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除栓素注射劑 XIGRIS Powder for Solution for Infusion 5 公絲 20 公絲 5 mg 20 mg 定性和定量組成 XIGRIS 5 公絲注射劑每小瓶含 5 公絲 Drotrecogin alfa (活化型)，以 2.5 毫升滅菌注射用水稀釋，配製後為每毫升含 2 公絲之溶液。 XIGRIS 20 公絲注射劑每小瓶含 20 公絲 Drotrecogin alfa (活化型)，以 10 毫升滅菌注射用水稀釋，配製後為每毫升含 2 公絲之溶液。 Drotrecogin alfa (活化型) 為內生性活化蛋白 C 的基因重組製劑，於已建立之人體細胞株，以基因工程技術製造。製劑注射劑臨床特性適應症成人重度敗血症伴隨急性器官功能異常且病患為高死亡危險族群 (定義如 APACHE II) 說明成人患有重度敗血症伴隨急性器官衰竭且病患為低死亡危險族群之療效尚未建立。小兒科病患患有重度敗血症伴隨急性器官衰竭使用本藥品之療效及安全性尚未建立。用法用量 Xigris 應由具經驗且熟知如何照護重度敗血症病患之醫院醫師使用。發現敗血症誘發第一個器官衰竭後 48 小時內(24 小時內更好)應開始投與治療。(參閱藥效性質欄) Xigris 的建議起始劑量為 24 µg/kg/hr，連續靜脈輸注 96 小時。建議使用輸液幫浦(infusion pump) 輸注 Xigris，以準確地控制輸注速度。若因任何因素以致輸注中斷，Xigris 應以 24 µg/kg/hr 輸注速度繼續給藥，並完成 96 小時之建議給藥時間。不需增加或使用高劑量 Xigris，彌補輸注中斷。治療成人病患之重度敗血症，不需因年齡、性別、肝功能(測量其轉氨基酶濃度)或腎功能調整劑量。Drotrecogin alfa (活化型) 對於重度敗血症合併晚期腎臟疾病或慢性肝臟疾病的藥物動力學尚未確立。小兒科病患: 一安慰劑對照的臨床試驗，於 477 位 0-17 歲的病患接受試驗用藥後，因無治療效益而終止試驗。本試驗所得資料未證實 Xigris 治療小兒科病患之療效，且顯示 Xigris 治療組，相較於安慰劑組，具較高的中樞神經系統出血發生率。因此，對於 18 歲以下的小兒科病患，不建議使用 Xigris 治療，亦無建議投與劑量。(参閱警語和注意事項欄) 禁忌 Drotrecogin alfa (活化型) 可能增加出血的發生，因此 Xigris 禁用於下列情況: ● 進行性內出血 ● 顱內病變，腫瘤或大腦疝氣 ● 目前使用 Heparin 治療，且劑量高於 15 IU/kg/hr ● 已知易出血體質，不包括敗血症引起之急性凝血病變 ● 慢性重度肝臟疾病 (晚期肝硬化，食道或胃靜脈曲張，或 INR(國際標準凝血時間比)>2.0 之慢性肝臟疾病) ● 血小板數小於 30，000×106/L，即使輸血後血小板數回升 ● 容易出血的高危險群(舉例)： 1) 任何大手術(需全身或脊髓麻醉的手術)，於術後 12 小時內立即輸注本劑；或任何術後病人具出血現象；或於輸注本劑期間，即將或預期進行手術的病人。 2) 頭部重度創傷需住院治療或顱內或脊椎手術的病史，或近三個月內曾發生出血性中風，或具顱內動靜脈血管變形、腦動脈瘤、中樞神經系統大型損傷的病史；病人接受硬腦膜外插管，或預期將於輸注本劑期間，接受硬腦膜外插管。 3) 先天性易出血體質 4) 近六週內曾發生胃腸道出血，且除非進行手術治療，必須以藥物控制病情。 5) 創傷伴隨高度出血危險 Xigris 禁用於已知對 drotrecogin alfa (活化型)、此藥品的任何賦形劑或牛凝血酶(製程中微量殘留) 過敏者。警語和注意事項單一器官功能異常與近期手術病患 Xigris 尚未核准用於治療單一器官功能異常病患，且 Xigris 不可用於治療一些特殊亞群病患，特別是近期(30 天內)手術病患。二個隨機安慰劑控制臨床試驗顯示(PROWESS 與 ENHANCE 試驗)(參閱藥理性質欄)，對於單一器官功能異常與近期手術亞群病患(PROWESS 試驗 98 位病患，ENHANCE 試驗 636 位病患)，Drotrecogin alfa (活化型)治療組之 28 天死亡率與住院死亡率高於安慰劑組。出血 Drotrecogin alfa (活化型)會增加出血的風險。因此使用 Xigris 治療下列情形時，應同時評估可能的風險與可預期的治療效果。 ● 近期(三天內)給與血栓溶解治療 ● 近期(七天內)投與口服抗凝血劑 ● 近期(七天內)投與 Aspirin 或其他血小板抑制劑 ● 近期(三個月內)發生缺血性中風 ● 醫師評估可能出血之任何情形對於可能出血的療程，必須於開始前 2 小時停用 Xigris。於侵入性療程或術後 12 小時，若已適當止血，可開始使用 Xigris。於簡易低侵入性療程後，若已適當止血，可立即使用 Xigris。輸注 Xigris 時之臨床照顧，必須監測病人的凝血機制(例如活化部份凝血酶原時間(APTT)、凝血酶原時間(PT)及血小板數)。若監測凝血機制的結果顯示凝血功能失調或不良，將增加出血的危險性；因此是否繼續輸注 Xigris，應同時評估治療的效益與可能出血的危險性。實驗室試驗 Drotrecogin alfa (活化型)對 PT 的影響很小。重度敗血症病患使用 Xigris 導致 APTT 延長，可能是由於潛在的凝血病變、Drotrecogin alfa (活化型)的藥效性質、和/或其他併用藥物的作用。Drotrecogin alfa (活化型) 藥效作用影響 APTT 的分析結果，與使用試劑、分析儀器、取樣至試驗所需時間有關。於輸注 Xigris 的病人取得的血液或血漿樣本，Drotrecogin alfa (活化 Final Truth - SPC20051115 – 17FEB2006 – v2 型)會逐漸被內生性血漿蛋白酶抑制劑中和。實際上，血液樣品取樣二小時後，已無法偵測 Drotrecogin alfa(活化型)的活性。由於生物與分析上的變異，並不宜用 APTT 評估 Drotrecogin alfa(活化型)的藥效性質。另外，停止輸注約二小時後，於病患循環系統中，亦無法偵測 Drotrecogin alfa(活化型)的活性；因此，於此時間點後抽取供 APTT 分析之血液樣品，已不受本藥影響。在判讀一系列 PT 和/或 APTT 的分析結果時，應將這些變異因素列入考慮。由於 Drotrecogin alfa(活化型)可能影響 APTT 的分析，於血液樣品中的 Drotrecogin alfa(活化型)，也可能干擾與 APTT 相關的第一期凝血反應分析(包括凝血因子 VIII、IX、XI 的分析)。反之，於血液樣品中的 Drotrecogin alfa(活化型)，不會干擾與 PT 相關的第一期凝血反應分析(包括凝血因子 II、V、VII、X 的分析)。當連續偵測凝血異常(包括血小板數)顯示嚴重或惡化之凝血病變時，應考慮治療之危險性與效益，以決定是否繼續輸注本藥。免疫性重度敗血症病患在接受單一療程治療後，產生抗活化型蛋白 C 抗體的情形並不常見(<1%)。於 APTT 分析試驗中，這些抗體無法中和活化型蛋白 C 的作用。然而，對於較敏感的病患，並不能完全排除對於其他組成物質產生過敏反應的可能性。若發生抗體性或過敏原性過敏反應時，應立即停藥並予以適當治療。Xigris 尚未重複投與於重度敗血症病患。若欲重複投予 Xigris 於病患，須特別謹慎小心。於健康人，未曾偵測到抗活化型蛋白 C 抗體的生成，甚至於重複投藥後亦然。小兒科病患安慰劑對照臨床試驗所得資料未證實 Xigris 治療小兒科病患之療效，這些病患患有重度敗血症、急性感染、全身性發炎及呼吸道和心血管器官功能異常。本試驗於 477 位病患接受試驗用藥後，因無治療效益而終止試驗(共 600 位病患有意願参與試驗)。原訂之期中分析(interim analysis) (收錄 400 位病患) 顯示，二組病患之主要試驗終點, CTCOFR 分數, 很可能沒有顯著差異(CTCOFR: Composite Time to Complete Organ Failure Resolution) (Xigris 治療組及安慰劑組之 CTCOFR 分數分別為 9.8 平均天與 9.7 平均天，以 14 天為基值)。二組病患之 28 天死亡率亦無差異(Xigris 治療組及安慰劑組分別為 17.1% 及 17.3%)。試驗醫師歸咎因出血而致死的病例，Xigris 治療組為 2 例，安慰劑組為 5 例。相較於安慰劑組， drotrecogin alfa (活化型)治療組具較高的中樞神經系統(CNS)出血發生率。藥物輸注期間(参與試驗第 0-6 天)，所有参與試驗病患中發生 CNS 出血的病患分別為 5 位及 1 位(2.1% 及 0.4%， drotrecogin alfa (活化型)治療組及安慰劑組)，drotrecogin alfa (活化型)治療組的 5 位病患中，有 4 位其年齡小於等於 60 天或體重小於等於 3.5 公斤。Drotrecogin alfa (活化型)治療組與安慰劑組發生致命中樞神經系統(CNS)出血、嚴重出血(包括輸注期間及 28 天試驗期間)、嚴重不良反應及嚴重截肢(major amputation)之情形相似。藥物交互作用及其他交互作用 Xigris 未曾以敗血症病患進行藥物交互作用的研究。當 Xigris 與其他止血作用相關的藥物併用時，應謹慎小心(見禁忌、警語和注意事項欄)，包括蛋白 C、血栓溶解劑(如 streptokinase、tPA、rPA、urokinase)、口服抗凝血劑(如 warfarin)、水蛭素、抗凝血酶、阿斯匹靈及其他抗血小板劑(如非固醇類抗發炎藥、ticlopidine、clopidogrel)、 glycoprotein IIb/IIIa 拮抗劑 (如 abciximab、eptifibatide、tirofiban)及 prostacyclins(如 iloprost)。肝素在第三期試驗中，2/3 病患以預防性劑量使用未萃取或小分子量的肝素。於同時使用 Drotrecogin alfa (活化型)與肝素的病患，並未發現有增加嚴重出血反應的危險性。未曾以隨機控制的的臨床試驗，評估預防性低劑量肝素與其他促凝血藥物對 Drotrecogin alfa (活化型)效用的影響。懷孕和授乳期的使用尚未以動物試驗，研究 Xigris 對懷孕，胚胎/胎兒發育，分娩及出生後發育的影響。因此對人類的潛在危險未知。懷孕期間不應投予 Xigris，除非有明確需要時方可使用。尚未得知 Xigris 是否會分泌至乳汁，或可能對授乳嬰兒造成不良反應。因此病患用藥期間應停止授乳。對駕駛和操作儀器能力的影響尚無資料。副作用 Xigris 會增加出血的風險。第三期全球多中心、隨機雙盲、安慰劑控制臨床試驗(PROWESS)，共包含 850 位接受 drotrecogin alfa (活化型)治療與 840 位接受安慰劑治療的病患。這二組病患，曾發生至少一次出血反應的百分比分別為 24.9%及 17.7%。這二組病患中，大部份的出血反應為斑狀出血或胃腸道出血。比較二組病患的嚴重出血反應發生率，發現差異主要發生於藥物輸注期間。共 2378 位接受 drotrecogin alfa (活化型)治療的成人嚴重敗血症病患，參與第 3b 期全球、單一治療組、開放標記臨床試驗(ENHANCE)。整理 PROWESS 與 ENHANCE 臨床試驗之嚴重出血反應發生率如下表。於這些試驗中，嚴重出血反應包含：任何顱內出血，任何危及生命或致命之出血，任何需要連續二天每天輸注大於或等於 3 單位袋裝紅血球之出血，或任何被醫師評估為嚴重不良反應之出血。第 3b 期全球多中心、隨機雙盲、安慰劑控制臨床試驗(ADDRESS)，共包含 1317 位接受 drotrecogin alfa (活化型)治療與 1293 位接受安慰劑治療的成人嚴重敗血症伴隨低死亡風險病患。這二組病患，曾發生至少一次出血反應的百分比分別為 10.9%及 6.4% (p<0.001)。這些出血反應包含嚴重出血反應、出血反應是否與試驗用藥有關由醫師評估、需紅血球輸注的出血反應、導致永久停用試驗用藥的出血反應。ADDRESS 試驗中，嚴重出血反應包含：致命出血、任何危及生命出血、任何中樞神經系統(CNS)出血、或任何被醫師評估為嚴重出血之不良反應。輸注期間發生之嚴重出血反應下表所列為：藥物輸注期間(定義為輸注期間及輸注結束後一天)，發生嚴重出血反應病患的百分比，依出血部位整理。 Drotrecogin alfa Drotrecogin alfa 安慰劑出血部位 (活化型) (活化型) [PROWESS] N=840 [ENHANCE] [PROWESS] N=2378 N=850 5 (0.6%) 4 (0.5%) 19 (0.8%) 胃腸道 2 (0.2%) 3 (0.4%) 18 (0.8%) 腹腔內 4 (0.5%) 0 11 (0.5%) 胸腔內 3 (0.4%) 0 4 (0.2%) 後腹腔 2 (0.2%) 0 15 (0.6%) 中樞神經系統 (CNS)1 2 (0.2%) 0 0 生殖泌尿道 1 (0.1%) 0 16 (0.7%) 皮膚/軟組織 0 0 4 (0.2%) 鼻咽腔 0 0 1 (0.04%) 關節/骨骼 1 (0.1%) 1 (0.1%) 6 (0.3%) 未知部位 2 20 (2.4%) 8 (1.0%) 853 (3.6%) 總計 1 CNS 出血定義為任何中樞神經系統出血，包含以下出血情形：斑狀出血、實質性出血、蛛網膜下出血、硬腦膜下出血與中風引起之出血 2 病患需連續二天每天輸注大於或等於 3 單位袋裝紅血球，但其出血部位未確定。 3 ENHANCE 臨床試驗中，6 位病患於藥物輸注期間發生多次嚴重出血反應。(85 位病患共發生 94 次不良反應)。 ADDRESS 臨床試驗中，接受治療病患發生嚴重出血反應的百分比(依出血部位整理)，與 PROWESS 臨床試驗中觀察到的情形相似。藥物輸注期間(定義為參與試驗第 0-6 天)，嚴重出血反應的發生率分別為 Drotrecogin alfa (活化型)組 31 位病患(2.4%)，安慰劑組 15 位(1.2%) (p=0.02)。藥物輸注期間，中樞神經系統出血的發生率分別為 Drotrecogin alfa (活化型)組 4 位病患(0.3%)，安慰劑組 3 位(0.2%)。無論對 Xigris 治療組或安慰劑組病患，近期手術(參與試驗前 30 天曾接受手術)明顯提高輸注期間嚴重出血的風險。(Xigris 組：近期手術病患之發生率為 3.6%、非近期手術病患為 1.6%；安慰劑組：近期手術病患之發生率為 1.6%、非近期手術病患為 0.9%) 於 28 天臨床試驗期間發生之嚴重出血反應於 PROWESS 臨床試驗的 28 天臨床試驗期間，drotrecogin alfa (活化型)治療組與安慰劑組的嚴重出血反應發生率分別為 3.5%與 2.0%。於 28 天臨床試驗期間，drotrecogin alfa (活化型)治療組與安慰劑組的中樞神經系統出血發生率分別為 0.2%與 0.1%。嚴重凝血病變與嚴重血小板減少症可能增加中樞神經系統出血的風險。(參閱禁忌欄、警語和注意事項欄) 於開放標記的 ENHANCE 臨床試驗的 28 天臨床試驗期間，嚴重出血反應發生率為 6.5%，中樞神經系統出血發生率為 1.5%。於安慰劑控制的 ADDRESS 臨床試驗的 28 天臨床試驗期間，Drotrecogin alfa (活化型)治療組與安慰劑組的嚴重出血反應發生率分別為 51 位(3.9%)與 28 位(2.2%) (p=0.01)。於 28 天臨床試驗期間，Drotrecogin alfa (活化型)治療組與安慰劑組的中樞神經系統出血發生率分別為 6 位(0.5%) 與 5 位(0.4%)。第一期臨床試驗中，發生率大於 5%之不良反應，包括頭痛(30.9%)，斑狀出血(23.0%)，及疼痛 (5.8%)。過量臨床試驗中，有一例 drotrecogin alfa (活化型)藥物過量的報告。重度敗血症病患使用 181µg/kg/hr 劑量二小時。關於此藥物過量，並未有嚴重不良反應發生。上市後經驗：有一些偶發的藥物過量報告。這些報告中，大部分沒有發生不良反應；其他報告發生的不良反應，與已知的藥物副作用(參閱副作用欄)、藥物於實驗室試驗的作用(參閱實驗室試驗欄)、或敗血症的潛在疾病後遺症有關。尚無已知 drotrecogin alfa (活化型)的解毒劑。一旦藥物過量，應立即停止輸注(見藥動性質)。藥理性質藥效性質藥理分類：抗血栓劑，酵素，ATC code 為 B01AD10 作用機轉 Xigris 為天然血漿活化蛋白 C 之基因重組製劑，其結構與天然活化蛋白 C 之差異，僅在於分子糖質區的一個特殊寡醣。活化蛋白 C 為重要的凝血調節因子。它藉由抑制 Va 和 VIIIa 因子的活性限制凝血酶的生成，因而負迴饋調節凝血反應。於微循環部位發生過度活化的凝血反應，為重度敗血症的重要病理表徵。此外，活化蛋白 C 亦為全身性感染反應的重要調節因子，且具抗血栓與纖維蛋白溶解原的特性。Xigris 與內生性人類活化蛋白 C 具相似的特性。藥效作用在以安慰劑控制的臨床試驗中，治療重度敗血症病患，Xigris 藉抑制凝血酶的生成與改善敗血症相關的凝血病變(可見其更迅速的增加凝血作用與纖維蛋白溶解作用的指標物質)，表現抗血栓作用。Xigris 快速減少血栓的指標物質，如 D-二聚體、凝血酶原 F1.2、凝血酶-抗凝血酶聚合物，且快速增加蛋白 C 與凝血酶原。Xigris 亦修復內生性纖維蛋白溶解的能力，證據顯示快速趨使胞漿素原正常化，且快速減少胞漿素原活化抑制劑-1。此外，重度敗血症病患使用 Xigris，會使白血球間質素 IL-6 (發炎反應的總體指標物質)快速下降，此與發炎反應降低的結果一致。臨床療效 Xigris 的第三期臨床試驗(PROWESS)，為多國性、多中心、隨機、雙盲、以安慰劑控制的臨床試驗，共 1690 位重度敗血症病患參加。重度敗血症定義為敗血症伴有急性器官衰竭。重度敗血症病患，於臨床上的診斷為 a)已知或疑似感染，b) 全身感染反應的臨床證據，包括發燒或發冷、白血球減少症或白血球增多症、心跳過速和心跳遲緩，及 c)急性器官衰竭。器官衰竭定義為休克、低血壓或雖回復足夠體液仍需血管收縮劑支持、相對性缺氧(動脈氧分壓以 mmHg 為單位，與吸入空氣含氧百分比以小數點表示，之比值(PaO2/FiO2) <250)、雖回復足夠體液仍少尿、血小板數顯著減少、及/或乳酸濃度增高。不列入臨床試驗者包括：出血高危險群病人(見禁忌、警語和注意事項欄)、因先前存在非敗血症相關疾病，而預估將無法存活 28 天的病人、愛滋病毒呈陽性反應的病人，且其近期 CD4 ≤ 50/mm3、長期接受透析的病人、曾接受骨髓、肺、肝、胰或小腸移植的病人、及曾患急性胰臟炎但未確定其感染源的病人。 PROWESS 臨床試驗中，病患於敗血症誘發第一個器官衰竭後 48 小時內開始接受治療。治療前的器官衰竭中位時間為 18 小時。病人接受 96 小時持續輸注 Xigris 24µg/kg/hr (n=850)或安慰劑 (n=840)，同時也接受最佳標準照護。最佳標準照護，包括適當的抗生素，來源管制，及支持性療法(依需要提供水份、肌肉收縮劑、血管收縮劑、衰竭器官的支持)。接受 Xigris 治療的病人與安慰劑組比較，其 28 天存活率有明顯改善。第 28 天，Xigris 治療組之總死亡率為 24.7%，安慰劑組為 30.8% (p=0.005)。顯著的絕對死亡數減少，受限於試驗病人的較嚴重病況，例如 APACHE II 評分 ≥ 25 或至少二種急性器官衰竭。(APACHE II 評分為評估致死率危險的標準，全名為急性生理學與長期健康評估 acute physiology and chronic health evaluation)。APACHE II ≥ 25 的試驗病人，其死亡率於 Xigris 治療組為 31% (128/414 人)，於安慰劑組為 44% (176/403 人)。病況較不嚴重的病人，未有降低死亡率的報告。至少二種急性器官衰竭的試驗病人，其死亡率於 Xigris 治療組為 26.5% (168/634 人)，於安慰劑組為 33.9% (216/637 人)。少於二種急性器官衰竭的試驗病人，未有明顯降低死亡率的報告。 Xigris 對於死亡的治療，於不同族群的效果一致，包括年齡、性別及感染種類。肝素(Heparin) 約 2/3 病人於治療期間使用預防性低劑量 Heparin。病人併用 Xigris 與預防性低劑量 Heparin 的死亡率為 24.9%，病人併用安慰劑與預防性低劑量 Heparin 的死亡率為 28.1% (p=0.20)。尚不能判定 Heparin 是否會影響 Xigris 的活性。低劑量 Heparin 對於 Xigris 的治療效果的影響，尚未以特定的隨機控制臨床試驗評估。 PROWESS 追蹤性臨床試驗以 PROWESS 追蹤性臨床試驗評估參與 PROWESS 臨床試驗存活病人的存活狀態。在 1690 位參與 PROWESS 臨床試驗的病人中，分別有 98%及 94%的病人列入 PROWESS 追蹤試驗住院存活率與三個月存活率的評估。在全部的受試者中，Xigris 治療組病人的住院死亡率明顯低於安慰劑組 (29.4% vs. 34.6%; p=0.023)。比較三個月存活率，Xigris 治療組亦較安慰劑組為佳(log rank p=0.048)。此項數據進一步證實 Xigris 臨床治療效益限於較嚴重敗血病人，例如伴隨多重器官衰竭與休克的敗血病人。進一步的臨床經驗第 3b 期全球、單一治療組、開放標記臨床試驗(ENHANCE)，共包含 2378 位接受 drotrecogin alfa (活化型)治療的成人嚴重敗血症病患。參與本試驗病患的條件與參與 PROWESS 臨床試驗病患的條件相似。病患於敗血症誘發第一個器官衰竭後 48 小時內開始接受治療。治療前的器官衰竭中位時間為 25 小時。第 3b 期臨床試驗中，Xigris 治療組的第 28 天死亡率為 25.3%。相較於器官衰竭發生後 24 小時以後接受治療的病患，器官衰竭發生後 24 小時內接受治療的病患死亡率較低，即使將疾病嚴重程度的差異調整後亦然。共 2640 位成人重度敗血症伴隨低死亡風險病患(病患 APACHE II 評分< 25 或病患僅伴隨一個因 Final Truth - SPC20051115 – 17FEB2006 – v2 敗血症引起之器官衰竭)參與隨機雙盲、安慰劑控制臨床試驗(ADDRESS)。本試驗於 interim analysis 後結束，因為試驗結束前之資料顯示，二組病患之 28 天死亡率沒有顯著差異。ADDRESS 臨床試驗共收錄 872 位多重器官功能異常病患。相較於 PROWESS 臨床試驗收錄之多重器官功能異常病患，參與 ADDRESS 病患接受試驗用藥治療前伴隨器官功能異常之時間較長(中位時間為 ADDRESS：25 小時、PROWESS：18 小時)，APACHE II 評分較低(中位分數為 ADDRESS： 20、PROWESS：25)，伴隨二個器官功能異常之病患較多(ADDRESS：76%、PROWESS：43%)。 ADDRESS 試驗中，多重器官功能異常病患之第 28 天死亡率分別為：Xigris 治療組 20.7%、安慰劑組 21.9%；住院死亡率則分別為：Xigris 治療組 23.1%、安慰劑組 25.3%。ADDRESS 與 PROWESS 臨床試驗對於雙重器官功能異常亞群病患之治療結果相似。這些安慰劑控制臨床試驗中，收錄較多病患的試驗中心呈現較顯著的治療療效。藥動性質 Drotrecogin alfa (activated) 及內生性人體活化型蛋白 C，於血漿中會被內生性蛋白酶抑制劑去活化，但其由血漿清除的機轉未知。健康人與重度敗血症病人，內生性活化型蛋白 C 的血漿濃度通常低於偵測限度(<5ng/ml)，且不會明顯影響 Drotrecogin alfa (activated)的藥動性質。健康受試者接受定速靜脈輸注 Xigris 2 小時內，超過 90% 的病人達到穩定狀態。輸注完成後， drotrecogin alfa (活化型)血中濃度的下降呈二相變化，包括較迅速的初始期(t1/2 α=13 分鐘)及較緩慢的第二期(t1/2 β=1.6 小時)。13 分鐘短半衰期約包含 80%血漿濃度曲線下面積，且調控 drotrecogin alfa (活化型)的血中濃度，由開始快速的治療效益至穩定狀態。drotrecogin alfa (活化型)的穩定血中濃度與輸注速率呈正比，輸注速率範圍由 12 µg/kg/hr 至 48 µg/kg/hr。健康受試者接受 24 µg/kg/hr 輸注的平均 drotrecogin alfa (活化型) 穩定血中濃度為 72 ng/ml。重度敗血症病人輸注 drotrecogin alfa (活化型)，速率由 12 µg/kg/hr 至 30 µg/kg/hr，其迅速達到的穩定血中濃度與輸注速率呈正比。第三期臨床試驗中，drotrecogin alfa (活化型)的藥動性質以 342 位重度敗血症病人接受 24 µg/kg/hr 連續輸注 96 小時做研究。drotrecogin alfa (活化型) 的藥動性質為輸注後 2 小時內達穩定血中濃度。大多數病人，輸注後 2 小時偵測的活化型蛋白 C 濃度低於可定量範圍，顯示 drotrecogin alfa (活化型) 快速自循環系統中清除。drotrecogin alfa (活化型) 之血漿廓清率，於敗血症病人為 41.8 l/hr，於健康人為 28.1 l/ hr。重度敗血症病人之 drotrecogin alfa (活化型)血漿廓清率會因腎功能受損(肌氨酸酐清除率 <50ml/min)及肝功能不良(>三倍 AST 正常值上限)而顯著降低，但不需因此廓清率的變化幅度 (<30%)做劑量調整。臨床前安全性資料重複投予人體最高劑量或稍微超過人體最高劑量於猴子，所觀察到的改變皆與 Xigris 的藥理性質相關，包括預期的 APTT 延長，血紅素、紅血球與血球容積降低，網狀血球數及 PT 增加。小鼠體內之微細胞核研究，或以經或不經大鼠肝代謝活化的人體週邊血液淋巴球之體外染色體變異研究，皆顯示 Xigris 不會致突變。尚未以 Xigris 進行致癌性及動物生殖影響的研究。因此，Xigris 對人體的潛在危險也未知，Xigris 不應於懷孕期間使用，除非明確需要才可投與本藥(見懷孕和授乳期的使用欄)。製劑特性賦型劑蔗糖、氯化鈉、檸檬酸鈉、檸檬酸、氫氯酸、氫氧化鈉。不相容性 Xigris 配製後，只容許與 0.9%氯化鈉注射液混合使用。其餘可與 Xigris 經由同一靜脈管投與之溶液，包括：0.9%氯化鈉注射液、乳酸 Ringer’s 注射液、葡萄糖液、葡萄糖和生理食鹽水混合液。當 Xigris 以低濃度(小於 200 微毫克/毫升)、低流速(小於 5 毫升/小時)給藥時，點滴裝置必須先以流速 5 毫升/小時，準備 15 分鐘。儲存期 3年 Xigris 配製後，建議立即使用；若無法立即使用，配製後溶液存於小瓶，可於室溫(15-30°C)保存 3 小時。 Xigris 靜脈輸注液配製後，可於室溫(15-30°C)使用達 14 小時。儲存時特殊注意事項儲存於 2-8°C (冰箱)；小瓶置於包裝盒中避光。包裝 5 公絲小瓶裝 20 公絲小瓶裝使用處理說明 1. 使用無菌技術配製 Xigris 靜脈輸注液。 2. 計算劑量與需要 Xigris 瓶數。Xigris 小瓶含 5 公絲或 20 公絲 drotrecogin alfa (activated)，每瓶皆含超量 drotrecogin alfa (activated)，以期達到標記劑量。 3. 投與前，20 公絲小瓶 Xigris 以 10 公撮無菌注射用水配製，5 公絲小瓶 Xigris 以 2.5 公撮無菌注射用水配製，得濃度 2mg/ml 之 Xigris 溶液。將無菌注射用水緩慢加入小瓶，避免反轉或振搖小瓶，輕輕搖勻直到粉末完全溶解。 4. 經前述配製之 Xigris 溶液，須再以無菌 0.9%氯化鈉注射液稀釋。緩慢自瓶中抽取適量 Xigirs 溶液，將其沿輸液袋袋壁，加入已含有無菌 0.9%氯化鈉注射液之輸注袋，以減少溶液之劇烈震動。輕輕轉動輸液袋，使溶液均勻混合。避免以機械性傳輸方式運送此輸液袋。 5. Xigris 配製後，建議立即使用；若無法立即使用，配製後溶液存於小瓶，可於室溫(15-30°C) 保存 3 小時。Xigris 靜脈輸注液配製後，可於室溫(15-30°C)使用達 14 小時。 6. 靜脈製劑給藥前，需以眼睛檢視溶液是否含有異物或變色現象。 7. 使用靜脈輸注幫浦給藥時，將 Xigris 配製溶液加入含 0.9%無菌氯化鈉注射液之輸液袋，稀釋為濃度 100-200 µg/ml。 8. 當 Xigris 以低濃度(小於 200 微毫克/毫升)、低流速(小於 5 毫升/小時)給藥時，點滴裝置必須先以流速 5 毫升/小時，準備 15 分鐘。 9. Xigris 應以專用靜脈管或多管腔之中央靜脈導管給藥。可與 Xigris 用同一靜脈管投與之溶液，僅包括：0.9%氯化鈉注射液、乳酸 Ringer’s 注射液、葡萄糖液、葡萄糖和生理食鹽水混合液。 10. Xigris 溶液應避免高熱和/或陽光曝曬。Xigris 與玻璃點滴瓶或聚氯乙烯、聚乙烯、聚丙烯、 polyolefin 材質之輸液袋無不相容性報告。使用其它材質之輸注裝置可能發生關於 Xigris 藥量或效力之負面影響。 11. 應小心以適當速度輸注 Xigris，輸注速度根據病患體重(kg)及正確輸注時間計算。建議將計算出之輸注速度標示於藥品瓶身。本藥限由醫師使用衛署菌疫輸字第 000786 號製造廠：DSM Pharmaceuticals， Inc. 5900 NW Greenville Blvd. Greenville， North Carolina 27834， USA. 包裝廠：Lilly Pharma Fertigung und Distributions GmbH & Co. KG Teichweg 3， 35396 Giessen， Germany 藥商：台灣禮來股份有限公司台北市復興北路 365 號 11 樓 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1 1. NAME OF THE MEDICINAL PRODUCT Xigris 20 mg powder for solution for infusion 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each vial contains: Drotrecogin alfa (activated): 2 mg per ml after reconstitution. A vial contains 20 mg of drotrecogin alfa (activated) to be reconstituted with 10 ml of Sterile Water for Injection. Drotrecogin alfa (activated) is a recombinant version of the endogenous activated Protein C and is produced by genetic engineering from an established human cell line. For excipients, see 6.1. 3. PHARMACEUTICAL FORM Powder for solution for infusion 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Xigris is indicated for the treatment of adult patients with severe sepsis with multiple organ failure when added to best standard care. The use of Xigris should be considered mainly in situations when therapy can be started within 24 hours after the onset of organ failure (for further information see Section 5.1). 4.2 Posology and method of administration Xigris should be used by experienced doctors in institutions skilled in the care of patients with severe sepsis. Treatment should be started within 48 hours, and preferably within 24 hours, of onset of the first documented sepsis-induced organ dysfunction (see Section 5.1). The recommended dose of Xigris is 24 µg/kg/hr given as a continuous intravenous infusion for a total duration of 96 hours. It is recommended that Xigris be infused with an infusion pump to accurately control the infusion rate. If the infusion is interrupted for any reason, Xigris should be restarted at the 24 µg/kg/hr infusion rate and continued to complete the full recommended 96 hours of dosing administration. Dose escalation or bolus doses of Xigris are not necessary to account for the interruption in the infusion. No dose adjustments are required in adult patients with severe sepsis with regard to age, gender, hepatic function (as measured by transaminase levels) or renal function. The pharmacokinetics of drotrecogin alfa (activated) have not been studied in patients with severe sepsis and preexisting endstage renal disease and chronic hepatic disease. Paediatrics: Data from a placebo-controlled clinical trial which was stopped for futility after 477 patients 0 to 17 years-old had received the study drug did not establish efficacy of Xigris in paediatric patients and showed a higher rate of central nervous system bleeding in the Xigris versus placebo 2 group. Therefore no dosage recommendation can be made and the use of Xigris is not recommended in children below the age of 18 (see Section 4.4). 4.3 Contraindications Because drotrecogin alfa (activated) may increase the risk of bleeding, Xigris is contraindicated in the following situations: • • • • • • • Active internal bleeding Patients with intracranial pathology; neoplasm or evidence of cerebral herniation Concurrent heparin therapy ≥ 15 International Units/kg/hr Known bleeding diathesis except for acute coagulopathy related to sepsis Chronic severe hepatic disease Platelet count < 30,000 x 106/l, even if the platelet count is increased after transfusions Patients at increased risk for bleeding (for example): a) any major surgery, defined as surgery that requires general or spinal anesthesia, performed within the 12-hour period immediately preceding drug infusion, or any postoperative patient who demonstrates evidence of active bleeding, or any patient with planned or anticipated surgery during the drug infusion period. b) history of severe head trauma that required hospitalization, intracranial or intraspinal surgery, or haemorrhagic stroke within the previous 3 months, or any history of intracerebral arteriovenous malformation, cerebral aneurysm, or central nervous system mass lesion; patients with an epidural catheter or who are anticipated to receive an epidural catheter during drug infusion c) history of congenital bleeding diatheses d) gastrointestinal bleeding within the last 6 weeks that has required medical intervention unless definitive surgery has been performed e) trauma patients at increased risk of bleeding Xigris is also contraindicated in patients with known hypersensitivity to drotrecogin alfa (activated), to any of the formulation excipients, or to bovine thrombin (a trace residue from the manufacturing process). 4.4 Special warnings and special precautions for use Patients with single organ dysfunction and recent surgery Xigris is not approved for the treatment of patients with single organ dysfunction and should not be used in this particular subgroup of patients, especially if they had recent surgery (within 30 days). In each of two randomised, placebo-controlled trials, PROWESS and ADDRESS (see Section 5.1), 28day and in-hospital mortality were higher in patients treated with drotrecogin alfa (activated) compared to placebo for the sub-population of patients with single organ dysfunction and recent surgery (n=98 in PROWESS and n=636 in ADDRESS). Bleeding Drotrecogin alfa (activated) increases the risk of bleeding. In the following conditions, the risks of the administration of Xigris should be weighed against the anticipated benefits: • • • • • Recent administration (within 3 days) of thrombolytic therapy Recent administration (within 7 days) of oral anticoagulants Recent administration (within 7 days) of aspirin or other platelet inhibitors Recent (within 3 months) ischaemic stroke Any other condition in which the physician considers significant bleeding is likely For procedures with an inherent bleeding risk, discontinue Xigris for 2 hours prior to the start of the procedure. Xigris may be restarted 12 hours after major invasive procedures or surgery if adequate 3 haemostasis has been achieved. Xigris may be restarted immediately after uncomplicated less invasive procedures if adequate haemostasis has been achieved. As a component of routine care, measures of haemostasis (e.g., activated partial thromboplastin time (APTT), prothrombin time (PT) and platelet count) should be obtained during the infusion of Xigris. If sequential tests of haemostasis indicate an uncontrolled or worsening coagulopathy that significantly increases the risk of bleeding, the benefits of continuing the infusion must be weighed against the potential increased risk of bleeding for that patient. Laboratory tests Drotrecogin alfa (activated) has minimal effect on the PT. Prolongation of the APTT in patients with severe sepsis receiving Xigris may be due to the underlying coagulopathy, the pharmacodynamic effect of drotrecogin alfa (activated), and/or the effect of other concurrent medications. The pharmacodynamic effect of drotrecogin alfa (activated) on the APTT assay is dependent on the reagent and instrument used to perform the assay and the time that elapses between sample acquisition and assay performance. Drotrecogin alfa (activated) that is present in a blood or plasma sample drawn from a patient who is being infused with the drug will be gradually neutralized by endogenous plasma protease inhibitors present in the sample. Virtually no measurable activity of drotrecogin alfa (activated) is present 2 hours after obtaining the blood sample. Due to these biological and analytical variables, the APTT should not be used to assess the pharmacodynamic effect of drotrecogin alfa (activated). In addition, approximately 2 hours after terminating the infusion of the drug, there is virtually no measurable activity of drotrecogin alfa (activated) remaining in the circulation of the patient; blood samples drawn for APTT determination after this point are no longer affected by the drug. The interpretation of sequential determinations of the PT and/or APTT should take these variables into consideration. Because drotrecogin alfa (activated) may affect the APTT assays, drotrecogin alfa (activated) present in plasma samples may interfere with one-stage coagulation assays based on the APTT (such as factor VIII, IX, and XI assays). Drotrecogin alfa (activated) present in plasma samples does not interfere with one-stage factor assays based on the PT (such as Factors II, V, VII and X assays). If sequential measures of coagulopathy (including platelet count) indicate severe or worsening coagulopathy, the risk of continuing the infusion should be weighed against the expected benefit. Immunogenicity In patients with severe sepsis, the formation of anti-Activated Protein C antibodies was uncommon (<1%) after a single course of therapy. These antibodies were not capable of neutralizing the effect of Activated Protein C on the APTT assay. However, the possibility of allergic reactions to constituents of the preparation cannot be completely excluded in certain predisposed patients. If allergic or anaphylactic reactions occur, treatment should be discontinued immediately and appropriate therapy initiated. Xigris has not been readministered to patients with severe sepsis. If Xigris is readministered to patients, caution should be employed. No anti-activated Protein C antibody formation was detected in healthy subjects, even after repeat administration. Paediatric patients Data from a placebo-controlled clinical trial did not establish efficacy of Xigris in paediatric patients suffering from severe sepsis, acute infection, systemic inflammation and respiratory and cardiovascular organ dysfunction. This trial was stopped for futility after 477 patients had received the study drug (out of 600 patients intended). A planned interim analysis (with 400 patients enrolled) showed a low likelihood of demonstrating a significant difference in the primary endpoint of “Composite Time to Complete Organ Failure Resolution” (CTCOFR score of 9.8 versus 9.7 mean days over 14 days). There was also no difference in 28-day mortality (17.1% versus 17.3% in the Xigris and placebo groups, respectively). Investigators attributed 2 deaths in the Xigris group and 5 deaths in the placebo group to bleeding events. There was a higher rate of central nervous system (CNS) bleeding in the drotrecogin alfa (activated) versus the placebo group. Over the infusion period (study days 0-6) the number of patients experiencing CNS bleeding was 5 versus 1 (2.1% versus 0.4%) for the overall population 4 (drotrecogin alfa (activated) versus placebo), with 4 of the 5 events in the drotrecogin alfa (activated) group occurring in patients ≤ 60 days old or ≤ 3.5 kg bodyweight. Fatal CNS bleeding events, serious bleeding events (over the infusion period and over the 28-day study period), serious adverse events, and major amputations were similar in the drotrecogin alfa (activated) and placebo groups. 4.5 Interaction with other medicinal products and other forms of interaction Drug interactions with Xigris have not been studied in patients with sepsis. Caution should be employed when Xigris is used with other drugs that affect haemostasis (see Sections 4.3 and 4.4) including Protein C, thrombolytics (e.g. streptokinase, tPA, rPA and urokinase), oral anticoagulants (e.g. warfarin), hirudins, antithrombin, aspirin and other anti platelets agents, e.g. non-steroidal anti-inflammatory drugs, ticlopidine and clopidogrel, glycoprotein IIb/IIIa antagonists (such as abciximab, eptifibatide, tirofiban) and prostacyclins such as iloprost. Heparin Two-thirds of patients in the phase 3 trial received prophylactic doses of unfractionated or low molecular weight heparin. There was no observed increase in the risk of bleeding events reported as serious adverse events in drotrecogin alfa (activated) patients receiving heparin. The effects of prophylactic low dose heparin and other coagulation-active medications on the efficacy of drotrecogin alfa (activated) have not been evaluated in a randomised controlled clinical trial. 4.6 Pregnancy and lactation Animal studies with respect to effects on pregnancy, embryonal/foetal development, parturition and postnatal development have not been conducted with Xigris. Therefore, the potential risk for humans is unknown. Xigris should not be used during pregnancy unless clearly necessary. It is not known whether Xigris is excreted in human milk or if there is a potential effect on the nursed infant. Therefore, the patient should not breast feed whilst treated with Xigris. 4.7 Effects on ability to drive and use machines Not applicable. 4.8 Undesirable effects Xigris increases the risk of bleeding. The Phase 3 international, multi-centre, randomised, double-blind, placebo-controlled clinical trial (PROWESS) involved 850 drotrecogin alfa (activated)-treated and 840 placebo-treated patients. The percentage of patients experiencing at least one bleeding event in the two treatment groups was 24.9% and 17.7%, respectively. In both treatment groups, the majority of bleeding events were ecchymosis or gastrointestinal tract bleeding. The difference in the incidence of serious bleeding events between the two treatment groups occurred primarily during study drug administration. A total of 2378 adult patients with severe sepsis received drotrecogin alfa (activated) in a Phase 3b, international, single-arm, open-label clinical trial (ENHANCE). The incidence of serious bleeding events in the PROWESS and ENHANCE studies is provided below. In these studies serious bleeding events included any intracranial haemorrhage, any life-threatening or fatal bleed, any bleeding event requiring the administration of ≥ 3 units of packed red blood cells per day for 2 consecutive days, or any bleeding event assessed as serious by the investigator. A Phase 3b international, multi-centre, randomised, double-blind, placebo-controlled clinical trial (ADDRESS) of adult severe sepsis patients at low risk of death, involved 1317 drotrecogin alfa 5 (activated)-treated and 1293 placebo-treated patients. The percentage of patients experiencing at least one bleeding event in the two treatment groups was 10.9% and 6.4%, respectively (p<0.001). Bleeding events included serious bleeding events, bleeding events assessed as possibly study-drug related by the investigator, bleeding events associated with the need for a red blood cell transfusion, and bleeding events that led to permanent discontinuation of the study drug. In the ADDRESS trial, serious bleeding events included any fatal bleed, any life-threatening bleed, any CNS bleed, or any bleeding event assessed as serious by the investigator. Serious bleeding events during the infusion period The following table lists the percent of patients in PROWESS and ENHANCE experiencing serious bleeding events by site of haemorrhage during the study drug infusion period (defined as the duration of infusion plus the next full calendar day following the end of the infusion). Site of haemorrhage Gastrointestinal Intra-abdominal Intra-thoracic Retroperitoneal Central Nervous System (CNS)1 Genitourinary Skin/soft tissue Nasopharyngeal Joint/Bone Site unknown2 Total Drotrecogin alfa (activated) [PROWESS] N=850 [PROWESS] N=840 Drotrecogin alfa (activated) [ENHANCE] N=2378 5 (0.6%) 2 (0.2%) 4 (0.5%) 3 (0.4%) 4(0.5%) 3 (0.4%) 0 0 19 (0.8%) 18 (0.8%) 11 (0.5%) 4 (0.2%) 2 (0.2%) 0 15 (0.6%) 2 (0.2%) 1 (0.1%) 0 0 1 (0.1%) 20 (2.4%) 0 0 0 0 1 (0.1%) 8 (1.0%) 0 16 (0.7%) 4 (0.2%) 1 (0.04%) 6 (0.3%) 853 (3.6%) Placebo 1 CNS bleeding is defined as any bleed in the central nervous system including the following types of haemorrhage: Petechial, parenchymal, subarachnoid, subdural, and stroke with haemorrhagic transformation. 2 Patients requiring the administration of ≥ 3 units of packed red blood cells per day for 2 consecutive days without an identified site of bleeding 3 In ENHANCE six patients experienced multiple serious bleeding events during the study drug infusion period (94 events observed in 85 patients). In ADDRESS, the percent of treated patients experiencing a serious bleeding event by site of haemorrhage was similar to that observed in PROWESS. The incidence of serious bleeding events during infusion (defined as study Day 0 through study Day 6) was 31 (2.4%) and 15 (1.2%) in drotrecogin alfa (activated)-treated and placebo-treated patients, respectively (p=0.02). The incidence of CNS bleeds during infusion was 4 (0.3%) and 3 (0.2%) for drotrecogin alfa (activated)-treated and placebo-treated patients, respectively. Recent surgery (within 30 days prior to study entry) was associated with a numerically higher risk of serious bleeding during infusion in both the Xigris-treated and the placebo-treated patients (Xigris: 3.6% in patients with recent surgery versus 1.6% in patients without recent surgery; placebo: 1.6% versus 0.9% respectively). Serious bleeding events during the 28-day study period In PROWESS, the incidence of serious bleeding events during the 28-day study period was 3.5% and 2.0% in drotrecogin alfa (activated)-treated and placebo-treated patients, respectively. The incidence of CNS bleeds during the 28-day study period was 0.2% and 0.1% for drotrecogin alfa (activated)treated and placebo-treated patients, respectively. The risk of CNS bleeding may increase with severe coagulopathy and severe thrombocytopenia (see sections 4.3 and 4.4). In the open-label ENHANCE study, the incidence of serious bleeding events during the 28-day study period was 6.5%, and the incidence of CNS bleeds during the 28-day study period was 1.5%. 6 In the placebo-controlled ADDRESS study, the incidence of serious bleeding events during the 28-day study period was 51 (3.9%) and 28 (2.2%) in drotrecogin alfa (activated)-treated and placebo-treated patients, respectively (p=0.01). The incidence of CNS bleeds during the 28-day study period was 6 (0.5%) and 5 (0.4%) for drotrecogin alfa (activated)-treated and placebo-treated patients, respectively. In the phase 1 studies, adverse events with a frequency of ≥ 5% included headache (30.9%), ecchymosis (23.0%), and pain (5.8%). 4.9 Overdose In clinical trials, there has been one reported overdose of drotrecogin alfa (activated). This patient with severe sepsis received a dose of 181 µg/kg/hr for 2 hours. There were no serious adverse events associated with the overdose. Post-marketing experience: There have been reports of accidental overdosing. In the majority of cases, no reactions have been observed. For the other reports, the observed events were consistent with known undesirable effects of the drug (see section 4.8), effects of the drug on laboratory tests (see section 4.4), or consequences of the underlying condition of sepsis. There is no known antidote for drotrecogin alfa (activated). In case of overdose, immediately stop the infusion (see Section 5.2). 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: antithrombotic agents, enzymes, ATC code: B01AD10 Mechanism of Action Xigris is a recombinant version of the natural plasma-derived activated Protein C, from which it differs only by unique oligosaccharides in the carbohydrate portion of the molecule. Activated Protein C is a crucial coagulation regulator. It limits thrombin formation by inactivating factors Va and VIIIa, thereby providing negative feedback regulation of coagulation. Excessive coagulation activation in the microcirculatory bed plays a significant part in the pathophysiology of severe sepsis. Furthermore, Activated Protein C is an important modulator of the systemic response to infection and has antithrombotic and profibrinolytic properties. Xigris has similar properties to those of endogenous human Activated Protein C. Pharmacodynamic Effects In placebo-controlled clinical trials in patients with severe sepsis, Xigris exerted an antithrombotic effect by limiting thrombin generation and improved sepsis-associated coagulopathy, as shown by a more rapid improvement in markers of coagulation and fibrinolysis. Xigris caused a more rapid decline in thrombotic markers such as D-dimer, prothrombin F1.2, and thrombin-antithrombin levels and a more rapid increase in Protein C and antithrombin levels. Xigris also restored endogenous fibrinolytic potential, as evidenced by a more rapid trend toward normalisation in plasminogen levels and a more rapid decline in plasminogen activator inhibitor-1 levels. Additionally, patients with severe sepsis treated with Xigris had a more rapid decline in interleukin-6 levels, a global marker of inflammation, consistent with a reduction in the inflammatory response. Clinical Efficacy Xigris was studied in one Phase 3 international, multi-centre, randomised, double-blind, placebocontrolled trial (PROWESS) in 1690 patients with severe sepsis. Severe sepsis is defined as sepsis associated with acute organ dysfunction. Patients meeting the clinical diagnosis of severe sepsis had a) known or suspected infection, b) clinical evidence of systemic response to infection including fever or hypothermia, leucopenia or leucocytosis, tachycardia and tachypnoea, and c) acute organ dysfunction. 7 Organ dysfunction was defined as shock, hypotension or the need for vasopressor support despite adequate fluid resuscitation, relative hypoxemia (ratio of partial pressure of oxygen in arterial blood in mmHg to the percentage of oxygen in the inspired air expressed as a decimal (PaO2/FiO2 ratio) < 250), oliguria despite adequate fluid resuscitation, marked reduction in blood platelet counts, and/or elevated lactic acid concentrations. Exclusion criteria encompassed patients at high risk of bleeding (see Sections 4.3 and 4.4), patients who were not expected to survive for 28 days due to a pre-existing, non-sepsis related medical condition, HIV positive patients whose most recent CD4 count was ≤ 50/mm3, patients on chronic dialysis, and patients who had undergone bone marrow, lung, liver, pancreas or small bowel transplantation, and patients with acute clinical pancreatitis without a proven source of infection. In the PROWESS trial, treatment was initiated within 48 hours of onset of the first sepsis-induced organ dysfunction. The median duration of organ dysfunction prior to treatment was 18 hours. Patients were given a 96-hour constant rate infusion of Xigris at 24 µg/kg/hr (n=850) or placebo (n=840). Xigris was added to best standard care. Best standard care includes adequate antibiotics, source control and supportive treatment (fluids, inotropes, vasopressors and support of failing organs, as required). Patients treated with Xigris experienced improved 28-day survival compared to those treated with placebo. At 28 days, the overall mortality rates were 24.7% for the Xigris-treated group and 30.8% for the placebo-treated group (p=0.005). Significant absolute death reduction was limited to the subgroup of patients with greater disease severity i.e. baseline APACHE II score ≥25 or at least 2 acute organ dysfunctions at baseline. (The APACHE II score is designed to assess the risk of mortality based on acute physiology and chronic health evaluation). In the subgroup of patients with an APACHE II score ≥25 at baseline, the mortality was 31% in the Xigris group (128 out of 414) and 44% in the placebo group (176 out of 403). No death reduction was observed in the subgroup of patients with lower disease severity. In the subgroup of patients with at least 2 acute organ dysfunctions at baseline, the mortality was 26.5% in the Xigris group (168 out of 634) and 33.9% in the placebo group (216 out of 637). No significant death reduction was observed in the subgroup of patients with less than 2 acute organ dysfunctions at baseline. A consistent treatment effect on mortality with Xigris administration was observed across patient subgroups defined by age, gender and infection type. Heparin Approximately 2/3 of the patients received prophylactic low dose heparin during the course of study. The mortality rate in patients receiving Xigris and concomitant prophylactic low dose heparin was 24.9% and the mortality rate in patients receiving placebo and concomitant prophylactic low dose heparin was 28.1% (p=0.20). There is uncertainty if heparin could interfere with the activity of Xigris. The effect of low dose heparin on the efficacy of Xigris has not been evaluated in specific randomised controlled clinical trials. PROWESS Follow-up Study Survival status was assessed in a follow-up study of PROWESS survivors. In-hospital and 3 month survival status was reported for 98% and 94% of the 1690 PROWESS subjects respectively. In the overall population, the in-hospital mortality was significantly lower in patients on Xigris than in patients on placebo (29.4% vs. 34.6%; p=0.023). Survival through 3 months was also better in the Xigris group compared to placebo (log rank p=0.048). These data confirmed that the benefit of Xigris is limited to the more severely affected sepsis patients such as patients with multiple organ failure and shock. Further Clinical Experience 8 In a Phase 3b international, single-arm, open-label clinical trial (ENHANCE), 2378 adult patients with severe sepsis received drotrecogin alfa (activated). The entry criteria were similar to those employed in PROWESS. Patients received drotrecogin alfa (activated) within 48 hours of onset of the first sepsisinduced organ dysfunction. The median duration of organ dysfunction prior to treatment was 25 hours. At 28 days, the mortality rate in the Phase 3b study was 25.3%. The mortality rate was lower for patients treated within 24 hours of organ dysfunction compared to those treated after 24 hours, even after adjustment for differences in disease severity. A total of 2640 adult patients with severe sepsis who were at low risk of death (e.g. patients with APACHE II<25 or with only one sepsis-induced organ failure) were enrolled in a randomised, doubleblind, placebo-controlled trial (ADDRESS). The trial was stopped after an interim analysis due to a low likelihood of demonstrating a significant difference in 28-day mortality by the end of the trial. The ADDRESS trial did enrol 872 patients with multiple organ dysfunction. Compared to multiple organ dysfunction patients in PROWESS, those in ADDRESS had organ dysfunction for longer prior to receiving study drug (median 25 vs. 18 hours), had lower APACHE II scores (median 20 vs. 25) and were more likely to have two organ dysfunctions (76% vs. 43%). At 28 days, the mortality rates for multiple organ dysfunction patients in ADDRESS were 20.7% versus 21.9% for drotrecogin alfa (activated)-treated and placebo-treated patients, respectively. In-hospital mortality rates were 23.1% and 25.3% respectively. In the subgroup with two organ dysfunctions, the results were similar to those seen in the PROWESS trial. In placebo controlled clinical trials, the treatment effect was most evident at sites enrolling larger numbers of patients. 5.2 Pharmacokinetic properties Drotrecogin alfa (activated) and endogenous human Activated Protein C are inactivated in plasma by endogenous protease inhibitors but the mechanism by which they are cleared from plasma is unknown. Plasma concentrations of endogenous Activated Protein C in healthy subjects and patients with severe sepsis are usually below detection limits (< 5 ng/ml) and do not significantly influence the pharmacokinetic properties of drotrecogin alfa (activated). In healthy subjects, greater than 90% of the steady state condition is attained within 2 hours following the start of a constant-rate intravenous infusion of Xigris. Following the completion of an infusion, the decline in plasma drotrecogin alfa (activated) concentrations is biphasic and is comprised of a rapid initial phase (t1/2 α=13 minutes) and a slower second phase (t1/2 β=1.6 hours). The short half-life of 13 minutes accounts for approximately 80% of the area under the plasma concentration curve and governs the initial rapid accrual of plasma drotrecogin alfa (activated) concentrations towards the steady-state. Plasma drotrecogin alfa (activated) steady-state concentrations are proportional to the infusion rate over a range of infusion rates from 12 µg/kg/hr to 48 µg/kg/hr. The mean steady-state plasma concentration of drotrecogin alfa (activated) in healthy subjects receiving 24 µg/kg/hr is 72 ng/ml. In patients with severe sepsis, infusion of drotrecogin alfa (activated) from 12 µg/kg/hr to 30 µg/kg/hr rapidly produced steady-state plasma concentrations that were proportional to infusion rates. In the Phase 3 trial, the pharmacokinetics of drotrecogin alfa (activated) were evaluated in 342 patients with severe sepsis administered a 96-hour continuous infusion at 24 µg/kg/hr. The pharmacokinetics of drotrecogin alfa (activated) were characterised by attainment of steady-state plasma concentration within 2 hours following the start of the infusion. In the majority of patients, measurements of Activated Protein C beyond 2 hours after termination of the infusion were below the quantifiable limit, suggesting rapid elimination of drotrecogin alfa (activated) from the systemic circulation. The plasma clearance of drotrecogin alfa (activated) is approximately 41.8 l/hr in sepsis patients as compared with 28.1 l/hr in healthy subjects. 9 In patients with severe sepsis, the plasma clearance of drotrecogin alfa (activated) was significantly decreased by renal impairment and hepatic dysfunction, but the magnitude of the differences in clearance (< 30 %) does not warrant any dosage adjustment. 5.3 Preclinical safety data Changes observed in monkeys at, or in small excess of, the maximum human exposure during repeated dose studies, were all related to the pharmacological effect of Xigris and include beside the expected prolongation of APTT, decreases in haemoglobin, erythrocytes and haematocrit, and increases in reticulocyte count and PT. Drotrecogin alfa (activated) was not mutagenic in an in vivo micronucleus study in mice or in an in vitro chromosomal aberration study in human peripheral blood lymphocytes with or without rat liver metabolic activation. Carcinogenicity studies and animal reproduction studies have not been conducted with Xigris. However, with respect to the latter, the potential risk for humans being unknown, Xigris should not be used during pregnancy unless clearly necessary (see section 4.6). 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Sucrose, sodium chloride, sodium citrate, citric acid, hydrochloric acid and sodium hydroxide. 6.2 Incompatibilities After reconstitution, Xigris should be compounded ONLY with 0.9% Sodium Chloride Injection. The ONLY other solutions that can be administered through the same intravenous line are 0.9% Sodium Chloride Injection, Lactated Ringer’s Injection, Dextrose or Dextrose and Saline mixtures. When administering drotrecogin alfa (activated) at low concentrations (less than approximately 200 µg/ml) at low flow rates (less than approximately 5 ml/hr), the infusion set must be primed for approximately 15 minutes at a flow rate of approximately 5 ml/hr. 6.3 Shelf life 3 years After reconstitution, immediate use is recommended. However, the reconstituted solution in the vial may be held for up to 3 hours at room temperature (15 to 30ºC). After preparation, the intravenous infusion solution can be used at room temperature (15 to 30ºC) for a period up to 14 hours. 6.4 Special precautions for storage Store at 2°C – 8°C (in a refrigerator). Keep the vial in the outer carton in order to protect it from light. 6.5 Nature and contents of container 20 mg of powder in vial (type I glass)- pack of 1. 6.6 Instructions for use and handling 1. Use appropriate aseptic technique during the preparation of Xigris for intravenous administration. 10 2. Calculate the dose and the number of Xigris vials needed. Each Xigris vial contains 20 mg of drotrecogin alfa (activated). The vial contains an excess of drotrecogin alfa (activated) to facilitate delivery of the label amount. 3. Prior to administration, 20 mg vials of Xigris must be reconstituted with 10 ml of Sterile Water for Injection, resulting in a solution with a concentration of approximately 2 mg/ml drotrecogin alfa (activated). Slowly add the Sterile Water for Injection to the vial and avoid inverting or shaking the vial. Gently swirl each vial until the powder is completely dissolved. 4. The solution of reconstituted Xigris must be further diluted with sterile 0.9% Sodium Chloride Injection. Slowly withdraw the appropriate amount of reconstituted drotrecogin alfa (activated) solution from the vial. Add the reconstituted drotrecogin alfa (activated) into a prepared infusion bag of sterile 0.9% Sodium Chloride Injection. When adding the reconstituted drotrecogin alfa (activated) into the infusion bag, direct the stream to the side of the bag to minimise the agitation of the solution. Gently invert the infusion bag to obtain a homogeneous solution. Do not transport the infusion bag between locations using mechanical delivery systems. 5. After reconstitution, immediate use is recommended. However, the reconstituted solution in the vial may be held for up to 3 hours at room temperature (15 to 30ºC). After preparation, the intravenous infusion solution can be used at room temperature (15 to 30ºC) for a period up to 14 hours. 6. Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration. 7. It is recommended that Xigris be infused with an infusion pump to accurately control the infusion rate. The solution of reconstituted Xigris is typically diluted into an infusion bag containing sterile 0.9% Sodium Chloride Injection to a final concentration of between 100 µg/ml and 200 µg/ml. 8. When administering drotrecogin alfa (activated) at low concentrations (less than approximately 200 µg/ml) at low flow rates (less than approximately 5 ml/hr), the infusion set must be primed for approximately 15 minutes at a flow rate of approximately 5 ml/hr. 9. Xigris should be administered via a dedicated intravenous line or a dedicated lumen of a multilumen central venous catheter. The ONLY other solutions that can be administered through the same line are 0.9% Sodium Chloride Injection, Lactated Ringer’s Injection, Dextrose or Dextrose and Saline mixtures. 10. Avoid exposing drotrecogin alfa (activated) solutions to heat and/or direct sunlight. No incompatibilities have been observed between drotrecogin alfa (activated) and glass infusion bottles or infusion bags made of polyvinylchloride, polyethylene, polypropylene, or polyolefin. The use of other types of infusion sets could have a negative impact on the amount and potency of drotrecogin alfa (activated) administered. 11. Care should be taken to administer Xigris at the appropriate rate, calculated based on kg of bodyweight and infused for the correct duration. It is recommended that the bag be labelled accordingly. 11 7. MARKETING AUTHORISATION HOLDER Eli Lilly Nederland B.V., Grootslag 1-5, 3991 RA, Houten, The Netherlands 8. MARKETING AUTHORISATION NUMBER (S) EU/1/02/225/002 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 22 August 2002 10. DATE OF REVISION OF THE TEXT 12 1. NAME OF THE MEDICINAL PRODUCT Xigris 5 mg powder for solution for infusion 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each vial contains: Drotrecogin alfa (activated): 2 mg per ml after reconstitution. A vial contains 5 mg of drotrecogin alfa (activated) to be reconstituted with 2.5 ml of Sterile Water for Injection. Drotrecogin alfa (activated) is a recombinant version of the endogenous activated Protein C and is produced by genetic engineering from an established human cell line. For excipients, see 6.1. 3. PHARMACEUTICAL FORM Powder for solution for infusion 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Xigris is indicated for the treatment of adult patients with severe sepsis with multiple organ failure when added to best standard care. The use of Xigris should be considered mainly in situations when therapy can be started within 24 hours after the onset of organ failure (for further information see Section 5.1). 4.2 Posology and method of administration Xigris should be used by experienced doctors in institutions skilled in the care of patients with severe sepsis. Treatment should be started within 48 hours, and preferably within 24 hours, of onset of the first documented sepsis-induced organ dysfunction (see Section 5.1). The recommended dose of Xigris is 24 µg/kg/hr given as a continuous intravenous infusion for a total duration of 96 hours. It is recommended that Xigris be infused with an infusion pump to accurately control the infusion rate. If the infusion is interrupted for any reason, Xigris should be restarted at the 24 µg/kg/hr infusion rate and continued to complete the full recommended 96 hours of dosing administration. Dose escalation or bolus doses of Xigris are not necessary to account for the interruption in the infusion. No dose adjustments are required in adult patients with severe sepsis with regard to age, gender, hepatic function (as measured by transaminase levels) or renal function. The pharmacokinetics of drotrecogin alfa (activated) have not been studied in patients with severe sepsis and preexisting endstage renal disease and chronic hepatic disease. Paediatrics: Data from a placebo-controlled clinical trial which was stopped for futility after 477 patients 0 to 17 years-old had received the study drug did not establish efficacy of Xigris in paediatric patients and showed a higher rate of central nervous system bleeding in the Xigris versus placebo 13 group. Therefore no dosage recommendation can be made and the use of Xigris is not recommended in children below the age of 18 (see Section 4.4). 4.3 Contraindications Because drotrecogin alfa (activated) may increase the risk of bleeding, Xigris is contraindicated in the following situations: • • • • • • • Active internal bleeding Patients with intracranial pathology; neoplasm or evidence of cerebral herniation Concurrent heparin therapy ≥ 15 International Units/kg/hr Known bleeding diathesis except for acute coagulopathy related to sepsis Chronic severe hepatic disease Platelet count < 30,000 x 106/l, even if the platelet count is increased after transfusions Patients at increased risk for bleeding (for example): a) any major surgery, defined as surgery that requires general or spinal anesthesia, performed within the 12-hour period immediately preceding drug infusion, or any postoperative patient who demonstrates evidence of active bleeding, or any patient with planned or anticipated surgery during the drug infusion period. b) history of severe head trauma that required hospitalization, intracranial or intraspinal surgery, or haemorrhagic stroke within the previous 3 months, or any history of intracerebral arteriovenous malformation, cerebral aneurysm, or central nervous system mass lesion; patients with an epidural catheter or who are anticipated to receive an epidural catheter during drug infusion c) history of congenital bleeding diatheses d) gastrointestinal bleeding within the last 6 weeks that has required medical intervention unless definitive surgery has been performed e) trauma patients at increased risk of bleeding Xigris is also contraindicated in patients with known hypersensitivity to drotrecogin alfa (activated), to any of the formulation excipients, or to bovine thrombin (a trace residue from the manufacturing process). 4.4 Special warnings and special precautions for use Patients with single organ dysfunction and recent surgery Xigris is not approved for the treatment of patients with single organ dysfunction and should not be used in this particular subgroup of patients, especially if they had recent surgery (within 30 days). In each of two randomised, placebo-controlled trials, PROWESS and ADDRESS (see Section 5.1), 28day and in-hospital mortality were higher in patients treated with drotrecogin alfa (activated) compared to placebo for the sub-population of patients with single organ dysfunction and recent surgery (n=98 in PROWESS and n=636 in ADDRESS). Bleeding Drotrecogin alfa (activated) increases the risk of bleeding. In the following conditions, the risks of the administration of Xigris should be weighed against the anticipated benefits: • • • • • Recent administration (within 3 days) of thrombolytic therapy Recent administration (within 7 days) of oral anticoagulants Recent administration (within 7 days) of aspirin or other platelet inhibitors Recent (within 3 months) ischaemic stroke Any other condition in which the physician considers significant bleeding is likely For procedures with an inherent bleeding risk, discontinue Xigris for 2 hours prior to the start of the procedure. Xigris may be restarted 12 hours after major invasive procedures or surgery if adequate 14 haemostasis has been achieved. Xigris may be restarted immediately after uncomplicated less invasive procedures if adequate haemostasis has been achieved. As a component of routine care, measures of haemostasis (e.g., activated partial thromboplastin time (APTT), prothrombin time (PT) and platelet count) should be obtained during the infusion of Xigris. If sequential tests of haemostasis indicate an uncontrolled or worsening coagulopathy that significantly increases the risk of bleeding, the benefits of continuing the infusion must be weighed against the potential increased risk of bleeding for that patient. Laboratory tests Drotrecogin alfa (activated) has minimal effect on the PT. Prolongation of the APTT in patients with severe sepsis receiving Xigris may be due to the underlying coagulopathy, the pharmacodynamic effect of drotrecogin alfa (activated), and/or the effect of other concurrent medications. The pharmacodynamic effect of drotrecogin alfa (activated) on the APTT assay is dependent on the reagent and instrument used to perform the assay and the time that elapses between sample acquisition and assay performance. Drotrecogin alfa (activated) that is present in a blood or plasma sample drawn from a patient who is being infused with the drug will be gradually neutralized by endogenous plasma protease inhibitors present in the sample. Virtually no measurable activity of drotrecogin alfa (activated) is present 2 hours after obtaining the blood sample. Due to these biological and analytical variables, the APTT should not be used to assess the pharmacodynamic effect of drotrecogin alfa (activated). In addition, approximately 2 hours after terminating the infusion of the drug, there is virtually no measurable activity of drotrecogin alfa (activated) remaining in the circulation of the patient; blood samples drawn for APTT determination after this point are no longer affected by the drug. The interpretation of sequential determinations of the PT and/or APTT should take these variables into consideration. Because drotrecogin alfa (activated) may affect the APTT assays, drotrecogin alfa (activated) present in plasma samples may interfere with one-stage coagulation assays based on the APTT (such as factor VIII, IX, and XI assays). Drotrecogin alfa (activated) present in plasma samples does not interfere with one-stage factor assays based on the PT (such as Factors II, V, VII and X assays). If sequential measures of coagulopathy (including platelet count) indicate severe or worsening coagulopathy, the risk of continuing the infusion should be weighed against the expected benefit. Immunogenicity In patients with severe sepsis, the formation of anti-Activated Protein C antibodies was uncommon (<1%) after a single course of therapy. These antibodies were not capable of neutralizing the effect of Activated Protein C on the APTT assay. However, the possibility of allergic reactions to constituents of the preparation cannot be completely excluded in certain predisposed patients. If allergic or anaphylactic reactions occur, treatment should be discontinued immediately and appropriate therapy initiated. Xigris has not been readministered to patients with severe sepsis. If Xigris is readministered to patients, caution should be employed. No anti-activated Protein C antibody formation was detected in healthy subjects, even after repeat administration. Paediatric patients Data from a placebo-controlled clinical trial did not establish efficacy of Xigris in paediatric patients suffering from severe sepsis, acute infection, systemic inflammation and respiratory and cardiovascular organ dysfunction. This trial was stopped for futility after 477 patients had received the study drug (out of 600 patients intended). A planned interim analysis (with 400 patients enrolled) showed a low likelihood of demonstrating a significant difference in the primary endpoint of “Composite Time to Complete Organ Failure Resolution” (CTCOFR score of 9.8 versus 9.7 mean days over 14 days). There was also no difference in 28-day mortality (17.1% versus 17.3% in the Xigris and placebo groups, respectively). Investigators attributed 2 deaths in the Xigris group and 5 deaths in the placebo group to bleeding events. There was a higher rate of central nervous system (CNS) bleeding in the drotrecogin alfa (activated) versus the placebo group. Over the infusion period (study days 0-6) the number of patients experiencing CNS bleeding was 5 versus 1 (2.1% versus 0.4%) for the overall population 15 (drotrecogin alfa (activated) versus placebo), with 4 of the 5 events in the drotrecogin alfa (activated) group occurring in patients ≤ 60 days old or ≤ 3.5 kg bodyweight. Fatal CNS bleeding events, serious bleeding events (over the infusion period and over the 28-day study period), serious adverse events, and major amputations were similar in the drotrecogin alfa (activated) and placebo groups. 4.5 Interaction with other medicinal products and other forms of interaction Drug interactions with Xigris have not been studied in patients with sepsis. Caution should be employed when Xigris is used with other drugs that affect haemostasis (see Sections 4.3 and 4.4) including Protein C, thrombolytics (e.g. streptokinase, tPA, rPA and urokinase), oral anticoagulants (e.g. warfarin), hirudins, antithrombin, aspirin and other anti platelets agents, e.g. non-steroidal anti-inflammatory drugs, ticlopidine and clopidogrel, glycoprotein IIb/IIIa antagonists (such as abciximab, eptifibatide, tirofiban) and prostacyclins such as iloprost. Heparin Two-thirds of patients in the phase 3 trial received prophylactic doses of unfractionated or low molecular weight heparin. There was no observed increase in the risk of bleeding events reported as serious adverse events in drotrecogin alfa (activated) patients receiving heparin. The effects of prophylactic low dose heparin and other coagulation-active medications on the efficacy of drotrecogin alfa (activated) have not been evaluated in a randomised controlled clinical trial. 4.6 Pregnancy and lactation Animal studies with respect to effects on pregnancy, embryonal/foetal development, parturition and postnatal development have not been conducted with Xigris. Therefore, the potential risk for humans is unknown. Xigris should not be used during pregnancy unless clearly necessary. It is not known whether Xigris is excreted in human milk or if there is a potential effect on the nursed infant. Therefore, the patient should not breast feed whilst treated with Xigris. 4.7 Effects on ability to drive and use machines Not applicable. 4.8 Undesirable effects Xigris increases the risk of bleeding. The Phase 3 international, multi-centre, randomised, double-blind, placebo-controlled clinical trial (PROWESS) involved 850 drotrecogin alfa (activated)-treated and 840 placebo-treated patients. The percentage of patients experiencing at least one bleeding event in the two treatment groups was 24.9% and 17.7%, respectively. In both treatment groups, the majority of bleeding events were ecchymosis or gastrointestinal tract bleeding. The difference in the incidence of serious bleeding events between the two treatment groups occurred primarily during study drug administration. A total of 2378 adult patients with severe sepsis received drotrecogin alfa (activated) in a Phase 3b, international, single-arm, open-label clinical trial (ENHANCE). The incidence of serious bleeding events in the PROWESS and ENHANCE studies is provided below. In these studies serious bleeding events included any intracranial haemorrhage, any life-threatening or fatal bleed, any bleeding event requiring the administration of ≥ 3 units of packed red blood cells per day for 2 consecutive days, or any bleeding event assessed as serious by the investigator. A Phase 3b international, multi-centre, randomised, double-blind, placebo-controlled clinical trial (ADDRESS) of adult severe sepsis patients at low risk of death, involved 1317 drotrecogin alfa 16 (activated)-treated and 1293 placebo-treated patients. The percentage of patients experiencing at least one bleeding event in the two treatment groups was 10.9% and 6.4%, respectively (p<0.001). Bleeding events included serious bleeding events, bleeding events assessed as possibly study-drug related by the investigator, bleeding events associated with the need for a red blood cell transfusion, and bleeding events that led to permanent discontinuation of the study drug. In the ADDRESS trial, serious bleeding events included any fatal bleed, any life-threatening bleed, any CNS bleed, or any bleeding event assessed as serious by the investigator. Serious bleeding events during the infusion period The following table lists the percent of patients in PROWESS and ENHANCE experiencing serious bleeding events by site of haemorrhage during the study drug infusion period (defined as the duration of infusion plus the next full calendar day following the end of the infusion). Site of haemorrhage Gastrointestinal Intra-abdominal Intra-thoracic Retroperitoneal Central Nervous System (CNS)1 Genitourinary Skin/soft tissue Nasopharyngeal Joint/Bone Site unknown2 Total Drotrecogin alfa (activated) [PROWESS] N=850 [PROWESS] N=840 Drotrecogin alfa (activated) [ENHANCE] N=2378 5 (0.6%) 2 (0.2%) 4 (0.5%) 3 (0.4%) 4(0.5%) 3 (0.4%) 0 0 19 (0.8%) 18 (0.8%) 11 (0.5%) 4 (0.2%) 2 (0.2%) 0 15 (0.6%) 2 (0.2%) 1 (0.1%) 0 0 1 (0.1%) 20 (2.4%) 0 0 0 0 1 (0.1%) 8 (1.0%) 0 16 (0.7%) 4 (0.2%) 1 (0.04%) 6 (0.3%) 853 (3.6%) Placebo 1 CNS bleeding is defined as any bleed in the central nervous system including the following types of haemorrhage: Petechial, parenchymal, subarachnoid, subdural, and stroke with haemorrhagic transformation. 2 Patients requiring the administration of ≥ 3 units of packed red blood cells per day for 2 consecutive days without an identified site of bleeding 3 In ENHANCE six patients experienced multiple serious bleeding events during the study drug infusion period (94 events observed in 85 patients). In ADDRESS, the percent of treated patients experiencing a serious bleeding event by site of haemorrhage was similar to that observed in PROWESS. The incidence of serious bleeding events during infusion (defined as study Day 0 through study Day 6) was 31 (2.4%) and 15 (1.2%) in drotrecogin alfa (activated)-treated and placebo-treated patients, respectively (p=0.02). The incidence of CNS bleeds during infusion was 4 (0.3%) and 3 (0.2%) for drotrecogin alfa (activated)-treated and placebo-treated patients, respectively. Recent surgery (within 30 days prior to study entry) was associated with a numerically higher risk of serious bleeding during infusion in both the Xigris-treated and the placebo-treated patients (Xigris: 3.6% in patients with recent surgery versus 1.6% in patients without recent surgery; placebo: 1.6% versus 0.9% respectively). Serious bleeding events during the 28-day study period In PROWESS, the incidence of serious bleeding events during the 28-day study period was 3.5% and 2.0% in drotrecogin alfa (activated)-treated and placebo-treated patients, respectively. The incidence of CNS bleeds during the 28-day study period was 0.2% and 0.1% for drotrecogin alfa (activated)treated and placebo-treated patients, respectively. The risk of CNS bleeding may increase with severe coagulopathy and severe thrombocytopenia (see sections 4.3 and 4.4). In the open-label ENHANCE study, the incidence of serious bleeding events during the 28-day study period was 6.5%, and the incidence of CNS bleeds during the 28-day study period was 1.5%. 17 In the placebo-controlled ADDRESS study, the incidence of serious bleeding events during the 28-day study period was 51 (3.9%) and 28 (2.2%) in drotrecogin alfa (activated)-treated and placebo-treated patients, respectively (p=0.01). The incidence of CNS bleeds during the 28-day study period was 6 (0.5%) and 5 (0.4%) for drotrecogin alfa (activated)-treated and placebo-treated patients, respectively. In the phase 1 studies, adverse events with a frequency of ≥ 5% included headache (30.9%), ecchymosis (23.0%), and pain (5.8%). 4.9 Overdose In clinical trials, there has been one reported overdose of drotrecogin alfa (activated). This patient with severe sepsis received a dose of 181 µg/kg/hr for 2 hours. There were no serious adverse events associated with the overdose. Post-marketing experience: There have been reports of accidental overdosing. In the majority of cases, no reactions have been observed. For the other reports, the observed events were consistent with known undesirable effects of the drug (see section 4.8), effects of the drug on laboratory tests (see section 4.4), or consequences of the underlying condition of sepsis. There is no known antidote for drotrecogin alfa (activated). In case of overdose, immediately stop the infusion (see Section 5.2). 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: antithrombotic agents, enzymes, ATC code: B01AD10 Mechanism of Action Xigris is a recombinant version of the natural plasma-derived activated Protein C, from which it differs only by unique oligosaccharides in the carbohydrate portion of the molecule. Activated Protein C is a crucial coagulation regulator. It limits thrombin formation by inactivating factors Va and VIIIa, thereby providing negative feedback regulation of coagulation. Excessive coagulation activation in the microcirculatory bed plays a significant part in the pathophysiology of severe sepsis. Furthermore, Activated Protein C is an important modulator of the systemic response to infection and has antithrombotic and profibrinolytic properties. Xigris has similar properties to those of endogenous human Activated Protein C. Pharmacodynamic Effects In placebo-controlled clinical trials in patients with severe sepsis, Xigris exerted an antithrombotic effect by limiting thrombin generation and improved sepsis-associated coagulopathy, as shown by a more rapid improvement in markers of coagulation and fibrinolysis. Xigris caused a more rapid decline in thrombotic markers such as D-dimer, prothrombin F1.2, and thrombin-antithrombin levels and a more rapid increase in Protein C and antithrombin levels. Xigris also restored endogenous fibrinolytic potential, as evidenced by a more rapid trend toward normalisation in plasminogen levels and a more rapid decline in plasminogen activator inhibitor-1 levels. Additionally, patients with severe sepsis treated with Xigris had a more rapid decline in interleukin-6 levels, a global marker of inflammation, consistent with a reduction in the inflammatory response. Clinical Efficacy Xigris was studied in one Phase 3 international, multi-centre, randomised, double-blind, placebocontrolled trial (PROWESS) in 1690 patients with severe sepsis. Severe sepsis is defined as sepsis associated with acute organ dysfunction. Patients meeting the clinical diagnosis of severe sepsis had a) known or suspected infection, b) clinical evidence of systemic response to infection including fever or hypothermia, leucopenia or leucocytosis, tachycardia and tachypnoea, and c) acute organ dysfunction. 18 Organ dysfunction was defined as shock, hypotension or the need for vasopressor support despite adequate fluid resuscitation, relative hypoxemia (ratio of partial pressure of oxygen in arterial blood in mmHg to the percentage of oxygen in the inspired air expressed as a decimal (PaO2/FiO2 ratio) < 250), oliguria despite adequate fluid resuscitation, marked reduction in blood platelet counts, and/or elevated lactic acid concentrations. Exclusion criteria encompassed patients at high risk of bleeding (see Sections 4.3 and 4.4), patients who were not expected to survive for 28 days due to a pre-existing, non-sepsis related medical condition, HIV positive patients whose most recent CD4 count was ≤ 50/mm3, patients on chronic dialysis, and patients who had undergone bone marrow, lung, liver, pancreas or small bowel transplantation, and patients with acute clinical pancreatitis without a proven source of infection. In the PROWESS trial, treatment was initiated within 48 hours of onset of the first sepsis-induced organ dysfunction. The median duration of organ dysfunction prior to treatment was 18 hours. Patients were given a 96-hour constant rate infusion of Xigris at 24 µg/kg/hr (n=850) or placebo (n=840). Xigris was added to best standard care. Best standard care includes adequate antibiotics, source control and supportive treatment (fluids, inotropes, vasopressors and support of failing organs, as required). Patients treated with Xigris experienced improved 28-day survival compared to those treated with placebo. At 28 days, the overall mortality rates were 24.7% for the Xigris-treated group and 30.8% for the placebo-treated group (p=0.005). Significant absolute death reduction was limited to the subgroup of patients with greater disease severity i.e. baseline APACHE II score ≥25 or at least 2 acute organ dysfunctions at baseline. (The APACHE II score is designed to assess the risk of mortality based on acute physiology and chronic health evaluation). In the subgroup of patients with an APACHE II score ≥25 at baseline, the mortality was 31% in the Xigris group (128 out of 414) and 44% in the placebo group (176 out of 403). No death reduction was observed in the subgroup of patients with lower disease severity. In the subgroup of patients with at least 2 acute organ dysfunctions at baseline, the mortality was 26.5% in the Xigris group (168 out of 634) and 33.9% in the placebo group (216 out of 637). No significant death reduction was observed in the subgroup of patients with less than 2 acute organ dysfunctions at baseline. A consistent treatment effect on mortality with Xigris administration was observed across patient subgroups defined by age, gender and infection type. Heparin Approximately 2/3 of the patients received prophylactic low dose heparin during the course of study. The mortality rate in patients receiving Xigris and concomitant prophylactic low dose heparin was 24.9% and the mortality rate in patients receiving placebo and concomitant prophylactic low dose heparin was 28.1% (p=0.20). There is uncertainty if heparin could interfere with the activity of Xigris. The effect of low dose heparin on the efficacy of Xigris has not been evaluated in specific randomised controlled clinical trials. PROWESS Follow-up Study Survival status was assessed in a follow-up study of PROWESS survivors. In-hospital and 3 month survival status was reported for 98% and 94% of the 1690 PROWESS subjects respectively. In the overall population, the in-hospital mortality was significantly lower in patients on Xigris than in patients on placebo (29.4% vs. 34.6%; p=0.023). Survival through 3 months was also better in the Xigris group compared to placebo (log rank p=0.048). These data confirmed that the benefit of Xigris is limited to the more severely affected sepsis patients such as patients with multiple organ failure and shock. Further Clinical Experience 19 In a Phase 3b international, single-arm, open-label clinical trial (ENHANCE), 2378 adult patients with severe sepsis received drotrecogin alfa (activated). The entry criteria were similar to those employed in PROWESS. Patients received drotrecogin alfa (activated) within 48 hours of onset of the first sepsisinduced organ dysfunction. The median duration of organ dysfunction prior to treatment was 25 hours. At 28 days, the mortality rate in the Phase 3b study was 25.3%. The mortality rate was lower for patients treated within 24 hours of organ dysfunction compared to those treated after 24 hours, even after adjustment for differences in disease severity. A total of 2640 adult patients with severe sepsis who were at low risk of death (e.g. patients with APACHE II<25 or with only one sepsis-induced organ failure) were enrolled in a randomised, doubleblind, placebo-controlled trial (ADDRESS). The trial was stopped after an interim analysis due to a low likelihood of demonstrating a significant difference in 28-day mortality by the end of the trial. The ADDRESS trial did enrol 872 patients with multiple organ dysfunction. Compared to multiple organ dysfunction patients in PROWESS, those in ADDRESS had organ dysfunction for longer prior to receiving study drug (median 25 vs. 18 hours), had lower APACHE II scores (median 20 vs. 25) and were more likely to have two organ dysfunctions (76% vs. 43%). At 28 days, the mortality rates for multiple organ dysfunction patients in ADDRESS were 20.7% versus 21.9% for drotrecogin alfa (activated)-treated and placebo-treated patients, respectively. In-hospital mortality rates were 23.1% and 25.3% respectively. In the subgroup with two organ dysfunctions, the results were similar to those seen in the PROWESS trial. In placebo controlled clinical trials, the treatment effect was most evident at sites enrolling larger numbers of patients. 5.2 Pharmacokinetic properties Drotrecogin alfa (activated) and endogenous human Activated Protein C are inactivated in plasma by endogenous protease inhibitors but the mechanism by which they are cleared from plasma is unknown. Plasma concentrations of endogenous Activated Protein C in healthy subjects and patients with severe sepsis are usually below detection limits (< 5 ng/ml) and do not significantly influence the pharmacokinetic properties of drotrecogin alfa (activated). In healthy subjects, greater than 90% of the steady state condition is attained within 2 hours following the start of a constant-rate intravenous infusion of Xigris. Following the completion of an infusion, the decline in plasma drotrecogin alfa (activated) concentrations is biphasic and is comprised of a rapid initial phase (t1/2 α=13 minutes) and a slower second phase (t1/2 β=1.6 hours). The short half-life of 13 minutes accounts for approximately 80% of the area under the plasma concentration curve and governs the initial rapid accrual of plasma drotrecogin alfa (activated) concentrations towards the steady-state. Plasma drotrecogin alfa (activated) steady-state concentrations are proportional to the infusion rate over a range of infusion rates from 12 µg/kg/hr to 48 µg/kg/hr. The mean steady-state plasma concentration of drotrecogin alfa (activated) in healthy subjects receiving 24 µg/kg/hr is 72 ng/ml. In patients with severe sepsis, infusion of drotrecogin alfa (activated) from 12 µg/kg/hr to 30 µg/kg/hr rapidly produced steady-state plasma concentrations that were proportional to infusion rates. In the Phase 3 trial, the pharmacokinetics of drotrecogin alfa (activated) were evaluated in 342 patients with severe sepsis administered a 96-hour continuous infusion at 24 µg/kg/hr. The pharmacokinetics of drotrecogin alfa (activated) were characterised by attainment of steady-state plasma concentration within 2 hours following the start of the infusion. In the majority of patients, measurements of Activated Protein C beyond 2 hours after termination of the infusion were below the quantifiable limit, suggesting rapid elimination of drotrecogin alfa (activated) from the systemic circulation. The plasma clearance of drotrecogin alfa (activated) is approximately 41.8 l/hr in sepsis patients as compared with 28.1 l/hr in healthy subjects. 20 In patients with severe sepsis, the plasma clearance of drotrecogin alfa (activated) was significantly decreased by renal impairment and hepatic dysfunction, but the magnitude of the differences in clearance (< 30 %) does not warrant any dosage adjustment. 5.3 Preclinical safety data Changes observed in monkeys at, or in small excess of, the maximum human exposure during repeated dose studies, were all related to the pharmacological effect of Xigris and include beside the expected prolongation of APTT, decreases in haemoglobin, erythrocytes and haematocrit, and increases in reticulocyte count and PT. Drotrecogin alfa (activated) was not mutagenic in an in vivo micronucleus study in mice or in an in vitro chromosomal aberration study in human peripheral blood lymphocytes with or without rat liver metabolic activation. Carcinogenicity studies and animal reproduction studies have not been conducted with Xigris. However, with respect to the latter, the potential risk for humans being unknown, Xigris should not be used during pregnancy unless clearly necessary (see section 4.6). 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Sucrose, sodium chloride, sodium citrate, citric acid, hydrochloric acid and sodium hydroxide. 6.2 Incompatibilities After reconstitution, Xigris should be compounded ONLY with 0.9% Sodium Chloride Injection. The ONLY other solutions that can be administered through the same intravenous line are 0.9% Sodium Chloride Injection, Lactated Ringer’s Injection, Dextrose or Dextrose and Saline mixtures. When administering drotrecogin alfa (activated) at low concentrations (less than approximately 200 µg/ml) at low flow rates (less than approximately 5 ml/hr), the infusion set must be primed for approximately 15 minutes at a flow rate of approximately 5 ml/hr. 6.3 Shelf life 3 years After reconstitution, immediate use is recommended. However, the reconstituted solution in the vial may be held for up to 3 hours at room temperature (15 to 30ºC). After preparation, the intravenous infusion solution can be used at room temperature (15 to 30ºC) for a period up to 14 hours. 6.4 Special precautions for storage Store at 2°C – 8°C (in a refrigerator). Keep the vial in the outer carton in order to protect it from light. 6.5 Nature and contents of container 5 mg of powder in vial (type I glass)- pack of 1. 6.6 Instructions for use and handling 1. Use appropriate aseptic technique during the preparation of Xigris for intravenous administration. 21 2. Calculate the dose and the number of Xigris vials needed. Each Xigris vial contains 5 mg of drotrecogin alfa (activated). The vial contains an excess of drotrecogin alfa (activated) to facilitate delivery of the label amount. 3. Prior to administration, 5 mg vials of Xigris must be reconstituted with 2.5 ml of Sterile Water for Injection, resulting in a solution with a concentration of approximately 2 mg/ml drotrecogin alfa (activated). Slowly add the Sterile Water for Injection to the vial and avoid inverting or shaking the vial. Gently swirl each vial until the powder is completely dissolved. 4. The solution of reconstituted Xigris must be further diluted with sterile 0.9% Sodium Chloride Injection. Slowly withdraw the appropriate amount of reconstituted drotrecogin alfa (activated) solution from the vial. Add the reconstituted drotrecogin alfa (activated) into a prepared infusion bag of sterile 0.9% Sodium Chloride Injection. When adding the reconstituted drotrecogin alfa (activated) into the infusion bag, direct the stream to the side of the bag to minimise the agitation of the solution. Gently invert the infusion bag to obtain a homogeneous solution. Do not transport the infusion bag between locations using mechanical delivery systems. 5. After reconstitution, immediate use is recommended. However, the reconstituted solution in the vial may be held for up to 3 hours at room temperature (15 to 30ºC). After preparation, the intravenous infusion solution can be used at room temperature (15 to 30ºC) for a period up to 14 hours. 6. Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration. 7. It is recommended that Xigris be infused with an infusion pump to accurately control the infusion rate. The solution of reconstituted Xigris is typically diluted into an infusion bag containing sterile 0.9% Sodium Chloride Injection to a final concentration of between 100 µg/ml and 200 µg/ml. 8. When administering drotrecogin alfa (activated) at low concentrations (less than approximately 200 µg/ml) at low flow rates (less than approximately 5 ml/hr), the infusion set must be primed for approximately 15 minutes at a flow rate of approximately 5 ml/hr. 9. Xigris should be administered via a dedicated intravenous line or a dedicated lumen of a multilumen central venous catheter. The ONLY other solutions that can be administered through the same line are 0.9% Sodium Chloride Injection, Lactated Ringer’s Injection, Dextrose or Dextrose and Saline mixtures. 10. Avoid exposing drotrecogin alfa (activated) solutions to heat and/or direct sunlight. No incompatibilities have been observed between drotrecogin alfa (activated) and glass infusion bottles or infusion bags made of polyvinylchloride, polyethylene, polypropylene, or polyolefin. The use of other types of infusion sets could have a negative impact on the amount and potency of drotrecogin alfa (activated) administered. 11. Care should be taken to administer Xigris at the appropriate rate, calculated based on kg of bodyweight and infused for the correct duration. It is recommended that the bag be labelled accordingly. 22 7. MARKETING AUTHORISATION HOLDER Eli Lilly Nederland B.V., Grootslag 1-5, 3991 RA, Houten, The Netherlands 8. MARKETING AUTHORISATION NUMBER (S) EU/1/02/225/001 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 22 August 2002 10. DATE OF REVISION OF THE TEXT 23 ANNEX II A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OF THE MARKETING AUTHORISATION C. SPECIFIC OBLIGATIONS TO BE FULFILLED BY THE MARKETING AUTHORISATION HOLDER 24 A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer of the biological active substance Lonza Biologicals Inc. 101 International Drive Portsmouth New Hampshire 03801-2815 USA Name and address of the manufacturer responsible for batch release Lilly Pharma Fertigung und Distribution GmbH & Co. KG Teichweg 3 D-35396 Giessen Germany B. • CONDITIONS OF THE MARKETING AUTHORISATION CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON THE MARKETING AUTHORISATION HOLDER Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product Characteristics, 4.2) • OTHER CONDITIONS The holder of this marketing authorisation must inform the European Commission about the marketing plans for the medicinal product authorised by this decision. C. SPECIFIC OBLIGATIONS TO BE FULFILLED BY THE MARKETING AUTHORISATION HOLDER The Marketing Authorisation Holder shall complete the following programme of studies within the specified time frame, the results of which shall form the basis of the annual reassessment of the benefit/risk profile. Clinical aspects 1. “A further clinical study (F1K-MC-EVBR) is being conducted to investigate the possible interaction between Xigris and heparin. Update on patient enrolment will be provided at the time of the annual license reassessment. The final study report will be provided by the end of February 2006.” 25 ANNEX III LABELLING AND PACKAGE LEAFLET 26 A. LABELLING 27 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OR, WHERE THERE IS NO OUTER PACKAGING, ON THE IMMEDIATE PACKAGING OUTER CARTON TEXT 1. NAME OF THE MEDICINAL PRODUCT Xigris 20 mg powder for solution for infusion drotrecogin alfa (activated) 2. STATEMENT OF ACTIVE SUBSTANCE(S) Provides 2 mg/ml of drotrecogin alfa (activated) when reconstituted with 10 ml of water for injections. 3. LIST OF EXCIPIENTS Excipients: sucrose, sodium chloride, sodium citrate, citric acid, hydrochloric acid and sodium hydroxide. 4. PHARMACEUTICAL FORM AND CONTENTS 1 vial 20 mg 5. METHOD AND ROUTE(S) OF ADMINISTRATION For intravenous infusion after reconstitution and dilution. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP {MM/YYYY} 9. SPECIAL STORAGE CONDITIONS Store at 2°C – 8°C (in a refrigerator). Keep the vial in the outer carton in order to protect it from light. 28 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Eli Lilly Nederland B.V., Grootslag 1-5, 3991 RA, Houten, The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/02/225/002 13. MANUFACTURER’S BATCH NUMBER Lot {number} 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription 15. INSTRUCTIONS ON USE 29 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS VIAL TEXT 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Xigris 20 mg powder for infusion 2. METHOD OF ADMINISTRATION For intravenous infusion after reconstitution and dilution 3. EXPIRY DATE EXP {MM/YYYY} 4. BATCH NUMBER Lot {number} 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 20 mg 30 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OR, WHERE THERE IS NO OUTER PACKAGING, ON THE IMMEDIATE PACKAGING OUTER CARTON TEXT 1. NAME OF THE MEDICINAL PRODUCT Xigris 5 mg powder for solution for infusion drotrecogin alfa (activated) 2. STATEMENT OF ACTIVE SUBSTANCE(S) Provides 2 mg/ml of drotrecogin alfa (activated) when reconstituted with 2.5 ml of water for injections. 3. LIST OF EXCIPIENTS Excipients: sucrose, sodium chloride, sodium citrate, citric acid, hydrochloric acid and sodium hydroxide. 4. PHARMACEUTICAL FORM AND CONTENTS 1 vial 5 mg 5. METHOD AND ROUTE(S) OF ADMINISTRATION For intravenous infusion after reconstitution and dilution. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP {MM/YYYY} 9. SPECIAL STORAGE CONDITIONS Store at 2°C – 8°C (in a refrigerator). Keep the vial in the outer carton in order to protect it from light. 31 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Eli Lilly Nederland B.V., Grootslag 1-5, 3991 RA, Houten, The Netherlands 12. MARKETING AUTHORISATION NUMBER(S) EU/1/02/225/001 13. MANUFACTURER’S BATCH NUMBER Lot {number} 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription 15. INSTRUCTIONS ON USE 32 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS VIAL TEXT 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Xigris 5 mg powder for infusion 2. METHOD OF ADMINISTRATION For intravenous infusion after reconstitution and dilution 3. EXPIRY DATE EXP {MM/YYYY} 4. BATCH NUMBER Lot {number} 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 5 mg 33 B. PACKAGE LEAFLET 34 PACKAGE LEAFLET This leaflet contains important information about Xigris. Please read all of this leaflet carefully. Please remember that you cannot take Xigris by yourself because both your illness and the use of this medicine need constant medical care. Keep this leaflet. You may need to read it again. If you have any questions or are not sure about anything, please ask your doctor or your pharmacist. Remember that this medicine has been prescribed for you personally. Never give it to anyone else. In this leaflet: 1. What Xigris is and what it is used for 2. Before you are given Xigris 3. How Xigris is used 4. Possible side effects 5. Storing Xigris 6. Further information Xigris 20 mg powder for solution for infusion drotrecogin alfa (activated) A vial contains 20 mg of drotrecogin alfa (activated) to be reconstituted with 10 ml of Sterile Water for Injection - The active substance is drotrecogin alfa (activated) 2 mg/ml. Drotrecogin alfa (activated) is a version of a natural protein in the blood called Activated Protein C and it is produced by recombinant technology. The other ingredients are sucrose, sodium chloride, sodium citrate, citric acid, hydrochloric acid and sodium hydroxide. Marketing Authorisation Holder: Eli Lilly Nederland B.V., Grootslag 1-5, 3991 RA, Houten, The Netherlands Manufacturer: Lilly Pharma Fertigung und Distribution GmbH & Co. KG, Teichweg 3, D- 35396 Giessen, Germany. 1. WHAT XIGRIS IS AND WHAT IT IS USED FOR Xigris is presented as a powder for solution for infusion in a vial. A hospital pharmacist, nurse or doctor will have dissolved the Xigris powder in water for injections and sodium chloride solution. This liquid is then passed from a bag through a tube into one of your veins for a period of 96 hours. Xigris is very similar to a protein that occurs naturally in your blood. This protein helps to control blood clotting and inflammation. When your body has a severe infection, clots can form in your blood. These can block the blood supply to important parts of your body such as the kidneys and lungs. This causes an illness called severe sepsis which can make you very ill. Some people will die from this illness. Xigris helps your body to get rid of the clots and also reduces the inflammation caused by the infection. Xigris is used to treat severe sepsis. 35 2. BEFORE YOU ARE GIVEN XIGRIS You should not have Xigris if: you are hypersensitive (allergic) to drotrecogin alfa (activated), any of the other ingredients of Xigris, or bovine (cattle-derived) thrombin (protein) you have internal bleeding you have a brain tumour, or pressure on the brain you are being given heparin at the same time (≥ 15 International Units/kg/hr) you have a bleeding tendency which is not related to sepsis you have a long-standing, severe problem with your liver your platelet (a type of cell in your blood) count is low, even if this has been increased by a transfusion you are at high risk of bleeding (for example): a) you have had surgery within the last twelve hours before you receive Xigris, or you are bleeding from a previous surgery, or you might have surgery while you receive Xigris b) you have been in hospital with a severe injury to your head, or you have had surgery on your brain or spine, or you have had a bleed in your brain (haemorrhagic stroke) within the past three months, or you have abnormal blood vessels in your brain, or a mass in your head; you have an epidural catheter (a tube in your spine) c) you have been born with bleeding tendencies d) you have bled from your bowels within the last six weeks, unless treated adequately e) you have had a major accident and are at increased risk of bleeding Special care should be taken with Xigris if you are at risk of bleeding, for example: if you are taking other drugs which affect how your blood clots if within the last three months, you have had a stroke caused by a blood clot if you have a known problem with bleeding Pregnancy It is not known whether drotrecogin alfa (activated) causes damage to an unborn child or affects your ability to have babies. If you are pregnant your doctor will only give you Xigris if necessary. Breast-feeding It is not known whether drotrecogin alfa (activated) appears in human milk and therefore you should not breast-feed whilst treated with Xigris. Driving and using machines: This is not applicable. Using other medicines: Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including any medicines not prescribed for you by a doctor. 3. HOW XIGRIS IS USED The recommended dose of Xigris is 24 micrograms (µg) per kilogram (kg) of body weight each hour for 96 hours. Xigris is dissolved and then given through a vein. 4. POSSIBLE SIDE EFFECTS 36 Like all medicines, Xigris can have side effects. Xigris may increase the risk of bleeding which can be serious or life-threatening. If you notice any side effects not mentioned in this leaflet, please tell your doctor or pharmacist. 5. STORING XIGRIS Keep out of the reach and sight of children. Store at 2°C – 8°C (in a refrigerator). Keep the vial in the carton in order to protect it from light. Do not use after the expiry date stated on the label. 37 6. FURTHER INFORMATION For any information about this medicinal product, please contact the representative of Eli Lilly in your country. Belgique/België/Belgien Eli Lilly Benelux S.A./N.V. Tél/Tel: + 32-(0)2 548 84 84 Česká republika ELI LILLY ČR, s.r.o. Tel: + 420 234 664 111 Danmark Eli Lilly Danmark A/S Tlf: +45 45 26 60 00 Deutschland Lilly Deutschland GmbH Tel. + 49-(0) 6172 273 2222 Eesti Eli Lilly Holdings Limited Eesti filiaal Tel: +3726441100 Ελλάδα ΦΑΡΜΑΣΕΡΒ-ΛΙΛΛΥ Α.Ε.Β.Ε. Τηλ: +30 210 629 4600 España Lilly S.A. Tel: + 34-91 663 50 00 France Lilly France SAS Tél: +33-(0) 1 55 49 34 34 Ireland Eli Lilly and Company (Ireland) Limited Tel: + 353-(0) 1 661 4377 Ísland Eli Lilly Danmark A/S, Útibú á Íslandi Tel: + 354 520 34 00 Italia Eli Lilly Italia S.p.A. Tel: + 39- 055 42571 Κύπρος Phadisco Ltd Τηλ: +357 22 715000 Latvija Eli Lilly Holdings Limited pārstāvniecība Latvijā Tel: +371 7364000 Lietuva Eli Lilly Holdings Limited atstovybė Tel. +370 (5) 2649600 Luxembourg/Luxemburg Eli Lilly Benelux S.A./N.V. Tél/Tel: + 32-(0)2 548 84 84 Magyarország Lilly Hungária Kft. Tel: + 36 1 328 5100 Malta Charles de Giorgio Ltd. Tel: + 356 25600 500 Nederland Eli Lilly Nederland B.V. Tel: + 31-(0) 30 60 25 800 Norge Eli Lilly Norge A.S. Tlf: + 47 22 88 18 00 Österreich Eli Lilly Ges. m.b.H. Tel: + 43-(0) 1 711 780 Polska Eli Lilly Polska Sp. z o.o. Tel.: +48 (0) 22 440 33 00 Portugal Lilly Portugal Produtos Farmacêuticos, Lda Tel: + 351-21-4126600 Slovenija Eli Lilly, Podružnica Ljubljana Tel: +386 (0)1 580 00 10 Slovenská republika Eli Lilly Slovakia, s.r.o. Tel: + 421 (2) 59224 111 Suomi/Finland Oy Eli Lilly Finland Ab Puh/Tel: + 358-(0) 9 85 45 250 Sverige Eli Lilly Sweden AB Tel: + 46-(0) 8 7378800 United Kingdom Eli Lilly and Company Limited Tel: + 44-(0) 1256 315999 This leaflet was last approved on {date} ------------------------------------------------------------------------------------------------------------------------------- 38 The following information is intended for medical or healthcare professionals only: Instructions for use and handling 1. Use appropriate aseptic technique during the preparation of Xigris for intravenous administration. 2. Calculate the dose and the number of Xigris vials needed. Each Xigris vial contains 20 mg of drotrecogin alfa (activated). The vial contains an excess of drotrecogin alfa (activated) to facilitate delivery of the label amount. 3. Prior to administration, 20 mg vials of Xigris must be reconstituted with 10 ml of Sterile Water for Injection, resulting in a solution with a concentration of approximately 2 mg/ml drotrecogin alfa (activated). Slowly add the Sterile Water for Injection to the vial and avoid inverting or shaking the vial. Gently swirl each vial until the powder is completely dissolved. 4. The solution of reconstituted Xigris must be further diluted with sterile 0.9% Sodium Chloride Injection. Slowly withdraw the appropriate amount of reconstituted drotrecogin alfa (activated) solution from the vial. Add the reconstituted drotrecogin alfa (activated) into a prepared infusion bag of sterile 0.9% Sodium Chloride Injection. When adding the reconstituted drotrecogin alfa (activated) into the infusion bag, direct the stream to the side of the bag to minimise the agitation of the solution. Gently invert the infusion bag to obtain a homogeneous solution. Do not transport the infusion bag between locations using mechanical delivery systems. 5. After reconstitution, immediate use is recommended. However, the reconstituted solution in the vial may be held for up to 3 hours at room temperature (15 to 30ºC). After preparation, the intravenous infusion solution can be used at room temperature (15 to 30ºC) for a period up to 14 hours. 6. Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration. 7. It is recommended that Xigris be infused with an infusion pump to accurately control the infusion rate. The solution of reconstituted Xigris is typically diluted into an infusion bag containing sterile 0.9% Sodium Chloride Injection to a final concentration of between 100 µg/ml and 200 µg/ml. 8. When administering drotrecogin alfa (activated) at low concentrations (less than approximately 200 µg/ml) at low flow rates (less than approximately 5 ml/hr), the infusion set must be primed for approximately 15 minutes at a flow rate of approximately 5 ml/hr. 9. Xigris should be administered via a dedicated intravenous line or a dedicated lumen of a multilumen central venous catheter. The ONLY other solutions that can be administered through the same line are 0.9% Sodium Chloride Injection, Lactated Ringer’s Injection, Dextrose or Dextrose and Saline mixtures. 10. Avoid exposing drotrecogin alfa (activated) solutions to heat and/or direct sunlight. No incompatibilities have been observed between drotrecogin alfa (activated) and glass infusion bottles or infusion bags made of polyvinylchloride, polyethylene, polypropylene, or polyolefin. 39 The use of other types of infusion sets could have a negative impact on the amount and potency of drotrecogin alfa (activated) administered. 11. Care should be taken to administer Xigris at the appropriate rate, calculated based on kg of bodyweight and infused for the correct duration. It is recommended that the bag be labelled accordingly. 40 PACKAGE LEAFLET This leaflet contains important information about Xigris. Please read all of this leaflet carefully. Please remember that you cannot take Xigris by yourself because both your illness and the use of this medicine need constant medical care. Keep this leaflet. You may need to read it again. If you have any questions or are not sure about anything, please ask your doctor or your pharmacist. Remember that this medicine has been prescribed for you personally. Never give it to anyone else. In this leaflet: 1. What Xigris is and what it is used for 2. Before you are given Xigris 3. How Xigris is used 4. Possible side effects 5. Storing Xigris 6. Further information Xigris 5 mg powder for solution for infusion drotrecogin alfa (activated) A vial contains 5 mg of drotrecogin alfa (activated) to be reconstituted with 2.5 ml of Sterile Water for Injection - The active substance is drotrecogin alfa (activated) 2 mg/ml. Drotrecogin alfa (activated) is a version of a natural protein in the blood called Activated Protein C and it is produced by recombinant technology. The other ingredients are sucrose, sodium chloride, sodium citrate, citric acid, hydrochloric acid and sodium hydroxide. Marketing Authorisation Holder: Eli Lilly Nederland B.V., Grootslag 1-5, 3991 RA, Houten, The Netherlands Manufacturer: Lilly Pharma Fertigung und Distribution GmbH & Co. KG, Teichweg 3, D- 35396 Giessen, Germany. 1. WHAT XIGRIS IS AND WHAT IT IS USED FOR Xigris is presented as a powder for solution for infusion in a vial. A hospital pharmacist, nurse or doctor will have dissolved the Xigris powder in water for injections and sodium chloride solution. This liquid is then passed from a bag through a tube into one of your veins for a period of 96 hours. Xigris is very similar to a protein that occurs naturally in your blood. This protein helps to control blood clotting and inflammation. When your body has a severe infection, clots can form in your blood. These can block the blood supply to important parts of your body such as the kidneys and lungs. This causes an illness called severe sepsis which can make you very ill. Some people will die from this illness. Xigris helps your body to get rid of the clots and also reduces the inflammation caused by the infection. Xigris is used to treat severe sepsis. 41 2. BEFORE YOU ARE GIVEN XIGRIS You should not have Xigris if: you are hypersensitive (allergic) to drotrecogin alfa (activated), any of the other ingredients of Xigris, or bovine (cattle-derived) thrombin (protein) you have internal bleeding you have a brain tumour, or pressure on the brain you are being given heparin at the same time (≥ 15 International Units/kg/hr) you have a bleeding tendency which is not related to sepsis you have a long-standing, severe problem with your liver your platelet (a type of cell in your blood) count is low, even if this has been increased by a transfusion you are at high risk of bleeding (for example): a) you have had surgery within the last twelve hours before you receive Xigris, or you are bleeding from a previous surgery, or you might have surgery while you receive Xigris b) you have been in hospital with a severe injury to your head, or you have had surgery on your brain or spine, or you have had a bleed in your brain (haemorrhagic stroke) within the past three months, or you have abnormal blood vessels in your brain, or a mass in your head; you have an epidural catheter (a tube in your spine) c) you have been born with bleeding tendencies d) you have bled from your bowels within the last six weeks, unless treated adequately e) you have had a major accident and are at increased risk of bleeding Special care should be taken with Xigris if you are at risk of bleeding, for example: if you are taking other drugs which affect how your blood clots if within the last three months, you have had a stroke caused by a blood clot if you have a known problem with bleeding Pregnancy It is not known whether drotrecogin alfa (activated) causes damage to an unborn child or affects your ability to have babies. If you are pregnant your doctor will only give you Xigris if necessary. Breast-feeding It is not known whether drotrecogin alfa (activated) appears in human milk and therefore you should not breast-feed whilst treated with Xigris. Driving and using machines: This is not applicable. Using other medicines: Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including any medicines not prescribed for you by a doctor. 3. HOW XIGRIS IS USED The recommended dose of Xigris is 24 micrograms (µg) per kilogram (kg) of body weight each hour for 96 hours. Xigris is dissolved and then given through a vein. 4. POSSIBLE SIDE EFFECTS 42 Like all medicines, Xigris can have side effects. Xigris may increase the risk of bleeding which can be serious or life-threatening. If you notice any side effects not mentioned in this leaflet, please tell your doctor or pharmacist. 5. STORING XIGRIS Keep out of the reach and sight of children. Store at 2°C – 8°C (in a refrigerator). Keep the vial in the carton in order to protect it from light. Do not use after the expiry date stated on the label. 43 6. FURTHER INFORMATION For any information about this medicinal product, please contact the representative of Eli Lilly in your country. Belgique/België/Belgien Eli Lilly Benelux S.A./N.V. Tél/Tel: + 32-(0)2 548 84 84 Česká republika ELI LILLY ČR, s.r.o. Tel: + 420 234 664 111 Danmark Eli Lilly Danmark A/S Tlf: +45 45 26 60 00 Deutschland Lilly Deutschland GmbH Tel. + 49-(0) 6172 273 2222 Eesti Eli Lilly Holdings Limited Eesti filiaal Tel: +3726441100 Ελλάδα ΦΑΡΜΑΣΕΡΒ-ΛΙΛΛΥ Α.Ε.Β.Ε. Τηλ: +30 210 629 4600 España Lilly S.A. Tel: + 34-91 663 50 00 France Lilly France SAS Tél: +33-(0) 1 55 49 34 34 Ireland Eli Lilly and Company (Ireland) Limited Tel: + 353-(0) 1 661 4377 Ísland Eli Lilly Danmark A/S, Útibú á Íslandi Tel: + 354 520 34 00 Italia Eli Lilly Italia S.p.A. Tel: + 39- 055 42571 Κύπρος Phadisco Ltd Τηλ: +357 22 715000 Latvija Eli Lilly Holdings Limited pārstāvniecība Latvijā Tel: +371 7364000 Lietuva Eli Lilly Holdings Limited atstovybė Tel. +370 (5) 2649600 Luxembourg/Luxemburg Eli Lilly Benelux S.A./N.V. Tél/Tel: + 32-(0)2 548 84 84 Magyarország Lilly Hungária Kft. Tel: + 36 1 328 5100 Malta Charles de Giorgio Ltd. Tel: + 356 25600 500 Nederland Eli Lilly Nederland B.V. Tel: + 31-(0) 30 60 25 800 Norge Eli Lilly Norge A.S. Tlf: + 47 22 88 18 00 Österreich Eli Lilly Ges. m.b.H. Tel: + 43-(0) 1 711 780 Polska Eli Lilly Polska Sp. z o.o. Tel.: +48 (0) 22 440 33 00 Portugal Lilly Portugal Produtos Farmacêuticos, Lda Tel: + 351-21-4126600 Slovenija Eli Lilly, Podružnica Ljubljana Tel: +386 (0)1 580 00 10 Slovenská republika Eli Lilly Slovakia, s.r.o. Tel: + 421 (2) 59224 111 Suomi/Finland Oy Eli Lilly Finland Ab Puh/Tel: + 358-(0) 9 85 45 250 Sverige Eli Lilly Sweden AB Tel: + 46-(0) 8 7378800 United Kingdom Eli Lilly and Company Limited Tel: + 44-(0) 1256 315999 This leaflet was last approved on {date} ------------------------------------------------------------------------------------------------------------------------------- 44 The following information is intended for medical or healthcare professionals only: Instructions for use and handling 1. Use appropriate aseptic technique during the preparation of Xigris for intravenous administration. 2. Calculate the dose and the number of Xigris vials needed. Each Xigris vial contains 5 mg of drotrecogin alfa (activated). The vial contains an excess of drotrecogin alfa (activated) to facilitate delivery of the label amount. 3. Prior to administration, 5 mg vials of Xigris must be reconstituted with 2.5 ml of Sterile Water for Injection, resulting in a solution with a concentration of approximately 2 mg/ml drotrecogin alfa (activated). Slowly add the Sterile Water for Injection to the vial and avoid inverting or shaking the vial. Gently swirl each vial until the powder is completely dissolved. 4. The solution of reconstituted Xigris must be further diluted with sterile 0.9% Sodium Chloride Injection. Slowly withdraw the appropriate amount of reconstituted drotrecogin alfa (activated) solution from the vial. Add the reconstituted drotrecogin alfa (activated) into a prepared infusion bag of sterile 0.9% Sodium Chloride Injection. When adding the reconstituted drotrecogin alfa (activated) into the infusion bag, direct the stream to the side of the bag to minimise the agitation of the solution. Gently invert the infusion bag to obtain a homogeneous solution. Do not transport the infusion bag between locations using mechanical delivery systems. 5. After reconstitution, immediate use is recommended. However, the reconstituted solution in the vial may be held for up to 3 hours at room temperature (15 to 30ºC). After preparation, the intravenous infusion solution can be used at room temperature (15 to 30ºC) for a period up to 14 hours. 6. Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration. 7. It is recommended that Xigris be infused with an infusion pump to accurately control the infusion rate. The solution of reconstituted Xigris is typically diluted into an infusion bag containing sterile 0.9% Sodium Chloride Injection to a final concentration of between 100 µg/ml and 200 µg/ml. 8. When administering drotrecogin alfa (activated) at low concentrations (less than approximately 200 µg/ml) at low flow rates (less than approximately 5 ml/hr), the infusion set must be primed for approximately 15 minutes at a flow rate of approximately 5 ml/hr. 9. Xigris should be administered via a dedicated intravenous line or a dedicated lumen of a multilumen central venous catheter. The ONLY other solutions that can be administered through the same line are 0.9% Sodium Chloride Injection, Lactated Ringer’s Injection, Dextrose or Dextrose and Saline mixtures. 10. Avoid exposing drotrecogin alfa (activated) solutions to heat and/or direct sunlight. No incompatibilities have been observed between drotrecogin alfa (activated) and glass infusion bottles or infusion bags made of polyvinylchloride, polyethylene, polypropylene, or polyolefin. 45 The use of other types of infusion sets could have a negative impact on the amount and potency of drotrecogin alfa (activated) administered. 11. Care should be taken to administer Xigris at the appropriate rate, calculated based on kg of bodyweight and infused for the correct duration. It is recommended that the bag be labelled accordingly. 46

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