◎造影剤の製品概要修正　ゲルベ社がＭＲＩ検査用で

PR25106 JＢＮ　外０１６１（産業、医療）（０７・２・１０） 【産業担当デスク殿】２５１０６ ◎造影剤の製品概要修正 　　ゲルベ社がＭＲＩ検査用で 　【ビルパント（フランス）９日ＰＲＮ＝共同ＪＢＮ】ＭＲＩスキャン（磁気共鳴断層撮影）を利用した腎不全患者の間で、数十例の腎性全身性線維症（ＮＳＦ）が世界で確認されている。このため、欧州医薬品審査庁（ＥＭＡ）の安全性監視作業部会は放射線スキャンで使用する造影剤の予防措置を強化する勧告書をまとめた。 　強化された造影剤使用予防措置はＭＲＩで使われるガドリニウム系の造影剤に適用される。この結果、ドタレム（Dotarem＝登録商標、一般名ガドテル酸、フランスのゲルベ社）の製品概要（ＳＰＣ）も修正された。現在まで、ＮＳＦとドタレムとの関連を示す例は１件もない。 　▽なぜ警告と新予防措置が出されたのか？ 　これらの措置は、最近ＮＳＦ（注２）と改称された腎性線維化性皮膚症（ＮＦＤ）（注１）と呼ばれる珍しい疾病の発生に絡み、特定のガドリニウム系ＭＲＩ関連製品を厳密に調べることと関連している。この新しい病変は１９９７年に初めて記述された。それ以来、数多くの症例（２００件以上）が米国では米食品医薬局（ＦＤＡ）により（注４）、また欧州で（注５）報告された（注３）。病状の特徴はさまざまな人体器官に影響を与えることのある拡散性病変で、そのひとつは皮膚である。それは次第に進行し、病変は安定する場合と進行が続く場合があり、幾つかの死体が解剖されたケースも観察されている（注６）。 　▽ＮＳＦとガドリニウム・キレート 　この病変の見られたすべての人は腎不全に罹っており、ほとんどの場合急性で一部は人工透析を受けていた（注１）。ＭＲＩスキャンは症状が現れる前の２日から１８カ月間の間に実施されたが、ほとんどの場合２カ月から３カ月にかけて行われた（注５）。 　ＮＳＦの進行とガドリニウム・キレート系の造影剤との関連は２００６年１月に初めて提言された（注７）。多くの場合、ＭＲＩに使用された製品はガドジアミド（OMNISCAN＝登録商標）で、少ない例ではガドペンテト酸ジメグルミン（MAGNEVIST＝登録商標）またはガドベルセトアミド（注４．５、８）（OPTIMARK＝登録商標）が使用された。 　この疾病の生理病理学は依然として不明確である。因果関係を明確には特定できない。しかし研究者がＮＳＦ症状の見られる患者の皮膚の生検でガドリニウムの存在を強調しているため、関連性はあり得るようだ（注９、１０）。 　腎不全は糸球体ろ過率の永続的な低減と規定される。重症型ではこの病状は慢性あるいは末期的腎不全を引き起こすことがある。治療には人工透析か腎臓移植が含まれる。 　▽ドタレム：有効性と耐性 　現在までドタレムを投与された患者の間でＮＳＦの症例は１件も報告されていないため、欧州医薬品庁（ＥＭＥＡ、２００４年５月にＥＭＡに改名）は慢性腎不全の患者にドタレムを使用するための予防措置を製品概要（ＳＰＣ）に追加することだけを求めた。臨床レベルでのドタレムの耐性と診断上の関心は、２００７年１月に医学雑誌「インベスティガティブ・レイディオロジー」（Investigative Radiology、注１０）に掲載された科学論文のテーマとなった。その研究は２００４年１月から２００５年１０月にかけてＭＲＩスキャンを利用した患者２万４３０８人を対象にドイツで行われた。副作用が認められたのはわずか０・４％で、それも主として発熱、吐き気、短期の味覚変化に限られていた。有害事象が報告されたのはわずか１件にとどまり、それはＮＳＦとは関係なく患者にいかなる影響も与えなかった。 　▽ドタレム：安定した化学構造 　ＥＭＥＡ安全性監視作業部会は結論として、慢性腎不全の症状が見られる患者のＮＳＦ進行を説明することができるガドリニウム・キレートには安定性で違いのあることを明記した。ガドリニウム・キレートの安定性はその構造と関連している。最も安定しているドタレムはマクロ循環的構造を有し、解離半減期が最長である。このため遊離状態において毒性のあるガドリニウムの放出が防止され、マクロ循環的構造の中に閉じ込められる。 　▽ドタレム 　ドタレムは脳、延髄、脊髄、その他（血管造影を含む）全身の病変で磁気共鳴画像を得るために成人、子ども、幼児の治療に適応される。ドタレムは１９８９年以来、世界中で広く商品化され、ＭＲＩスキャンを利用した１０００万人以上の人々に投与されてきた。ドタレムの使用が認可された適応症は国によって異なる。 　▽ゲルベ社について 　ゲルベ社（www.guerbet.com）は画像診断を専門とする唯一の製薬グループである。世界市場でＸ線とＭＲＩ検査用の幅広い造影剤を備えている。これらの製品は医療専門家（放射線科医、心臓内科医、腫瘍専門家など）がその患者（心臓血管疾患、炎症性疾患、変性疾患、がん）の病変を診断、治療するのに役立つ。新薬の開発と将来の発展のために同社はＲ＆Ｄに毎年大きな資源を投資し、１６０人のスタッフと売上高の１０％に相当する額を向けている。欧州での市場シェアは２５％とその基盤は確立しており、現在、米国と日本で活動を拡大している。 　▽参考文献 (注1) Cowper SE, Robin HS, Steinberg SM, Su LD, Gupta S, LeBoit PE. Scleromyxoedema-like cutaneous diseases in renal-dialysis patients. Lancet 2000;356:1000-1001 (注2) Cowper SE, Su LD, Bhawan J, Robin HS, LeBoit PE. Nephrogenic fibrosing dermopathy. Am J Dermatopathol 2001; 23: 383-93 (注3) A reporting register has been set up on the web: International Center for Nephrogenic Fibrosing Dermopathy Research (ICNFDR) www.icnfdr.org (注4) FDA, Public Health Advisory Update on Magnetic Resonance Imaging (MRI) Contrast Agents Containing Gadolinium and Nephrogenic Fibrosing Dermopathy http://www.fda.gov/cder/drug/advisory/gadolinium_agents_20061222.htm (注5) Thomsen HS. Nephrogenic systemic fibrosis: a serious late adverse reaction to gadodiamide. Eur Radiol. 2006 Dec;16(12):2619-21 (注6) NSF/NFD update. MRI Summit 2006. Dearborn, Michigan, USA. October 21-22, 2006; (注7) Grobner T. Gadolinium: a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant 2006;21:1104-1108. (注8) Thomsen HS, Morcos SK, Dawson P. Is there a causal relation between the administration of gadolinium based contrast media and the development of nephrogenic systemic fibrosis (NSF)? Clin Radiol. 2006 Nov;61(11):905- (注9)High WA et al. Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis. J Am Acad Dermatol 2006 In Press. (注10) Boyd AS et al. Gadolinium deposition in nephrogenic fibrosing dermopathy. J Am Acad Dermatol 2006, In press (注11) 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. (注12) Caravan P, Ellison JJ, McMurry TJ, Lauffer RB. Gadolinium(III) Chelates as MRI Contrast Agents: Structure, Dynamics, and Applications. Chem Rev. 1999 Sep 8;99(9):2293-352 （了） ▽問い合わせ先 Marina Rosoff - Ruder Finn France, +33-(0)1-56-81-15-03, or mrosoff@ruderfinn.fr Web site:  http://www.guerbet.com

Contrast Media Used in MRI and Nephrogenic Systemic Fibrosis in Patients With Chronic Renal Failure: Guerbet Modifies the SPC of Dotarem(R) and Confir

VILLEPINTE, Feb. 9 /PRN =KYODO JBN/ --          Several dozen cases of nephrogenic systemic fibrosis among patients with renal failure who have benefited from a Magnetic Resonance Imaging (MRI) scan have been identified in the world. As a result, the Pharmacovigilance Working Party of the European Medicines Agency has drawn up recommendations to reinforce the precautions for contrast media used during the radiological scan.     The reinforced usage precautions apply to all gadolinium-based contrast media used in MRI. As a result, the summary of product characteristics (SPC) of Dotarem(R) (Gadoteric acid, Guerbet) has been modified. Up until now, no case of nephrogenic systemic fibrosis has yet been linked to DOTAREM(R).     Why the warning and the new precautions?     These measures are linked to the challenging of certain gadolinium-based MRI products in the development of a rare illness called nephrogenic fibrosing dermopathy NFD (1), recently renamed as nephrogenic systemic fibrosis NSF (2).     This new pathology was described for the first time in 1997. Since then, a number of cases (more than 200) have been reported (3), in the United States by the Food and Drug Administration (4) and in Europe (5).     The condition is characterized by diffuse lesions that can affect different organs, one of which is the skin. It evolves progressively. Certain lesions stabilize while others continue to evolve and some cadavers have been observed (6).     Nephrogenic systemic fibrosis and gadolinium chelates     All those who have presented with this illness were suffering from renal failure, most of the cases were acute and some were receiving dialysis (1). An MRI scan had been carried out on some patients within a time period of between two days and 18 months before the symptoms emerged, in most of the cases two to three months beforehand (5).     The link between the development of nephrogenic systemic fibrosis and using the gadolinium chelates-based contrast medium was suggested for the first time in January 2006 (7). In the large majority of cases, the product used for MRI was gadodiamide (OMNISCAN(R)), in a smaller number of cases gadopentetate dimeglumine (MAGNEVIST(R)) or gadoversetamide (4,5,8) (OPTIMARK(R)) were used. The physiopathology of this illness remains unclear.     The link between cause and effect cannot be determined for definite. The link appears conceivable however because researchers have underlined the presence of gadolinium in the skin biopsies of patients presenting with nephrogenic systemic fibrosis (9,10).     Renal failure is defined as a permanent reduction in the glomerular filtration rate. In a severe form, this condition can lead to chronic or even terminal renal failure. Treatment involves dialysis or kidney transplants.     DOTAREM(R): effectiveness and tolerance     As no case of nephrogenic systemic fibrosis has up until now been reported among patients who have received DOTAREM(R), the EMEA has demanded only the addition in the SPC of a precaution for using DOTAREM(R) among patients suffering from chronic renal failure. The tolerance of DOTAREM(R) on the clinical level and its diagnostic interest were the subject of a scientific article that appeared in January 2007 in the Investigative Radiology (10) journal. The study was carried out in Germany among 24,308 patients who had benefited from an MRI scan between January 2004 and October 2005. Secondary effects, observed in only 0.4% of cases, limited themselves mainly to feelings of heat, nausea or a short-term change in taste. Only one serious event was reported, which was not connected to nephrogenic systemic fibrosis and there were no repercussions for the patient.     DOTAREM(R), a stable chemical structure     In its conclusions, the EMEA Pharmacovigilance Working Party specifies that there are differences in stability between the gadolinium chelates, which can explain the development of nephrogenic systemic fibrosis among patients presenting with chronic renal failure.     The stability of gadolinium chelates is linked to their structure: the most stable, DOTAREM(R), has a macrocyclical structure and the longest dissociation half-life. This prevents the release of gadolinium, toxic in the free state, which remains imprisoned in the macrocyclical structure (11,12).     DOTAREM(R)     DOTAREM(R) is indicated for adults, children and infants for magnetic resonance imaging for cerebral and medullary pathologies, rachis pathologies and other whole-body pathologies (including angiography). Largely commercialized around the world since 1989, DOTAREM(R) has been administered to more than 10 million people who have benefited from an MRI scan. The approved indications for Dotarem(R) can vary between countries.     Guerbet     Guerbet (www.guerbet.com) is on the only pharmaceutical group dedicated entirely to medical imaging. It has a complete range of contrast media for X-ray and MRI on the world market. These products help the medical profession (radiologists, cardiologists, oncologists etc.) diagnose and treat the pathologies of their patients (cardiovascular, inflammatory and degenerative pathologies and cancers). To discover new products and ensure its future development, Guerbet invests major resources in to R&D every year: 160 people and a sum equivalent to 10% of company sales. Guerbet is well established in Europe with a 25% market share and it is currently developing its presence in the US and Japan.     References:     (1) Cowper SE, Robin HS, Steinberg SM, Su LD, Gupta S, LeBoit PE. Scleromyxoedema-like cutaneous diseases in renal-dialysis patients. Lancet 2000;356:1000-1001     (2) Cowper SE, Su LD, Bhawan J, Robin HS, LeBoit PE. Nephrogenic fibrosing dermopathy. Am J Dermatopathol 2001; 23: 383-93     (3) A reporting register has been set up on the web: International Center for Nephrogenic Fibrosing Dermopathy Research (ICNFDR) www.icnfdr.org     (4) FDA, Public Health Advisory Update on Magnetic Resonance Imaging (MRI) Contrast Agents Containing Gadolinium and Nephrogenic Fibrosing Dermopathy http://www.fda.gov/cder/drug/advisory/gadolinium_agents_20061222.htm     (5) Thomsen HS. Nephrogenic systemic fibrosis: a serious late adverse reaction to gadodiamide. Eur Radiol. 2006 Dec;16(12):2619-21     (6) NSF/NFD update. MRI Summit 2006. Dearborn, Michigan, USA. October 21-22, 2006;     (7) Grobner T. Gadolinium: a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant 2006;21:1104-1108.     (8) Thomsen HS, Morcos SK, Dawson P. Is there a causal relation between   the administration of gadolinium based contrast media and the development of nephrogenic systemic fibrosis (NSF)? Clin Radiol. 2006 Nov;61(11):905-     (9)High WA et al. Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis. J Am Acad Dermatol 2006 In Press.     (10) Boyd AS et al. Gadolinium deposition in nephrogenic fibrosing dermopathy. J Am Acad Dermatol 2006, In press     (11) 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.     (12) Caravan P, Ellison JJ, McMurry TJ, Lauffer RB. Gadolinium(III) Chelates as MRI Contrast Agents: Structure, Dynamics, and Applications. Chem Rev. 1999 Sep 8;99(9):2293-352   SOURCE:  Guerbet CONTACT:  Media:              Marina Rosoff - Ruder Finn France,              +33-(0)1-56-81-15-03, or              mrosoff@ruderfinn.fr Web site:  http://www.guerbet.com