Gadolinium Containing Contrast Agents
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06 July 2017 EMA/411650/2017 Pharmacovigilance Risk Assessment Committee (PRAC) Assessment report Referral under Article 31 of Directive 2001/83/EC resulting from pharmacovigilance data Gadolinium containing contrast agents Procedure number(s): EMEA/H/A-31/1437 Optimark EMEA/H/A-31/1437/C/000745/0034 Note: Assessment report as adopted by the PRAC and considered by the CHMP with all information of a commercially confidential nature deleted. 30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact An agency of the European Union © European Medicines Agency, 2017. Reproduction is authorised provided the source is acknowledged. Table of contents Table of contents ......................................................................................... 2 1. Information on the procedure ................................................................. 4 2. Scientific discussion ................................................................................ 4 2.1. Introduction......................................................................................................... 4 2.2. Non-clinical aspects .............................................................................................. 5 2.2.1. Non-chelated gadolinium toxicity ......................................................................... 5 2.2.2. Deposition in the brain ....................................................................................... 5 2.2.3. Impact of renal impairment on brain accumulation .............................................. 13 2.2.4. Discussion on non-clinical data .......................................................................... 13 2.2.5. Non-clinical conclusions .................................................................................... 14 2.3. Clinical Data on efficacy ...................................................................................... 15 2.3.1. Discussion on efficacy ...................................................................................... 20 2.3.2. Conclusion on efficacy ...................................................................................... 21 2.4. Data on clinical safety ......................................................................................... 21 2.4.2. Discussion on clinical safety .............................................................................. 33 2.4.3. Conclusions on clinical safety ............................................................................ 39 Future studies .......................................................................................................... 40 Risk minimisation measures ....................................................................................... 40 3. Expert consultation ............................................................................... 41 4. Benefit-risk balance (initial referral procedure) .................................... 42 4.1. Benefit-risk balance assessment ........................................................................... 42 4.1.1. Gadoteridol ..................................................................................................... 42 4.1.2. Gadobutrol ..................................................................................................... 42 4.1.3. Gadoteric acid ................................................................................................. 43 4.1.4. Gadopentetic acid ............................................................................................ 44 4.1.5. Gadodiamide ................................................................................................... 45 4.1.6. Gadoversetamide ............................................................................................ 46 4.1.7. Gadoxetic acid ................................................................................................ 46 4.1.8. Gadobenic acid ................................................................................................ 47 4.2. Benefit risk conclusions ( initial referral procedure) ................................................. 48 4.3. Re-examination procedure ................................................................................... 50 4.3.1. Detailed grounds for re-examination submitted by the MAHs................................. 50 4.3.2. PRAC discussion on grounds for re-examination .................................................. 53 4.3.3. Final benefit-risk balance following re-examination .............................................. 59 5. Risk management .................................................................................. 60 5.1.1. Amendments to the product information ............................................................. 60 5.1.2. Direct Healthcare Professional Communications/Communication plan ..................... 61 Assessment report Gadolinium containing contrast agents EMA/411650/2017 Page 2/82 6. Condition(s) for lifting the suspension of the marketing authorisations 61 7. Grounds for Recommendation following the re-examination procedure 62 8. References ............................................................................................ 64 Assessment report Gadolinium containing contrast agents EMA/411650/2017 Page 3/82 1. Information on the procedure Gadolinium containing contrast agents (GdCAs) are complexes of gadolinium (III) with different types of organic chelators. They are used for contrast enhancement in magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA). Intra-articular GdCA formulations are also used in arthrography for MR of joints. Within the class, they can be differentiated in linear or macrocyclic compounds and whether they are ionic or non-ionic. In a previous referral under Article 31 of Directive 20010/83/EC finalised in 2010, the Committee for Medicinal Products for Human Use (CHMP) concluded that the use of GdCAs is associated with the risk of nephrogenic systemic fibrosis (NSF), a serious and life-threatening syndrome involving fibrosis of the skin, joints and internal organs in patients with renal impairment. The CHMP concluded that the risk of NSF is different for the different GdCAs, which were then categorised into three groups for NSF risk (high risk, medium risk and low risk). In addition, since the finalisation of the previous referral, data in animals and humans indicates the accumulation of gadolinium following administration of GdCAs in other tissues, including the liver, kidney, muscle, skin and bone. Furthermore, recent publications indicated the accumulation of gadolinium in the brain, which was initially found in unenhanced MRI scans in patients that had received GdCAs in the past. In January 2016, in the framework of a PSUSA procedure, the PRAC reviewed all available literature and data related to the accumulation of gadolinium in the brain and recommended the removal of statements from the product information of all GdCAs that the products do not pass the intact blood brain barrier. The MAHs were also requested to update the safety specifications in the Risk Management Plans for these products to reflect these findings. However, the PRAC considered that the knowledge about brain accumulation and its clinical consequences needed to be further investigated in the appropriate framework, requiring therefore a review at EU level. On 9 March 2016, the European Commission triggered a referral under Article 31 of Directive 2001/83/EC resulting from pharmacovigilance data and requested the PRAC to assess the impact of the above concerns on the benefit-risk balance of gadolinium containing medicinal products and to issue a recommendation on whether the relevant marketing authorisations should be maintained, varied, suspended or revoked. 2. Scientific discussion 2.1. Introduction Gadolinium-containing contrast agents (GdCAs) consist of a gadolinium ion that is bound to a carrier molecule (a chelator or chelating agent). Interactions between the gadolinium ion and water molecules alter the relaxation time of protons in the water molecules within a magnetic field, which increases the signal intensity on T1-weighted magnetic resonance (MR) imaging. GdCAs are used to provide image enhancement of magnetic resonance imaging (MRI), magnetic resonance angiography (MRA) and MR arthrography. The eight GdCAs authorised in the EU have different carrier molecules with different physicochemical properties. The GdCAs may be categorised by their structure: whether they are linear of macrocyclic, and whether the molecule is ionic or non-ionic. The carrier molecules of the authorised GdCAs include examples of all combinations of these two properties. The GdCAs are generally injected into a vein and are cleared from the body by the kidneys. Assessment report Gadolinium containing contrast agents EMA/411650/2017 Page 4/82 Most products are indicated for whole body MRI or have specific organs or areas of the body indications for enhancement of MRI. There are two GdCAs that undergo hepatic uptake, and can therefore provide delayed-phase enhancement of hepatic MRI; these are Primovist (gadoxetic acid) and Multihance (gadobenic acid). Primovist only has a liver imaging indication. Multihance has also other indications. Two GdCAs products, gadopentetic acid (Magnevist 2mmol/l) and gadoteric acid (Artirem), are authorised at lower doses for intra-articular