MLリソース：甲状腺ホルモン
[1108,1192]●levothyroxine sodium(Synthroid[Abbott]) レボチロキシンナトリウム日本語版註）levothyroxine sodium(Synthroid[Abbott]) レボチロキシンナトリウム
【別名】 【開発元】 [DBR_ID]24867-2430
【化学名】Monosodium O-(4-hydroxy-3,5-diiodophenyl)-3,5-diiodo-L-tyrosinate hydrate; synthetic crystalline L-3,3',5,5'-tetraiodothyronine sodium salt [levothyroxine (T4) sodium].
【承認】FDA申請=31-Jul-2001、FDA承認=24-Jul-2002[Abbott;] ; 【製剤】錠 【製剤～日本】1錠中日局レボチロキシンナトリウム(乾燥物)25,50,100μg 【適応】1)Hypothyroidism 2)Pituitary TSH Suppression 【適応～日本】粘液水腫，クレチン病，甲状腺機能低下症(原発性及び下垂体性)，甲状腺腫 【用法用量】 【用法用量～日本】[錠剤]レボチロキシンナトリウムとして通常，成人25～400μgを1日1回経口投与する． 一般に，投与開始量には25～100μg，維持量には100～400μgを投与することが多い． なお，年齢，症状により適宜増減する． 【作用】 【特徴】 【製品情報】 【添付文書】 【EU】 【日本】第十四改正日本薬局方第一部収載品 【その他】Abbott社はKnoll社買収(2001.3)により本剤を取得。【日本語版コメント1317～【短信】甲状腺機能亢進症治療薬プロピルチオウラシル】
抗甲状腺薬のプロピルチオウラシル(PTU)はバセドウ病(グレーブス病)による甲状腺機能亢進症に使われ、肝障害があることは日本の添付文書に記載されているが、米FDAは1969年～2008年の32例の重篤な肝障害の報告(死亡13)にもとずきワークショップ(2009.4.18;詳細資料;http://www.fda.gov/Drugs/NewsEvents/ucm164445.htm)で検討後、2009.6.4 FDAアラートを発行、ATA(米国甲状腺学会)もグレーブス病(Graves'disease/バセドウ病)の治療ガイドラインを改訂することとなった。→詳細は参考資料●MLリソース：甲状腺ホルモンに纏めた。★
★1317★25/15★09.07.27★057★【短信】甲状腺機能亢進症治療薬プロピルチオウラシル/1p●MLリソース：甲状腺ホルモン
●02987-2430 PROPYLTHIOURACIL[INN ﾌﾟﾛﾋﾟﾙﾁｵｳﾗｼﾙ
PROCASIL;PROPACIL;PROPILTIOURACLE[DCIT];PROPYCIL;PROPYLTHIOURACIL[INN][BP][BPC][DCF][IP][JP][NFN];PROPYL-THYRACIL;PROTHYRAN;PTH[=PROPYLTHIOURACIL];PTU;THIURAGYL;THYREOSTATII;ﾌﾟﾛﾋﾟﾙﾁｵｳﾗｼﾙThe thionamides propylthiouracil and methimazole are both used to treat hyperthyroidism.1 Propylthiouracil causes severe hepatic toxicity or hepatic failure in about 0.1% of adults and children.2,3 It is the third leading cause of liver transplants due to drug toxicity (acetaminophen and isoniazid are the first two). Methimazole may cause less serious hepatic toxicity; reversible cholestatic jaundice has been reported. There is generally no good reason to continue to use propylthiouracil, with 2 possible exceptions. First, propylthiouracil may be preferred for treatment of life-threatening thyroid storm because it inhibits conversion of T4 to T3, while methimazole does not. Second, propylthiouracil may be preferable for use in pregnancy because use of methimazole has rarely been associated with aplasia cutis and with choanal and esophageal atresia.
1. Drugs for thyroid disorders.Treat Guidel Med Lett 2009; 7:57.
2. SA Rivkees and DR Mattison. Ending propylthiouracilinduced liver failure in children. N Engl J Med 2009; 360:1574.
3. DS Cooper and SA Rivkees. Putting propylthiouracil in perspective. J Clin Endocrinol Metab 2009; 94:1881.
●FDA ●FDA Newsroom - FDA Press Releases - FDA Warns About Serious Liver Injury Associated With Anti-Thyroid Drug[2009.6.3] - Propylthiouracyl-Related Liver Toxicity; Public Workshop; April 18, 2009, Washington, D.C. ～詳細な検討資料がある。 ●Index to Drug-Specific Information Propylthiouracil Risk of serious liver injury, including liver failure and death, associated with the use of propylthiouracil in adult and pediatric patients. Posted 06/04/2009 ●MedWatch Propylthiouracil Risk of serious liver injury, including liver failure and death, associated with the use of propylthiouracil in adult and pediatric patients. Posted 06/04/2009 ●Drug Safety Oversight Board Drug Safety Oversight Board Meeting, June 18, 2009 - June 4, 2009 - Propylthiouracil and hepatic failure - FDA Alert 2009.6.4 Propylthiouracilは1947年，methimazoleは1950年に製造販売承認を受けている。 FDA は，1969年～2008年にpropylthiouracil使用に関連する重篤な肝障害のAERS症例 (有害事象報告システム)を32例（成人が22例，小児が10例）特定している。 成人患者の症例のうち，死亡が12例，肝移植が6例発生した。小児患者の症例では， 死亡が1例，肝移植が6例であった。 一方，methimazoleでは重篤な肝障害のAERS症例が5例特定されている。5例とも成人患者 であり，うち3例が死亡した。 ATA(米国甲状腺学会)もグレーブス病(Graves'disease/バセドウ病)の治療ガイドラインを 数カ月以内に改訂予定。 ●「医薬品安全性情報（海外規制機関）」 ★医薬品安全性情報 Vol.7 No.14（2009/07/09） 【米FDA(U. S. Food and Drug Administration)】 ﾙ� 抗甲状腺薬propylthiouracil：肝不全などの重篤な薬剤性肝障害のリスク........... 7 Propylthiouracil-induced liver failure FDA Alert 通知日：2009/06/03（2009/06/04：一部修正） http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm162701.htm ◆医療従事者向け情報 FDA 警告 A FDA は医療従事者に対し，成人および小児患者への抗甲状腺薬propylthiouracilの使用に伴う 重篤な肝障害（肝不全や死亡を含む）のリスクについて通知する*1。 FDAのAERS（有害事象報告システム）への報告では，propylthiouracilは抗甲状腺薬の methimazoleと比較して，肝毒性のリスクが高いことが示唆されている。Propylthiouracilと methimazoleはどちらもグレーブス病（バセドウ病）による甲状腺機能亢進症の治療を適応としてい るが，医療従事者はグレーブス病と最近診断された患者に対し，どちらの医薬品で治療を開始す A原文にはこのFDA警告に関する説明として以下の内容が記載されている。 「本情報は，propylthiouracilについて入手したデータのFDAによる現時点での解析結果を反映している。本情 報の公表は，この医薬品と新たに提起された安全性問題に因果関係があるとFDAが結論したことを示すもので はない。また，FDAがこの医薬品を処方しないよう医療従事者に助言するものでもない。新たな情報や解析結果 が得られた場合，FDAは本情報を更新する予定である。」 るかについて慎重に検討すべきである。医師は，propylthiouracilによる治療中の患者に肝障害の 症状・徴候が見られないか，入念にモニタリングすべきである（特に治療開始後6カ月間）。 Propylthiouracilは1947年，methimazoleは1950年に製造販売承認を受けている。 FDAは，propylthiouracil使用に関連する重篤な肝障害のAERS症例を32例（成人が22例， 小児が10例）特定している。成人患者の症例のうち，死亡が12例，肝移植が6例発生した。小児 患者の症例では，死亡が1例，肝移植が6例であった。 一方，methimazoleでは重篤な肝障害のAERS症例が5例特定されている。5例とも成人患者 であり，うち3例が死亡した。 一般にpropylthiouracilは，methimazoleにアレルギー反応があるか忍容性がない患者を除き， 第二選択薬とされている。妊娠中のmethimazole使用については胎芽病（皮膚形成不全症を含 む）の症例がまれに報告されているのに対し，propylthiouracilではこれらの症例報告がない。した がって，妊娠第1三半期のグレーブス病患者には，propylthiouracilの使用がより適切である可能 性がある。 FDAは2009年4月18日，ATA（American Thyroid Association：米国甲状腺学会）と公開研究 会を共催し，propylthiouracilが関係する肝毒性について議論した2）。FDAは，重篤な肝有害事象 報告のモニタリングを継続するとともに，propylthiouracilの処方情報（特に小児患者への使用）を 変更する作業を行っている。なお，ATAもグレーブス病の治療ガイドラインを数カ月以内に改訂す る予定である。 ◇医療従事者に対する推奨および情報 ・妊娠第1三半期の患者，またはmethimazoleにアレルギー反応があるか忍容性がない患者には， propylthiouracilの使用が望ましい。 ・Propylthiouracilによる治療中の患者に肝障害の症状・徴候が見られないか，入念にモニタリン グすること（特に治療開始後6カ月間）。 ・患者に肝障害が疑われる場合は，propylthiouracilによる治療を直ちに中止し，肝障害のエビデ ンスを評価するとともに，対症療法を行うこと。 ・Methimazoleにアレルギー反応があるか忍容性がなく，他に治療選択肢がない場合を除き， propylthiouracilを小児患者に使用しないこと。 ・妊娠中のmethimazole使用については，胎芽病（皮膚形成不全症を含む）の症例がまれに報告 されている。一方，propylthiouracilではこれらの症例報告がない。したがって，妊娠第1三半期 のグレーブス病患者には，propylthiouracilの使用がより適切である可能性がある。 ・疲労感，脱力，漠然とした腹痛，食欲喪失，そう痒，挫傷の起きやすさ，眼や皮膚の黄変といっ た肝障害の徴候・症状のいずれかを患者が自覚した場合は，直ちに医療従事者に連絡するよう 助言すること。 文 献 1） Rivkees SA. The treatment of Graves’ disease in children. J Pediatr Endocrinol Metab 2006 Sep;19(9):1095-111. 2） The Food and Drug Administration and American Thyroid Association. Propylthiouracil-Related Liver Toxicity: Public Workshop, April 19, 2009, Washington, D.C. http://www.fda.gov/Drugs/NewsEvents/ucm164445.htm 参考情報 ＊1： 本件について，FDA News Release が同日付で通知された（下記のリンクを参照）。 http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm164207.htm ◎Propylthiouracil〔プロピルチオウラシル，甲状腺ホルモン生合成抑制薬，抗甲状腺薬〕 国内：発売済 海外：発売済 ◎Methimazole〔メチマゾール，thiamazole（チアマゾール，JAN），甲状腺ホルモン生合成抑制薬， 抗甲状腺薬〕国内：発売済 海外：発売済 ●プロピルチオウラシル - Wikipedia
【日本語版コメント to 1108】
最初の合成甲状腺製剤シンスロイドは，1938年に販売開始，当時は現在の基準に則った承認データを必要としなかった。年間600億円の売上の薬で，他の甲状腺製剤も販売されるようになると，それらの効果の比較を求める声が高まってきた。そこで1987年に，シンスロイドの製造企業ブーツ社は，カリフォルニア大学サンフランシスコ校のベティ・ドン薬学博士にその比較研究を依頼。その結果，「シンスロイドの甲状腺ホルモン含有量が他の新薬と比較して高い」という，ブーツ社側にとってよい結果を得た。この時以来シンスロイドに関する疑義が問題となり今日に至っている。 その経緯は●〔第２回〕新GCPで薬害から患者を守れ /ブーツ社とカリフォルニア大学の攻防[医学界新聞第２４４２号 2001年6月25日]を参照。
メーカーもBoots社からクノール社[Knoll]、そして現在のアボツト社(2001.3 Knoll買収)に変わっているが。またAbbott社は競争相手Watson社がSynthroidの中傷広告を出したとして2001.6.12訴訟を起こすなど騒然としている。
この問題に関しては以下のサイトも参考になる。http://www.synthroid.com/ ; http://www.abbott.com/ ; http://abbott.com/news/press_release.cfm?id=274 ; FDA -CDER -Guidance
【市場】 ●Abbott ($ millions) 2003 2002 2001 米国内 海外 米国内 海外 米国内 海外 Synthroid 565(+15.5) 44(+42.9) 489(+9.9) 31(+42.9) 445(-) 22(-) (levothyroxine sodium) ●King Pharmaceuticals Inc. ($Million) 2003 2002 2001 2000 1999 Levoxyl 134.1(-21) 169.5(+61) 105.1 58.1 32.8 (levothyroxine sodium tablets, USP) -2000.8 Jones Pharma Incorporated.と合併。 同社の甲状腺製剤、止血剤Thrombin 麻酔薬Brevital Sodium(methohexital sodium注)を製品ラインに加えた。 ★帝国臓器製薬 売上(億円) 04/3 03/3 チラーヂンＳ 27 26 [レボチロキシンNa]甲状腺ホルモン製剤 【開発中の新薬】 ●「治験」ホームページ[厚生労働省] - 開発中の新薬[＜情報提供：日本製薬工業協会＞] /2009.11.9 会社別開発中新薬一覧。 検索機能なし。７９社から情報提供●New Medicines in Development[PhRMA 米製薬協] /2009.11.9
治験薬記号(一般名)
および剤型予定される効能又は効果、
対象疾患名および症状名開発段階 その他 国内 海外 (地域) 「テリパラチド酢酸塩静注用100「旭化成」」PTH 注[旭化成ファーマ] 【適応拡大】副甲状腺ホルモン（骨粗鬆症） 第Ⅲ相 自社：承認済（特発性副甲状腺機能低下症と偽性副甲状腺機能低下症との鑑別診断） ITM-058 注射剤（皮下投与）（海外開発コード：BIM44058)[帝人ファーマ] 骨粗鬆症 第I相 導入：イプセン社（仏） 【メモ】副甲状腺ホルモン（ヒトPTHrP）1-34フラグメント･アナログ（ヒトPTHrP（1-34）の新規誘導体） 【特徴】kﾎ短期間で骨密度増加と骨折抑制効果を発現する kﾎ先行開発品に比べ、強い骨形成促進作用と高い安全性（高カルシウム血症のリスク低減）を期待 from 投資家向け医薬医療事業スモールミーティング資料（2008年9月1日）≪帝人≫[pdf,37p] LY333334（テリパラチドteriparatide）皮下注製剤[日本イーライリリー] 骨粗鬆症 申請2009.4.28 米欧発売 自社開発、自社品 【メモ】米国販売名Forteo(R)の追加適応「骨折リスクの高い男女における継続的全身グルココルチコイド（ステロイド）療法に関連する骨粗鬆症の治療」が2009.7.23承認 骨形成促進剤のテリパラチドが、グルココルチコイド（ステロイド）誘発性骨粗鬆症治療薬としてEUで適応追加承認[2008.4.9]
2008年4月4日―イーライリリー・アンド・カンパニーは、欧州委員会（EC: European Commission）がFORSTEO(R)（一般名：テリパラチド[遺伝子組換え]注射剤）の追加適応症を承認した、と発表しました。新しい適応は、「骨折リスクの高い男女における全身的継続グルココルチコイド(ステロイド)療法に関連する骨粗鬆症の治療」です。今回の承認は、欧州医薬品審査庁（EMEA: European Medicines Evaluation Agency）のヒト用医薬品委員会（CHMP: Committee for Medicinal Prod-ucts for Human Use）が2月に提出した肯定的意見を受けたものです。 グルココルチコイド(ステロイド)誘発性骨粗鬆症（GIOP: glucocorticoid-induced osteoporosis）はグルココルチコイド剤の長期使用が関与して起きる骨量低下です。グルココルチコイド剤は慢性関節リウマチや閉塞性肺疾患などの炎症性疾患に対して処方されることが多く、世界的にも、50歳以上の人口の1～3％がグルココルチコイド剤の使用者だとされています。
テリパラチドは、「骨芽細胞」（osteoblasts）と呼ばれる骨形成細胞の数と活動を増強することにより、骨形成を促進します。テリパラチドは、EUでは、「骨折リスクの大きい閉経後女性の骨粗鬆症治療薬」として、2003年に承認を獲得しました。2007年には、適応が「骨折リスクの高い男性における骨粗鬆症の治療」に拡大されました。テリパラチドはヒト副甲状腺ホルモンの有効成分（1-34）であり、骨形成細胞（骨芽細胞）への直接的な作用、腸におけるカルシウム吸収の間接的な増強、および、腎臓によるカルシウム再吸収とリン酸塩排出の促進によって骨形成を活発化させます。テリパラチドは2002年以来米国で販売されており、2003年には、骨折リスクの高い閉経後女性における重症骨粗鬆症の治療薬として、EUで承認されました。
●表から削除～承認 ●表から削除～開発中止など CHS13340 経鼻[中外製薬] 骨粗鬆症 遺伝子組換え副甲状腺ホルモン（rhPTH1-34) 第Ⅱ相 導入･共同開発/アスビオファーマ
2006.12期提携解消CAL 注[中外製薬] 悪性腫瘍に伴う高カルシウム血症 がんの骨転移 ヒト化抗PTHrPモノクローナル抗体 第Ⅰ相終了 第Ⅰ/Ⅱ相（米） 自社：2006前期除外 from Wolters Kluwer Health's Adis R&D Insight 【解説資料】 ●メルクマニュアル |第02節 内分泌・代謝疾患 甲状腺疾患 ●薬のメモ：甲状腺及び抗甲状腺薬 ●発掘！やくやく大事典：甲状腺ホルモン ---個別製品の組成、適応・投与方法、使用上の注意、副作用など ●甲状腺ホルモン剤 by 畑内科クリニック 院長 畑 直成 ■ICD-9 codes[American Thyroid Association] 【疫学資料】
Registered Name Company Status Indication 備考 NPSP 558(parathyroid hormone 1-84 [rDNA origin] injection) NPS Pharmaceuticals(Originator) 米III Hypoparathyroidism NPSP558 is our proprietary recombinant, full-length (1-84), human parathyroid hormone (PTH 1-84) that we are developing in the U.S. as a potential treatment for hypoparathyroidism, a rare condition in which the body produces insufficient levels of parathyroid hormone. Because the primary role of parathyroid hormone is to maintain normal calcium levels in the blood, the consequences of its absence is low circulating calcium levels or hypocalcemia, which can cause tingling of the hands, fingers, and mouth, serious muscle cramping, tetany or convulsions. The consequences of hypoparathyroidism include vitamin D deficiency, hypercalciuria, and bones of poor material quality. Because NPSP558 is identical in structure to the 84 amino acid single-chain polypeptide human parathyroid hormone and mimics the action of natural parathyroid hormone, we believe it has the potential to be the first true hormone therapy for hypoparathyroidism and return the body to a physiological or “eucalcemic” state. We are currently advancing a Phase 3 registration study, known as REPLACE, evaluating NPSP558 for the treatment of hypoparathyroidism. REPLACE is a double-blind, placebo-controlled trial that will randomize approximately 110 patients at over a dozen sites. The primary objective is to demonstrate, over a 24-week treatment period, that once-daily subcutaneous dosing with NPSP558 at doses of 50μg, 75μg or 100μg is a safe and effective hormone therapy for the treatment of patients with hypoparathyroidism. We believe positive results from REPLACE will enable us to seek U.S. marketing approval for NPSP558 for the treatment of hypoparathyroidism. from NPS Pharmaceuticals Initiates Phase 3 'REPLACE' Study of NPSP558 in Hypoparathyroidism[2008.12.22]
★Hypoparathyroidismの市場性
An estimated 65,000 patients suffer from hypoparathyroidism in the U.S. The most common cause of hypoparathyroidism is injury to or removal of the parathyroid glands during neck surgery. The definition of permanent post-surgical hypoparathyroidism is generally accepted to be insufficient parathyroid hormone to maintain normal calcium levels six months after surgery. Hypoparathyroidism can also be associated with autoimmune or other disorders or it can be idiopathic in nature.Hypoparathyroidism is one of the few hormonal deficiency syndromes in which replacement therapy using the native hormone is not clinically available. Treatment of hypoparathyroidism is further complicated by the lack of national or international consensus management guidelines.
Presently, the only available treatments approved for hypoparathyroidism are life-long high-dose oral supplementation of calcium and active vitamin D metabolites or analogs. The goal of current therapies is to reduce the severity of symptoms; however, these therapies do not return calcium metabolism to a normal or physiological state and present specific challenges for adequate clinical care. Under treatment or missed doses may result in persistent symptoms. Treatment with high doses of oral calcium can contribute to soft tissue calcification and organ damage, with the kidneys being especially vulnerable to hypercalciuria, hypercalcemia, nephrolithiasis, nephrocalcinosis, and renal failure, a common and severe adverse outcome in hypoparathyroidism patients.
Because NPSP558 is identical in structure to the 84-amino acid single-chain polypeptide human parathyroid hormone and mimics the action of natural parathyroid hormone, we believe it has the ideal mechanism of action to fulfill the unmet need of this chronic condition and offer a more physiological treatment outcome than is possible with existing treatments.
In 2007, the FDA granted orphan drug status for NPSP558 for the treatment of hypoparathyroidism. from NPS Pharmaceuticals SEC Filing 10K[2009.3.16] - [pdf]
Sensipar(R)/Mimpara(R)(Cinacalcet HCl) NPS Pharmaceuticals(Originator) 米II 【適応追加】Hyperparathyroidism(Primary) 製品としては発売済みで、海外はAmgenに導出済み(Worldwide Ex-Asia、適応症Secondary hyperparathyroidismおよびHypercalcemia in parathyroid cancer)、日本を含むアジアへは協和キリンに導出(商品名Regpara、適応Secondary hyperparathyroidism; 契約1995年、日本承認2007年10月)。 from NPS Pharmaceuticals SEC Filing 10K[2009.3.16] - [pdf] Liothyronine modified release Archimedes/T3 Therapeutics LLC(Originator) 米I Hypothyroidism Parathyroid hormone oral GlaxoSmithKline/Unigene Laboratories(Originator) 米I Osteoporosis Teriparatide Zelos Therapeutics Inc(Originator) 米I Osteoporosis Teriparatide intranasal MDRNA/Nastech Pharmaceutical Company(Originator) 米II Osteoporosis Teriparatide transdermal Zosano Pharma/ALZA Corporation(Originator) 米II Osteoporosis PREOS(parathyroid hormone 1-84 [rDNA origin] injection) NPS Pharmaceuticals(Originator) 米III Osteoporosis 骨粗鬆症では発売済み、海外はAmgenにライセンス(Worldwide Ex-U.S., Ex-Israel, Ex-Japan)。 Nycomed (Preotact(R) (parathyroid hormone 1-84 [rDNA origin] injection))
In April 2004, we signed a distribution and license agreement with Nycomed , in which we granted Nycomed the exclusive right to develop and market Preotact in Europe. Preotact is the brand name that Nycomed uses to market parathyroid hormone 1-84 [rDNA origin] injection. Nycomed also made an equity investment in our business of $40.0 million through the purchase of 1.3 million shares of our common stock in a private placement, which closed in July 2004. The 2004 Agreement required Nycomed to purchase drug product and devices from us and to pay us royalties on product sales. Additionally, the 2004 Agreement required Nycomed to pay us up to Eur 20.8 million in milestone payments upon the receipt of specified regulatory approvals and the achievement of certain sales targets, to purchase drug product and devices from us, and to pay us royalties on product sales. Through December 31, 2008, we have received Eur 5.6 million in milestone payments from Nycomed under the 2004 Agreement. In July 2007, we entered into a new license agreement with Nycomed ("2007 Agreement"), as described below, which superseded the 2004 Agreement.
Under the 2007 Agreement, we granted to Nycomed an exclusive license to sell, market and commercialize Preotact in all non-U.S. territories, excluding Japan and Israel. We also granted Nycomed a non-exclusive license to manufacture and develop Preotact. If parathyroid hormone 1-84 [rDNA origin] injection is approved in the U.S., Nycomed's licensed rights in Canada and Mexico will revert to us or to a third-party whom we select. We also granted Nycomed a right to negotiate for any new product we offer via a competitive process. Nycomed is required to commercialize Preotact in most countries in Europe. If Nycomed unreasonably delays the launch of Preotact in any country, then we have the right to ensure the launch of Preotact in that country. Nycomed also assumed primary responsibility for manufacturing Preotact and for its further development and improvement. As part of Nycomed's assumption of manufacturing responsibility for Preotact, Nycomed paid us $11.0 million for a significant portion of our existing bulk drug inventory.
The 2007 Agreement requires Nycomed to make milestone payments upon the receipt of certain approvals in Europe and the achievement of certain sales targets for Preotact. Nycomed is also required to pay us a royalty on a quarterly basis based upon sales of Preotact only in the European Union, European countries outside the European Union, the Commonwealth of Independent States and Turkey. Nycomed is also responsible to maintain our patents in its territories under the 2007 license agreement. If Nycomed reasonably determines that it has no prospects for making a reasonable profit under the 2007 Agreement, and it is unable to agree to terms on a renegotiated agreement with us within eight weeks, Nycomed may terminate the agreement by providing us with six months prior written notice; provided, however, that, upon any such termination the ownership of all rights to Preotact technology, products, regulatory filings and know-how will revert to us.
In July 2007, we entered into an agreement with DRI Capital, or DRI (formerly Drug Royalty L.P.3) under which we sold to DRI our right to receive future royalty payments arising from sales of Preotact under the 2007 Agreement. Under the agreement, DRI paid us an up-front purchase price of $50.0 million for the royalty rights. An additional $25.0 million will be due in 2010 if certain Preotact sales thresholds are exceeded. The agreement provides that if DRI receives royalties representing two and a half times the purchase price paid to us, the agreement will terminate and the remainder of the royalties paid by Nycomed under the 2007 Agreement, if any, will revert to us. In connection with our agreement with DRI, we granted DRI a security interest in the 2007 Agreement and certain of our patents and other intellectual property underlying that agreement.
PREOS for Osteoporosis
We have studied PREOS in a number of clinical settings to document its safety and effects on bone. The pivotal Phase 3 study, known as TOP (Treatment of Osteoporosis with PTH), was a multi-center, randomized, double blind, placebo-controlled trial designed to evaluate the potential of PTH to reduce the risk of first and subsequent vertebral fractures in post-menopausal women. In the TOP study, PREOS demonstrated a statistically significant reduction in the risk of new vertebral fractures in women with and without pre-existing osteoporosis-related fractures.
In May 2005, we filed an NDA with the FDA seeking approval to market PREOS in the U.S. In March 2006, we received notification from the FDA that the PREOS NDA is approvable. In the approvable letter, the FDA indicated that our pivotal Phase 3 study with PREOS demonstrated significant fracture risk reductions in post-menopausal women with osteoporosis, but noted the higher incidence of hypercalcemia with PREOS compared to placebo. The FDA expressed concern regarding hypercalcemia associated with the proposed daily dose of PREOS and requested additional clinical information. The FDA also requested additional information regarding the reliability and use of the injection device for delivery of PREOS.
We have had further communications with the FDA since receiving the approvable letter from the FDA, including an in-person meeting with senior staff from the FDA's Division of Endocrine and Metabolism Drug Products. During the meeting, the FDA proposed that we generate additional clinical data through a new clinical trial to address the hypercalcemia issue raised in the approvable letter. Since receiving the approvable letter, we have been carefully evaluating the appropriate regulatory path forward for PREOS. We submitted a new clinical trial protocol for PREOS to the FDA to support U.S. registration, and believe the protocol design is now finalized following communications with the FDA. Under this protocol, the clinical study will be a 12-month bone-mineral density bridging trial designed to evaluate the relative efficacy and safety of three dosing regimens of PREOS (100 mcg once daily, 100 mcg every-other-day, and 75 mcg once daily) compared to placebo in women with post-menopausal osteoporosis. As noted above, we would only continue our efforts to develop and commercialize PREOS for osteoporosis in the U.S. market if we were to secure a partner who would be willing to assume part of the cost and risk of such development. from NPS Pharmaceuticals SEC Filing 10K[2009.3.16] - [pdf]
【臨床ガイドライン】 ●Primary Care Clinical Practice Guidelines 3: Thyroid American Thyroid Association Guidelines for the diagnosis and management of thyroid disease. ■AACE.COM: Clinical Information: Clinical Guidelines 【ニュース・トピックス】 「品質再評価」では「甲状腺及び副甲状腺ホルモン剤」は第２２次(予試験指示平成１４年１０月、指定告示平成１５年１月) 医療用医薬品の品質再評価（第２２次）に関し予試験の資料提出を必要とする医薬品の範囲等について [2002.11.11] オレンジブック総合版 243 レボチロキシンナトリウム 先発予試験H14.10.1 | 後発予試験H14.11.11 ●〔第２回〕新GCPで薬害から患者を守れ /ブーツ社とカリフォルニア大学の攻防 医学界新聞第２４４２号 2001年6月25日 【リソース・オンライン雑誌】 MEDLINEplus: Thyroid Diseases National Library of Medicine ●リンク 甲状腺疾患関連リンク集 リンク：甲状腺関係＜国内＞＜海外＞[田尻クリニック] ●団体 日本甲状腺協会[Thyroid Foundation of Japan] - 国際甲状腺連盟Thyroid Federation International加盟。 ●学会 日本甲状腺学会 - 甲状腺疾患診断ガイドライン - ヨード欠乏対策 甲状腺外科研究会 - 「甲状腺癌取扱い規約」「甲状腺悪性腫瘍登録」等; - 概要 - 第36回 甲状腺外科研究会[2003.10.30-31,京都] 甲状腺PEIT研究会 - 甲状腺エタノール注入療法[目次のみ；研究会記録] - 甲状腺PEITガイドライン 副甲状腺インターベンション研究会 - 第１回(1996)以降の研究会記録を掲載。(要ID) 【主要サイト】 日本甲状腺学会 - 甲状腺疾患診断ガイドライン - ヨード欠乏対策 - - Thyroid Federation International - Home Page American Thyroid Association - Thyroid Experts Warn of Clinically Important Differences in Potency of
疾病分類名 1999年度 2002年度 2005年度 ●甲状腺障害(Ｅ00－Ｅ07) (323) (299) Ｅ00 先天性ヨード欠乏症候群 (5) (1) E000 先天性ヨード欠乏症候群，神経型[糖尿病(E00-E14)] - - E001 先天性ヨード欠乏症候群，粘液水腫型 - - E002 先天性ヨード欠乏症候群，混合型 - - E009 先天性ヨード欠乏症候群，詳細不明 5 1 Ｅ01 ヨード欠乏による甲状腺障害及び類縁病態 (-) (-) E010 ヨード欠乏によるびまん性（地方病性）甲状腺腫 - - E011 ヨード欠乏による多結節性（地方病性）甲状腺腫 - - E012 ヨード欠乏による（地方病性）甲状腺腫，詳細不明 - - E018 その他のヨード欠乏による甲状腺障害および類縁病態 - - Ｅ02 無症候性ヨード欠乏性甲状腺機能低下症 (-) (-) E02 無症候性ヨード欠乏性甲状腺機能低下症 - - Ｅ03 その他の甲状腺機能低下症 (91) (98) E030 びまん性甲状腺腫を伴う先天性甲状腺機能低下症 - - E031 甲状腺腫を伴わない先天性甲状腺機能低下症 1 1 E032 薬剤およびその他の外因性物質による甲状腺機能低下症 - - E033 感染後甲状腺機能低下症 - - E034 甲状腺萎縮（後天性） - - E035 粘液水腫性昏睡 - - E038 その他の明示された甲状腺機能低下症 - 0 E039 甲状腺機能低下症，詳細不明 90 97 Ｅ04 その他の非中毒性甲状腺腫 (30) (29) E040 非中毒性びまん性甲状腺腫 1 0 E041 非中毒性単発性甲状腺結節 0 - E042 非中毒性多結節性甲状腺腫 - 0 E048 その他の明示された非中毒性甲状腺腫 - 0 E049 非中毒性甲状腺腫，詳細不明 29 29 Ｅ05 甲状腺中毒症[甲状腺機能亢進症] (130) (117) E050 びまん性甲状腺腫を伴う甲状腺中毒症 44 42 E051 中毒性単発性甲状腺結節を伴う甲状腺中毒症 - - E052 中毒性多結節性甲状腺腫を伴う甲状腺中毒症 0 0 E053 異所性甲状腺組織による甲状腺中毒症 - - E054 人工的甲状腺中毒症 - - E055 甲状腺クリーゼまたは急性発症 0 0 E058 その他の甲状腺中毒症 0 0 E059 甲状腺中毒症，詳細不明 86 75 Ｅ06 甲状腺炎 (53) (47) E060 急性甲状腺炎 0 0 E061 亜急性甲状腺炎 1 2 E062 一過性甲状腺中毒症を伴う慢性甲状腺炎 - - E063 自己免疫性甲状腺炎 27 23 E064 薬物誘発性甲状腺炎 - - E065 その他の慢性甲状腺炎 23 21 E069 甲状腺炎，詳細不明 2 1 Ｅ07 その他の甲状腺障害 (14) (7) E070 カルシトニンの分泌過剰 - - E071 甲状腺ホルモン合成障害による甲状腺腫 - - E078 その他の明示された甲状腺障害 - - E079 甲状腺障害，詳細不明 14 7
FDA-Approved Levothyroxine Products[2004.8.11] - 機関誌Thyroids[月刊]ISSN 1050-7256 ～抄録公開・全文有償 - Guidelines～各種ガイドライン AACE.COM ---The Official Web Site of The American Association of Clinical Endocrinologists
●解説
●薬のメモ：甲状腺及び抗甲状腺薬 ●発掘！やくやく大事典：甲状腺ホルモン ---個別製品の組成、適応・投与方法、使用上の注意、副作用など ●甲状腺ホルモン剤 by 畑内科クリニック 院長 畑 直成
■メルクマニュアル |第02節 内分泌・代謝疾患 甲状腺疾患 甲状腺疾患にはeuthyroid甲状腺腫，euthyroid sick症候群，甲状腺機能亢進症，甲状腺機能低下症，甲状腺炎，および甲状腺癌がある。これらの疾患の徹底的な理解には甲状腺ホルモンの生合成と生理学，および甲状腺機能の検査試験が不可欠である。
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甲状腺ホルモンの作用
甲状腺ホルモンには2つの主要な生理作用がある：（1）実質的にほとんど全ての組織での蛋白合成を増加させる（T3とT4は細胞に入り，そこで血流および細胞内におけるT4のT3への転換から誘導されたT3は別々の核受容体に結合してmRNA生成に影響を与える）。（2）T3は，主に基礎酸素消費に関する組織（例，肝臓，腎臓，心臓，骨格筋）で，Na＋，K＋-ATPase（Naポンプ）活性を亢進させて，酸素消費量を増加させる。Na＋，K＋-ATPase活性亢進はこの酵素の合成亢進による二次的なものである；したがって，酸素消費の増加も甲状腺ホルモンの核との結合に関連していると考えられている。しかしT3のミトコンドリアに対する直接的な作用は否定されていない。T4自身も生物学的に活性があるようだが，T3は活性のある甲状腺ホルモンと信じられている。
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以下略
●データ
■ICD-9 codes[American Thyroid Association]
ICD-9 CODES RECOMMENDED TO MEDICARE BY THE AMERICAN THYROID ASSOCIATION Almost all hyperthyroid codes require a 5th digit, which is either a 0 or a 1, 0 means WITHOUTcrisis, 1 means WITH crisis 242.90 or 242.91 Hyperthyroidism: Cause not specified This includes TSH-mediated, Postpartum, Destructive, and Recurrent 242.00 or 242.01 Hyperthyroidism: Graves Disease; Autoimmune Stimulatory. This includes Postpartum, Stimulatory 242.20 or 242.21Hyperthyroidism: Toxic Nodular Goiter (multinodular) 242.10 or 242.11Hyperthyroidism: Toxic Nodule (uninodular) 242.80 or 242.81Hyperthyroidism: Excessive Thyroid Hormone Ingestion 245.1 Thyroiditis, subacute 245.2 Thyroiditis, lymphocytic 775.3 Hyperthyroidism: Neonatal 246.8 Abnormal Thyroid Hormone Binding Protein: 244.9 Hypothyroidism: Any Etiology 243 Hypothyroidism, congenital 244.0 Hypothyroidism, Post-surgical 244.1 Hypothyroidism, Post-ablative 193 Thyroid Cancer: All Types 785.6 Lymphadenopathy 246.0 Disorder of Calcitonin 241.0 Thyroid Nodule: Nontoxic (uninodular) 241.1 Euthyroid Goiter: Multinodular 226 Thyroid Adenoma: 246.2 Thyroid Cyst: 246.3 Hemorrhage of thyroid 245.2 Euthyroid Goiter: Autoimmune chronic lymphocytic thyroiditis) 246.1 Euthyroid Goiter: Biosynthetic Defect 240.0 Euthyroid Goiter: Simple 759.2 Thyroglossal Duct Cyst 376.21 Thyroid Eye Disease: 227.3 Pituitary Tumor: Includes craniopharyngioma, Rathke痴 cleft cyst 253.2 Pituitary Insufficiency: 704.3 Premature Grey Hair 701.1 Dry Skin 780.79 Fatigue 311 Depression: 272.4 Hyperlipidemia: 272.0 Hypercholesterolemia: 427.31 Atrial Fib: 783.2 Weight Loss: Unexplained 783.1 Weight Gain: Unexplained 278.00 Obesity: 780.09 Delirium: 294.8 Dementia: 297.1 Paranoia: Diagnoses with accompanying medical record documentation items: CLINICAL DX SX PHYSICAL SIGN OR OTHER LAB DATA SUGGESTING PRESENCE OF THYROID DISEASE Hypothyroidism Fatigue Muscle Weakness Cold Intolerance Constipation Weight Gain Dry Skin Decreased Hearing Decreased Sweat Paresthesias Arthralgias Impaired Cognitive Function Disorientation/Delirium Coarse Skin & Hair Cold Skin Slowed Neuromuscular Function Periorbital Puffiness Slow Reflex Relax Bradycardia Thyromegaly Hyperlipidemia Hypercholesterolemia Elevated Muscle Enzymes Hyperthyroidism Fatigue Muscle Weakness Dyspnea on Exertion Nervousness Anxiety Weight Loss Tachycardia Palpitations Heat Intolerance Diaphoresis Hyperphagia Hyperdefecation Polyuria Attention Deficit Hyperactivity Mood Disorder Disorientation/Delirium CLINICAL DX SX PHYSICAL SIGN OR OTHER LAB DATA SUGGESTING PRESENCE OF THYROID DISEASE Tachycardia Atrial Fibrillation Arrhythmia Hyperactivity Thyromegaly Muscle Weakness Tremor Thyroid Eye Disease Thyroid Nodule or Thyroid Cancer Visible Mass Obstruction to Swallowing Changed Voice Airway Obstruction Neck Pain Neck/Thyroid Mass Latest Revision: July 16, 2000
●臨床ガイドラインなど
●Primary Care Clinical Practice Guidelines 3: Thyroid
3 - Endo - Endocrine, metabolic, and nutritional, allergic disorders
- National Guideline Clearinghouse - NEW: 10-27
Endocrine Diseases
Nutritional and Metabolic Diseases
Immunologic Diseases- CPG Infobase - NEW: 10-31
Endocrinology and metabolism
Clinical immunology and allergy
- Ann Int Med 1998 Nov 1 Update in Endocrinology
- MEDLINEplus: Endocrine Diseases (General) National Library of Medicine NEW: 12-15
- Diabetes
- ●Thyroid
- Subclinical thyroid disease: Observe (ACP-ASIM) or Treat (AACE, ATA)?
- Subclinical Thyroid Disease editorial and position papers Screening for Thyroid Disease - ACP/ Annal of Internal Medicine Jul 15, 98
- Am Assn of Clinical Endocrinologist guidelines hypogonadism, thyroid, diabetes, osteoporosis, obesity
- American Thyroid Association Guidelines for the diagnosis and management of thyroid disease.
- BMJ 1999 Oct 2 Clinical review - Fortnightly review: Controversial aspects of thyroid disease NEW: 10-2
- Hosp Pract 1998 Mar - Decision Making in Medicine: Recognizing the Faces of Hypothyroidism
- Medical Treatment of Benign Thyroid Nodules editorial and review articles Ann Int Med 1 Mar 98
- Am Fam Physician 1998 Feb 15 - Subclinical Hypothyroidism: Deciding When to Treat NEW: 7-1
- MEDLINEplus: Thyroid Diseases National Library of Medicine
- MEDLINEplus: Thyroid Cancer National Library of Medicine NEW: 9-24
- ●Parathyroid
1999 Dec 2,3,15 2000 Feb 5,16,23,29 Mar 16 Jun 14
- Am Fam Physician 1998 Apr 15 - Hyperparathyroidism with pt info handout
ref to NIH Conference. Diagnosis and management of asymptomatic primary hyperparathyroidism: Consensus Development Conference statement. Ann Intern Med 1991;114:593-7- MEDLINEplus: Parathyroid Disorders National Library of Medicine NEW: 12-3
■Guidelines for Physicians[American Thyroid Association]
The American Thyroid Association has published 4 peer guidelines for the diagnosis and management of thyroid disease. Reprints may be obtained from the American Thyroid Association office: The diagnosis and treatment guidelines may be viewed directly on the American Medical Association web site. American Thyroid Association Guidelines for Detection of Thyroid Dysfunction Paul W. Ladenson, M.D., Peter A. Singer, M.D., Kenneth B. Ain, M.D., Nandalal Bagchi, M.D., PhD; S. Thomas Bigos, M.D., Elliot G. Levy, M.D., Steven A. Smith, M.D., Gilbert H. Daniels, M.D. & Harvey Cohen, M.D. American Thyroid Association Guidelines For Use of Laboratory Tests in Thyroid Disorders Martin I. Surks, M.D., Inder J. Chopra, M.D., Cary N. Mariash, M.D., John T. Nicoloff, M.D., David H. Solomon, M.D. JAMA 263: 1529 -1532, 1990 Treatment Guidelines for Patient with Hyperthyroidism and Hypothyroidism Peter A. Singer, M.D., Paul W. Ladenson, M.D., Lewis E. Braverman,M.D., Gilbert Daniels, M.D., Francis S. Greenspan, M.D., L. Ross McDougall, MB, ChB, PhD, Thomas F. Nilzola, M.D. JAMA 273: 808-812, 1995 Treatment Guidelines for patients with thyroid nodules and well-differentiated thyroid cancer. Peter A. Singer, M.D., David S. Cooper, M.D., Gilbert H. Daniels, M.D., Paul W. Ladenson, M.D.,Francis S. Greenspan, M.D., Elliot G. Levy, M. D., Lewis E. Braverman, M.D., Orlo H. Clark, M.D., I. Ross McDougall, M. B., Ch.B., Ph.D., Kenneth V. Ain, M. D., Steven G. Dorfman, M.D. Arch Intern Med 156: 2165-2172, 1996 Latest Revision: July 16, 2000
■AACE.COM: Clinical Information: Clinical Guidelines
・ Thyroid Carcinoma © 2001 ・ AACE/ACE Position Statement on Subclinical Hypothyroidism During Pregnancy ・ [pdf]|Hypogonadism ・ [pdf]|Hyperthyroidism and Hypothyroidism ・ [pdf]|Thyroid Nodule
●総説記事・文献
●ニュース・トピックス
●リンク＆リソース
■MEDLINEplus: Thyroid Diseases
Contents of this page: News General/Overviews Clinical Trials Diagnosis/Symptoms Pictures/Diagrams Research Specific Conditions/Aspects Treatment Directories Organizations Children Seniors Teenagers Women The primary NIH organization for research on Thyroid Diseases is the National Institute of Diabetes and Digestive and Kidney Diseases Search MEDLINE for recent research articles on ・ Thyroid Diseases You may also be interested in these MEDLINEplus related pages: ・ Thyroid Cancer ・ Ear, Nose, and Throat ・ Endocrine System (Hormones) ●Latest News FDA Will Not Yet Withdraw Unapproved Thyroid Drug (07/12/2001, Reuters) ●General/Overviews Doctor, Tell Me More About My Thyroid Gland (American Academy of Otolaryngology-Head and Neck Surgery, Inc.) Important Information for Thyroid Patients (Thyroid Federation International) ●Clinical Trials ClinicalTrials.gov: Graves' Disease (National Institutes of Health) ClinicalTrials.gov: Hyperthyroidism (National Institutes of Health) ClinicalTrials.gov: Hypothyroidism (National Institutes of Health) ClinicalTrials.gov: Thyroid Diseases (National Institutes of Health) ●Diagnosis/Symptoms Neck Swelling: Self-Care Flowcharts (American Academy of Family Physicians) Testing for Mild Thyroid Failure (American Medical Women's Association) Thyroid Gland Tests (Novartis Foundation for Gerontology) Thyroid Scan (MedicineNet, Inc.) ●Pictures/Diagrams Atlas of the Body: The Endocrine System (American Medical Association) ●Research Hypothyroidism During Pregnancy Linked to Lower IQ For Child (National Institute of Child Health and Human Development) ●Specific Conditions/Aspects Frequently Asked Questions About Graves' Disease (National Graves' Disease Foundation) Goiter (Enlarged Thyroid) (Mayo Foundation for Medical Education and Research) Hashimoto's Disease: What It Is and How It's Treated (American Academy of Family Physicians) Thyroid Cysts (Mayo Foundation for Medical Education and Research) Thyroid Disease and the Eye (American Society of Ophthalmic Plastic and Reconstructive Surgery) What is Grave's Disease? (Mayo Foundation for Medical Education and Research) What is Hyperthyroidism? (Mayo Foundation for Medical Education and Research) What is Hypothyroidism? (Mayo Foundation for Medical Education and Research) ●Treatment Guidelines for Patients Receiving Radioiodine Treatment (Society of Nuclear Medicine) ●Directories Find an Endocrinologist (American Association of Clinical Endocrinologists) ●Organizations American Thyroid Association National Graves' Disease Foundation Pituitary Tumor Network Association Thyroid Federation International (Thyroid Federation International) ●Children Clinical Hypothyroidism (MAGIC Foundation) Congenital Hypothyroidism (MAGIC Foundation) Thyroid Disorders (Nemours Foundation) Thyroid Through the Ages: Birth and Early Childhood (Growth) (American Association of Clinical Endocrinologists) ●Seniors Disorders of the Thyroid Gland (Novartis Foundation for Gerontology) Thyroid Through the Ages: The Senior Years (Aging) (American Association of Clinical Endocrinologists) ●Teenagers Thyroid Disease and Teens (Nemours Foundation) ●Women Hypothyroidism and Pregnancy (Mayo Foundation for Medical Education and Research) Postpartum Thyroiditis (Mayo Foundation for Medical Education and Research) Thyroid Conditions (American Medical Women's Association) Thyroid Through the Ages: Midlife (Menopause) (American Association of Clinical Endocrinologists) Thyroid Through the Ages: The Reproductive Years (Pregnancy) (American Association of Clinical Endocrinologists) Last updated: 27 July 2001
■MEDLINEplus: Parathyroid Disorders
Contents of this page: Clinical Trials Pictures/Diagrams Specific Conditions/Aspects Treatment Directories Organizations The primary NIH organization for research on Parathyroid Disorders is the National Institute of Diabetes and Digestive and Kidney Diseases Search MEDLINE for recent research articles on ・ Parathyroid Disorders You may also be interested in these MEDLINEplus related pages: ・ Endocrine System (Hormones) ●Clinical Trials ClinicalTrials.gov: Hyperparathyroidism (National Institutes of Health) ClinicalTrials.gov: Hypoparathyroidism (National Institutes of Health) ClinicalTrials.gov: Parathyroid Diseases (National Institutes of Health) ●Pictures/Diagrams Atlas of the Body: The Endocrine System (American Medical Association) ●Specific Conditions/Aspects Calcium and Parathyroid Glands (Mayo Foundation for Medical Education and Research) Hyperparathyroidism (National Institute of Diabetes and Digestive and Kidney Diseases) Hyperparathyroidism: What It Is and How It's Treated (American Academy of Family Physicians) Hypoparathyroidism (MedicineNet, Inc.) Information for Patients About Primary Hyperparathyroidism (Osteoporosis and Related Bone Diseases-National Resource Center) ●Treatment PDQ-Treatment-Patients: Parathyroid Cancer (National Cancer Institute) Parathyroidectomy (Animation Education Group) ●Directories Find an Endocrinologist (American Association of Clinical Endocrinologists) ●Organizations National Institute of Diabetes and Digestive and Kidney Diseases Last updated: 11 July 2001
●主要サイト
■Thyroid Federation International - Home Page
Member Organizations| Board| Mission statement For Endocrinologists| For Thyroid Patients| ThyroWorld Newsletter Meetings| How to start an association| Thyroid Video Online
■American Thyroid Association
introduction | Meeting notes | abstracts | misc.info | contact info -----------------------------------●Background
The American Thyroid Association, founded in 1923, is a professional society of physicians and scientists dedicated to research and treatment of thyroid pathophysiology. Since 1923, the ATA has provided access to the latest research and discoveries regarding the thyroid. Currently, the ATA has over 800 members from North America, Europe, Asia, Australia, the Middle East and South America.
●Mission
The mission of the American Thyroid Association is to promote scientific and public understanding of the biology of the thyroid gland and the pathogenesis and management of its diseases in order to prevent, diagnose and treat thyroid diseases and thereby improve quality of life.
Comment on Latest Draft: Lab Support for Thyroid Disease Dx●General Information Purpose and History | How to Become a Member | Officers and Directors Committees | Patient Information | Sponsors ATA Supports Patient Access to Thyroxine | Guidelines for Physicians★ | Other Sites of Professional Interest Announcements | 2001 Research Grant Information | Physician Guidelines & ICD 9 Codes★ ATA Statement on "Wilson's Syndrome" | Registration Information 73rd Annual Meeting Washington, DC | ATA Supports FDA Warning on Triax NRC Requires States to Consider Potassium Iodide | ATA Journal "Thyroid" | ATA SIGNAL Newsletter Ipodate Discontinued | Photo's from the 72nd Annual Meeting | ATA Presidents Message - 2000
■AACE.COM: The Official Web Site of The American Association of Clinical Endocrinologists
Organization Publications Services Education Clinical Info The College Bioterrorism Information Members Only Resources Contact ●Organization Introduction Our History Our Mission Board Officers AACE Past Presidents Staff To Join AACE Corporate Advisory Board Dues Payments ACE Past Presidents ●Publications Endocrine Practice First Messenger Clinical Guidelines Consensus Conferences Press Releases Stand Strong (Osteoporosis) Thyroid Awareness Patients First (Diabetes) Online News ●Services Calendar Media Resource Room Find an Endocrinologist Endocrinology Employment Links ●Education Clinical Symposia 2003 Annual Meeting 2002 Annual Meeting Highlights 2001 Annual Meeting Highlights ●Clinical Info Clinical Guidelines Fellows Clinical Corner Clinical Research Database ●The College Mission Statement Consensus Conferences Benefits Programs Criteria Application
●AACE.COM: Clinical Information: Clinical Guidelines [pdf] 2003.1.29現在 AACE Position: Women's Health Initiative Hypogonadism © 2002 Hyperthyroidism and Hypothyroidism © 2002 Diabetes Mellitus © 2002- 2002 update 2001 Thyroid Carcinoma © 2001 2001 Hyperandrogenism © 2001 2001 Postmenopausal Osteoporosis © 2001 Dyslipidemia and Atherogenesis © 2002 Clinical Practice for Management of Menopause © 1999 Position Statement on Subclinical Hypothyroidism During Pregnancy Growth Hormone Use in Adults and Children © 1998 Obesity Position Statement © 1998 Thyroid Nodule © 1996 Male Sexual Dysfunction © 1998
[1108,1192]●製品levothyroxine sodium(Synthroid[Abbott]) レボチロキシンナトリウム
日本語版註）levothyroxine sodium(Synthroid[Abbott]) レボチロキシンナトリウム
【別名】 【開発元】 [DBR_ID]24867-2430
【化学名】Monosodium O-(4-hydroxy-3,5-diiodophenyl)-3,5-diiodo-L-tyrosinate hydrate; synthetic crystalline L-3,3',5,5'-tetraiodothyronine sodium salt [levothyroxine (T4) sodium].
【承認】FDA申請=31-Jul-2001、FDA承認=24-Jul-2002[Abbott;] ; 【製剤】錠 【製剤～日本】1錠中日局レボチロキシンナトリウム(乾燥物)25,50,100μg 【適応】1)Hypothyroidism 2)Pituitary TSH Suppression 【適応～日本】粘液水腫，クレチン病，甲状腺機能低下症(原発性及び下垂体性)，甲状腺腫 【用法用量】 【用法用量～日本】[錠剤]レボチロキシンナトリウムとして通常，成人25～400μgを1日1回経口投与する． 一般に，投与開始量には25～100μg，維持量には100～400μgを投与することが多い． なお，年齢，症状により適宜増減する． 【作用】 【特徴】 【製品情報】 【添付文書】 【EU】 【日本】第十四改正日本薬局方第一部収載品 【その他】Abbott社はKnoll社買収(2001.3)により本剤を取得。●24867-2430
L-3,3',5,5'-TETRAIODOTHYRONINE SODIUM SALT;LEVOTHYROXIN SODIUM;L-T4;L-THYROXINE SODIUM SALT;L-THYROXIN NA;SODIUM LEVOTHYROXINE;THYRADIN S[ﾖｳｼﾞｺｳｼﾞｮｳｾﾝｷﾉｳﾃｲｶ];THYROXIN SODIUM[INN][IP][USP][BP][BPC];TIROSSINA NA[DCIT];ﾁﾗｰｼﾞﾝS;ﾁﾛｷｼﾝ･ﾅﾄﾘｳﾑ;ﾚﾎﾞﾁﾛｷｼﾝ･ﾅﾄﾘｳﾑ
《JA》THYRADIN S[ﾖｳｼﾞｺｳｼﾞｮｳｾﾝｷﾉｳﾃｲｶ]（帝国臓器製薬㈱）ｼﾝｾｲ＊
第十四改正日本薬局方 名称データベース - レボチロキシンナトリウム錠|レボチロキシンナトリウム ●医薬品添付文書 チラーヂンS錠25,50,100[製造発売元／帝国臓器製薬株式会社] チラーヂンS散[製造発売元／帝国臓器製薬株式会社] [効能又は効果]粘液水腫，クレチン病，甲状腺機能低下症(原発性及び下垂体性)，甲状腺腫 ●日本語版註）収録文献
【日本語版コメント】 「治療学的同等性」の論議が甲状腺製剤レボチロキシンをめぐって起こっている。 先発品はシンスロイドSynthroid[米アボット社]で市場の３分の２を占めていた。
同等性問題は1980年代に始まり、2001年7月にFDAはレボチロキシンのガイダンスを発行しメーカーに新薬申請を行うようにさせた。 アボット社は同等性に関する市民誓願をFDAに提出[2003.8]したが、FDAは2004.6にこれを却下し、ジェネリック剤とは同等に差がないと決定したもの。ちなみに日本での「甲状腺及び副甲状腺ホルモン剤」品質再評価は第２２次(2002)で実施。 日本の場合、レボチロキシンNa(チラーヂンS錠25,50,100,S散[帝国臓器製薬-武田薬工=住友製薬])も１社のみの販売であるため、こうした同等性の論議は全くなされていない。 しかし日本でも行政側のバックアップもあり、ジェネリック製品は急速に普及しつつあるので、本剤のように不安定な薬剤は同様の問題が起こる。
* 治療学的同等性基準については→Therapeutic Equivalence (TE) Codes
→詳細は参考資料●MLリソース：甲状腺ホルモンに纏めた。＜日本語版コメント用要約＞
・FDAは、ジェネリックのレボチロキシン製剤3剤が先発品と治療学的に同等であるとの判断を下した。
・この判定によって、薬剤師は処方医に知らせることなく、レボチロキシン製剤を別の製剤に変更できるようになった。
・生物学的に同等のジェネリック製品が先発品よりも信頼性に劣ると考える根拠はないが、1回量の有効性を変動させる原因は数多くある。
・製剤を切り替えた際には6～8週間後にTSH濃度を検査したほうがよいだろう。
●承認データ：FDA ●2004.5.1 以降 Drugs@FDA
Drug Name(s) =SYNTHROID (LEVOTHYROXINE SODIUM) FDA Application No. =NDA # 021402 Active Ingredient(s)=LEVOTHYROXINE SODIUM Company =Abbott Dosage Form/Route =TABLET; ORAL Strength =0.025MG ;0.05MG ;0.075MG ;0.088MG ;0.112MG ;0.125MG ;0.137MG ;0.15MG ;0.175MG ;0.1MG ;0.2MG ;0.3MG Label Information | Therapeutic Equivalents Approval History - Approval Date=07/24/2002 :Label[添付文書]|Letter[承認書]|Review FDA APPROVES FIRST NDA FOR LEVOTHYROXINE SODIUM[2000.8.22] - levothyroxine sodium (Unithroid) Unithroid Information Page
- 情報ソース●CDER New and Generic Drug Approvals: 1998-2004 Application #= Approval Date= Letter Posted= 承認書 Label Posted = 添付文書 Review Posted=
- 情報ソース●Drug Approvals -S Synthroid (levothyroxine sodium) Tablets USP, 25, 50, 75, 88, 100, 112, 125, 137, 150, 175, 200, and 300 mcg, Rx Abbott Laboratories Application #=NDA 21-402 Approval Date=7/24/02 Letter Posted=8/6/02 Label Posted =7/24/02 Review Posted=11/25/02
- 情報ソース●Drug Approvals -L Levothyroxine Sodium Tablets USP, 0.025, 0.05, 0.075, 0.088, 0.1, 0.112, 0.125, 0.15, 0.175, 0.2 & 0.3 mg, Rx Mylan Pharmaceuticals Inc Application #=ANDA 76-187 Approval Date=6/5/02 Letter Posted= Label Posted = Review Posted= Levoxyl (levothyroxine sodium) Tablets, Jones Pharma Inc. Application #=NDA 21-301/S2 Approval Date=7/17/02 Letter Posted=7/24/02 Label Posted = Review Posted= Levoxyl (levothyroxine sodium) Tablets, 25, 50, 88, 100, 125, 137, 150, 175 200 and 300 mcg strengths Jones Pharma Inc. Application #=NDA 21-301 Approval Date=5/25/01 Letter Posted=6/14/01 Label Posted =6/14/01 Review Posted=1/7/02
■FDAから
●FDA -CDER -Guidance
http://www.fda.gov/cder/guidance/index.htm ●Procedural Levothyroxine Sodium Products Enforcement of August 14, 2001 Compliance Date and Submission of New Applications [HTML] or [PDF] (Issued 7/2001, Posted 7/12/2001) Levothyroxine Sodium Questions and Answers [HTML] or [PDF] (Issued 3/2001, Posted 3/8/2001) ●Clinical/Medical Levothyroxine Sodium Tablets - In Vivo Pharmacokinetic and Bioavailability Studies and In Vitro Dissolution Testing [HTML] or [PDF] (Issued 2/2001, Posted 3/8/2001)
●Guidance for Industry Levothyroxine Sodium Questions and Answers
U.S. Food and Drug Administration ・ Center for Drug Evaluation and Research Guidance for Industry Levothyroxine Sodium Questions and Answers [PDF version of this guidance] U.S. Department of Health and Human Services,Food and Drug Administration Center for Drug Evaluation and Research (CDER) February 2001 Procedural Additional copies are available from:Office of Training and Communications Division of Communications Management,Drug Information Branch (HFD-210) 5600 Fishers Lane, Rockville, MD 20857 (Tel) 301-827-4573 (Internet) http://www.fda.gov/cder/guidance/index/htm Procedural Table of Contents I. INTRODUCTION II. REGULATORY QUESTIONS AND ANSWERS A. Status of Marketed Products B. Cutoff Date for 505(b)(2) Applications C. Requirements for 505(b)(2) Applications D. Exclusivity E. Therapeutic Equivalence Ratings for Levothyroxine Sodium Products F. ANDAs for Levothyroxine Sodium Products III. SCIENTIFIC QUESTIONS AND ANSWERS A. Stability Data B. Dissolution Method C. OverageGuidance for Industry1
Levothyroxine Sodium - Questions and Answers
This guidance represents the Food and Drug Administration's current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statutes and regulations.
●I. INTRODUCTION
This guidance is intended to assist sponsors who have questions about submitting new drug applications (NDAs) for orally administered levothyroxine sodium products.
On August 14, 1997, FDA announced in the Federal Register (62 FR 43535) that orally administered levothyroxine sodium drug products are new drugs. The notice stated that manufacturers who wish to continue to market these products must submit applications as required by section 505 of the Federal Food, Drug, and Cosmetic Act (the Act) and 21 CFR part 314 by August 14, 2000. On April 26, 2000, FDA issued a second Federal Register notice extending the deadline for filing applications until August 14, 2001.
The August 14, 1997, notice stated that FDA is prepared to accept new drug applications (NDAs) for these products, including section 505(b)(2) applications.2 An applicant making a submission under section 505(b)(2) of the Act may rely on investigations described in section 505(b)(1)(A) that were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted. A number of questions have arisen with respect to applications for levothyroxine sodium products. This guidance is intended to answer these general questions. Sponsors should consult with the Division of Metabolic and Endocrine Drug Products for answers to specific questions.
[以下略]
●Guidance for Industry Levothyroxine Sodium Tablets - In Vivo Pharmacokinetic and Bioavailability
U.S. Food and Drug Administration ・ Center for Drug Evaluation and Research ●Guidance for Industry Levothyroxine Sodium Tablets - In Vivo Pharmacokinetic and Bioavailability Studies and In Vitro Dissolution Testing [PDF version of this document] U.S. Department of Health and Human Services,Food and Drug Administration Center for Drug Evaluation and Research (CDER) February 2001 Clinical Medical Additional copies are available from: the Drug Information Branch (HFD-210), Center for Drug Evaluation and Research (CDER), 5600 Fishers Lane, Rockville, MD 20857 (Tel) 301-827-4573 Internet at http://www.fda.gov/cder/guidance/index.htm TABLE OF CONTENTS I. INTRODUCTION II. BACKGROUND III. PHARMACOKINETIC AND BIOAVAILABILITY STUDIES IN VIVO A. Inclusion Criteria B. Single-Dose Bioavailability Study C. Dosage-Form Proportionality Study IV. DISSOLUTION TESTING IN VITRO V. FORMULATION VI. BIOWAIVER VII. ASSAY VALIDATIONGUIDANCE FOR INDUSTRY1
Levothyroxine Sodium Tablets -
In Vivo Pharmacokinetic and Bioavailability Studies
and In Vitro Dissolution Testing
This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statutes and regulations.
●I. INTRODUCTION
This guidance is intended to assist sponsors of new drug applications (NDAs) for levothyroxine sodium tablets who wish to conduct in vivo pharmacokinetic and bioavailability studies and in vitro dissolution testing for their products. Information from these studies would generally be submitted in section 6 of an NDA. Sponsors who wish to use approaches other than those recommended in this guidance should discuss their plans with the FDA prior to preparing an NDA.
●II. BACKGROUND
Levothyroxine sodium is the sodium salt of the levo isomer of the thyroid hormone thyroxine. Thyroid hormones affect protein, lipid, and carbohydrate metabolism, growth, and development. They stimulate the oxygen consumption of most cells of the body, resulting in increased energy expenditure and heat production, and possess a cardiostimulatory effect that may be the result of a direct action on the heart.
The production of levothyroxine hormone is regulated by the hypothalamus-pituitary axis through a negative feedback system. When hormone levels are inadequate, the hypothalamus secretes thyroid stimulating hormone-releasing hormone (TSH-RH), which stimulates the anterior pituitary to produce thyroid stimulating-hormone (TSH). TSH then stimulates the thyroid gland to produce levothyroxine (T4) and triiodothyronine (T3). T4 is subsequently converted to the highly active T3 in the peripheral tissues. High levels of T4 inhibit the production of TSH and (to a lesser degree) TSH-RH. This effect in turn decreases the further production of T4 (Farwell 1996).
Orally administered levothyroxine sodium is used as replacement therapy in conditions characterized by diminished or absent thyroid function such as cretinism, myxedema, nontoxic goiter, or hypothyroidism. The diminished or absent thyroid function may result from functional deficiency, primary atrophy, partial or complete absence of the thyroid gland, or the effects of surgery, radiation, or antithyroid agents. Levothyroxine sodium may also be used for replacement or supplemental therapy in patients with secondary (pituitary) or tertiary (hypothalamic) hypothyroidism.
Levothyroxine sodium is a compound with a narrow therapeutic range. If a drug product of lesser potency or bioavailability is substituted in the regimen of a patient who has been controlled on another product, a suboptimal response and hypothyroidism could result. Conversely, substitution of a drug product of greater potency or bioavailability could result in toxic manifestation of hyperthyroidism such as cardiac pain, palpitation, or cardiac arrhythmia. In patients with coronary heart disease, even a small increase in the dose of levothyroxine sodium may be hazardous. Hyperthyroidism is a known risk factor for osteoporosis (Paul et al. 1988). To minimize the risk of osteoporosis, it is advisable that levothyroxine sodium be titrated to the lowest effective dose. Because of the risks associated with over- or under-treatment with levothyroxine sodium, it is critical that patients have available to them products that are consistent in potency and bioavailability.
It is a challenge to determine the bioavailability of levothyroxine sodium products because levothyroxine is naturally present in minute quantities in the blood, with the total levels reaching 5.0-12.0 _g/dl and free (or unbound) levels reaching 0.8-2.7 ng/dl in a healthy adult. To assess the bioavailability of levothyroxine sodium after a single dose, several times the normal dose should be given to raise the levels of the drug significantly above baseline to allow measurement. Furthermore, levothyroxine has a long half-life of 6 to 9 days, and therefore, a long washout period is necessary between treatments.
[以下略]
●4 See FDA's guidance for industry on Dissolution Testing of Immediate Release Solid Oral Dosage Forms
PDF (August 1997).
Last Updated: March 08, 2001
●FDA Issues Guidance on Levothyroxine Sodium Products Compliance FDA Talk paper July 12, 2001
The Food and Drug Administration today published a guidance for industry explaining how the agency plans to handle oral levothyroxine sodium products that are being marketed without an approved application after August 14, 2001.
On August 14, 1997, FDA announced in the Federal Register (62 FR 43535) that orally administered levothyroxine sodium drug products are "new drugs" and that manufacturers who wish to continue marketing these products must submit a new drug application (NDA) for approval. The agency based its decision on a history of potency and stability problems with orally administered levothyroxine sodium products. The notice stated that after August 14, 2000, any unapproved levothyroxine sodium drug product on the market would be subject to regulatory action by FDA.
On April 26, 2000, FDA extended the deadline to August 14, 2001. As of July 2001, two levothyroxine sodium products have been approved by FDA to treat hypothyroidism. Unithroid, manufactured by Jerome Stevens Pharmaceuticals, was approved on August 21, 2000. Levoxyl, manufactured by Jones Pharma, was approved on May 25, 2001. Now that two products have been approved, FDA is issuing guidance regarding the transition of patients from unapproved to approved products.
Because there is no public health emergency that requires an immediate switch to the approved drugs, FDA has established a gradual phase out of distribution of the unapproved products to allow manufacturers of approved products to scale up to meet demand and to allow adequate time for patients and health care providers to make an orderly transition from unapproved to approved products.
On August 14, 2001, there will be two types of unapproved marketed levothyroxine sodium products: (1) those with NDAs that have been submitted to FDA and are under review and (2) those with no pending NDAs.
Under the phase out outlined in the guidance, manufacturers of unapproved oral levothyroxine sodium drug products with NDAs pending as of August 14, 2001, should reduce the distribution of these products according to an incremental reduction of average monthly distribution. This phase-out schedule is explained in the guidance. By August 14, 2003, all distribution of unapproved oral levothyroxine sodium products must cease.
Manufacturers of unapproved oral levothyroxine sodium drug products who do not have an NDA pending with the FDA by August 14, 2001, should cease distribution of their products by that date or they will be subject to regulatory action.
For more information, physicians and manufacturers may refer to the guidance for industry, Levothyroxine Sodium Products Enforcement of August 14, 2001, Compliance Date and Submission of New Applications, which can be found on the FDA Web site (http://www.fda.gov/cder/guidance/4647fnl.htm). Patients should consult their physicians regarding their choice of approved levothyroxine sodium products.
●Compliance【用語解説】
---医学系---[Stedman]
1)コンプライアンス，伸展性（容器の拡張性の測定方法で，圧の変化に対する容積の変化で表される）．2)コンプライアンス（医師等により処方された治療法に患者が従う確かさ．ｃｆ． ａｄｈｅｒｅｎｃｅ （２）； ｍａｉｎｔｅｎａｎｃｅ）．3)コンプライアンス，伸展性（構造物あるいは物体の変形されやすさの指標．内科学および生理学では通常，肺，膀胱，胆嚢などの空洞臓器の膨張しやすさの指標をいう．これらの臓器の内壁と外壁の単位面積当たりの圧力差によって生じる容積の変化率を表す．エラスタンスの逆数）
---一般---
(要求・命令などへの)承諾,応諾服従,盲従
■アボット社からのニュース June 2004★U.S. Food and Drug Administration (FDA) Denies Abbott's Citizen Petition Regarding Levothyroxine Sodium Products★甲状腺ホルモンSynthroid (Levothyroxine Sodium Tablets, USP)
May 2004★Abbott Expands Its Medicare Assistance Program (MAP) To Offer Synthroid (Levothyroxine Sodium Tablets, USP) For $5 and Other Chronic Care Drugs For $12, Monthly, To Low-Income Seniors★甲状腺ホルモンSynthroid (Levothyroxine Sodium Tablets, USP)
July 2002★Abbott Laboratories' Synthroid(R) (levothyroxine sodium tablets, USP) Confirmed Safe and Effective Through FDA Approval★甲状腺ホルモンSynthroid (Levothyroxine Sodium Tablets, USP)
August 2001★Abbott Laboratories Submits New Drug Application for Synthroid(R) (Levothyroxine Sodium, USP) to FDA in Advance of Deadline★甲状腺ホルモンSynthroid (Levothyroxine Sodium Tablets, USP)
July 2001★Abbott Laboratories Gratified By Court's Decision Granting Preliminary Injunction Against Watson Pharmaceuticals' False Advertising Against Synthroid(R) ★甲状腺ホルモンSynthroid (Levothyroxine Sodium Tablets, USP)
July 2001★FDA Guidance on Levothyroxine Sodium Products Assures Synthroid(R) (levothyroxine sodium, USP) Will Remain on Market While NDA Reviewed★甲状腺ホルモンSynthroid (Levothyroxine Sodium Tablets, USP)
June 2001★Abbott Laboratories Asks Federal Court to Help Protect Patients Against Misleading Information About Synthroid(R) (levothyroxine sodium, USP)★甲状腺ホルモンSynthroid (Levothyroxine Sodium Tablets, USP)
June 2001★Abbott Response to News Reports on Synthroid(R)★甲状腺ホルモンSynthroid (Levothyroxine Sodium Tablets, USP)
April 2001★Abbott Laboratories to Submit New Drug Application for Synthroid(R) (levothyroxine sodium, USP)★甲状腺ホルモンSynthroid (Levothyroxine Sodium Tablets, USP)
●FDA GUIDANCE ON LEVOTHYROXINE SODIUM PRODUCTS ASSURES SYNTHROID(R) (LEVOTHYROXINE SODIUM, USP) WILL REMAIN ON MARKET WHILE NDA REVIEWED － ABBOTT WILL SUBMIT NDA FOR SYNTHROID IN ADVANCE OF GUIDELINE; CONFIDENT THAT APPLICATION WILL DEMONSTRATE SAFETY, EFFICACY OF SYNTHROID －
Abbott Park, Illinois, July 11, 2001 － Abbott Laboratories today said the guidance issued by the Food and Drug Administration (FDA) on levothyroxine sodium products provides assurance that Synthroid(R) (levothyroxine sodium, USP)will remain on the market while the agency reviews the New Drug Application (NDA) Abbott will be submitting for Synthroid.
The FDA's decision to keep Synthroid on the market is consistent with the product's 42-year history of safety and efficacy, and its successful use by eight million patients today in treating their thyroid disease.
As previously reported, Abbott will submit an NDA in advance of the agency's required submission date of August 14, 2001.
"Abbott is confident that the Synthroid NDA will demonstrate safety and efficacy and will be approved," said Dr. David Pizzuti, M.D., Vice President, Global Medical Affairs, at Abbott.
There is a large supply of Synthroid that is currently available on the market and Abbott will continue to manufacture and ship this product while the NDA is under review.
"Therefore, patients can be assured of a continued adequate supply of Synthroid while the FDA reviews the NDA for this product," Dr. Pizzuti said.
At the same time, Abbott said it is concerned that the FDA's unprecedented distribution schedule, which calls for a gradual phase-down in distribution while the NDA is under review, could:
Create health risks by causing patients to unnecessarily switch to products that the FDA has not determined to be therapeutically equivalent; and,
Add a significant cost burden to patients and the healthcare system due to additional physician visits and testing.
Synthroid, which has been in use since 1955, was the first orally administered levothyroxine sodium product. Today, it is the third most-prescribed drug in the United States. It is the most studied form of levothyroxine sodium. Its acceptance is based upon hundreds of scientific studies and articles, as well as its continued use by millions of patients over many decades.
Major medical societies and patient-focused organizations - including the American Association of Clinical Endocrinologists, the American Thyroid Association, the Thyroid Foundation of America, and the Thyroid Cancer Survivors’ Association - have publicly supported keeping Synthroid available for the millions of patients who are currently well controlled on the medication.
“If their medication is switched, patients must be reevaluated and retested,” Dr. Pizzuti said. “Otherwise, their health may be at risk. Switching prescription thyroid drugs is not as simple as merely matching dosage. In addition to the lack of any medical need for switching, there is the inconvenience to patients, their possible loss of work time and the considerable expense involved in switching - much of which will be incurred by patients, many of whom are elderly."
In 1997, the FDA announced that every manufacturer of levothyroxine drug products, most of which had been on the market for many years, would be required as part of the agency’s regulatory process to file either an NDA, or a citizen petition showing that their products are not new drugs and therefore do not require an NDA.
Synthroid's manufacturer at the time, Knoll Pharmaceutical Company, which Abbott acquired in March 2001, exercised the citizen petition option because of Synthroid’s long history and track record. On April 26, the FDA denied Knoll’s petition. Abbott promptly responded to the FDA that the company would submit an NDA for Synthroid.
Abbott said the FDA guidance will have no impact on the company's earnings guidance for 2001 of $1.88 per share, before one-time charges, and Abbott's earnings expectations for 2002.
Thyroid hormones, either alone or together with other medicines, should not be used for the treatment of obesity, and should not be taken by patients with untreated thyrotoxicosis (excess of thyroid hormone), uncorrected adrenal insufficiency, or apparent hypersensitivity to thyroid hormones or any inactive product constituents. Adverse events to Synthroid other than those related to thyrotoxicosis as a result of overdosage are rare; however, if a patient experiences any unusual symptoms, he or she should consult with their health care provider.
Further information on Synthroid is available at www.synthroid.com or by calling 1 (800) 255-5162.
Abbott Laboratories is a global, diversified health care company devoted to the discovery, development, manufacture and marketing of pharmaceuticals, nutritionals, and medical products, including devices and diagnostics. The company employs approximately 70,000 people and markets its products in more than 130 countries.
Private Securities Litigation Reform Act of 1995 －
A Caution Concerning Forward-Looking Statements
Some statements in this news release may be forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. Abbott cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements. Economic, competitive, governmental, technological and other factors that may affect Abbott's operations are discussed in Exhibit 99.1 of our 2000 Form 10-K and in our periodic reports on Form 10-Q and Form 8-K, and are incorporated by reference. Abbott undertakes no obligation to release publicly any revisions to forward-looking statements as the result of subsequent events or developments.
●Abbott Diagnostics Division: Thyroid
Function ---organs and hormones involved in thyroid function Disorders ---thyroid dysfunction, signs and symptoms, reference tools Testing ---thyroid profiles, clinical utility, quality control Products ---assay information, how to order, customer support Additional Info ---The Thyroid is one of the largest glands of the endocrine system. It is positioned anterior to the trachea and below the larynx.
Thyroid disorders afflict 200 million people worldwide; many do not realize that they are affected.
The thyroid is a critical component of the body's metabolism; an overactive (hyperthyroidism) or underactive (hypothyroidism) thyroid can have a debilitating effect on the ability of the body to function properly. Profiling the status of the thyroid is critical for diagnosing a thyroid disorder and for monitoring the progress of treatment.
This web site includes comprehensive information about the thyroid and thyroid testing, as well as education and training tools for anyone involved in thyroid testing.
・Explore our Interactive Slide rule to see how thyroid disorders affect levels of relevant hormones and analytes.
・You can view our Thyroid Testing Strategies — a graphical tool for evaluating a patient's hormone levels.
・Learn the fundamental chemistry behind our FPIA and MEIA technologies with easy to understand animated graphics.
●ABBOTT LABORATORIES ASKS FEDERAL COURT TO HELP PROTECT PATIENTS AGAINST MISLEADING INFORMATION ABOUT SYNTHROIDR (LEVOTHYROXINE SODIUM, USP) COMPANY SEEKS INJUNCTION TO HALT 'ORCHESTRATED CAMPAIGN OF FEAR AND CONFUSION' BY WATSON PHARMACEUTICALS
Abbott Park, Illinois, June 12, 2001 - Abbott Laboratories today announced that it has filed suit against Watson Pharmaceuticals, Inc., Corona, Calif., seeking a Federal court injunction to immediately stop Watson's false advertising and deceptive trade practices regarding Abbott's prescription thyroid drug SynthroidR (levothyroxine sodium, USP). The suit also asks the court to order Watson to undertake an advertising campaign to correct the deliberate misinformation it has created within the medical community.
Abbott is taking this action to ensure patient safety and put an end to the fears, concerns and confusion that are being created among the more than eight million thyroid patients who depend on Synthroid everyday to successfully treat their thyroid disease.
"Abbott had no choice but to take this action to protect patients who have been inundated with alarming, medically-inaccurate information," said David Pizzuti, M.D., Abbott's Vice President, Global Medical Affairs. "Synthroid has been used safely and effectively by millions of patients for decades and it is false and misleading for Watson to claim otherwise. Worse, are Watson's false assertions that Synthroid will be unavailable in the near future to the millions of patients who depend on it."
Synthroid is a trusted therapy and accounts for more than 60 percent of prescriptions for thyroid replacement therapy. Major medical societies and patient-focused organizations, including the American Association of Clinical Endocrinologists, the American Thyroid Association, the Thyroid Foundation of America and the Thyroid Cancer Survivors' Association, have publicly stated support for keeping Synthroid available for the millions of patients who are currently well controlled on the medication.
Abbott will submit a New Drug Application (NDA) for Synthroid to meet the U.S. Food and Drug Administration's (FDA) filing requirements of August, 2001. Synthroid is the most studied form of levothyroxine sodium, with hundreds of clinical studies and publications in prominent peer-reviewed medical journals.
In its suit, Abbott charges that Watson is attempting to achieve through an orchestrated campaign designed to concern and confuse patients - including misrepresentation of the FDA's regulatory process - what Watson has evidently concluded it cannot gain by promoting its product on its own merits. The suit was filed today in Chicago.
"It is particularly disturbing," Dr. Pizzuti said, "that misleading information is being provided about the switching of prescription thyroid drugs. Guidelines of several of the leading endocrinology associations recommend that patients remain on their brand of levothyroxine sodium if they are well controlled; if their medication is switched, patients must be reevaluated and retested. Otherwise, the health of patients may be at risk. Switching prescription thyroid drugs is not as simple as merely matching dosage. Because of the medical implications of switching, it is extremely irresponsible for Watson to falsely generate concerns about the continued availability of Synthroid."
Additionally, the FDA Publication, Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book), does not list any levothyroxine sodium product as therapeutically interchangeable.
Synthroid, which was introduced in 1955, was the first orally administered levothyroxine product. Today, it is the third most-prescribed drug in the United States. Its acceptance is based upon hundreds of scientific studies and articles, as well as its continued use by millions of patients over many decades.
In 1997, the FDA announced that every manufacturer of levothyroxine drug products, most of which had been on the market for many years, would be required to file - as part of that agency's regulatory review process - either an NDA, or a citizen petition showing that their products are not new drugs and therefore do not require an NDA.
Synthroid's manufacturer at the time, Knoll Pharmaceutical Company, which Abbott acquired in March 2001, exercised the citizen petition option because of Synthroid's long history and track record. On April 26, the FDA denied Knoll's petition. Abbott promptly responded to the FDA that the company would submit an NDA for Synthroid.
■一般ニュースから
●〔第２回〕新GCPで薬害から患者を守れ /ブーツ社とカリフォルニア大学の攻防 医学界新聞第２４４２号 2001年6月25日
最初の合成甲状腺製剤であるシンスロイドは，1938年に販売開始となり，現在の基準に則ったデータを必要としませんでした。年間600億円の売上のある薬でしたが，他の甲状腺製剤も販売されるようになると，それらの効果の比較を求める声が高まってきました。そこで1987年に，シンスロイドの製造企業ブーツ社は，カリフォルニア大学サンフランシスコ校のベティ・ドン薬学博士（女性）にその比較研究を依頼しました。その結果，「シンスロイドの薬剤当たりの甲状腺ホルモン含有量が他の新薬と比較して高い」という，ブーツ社側にとってはよい結果を得ることができました。そこでブーツ社は，彼女に研究費をつけて薬物動態，臨床効果などを含む他社製品との比較研究を引き続き依頼したのでした。
しかしながら，彼女は1990年に「比較した4つの薬の効果は同じである」という結論に至りました。当然ブーツ社側はデータを痛烈に批判し，紙面発表を阻止しようとしました。一方ドン博士側も，「研究データは正当である」として抗議したのです。この闘いは，ブーツ社と大学との闘いにまで発展しました。ブーツ社は，「患者選択基準に問題がある」「実験手技の信憑性が低い」「統計が間違っている」「倫理的問題をクリアしていない」など，諸々の点で難癖をつけて論文発表を阻止しようとしました。
結局は，ブーツ社の言い分を一部受け入れた形で1994年「JAMA」（アメリカ医師会雑誌）に投稿の運びとなりました。薬剤の半減期を考慮しながら，キャリーオーバー効果が生じないように工夫するなど，よくデザインされ優れた薬効評価の研究でした。さらに，彼女はカバーレターに「ブーツ社は，われわれが逐一データを送り，数多く会合を持ったにもかかわらず，とても結果に対して批判的でした。よってブーツ社の関連の者が査読にあたらないようにお願いします」と書き加えたのです。
この論文は5人の査読官（そのうちブーツ社の相談役も含まれていた）に送られ，一部訂正の後に受理され，翌年1月発行の予定となりました。ところが，今度はドン博士が突然論文発表を取り下げたいと言い出したのです。その理由は，最初に彼女がブーツ社と研究契約を結んだ際，「この研究で得られたすべての情報は秘密であり，これを公表する時は製造元の許可を必要とする」という記載にサインをしていたために，企業側がこれを理由として大学を相手取り訴訟を起こすと言い出したからです。そして大学側は，博士に論文を取り下げるように要請しました。その当時，このような記載はまれで，博士は熟読せずにサインをしてしまっていたのでした。
学術研究の発表は，大学の基本原理であり，中立が保たれなくてはなりません。しかし，博士が契約を結んだ段階で問題があり，中立を保ち論文発表できないのであれば，研究費をもらって研究するべきではなかった，という批判が大学内部でも起こりました。しかしそれは後の祭りです。またブーツ社はJAMAに博士と研究を批判する手紙を送りつけました。さらにブーツ社のメイヤー博士は，ドン博士に何の通達もなく，博士たちのデータを使用しつつも，解釈を変えて反対の結論を出し論文発表してしまったのです。メイヤー博士は「Am J Therapeutics」の編集委員であり，自分の雑誌に掲載するという手を使ったのです。
1996年にこれらの事実が「ウォールストリート・ジャーナル」に載り，問題が再浮上しました。FDA（Food and Drug Administration；米・食品医薬品局）はこの記事に着目し，メイヤー博士の論文に対して「甲状腺製剤の半減期が7.6日なのに48時間しか検討していないのはおかしいのではないか」と批判。これに対してブーツ社は，「この論文はこれらの薬剤が同じであることを証明しようとしたものではなく，異なることを証明しようとしたものなので，48時間でも構わない」と反論しました。また「薬効が同じであることを言うには，より多くの人に対してより長期に観察しなければ結論できない」とも付け加えました。
しかしながら，FDAはブーツ社に対し「シンスロイドを実際の薬効以上に評価している」として厳重注意の判決を下しました。最終的にブーツ社側は分が悪いと悟り，大学と交渉して一部修正を加え，ドン博士の論文は，1997年になり当初より7年後れて「JAMA」に発表となったのでした。
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