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艾炎寧 10/20/100 公絲 膜衣錠

Arava® 10mg/20mg/100mg Film-Coated Tablets


衛署藥輸字第 023615 號
衛署藥輸字第 023616 號
衛署藥輸字第 023617 號 本藥須由醫師處方使用

[組成]
Arava™ 10mg 膜衣錠,每顆膜衣錠含 10mg 之 Leflunomide。
Arava™ 20mg 膜衣錠,每顆膜衣錠含 20mg 之 Leflunomide。
Arava™ 100mg 膜衣錠,每顆膜衣錠含 100mg 之 Leflunomide。

[賦形劑]
核心:Maize starch、povidone、crospovidone、silica colloidal anhydrous、magnesium stearate、lactose
monohydrate,Arava® 100mg 膜衣錠另含有 Talc。
膜衣:Talc、hypromellose、titanium dioxide、macrogol 8000,Arava® 20mg 膜衣錠另含有黃色氧
化鐵。

[適應症]
治療成人類風濕性關節炎,並減緩於 X 光所顯現之關節磨損與關節間隙狹等結構性損害。

[說明]
最近曾服用或併用具有肝毒性或血液毒性之 DMARDs(如 methotrexate)治療時可能增加嚴重
性不良反應的危險性,因此,開始用 Leflunomide 治療時應謹慎評估藥物效益/危險比率
(benefit/risk ratio)。

此外,從 Leflunomide 轉換成其它 DMARD,如未遵守藥物排除步驟(washout procedure),即


使經過一段長時間以後,嚴重性不良反應的危險性也可能增加。

[劑量及用法]
ALT(SGPT)值及完整的血液細胞數檢查,包括各種白血球細胞與血小板數量,須同時及頻繁
地檢測:

• 服用 Leflunomide 前。
• 開始服藥後的前 6 個月每隔 2 週。
• 之後每隔 8 週檢測(詳見[警語與注意事項]節)。

Leflunomide 治療由 100mg 起始劑量(loading dose)開始,一天一次,服用 3 天,維持劑量


(maintenance dose)建議為 10mg 至 20mg,一天一次。

通常 4 到 6 週後開始出現治療效果,4 到 6 個月後效果更好。

輕度腎臟功能不全之病患不需要調整劑量。

65 歲以上之病患不需要調整劑量。

本藥必須由有治療類風濕性關節炎經驗的醫師處方使用。
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[用法]
喝足夠量的白開水將 Arava 錠整顆吞服,食物不會影響 Leflunomide 的吸收。

[禁忌]
對 Leflunomide 及藥物內所含的賦型劑過敏的病患(尤其是曾患有 Stevens-Johnson 徵候群、毒
性表皮壞死與多型性紅斑)禁用 Arava。

下列病患禁用 Leflunomide:
肝功能不全之病患。
重度免疫系統功能缺乏之病患,如 AIDS。
非類風濕性關節炎引起的明顯骨髓功能不全或貧血、白血球減少症、嗜中性白血球減少
症或血小板減少症之病患。
重度感染之病患。
中度至重度腎臟功能不全之病患,因為這些病患臨床用藥的經驗不足。
重度低蛋白血症之病患,如腎病症候群。
懷孕婦女,或 Leflunomide 治療期間未使用有效避孕方法之可能懷孕的婦女,其後只要活
性代謝物之血漿濃度高於 0.02mg/l 不可懷孕,開始用 Leflunomide 治療之前應排除懷孕的
可能。

服用 Leflunomide 治療的婦女不可以授乳。

男性病患應注意可能有男性-引起的胎兒毒性,服藥期間應使用有效的避孕方法。

由於尚無療效性與安全性的資料,18 歲以下的病患不建議使用 Arava。

[警語與注意事項]
病患應在小心醫療監督下服用 Arava。

不建議併用具有肝毒性或血液毒性的 DMARDs(如 methotrexate)。

Leflunomide 的活性代謝物 A771726 半衰期長,通常為 1 至 4 週,即使已經停藥仍可能發生嚴


重性不良反應(如肝毒性、血液毒性或過敏反應),因此,當發生這些毒性或 Leflunomide 治
療後轉換成其它 DMARD(如 methotrexate)均應施行藥物排除步驟。

萬一想要懷孕或不慎懷孕時,藥物排除步驟及其他建議事項請參閱”懷孕與授乳”。

肝臟反應:
Leflunomide 治療期間,曾有少數案例產生重度肝臟損傷,甚至死亡。大多數的例子在初期六
個月發生,與其他具有肝毒性的藥物併用時經常發生,因此必須嚴格監測。

開使用 Leflunomide 治療前及用藥後的前 6 個月每隔 2 週,必須檢測 ALT(SGPT)值及完整的


血液細胞數檢查,以後每隔 8 週檢測。

當 ALT(SGPT)值升高為正常範圍上限值的 2 至 3 倍時,可考慮將劑量由 20mg 降為 10mg,並


且每週監測,若 ALT(SGPT)值持續高於正常範圍上限值的 2 倍以上,或 ALT 值升高為正常範
圍上限值的 3 倍時,Leflunomide 必須停藥,並施行藥物排除步驟。Leflunomide 停藥後,建議
應持續監視肝臟酵素值直到肝臟酵素值恢復正常。

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因可能加強肝毒性反應,故用藥期間應避免喝酒。

因為 Leflunomide 的活性代謝物 A771726 與蛋白質結合能力高,且經由肝臟代謝及膽汁分泌排


除,故低蛋白血症之病患的 A771726 血漿濃度會上升,重度低蛋白血症或肝功能不全之病患
禁用 Arava。

因為 Leflunomide 可能有增加肝毒性的風險以及肝臟會參與藥物之活化排除和在循環的作用,
因此 ARAVA 並不建議用於顯著之肝功能不全或 B/C 型肝炎帶原之患者。

血液學反應:
服藥前及用藥後的前 6 個月必須每隔 2 週做完整的血液細胞數量檢查與檢測 ALT(SGPT),包
括各種白血球細胞與血小板數量,以後每隔 8 週檢測。

已經有貧血、白血球減少症或血小板減少症之病患,以及骨髓功能受損或有骨髓抑制危險性
之病患,血液學疾病之危險性會升高,如發生這些反應,應考慮將藥物洗出以降低 A771726
的血漿濃度。

萬一有嚴重性血液學反應,包括全部血球減少症,則應停用 Arava 及任何併用之骨髓抑制藥


物,並施行藥物排除步驟。

併用其他藥物治療:
迄今尚無 Leflunomide 與治療風濕性疾病的抗瘧疾藥物(如 chloroquine 與
hydroxychloroquine)、肌肉注射或口服金製劑、D-penicillamine、azathioprine 及其他免疫抑制
劑併用(methotrexate 除外)之研究,併用藥物治療的危險性,尤其是長期性資料仍未可知,
因這種療法可能導致毒性相加或相乘(如肝或血液毒性),因而不建議與其他 DMARD(如
methotrexate)併用。

除 NSAIDs 以外,Leflunomide 與經由 CYP2C9 代謝之藥物如 phenytoin、warfarin 與 tolbutamide


藥物併用時應小心。

轉換其它藥物治療:
因 Leflunomide 在體內停留時間較長,如未經過藥物排除步驟,轉換其它 DMARD(如
methotrexate)治療時,即使經過長時間以後危險性(如動力學交互作用、器官毒性)仍可能
增加。

同樣地,最近曾用過具有肝毒性或血液毒性的藥物(如 methotrexate)治療時可能使副作用增
加,因此開始用 Leflunomide 治療時應謹慎評估藥物效益/危險比且於轉換藥物後的初期階段
建議應小心監視肝臟酵素值。

皮膚反應:
萬一有潰瘍性口腔炎時應停用 Leflunomide。

Leflunomide 治療時很少數的病患曾發生 Stevens-Johnson 徵候群或毒性表皮壞死,只要出現皮


膚或黏膜反應,則應懷疑嚴重性反應,且必須停用 Leflunomide 及其他可能相關藥物,並立刻
施行藥物排除步驟,藥物必須完全洗出,而且禁止再用 Leflunomide。

感染:
已知免疫抑制劑如 Leflunomide 可能使病患容易受到感染,包含伺機感染。感染本質上可能更
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嚴重,因此可能需要早期且強力的治療。當發生重度無法控制的感染時,可能需要停用
Leflunomide,並服用 cholestyramine 將藥物洗出。
因有結核病再發的危險性,故有結核菌素反應的病患必須小心監視。

血壓:
開始用 Leflunomide 治療前應測量血壓,往後定期測量。

生育(對男性的建議):
對於男性引起的胎兒毒性之危險性尚無特別資料。然而,並無動物試驗探討此危險性。為減
低任何可能的危險性,想要有小孩的男性應考慮停用 Leflunomide,並服用 cholestyramine 8g,
一天 3 次服用 11 天,或活性碳粉末 50g,一天 4 次服用 11 天。

施行 cholestyramine 或活性碳粉末 11 天後,第一次測量 A771726 的血漿濃度,然後至少間隔


14 天後再次測量 A771726 的血漿濃度,如兩次血漿濃度值都低於 0.02mg/l,則至少再經過 3
個月的等待期後,胎兒毒性的危險性很低。

藥物排除步驟:
服用 cholestyramine 8g,一天 3 次,或活性碳粉末 50g,一天 4 次,將藥物完全洗出通常需要
11 天,臨床或實驗室的變數決定時間長短。

[藥物交互作用]
最近曾用過具有肝毒性或血液毒性的藥物,或 Leflunomide 與這些藥物併用,或以 Leflunomide
治療後未施行藥物排除步驟繼續服用這些藥物都可能使副作用增加。轉換藥物後的初期階段
建議應小心監視肝臟酵素值及血液學參數。

在一項小型的試驗(n=30),併用 Leflunomide(每天 12 至 20mg)與 methotrexate(每週 10


至 25mg) ,30 位病患中有 5 位可見肝臟酵素上升 2 至 3 倍,2 位持續服用兩種藥物,3 位停用
Leflunomide 後,酵素上升情況消失。另外 5 位病患上升 3 倍以上,2 位持續服用兩種藥物,3
位停用 Leflunomide 後,這些狀況也全消失,因此,轉換藥物後的初期階段建議應小心監視肝
臟酵素值。

在類風濕性關節炎的病患,藥物動力學上並未顯示 Leflunomide(每天 12 至 20mg)與


methotrexate(每週 10 至 25mg)之間具有交互作用。

以 Leflunomide 治療的病患建議不要服用 cholestyramine 或活性碳粉末,因會導致 A771726


(Leflunomide 的活性代謝物)的血漿濃度快速且明顯降低,其作用機轉是干擾 A771726 之腸
肝循環或胃腸道內透析。

如病患已在服用非類固醇抗發炎藥(NSAIDs)或類固醇藥,服用 Leflunomide 後仍可繼續使用。

Leflunomide 及其代謝物代謝所需要的酵素尚未確實瞭解,在體內試驗顯示與 cimetidine(非


特異性 cytochrome P450 抑制劑)之間並無明顯的交互作用,Leflunomide 單一劑量與 rifampicin
(非特異性 cytochrome P450 誘導劑)多次劑量併用後,A771726 最高血漿濃度大約增加 40%,
然而曲線下面積(AUC)並無明顯變化,此作用機轉並不清楚。

在體外試驗顯示 A771726 會抑制 P4502C9(CYP2C9)之活性,當 Leflunomide 與需經由 CYP2C9


代謝之 NSAIDs 併用時臨床上並無安全性的疑慮,但 Leflunomide 與 NSAIDs 以外需經由 CYP2C9
代謝之的藥物如 phenytoin、warfarin 及 tolbutamid 併用時則應小心。
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在一項由健康女性志願者併用 Leflunomide 與 30 g 之 ethinyloestradiol 三期式(triphasic)口
服避孕藥的試驗中,避孕藥的效果並未降低,而且 A771726 的藥物動力學仍在預測範圍內。

疫苗接種:
尚無服用 Leflunomide 治療後有關疫苗接種的藥效與安全性的臨床資料,因此治療期間不建議
使用活性減毒疫苗,而且 Arava 停藥後有意使用活性減毒疫苗時應考慮 Leflunomide 的半衰期
較長。

[懷孕與授乳]
懷孕
在花鼠及兔子,Leflunomide 的活性代謝物 A771726 具有催畸性,在人類可能使胎兒受到傷害。

懷孕婦女與未使用有效避孕方法之可能懷孕的婦女絕不可服用 Leflunomide,而且必須等待一
段時間才可懷孕,使用 Leflunomide 治療前必須排除懷孕的可能性。

如有月經延遲或其它理由懷疑可能懷孕時,應立刻告知醫師並做懷孕測試,如呈陽性反應,
醫師與病患必須考慮懷孕的危險性,在月經遲來的初期即進行藥物排除步驟,快速降低活性
代謝物的血中濃度,可以減少 Leflunomide 對胎兒的危險性。

服用 Leflunomide 治療的婦女如想要懷孕,建議採用下列方法之一以確定胎兒不會接觸到毒性
濃度的 A771726(目標濃度是低於 0.02mg/l)。

等待期:
A771726 的血漿濃度可能持續一段時間高於 0.02mg/l,Leflunomide 停藥兩年後可降至 0.02mg/l
以下。

兩年等待期過後,第一次檢測 A771726 的血漿濃度,至少間隔 14 天後必須再測,如果兩次血


漿濃度都低於 0.02mg/l,則無胎兒畸型之危險性。

藥物排除步驟:
停止 Leflunomide 治療後:

服用 cholestyramine 8g,一天 3 次,服用 11 天。


或活性碳粉末 50g,一天 4 次,服用 11 天。

無論採取任何一種排除步驟,至少間隔 14 天後分別做兩次檢測確認,第一次測得血漿濃度低
於 0.02mg/l 需經過一個半月的等待期才能懷孕。

應告知可能懷孕的婦女停藥後必須經過兩年的等待期才可懷孕,如果有效避孕且長達兩年的
等待期不實際,則可能需要施行藥物排除步驟來預防。

Cholestyramine 與活性碳粉末可能會影響動情素與黃體素之吸收,因此以 cholestyramine 或活


性碳粉末施行藥物排除步驟時無法保證口服避孕藥的效果,建議應採用其它方法避孕。

授乳:
動物試驗顯示 Leflunomide 或其代謝物會分泌至乳汁中,因此授乳婦女不可服用
Leflunomide。

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[對開車及機器操作的影響]
發生暈眩時會影響病患的專注力及正常反應力,此時病患不可開車及使用機器。

副作用
依發生頻率分為:
常見=1-10%之病患;少見=0.1-1%之病患;罕見=0.01-0.1%之病患;極罕見=0.01%或以下之病
患。

心臟疾病
常見:血壓輕微上升。
罕見:血壓劇烈上升。

胃腸疾病
常見:腹瀉、噁心、嘔吐、食慾不振、口腔黏膜疾病(如口瘡性口腔炎、口腔潰爛)
、腹痛。

肝膽疾病
常見:肝功能指數上升(轉胺酵素【尤其是 ALT】
、gamma-GT、鹼性磷酸酶、膽紅素較少見)。
罕見:肝炎、黃疸/膽汁鬱滯,極罕見嚴重性肝臟受損如致死性肝衰竭及急性肝臟壞死。
極罕見:胰臟炎。

感染
極罕見:嚴重感染,包含可能致命的敗血症。

如同其他免疫抑制劑,Leflunomide 可能會增加感染的敏感性,包含伺機感染。因此感染的機
率可能增加(尤其是鼻炎、支氣管炎與肺炎)。

代謝與營養異常
常見:體重減輕(通常不明顯)。
少見:低血鉀症。

神經系統疾病
常見:頭痛、暈眩、虛弱感、感覺異常。
少見:味覺障礙、焦慮。
極罕見:末梢神經病變。

骨骼肌肉及結締組織疾病
常見:肌腱及腱鞘發炎。
少見:肌腱裂傷。

皮膚及皮下組織疾病
常見:落髮增加、濕疹、皮膚乾燥。
少見:蕁麻疹。
極罕見:Stevens-Johnson 徵候群、毒性表皮壞死、多型性紅斑。

免疫系統疾病
常見:輕度過敏反應、發疹(包括丘疹)、發癢。
少見:蕁麻疹。
極罕見:嚴重性過敏與類過敏反應。
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呼吸胸廓縱隔腔疾病
極罕見:肺間質疾病。

血液與淋巴系統疾病
常見:白血球減少症(白血球>2G/l)(G=109)。
少見:貧血、輕度血小板減少症(血小板<100G/l)(G=109)。
罕見:嗜伊紅血球增多症、白血球減少症(白血球<2G/l)(G=109)、全部血球減少症(作用機
轉可能是抗增殖作用)。
極罕見:顆粒性白血球減少症、脈管炎。

最近曾用過、併用或連續使用對骨髓具有潛在毒性之藥物時可能增加血液毒性的危險性。

有些免疫抑制劑會增加惡性腫瘤的危險性,尤其是淋巴組織增生的疾病。

可能發生輕微的高脂血症,通常尿酸濃度減少。LDH 及 CK 實驗室參數值稍微上升但無臨床症
狀,輕度低磷酸鹽血症則少見。

不能排除精子濃度、總精子數量減少,活動力下降,但程度輕微且為可逆性。

Leflunomide 的活性代謝物 A771726 半衰期較長,通常為 1 至 4 週,如發生嚴重性的不良反應


或其他理由,必須從體內迅速清除 A771726 時則須施行藥物排除步驟,若臨床需要可重覆施
行,若懷疑有嚴重性免疫過敏反應如 Stevens-Johnson 徵候群或毒性表皮壞死時則必須將藥物
完全洗出。

[藥物過量]
症狀
曾有病患服用 Arava 劑量超過每日建議劑量 5 倍及相關成人及小孩服用過量之慢性藥物過量
報告。
目前並無服用藥物過量之不良反應報告。
服用 Leflunomide 不良反應皆符合安全範圍:腹痛、噁心、腹瀉、肝功能指數上升、貧血、白
血球減少、搔癢及皮疹。

處理方法
當藥物過量或中毒時,建議使用 cholestyramine 或活性碳加速排除,3 位健康志願者口服投與
cholestyramine 8g,一天 3 次,服用 24 小時,24 小時後 A771726 的血漿濃度大約減少 40%,48
小時後減少 49%至 65%。

口服或經由鼻胃管給與活性碳(粉末泡成懸浮液),每 6 小時 50g,服用 24 小時,24 小時後


活性代謝物 A771726 的血漿濃度大約減少 37%,48 小時後減少 48%。

若臨床需要可重覆施行藥物排除步驟。

經由血液透析及腹膜透析(CAPD)研究指出 Leflunomide 的原始活性代謝物 A771726 並非可透


析的。

7
[藥理性質]
藥效性質:
藥理分類:選擇性免疫抑制劑,ATC code:L04AA13。

人體藥理學:
Leflunomide 是一種具有抗增殖作用之疾病修飾性抗風濕病藥物。

動物藥理學
在動物體,只要在敏感期間內給藥,Leflunomide 對關節炎、其他自體免疫疾病與器官移植有
效,它具有免疫調節/免疫抑制性質,具抗增殖作用而產生抗發炎效果,在自體免疫疾病的動
物體,疾病發生初期給與 Leflunomide,可達到最好的預防效果。
在體內,Leflunomide 快速且完全代謝成 A771726,在體外仍具有活性,而且它可能是產生藥
效的成分。

作用機轉:
Leflunomide 的活性代謝物 A771726 會抑制人體酵素 dihydroorotate dehydrogenase(DHODH)而
產生抗增殖作用。

臨床試驗:
有 4 個含對照組的臨床試驗證實 Arava 治療類風濕性關節炎有效(1 個第 II 期試驗, 3 個第
III 期試驗),第 II 期試驗,YU203,將 402 位活性類風濕性關節炎的病患隨機分組為安慰劑組
(n=102) , 5mg 之 Leflunomide 組(n=95)
,10mg 組(n=101)或 25mg/day 組(n=104)
,治
療 6 個月。
第 III 期試驗所有 Leflunomide 組的病患投與起始(loading dose)劑量 100mg 服用 3 天,MN301
試驗將 358 位活動性類風濕性關節炎的病患隨機分組成 Leflunomide 20mg/day 組(n=133)、
sulphasalazine 2g/day 組(n=133)或安慰劑組(n=92),治療 6 個月。MN303 試驗是 MN301
試驗後續 6 個月的雙盲試驗,不含安慰劑組,比較 Leflunomide 與 sulphasalazine 治療 12 個月
的效果。
MN302 試驗將 999 位活性類風濕性關節炎的病患隨機分組成 Leflunomide 20mg/day 組
(n=501),或 methotrexate 由每週 7.5mg 增加至每週 15mg 組(n=498)
,10%的病患補充葉酸,治療 12 個月。
US301 試驗將 482 位活動性類風濕性關節炎的病患隨機分組成 Leflunomide 20mg/day 組
(n=182) ,methotrexate 由每週 7.5mg 增加至每週 15mg 組(n=182),或安慰劑組(n=118),
所有的病患給與 1mg 之葉酸鹽,每天兩次,治療 12 個月。

臨床試驗結果:
在 3 個含安慰劑對照之試驗中,至少 10mg/day 劑量之 Leflunomide(YU203 試驗 10mg 至 25mg,
MN301 與 US301 試驗 20mg)對於減少類風濕性關節炎的徵象與症狀統計學上明顯優於安慰
劑,依美國風濕病學會(ACR)的反應率(response rates) ,在 YU203 試驗安慰劑是 27.7%,5mg
是 31.9%,10mg 是 50.5%,25mg/day 是 54.5%。第 III 期試驗依 ACR 的反應率,Leflunomide
20mg/day 與安慰劑之比是 54.6%與 28.6%(MN301 試驗),以及 49.4%與 26.3%(US301 試驗)。
有效藥物治療 12 個月後,依 ACR 的反應率 Leflunomide 組的病患是 52.3%(MN301/303 試驗) ,
50.5%(MN302 試驗)與 49.4%(US301 試驗) ,sulphasalazine 組的病患是 53.8%(MN301/303
試驗),methotrexate 組的病患是 64.8%(MN302 試驗)與 43.9%(US301 試驗)。在 MN302 試
驗中,Leflunomide 的效果明顯低於 methotrexate,然而,在 US301 試驗中 Leflunomide 與
methotrexate 兩組主要的有效參數並無明顯差異。MN301 試驗中 Leflunomide 與 sulphasalazine
兩組間並無差異。Leflunomide 治療 1 個月後效果明顯,3 至 6 個月後效果穩定且持續整個療
8
程。

[藥動學性質]
Leflunomide 在腸壁和肝臟中經過首渡代謝(first-pass metabolism)
,將環打開而快速轉變成活
性代謝物 A771726,3 位健康志願者在一項用同位素 C 標的 Leflunomide 的試驗中,血漿、尿
14

液或糞便中並未檢測出未經代謝的 Leflunomide。在其他試驗,少數曾在血漿中檢測出未經代
謝的 Leflunomide,然而血漿濃度值為 ng/ml,血漿中僅有的同位素代謝物是 A771726,此代謝
物是 Arava 在體內產生藥效之主要物質。

吸收:
從 14C 試驗所得的藥物排除資料顯示至少有 82 至 95%的藥物被吸收,單一劑量投與後,A771726
達到最高血漿濃度的時間差異很大,界於 1 至 24 小時之間。Leflunomide 可和食物一起使用,
因為進食後與空腹時的吸收情形相當,由於 A771726 的半衰期很長(約 2 週) ,臨床試驗採用
100mg 之起始劑量服用 3 天,使 A771726 快速達到穩定狀態的濃度,若未給與速效劑量,欲
達到穩定狀態血漿濃度的時間將需要兩個月。類風濕性關節炎的病患給與多次劑量的試驗
中,A771726 在 5 至 25mg 劑量間藥動學參數呈線性,這些試驗中,臨床效果與 A771726 之血
漿濃度及 Leflunomide 之日劑量有密切關係,20mg/day 之劑量,穩定狀態時 A771726 的血漿濃
度平均值大約是 35µg/ml,與單一劑量比較,穩定狀態時的血漿濃度大約蓄積 33 至 35 倍。

分佈:
在人體血漿中,A771726 廣泛地與蛋白質(白蛋白)結合,A771726 未結合的部分約佔 0.62%,
在療效濃度範圍內 A771726 的結合呈線性,類風濕性關節炎或慢性腎功能不全的病患 A771726
在血漿中的結合明顯稍微降低且差異性較大,A771726 廣泛與蛋白質結合可能會取代其它高蛋
白結合率的藥物,在體外血漿蛋白結合交互反應的試驗結果顯示 warfarin 在臨床有效的濃度
下並無交互作用,類似試驗顯示 ibuprofen 與 diclofenac 不會取代 A771726,然而 tolbutamide
存在下 A771726 游離態的部分增加 2 至 3 倍, A771726 會取代 ibuprofen、diclofenac 與
tolbutamide,但這些藥物游離態的部分僅增加 10%至 50%,無資料顯示這些作用具有臨床意
義,A771726 分佈體積較少(約 11 公升),此與蛋白質廣泛結合一致,紅血球的攝取(uptake)
並無差別。

代謝:
Leflunomide 被代謝為一個主要的代謝物 A771726 及許多少量的代謝物包括 TFMA
(4-trifluoromethylaniline),Leflunomide 代謝為 A771726 及 A771726 後續的代謝並非僅由一個
酵素控制,但在微粒體及細胞質(cytosolic cellular fractions)中進行,與 cimetidine(非特異
性 cytochrome P450 抑制劑)及 rifampicin(非特異性 cytochrome P450 誘導劑)之交互作用試
驗中顯示,在體內僅有少數的 CYP 酵素參與 Leflunomide 之代謝。

排除:
A771726 排除緩慢,其廓清率約為 31ml/hr,病患之排除半衰期約為 2 週,投與同位素標的的
Leflunomide 後,由糞便(可能經由膽汁排除)與尿液排除的同位素數量相同,投與單一劑量
36 天後,尿液與糞便中仍可檢測出 A771726,尿液中主要的代謝物是 Leflunomide 的 glucuronide
產物(主要是 0 到 24 小時的檢體)及一種 A771726 之 oxanilic acid 衍生物,糞便中主要的代
謝物是 A771726。

在人體已經證實口服活性碳之懸浮液或 cholestyramine 會導致 A771726 排除速率變快且明顯增


加,血漿濃度下降,這可能是胃腸道透析機轉或干擾腸肝循環的結果。

9
腎衰竭之藥動學:
3 位血液透析與 3 位腹膜透析(CAPD)之病患口服 100mg 單一劑量之 Leflunomide,腹膜透析
之藥動學參數值與健康志願者一致,血液透析之病患其 A771726 排除速率較快,其並非因藥
物被透析液所移除。

肝衰竭之藥動學:
尚無肝功能不全之病患的治療資料,活性代謝物 A771726 廣泛地與蛋白質結合,並經由肝臟
代謝與膽汁分泌排除,肝功能不良可能會影響這些過程。

年紀的影響:
尚無 18 歲以下病患的藥動學資料,老年人(>65 歲)的藥動學資料有限,但與成年人的藥動
學一致。

[臨床前安全性資料]
在急性毒性試驗,小鼠與花鼠口服和腹腔注射 Leflunomide,小鼠口服重覆投與 Leflunomide
連續 3 個月,花鼠與狗連續 6 個月,猴子連續 1 個月,結果顯示產生毒性反應最主要的器
官是骨髓、血液、胃腸道、皮膚、脾臟、胸腺與淋巴結,主要的作用是貧血、白血球減少症、
血小板數量減少與全脊髓病,並表現出藥物的基本作用模式(抑制 DNA 合成) ,在花鼠與狗
產生 Heinz 體與 Howell-Jolly 體,其它在心臟、肝臟、角膜與呼吸道的作用是因免疫抑制導致
感染而來,動物產生毒性的劑量與人體治療劑量相同。

Leflunomide 不具突變性,然而,少量的代謝物 TFMA(4-trifluoromethylaniline)在體外造成


clastogenicity 與點狀突變,但在體內這些作用的資料仍不足。

在花鼠的致癌性試驗中,Leflunomide 不具致癌性,而小鼠的致癌性試驗則發現雄鼠給與最高
劑量時,產生惡性淋巴瘤的機率增加,此可能與 Leflunomide 免疫抑制作用有關。雌鼠的細支
氣管-肺泡腺癌(bronchiolo-alveolar)與肺癌的機率增高,此與劑量有關,在小鼠的發現與臨
床使用 Leflunomide 的關係仍不確定。

在動物體 Leflunomide 不具抗原性。


在花鼠與兔子,當劑量與人體治療劑量相同時會產生胎兒毒性與催畸性,重覆劑量之毒性試
驗中對雄性生殖器官有不良作用,但生育力不會降低。

[儲存條件]
25℃。

[有效期限]
3 年。超過有效日期,請勿服用。

[包裝]
Arava™ 10mg 膜衣錠的包裝為: 2-1000 顆塑膠瓶裝。
Arava™ 20mg 膜衣錠的包裝為: 2-1000 顆塑膠瓶裝。
Arava™ 100mg 膜衣錠的包裝為: 2-1000 顆鋁箔盒裝。

製造廠:Usiphar
廠 址:56 route de Choisy au Bac, F-60205, compiegne, France
藥 商:台灣安萬特藥品股份有限公司
地 址:台北市敦化南路一段 108 號 9 樓 AA9301
10
1. NAME OF THE MEDICINAL PRODUCT
Arava 10 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 10 mg of the active ingredient leflunomide.

For excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Leflunomide is indicated for the treatment of adult patients with active rheumatoid arthritis as a
"disease-modifying antirheumatic drug" (DMARD).

Recent or concurrent treatment with hepatotoxic or haematotoxic DMARDs (e.g. methotrexate)


may result in an increased risk of serious adverse reactions; therefore, the initiation of leflunomide
treatment has to be carefully considered regarding these benefit/risk aspects.

Moreover, switching from leflunomide to another DMARD without following the washout
procedure (see section 4.4) may also increase the risk of serious adverse reactions even for a long
time after the switching.

4.2 Posology and method of administration

ALT (SGPT) and a complete blood cell count, including a differential white blood cell count and a
platelet count, must be checked simultaneously and with the same frequency:
• Before initiation of leflunomide,
• every two weeks during the first six months of treatment, and
• every 8 weeks thereafter (see also section 4.4).

Leflunomide therapy is started with a loading dose of 100 mg once daily for 3 days. The
recommended maintenance dose is leflunomide 10 mg to 20 mg once daily (see section 5.1).

The therapeutic effect usually starts after 4 to 6 weeks and may further improve up to 4 to 6 months.

There is no dose adjustment recommended in patients with mild renal insufficiency.

No dosage adjustment is required in patients above 65 years of age.

The product should be prescribed by specialists experienced in the treatment of rheumatoid diseases.

1
Administration

Arava tablets should be swallowed whole with sufficient amounts of liquid. The extent of
leflunomide absorption is not affected if it is taken with food.

4.3 Contraindications

Arava must not be used in patients with hypersensitivity to leflunomide (especially previous
Stevens- Johnson syndrome, toxic epidermal necrolysis, erythema multiforme) or to any of the
excipients in the tablets.

Leflunomide is contraindicated in:

• patients with impairment of liver function,

• patients with severe immunodeficiency states, e.g. AIDS,

• patients with significantly impaired bone marrow function or significant anaemia, leukopenia,
neutropenia or thrombocytopenia due to causes other than rheumatoid arthritis,

• patients with serious infections,

• patients with moderate to severe renal insufficiency, because insufficient clinical experience
is available in this patient group,

• patients with severe hypoproteinaemia, e.g. in nephrotic syndrome,

• pregnant women, or women of childbearing potential who are not using reliable contraception
during treatment with leflunomide and thereafter as long as the plasma levels of the active
metabolite are above 0.02 mg/l (see also section 4.6). Pregnancy must be excluded before start
of treatment with leflunomide.

Women must not breast-feed while they are receiving leflunomide. See also section 4.6.

Male patients should be aware of the possible male-mediated foetal toxicity (see also section 4.4).
Reliable contraception during treatment with leflunomide should also be guaranteed.

Arava is not recommended for use in patients under 18 years as its safety and efficacy have not
been studied in this age group.

4.4 Special warnings and special precautions for use

Arava should be administered to patients only under careful medical supervision.

Concomitant administration of hepatotoxic or haematotoxic DMARDs (e.g. methotrexate) is not


advisable.

The active metabolite of leflunomide, A771726, has a long half-life, usually 1 to 4 weeks. Serious
undesirable effects might occur (e.g. hepatotoxicity, haematotoxicity or allergic reactions, see
below), even if the treatment with leflunomide has been stopped. Therefore, when such toxicities
occur or when switching to another DMARD (e.g. methotrexate) after treatment with leflunomide a
washout procedure should be performed (see below).

2
For washout procedures and other recommended actions in case of desired or unintended pregnancy
see section 4.6.

Liver reactions

Rare cases of severe liver injury, including cases with fatal outcome, have been reported during
treatment with leflunomide. Most of the cases occurred within the first 6 months of treatment. Co
medication with other hepatotoxic medicinal products was frequently present. It is considered
essential that monitoring recommendations are strictly adhered to.

ALT (SGPT) must be checked before initiation of leflunomide and at the same frequency as the
complete blood cell count (every two weeks) during the first six months of treatment and every
8 weeks thereafter.

For ALT (SGPT) elevations between 2- and 3-fold the upper limit of normal, dose reduction from
20 mg to 10 mg may be considered and monitoring must be performed weekly. If ALT (SGPT)
elevations of more than 2-fold the upper limit of normal persist or if ALT elevations of more than
3-fold the upper limit of normal are present, leflunomide must be discontinued and wash-out
procedures initiated. It is recommended that monitoring of liver enzymes be maintained after
discontinuation of leflunomide treatment, until liver enzyme levels have normalised.

Due to a potential for additive hepatotoxic effects, it is recommended that alcohol consumption be
avoided during treatment with leflunomide.

Since the active metabolite of leflunomide, A771726, is highly protein bound and cleared via
hepatic metabolism and biliary secretion, plasma levels of A771726 are expected to be increased in
patients with hypoproteinaemia. Arava is contraindicated in patients with severe hypoproteinaemia
or impairment of liver function (see section 4.3).
Haematological reactions

Together with ALT, a complete blood cell count, including differential white blood cell count and
platelets, must be performed before start of leflunomide treatment as well as every 2 weeks for the
first 6 months of treatment and every 8 weeks thereafter.

In patients with pre-existing anaemia, leucopoenia, and/or thrombocytopenia as well as in patients


with impaired bone marrow function or those at risk of bone marrow suppression, the risk of
haematological disorders is increased. If such effects occur, a washout (see below) to reduce plasma
levels of A771726 should be considered.

In case of severe haematological reactions, including pancytopenia, Arava and any concomitant
myelosuppressive medication must be discontinued and a leflunomide washout procedure initiated.
Combinations with other treatments

The use of leflunomide with antimalarials used in rheumatic diseases (e.g. chloroquine and
hydroxychloroquine), intramuscular or oral gold, D-penicillamine, azathioprine and other
immunosuppressive agents (with the exception of methotrexate, see section 4.5) has not been
studied up to now. The risk associated with combination therapy, in particular in long-term
treatment, is unknown. Since such therapy can lead to additive or even synergistic toxicity (e.g.
hepato- or haematotoxicity), combination with another DMARD (e.g. methotrexate) is not advisable.

3
Caution is advised when leflunomide is given together with drugs, other than NSAIDs, metabolised
by CYP2C9 such as phenytoin, warfarin and tolbutamide.

Switching to other treatments

As leflunomide has a long persistence in the body, a switching to another DMARD (e.g.
methotrexate) without performing the washout procedure (see below) may raise the possibility of
additive risks even for a long time after the switching (i.e. kinetic interaction, organ toxicity).

Similarly, recent treatment with hepatotoxic or haematotoxic drugs (e.g. methotrexate) may result in
increased side effects; therefore, the initiation of leflunomide treatment has to carefully be
considered regarding these benefit/risk aspects and closer monitoring is recommended in the initial
phase after switching.
Skin reactions

In case of ulcerative stomatitis, leflunomide administration should be discontinued.

Very rare cases of Stevens Johnson syndrome or toxic epidermal necrolysis have been reported in
patients treated with leflunomide. As soon as skin and/or mucosal reactions are observed which
raise the suspicion of such severe reactions, Arava and any other possibly associated medication
must be discontinued, and a leflunomide washout procedure initiated immediately. A complete
washout is essential in such cases. In such cases re-exposure to leflunomide is contra-indicated (see
section 4.3).

Infections

It is known that medications with immunosuppressive properties - like leflunomide - may cause
patients to be more susceptible to infections, including opportunistic infections. Infections may be
more severe in nature and may, therefore, require early and vigorous treatment. In the event that
severe, uncontrolled infections occur, it may be necessary to interrupt leflunomide treatment and
administer a washout procedure as described below.
Patients with tuberculin reactivity must be carefully monitored because of the risk of tuberculosis
reactivation.

Blood pressure

Blood pressure must be checked before the start of leflunomide treatment and periodically
thereafter.

Procreation (recommendations for men)

There are no specific data on the risk of male-mediated foetal toxicity. However, animal studies to
evaluate this specific risk have not been conducted. To minimise any possible risk, men wishing to
father a child should consider discontinuing use of leflunomide and taking cholestyramine 8 g
3 times daily for 11 days or 50 g of activated powdered charcoal 4 times daily for 11 days.

In either case the A771726 plasma concentration is then measured for the first time. Thereafter, the
A771726 plasma concentration must be determined again after an interval of at least 14 days. If
both plasma concentrations are below 0.02 mg/l, and after a waiting period of at least 3 months, the
risk of foetal toxicity is very low.

4
Washout procedure

Cholestyramine 8 g is administered 3 times daily. Alternatively, 50 g of activated powdered


charcoal is administered 4 times daily. Duration of a complete washout is usually 11 days. The
duration may be modified depending on clinical or laboratory variables.

4.5 Interaction with other medicinal products and other forms of interaction

Increased side effects may occur in case of recent or concomitant use of hepatotoxic or
haematotoxic drugs or when leflunomide treatment is followed by such drugs without a washout
period (see also guidance concerning combination with other treatments, section 4.4). Therefore,
closer monitoring of liver and haematological parameters is recommended in the initial phase after
switching.

In a small (n=30) study with co-administration of leflunomide (10 to 20 mg per day) with
methotrexate (10 to 25 mg per week) a 2- to 3-fold elevation in liver enzymes was seen on 5 of
30 patients. All elevations resolved, 2 with continuation of both drugs and 3 after discontinuation of
leflunomide. A more than 3-fold increase was seen in another 5 patients. All of these also resolved,
2 with continuation of both drugs and 3 after discontinuation of leflunomide.

In patients with rheumatoid arthritis, no pharmacokinetic interaction between the leflunomide (10 to
20 mg per day) and methotrexate (10 to 25 mg per week) was demonstrated.

It is recommended that patients receiving leflunomide are not treated with cholestyramine or
activated powdered charcoal because this leads to a rapid and significant decrease in plasma
A771726 (the active metabolite of leflunomide; see also section 5) concentration. The mechanism is
thought to be by interruption of enterohepatic recycling and/or gastrointestinal dialysis of A771726.

If the patient is already receiving nonsteroidal anti-inflammatory drugs (NSAIDs) and/or


corticosteroids, these may be continued after starting leflunomide.

The enzymes involved in the metabolism of leflunomide and its metabolites are not exactly known.
An in vivo interaction study with cimetidine (non-specific cytochrome P450 inhibitor) has
demonstrated a lack of a significant interaction. Following concomitant administration of a single
dose of leflunomide to subjects receiving multiple doses of rifampicin (non-specific cytochrome
P450 inducer) A771726 peak levels were increased by approximately 40%, whereas the AUC was
not significantly changed. The mechanism of this effect is unclear.

In vitro studies indicate that A771726 inhibits cytochrome P4502C9 (CYP2C9) activity. In clinical
trials no safety problems were observed when leflunomide and NSAIDs metabolised by CYP2C9
were co-administered. Caution is advised when leflunomide is given together with drugs, other than
NSAIDs, metabolised by CYP2C9 such as phenytoin, warfarin and tolbutamide.

In a study in which leflunomide was given concomitantly with a triphasic oral contraceptive pill
containing 30 µg ethinyloestradiol to healthy female volunteers, there was no reduction in
contraceptive activity of the pill, and A771726 pharmacokinetics were within predicted ranges.

Vaccinations

No clinical data are available on the efficacy and safety of vaccinations under leflunomide treatment.
Vaccination with live attenuated vaccines is, however, not recommended. The long half-life of
leflunomide should be considered when contemplating administration of a live attenuated vaccine
after stopping Arava.
5
4.6 Pregnancy and lactation

Pregnancy

The active metabolite of leflunomide, A771726, is teratogenic in rats and rabbits and it may cause
foetal harm in humans.

Leflunomide must not be given to pregnant women, or women of childbearing potential who are not
using reliable contraception during treatment with leflunomide and for a certain period of time
thereafter (waiting period or abbreviated washout period; see below). Pregnancy must be excluded
before start of treatment with leflunomide.

The patient must be advised that if there is any delay in onset of menses or any other reason to
suspect pregnancy, they must notify the physician immediately for pregnancy testing, and if
positive, the physician and patient must discuss the risk to the pregnancy. It is possible that rapidly
lowering the blood level of the active metabolite, by instituting the drug elimination procedure
described below, at the first delay of menses may decrease the risk to the foetus from leflunomide.

For women receiving leflunomide treatment and who wish to become pregnant, one of the
following procedures is recommended in order to ascertain that the foetus is not exposed to toxic
concentrations of A771726 (target concentration below 0.02 mg/l):

Waiting period:

A771726 plasma levels can be expected to be above 0.02 mg/l for a prolonged period. The
concentration may be expected to decrease below 0.02 mg/l about 2 years after stopping the
treatment with leflunomide.

After a 2-year waiting period, the A771726 plasma concentration is measured for the first time.
Thereafter, the A771726 plasma concentration must be determined again after an interval of at least
14 days. If both plasma concentrations are below 0.02 mg/l no teratogenic risk is to be expected.

For further information on the sample testing please contact the Marketing Authorisation Holder or
its local representative (see section 7).

Washout procedure:

After stopping treatment with leflunomide:

• cholestyramine 8 g is administered 3 times daily for a period of 11 days.

• alternatively, 50 g of activated powdered charcoal is administered 4 times daily for a period of


11 days.

However, also following either of the washout procedures, verification by 2 separate tests at an
interval of at least 14 days and a waiting period of one-and-a-half months between the first
occurrence of a plasma concentration below 0.02 mg/l and fertilisation is required.

Women of childbearing potential should be told that a waiting period of 2 years after treatment
discontinuation is required before they may become pregnant. If a waiting period of up to
approximately 2 years under reliable contraception is considered unpractical, prophylactic
institution of a washout procedure may be advisable.

6
Both cholestyramine and activated powdered charcoal may influence the absorption of oestrogens
and progestogens such that reliable contraception with oral contraceptives may not be guaranteed
during the washout procedure with cholestyramine or activated powdered charcoal. Use of
alternative contraceptive methods is recommended.

Lactation

Animal studies indicate that leflunomide or its metabolites pass into breast milk. Breast-feeding
women must, therefore, not receive leflunomide.

4.7 Effects on ability to drive and use machines

In the case of side effects such as dizziness the patient's ability to concentrate and to react properly
may be impaired. In such cases patients should refrain from driving cars and using machines.

4.8 Undesirable effects

Classification of expected frequencies:

Common = 1 - 10 % of patients; uncommon = 0.1 - 1 % of patients; rare = 0.01 - 0.1 % of patients;


very rare = 0.01 % of patients or less.
Cardiac disorders

Common: mild increase in blood pressure

Rare: severe increase in blood pressure

Gastrointestinal disorders

Common: diarrhoea, nausea, vomiting, anorexia, oral mucosal disorders (e.g., aphthous stomatitis,
mouth ulceration), abdominal pain,

Hepato-biliary disorders

Common: elevation of liver parameters (transaminases [especially ALT], less often gamma-GT,
alkaline phosphatase, bilirubin)

Rare: hepatitis, jaundice/cholestasis and very rarely, severe liver injury such as hepatic
failure and acute hepatic necrosis that may be fatal

Very rare: pancreatitis.

Infections and infestations

Very rare: severe infections, including sepsis which may be fatal.

Like other agents with immunosuppressive potential, leflunomide may increase susceptibility to
infections, including opportunistic infections (see also section 4.4). Thus, the overall incidence of
infections can increase (in particular of rhinitis, bronchitis and pneumonia).

Metabolism and nutrition disorders

Common: weight loss (usually insignificant)


Uncommon: hypokalaemia

7
Nervous system disorders

Common: headache, dizziness, asthenia, paraesthesia

Uncommon: taste disturbances, anxiety

Very rare: peripheral neuropathy

Musculoskeletal and connective tissue disorders

Common: tenosynovitis

Uncommon: tendon rupture

Skin and subcutaneous tissue disorders

Common: increased hair loss, eczema, dry skin

Uncommon: urticaria

Very rare: Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme

Immune system disorders

Common: mild allergic reactions, rash (including maculopapular rash), pruritus

Very rare: severe anaphylactic/anaphylactoid reactions

Respiratory, thoracic and mediastinal disorders

Very rare: interstitial lung disease.

Blood and lymphatic system disorders

Common: leukopenia (leukocytes >2 G/l)

Uncommon: anaemia, mild thrombocytopenia (platelets <100 G/l)

Rare: eosinophilia, leukopenia (leukocytes <2 G/l), pancytopenia (probably by antiproliferative


mechanism)

Very rare: agranulocytosis, vasculitis

Recent, concomitant or consecutive use of potentially myelotoxic agents may be associated with a higher
risk of haematological effects.

The risk of malignancy, particularly lymphoproliferative disorders, is increased with use of some
immunosuppressive agents.

Mild hyperlipidaemia may occur. Uric acid levels usually decrease.


Laboratory findings for which a clinical relevance could not be established include small increases
in LDH and CK. Mild hypophosphataemia is uncommon.
Marginal (reversible) decreases in sperm concentration, total sperm count and rapid progressive motility
cannot be excluded.

8
The active metabolite of leflunomide, A771726, has a long half-life, usually 1 to 4 weeks. If a severe
undesirable effect of leflunomide occurs, or if for any other reason A771726 needs to be cleared rapidly from
the body, the washout procedure described in section 4.4 has to be followed. The procedure may be repeated
as clinically necessary. For suspected severe immunological/allergic reactions such as Stevens-Johnson
syndrome or toxic epidermal necrolysis, a complete washout is essential.

4.9 Overdose

Symptoms

There have been reports of chronic overdose in patients taking Arava at daily doses up to five times
the recommended daily dose, and reports of acute overdose in adults and children. There were no
adverse events reported in the majority of case reports of overdose. Adverse events consistent with
the safety profile for leflunomide were: abdominal pain, nausea, diarrhoea, elevated liver enzymes,
anaemia, leucopenia, pruritus and rash.

Management

In the event of an overdose or toxicity, cholestyramine or charcoal is recommended to accelerate elimination.


Cholestyramine given orally at a dose of 8 g three times a day for 24 hours to three healthy volunteers
decreased plasma levels of A771726 by approximately 40% in 24 hours and by 49% to 65% in 48 hours.
Administration of activated charcoal (powder made into a suspension) orally or via nasogastric tube
(50 g every 6 hours for 24 hours) has been shown to reduce plasma concentrations of the active
metabolite A771726 by 37% in 24 hours and by 48% in 48 hours.
These washout procedures may be repeated if clinically necessary.

Studies with both hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that A771726,
the primary metabolite of leflunomide, is not dialysable.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: selective immunosuppressive agents, ATC code: L04AA13.

Human pharmacology

Leflunomide is a disease-modifying anti-rheumatic agent with antiproliferative properties.

Animal pharmacology

Leflunomide is effective in animal models of arthritis and of other autoimmune diseases and
transplantation, mainly if administered during the sensitisation phase. It has immunomodulating/
immunosuppressive characteristics, acts as an antiproliferative agent, and displays anti-
inflammatory properties. Leflunomide exhibits the best protective effects on animal models of
autoimmune diseases when administered in the early phase of the disease progression.
In vivo, it is rapidly and almost completely metabolised to A771726 which is active in vitro, and is
presumed to be responsible for the therapeutic effect.

Mode of action

A771726, the active metabolite of leflunomide, inhibits the human enzyme dihydroorotate
dehydrogenase (DHODH) and exhibits antiproliferative activity.

9
Clinical Studies

The efficacy of Arava in the treatment of rheumatoid arthritis was demonstrated in 4 controlled trials (1 in
phase II and 3 in phase III). The phase II trial, study YU203, randomised 402 subjects with active
rheumatoid arthritis to placebo (n=102), leflunomide 5 mg (n=95), 10 mg (n=101) or 25 mg/day (n=104).
The treatment duration was 6 months.
All leflunomide patients in the phase III trials used an initial dose of 100 mg for 3 days.
Study MN301 randomised 358 subjects with active rheumatoid arthritis to leflunomide 20 mg/day (n=133),
sulphasalazine 2 g/day (n=133), or placebo (n=92). Treatment duration was 6 months. Study MN303 was an
optional 6-month blinded continuation of MN301 without the placebo arm, resulting in a 12-month
comparison of leflunomide and sulphasalazine.
Study MN302 randomised 999 subjects with active rheumatoid arthritis to leflunomide 20 mg/day (n=501)
or methotrexate at 7.5 mg/week increasing to 15 mg/week (n=498). Folate supplementation was optional and
only used in 10% of patients. Treatment duration was 12-months.
Study US301 randomised 482 subjects with active rheumatoid arthritis to leflunomide 20 mg/day (n=182),
methotrexate 7.5 mg/week increasing to 15 mg/week (n=182), or placebo (n=118). All patients received
folate 1 mg bid. Treatment duration was 12 months.

Clinical Trial Results

Leflunomide at a daily dose of at least 10 mg (10 to 25 mg in study YU203, 20 mg in studies MN301 and
US301) was statistically significantly superior to placebo in reducing the signs and symptoms of rheumatoid
arthritis in all 3 placebo-controlled trials. The ACR (American College of Rheumatology) response rates in
study YU203 were 27.7% for placebo, 31.9% for 5 mg, 50.5% for 10 mg and 54.5% for 25 mg/day. In the
phase III trials, the ACR response rates for leflunomide 20 mg/day vs. placebo were 54.6% vs. 28.6% (study
MN301), and 49.4% vs. 26.3% (study US301).After 12 months with active treatment, the ACR response
rates in leflunomide patients were 52.3% (studies MN301/303), 50.5% (study MN302) and 49.4% (study
US301), compared to 53.8% (studies MN301/303) in sulphasalazine patients, 64.8% (study MN302), and
43.9% (study US301) in methotrexate patients.
In study MN302 leflunomide was significantly less effective than methotrexate. However, in study US301
no significant differences were observed between leflunomide and methotrexate in the primary efficacy
parameters. No difference was observed between leflunomide and sulphasalazine (study MN301). The
leflunomide treatment effect was evident by 1 month, stabilised by 3 to 6 months and continued throughout
the course of treatment.

5.2 Pharmacokinetic properties

Leflunomide is rapidly converted to the active metabolite, A771726, by first-pass metabolism (ring
opening) in gut wall and liver. In a study with radiolabelled 14C-leflunomide in three healthy
volunteers, no unchanged leflunomide was detected in plasma, urine or faeces. In other studies,
unchanged leflunomide levels in plasma have rarely been detected, however, at ng/ml plasma levels.
The only plasma-radiolabelled metabolite detected was A771726. This metabolite is responsible for
essentially all the in-vivo activity of Arava.

Absorption

Excretion data from the 14C study indicated that at least about 82 to 95% of the dose is absorbed.
The time to peak plasma concentrations of A771726 is very variable; peak plasma levels can occur
between 1 hour and 24 hours after single administration. Leflunomide can be administered with
food, since the extent of absorption is comparable in the fed and fasting state. Due to the very long
half-life of A771726 (approximately 2 weeks), a loading dose of 100 mg for 3 days was used in
clinical studies to facilitate the rapid attainment of steady-state levels of A771726. Without a
loading dose, it is estimated that attainment of steady-state plasma concentrations would require
nearly two months of dosing. In multiple dose studies in patients with rheumatoid arthritis, the

10
pharmacokinetic parameters of A771726 were linear over the dose range of 5 to 25 mg. In these
studies, the clinical effect was closely related to the plasma concentration of A771726 and to the
daily dose of leflunomide. At a dose level of 20 mg/day, average plasma concentration of A771726
at steady state is approximately 35 µg/ml. At steady state plasma levels accumulate about 33- to
35-fold compared with single dose.

Distribution

In human plasma, A771726 is extensively bound to protein (albumin). The unbound fraction of
A771726 is about 0.62%. Binding of A771726 is linear in the therapeutic concentration range.
Binding of A771726 appeared slightly reduced and more variable in plasma from patients with
rheumatoid arthritis or chronic renal insufficiency. The extensive protein binding of A771726 could
lead to displacement of other highly-bound drugs. In vitro plasma protein binding interaction
studies with warfarin at clinically relevant concentrations, however, showed no interaction. Similar
studies showed that ibuprofen and diclofenac did not displace A771726, whereas the unbound
fraction of A771726 is increased 2- to 3-fold in the presence of tolbutamide. A771726 displaced
ibuprofen, diclofenac and tolbutamide but the unbound fraction of these drugs is only increased by
10% to 50%. There is no indication that these effects are of clinical relevance. Consistent with
extensive protein binding A771726 has a low apparent volume of distribution (approximately
11 litres). There is no preferential uptake in erythrocytes.

Metabolism

Leflunomide is metabolised to one primary (A771726) and many minor metabolites including
TFMA (4-trifluoromethylaniline). The metabolic biotransformation of leflunomide to A771726 and
subsequent metabolism of A771726 is not controlled by a single enzyme and has been shown to
occur in microsomal and cytosolic cellular fractions. Interaction studies with cimetidine (non-
specific cytochrome P450 inhibitor) and rifampicin (non-specific cytochrome P450 inducer),
indicate that in vivo CYP enzymes are involved in the metabolism of leflunomide only to a small
extent.

Elimination

Elimination of A771726 is slow and characterised by an apparent clearance of about 31 ml/hr. The
elimination half-life in patients is approximately 2 weeks. After administration of a radiolabelled
dose of leflunomide, radioactivity was equally excreted in faeces, probably by biliary elimination,
and in urine. A771726 was still detectable in urine and faeces 36 days after a single administration.
The principal urinary metabolites were glucuronide products derived from leflunomide (mainly in 0
to 24 hour samples) and an oxanilic acid derivative of A771726. The principal faecal component
was A771726.

It has been shown in man that administration of an oral suspension of activated powdered charcoal or
cholestyramine leads to a rapid and significant increase in A771726 elimination rate and decline in plasma
concentrations (see section 4.9). This is thought to be achieved by a gastrointestinal dialysis mechanism
and/or by interrupting enterohepatic recycling.

Pharmacokinetics in renal failure

Leflunomide was administered as a single oral 100 mg dose to 3 haemodialysis patients and 3 patients on
continuous peritoneal dialysis (CAPD). The pharmacokinetics of A771726 in CAPD subjects appeared to be
similar to healthy volunteers. A more rapid elimination of A771726 was observed in haemodialysis subjects
which was not due to extraction of drug in the dialysate.

11
Pharmacokinetics in liver failure

No data are available regarding treatment of patients with hepatic impairment. The active
metabolite A771726 is extensively protein bound and cleared via hepatic metabolism and biliary
secretion. These processes may be affected by hepatic dysfunction.

Influence of age

Pharmacokinetics in subjects under 18 years have not been studied. Pharmacokinetic data in elderly
(>65 years) are limited but consistent with pharmacokinetics in younger adults.

5.3 Preclinical safety data

Leflunomide, administered orally and intraperitoneally, has been studied in acute toxicity studies in
mice and rats. Repeated oral administration of leflunomide to mice for up to 3 months, to rats and
dogs for up to 6 months and to monkeys for up to 1 month's duration revealed that the major target
organs for toxicity were bone marrow, blood, gastrointestinal tract, skin, spleen, thymus and lymph
nodes. The main effects were anaemia, leukopenia, decreased platelet counts and panmyelopathy
and reflect the basic mode of action of the compound (inhibition of DNA synthesis). In rats and
dogs, Heinz bodies and/or Howell-Jolly bodies were found. Other effects found on heart, liver,
cornea and respiratory tract could be explained as infections due to immunosuppression. Toxicity in
animals was found at doses equivalent to human therapeutic doses.

Leflunomide was not mutagenic. However, the minor metabolite TFMA (4-trifluoromethylaniline)
caused clastogenicity and point mutations in vitro, whilst insufficient information was available on
its potential to exert this effect in vivo.

In a carcinogenicity study in rats, leflunomide did not show carcinogenic potential. In a


carcinogenicity study in mice an increased incidence of malignant lymphoma occurred in males of
the highest dose group, considered to be due to the immunosuppressive activity of leflunomide. In
female mice an increased incidence, dose-dependent, of bronchiolo-alveolar adenomas and
carcinomas of the lung was noted. The relevance of the findings in mice relative to the clinical use
of leflunomide is uncertain.

Leflunomide was not antigenic in animal models.


Leflunomide was embryotoxic and teratogenic in rats and rabbits at doses in the human therapeutic
range and exerted adverse effects on male reproductive organs in repeated dose toxicity studies.
Fertility was not reduced.

12
6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core: Maize starch, povidone, crospovidone, silica colloidal anhydrous, magnesium stearate,
lactose monohydrate.

Film-Coating: Talc, hypromellose, titanium dioxide, macrogol 8000.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Blister: Store in the original package.

Bottle: Keep the container tightly closed.

6.5 Nature and contents of container

Blister: Aluminium / Aluminium blister. Pack sizes: 30 and 100 tablets.

Bottle: HDPE-wide-necked bottle, 100 ml with screw cap with integrated desiccant container.
Pack sizes: 30 and 100 tablets.

6.6 Instructions for use and handling

No special requirements.

7. MARKETING AUTHORISATION HOLDER

Aventis Pharma Deutschland GmbH, D-65926 Frankfurt am Main, Germany

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/99/118/001-004

9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION

02.09.1999

10. DATE OF REVISION OF THE TEXT

13