: 0.5 mmol/mL

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection in prefilled syringes.

Clear, colourless to pale yellow solution.

Osmolality: 1350 mOsm.kg-1

Viscosity at 20°C: 3.2 mPa.s

Viscosity at 37°C: 2.0 mPa.s

pH: 6.5 to 8.0

4. CLINICAL PARTICULARS

4.1. Therapeutic indications

This medicinal product is for diagnostic use only.

Magnetic resonance imaging for:

cerebral and spinal disease, diseases of the vertebral column, and other whole body pathologies (including angiography).

4.2. Posology and method of administration

Posology

The recommended dose is 0.1 mmol/kg, i.e. 0.2 mL/kg, in adults, children and infants.

In angiography, depending on the results of the examination being performed, a second injection maybe administered during the same session if necessary.

In some exceptional cases, as when confirming isolated metastasis or detecting leptomeningealtumours, a second injection of 0.2 mmol/kg can be administered.

Special populations

Impaired renal function


80

Dotarem should only be used in patients with severe renal impairment (GFR < 30 mL/min/1.73m2) andin patients in the perioperative liver transplantation period after careful benefit/risk assessment and ifthe diagnostic information is essential and not available with non-enhanced MRI (see section 4.4).

If it is necessary to use Dotarem, the dose should not exceed 0.1 mmol/kg body weight. More thanone dose should not be used during a scan. Because of the lack of information on repeatedadministration, Dotarem injections should not be repeated unless the interval between injections is atleast 7 days.

Paediatric population

Neonates up to 4 weeks of age and infants up to 1 year of age

Due to immature renal function in neonates up to 4 weeks of age and infants up to 1 year of age,Dotarem should only be used in these patients after careful consideration, at a dose not exceeding 0.1mmol/kg body weight. More than one dose should not be used during a scan. Because of the lack ofinformation on repeated administration, Dotarem injections should not be repeated unless the intervalbetween injections is at least 7 days.

Dotarem is not recommended for angiography in children under the age of 18 because of insufficientdata on efficacy and safety in this indication.

Elderly (65 years of age and above)

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

Method of administration

The product must be administered by strict intravenous injection.

4.3. Contraindications

History of hypersensitivity to gadoteric acid or to gadolinium contrast agents or to meglumine.

4.4. Special warnings and precautions for use

Administer only by intravenous injection.

Gadoteric acid must not be injected via the subarachnoid (or epidural) route.

There is always a risk of hypersensitivity regardless of the dose injected.

4.4.1 Warnings

All MRI contrast agents can cause minor or major hypersensitivity reactions that may be life-threatening. These hypersensitivity reactions may be either allergic (described as anaphylacticreactions when serious) or non-allergic. They may be immediate (within 60 minutes) or delayed (up to7 days). Anaphylactic reactions occur immediately and can be fatal. They are independent of the dose,can occur after even the first dose of the product, and are often unpredictable.

There is a risk of hypersensitivity whatever the dose injected.

Emergency resuscitation equipment must be immediately available due to the risk of a major reaction.

Patients who already experienced a reaction during previous administration of a gadolinium-containingMRI contrast agent are at higher risk for another reaction to the same or even a different contrastagent, and consequently they are considered to be subjects at risk.

Injection of gadoteric acid may exacerbate pre-existing asthma. In patients with uncontrolled asthma,the decision to administer gadoteric acid must be made after a careful assessment of the benefit-to-risk ratio.

As with iodinated contrast agents, hypersensitivity reactions may be more difficult to treat in patientstaking beta blockers, particularly if they are asthmatic. These patients may be refractory to standardtreatments for hypersensitivity reactions using beta-stimulants.

4.4.2 Precautions for use


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4.4.2.1. Hypersensitivity to MRI contrast agents

Before the examination:

identify subjects at risk in a precise interview on their history. Corticosteroids and H1antihistamines have been proposed as premedication in patients at greatest risk forhypersensitivity reactions (patients with known hypersensitivity to a contrast agent). However, theydo not prevent the occurrence of serious or fatal anaphylactic shock.

Throughout the examination, maintain:

medical monitoring an indwelling intravenous catheter.

After the examination:

After contrast agent administration, the patient must be kept under observation for at least 30minutes, as most serious adverse reactions occur within this time period.

The patient must be warned of the possibility of delayed reactions (for up to 7 days) (see section4.8).

4.4.2.2 Impaired renal function

Prior to administration of gadoteric acid, it is recommended that all patients are screened for renal dysfunction by obtaining laboratorytests.

There have been reports of nephrogenic systemic fibrosis (NSF) associated with use of somegadolinium-containing contrast agents in patients with acute or chronic severe renal impairment (GFR< 30 ml/min/1.73m2). Patients undergoing liver transplantation are at particular risk since theincidence of acute renal failure is high in this group. As there is a possibility that NSF may occur withgadoteric acid, it should therefore only be used in patients with severe renal impairment and inpatients in the perioperative liver transplantation period after careful risk/benefit assessment and if thediagnostic information is essential and not available with non-contrast enhanced MRI.

Haemodialysis shortly after gadoteric acid administration may be useful at removing gadoteric acidfrom the body. There is no evidence to support the initiation of haemodialysis for prevention ortreatment of NSF in patients not already undergoing haemodialysis.

4.4.2.3 Neonates and infants

Due to immature renal function in neonates up to 4 weeks of age and infants up to 1 year of age,gadoteric acid should only be used in these patients after careful consideration.

In neonates and infants, the required dose must be administered manually.

Depending on the amount of gadoteric acid to be administered to the child, it is preferable to use vialsof gadoteric acid and a disposable syringe of appropriate volume to obtain a more precise injectionvolume.

4.4.2.4 Elderly

As the renal clearance of gadoteric acid may be impaired in the elderly, it is particularly important toscreen patients 65 years of age and older for an eventual renal dysfunction.

4.4.2.5 Central nervous system disorders

Patients with a history of seizures are at higher risk for seizures.

Combinations requiring caution

Beta-blockers, vasoactive substances, angiotensin-converting enzyme inhibitors, angiotensin receptorantagonists: these medicinal products decrease the efficacy of the mechanisms of cardiovascularcompensation for blood pressure disorders. The physician must be informed before injection ofgadolinium complexes and resuscitation equipment must be on hand.


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4.5. Interaction with other medicinal products and other forms of interaction

Interactions with other medicinal products have not been reported. No formal studies on interactionshave been carried out.

4.6. Pregnancy and lactation

Pregnancy

There are no data on the use of gadoteric acid in pregnant women. Preclinical studies have notprovided direct or indirect evidence of deleterious effects with respect to reproductive toxicity (seesection 5.3.). Gadoteric acid should not be used during pregnancy unless the patient's clinical situationrequires administration of the product.

Breast-feeding

Gadolinium containing contrast agents are excreted into breast milk in very small amounts (seesection 5.3). At clinical doses, no effects on the infant are anticipated due to the small amountexcreted in milk and poor absorption from the gut. The physician and breast-feeding mother shoulddecide whether to continue breast-feeding or to interrupt it for 24 hours following administration ofgadoteric acid.

4.7. Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8. Undesirable effects

During clinical studies on 1,941 patients, 3.6% of them experienced an adverse reaction related toadministration of gadoteric acid, the most common being pain and sensations of heat or cold at theinjection site and nausea.

Adverse reactions related to the use of gadoteric acid are generally mild to moderate and aretransient.

During clinical trials, headache and paresthesia were the very commonly observed (> 1/10), andnausea, vomiting and skin reactions such as eruptions and pruritus were common (> 1/100 to < 1/10).

The adverse reactions most commonly reported during the administration of gadoteric acid since it hasbeen marketed are nausea, vomiting, pruritus and hypersensitivity reactions.

The effects most commonly observed during hypersensitivity reactions are skin rashes, which can belocalized, extensive or generalized. These reactions are usually immediate (during the injection or overthe hour following the start of the injection) or sometimes delayed (one hour to several days after theinjection), and then appear in the form of adverse skin reactions.

Immediate reactions comprise one or several, successive or concomitant effects, usually includingskin reactions, respiratory and/or cardiovascular disorders, which may be the first signs of shock,which can rarely be fatal.

Isolated cases of nephrogenic systemic fibrosis (NSF) have been reported with gadoteric acid, most ofwhich were in patients co-administered other gadolinium-containing contrast agents (see section 4.4).

Adverse reactions are presented in the following table according to system organ class and frequency,using the following categories: very common (≥1/10), common (≥1/100 to 1<1/10), uncommon (≥1/1,000 to 1<1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), undetermined frequency (cannot be estimated on the basis of available data). The frequencies presented were obtained fromthe data of an observational study on 82,103 patients.

System Organ Class Frequency: adverse reactions

Immune system disorders Uncommon: hypersensitivity, anaphylactic reactions,anaphylactoid reactions

Psychiatric disorders Very rare: agitation, anxiety


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System Organ Class Frequency: adverse reactions

Nervous system disorders Very common: paresthesia, headacheRare: dysgeusiaVery rare: coma, seizures, syncope, faintness, dizziness,parosmia, tremor

Eye disorders Very rare: conjunctivitis, ocular hyperaemia, blurred vision,increased lacrimal secretion, eyelid oedema

Cardiac disorders Very rare: cardiac arrest, bradycardia, tachycardia,arrhythmia, palpitations

Vascular disorders Very rare: hypotension, hypertension, vasodilatation, pallorRespiratory, thoracic and mediastinal disorders: Very rare: respiratory arrest, pulmonary oedema,

bronchospasm, laryngospasm, pharyngeal oedema,dyspnoea, nasal congestion, sneezing, cough, dry throat

Gastrointestinal disorders Common: nausea, vomiting,Very rare: diarrhoea, abdominal pain, excessive salivation

Skin and subcutaneous tissue disorders Common: pruritus, erythema, eruptionsRare: urticaria, hyperhidrosis,Very rare: eczema, angioneurotic oedema (angioedema)Undetermined frequency: nephrogenic systemic fibrosis

Musculoskeletal and connective tissue disorders Very rare: muscle contractures, muscle weakness, backpain

General disorders and administration siteconditions:

Common: warm sensation, cold sensation, injection sitepainVery rare: malaise, chest pain, chest discomfort, fever,chills, facial oedema, asthenia, injection site discomfort,injection site reaction, injection site oedema, extravasationat injection site, injection site inflammation followingextravasation, injection site necrosis followingextravasation, superficial thrombophlebitis

Investigations Very rare: low oxygen saturation

The following adverse reactions have been reported with other intravenous MRI contrast agents.Consequently, they may also occur during treatment with Dotarem:

System Organ Class Adverse reaction

Blood and lymphatic system disorders HaemolysisPsychiatric disorders ConfusionEye disorders Transient blindness, eye painEar and labyrinth disorders Tinnitus, ear painRespiratory, thoracic and mediastinal disorders: AsthmaGastrointestinal disorders Dry mouthSkin and subcutaneous tissue disorders Bullous dermatitisRenal and urinary disorders Urinary incontinence, renal tubular necrosis, acute renal

failureInvestigations Prolonged PR on electrocardiogram, elevated serum iron,

elevated serum bilirubin, elevated serum ferritin, abnormalliver function tests

Adverse reactions in children

Adverse reactions related to gadoteric acid are uncommon in children. The expected types of reactionare identical to those reported in adults. When they occur, the reactions are less severe than in adults.

4.9. Overdose

No overdose has been reported.

In the event of a very high dose, water and electrolyte loss must be compensated by suitablerehydration. Renal function must be monitored for at least three days.


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Gadoteric acid can be removed from the body by haemodialysis. However, there is no evidence thathaemodialysis is suitable for prevention of nephrogenic systemic fibrosis (NSF).

5. PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic properties

Pharmacotherapeutic group: paramagnetic contrast media for MRI, ATC code: V08 CA02.

Gadoteric acid has paramagnetic properties allowing MRI contrast enhancement. It has no specificpharmacodynamic activity and is biologically very inert.

5.2. Pharmacokinetic properties

Following intravenous injection, gadoteric acid is mainly distributed in the extracellular fluid. It is notbound to plasma albumin and does not cross the healthy blood-brain barrier.

In patients with normal renal function, the plasma half-life is about 90 minutes. Gadoteric acid iseliminated in unchanged form by glomerular filtration.

Plasma clearance is delayed in patients with impaired renal function.

A small amount of gadoteric acid is excreted in breast milk and crosses the placenta.

5.3. Preclinical safety data

Non-clinical data reveal no special hazard for humans, based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, or toxicity to reproduction.

In acute toxicity studies of intravenous gadoteric acid in mice and rats, adverse effects (seizures,transient respiratory disorders) were only reported at doses much higher than those used in man.

Administration of gadoteric acid at daily doses of up to 15 times the recommended dose in clinicalpractice and for 28 days did not induce any marked effect apart from reversible vacuolization of renalproximal tubule cells.

Animal studies showed negligible (less than 1% of the administered dose) secretion of gadoteric acidin maternal milk.

No teratogenic effect was demonstrated in rats and rabbits.

No mutagenic effect was demonstrated on the reagent systems used.

6. PHARMACEUTICAL PARTICULARS

6.1. List of excipients

Meglumine, water for injections.

6.2. Incompatibilities

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

6.3. Shelf life

3 years.

6.4. Special precautions for storage

Do not freeze.

6.5. Nature and contents of container

Prefilled 10, 15 and 20 mL type I glass syringes with latex-free elastomeric seals.


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Prefilled 15 or 20 mL type I glass syringes with latex-free elastomeric seals with administration set(polyvinyl chloride-based extension line and polyurethane-based safety catheter 22G).

Not all pack sizes may be marketed.

6.6. Special precautions for disposal and other handling

Screw the piston rod onto the syringe and intravenously inject the quantity of the product required forthe examination.

The peel-off tracking label on the syringes should be stuck onto the patient record to enable accuraterecording of the gadolinium contrast agent used. The dose used should also be recorded.

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

7. MARKETING AUTHORISATION HOLDER

GUERBETBP 5740095943 ROISSY CHARLES DE GAULLE Cedex - FRANCE

8. MARKETING AUTHORISATION NUMBER(S)

358 953-6 or 34009 358 953.6 3 : 10 mL in prefilled syringes (glass) 338 403-0 or 34009 338 403 0 3 : 15 mL in prefilled syringes (glass) 338 404-7 or 34009 338 404 7 1 : 20 mL in prefilled syringes (glass) 279 469-4 or 34009 279 469 4 3 : 15 mL in prefilled syringes (glass) with administration set

(extension line + safety catheter 22G). 279 470-2 or 34009 279 470 2 5 : 20 mL in prefilled syringes (glass) with administration set

(extension line + safety catheter 22G).

9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION

13 February 1995 / 30 November 2007

10. DATE OF REVISION OF THE TEXT

17 July 20174

PRESCRIBING AND DISPENSING CONDITIONS

List I

Documents

1. SUMMARY STATEMENT OF THE PROPOSAL FOR INCLUSION4 … · interventional radiology techniques, in cardiology and in oncology or for the treatment of vascular malformations, for example