WHO list of essential medicines
CONTENTS
1. SUMMARY STATEMENT OF THE PROPOSAL FOR INCLUSION...... 4
2. NAME OF THE FOCAL POINT IN WHO SUBMITTING OR SUPPORTING THE APPLICATION ...... 12
3. NAME OF THE ORGANIZATION(S) CONSULTED AND/OR SUPPORTING THE APPLICATION ...... 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 TRADE NAMES...... 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 AN EXAMPLE OF A THERAPEUTIC GROUP...... 14
8. INFORMATION SUPPORTING THE PUBLIC HEALTH RELEVANCE (EPIDEMIOLOGICAL INFORMATION ON DISEASE BURDEN, ASSESSMENT OF CURRENT USE, TARGET POPULATION)...... 15
9. TREATMENT DETAILS (DOSAGE REGIMEN, DURATION; REFERENCE TO EXISTING WHO AND OTHER CLINICAL GUIDELINES; NEED FOR SPECIAL DIAGNOSTICS, TREATMENT OR MONITORING FACILITIES AND SKILLS)...... 15
9.1 Dosage regimen...... 15 Brain and spinal cord MRI ...... 15 MRI 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...... 16 9.3.1 American College of Radiology guideline...... 16 9.3.2 Royal College of Radiology guideline ...... 17 9.3.3 European Society of Urogenital Radiology (ESUR) guideline ...... 17
9.4 Treatment Facilities and Skills ...... 17
10. SUMMARY OF COMPARATIVE EFFECTIVENESS IN A VARIETY OF CLINICAL SETTING ...... 18
10.1 Efficacy studies in CNS imaging...... 18 10.1.1 Gadoterate meglumine in CNS imaging in clinical studies at single dose...... 20 10.1.2 Gadoterate meglumine in CNS imaging in non-randomized studies at single dose ...... 20 10.1.3 Gadoterate meglumine in CNS imaging in non-randomized studies at higher dose ...... 23 10.1.4 Gadoterate meglumine in CNS imaging in non-randomized studies in a pediatric population ...... 24
10.2 Efficacy studies in whole body imaging...... 25 10.2.1 Hepatic and pancreatic imaging ...... 26 10.2.2 Musculoskeletal imaging...... 27 10.2.3 Female pelvis imaging ...... 29 10.2.4 Renal imaging ...... 30 10.2.5 Cardiac imaging ...... 32 10.2.6 Breast imaging...... 35 10.2.7 Pulmonary and chest imaging ...... 36 10.2.8 Pediatric imaging...... 36
10.3 Efficacy studies in MR angiography ...... 38 10.3.1 Randomized studies in MRA...... 39 10.3.2 Non-Randomized studies in MRA...... 40 10.3.3 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 ...... 53 11.1.1 Adult population...... 53 11.1.2 Paediatric population ...... 54
11.2 Safety finding from clinical studies and post-marketing experience ...... 56 11.2.1 Safety findings from Guerbet sponsored trials and from published trials ...... 56 11.2.2 Safety findings from Guerbet observational post-marketing studies ...... 58 11.2.3 Safety findings from post-marketing pharmacovigilance (cut-off 2014) ...... 60 11.2.4 Occurrence of Nephrogenic Systemic Fibrosis (NSF) ...... 61 11.2.5 Deaths and other serious adverse events ...... 63
11.3 Gadoterate meglumine safety profile in special groups and situations...... 66 11.3.1 Patients with renal impairment...... 66 11.3.2 Patients with cardiovascular risk...... 67 11.3.3 Children below 2 years old...... 68 11.3.4 Use in pregnancy...... 70
11.4 Gadoterate meglumine safety: laboratory tests, and vital signs ...... 70 11.4.1 Laboratory evaluations...... 70
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11.4.2 Vital signs...... 71
11.5 Gadoterate meglumine comparative safety data ...... 71 11.5.1 Clinical studies with gadoterate meglumine conducted by Guerbet (n=50)...... 71 11.5.2 Gadoterate meglumine published trials...... 72
12. SUMMARY OF AVAILABLE DATA ON COMPARATIVE COST AND COST- EFFECTIVENESS WITHIN THE PHARMACOLOGICAL CLASS OR THERAPEUTIC GROUP...... 75
13. SUMMARY OF REGULATORY STATUS OF THE MEDICINE (IN VARIOUS COUNTRIES)...... 76
14. AVAILABILITY OF PHARMACOPOEIAL STANDARDS ...... 77
15. PROPOSED TEXT THAT COULD BE INCLUDED IN A REVISED WHO MODEL FORMULARY ...... 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
4 WHO list of essential medicines 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)
Generic Name Gadopentetate Gadoxetic Gadobenate Gadofosveset, Gadodiamide Gadoversetamide Gadoteridol Gadobutrol Gadoterate dimeglumine acid, dimeglumine trisodium salt meglumine GC disodium salt
Trade Name Magnevist Primovist® MultiHance Ablavar® Omniscan OptiMARK ProHance Gadovist Dotarem Eovist® Vasovist Magnescope Company Bayer Healthcare Bayer Bracco Imaging Lantheus Medical GE-Healthcare Covidien Bracco Bayer Guerbet Healthcare Imaging Imaging Healthcare Bayer Healthcare 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 marketed 0.5 0.25 0.5 0.25 0.5 0.5 0.5 1.0 0.5 solution (M)
Ca-EOB-DTPA No added ligand Fosveset Ca-DTPA-BMA Ca-DTPA-BMEA [Ca-HP- Ca-BT-DO3A No added ligand + + Formulation of the marketed Free DTPA (trisodium (0.325 mmol/l) (caldiamide) (Na salt) DO3A]2 (Na salt) solution (1 mmol/l) salt) (Na+ salt) (50 mmol/l) (Ca2+ salt) 1.0 mmol/l 1.5 mmol/l (25 mmol/l) 0.5 mmol/l
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)
Risk class LOW RISK: MEDIUM RISK: HIGH RISK: Dotarem, ProHance, Gadovist Primovist, Vasovist, Omniscan, Optimark, Magnevist MultiHance, Eovist, Ablavar
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 Discontinuation for at least 24h (in consultation with the physician)
Renal insufficiency (RI), Precaution in severe renal insufficiency (RI) and liver To be avoided in patients with Contraindication in severe RI and liver transplant recipients liver transplantation, transplant recipients: minimum diagnostic dose and a severe RI and liver transplant Precaution in patients with moderate RI, depending on the dialysis minimum of 7 days between 2 doses recipients benefit/risk balance, minimum diagnostic dose and minimum of If used, minimum diagnostic dose 7 days between 2 doses and minimum of 7 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 renal dysfunction
*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
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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 Discontinuation at least 24h (in consultation with the physician)
Renal insufficiency (RI), Should be used with caution in patients with Chronic Kidney Disease (CDK) 4 and Contra-indication in patients with CDK 4 and 5 (GFR<30mL/min) and with acute hepatic transplantation, 5 (GFR<30mL/min), including patients on dialysis, with at least 7 days between 2 renal insufficiency. dialysis administrations. 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 Contra-indication in neonates < 4 weeks 2 doses
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 Contra-indication in patients with NSF vital
Screening of renal function Laboratory testing of renal function (eGFR) is not mandatory but renal function Mandatory laboratory test to screen all patients for renal dysfunction assessment by questionnaire should be used if serum creatinine is not measured.
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 and kinetic stability of marketed gadolinium chelates and their possible clinical consequences: a critical review. Biometals. 2008 Aug;21(4):469-90.
Port M, Idee JM, Medina C, Dencausse A, Corot C. Stability of gadolinium chelates and their biological 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: a proton relaxometric protocol for transmetallation assessment. Invest Radiol. 2001 Feb;36(2):115-22.
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Laurent S, Elst LV, Muller RN. Comparative study of the physicochemical properties of six clinical low molecular weight gadolinium contrast agents. Contrast Media Mol Imaging. 2006 May-Jun;1(3):128-37. Frenzel T, Lengsfeld P, Schirmer H, Hütter J, Weinmann HJ. Stability of gadolinium-based magnetic 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 GUERBET 16, Avenue des Fours à Chaux BP 57400 17230 MARANS 95943 Roissy CdG cedex FRANCE 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
16 WHO list of essential medicines 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.
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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 Imaging No of No of gadoterate Design cases meglumine cases
DGD-3-17 R, DB, U, CNS 20 10 C DGD-3-31 R, DB, M, CNS 299 149 C Baleriaux et al., R, DB, M, CNS 58 30 1993 C Oudkerk et al., R, DB, M, CNS 1038 518 1995 C 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.
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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
Study reference Study Imaging No of evaluable No of gadoterate meglumine Design cases 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
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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 single dose
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
20 WHO list of essential medicines 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.
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Table 7 : Non-randomized studies in CNS and spinal cord imaging at single dose
Study reference Study Inclusion diagnostic Total No of Diagnostic Change Modification design patients contribution in of therapeutic diagnostic management Good Excellent DGD-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-3-4 U, O, NR, C Neurological MRI for various reasons 20 10% 90% 75% 85%
DGD-3-8 U, O, NR, C Neurological MRI for various reasons 54 91% - 89% * 94%** 96%
DGD-3-1 U, O, NR, C Neurological MRI for various reasons 10 60% 10% 70% 60%
DGD-3-12 U, O, NR, C Neurological MRI for various reasons 50 42% 38% 67% 61%
DGD-3-14 U, O, NR, C Neurological MRI for various reasons 55 22% 69% 69% 73%
DGD-3-23 U, O, NR, C Neurological MRI for various reasons 50 70% - 97% **** 15% 29%
DGD-3-5 U, O, NR, C Neurological MRI for various reasons 10 50% 50% 50% 30%
DGD-3-9 U, O, NR, C Neurological MRI for various reasons 22 27% 68% 45% 36%
DGD-3-3 U, O, NR, C Neurological MRI for various reasons 30 17% 77% 80% 67%
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% ° 6% ° 60% °° 77% °° U: Unicentric; O: Open; NR: Not Randomized; C: Comparative a 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% of cases. ** 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 and 78% 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,
22 WHO list of essential medicines 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 higher dose
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.
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10.1.4 Gadoterate meglumine in CNS imaging in non-randomized studies in a pediatric 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
Study reference Study Imaging No of evaluable No of gadoterate meglumine Design cases cases DGD-3-16 NR, O, U, C Paediatric 20 20 DGD-3-15 NR, O, U, C Paediatric 29 29 DGD-3-29 NR, O, U, C Paediatric 50 53 Herve-Somma et al., 1992 NR, O, U, C Paediatric 24 24 Bonnerot et al., 1994 NR, O, U, C Paediatric 9 9 Ducou 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
24 WHO list of essential medicines 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 Study Imaging Conducted by the No of gadoterate meglumine Design sponsor cases Neiss et al., 1991 NR, O, U CNS Yes, Post-marketing 4,169 Briand et al., 1992 NR, O, U Paediatric Yes, Post-marketing 402 Ishiguchi et al., NR, O, M Various Yes, Post-marketing 3,444 2010 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; * Study report 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
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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 MRI for hepatic and pancreatic imaging Study reference Study Design Imaging No of evaluable No of gadoterate meglumine cases cases DGD-3-22 NR, O, U, C Hepatic, Pancreatic 24 24 DGD-3-13 NR, O, U, C Hepatic, Pancreatic 30 30 Cuenod et al., 1991 NR, O, U, C Hepatic, Pancreatic 39 39 Soyer et al., 1994 NR, O, U, C Hepatic, Pancreatic 12 12
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Von Hagspiel et al., 1994 NR, O, U, C Hepatic, Pancreatic 55 55 Soyer et al., 1996 NR, O, U, C Hepatic, Pancreatic 50 50 Total 210 C: Comparative; U: Unicentric; M: Multicentric; O: Open; NR: Not Randomized; R: Randomized; DB: double-blinded
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 No of gadoterate meglumine cases cases DGD-3-2 NR, O, U, C Musculoskeletal 20 20 Hodler et al., 1990 NR, O, U, C Musculoskeletal 42 42 Vande Berg et al., 1992 NR, O, U, C Musculoskeletal 15 15 Chastanet et al., 1993 NR, O, U, C Musculoskeletal 8 8 Drape et al., 1993 NR, O, U, C Musculoskeletal 53 53 Daenen 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-
27 WHO list of essential medicines 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
28 WHO list of essential medicines 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 Study reference Study Design Imaging No of evaluable No of gadoterate meglumine cases cases Ghossain et al., 1991 NR, O, U, C Female pelvis 40 8 Thurnher et al., 1992 NR, O, U, C Female pelvis 97 97 Total 105 C: Comparative; U: Unicentric; M: Multicentric; O: Open; NR: Not Randomized; R: Randomized; DB: double-blinded
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.
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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 Study reference Study Design Imaging No of evaluable No of gadoterate meglumine cases cases Brichaux et al., 1991 NR, O, U, C Kidney 26 26 Hanna et al., 1991 NR, O, U, C Kidney 8 8 Helenon et al., 1992 NR, O, U, C Kidney 21 21 Laissy et al., 1994 NR, O, U, C Kidney 7 7 Levy et al., 1994 NR, O, U, C Kidney 11 11 Grenier et al., 1996 NR, O, U, C Kidney 15 15 Total 88 C: Comparative; U: Unicentric; M: Multicentric; O: Open; NR: Not Randomized; R: Randomized; DB: double-blinded
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.
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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
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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 Study reference Study Design Imaging No of evaluable No of gadoterate meglumine cases cases Richoz et al., 1990 NR, O, U, C Cardiac 15 15
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Jau et al.,1991 NR, O, U, C Cardiac 10 10 Loubeyre et al., 1992 NR, O, U, C Cardiac 12 12 Mousseaux et al., 1993 NR, O, U, C Cardiac 39 39 Eichenberger et al., 1994 NR, O, U, C Cardiac 8 8 Total 84 C: Comparative; U: Unicentric; M: Multicentric; O: Open; NR: Not Randomized; R: Randomized
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.
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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.
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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 Study reference Study Design Imaging No of evaluable No of gadoterate meglumine cases cases Gilles et al.,1993 NR, O, M, C Breast 26 26 Ha Dao et al.,1993 NR, O, U, C Breast 35 35 DGD-3-32 NR, O, U, C Breast 80 80 Total 141 C: Comparative; U: Unicentric; M: Multicentric; O: Open; NR: Not Randomized; R: Randomized
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
35 WHO list of essential medicines 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
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(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.
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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 40 DGD-3-37 R, SB, U, C MRA 35 Brichaux et al., 1991* NR, O, U, C MRA 24 Revel et al., 1993 NR, O, U, C MRA 26 Loubeyre et al., 1994 NR, O, U, C MRA 23 Laissyetal.,1995 MRA 28 Laissyetal.,1995 MRA 20 Perrier et al., 1998 MRA 23 Laissyetal.,1998 MRA 20 DGD-3-36 NR, O, M, C MRA 41 DGD-3-38 NR, O, M, C MRA 40 Randoux et al., 2001 MRA 22 Nchimietal.,2002 MRA 49 Cottier et al., 2003 MRA 58 Randoux et al., 2003 MRA 33 Wyttenbach et al., 2003 MRA 56 Loewe et al., 2003 MRA 39 Loewe et al., 2004 MRA 28 Lapeyreetal.,2005 MRA 31 Gauvrit et al., 2006 MRA 54 Feydy et al., 2006 MRA 30 DGD-44-38 NR, O, M, C MRA 100 Vogt et al., 2007 MRA 9 DGD-44-42 NR, O, U, C MRA 92 DGD-44-48 NR, O, M, C MRA 222 DGD-44-49 NR, O, M, C MRA 211 DGD-44-45 R, DB, M, C MRA 93 Total 829 C: 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).
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** 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.
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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.
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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.
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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.
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Table 17: Gadoterate meglumine clinical trials publications (1994 to date) Study indication Arterial Country Dose Nb of Stat sensitivity Specificit reference territor patient unit y y s N%N%
Laissy et Detection of Aorto France 0.2 20 lesion 5 100 35 97 al., renal artery ilio ml/kg 1995 stenoses in femoral patients with abdominal aortic aneurysms Perrier et Detection of Aorto France 0.2 23 segmen 77 98 200 82 al., stenoses in ilio ml/kg** t 1998* ilio femoral femoral arteries (reader 1) Perrier et (reader 2) Aorto France 0.2 23 segmen 78 98 198 82 al., ilio ml/kg** t 1998* femoral Nchimi et Detection of Aorto Belgium 17 ml 49 segmen 138 94 437 96 al., stenoses in ilio t 2002 aorta and femoral femoral arteries Randoux Detection of Head & France 20 ml 22 segmen 18 93 26 100 et al., 2001 carotid artery neck t stenoses Cottier et Depiction of Head & France 0.2 58 lesion 36 83 35 100 al., remnant neck ml/kg 2003 aneurysm in treated intracranial aneurysms Gauvrit et Detection of Head & France 10ml 54 lesion 32 81 22 100 al., 2006 residual neck nidus or venous drainage in treated cerebral arteriovenous malformation s Loubeyre Diagnosis of Thorax France 0.2 23 segmen 12 70 M 100 et al., 1994 pulmonary ml/kg t D embolism Laissy et Diagnosis of Thorax France 0.2 28 patient 12 88 16 85 al., pulmonary ml/kg 1995 embolism Randoux Detection of Thorax France 20 ml 33 segmen 10 100 137 85 et al., ostial t 2003* stenoses in aortic arch (vertebral arteries) Randoux (other Thorax France 20 ml 33 segmen 11 100 55 98 et al., arteries) t 2003* Loewe et Detection of Thorax Switzerlan 25 ml** 28 segmen 27 93 162 99 al., stenoses in d t 2004 aortic arch vessels Laissy et Detection of Periph France 0.2 20 segmen 113 100 413 97 al., significant ml/kg t
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1998 stenoses in lower limbs Wyttenbac Detection of Periph Switzerlan 34 ml 56 segmen 167 96 610 93 h et al., stenosis and d t 2003* occlusion in peripheral arteries (reader 1) Wyttenbac (reader 2) Periph Switzerlan 34 ml 56 segmen 167 96 614 85 h et al., d t 2003* Loewe et Detection of Periph Switzerlan 40 ml** 39 segmen 17 82 30 98 al., stenoses in d t 2003* bypass grafts of peripheral arteries Loewe et Detection of Periph Switzerlan 40 ml** 39 segmen 60 78 878 96 al., stenoses in d t 2003* native peripheral arteries Lapeyre et Detection of Periph France 0.24 31 segmen 335 95 285 98 al., 2005* stenoses in ml/kg t limb ischemia in diabetes (reader 1) Lapeyre et Detection of Periph France 0.24 31 segmen 335 95 285 98 al., 2005* occlusions in ml/kg t limb ischemia in diabetes (reader 1) Lapeyre et Detection of Periph France 0.24 31 segmen 335 96 285 98 al., 2005* stenoses in ml/kg t limb ischemia in diabetes (reader 2) Lapeyre et Detection of Periph France 0.24 31 segmen 335 90 285 99 al., 2005* occlusions in ml/kg t limb ischemia in diabetes (reader 2) Feydy et Detection of Periph France 0.2 30 patient 11 82 20 85 al., tumor ml/kg 2006 invasion in lower limbs arteries Vogt et al., Detection of Periph Germany 0.2 9 segmen 43 100 129 89 2007* peripheral ml/kg t arterial disease (all segments) Vogt et al., Detection of Periph Germany 0.2 9 segmen M 100 M 86 2007* peripheral ml/kg t D D arterial disease (infra popliteal segments) Nielsen et Detection of Periph Denmark 0.3 26 segmen 13 73 13 94 al., 2010 peripheral mmol/k t arterial g disease Attenberge Detection of Periph Germany 0.07 31 segmen 31 86 31 76
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r et al., peripheral mmol/k t 2010 arterial g disease Shah et al., Detection of Periph Korea 0.1 162 segmen 162 93. 162 89. 2012 non-coronary mmol/k t 3 7 artery disease g Lee et al., Detection of Head Korea 0.1 30 segmen 30 88. 30 99. 2014 supra-aortic and mmol/k t 2 3 arterial Neck g stenosis *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 agent MD: 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.
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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 1 Dotarem Gadoterate Meglumine. FDA Reference ID: 3258714) Study reference Study title number DGD-3-1 G449-06 Magnetic resonance irnaging.Renal Safety/Diagnostic efficacy. Phase II Clinical 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 volunteers DGD-3-7 G449.06 Magnetic Resonance Imaging. General safety and Diagnostic efficacy. Phase II clinical trial DGD-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 paediatrics DGD-3-17 G449-06 versus Gadolinium-DTPA. Magnetic resonance imaging Comparative, randomised, double-blind study. Clinical phase II study. Diagnostic efficacy/ Clinical and laboratory safety. DGD-3-20 G449-06 Magnetic Resonance Imaging General safety/Diagnostic efficacy open Phase III clinical trial. DGD-3-21 G449-06 in Neurological Magnetic Resonance Imaging General safety/Diagnostic
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Study reference Study title number 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 metastases DGD-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 or spinal tumors. DGD-3-50 Evaluation of MRI with DOtarem® in the characterization of abdominal and pelvic lesions. DGD-44-038 Evaluation of Dotarem®-enhanced MRA compared to time-of- flight MRA in the diagnosis of clinically significant non-coronary arterial disease. DGD-44-039 Gd-DOTA (Dotarem®) : evaluation of the electrocardiographic safety in patients Phase IIb clinical trial. DGD-44-042 Evaluation of Dotarem®-enhanced MRA compared to time-of-flight MRA in the diagnosis of clinically significant non-coronary arterial disease. DGD-44-044 Renal safety evaluation after Dotarem®-enhanced MRI compared with non-enhanced MRI 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 MRA in 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) in patients 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 or spinal tumors. Re-reading of MRI images. DGD-55-001 SECURE: Observational Study on the Safety and the Efficacy of DOTAREM.
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Gauvrit JY, Oppenheim C, Nataf F, et al. Three-Dimensional Dynamic Magnetic Resonance Angiography For The Evaluation Of Radiosurgically Treated Cerebral Arteriovenous Malformations. Eur Radiol 2006; 16: 583-591. Ghossain MA, Buy JN, Ligneres C, et al. Epithelial tumors of the ovary: comparison of MR and CT findings. Radiology 1991; 181(3): 863-870. Gilles R, Guinebretiere JM, Shapeero LG, et al. Assessment of breast cancer recurrence with contrast-enhanced subtraction MR imaging: preliminary results in 26 patients. Radiology 1993; 188(2): 473-478. Grenier N, Trillaud H, Combe C, et al. Diagnosis of renovascular hypertension: feasibility of captopril-sensitized dynamic MR imaging and comparison with captopril scintigraphy. AJR Am J Roentgenol 1996; 166(4): 835-843. Ha Dao T, Rahmouni A, Campana F, et al. Tumor recurrence versus fibrosis in the irradiated breast: Differentiation with dynamic gadolinium-enhanced MR imaging. Radiology 1993; 187: 751-755. Hanna S, Helenon O, Legendre C, et al. MR imaging of renal transplant rejection. Acta Radiol 1991; 32(1): 42-46. Haustein J, Laniado M, Niendorf HP, et al. Triple-dose versus standard-dose gadopentetate dimeglumine: a randomized study in 199 patients. Radiology 1993; 186(3): 855-860. Helenon O, Attlan E, Legendre C, et al. Gd-DOTA-enhanced MR imaging and color Doppler US of renal allograft necrosis. Radiographics 1992; 12(1): 21-33. Herborn CU, Honold E, Wolf M, Kemper J, Kinner S, Adam G, Barkhausen J. Clinical safety and diagnostic value of the gadolinium chelate gadoterate meglumine (Gd-DOTA). Invest Radiol. 2007 Jan;42(1):58-62.
Herve-Somma CM, Sebag GH, Prieur AM, et al. Juvenile rheumatoid arthritis of the knee: MR evaluation with Gd-DOTA. Radiology 1992; 182(1): 93-98. Hodler J, Orellano J, Thurnher S, et al. [Gd-DOTA in musculoskeletal diseases]. Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr 1990; 153(5): 535-539. Ishiguchi T, Takahashi S. Safety of gadoterate meglumine (Gd-DOTA) as a contrast agent for magnetic resonance imaging results of a post-marketing surveillance study in Japan. Drugs R&D 2010; 10 (3): 133-145.
Jau P, Bonnet JL, Joly P, et al. Etude de l'infarctus du myocarde récent en imagerie par résonance magnétique avec injection de Dota-gadolinium. Arch Mal Coeur Vaiss 1991; 84(2): 195-200. Jevtic V, Watt I, Rozman B, et al. Contrast enhanced Gd-DTPA magnetic resonance imaging in the evaluation of rheumatoid arthritis during a clinical trial with DMARDs. A prospective two-year follow-up study on hand joints in 31 patients. Clin Exp Rheumatol 1997; 15(2): 151- 156. Kransdorf MJ. The use of gadolinium in the MR evaluation of musculoskeletal tumors. Top Magn Reson Imaging 1996; 8(1): 15-23.
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Kuhn MJ, Hammer GM, Swenson LC, et al. MRI evaluation of "solitary" brain metastases with triple-dose gadoteridol: comparison with contrast-enhanced CT and conventional-dose gadopentetate dimeglumine MRI studies in the same patients. Comput Med Imaging Graph 1994; 18(5): 391-399. Laissy JP, Debray MP, Menegazzo D, et al. Prospective evaluation of peripheral arterial occlusive disease by 2D MR subtraction angiography. JMRI 1998; 8: 1060-1065. Laissy JP, Soyer P, Tebboune D, et al. Abdominal aortic aneurysms: Assessment with gadolinium-enhanced time of flight coronal MR angiography (MRA). Eur J Radiol 1995; 20: 1-8. Laissy JP, Bancal C, Sekkal S, et al. Pulmonary MR angiography at 1.0T: Early results with K-space segmented and post-contrast turboflash two-dimensional time of flight sequences. Eur J Radiol 1995; 20: 9-15. Laissy JP, Gay-Depassier P, Soyer P, et al. Enlarged mediastinal lymph nodes in bronchogenic carcinoma: assessment with dynamic contrast-enhanced MR imaging. Work in progress. Radiology 1994; 191(1): 263-267. Laissy JP, Faraggi M, Lebtahi R, et al. Functional evaluation of normal and ischemic kidney by means of gadolinium-DOTA enhanced TurboFlash MR imaging: a preliminary comparison with 99Tc-MAG3 dynamic scintigraphy. Magn Reson Imaging 1994; 12(3): 413-419. Lapeyre M, Kobeiter H, Desgranges P, et al. Assessment of critical limb ischemia in patients with diabetes: comparison of MR Angiography and digital subtraction angiography. AJR 2005; 185: 1641-1650. Lee YJ, Kim BS, Koo JS, Kim BY, Jang J, Choi HS, Jung SL, Ahn KJ. Supra-aortic low-dose contrast-enhanced time-resolved magnetic resonance (MR) angiography at 3 T: comparison with time-of-flight MR angiography and high-resolution contrast-enhanced MR angiography. Acta Radiol. 2014 Jun 20.
Levy Ph, Helenon O, Melki Ph, et al. Kystes atypiques bénins du rein: Aspects MRI Benign atypical cysts of the kidney: MRI aspects. J Radiol 1994; 75(10): 543-552. Loubeyre P, Revel D, Delignette A, et al. Perfusion evaluation of acute myocardial infarction using ultrafast cardiac MR imaging with gadolinium DOTA. Eleventh Annual Scientific Meeting of the Society of Magnetic Resonance in Medicine 1992, Berlin: 606. Loubeyre P, Revel D, Douek P, et al. Dynamic contrast-enhanced MR angiography of pulmonary embolism: comparison with pulmonary angiography. AJR Am J Roentgenol 1994; 162(5): 1035-109. Loewe C, Schillinger M, Haumer M et al. MRA versus DSA in the assessment of occlusive disease in the aortic arch vessels : Accuracy in detecting the severity number and length of Stenoses. J Endovasc Ther 2004; 11: 152-160. Loewe C, Cejna M, Schoder M, et al. Contrast material-enhanced, moving-table MR angiography versus digital subtraction angiography for surveillance of peripheral arterial bypass grafts. JVIR 2003; 14: 1129-1137. Mathews VP, King JC, Elster AD, et al. Cerebral infarction: effects of dose and magnetization transfer saturation at gadolinium-enhanced MR Imaging. Radiology 1994; 190: 547-552.
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Maurer M, Heine O, Wolf M, et al. Tolerability and diagnostic value of gadoteric acid in the general population and in patients with risk factors: Results in more than 84,000 patients. Eur J Radiol 2012; 81(5): 885-890.
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Nchimi A, Brisbois D, Donkers E, et al. Aortofemorographie par résonance magnétique nucléaire versus artériographie conventionnelle : évaluation prospective. MR aortofemorography versus DSA: prospective evaluation (article in French, English abstract available). J Belge Radiol. 2002; 85: 246-251. Neiss AC, Le Mignon MM, Vitry A, et al. Efficacité et tolérance du DOTA-Gd lors d'une enquête multricentique européenne. Rev Im Med 1991; 3: 383-387. Nielsen YW, Eiberg JP, Løgager VB, Just S, Schroeder TV, Thomsen HS. Whole-body magnetic resonance angiography with additional steady-state acquisition of the infragenicular arteries in patients with peripheral arterial disease. Cardiovasc Intervent Radiol. 2010 Jun;33(3):484-91
Oudkerk M, Sijens PE, Van Beek EJ, et al. Safety and efficacy of Dotarem(Gd-DOTA) versus Magnevist(Gd-DTPA) in magnetic resonance imaging of the central nervous system. Invest Radiol 1995; 30(2): 75-78. Perrier E, Dubayle P, Boyer B, et al. Comparaison de l'angiographie par résonance magnetique avec injection de gadolinium et de l'arteriographie conventionnelle des axes ilio- femoraux. Comparison of 3D contrast enhanced magnetic resonance angiography and conventional arteriography in iliofemoral arteries (article in French, English abstract available). J Radiol 1998; 79: 1493-1498. Randoux B, Marro B, Koskas F, et al. Proximal great vessels of aortic arch: Comparison of three-dimensional gadolinium-enhanced MR angiography and digital subtraction angiography. Radiology 2003; 229: 697-702. Randoux B, Marro B, Koskas F, et al. Carotid artery stenosis: Prospective comparaison of CT, three dimensional gadolinium-enhanced MR, and conventional angiography. Radiology 2001; 220: 179-185. Revel D, Loubeyre P, Delignette A, et al. Contrast-enhanced magnetic resonance tomoangiography: a new imaging technique for studying thoracic great vessels. Magn Reson Imaging 1993; 11(8): 1101-1105. Richoz B, Delcour C, Depelchin P, et al. IRM de l'infarctus myocardique aigu avec injection de Gd-DOTA (quinze patients). Ann Radiol 1990; 33(2): 93-98. Runge V, Kirsch JE, Burke VJ, et al. High doses of gadoteridol in MR Imaging of intracranial neoplasms. JMRI 1992; 2: 9-18. Shah DJ, Lim TH. Evaluation of meglumine gadoterate-enhanced MR angiography (MRA) compared with time-of-flight MRA in the diagnosis of clinically significant non-coronary arterial disease: a pooled analysis of data from two clinical trials. Br J Radiol. 2012 May;85(1013):596-605.
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Soyer P, Tidjani K, Laissy JP, et al. Dynamic Gd-DOTA-enhanced MR imaging of hepatic metastases from pancreatic neuroendocrine tumors. Eur J Radiol 1994; 18(3): 180-184. Soyer P, Laissy J-P, Sibert A, et al. Dynamic gadolinium-DOTA-enhanced MR imaging at 1.0 T. Value in differentiation of hepatic tumors. Clinical Imaging 1996; 20: 118-125. Svaland MG, Christensen T, Lundorf E. Comparison of the safety of standard and triple dose gadodiamide injection in MR imaging of the central nervous system. A double-blind study. Acta Radiol 1994; 35(4): 396-399. Thurnher SA. MR imaging of pelvic masses in women: contrast-enhanced vs unenhanced images. AJR Am J Roentgenol 1992; 159(6): 1243-1250. Towers JD. The use of intravenous contrast in MRI of extremity infection. Semin Ultrasound CT MR 1997; 18(4): 269-275. Vande Berg B, Malghem J, Labaisse MA, et al. Avascular necrosis of the hip: comparison of contrast-enhanced and nonenhanced MR imaging with histologic correlation. Work in progress. Radiology 1992; 182(2): 445-450. Vives MJ, Homesley D, Ciccotti MG, Schweitzer ME. Evaluation of recurring meniscal tears with Gadolinium-enhanced magnetic resonance imaging. A randomized prospective study. Am J Sports Med 2003; 31 (6): 868-873. Vogl TJ, Mack MG, Juergens M, et al. MR diagnosis of head and neck tumors: comparison of contrast enhancement with triple-dose gadodiamide and standard-dose gadopentetate dimeglumine in the same patients. AJR Am J Roentgenol 1994; 163(2): 425-432. Vogt FM, Zenge MO, Ladd ME, et al. Peripheral Vascular Disease: Comparison of continuous MR angiography and conventional MR angiography pilot study. Radiology 2007; 243(1): 229- 238. Von Hagspiel KD, Neidl KF, Hauser M, et al. [Fat-suppressed MR imaging sequences in the diagnosis of liver and pancreatic neoplasms at 1.5 tesla]. Fettunterdruckte MR-Bildsequenzen in der Diagnostik von Neoplasien der Leber und des Pankreas bei 1,5 Tesla. Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr 1994; 160(3): 235-242. Wolansky LJ, Bardini JA, Cook SD, et al. Triple-dose versus single-dose gadoteridol in multiple sclerosis patients. J Neuroimaging 1994; 4(3): 141-145. Wyttenbach R, Gianella S, Alerci M, et al. Prospective blinded evaluation of Gd-Dota- versus Gd-Bopta-enhanced peripheral MR angiography, as compared with digital subtraction angiography. Radiology 2003; 227: 261-269. Yue NC. Advances in brain tumor imaging. Curr Opin Neurol 1993; 6(6): 831-840. Yuh W, Tali ET, Nguyen HD, et al. The effect of contrast dose, imaging time and lesion size in the MR detection of intracerebral metastasis. AM J Neuroradiol. 1995; 16: 373-380.
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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 studies conducted by Guerbet Total nb Patients % of with of patients patients* at least one AE PK, CNS (0.1 mmol/kg) and total body imaging (0.1 to 871 76 8.7% 0.2 mmol/kg) 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 0.1 156 1 0.6% mmol/kg) Total 2813 81 6.6% * Patients who received Gd-DOTA; PK: pharmacokinetics studies
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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.
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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 meglumine between 2005 and 2012 Country Total number Total number of Estimated number of of MR Children below 2 years gadoterate examinations of age meglumine with gadoterate injected with gadoterate sold (Liters) meglumine 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.
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11.2 Safety finding from clinical studies and post-marketing experience
Preclinical data has highlighted the very large safety margin of gadoterate meglumine without identifying any particular target organ at risk and no teratogenic, immunotoxic or mutagenic potential nor effects on fertility were observed. The good safety profile was confirmed 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.
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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).
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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 StudyDesign 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 NR, O, M Various (including CNS) 3444 Emond et al., 2011 NR, O, S Various (including CNS) 104 Maurer et al., 2012 NR, O, M Various (including CNS) 104,033 SECURE study (DGD-55-001) NR, O, M Various (including CNS) 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.
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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 Eczema, erythema, urticaria, pruritus and rash disorders Musculoskeletal, connective tissue Muscle cramps, muscle weakness and bone disorders Nervous System disorders Dizziness, generalized convulsions, tremor, fatigue and somnolence. Psychiatry: Anxiety, confusion, insomnia, somnolence Gastro-Intestinal disorders Abdominal pain Respiratory, thoracic and Laryngitis, laryngismus, rhinitis, respiratory mediastinal disorders disorders General disorders & administration Chest pain, back pain, malaise, fever, sweating sites conditions 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.
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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 drug reactions (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 according their 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).
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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 million doses were used. A cumulative review of pharmacovigilance data from March 8, 1989 to February 2013 identified 16 cases of NSF. A summary of these 16 cases is presented in Figure 1. Figure 1: NSF cases reported for patients having received gadoterate meglumine
More than 41 million doses sold
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16 reported cases of NSF
5 confirmed or very likely cases of NSF 11 unconfirmed or doubtful cases of NSF
Confirmed or consistent diagnosis (Girardi Due to missing information the Girardi score), information sufficient to rule out score cannot be applied and/or the the differential diagnoses differential diagnoses cannot be ruled out
0 Single- 5 0 Non 1 9 1 Non agent case Multiple- qualifiable Single- Multiple- qualifiable agent case* agent agent case*
*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).
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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.
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Table 23: Summary of all deaths reported with gadoterate meglumine Patient Clinical ReactionDescription Outcome Relationship Country trial gadoterate meglumine 05001 DGD- 3- Cardiac failure Death due to adverse event No France 50 06001 DGD-3- Heart failure Death due to adverse event No France 44 06005 DGD-3- Pulmonaryembolism Deathduetoadverseevent No France 44 02012 DGD-3- Thrombophlebitis Death due to adverse event No France 44 Cerebral haemorrhage 08005 DGD-3- Intracranial pressure increased Adverse event may have contributed to the death No France 44 10001 DGD-3- Post-operative haemorrhage, Adverse event may have contributed to the death No France 44 Vasospasm 01017 DGD-3- Cerebral ischaemia Death due to adverse event No France 44 03029 DGD-3- Condition aggravated, Death due to adverse event No France 44 Metastases neoplasm
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).
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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
65 WHO list of essential medicines 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).
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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.
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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 Type of examination Children Mean Patients (years or with risk injected with at months) factors volume* least one adverse event German PMS 2 males Neurological =6 (Maurer et 7 females 8.7±3.2 months 0 4.2 ±1.6ml 0 Musculoskeletal =3 al., 2012) 1 unknown Japanese Child#1= PMS Child#1= neurological 2 females Child#1: 0.1 y. 0 1mL 0 (Ishiguchi et Child#2: chest Child#2: 1.8 y. Child#1=2mL al., 2010) French PMS Male: 58 8.1 ±5.2 Primary diagnosis= Median: 2 50.8% (Emond (55.8%) months mL Evaluation of the 0 0 2011) Female: 45 (range: 3 days- (range: 0.6 – extension of a known (43.3%) 18 months) condition= 31.7% 4 mL)
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1 unknown Postoperative control= 11.1% Follow-up= 6.3% SECURE Male: 44 CNS: 70 (84.1%) Impaired (DGD-55- (51.2%) Whole-body: 6 (7.0%) renal Muskulosqueletal: 7 function 3.8 001) Female: 42 0.8 ±0.4 years (8.1%) (creatinine (range: 0.6- 0 (48.8%) (range: 0-1.9) Angiography: 1 (1.2%) clearance < 25) Others: 2 (2.3%) 60 ml/min): 2 (2.3%) French PMS 26 children (Briand et (6.5% of 402 CNS in most cases Not Mean dose= Not available 0 al., 1992) were below 2 available 0.22 ml/kg years) French PMS 6 (5 females Range: 1 to 1.5 Not (Neiss et al., CNS 1.6 to 3 ml 0 and 1 male) years available 1991) Total number 234 of patients < 2 years
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.
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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
70 WHO list of essential medicines 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%).
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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-body magnetic resonance angiography with additional steady-state acquisition of the infragenicular arteries in patients with peripheral arterial disease. Cardiovasc Intervent Radiol. 2010 Jun;33(3):484-91
OudkerkThe results of these 3 trials showed that gadolinium chelates are safe agents and that their safety profiles are similar.
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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 temporal resolution 3-T MR protocol with a low total dose of gadolinium versus conventional angiography. Radiology. 2010 Dec;257(3):879-87.
Baleriaux D, Matos C, De Greef D. Gadodiamide injection as a contrast medium for MRI 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 Clin Immunol 2003; 35(10): 382-5.
Bellin MF, Deray G, Assogba U, et al. Dotarem: evaluation of its renal tolerance in patients with chronic renal failure. Magn Reson Med 1992; 10: 115-118.
Briand Y, Neiss AC, Vitry A. Efficacy and safety of the macrocyclic complex Gadoterate megluminein children: results of a multi-centre study. 29th congress of the European 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-risk patients 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 the EuroCMR registry. JACC: cardiovascular imaging 2011; 4(11): 1171-1176.
Brugieres P, Gaston A, Degryse HR, et al. Randomised double blind trial of the safety and efficacy of two gadolinium complexes (Gd-DTPA and Dotarem). Neuroradiology
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1994; 36(1): 27-30.
Chanalet S, Masson B, Boyer L, et al. Etudes comparatives de la tolérance du gadodiamide, du gadopentetate de diméglumine et du gadotérate de méglumine au cours d'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 of gadolinium. 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 study comparing 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 adverse reactions with contrast agents for magnetic resonance: clinical experience in 30,000 MR examinations. JBR-BTR. 2001; 84(4): 150-62.
Emond S., Brunelle F. Gd-DOTA administration at MRI in children younger than 18 months 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 gadoterate meglumine 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 systemic fibrosis: clinicopathological definition and workup recommendations. J Am Acad Dermatol. 2011 Dec;65(6):1095-1106.e7.
Hanna S, Helenon O, Legendre C, et al. MR imaging of renal transplant rejection. Acta Radiol 1991; 32(1): 42-46.
Helenon O, Attlan E, Legendre C, et al. Gd-DOTA-enhanced MR imaging and color Doppler 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 the gadolinium chelate gadoterate meglumine (Gd-DOTA). Investigative Radiology 2007; 42 (1): 58-62.
Ishiguchi T., Takahashi S. Safety of gadoterate meglumine (Gd-DOTA) as a contrast agent for magnetic resonance imaging results of a post-marketing surveillance study in Japan. Drugs R&D 2010; 10 (3): 133-145.
Jung JW, Kang HR, Kim MH, et al. Immediate Hypersensitivity Reaction to Gadolinium-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
74 WHO list of essential medicines 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 resonance contrast 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 acid in the general population and in patients with risk factors: Results in more than 84,000 patients. Eur J Radiol 2012; 81(5): 885-890.
Neiss AC, Le Mignon MM, Vitry A, et al. Efficacité et tolérance du DOTA-Gd lors d'une enquête multricentique européenne. Rev Im Med 1991; 3: 383-387.
Nielsen YW, Eiberg JP, Løgager VB, Just S, Schroeder TV, Thomsen HS. Whole-body magnetic resonance angiography with additional steady-state acquisition of the infragenicular arteries in patients with peripheral arterial disease. Cardiovasc Intervent Radiol. 2010 Jun;33(3):484-91
Oudkerk M, Sijens PE, Van Beek EJ, et al. Safety and efficacy of Gadoterate meglumine (Gd-DOTA) versus Magnevist(Gd-DTPA) in magnetic resonance imaging of the central nervous system. Invest Radiol 1995; 30(2): 75-78.
Reimer P, Vosshenrich R. Contrast agents in MRT. Substance, effects, pharmacology and validity. Radiologe 2004; 44(3): 273-83.
Runge VM. Safety of approved MR contrast media for intravenous injection. J Magn Reson Imaging 2000; 12(2): 205-13. Review.
12. Summary of available data on comparative cost and cost- effectiveness within the pharmacological class or therapeutic group No data are available for diagnostic agents.
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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
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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 the vertebral column, and other whole body diseases (including angiography). Contraindications: Hypersensitivity to gadoteric acid, meglumine or any medicinal products containing gadolinium. Precautions: usual precautionary measures for MRI examination; hypersensitivity; impaired renal function (Appendix 1); impaired hepatic function (perioperative liver transplantation period); the elderly (screen for renal dysfunction); neonates and infants (immature renal function – same precaution as for impaired renal function – see Appendix 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, an additional dose of 0.2 mmol/kg BW after administration of 0.1 mmol/kg BW may improve tumor characterization and facilitate therapeutic decision-making. MRI of other organs and Angiography: 0.1 mmol/kg. In angiography, a second injection of 0.1 mmol/kg may be justified; if anticipated, use of 0.05 mmol/kg for each dose may be 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 of hypersensitivity 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,
77 WHO list of essential medicines 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 site extravasation, injection site inflammation (in case of extravasation), injection site necrosis (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).
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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’’’ tetraacetic acid. 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 may be administered during the same session if necessary. In some exceptional cases, as when confirming isolated metastasis or detecting leptomeningeal tumours, a second injection of 0.2 mmol/kg can be administered. Special populations Impaired renal function
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Dotarem should only be used in patients with severe renal impairment (GFR < 30 mL/min/1.73m2) and in patients in the perioperative liver transplantation period after careful benefit/risk assessment and if the 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 than one dose should not be used during a scan. Because of the lack of information on repeated administration, Dotarem injections should not be repeated unless the interval between injections is at least 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 0.1 mmol/kg body weight. More than one dose should not be used during a scan. Because of the lack of information on repeated administration, Dotarem injections should not be repeated unless the interval between injections is at least 7 days. Dotarem is not recommended for angiography in children under the age of 18 because of insufficient data 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 (see section 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 anaphylactic reactions when serious) or non-allergic. They may be immediate (within 60 minutes) or delayed (up to 7 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-containing MRI contrast agent are at higher risk for another reaction to the same or even a different contrast agent, 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 patients taking beta blockers, particularly if they are asthmatic. These patients may be refractory to standard treatments 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 H1 antihistamines have been proposed as premedication in patients at greatest risk for hypersensitivity reactions (patients with known hypersensitivity to a contrast agent). However, they do 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 30 minutes, 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 section 4.8). 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 laboratory tests.
There have been reports of nephrogenic systemic fibrosis (NSF) associated with use of some gadolinium-containing contrast agents in patients with acute or chronic severe renal impairment (GFR < 30 ml/min/1.73m2). Patients undergoing liver transplantation are at particular risk since the incidence of acute renal failure is high in this group. As there is a possibility that NSF may occur with gadoteric acid, it should therefore only be used in patients with severe renal impairment and in patients in the perioperative liver transplantation period after careful risk/benefit assessment and if the diagnostic information is essential and not available with non-contrast enhanced MRI. Haemodialysis shortly after gadoteric acid administration may be useful at removing gadoteric acid from the body. There is no evidence to support the initiation of haemodialysis for prevention or treatment of NSF in patients not already undergoing haemodialysis. 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 vials of gadoteric acid and a disposable syringe of appropriate volume to obtain a more precise injection volume. 4.4.2.4 Elderly
As the renal clearance of gadoteric acid may be impaired in the elderly, it is particularly important to screen 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 receptor antagonists: these medicinal products decrease the efficacy of the mechanisms of cardiovascular compensation for blood pressure disorders. The physician must be informed before injection of gadolinium 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 interactions have 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 not provided direct or indirect evidence of deleterious effects with respect to reproductive toxicity (see section 5.3.). Gadoteric acid should not be used during pregnancy unless the patient's clinical situation requires administration of the product. Breast-feeding Gadolinium containing contrast agents are excreted into breast milk in very small amounts (see section 5.3). At clinical doses, no effects on the infant are anticipated due to the small amount excreted in milk and poor absorption from the gut. The physician and breast-feeding mother should decide whether to continue breast-feeding or to interrupt it for 24 hours following administration of gadoteric 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 to administration of gadoteric acid, the most common being pain and sensations of heat or cold at the injection site and nausea. Adverse reactions related to the use of gadoteric acid are generally mild to moderate and are transient. During clinical trials, headache and paresthesia were the very commonly observed (> 1/10), and nausea, 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 has been marketed are nausea, vomiting, pruritus and hypersensitivity reactions. The effects most commonly observed during hypersensitivity reactions are skin rashes, which can be localized, extensive or generalized. These reactions are usually immediate (during the injection or over the hour following the start of the injection) or sometimes delayed (one hour to several days after the injection), and then appear in the form of adverse skin reactions. Immediate reactions comprise one or several, successive or concomitant effects, usually including skin 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 of which 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 from the 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, headache Rare: dysgeusia Very 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, pallor Respiratory, 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, eruptions Rare: urticaria, hyperhidrosis, Very rare: eczema, angioneurotic oedema (angioedema) Undetermined frequency: nephrogenic systemic fibrosis Musculoskeletal and connective tissue disorders Very rare: muscle contractures, muscle weakness, back pain General disorders and administration site Common: warm sensation, cold sensation, injection site conditions: pain Very rare: malaise, chest pain, chest discomfort, fever, chills, facial oedema, asthenia, injection site discomfort, injection site reaction, injection site oedema, extravasation at injection site, injection site inflammation following extravasation, injection site necrosis following extravasation, 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 Haemolysis Psychiatric disorders Confusion Eye disorders Transient blindness, eye pain Ear and labyrinth disorders Tinnitus, ear pain Respiratory, thoracic and mediastinal disorders: Asthma Gastrointestinal disorders Dry mouth Skin and subcutaneous tissue disorders Bullous dermatitis Renal and urinary disorders Urinary incontinence, renal tubular necrosis, acute renal failure Investigations Prolonged PR on electrocardiogram, elevated serum iron, elevated serum bilirubin, elevated serum ferritin, abnormal liver function tests Adverse reactions in children Adverse reactions related to gadoteric acid are uncommon in children. The expected types of reaction are 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 suitable rehydration. 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 that haemodialysis 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 specific pharmacodynamic activity and is biologically very inert. 5.2. Pharmacokinetic properties
Following intravenous injection, gadoteric acid is mainly distributed in the extracellular fluid. It is not bound 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 is eliminated 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 safety pharmacology, 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 clinical practice and for 28 days did not induce any marked effect apart from reversible vacuolization of renal proximal tubule cells. Animal studies showed negligible (less than 1% of the administered dose) secretion of gadoteric acid in 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 medicinal products. 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 for the examination. The peel-off tracking label on the syringes should be stuck onto the patient record to enable accurate recording 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
GUERBET BP 57400 95943 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
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