立妥威 TM 膠囊 100 毫克

RETROVIR TM Capsules 100 mg 衛署藥輸字第 016120 號

立妥威 TM 膠囊 250 毫克

RETROVIR TM Capsules 250 mg 衛署藥輸字第 021443 號

立妥威 TM 溶液劑

RETROVIR TM Syrup 衛署藥輸字第 022014 號

定性與定量組成

膠囊含 100 毫克或 250 毫克 - 為一有白色不透明膠囊帽，和中央有一深藍色條紋膠囊體之硬膠囊劑，其上印有 "Wellcome"，"100" 和 "Y9C" 字樣。 - 為一有白色不透明膠囊帽，和中央有一深藍色條紋膠囊體之硬膠囊劑，其上印有 "Wellcome"，"250" 和 "H2F" 字樣。 立妥威溶液劑 清澈，微黃色，草莓香味，不含糖的內服液劑，每 5 ml 含 zidovudine 50 mg。包裝內附 有一支 10 ml 口服劑量唧筒，使用前應將其安裝在藥瓶上，並用所附之瓶蓋蓋緊。

劑型

硬膠囊劑 口服溶液劑

臨床特性

【適應症】 後天性免疫缺乏症候群(AIDS)或與其有關之症狀(ARC, AIDS related complex)；受到人類 3 免疫缺乏病毒(HIV)感染沒有症狀或只有初期輕度症狀而 CD4T 淋巴球數目小於 500/mm 病人的治療。 【說明】 RETROVIR 口服製劑適用於治療遭受人體免疫缺乏病毒(HIV)感染，卻沒有症狀，或具有 早期 HIV 相關症狀的患者。 RETROVIR 口服製劑亦適用於治療惡化 HIV 疾病患者，諸如患有後天性免疫缺乏症候群 (AIDS)或與 AIDS 相關的症狀(ARC)。 RETROVIR 口服製劑適用於治療遭受人體免疫缺乏病毒(HIV)感染，具有 HIV 相關症狀； 或無症狀，但標記卻顯示有顯著 HIV 相關免疫抑制現象的兒童。 以現有的資料為基礎，來評估用藥的利弊顯示，早期治療是有必要的。 惡化 HIV 感染的合併療法 治療惡化 HIV 感染(CD4+細胞數目< 300/mm3)時，可考慮併用 HIVID。RETROVIR 單一 療法仍適合作為符合核准適應症的 HIV 感染成人患者的起始治療。 【劑量與用法】 本藥須由醫師處方使用 宜由治療 HIV 感染有經驗的醫師，進行 RETROVIR 治療。  成人 雖然曾被使用的劑量範圍很寬廣，但一般使用劑量為一天 500 或 600 mg，分 3-5 次服用。 此外，一天 1000 mg，分 2 (或 4)次服用也有效。低劑量用於治療或預防與 HIV 相關的神 經官能異常及惡性病之有效性仍未知。  惡化 HIV 感染之合併療法劑量 每隔 8 小時同時服用 RETROVIR 200 mg 以及 HIVID 0.75 mg (RETROVIR 的每日總劑量為 600 mg，HIVID 的每日總劑量為 2.25 mg)。  兒童 三個月以上兒童的建議起始劑量為每隔 6 小時服用 180 mg/m2 體表面積(每日 720 mg/m2)。最大劑量不可超過每 6 小時 200 mg。 最適當的劑量仍待確定，且因人而異。劑量範圍一般為每 6 小時給予 120-180 mg/m2 體表 面積(即每日 480-720 mg/m2)。低劑量用於治療或預防與 HIV 相關的神經官能異常及惡性 病之有效性仍未知。對兒童而言，少次給藥的有效性仍待確立。  發生血液不良反應患者之劑量調整 發生血液不良反應患者可能需要調整劑量。在治療前已有骨髓儲存不良的患者，尤其是 有惡化 HIV 疾病的患者較容易出現血液不良反應。如果血紅素值降至 7.5-9 g/dl (4.65-5.59 mmol/l)，或嗜中性白血球數降至 0.75-1.0 x 109/l 時，也許應減低每日劑量，直到骨髓復 原。另外，暫停 RETROVIR 療法(約 2-4 週)可加速復原。如果考慮減低劑量，舉例而言， 可先將每日劑量減半，再視患者的耐受性逐漸增加劑量，直到回復原來的劑量。如果血 紅素值降至 7.5 g/dl (4.65 mmol/l)以下，或嗜中性白血球數降至 0.75 x 109/l 以下，則必須 中斷 RETROVIR 療法。中斷 RETROVIR 療法後的兩週內，骨髓通常便可復原，此後可重 新開始低劑量的 RETROVIR。再過 2-4 週，可依患者的耐受性逐漸增加劑量，直到回復原 來的劑量。  接受 RETROVIR 及 HIVID 合併療法者之劑量調整 對於接受 RETROVIR 及 HIVID 合併療法的患者而言，各種藥物的劑量調整均需遵循該藥 的準則。發生嚴重副作用時，如果不知道是哪種藥物引起的，或是暫停其中一種藥物或 減量後，副作用依然持續，則另一種藥物也必須暫停使用或減量。醫師應參閱完整的 HIVID 產品資訊，以了解與 HIVID 相關的副作用。  老年人 目前沒有明確的資料。然而，由於老化會導致生理功能改變，如腎功能減退以及血液學 參數的改變，故建議對此年齡層應特別小心。  腎功能不全患者 嚴重腎衰竭患者的 zidovudine 最高血中濃度比健康人高 50%。 全身暴露(以 zidovudine 濃度時間曲線下面積來衡量)增加 100%，其半衰期並沒有明顯變化。腎衰竭患者有明顯 的主要尿甘酸化物代謝物蓄積現象，但並不會引起毒性。有嚴重腎衰竭的患者應服用低 劑量的 RETROVIR。血液學參數及臨床反應可能會影響之後的劑量調整。血液透析及腹 膜透析對於 zidovudine 的排除沒有顯著影響；卻會促進尿甘酸化物代謝物的排除。  肝功能不全患者 少數有關肝硬化患者的資料顯示，肝功能不全的患者會發生 zidovudine 的蓄積，因為其 尿甘酸化作用減少。可能需要調整劑量，但是目前還沒有明確的推薦劑量。如果無法監 測 zidovudine 的血中濃度，則醫師必須特別注意無耐受性的跡象，並適時增加用藥的間 隔期間。 【禁忌症】 RETROVIR 口服製劑禁用於已知對 zidovudine 或配方中任何成分過敏之患者。 RETROVIR 口服製劑不可用於嗜中性白血球數極低(少於 0.75 x 109/l)或血紅素值極低(少 於 7.5 g/dl 或 4.65 mmol/l)的患者(見警語及注意事項)。 【警語及注意事項】 應警告患者不要隨意自行併用藥物(見藥物交互作用)。 應勸告患者，zidovudine 療法並無法減低經由性接觸或血液污染傳染 HIV 的危險性。適 當之警示應持續。 RETROVIR 無法治癒 HIV 感染，患者仍有產生與免疫抑制相關疾病的危險，包括伺機性 感染與腫瘤。雖然已經證實它可以減少伺機性感染的危險性，但關於包括淋巴瘤在內的 腫瘤產生數據依然很少。目前的數據顯示，接受治療的惡化 HIV 疾患者發生淋巴瘤的危 險性與未接受治療的患者一致。至於接受長期治療的早期 HIV 疾患者發生淋巴瘤的危險 性則仍未知。 對於在懷孕期間內，考慮以 RETROVIR 預防將 HIV 傳染給嬰兒的孕婦，應告知即使接 受治療，但在某些案例中，仍可能發生傳染。 血液不良反應︰貧血(通常發生於 zidovudine 治療的六週後，但有時會提早發生)，嗜中 性白血球減少症(通常發生於 zidovudine 治療的四週後，但有時會提早發生)，及白血球 減少症(通常續發於嗜中性白血球減少症)通常被認為經常發生於惡化的 HIV 疾病患者接 受 RETROVIR 後。這些較常發生於較高的劑量(1200 至 1500 毫克/天)，以及進行治療前， 骨髓功能較差的病患，尤其是末期 HIV 疾病的患者。 必須小心監測血液學參數。用於惡化的 HIV 疾病患者時，建議在治療後的三個月內，至 少每兩週做一次血液檢驗，其後至少每個月一次。初期的 HIV 患者(其骨髓儲存通常良 好)，血液不良反應較少見。視患者的整體情況而定，血液檢驗可以不必做的那麼頻繁， 例如每 1-3 個月檢查一次即可。 如果血紅素值降至 7.5 g/dl (4.65 mmol/l)到 9 g/dl (5.59 mmol/l)，或嗜中性白血球數降至 0.75 x 109/l 到 1.0 x 109/l，應減少每日劑量至骨髓復原。短暫中斷 RETROVIR 療法(2-4 週)可能增加骨髓復原速度。減少 RETROVIR 療法後的兩週，骨髓通常便可復原。有顯 著貧血的患者，除了調整劑量之外，可能還需要輸血(見禁忌症)。 乳酸性酸中毒及具脂肪變性的嚴重肝腫大：單獨或合併使用抗反轉錄病毒核苷類似物， 包括 zidovudine，均曾出現有乳酸中毒與嚴重肝腫大合併脂肪變性，包括致命案例。這 些案例以女性為主。 可能代表出現乳酸中毒的臨床特徵包括全身性的虛弱、厭食與突發且無法解釋的失重、 腸胃道症狀與呼吸道症狀(呼吸困難與呼吸急促)。 RETROVIR 用於病患及特別是有肝臟疾病之高危險群，應謹慎。在臨床或實驗室判定疑 似乳酸中毒或肝毒素之患者中(可能包括肝腫大及脂肪變性，即使未出現明顯的轉氨酶濃 度上升)，應暫停 RETROVIR 治療。 脂肪分佈改變：在單獨使用或同時接受抗反轉錄病毒藥物複方製劑的患者中，曾觀察到 體脂肪的重新分佈/累積，包括中央型肥胖症、背頸部脂肪變大(水牛背)、周邊消瘦、臉 部消瘦與胸部變大、血脂濃度與血糖濃度上升(見不良反應)。 雖然所有使用 PI 或 NRTI 類藥物製劑的患者，都曾被指出與一種或多種此類特殊的不良 反應有關，但常被提到的全身性症狀通常包括脂肪分佈異常(位)，且資料指出使用不同治 療種類的患者，具有不同的風險程度。 此外，脂肪分佈異常(位)症候群具有多面向的病原學；例如 HIV 疾病狀況、老年以及接 受抗反轉錄病毒治療的時間，均扮演重要且可能具協同作用的角色。 目前尚不瞭解這些不良反應的長期結果為何。 臨床檢查應包括脂肪分佈改變之生理病症的評估。應考慮量測血脂質與血糖濃度。應在 臨床許可的情況下，適當處置脂質疾病。 免疫重建症候群：在開始接受抗反轉錄病毒藥物治療(ART)時患有嚴重免疫缺乏的 HIV 感染病患中，可能會增加無症狀發炎反應或殘餘伺機性感染的風險，並造成嚴重的臨床 病症或使症狀加劇。一般來說，會在開始 ART 治療的前幾週或前幾個月內觀察到這些反 應。相關的範例為巨細胞病毒視網膜炎、全身性和/或局部性的分枝桿菌感染，以及肺囊 蟲(卡氏肺囊蟲)肺炎。任何發炎症狀均必須立即接受評估而請勿延宕，並視需要進行治療。 合併感染C型肝炎病毒的病患：使用zidovudine作為HIV治療方法之一時，曾有貧血加劇 的報告，雖然確實的機制仍有待闡明。因此，並不建議同時給予ribavirin與zidovudine， 且如果已經給予此處方，應考慮ART合併療法中取代zidovudine。這對於已知會因為 zidovudine而誘發貧血的患者而言，尤為重要。 【藥物交互作用】 Zidovudine 主要係經由肝結合作用代謝為不具活性的葡萄糖醛酸化代謝物來排除。主要 由肝臟代謝排泄至體外的活性物質，尤其是經由葡萄糖醛酸化作用，可能會抑制 zidovudine 的新陳代謝。以下所列的交互作用雖然無法闡述詳盡，但已將需注意的藥物 類別列舉出來。 Atovaquone：Zidovudine 似乎不會影響 atovaquone 的藥物動力學。不過，藥物動力學資 料已證實 atovaquone 似乎會降低 zidovudine 代謝為葡萄醛代謝物的速率(zidovudine 穩 定狀態的曲線下面積增加 33%，葡萄醛代謝物血漿濃度峰值下降 19%)。在 500 或 600 毫克/天的 zidovudine 劑量下，同時使用 atovaquone 三週治療急性 PCP 時，似乎不會增 加血中 zidovudine 濃度偏高所導致的不良反應發生率。應小心監控長期接受 atovaquone 治療的病患。 Clarithromycin：Clarithromycin 錠劑會降低 zidovudine 的吸收。避免此反應的方法為服 用 zidovudine 與 clarithromycin 間至少間隔兩小時。 ：搭配 lamivudine 服用 zidovudine 時，可觀察到血中最高濃度的微量增加 (28%)，不過整體暴露量(AUC)並無顯著變化。Zidovudine 並不會影響 lamivudine 的藥 物動力學。 Phenytoin：報導指出，某些服用 zidovudine 患者的 phenytoin 血中濃度較低，而有一患 者的濃度卻升高。這些觀察建議，當患者同時服用這兩種藥物時，必須小心監測 phenytoin 的血中濃度。 Probenecid：少數資料暗示，probenecid 藉著減少尿甘酸化作用，而增加 zidovudine 的 血中濃度-時間曲線下面積。由於 probenecid 的存在，尿甘酸化物的腎排泄減少，或許 zidovudine 本身亦然。 ：有限的資料指出，同時給予 zidovudine 與 Rifampicin 可降低 zidovudine 的 AUC 達 48% ± 34%。不過，尚不瞭解臨床上的意義。 ：同時使用這兩種藥物製劑時，zidovudine 可能會抑制 stavudine 的胞內磷酸化 作用。因此並不建議 RETROVIR 與 stavudine 同時使用。 其他：其他活性物質包括但不侷限於：阿斯匹靈、可待因、嗎啡、methadone、 indomethacin、ketoprofen、naproxen、oxazepam、lorazepam、cimetidine、clofibrate、 dapsone、isoprinosine，可能會競爭性地抑制葡萄糖醛酸化或直接抑制肝微粒體的代謝作 用而導致 zidovudine 代謝改變。在使用這些藥物製劑前，應小心考量這些交互作用的可 能性，尤其是與 RETROVIR 併用於慢性療法中。 RETROVIR 和具腎毒性或骨髓抑制藥物一起使用時(例如全身性給予 pentamidine， dapsone，pyrimethamine，co-trimoxazole，amphotericin，flucytosine，， ，vincristine，vinblastine 及 doxorubicin)也會增加不良反應的危險。若需要和 這些藥物的任一種同時使用時，必須特別小心監測腎功能和血液學參數，必要時，應減 低其中一種或更多種藥物的劑量。 由於某些患者接受 RETROVIR 後，仍會繼續遭遇伺機感染，可能必須考慮併用預防性抗 微生物劑療法。這類預防性藥物包括 co-trimoxazole，pentamidine 噴霧劑，pyrimethamine 及 acyclovir。有限的臨床詴驗資料未指出 RETROVIR 與這些藥物併用會明顯增加不良反 應的危險。 【懷孕與授乳】 生育力︰目前尚無資料證實 RETROVIR 是否會影響婦女的生育力。Zidovudine 證實不會 影響男性精子的數目、形態或活動力。 懷孕︰Zidovudine 在人體中已被證實會穿越胎盤(請見藥物動力學).由於在懷孕期間使用 RETROVIR 的資料有限，僅有在該藥物對母親的潛在效益大過於對胚胎的風險時，才得 考慮在懷孕期第 14 週前使用 RETROVIR(請見臨床前安全性資料)。 在胎兒期或週產期暴露至核苷酸反轉錄酶抑制劑(NRTI)的新生兒與嬰兒，曾有暫時性血 中乳酸鹽濃度輕微上升的報告，且可能是導因於粒線體功能障礙。尚不瞭解血中乳酸鹽 濃度暫時性上升的臨床相關性。也有非常罕見關於發展遲緩、癲癇及其他神經學疾病的 報告。不過，尚未建立這些不良反應與胎兒或週產期之 NRTI 暴露量間的因果關係。這 些發現並不會影響目前對於孕婦使用抗反轉錄病毒藥物治療防止 HIV 垂直傳染的建議。 母體－胎兒傳染：在 ACTG 076 中，於妊娠超過 14 週之孕婦中使用 RETROVIR，之後 並提供新生嬰兒治療，已證實可明顯降低母體－胎兒間的 HIV 傳染(安慰劑組的感染率 為 23%，相較於 RETROVIR 的 8%)。在此研究報告中，在妊娠第 14 週與第 34 週間， 開始給予口服 RETROVIR 治療，並持續使用至陣痛開始為止。在陣痛與分娩期間內，改 以靜脈注射方式給予 RETROVIR。新生嬰兒口服 RETROVIR 直到 6 週大為止。無法口 服藥物的嬰兒，改以靜脈注射配方進行投藥。 在 1998 年泰國的 CDC 研究中，從妊娠 36 週至分娩期間，僅使用口服 RETROVIR 治療， 可明顯降低 HIV 的母體－胎兒傳染率(安慰劑組的感染率為 19%，相較於 RETROVIR 的 9%)。在該研究中，所有的母親均未對嬰兒進行哺乳。 並不瞭解子宮內與嬰兒暴露至 zidovudine 後，是否出現任何長期結果。以動物致癌性/ 致突變性的研究發現為基礎，並無法排除對人體的致癌性風險(請見臨床前安全性資料)。 尚不瞭解這些發現與暴露至 zidovudine 後發生感染與未發生感染之嬰兒間的相關性。不 過，在懷孕期間內考慮使用 RETROVIR 的孕婦，應瞭解這些研究發現。 授乳︰醫療人員建議感染 HIV 的女性，勿對嬰兒進行哺乳，以避免傳染 HIV。在感染 HIV 之女性使用單劑 200 毫克的 RETROVIR 後，其乳汁中的 zidovudine 平均濃度與血 清中的濃度相似。因此，zidovudine 和病毒可能分泌至乳汁中，故建議母親在服用 RETROVIR 期間不要哺乳。 【對駕駛及機械操作能力的影響】 至今尚無研究調查 RETROVIR 對於駕駛或操作機器能力的影響。從此藥有效成分的藥理 學也無法預期它對這些行為有不良的影響。然而，考慮患者駕駛及操作機器的能力時， 應記得患者的臨床狀況及 RETROVIR 的副作用概況。 【不良反應】 成人與兒童發生之不良反應相似。以下為接受 RETROVIR 治療之不良反應的報告。 以下為常用頻率分類：極常見(≥1/10)；常見(≥1/100，但<1/10)；不常見(≥1/1,000，但 <1/100)；罕見(≥1/10,000，但<1/1,000)；極罕見(<1/10,000)。 血液及淋巴系統疾患 常 見： 貧血(常常需要輸血)，嗜中性白血球減少症及白血球減少症。 這些較常發生於服用高劑量(1200-1500 mg/天)及惡化的 HIV 疾病患者(尤其是在治療前 即有骨髓儲存不良者)，和特別是 CD4 細胞數低於 100/mm3 的患者。有時可能需要減低 劑量或中斷治療(見警語及注意事項)。嗜中性白血球減少症較易發生在 RETROVIR 治療

開始時，已有嗜中性白血球、血紅素值及維生素 B12 的血中濃度降低現象的患者。 不常見： 血小板減少症及全血球減少症(伴隨骨髓發育不全) 罕 見： 紅血球發育不全 極罕見： 再生不能性貧血 代謝及營養疾患 常 見： 乳酸過高 罕 見： 乳酸性酸中毒(見警語及注意事項)、厭食 體脂肪的重新分佈/累積(見警語及注意事項)。此不良反應的發生率與許多因子有關，包 括特殊的抗反轉錄病毒藥物複方製劑。 精神疾患 罕 見： 焦慮及憂鬱 神經系統疾患 極常見： 頭痛 常 見： 眩暈 罕 見： 失眠、感覺異常、嗜睡、喪失心智的敏銳度、痙攣 心臟疾患 罕 見： 心肌病 呼吸道、胸腔與橫膈膜疾患 不常見： 呼吸困難 罕 見： 咳嗽 胃腸道疾患 極常見： 噁心 常 見： 嘔吐、腹痛、腹瀉 不常見： 胃腸脹氣 罕 見： 口腔黏膜色素沈著、味覺異常、消化不良、胰臟炎 肝膽疾患 常 見： 肝臟酵素和膽紅素血中濃度上升 罕 見： 肝臟疾病如脂肪變性的嚴重肝腫大 皮膚與皮下組織疾患 不常見： 皮疹、搔癢 罕 見： 指甲和皮膚色素沈著、蕁麻疹、發汗 骨骼與結締組織疾患 常 見： 肌肉疼痛 不常見： 肌肉病變 腎臟與泌尿系統疾患 罕 見： 頻尿 生殖系統與乳房疾患 罕 見： 乳腺肥大症 一般性疾病及給藥部位狀患 常 見： 身體不適 不常見： 發燒、一般性疼痛與衰弱 罕 見： 寒顫、胸痛、類似流行性感冒症候群 安慰劑對照及開放性研究的資料均指出，在使用 RETROVIR 進行治療的前幾週內，可一 致性地降低噁心及其他常見之臨床不良反應的發生率。 使用 RETROVIR 於孕婦之不良反應 在一篇安慰劑對照詴驗中(ACTG 076)，暴露於 RETROVIR 之嬰兒的血紅素濃度，稍微 低於安慰劑組的嬰兒。在 RETROVIR 投與後 6 週內，貧血可獲得緩解。尚不瞭解子宮內 及嬰兒暴露至 RETROVIR 後的長期結果。 【過量】 除了列為不良反應的症狀外，例如疲勞、頭痛、嘔吐及偶發性的血液功能障礙，在 RETROVIR 急性劑量過高，並未發現特殊的症狀或病症。在服用非指定用量之 RETROVIR 後的病患通報後，血中 zidovudine 濃度會高於正常治療濃度的 16 倍，但並 未發現短期的臨床、生化或血液學後遺症。 必須密切觀察患者的毒性證據(見不良反應)，並給予必要的支持療法。 血液透析與腹膜透析對 zidovudine 的排除影響有限，但會促進尿甘酸化物代謝物的排除。 藥理學特性

【藥效學】 藥理治療群-核苷類似物，ATC Code: J05 A F01。 Zidovudine 為一抗病毒劑，在活體外具有高度的對抗 retroviruses 活性，包括對抗人體免 疫缺乏病毒(HIV)。 Zidovudine 可經由細胞 thymidine kinase，在感染及非感染細胞磷酸酯化，而形成單磷酸 鹽衍生物(MP)。接著 zidovudine-MP 磷酸酯化形成二磷酸鹽(DP)，分別經由細胞 thymidine kinase 及非特異性的催化酵素催化成三磷酸衍生物(TP)。Zidovudine-TP 為病毒的 之抑制者及酵解物。潛伏病毒 DNA 的進一步形成被 zidovudine-TP 的結合入 鏈所阻斷，接著鏈即終結。Zidovudine-TP 對 HIV reverse transcriptase 之競爭力，大約要 比細胞的 DNA 聚合酵素大 100 倍。 已證實 zidovudine 與多種抗 HIV 製劑間具有加成或協同作用，例如：lamivudine、 與干擾素 α，進而抑制細胞培養中 HIV 的複製。 對於胸腺嘧啶類似物(zidovudine 屬於其中一種)的抗藥性已有詳細的瞭解，亦即是由位於 HIV 反轉錄酶密碼子 41、67、70、210、215 與 219 多達六處之專一突變的逐步累積所導 致。病毒經由密碼子 41 與 215 兩處的突變或至少六處中四處突變的累積作用，獲得對胸 腺嘧啶類似物的表現型抗藥性。這些胸腺嘧啶類似物突變，本身並不會對任何其他核苷 造成高度的交叉抗藥性，故可接著使用任何其他獲准使用的反轉錄酶抑制劑。 共有兩種多重藥物抗藥性突變，第一種的特性為密碼子 62、75、77、116 與 151 的 HIV 反轉錄酶突變，第二種一般涉及 T69S 的突變合併相同部位的 6 鹼基對插入，而引起對 zidovudine 及其他獲准使用之核苷酸反轉錄酶抑制劑的表現型抗藥性。這兩種類型的多核 苷酸抗藥性突變均會嚴重限制未來的治療選擇。 從長期接受 RETROVIR 治療之患者中取出的 HIV 分離菌株，曾有降低生體外對 zidovudine 之敏感性的報告。得到的資訊指出早期 HIV 疾病比末期疾病患者，明顯具有較低的生體 外敏感性下降發生率與下降幅度。 HIV 對 zidovudine 之生體外敏感性和對治療之臨床反應間的關係，仍在進行研究中。尚 未建立標準化的生體外敏感性測驗，因而可能會隨測驗方法的不同而有不同的測詴結果。 Zidovudine 合併 lamivudine 的生體外詴驗指出，當 zidovudine 抗藥性病毒分離菌株同時 出現 lamivudine 抗藥性時，會轉變為對 zidovudine 具有敏感性。臨床研究的證據指出， lamivudine 合併 zidovudine 可延緩過去未曾接受抗反轉錄病毒藥物治療的患者出現 zidovudine 抗藥性病毒分離菌株。 Zidovudine 已被廣泛用為抗反轉錄病毒合併治療的成分之一，並搭配其他相同類別(核苷 酸反轉錄酶抑制劑)或不同類別(蛋白酶抑制劑、非核苷酸反轉錄酶抑制劑)的抗反轉錄病 毒藥物一起使用。 【藥物動力學】 【吸收】 Zidovudine 經腸吸收良好，在所有的研究劑量下，其生體可用率為 60-70%。服用 zidovudine 口服液，每 4 小時口服 5 mg/kg，測得其平均穩定狀態的最高血中濃度(CSS max)及最低血 中濃度(CSS min)分別為 7.1 及 0.4 μM (或 1.9 及 0.1 μg/ml)。從生體相等性的研究得知，每 4 小時給藥標準劑量 200 mg 的 RETROVIR 膠囊後，得到平均 CSS max 及 CSS min 值分別 為 4.5 μM (或 1.2 μg/ml)及 0.4 μM(或 0.1 μg/ml)。 【生體相等性】 由 zidovudine 血漿濃度-時間曲線下面積(AUC)看來，RETROVIR 內服液劑用於患者與 RETROVIR 膠囊具有生體相等性。RETROVIR 內服液劑的吸收比膠囊稍快，平均尖峰濃 度時間分別為 0.5 及 0.8 小時。內服液劑與膠囊劑在標準劑量 200 mg 下，平均 CSS max 值分別是 5.8 μM (或 1.55 μg/ml)及 4.5 μM (或 1.2 μg/ml)。這些資料乃是由使用美國口服 RETROVIR 糖漿劑衍生而來，但同樣可以適用於 RETROVIR 內服液劑。 【分佈】 由 RETROVIR 的靜脈注射研究得知，平均最終血漿半衰期為 1.1 小時，平均總身體廓清 率為 27.1 ml/min/kg，而分佈體積為 1.6 l/kg。 給予劑量後 2-4 小時，成人的平均腻脊髓液/血漿中 zidovudine 濃度的比率約為 0.5。少數 資料顯示，zidovudine 可通過胎盤，而出現於羊膜液及胎兒血液中。精液及母乳中也曾檢 測到 zidovudine。 血漿蛋白結合率相當低(34-38%)，所以不預期會發生取代結合部位的藥品交互作用。 【代謝】 Zidovudine 的 5'-尿甘酸化物是血漿及尿液中的主要代謝物，約有 50-80%的給藥劑量由腎 臟排泄。3'-amino 3'-deoxythymidine (AMT)已被確認為靜脈注射 zidovudine 的代謝物。 【排除】 Zidovudine 的腎臟廓清率遠超過肌酸酐廓清率，這表示進行了顯著的腎小管分泌。 【特殊病患族群】  兒童 用於五至六個月以上的兒童，zidovudine 的藥物動力學性質與成人相似。 Zidovudine 經腸吸收良好，在所有的研究劑量下，其生體可用率為 60-74%，平均 65%。 口服 zidovudine (溶液) 120 mg/m2 體表面積及 180 mg/m2 體表面積後，得到的 CSS max 值 分別是 4.45 μM (或 1.19 μg/ml)及 7.7 μM (或 2.06 μg/ml)。 靜脈注射的平均最終血漿半衰期及總身體廓清率分別為 1.5 小時及 30.9 l/min/kg。主要的 代謝物是 5'-尿甘酸化物。靜脈注射後，29%以原型出現於尿中，45%以尿甘酸化物的形 式排出。Zidovudine 的腎臟廓清率遠超過肌酸酐廓清率，這表示進行了顯著的腎小管分 泌。 源自新生兒及年幼嬰兒的藥物動力學資料指出，zidovudine 的葡萄糖醛酸化會因生體可用 率的上升而下降，且在出生未滿 14 天的嬰兒中會有較低的清除率與較長的半衰期，但之 後的藥物動力學似乎與成人的報告差不多。  老年人 並未在年逾 65 歲的患者中研究 zidovudine 的藥物動力學。  腎功能損傷者 相較於健康受詴者，患有末期腎衰竭的病患會有高出 50%的機率出現偏高的 zidovudine 血漿濃度峰值。全身暴露量會增加 100% (以 zidovudine 的濃度時間曲線下面積量測之)； 半衰期並無明顯變化。在腎衰竭的案例中，會有大量的主要代謝物堆積，亦即葡萄醛代 謝物，但似乎並不會引起毒性。血液透析與腹膜透析對於 zidovudine 的排泄並無顯著的 影響，然而會促進葡萄醛代謝物的排泄(見劑量與用法)。  肝功能損傷者 在罹患肝硬化之患者中的資料，建議 zidovudine 可使用在導因於葡萄糖醛酸化下降所引 起的肝功能不全。可能需要調整劑量，但因為可取得的資料有限，故無法提供準確的建 議(見劑量與用法)。  孕婦 在針對 8 位進入最後懷孕週產期之女性研究中，曾研究 zidovudine 的藥物動力學。隨著 懷孕的進展，並沒有 zidovudine 的累積證據。Zidovudine 的藥物動力學與未懷孕的成人 相似。與 zidovudine 經由胎盤的被動傳染一樣，出生嬰兒血漿中的 zidovudine 濃度，與 分娩時的母體血漿濃度相似。 【臨床前安全性資料】  致突變性與致癌性 在 Ames 詴驗中未觀察到致突變性。但有一個老鼠淋巴瘤細胞檢定顯示，zidovudine 具有 弱的致遺傳突變性，且在一個活體外的細胞變性檢定呈陽性反應。在人體淋巴球活體外 研究，與口服重複劑量的大老鼠與小老鼠核仁研究中，觀察到基因破碎作用(染色體損 害)。大老鼠的細胞遺傳研究未顯現染色體損傷。由 11 位 AIDS 患者的周邊血液淋巴球研 究顯示，接受 RETROVIR 治療的病患有較高的染色體破損發生率。一項先導詴驗已發現 zidovudine 可進入成人的白血球細胞核 DNA (包括服用 RETROVIR 作為 HIV-1 感染的治 療，或用以防止母體對孩童的病毒感染的孕婦)。Zidovudine 亦可從使用 zidovudine 治療 之母體併入嬰兒的臍帶血白血球的 DNA 中。這些發現的臨床意義未知。 在小鼠、老鼠中使用 zidovudine 的口服致癌性研究中，觀察到較晚才會出現陰道表皮腫 瘤。在各種性別與族群中，並未觀察到其他與 zidovudine 有關的腫瘤。後續進行的陰道 內致癌性詴驗，已證實陰道腫瘤係由於齧齒目動物之陰道上皮，長期局部性暴露於尿液 中高濃度未代謝的 zidovudine 所致。並不確定齧齒目動物致癌性詴驗對人體的預期價值， 且仍不清楚這些發現的臨床重要性。 此外，在小鼠中已進行過兩次經胎盤致癌性詴驗。其中一項由美國國家癌症研究組織進 行的研究，從懷孕第 12 週至第 18 週給予最大耐受劑量的 zidovudine。在出生一年後，暴 露於最高劑量(420 毫克/公斤/出生時體重)的後代，會有較高的肺臟、肝臟及雌性生殖道 腫瘤發生率。 在第二篇研究中，提供劑量高達 40 毫克/公斤的 zidovudine 予小鼠共 24 個月，並在妊娠 第 10 天開始產前暴露。與治療有關的發現侷限於晚期出現的陰道表皮腫瘤，這與標準口 服致癌性詴驗的研究結果具有相似的發生率與發生時間。因此第二項詴驗並未提供證據 支持 zidovudine 具有經胎盤致癌性。 結論為，出自第一篇研究的經胎盤致癌性資料，代表假設的風險，然而證實在孕婦中使 用 zidovudine 可降低母體將 HIV 轉染給未受感染之兒童的風險。  生殖毒性 在使用 zidovudine 之懷孕大鼠與兔子中的研究已證實會增加早期的胚胎死亡率。另一項 單獨在大鼠中進行的研究，發現非常接近口服致命劑量中位數的藥物，會增加胎兒畸形 的發生率。在較低的劑量測詴中，則未觀察到致畸胎性的證據。 研究中，zidovudine 不會對公鼠與母鼠的生殖力造成損害。

藥劑學特性

【賦形劑】 RETROVIR 膠囊外殼： titanium dioxide, gelatin, indigo carmine, polysorbate 80, opacode S-1-8100 HV Black. RETROVIR 膠囊內容物： starches, microcrystalline cellulose, sodium starch glycollate, magnesium stearate RETROVIR 溶液劑： sodium benzoate, strawberry flavour, purified water, glycerol, sucrose (sugar refined), citric acid anhydrous, artificial candied sugar flavour. 【不相容性】 無 【有效期限】 有效期限標示於包裝上。 【貯存注意事項】 膠囊劑：請於 30℃以下避光儲存，並保持乾燥。 溶液劑：請儲存於 25℃以下。 【容器之性質與內容物】 RETROVIR 膠囊 100 mg：100 顆瓶裝。 RETROVIR 膠囊 250 mg：6~1000 顆鋁箔盒裝。 溶液劑：4000 毫升以下塑膠瓶裝[內附口服劑量唧筒] 【使用及操作說明】 無特殊使用說明

版本編號：VGDS26/IPI03 版本日期：15 June 2007

藥 商：荷商葛蘭素史克藥廠股份有限公司台灣分公司 地 址：台北市忠孝西路一段 66 號 24 樓 [溶液劑] 製造廠：GlaxoSmithKline Inc. 廠 址：7333 Mississauga Road North Mississauga, Ontario Canada L5N 6L4 [膠囊 100 毫克] 製造廠：SmithKline Beecham PLC 廠 址：Manor Royal, Crawley, West Sussex RH10 9QJ, UK [膠囊 250 毫克] 製造廠：SmithKline Beecham PLC 廠 址：Manor Royal, Crawley, West Sussex RH10 9QJ, UK

CONFIDENTIAL

RETROVIR™ Zidovudine

QUALITATIVE AND QUANTITATIVE COMPOSITION Capsules containing either 100 mg or 250 mg zidovudine. – 100 mg gelatin capsules with opaque white cap and body and a central dark-blue band, printed Wellcome, 100 and coded Y9C. – 250 mg gelatin capsules with opaque blue cap, opaque white body and a central dark- blue band, printed Wellcome, 250 and coded H2F. Oral solution/syrup containing 50 mg zidovudine per 5 ml. It is clear, pale yellow, strawberry-flavoured, and sugar-free. PHARMACEUTICAL FORM Hard capsules. Oral solution/syrup. CLINICAL PARTICULARS Indications RETROVIR is indicated for the management of patients with Human Immunodeficiency Virus (HIV) who are asymptomatic, or who have early symptoms associated with HIV disease progression. RETROVIR is also indicated for the management of patients with advanced HIV diseases, such as those with the Acquired Immune Deficiency Syndrome (AIDS) or AIDS-related complex (ARC). RETROVIR is indicated for HIV-infected children who have HIV-related symptoms or who are asymptomatic with markers indicating significant HIV-related immune suppression. The benefit/risk assessments based on available data support early therapeutic intervention. Combination in advanced HIV infection The addition of HIVID may be considered for the management of adult patients with advanced HIV infection (CD4 + cell counts < 300/mm3). RETROVIR monotherapy is still indicated as initial therapy for adult patients with HIV who fulfil the approved indications. Dosage and Administration RETROVIR therapy should be initiated by a physician experienced in the management of HIV infection. CONFIDENTIAL

 Dosage in Adults Although a broad range of dosage has been employed, 500 or 600 mg/day in three to five divided doses is commonly used worldwide. Alternatively 1000 mg/day in two (or four) divided doses is effective. The effectiveness of the lower dosages in the treatment or prevention of HIV-associated neurological dysfunction and malignancies is unknown.  Dosage of combination therapy in advanced HIV infection 200 mg RETROVIR administered concomitantly with 0.75 mg of HIVID orally every 8 hours (600 mg RETROVIR total daily dosage, 2.25 mg HIVID total daily dosage).  Dosage in Children In children over the age of 3 months the recommended starting dosage is 180 mg/m2 body surface area every 6 hours (720 mg/m2/day). The maximum dosage should not exceed 200 mg every 6 hours. The optimum dosage regimen remains to be determined and may vary from patient to patient. A range of dosages, generally between 120 and 180 mg/m2 body surface area every 6 hours (between 480 and 720 mg/m2/day), has been used. The effectiveness of lower dosages in the treatment or prevention of HIV-associated neurological dysfunction and malignancies is unknown. The effectiveness of less frequent dosing in children remains to be established.  Dosage adjustment in patients with haematological adverse reactions Dosage adjustments may be necessary in patients with haematological adverse reactions. This is more likely in patients with poor bone marrow reserve prior to treatment, particularly in patients with advanced HIV disease. If the haemoglobin level falls to between 7.5 g/dl (4.65 mmol/l) and 9 g/dl (5.59 mmol/l) or the neutrophil count falls to between 0.75 x 109/l and 1.0 x 109/l, the daily dosage may be reduced until there is evidence of marrow recovery; alternately, recovery may be enhanced by a brief (2-4 weeks) interruption of RETROVIR therapy. If dosage reduction is considered, the daily dosage may, for example, be halved and subsequently increased, depending on patient tolerance, up to the original dosage. Therapy with RETROVIR should be interrupted if the haemoglobin level falls below 7.5 g/dl (4.65 mmol/l) or the neutrophil count falls to less than 0.75 x 109/l. marrow recovery is usually observed within 2 weeks after which time RETROVIR therapy at a reduced dosage may be reinstituted. After a further 2-4 weeks the dosage may be gradually increased, depending on patient tolerance, up to the original dosage.  Dosage adjustment in recipients of combination RETROVIR and HIVID therapy For recipients of combination RETROVIR and HIVID therapy, dosage adjustments for either drug should follow guidelines for the individual drug. For severe adverse events, those I which the causative drug is unclear, or those persisting after dose interruption or reduction of one drug, the other drug should also be interrupted or dose-reduced. Physicians should refer to the complete product information for HIVID for a description of known HIVID-associated adverse reactions.  Dosage in Elderly CONFIDENTIAL

No specific data are available; however, special care is advised in this age group due to age-associated changes such as the decrease in renal function and alterations in haematological parameters.  Dosage in Renal impairment Compared to healthy subjects, patients with advanced renal failure have a 50% higher maximum plasma concentration of zidovudine. Systemic exposure (measured as area under the zidovudine concentration time cure) is increased 100%; the half life is not significantly altered. In renal failure there is substantial accumulation of the major, glucuronide metabolite but this does not appear to cause toxicity. Patients with advanced renal failure should receive RETROVIR at the lower end of the dosage range. Haemodialysis and peritoneal dialysis have no significant effect on zidovudine elimination whereas elimination of glucuronide metabolite is increased.  Dosage in Hepatic impairment Limited data in patients with cirrhosis suggest that accumulation of zidovudine may occur in patients with hepatic impairment because of decreased glucuronidation. Dosage adjustments may be necessary, but precise recommendations cannot be made at present. If monitoring of plasma zidovudine levels is not feasible, physicians will need to pay particular attention to signs of intolerance and increase the interval between doses as appropriate. Contraindications RETROVIR is contra-indicated in patients known to be hypersensitive to zidovudine, or to any of the components of the formulations. RETROVIR should not be given to patients with abnormally low neutrophil counts (less than 0.75 x 109/l) or abnormally low haemoglobin levels (less than 7.5 g/dl or 4.65 mmol/l) (see Warnings and Precautions). Warnings and Precautions Patients should be cautioned about the concomitant use of self-administered (see Interactions). Patients should be advised that therapy has not been proven to prevent the transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be taken. RETROVIR is not a cure for HIV infection and patients remain at risk of developing illnesses which are associated with immune suppression, including opportunistic infections and neoplasms. Whilst it has been shown to reduce the risks of opportunistic infections, data on the development of neoplasms, including lymphomas, are limited. The available data on patients treated for advanced HIV disease indicate that the risk of lymphoma development is consistent with that observed in untreated patients. In patients with early HIV disease on long-term treatment the risk of lymphoma development is unknown. CONFIDENTIAL

Pregnant women considering the use of RETROVIR during pregnancy for prevention of HIV transmission to their infants should be advised that transmission may still occur in some cases despite therapy. Haematological adverse reactions: Anaemia (usually not observed before 6 weeks of RETROVIR therapy but occasionally occurring earlier), neutropenia (usually not observed before 4 weeks' therapy but sometimes occurring earlier) and leucopenia (usually secondary to neutropenia) can be expected to occur in patients with advanced symptomatic HIV disease receiving RETROVIR. These occurred more frequently at higher dosages (1200-1500 mg/day) and in patients with poor bone marrow reserve prior to treatment, particularly with advanced HIV disease. Haematological parameters should be carefully monitored. For patients with advanced symptomatic HIV disease it is generally recommended that blood tests are performed at least every 2 weeks for the first 3 months of therapy and at least monthly thereafter. In patients with early HIV disease (where bone marrow reserve is generally good), haematological adverse reactions are infrequent. Depending on the overall condition of the patient, blood tests may be performed less often, for example every 1 to 3 months. If the haemoglobin level falls to between 7.5 g/dl (4.65 mmol/l) and 9 g/dl (5.59 mmol/l) or the neutrophil count falls to between 0.75 x 109/l and 1.0 x 109/l, the daily dosage may be reduced until there is evidence of marrow recovery; alternatively, recovery may be enhanced by brief (2-4 weeks) interruption of RETROVIR therapy. Marrow recovery is usually observed within 2 weeks after which time RETROVIR therapy at a reduced dosage may be reinstituted. In patients with significant anaemia, dosage adjustments do not necessarily eliminate the need for transfusions (see Contraindications). Lactic acidosis/severe hepatomegaly with steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of antiretroviral analogues either alone or in combination, including zidovudine. A majority of these cases have been in women. Clinical features which may be indicative of the development of lactic acidosis include generalised weakness, anorexia and sudden unexplained weight loss, gastrointestinal symptoms and respiratory symptoms (dyspnoea and tachypnoea). Caution should be exercised when administering RETROVIR to any patient, and particularly to those with known risk factors for liver disease. Treatment with RETROVIR should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). Fat redistribution: Redistribution / accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting and breast enlargement, elevated serum lipid and blood glucose levels have been observed either separately or together in some patients receiving combination anti retroviral therapy (see Adverse Reactions). Whilst all members of the PI and NRTI classes of medicinal products have been associated with one or more of these specific adverse events, linked to a general CONFIDENTIAL

syndrome commonly referred to as lipodystrophy, data indicate that there are differences in the risk between individual members of the respective therapeutic classes. In addition, the lipodystrophy syndrome has a multi-factorial aetiology; with for example HIV disease status, older age and duration of anti retroviral treatment all playing important, possibly synergistic roles. The long-term consequences of these events are currently unknown. Clinical examination should include evaluation for physical signs of fat redistribution. Consideration should be given to the measurement of serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate. Immune Reconstitution Syndrome: In HIV-infected patients with severe immune deficiency at the time of initiation of anti-retroviral therapy (ART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of ART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and Pneumocystis jiroveci (P. carinii) pneumonia. Any inflammatory symptoms must be evaluated without delay and treatment initiated when necessary. Patients co-infected with virus: Exacerbation of anaemia due to has been reported when zidovudine is part of the regimen used to treat HIV although the exact mechanism remains to be elucidated. Therefore, the co-administration of ribavirin and zidovudine is not advised and consideration should be given to replacing zidovudine in a combination ART regimen if this is already established. This is particularly important in patients with a known history of zidovudine induced anaemia. Interactions Zidovudine is primarily eliminated by hepatic conjugation to an inactive glucuronidated metabolite. Active substances which are primarily eliminated by hepatic metabolism especially via glucuronidation may have the potential to inhibit metabolism of zidovudine. The interactions listed below should not be considered exhaustive but are representative of the classes of medicinal products where caution should be exercised. Atovaquone: zidovudine does not appear to affect the pharmacokinetics of atovaquone. However, pharmacokinetic data have shown that atovaquone appears to decrease the rate of metabolism of zidovudine to its glucuronide metabolite (steady state AUC of zidovudine was increased by 33% and peak plasma concentration of the glucuronide was decreased by 19%). At zidovudine dosages of 500 or 600 mg/day it would seem unlikely that a three week, concomitant course of atovaquone for the treatment of acute PCP would result in an increased incidence of adverse reactions attributable to higher plasma concentrations of zidovudine. Extra care should be taken in monitoring patients receiving prolonged atovaquone therapy. Clarithromycin: clarithromycin tablets reduce the absorption of zidovudine. This can be avoided by separating the administration of zidovudine and clarithromycin by at least two hours. CONFIDENTIAL

Lamivudine: A modest increase in Cmax (28%) was observed for zidovudine when administered with lamivudine, however overall exposure (AUC) was not significantly altered. Zidovudine has no effect on the pharmacokinetics of lamivudine. Phenytoin: Phenytoin blood levels have been reported to be low in some patients receiving RETROVIR, while in one patient a high level was noted. These observations suggest that phenytoin levels should be carefully monitored in patients receiving both medicinal products. Probenecid: Limited data suggest that probenecid increases the mean half-life and AUC of zidovudine by decreasing glucuronidation. Renal excretion of the glucuronide (and possibly zidovudine itself) is reduced in the presence of probenecid. Rifampicin: Limited data suggests that co-administration of zidovudine and rifampicin decreases AUC of zidovudine by 48%  34%. However the clinical significance of this is unknown. Stavudine: Zidovudine may inhibit the intracellular phosphorylation of stavudine when the two medicinal products are used concurrently. Stavudine is therefore not recommended to be used in combination with RETROVIR. Miscellaneous: Other active substances including but not limited to aspirin, codeine, morphine, methadone, indomethacin, ketoprofen, naproxen, oxazepam, lorazepam, cimetidine, clofibrate, dapsone and isoprinosine may alter the metabolism of zidovudine by competitively inhibiting glucuronidation or directly inhibiting hepatic microsomal metabolism. Careful thought should be given to the possibilities of interactions before using such medicinal products, particularly for chronic therapy, in combination with RETROVIR. Concomitant treatment, especially acute therapy, with potentially nephrotoxic or myelosuppressive medicinal products (for example systemic pentamidine, dapsone, pyrimethamine, co-trimoxazole, amphotericin, flucytosine, ganciclovir, interferon, vincristine, vinblastine and doxorubicin) may also increase the risk of adverse reactions to RETROVIR. If concomitant therapy with any of these medicinal products is necessary then extra care should be taken in monitoring renal function and haematological parameters and, if required, the dosage of one or more agents should be reduced. Since some patients receiving RETROVIR may continue to experience opportunistic infections, concomitant use of prophylactic antimicrobial therapy may have to be considered. Such prophylaxis has included co-trimoxazole, aerosolised pentamidine, pyrimethamine and . Limited data from clinical trials do not indicate a significantly increased risk of adverse reactions to RETROVIR with these medicinal products. Pregnancy and Lactation Fertility: There are no data on the effect of RETROVIR on human female fertility. In men, zidovudine has been shown to have no effect on sperm count, morphology or motility. Pregnancy: Zidovudine has been shown to cross the placenta in humans (see Pharmacokinetis). Given the limited data available on the general use of RETROVIR in pregnancy, the use of RETROVIR prior to the 14th week of gestation should be CONFIDENTIAL

considered only when the potential benefit to the mother outweighs the risk to the foetus (see Preclinical Safety Data). There have been reports of mild, transient elevations in serum lactate levels, which may be due to mitochondrial dysfunction, in neonates and infants exposed in utero or peri- partum to nucleoside reverse transcriptase inhibitors (NRTIs). The clinical relevance of transient elevations in serum lactate is unknown. There have also been very rare reports of developmental delay, seizures and other neurological disease. However, a causal relationship between these events and NRTI exposure in utero or peri-partum has not been established. These findings do not affect current recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV. Maternal-foetal transmission: In ACTG 076 the use of RETROVIR in pregnant women over 14 weeks of gestation, with subsequent treatment of their newborn infants, has been shown to significantly reduce the rate of maternal-foetal transmission of HIV (23% infection rate for placebo versus 8% for RETROVIR). In this report, oral RETROVIR therapy began between weeks 14 and 34 of gestation and continued until onset of labour. During labour and delivery RETROVIR was administered intravenously. The newborn infants received RETROVIR orally until 6 weeks old. Infants unable to receive oral dosing were given the intravenous formulation. In the 1998 Thailand CDC study, use of oral RETROVIR therapy only, from week 36 of gestation until delivery, significantly reduced the rate of maternal-foetal transmission of HIV (19% infection rate for placebo versus 9% for RETROVIR). No mothers in this study breast fed their infants. It is unknown whether there are any long-term consequences of in utero and infant exposure to zidovudine. Based on the animal carcinogenicity/mutagenicity findings a carcinogenic risk to humans cannot be excluded (see Preclinical Safety Data). The relevance of these findings to both infected and uninfected infants exposed to zidovudine is unknown. However, pregnant women considering using RETROVIR during pregnancy should be made aware of these findings. Lactation: Health experts recommend that where possible women infected with HIV do not breast feed their infants in order to avoid the transmission of HIV. After administration of a single dose of 200 mg RETROVIR to HIV-infected women, the mean concentration of zidovudine was similar in human milk and serum. Therefore, as zidovudine and the virus pass into breast milk it is recommended that mothers taking RETROVIR do not breast feed their infants. Effects on Ability to Drive and Use Machines There have been no studies to investigate the effect of RETROVIR on driving performance or the ability to operate machinery. Further, a detrimental effect on such activities cannot be predicted from the pharmacology of the active substance. Nevertheless, the clinical status of the patient and the adverse event profile of RETROVIR should be borne in mind when considering the patient's ability to drive or operate machinery. CONFIDENTIAL

Adverse Reactions The adverse event profile appears similar for adults and children. The following events have been reported in patients treated with RETROVIR. The following convention has been utilised for the classification of undesirable effects: very common (>1/10), common (>1/100, <1/10), uncommon (>1/1,000, <1/100), rare (>1/10,000, <1/1,000) very rare (<1/10,000).

Blood and lymphatic system disorders Common: Anaemia (which may require transfusions), neutropenia and leucopenia. These occur more frequently at higher dosages (1200-1500mg/day) and in patients with advanced HIV disease (especially when there is poor bone marrow reserve prior to treatment), and particularly in patients with CD4 cell counts less than 100/mm3. Dosage reduction or cessation of therapy may become necessary (see Warnings and Precautions). The incidence of neutropenia was also increased in those patients whose neutrophil counts, haemoglobin levels and serum vitamin B12 levels were low at the start of RETROVIR therapy. Uncommon: Thrombocytopenia and pancytopenia (with marrow hypoplasia). Rare: Pure red cell aplasia. Very rare: Aplastic anaemia. Metabolism and nutrition disorders Common: Hyperlactataemia. Rare: Lactic acidosis (see Warnings and Precautions), anorexia. Redistribution/accumulation of body fat (see Warnings and Precautions). The incidence of this event is dependent on multiple factors including the particular antiretroviral drug combination. Psychiatric disorders Rare: Anxiety and depression. Nervous system disorders Very common: Headache. Common: Dizziness. Rare: Insomnia, paraesthesia, somnolence, loss of mental acuity, convulsions. Cardiac disorders Rare: Cardiomyopathy. Respiratory, thoracic and mediastinal disorders Uncommon: Dyspnoea. Rare: Cough. CONFIDENTIAL

Gastrointestinal disorders Very common: Nausea. Common: Vomiting, abdominal pain, and diarrhoea. Uncommon: Flatulence. Rare: Oral mucosa pigmentation, taste disturbance and dyspepsia. Pancreatitis. Hepatobilary disorders Common: Raised blood levels of liver enzymes and bilirubin. Rare: Liver disorders such as severe hepatomegaly with steatosis. Skin and subcutaneous tissue disorders Uncommon: Rash and pruritus. Rare: Nail and skin pigmentation, urticaria and sweating. Musculoskeletal and connective tissue disorders Common: Myalgia. Uncommon: Myopathy. Renal and urinary disorders Rare: Urinary frequency. Reproductive system and breast disorders Rare: Gynaecomastia. General disorders and administration site conditions Common: Malaise. Uncommon: Fever, generalised pain and asthenia. Rare: Chills, chest pain and -like syndrome. The available data from both placebo-controlled and open-labelled studies indicate that the incidence of nausea and other frequently reported clinical adverse events consistently decreases over time during the first few weeks of therapy with RETROVIR. Adverse reactions with RETROVIR in pregancy women In a placebo-controlled trial (ACTG 076), haemoglobin concentrations in infants exposed to RETROVIR were marginally lower than in infants in the placebo group. Anaemia resolved within 6 weeks after RETROVIR therapy. The long-term consequences of in utero and infant exposure to RETROVIR are unknown. Overdose No specific symptoms or signs have been identified following acute overdose with RETROVIR, apart from those listed as undesirable effects such as fatigue, headache, vomiting, and occasional reports of haematological disturbances. Following a report where a patient took an unspecified quantity of RETROVIR, blood zidovudine levels were CONFIDENTIAL

over sixteen times the normal therapeutic level, but there were no short term clinical, biochemical or haematological sequelae identified. Patients should be observed closely for evidence of toxicity (see Adverse Reactions) and given the necessary supportive therapy. Haemodialysis and peritoneal dialysis appear to have a limited effect on elimination of zidovudine but enhance the elimination of the glucuronide metabolite. PHARMACOLOGICAL PROPERTIES Pharmacodynamics Pharmacotherapeutic group - - ATC Code J05A F01. Zidovudine is an antiviral agent which is highly active in vitro against retroviruses including the Human Immunodeficiency Virus (HIV). Zidovudine is phosphorylated in both infected and uninfected cells to the monophosphate (MP) derivative by cellular thymidine kinase. Subsequent phosphorylation of zidovudine-MP to the diphosphate (DP), and then the triphosphate (TP) derivative is catalysed by cellular thymidylate kinase and non-specific kinases respectively. Zidovudine-TP acts as an inhibitor of and substrate for the viral reverse transcriptase. The formation of further proviral DNA is blocked by incorporation of zidovudine-TP into the chain and subsequent chain termination. Competition by zidovudine-TP for HIV reverse transcriptase is approximately 100-fold greater than for cellular DNA polymerase alpha. Zidovudine has been shown to act additively or synergistically with a number of anti-HIV agents, such as lamivudine, didanosine, and interferon-α , inhibiting the replication of HIV in cell culture. Resistance to thymidine analogues (of which zidovudine is one) is well characterised and is conferred by the stepwise accumulation of up to six specific mutations in the HIV reverse transcriptase at codons 41, 67, 70, 210, 215 and 219. Viruses acquire phenotypic resistance to thymidine analogues through the combination of mutations at codons 41 and 215 or by the accumulation of at least four of the six mutations. These thymidine analogue mutations alone do not cause high-level cross-resistance to any of the other , allowing for the subsequent use of any of the other approved reverse transcriptase inhibitors. Two patterns of multi-drug resistance mutations, the first characterised by mutations in the HIV reverse transcriptase at codons 62, 75, 77, 116 and 151 and the second typically involving a T69S mutation plus a 6-base pair insert at the same position, result in phenotypic resistance to zidovudine as well as to the other approved nucleoside reverse transcriptase inhibitors. Either of these two patterns of multinucleoside resistance mutations severely limits future therapeutic options. Reduced in vitro sensitivity to zidovudine has been reported for HIV isolates from patients who have received prolonged courses of RETROVIR therapy. The available information indicates that for early HIV disease, the frequency and degree of reduction of in vitro sensitivity is notably less than for advanced disease. CONFIDENTIAL

The relationships between in vitro susceptibility of HIV to zidovudine and clinical response to therapy remain under investigation. In vitro susceptibility testing has not been standardised and results may therefore vary according to methodological factors. Studies in vitro of zidovudine in combination with lamivudine indicate that zidovudine-resistant virus isolates can become zidovudine sensitive when they simultaneously acquire resistance to lamivudine. Evidence from clinical studies show that lamivudine plus zidovudine delays the emergence of zidovudine-resistant isolates in individuals with no prior anti- retroviral therapy. . Zidovudine has been widely used as a component of anti retroviral combination therapy with other anti retroviral agents of the same class (nucleoside reverse transcriptase inhibitors) or different classes (protease inhibitors, non-nucleoside reverse transcriptase inhibitors). Pharmacokinetics ‧ Absorption Zidovudine is well absorbed from the gut and, at all dose levels studied, the bioavailability was 60 to 70%. From a Phase I study, mean steady state peak (C[ss]max) and trough (C[ss]min) plasma concentrations following oral administration of zidovudine (in solution) at doses of 5 mg/kg every 4 h were 7.1 and 0.4 micromol (or 1.9 and 0.1 micrograms/ml) respectively. From a bioequivalence study, mean C[ss]max and C[ss] min levels following oral administration of zidovudine capsules every 4 h and dose normalised to 200 mg were 4.5 micromol (or 1.2 micrograms/ml) and 0.4 micromol (or 0.1 micrograms/ml) respectively. . Bioequivalence RETROVIR oral solution was shown, in patients, to be bioequivalent to RETROVIR capsules in respect to the area under the zidovudine plasma concentration-time curve (AUC). The absorption of RETROVIR following the administration of the oral solution was marginally faster than that following the administration of capsules, with mean times to peak concentrations of 0.5 and 0.8 h respectively. Mean values for C[ss]max, dose- normalised to 200 mg were 5.8 micromol (or 1.55 micrograms/ml) and 4.5 micromol (1.2 micrograms/ml) for oral solution and capsules respectively. These data were generated using the US oral RETROVIR syrup but can be considered to apply equally to RETROVIR oral solution. Distribution From studies with i.v.zidovudine, the mean terminal plasma half- life was 1.1 h, the mean total body clearance was 27.1 ml/min/kg and the apparent volume of distribution was 1.6 l/kg. In adults, the average cerebrospinal fluid/plasma zidovudine concentration ratio 2 to 4 h after dosing was found to be approximately 0.5. Data indicate that zidovudine crosses the placenta and is found in amniotic fluid and foetal blood. Zidovudine has also been detected in semen and milk. Plasma protein binding is relatively low (34 to 38%) and interactions with other active substances involving binding site displacement are not anticipated. CONFIDENTIAL

Metabolism The 5'-glucuronide of zidovudine is the major metabolite in both plasma and urine, accounting for approximately 50 to 80% of the administered dose eliminated by renal excretion. 3'amino- 3'- deoxythymidine (AMT) has been identified as a metabolite of zidovudine following i.v. dosing. Elimination Renal clearance of zidovudine greatly exceeds creatinine clearance, indicating that significant tubular secretion takes place. Special Patient Populations  Children In children over the age of 5 to 6 months, the pharmacokinetic profile of zidovudine is similar to that in adults. Zidovudine is well absorbed from the gut and, at all dose levels studied, its bioavailability was 60 to 74% with a mean of 65%. C[ss]max levels were 4.45 micromol (1.19 micrograms/ml) following a dose of 120 mg zidovudine (in solution)/m2 body surface area and 7.7 micromol (2.06 micrograms/ml) at 180 mg/m2 body surface area. With i.v. dosing, the mean terminal plasma half-life and total body clearance were 1.5 h and 30.9 ml/min/kg respectively. The major metabolite is the 5'-glucuronide. After i.v. dosing, 29% of the dose was recovered unchanged in the urine and 45% excreted as the glucuronide. Renal clearance of zidovudine greatly exceeds creatinine clearance indicating that significant tubular secretion takes place. The data available on the pharmacokinetics in neonates and young infants indicate that glucuronidation of zidovudine is reduced with a consequent increase in bioavailability, reduction in clearance and longer half-life in infants less than 14 days old but thereafter the pharmacokinetics appear similar to those reported in adults.  Elderly The pharmacokinetics of zidovudine have not been studied in patients over 65 years of age.  Renal Impairment Compared to healthy subjects, patients with advanced renal failure have a 50% higher peak plasma concentration of zidovudine. Systemic exposure (measured as area under the zidovudine concentration-time curve) is increased 100%; the half- life is not significantly altered. In renal failure there is substantial accumulation of the major, glucuronide metabolite but this does not appear to cause toxicity. Haemodialysis and peritoneal dialysis have no significant effect on zidovudine elimination whereas elimination of the glucuronide metabolite is increased (see Dosage and Administration).  Hepatic Impairment Data in patients with cirrhosis suggest that accumulation of zidovudine may occur in patients with hepatic impairment because of decreased glucuronidation. Dosage CONFIDENTIAL

adjustments may be necessary, but as there is only limited data available precise recommendations cannot be made (see Dosage and Administration).  Pregnancy The pharmacokinetics of zidovudine has been investigated in a study of eight women during the last trimester of pregnancy. As pregnancy progressed, there was no evidence of accumulation of zidovudine. The pharmacokinetics of zidovudine was similar to that of non-pregnant adults. Consistent with passive transmission of zidovudine across the placenta, zidovudine concentrations in infant plasma at birth were essentially equal to those in maternal plasma at delivery. Pre-clinical Safety Data  Carcinogenicity, Mutagenicity No evidence of mutagenicity was observed in the Ames test. However, zidovudine was weakly mutagenic in a mouse lymphoma cell assay and was positive in an in vitro cell transformation assay. Clastogenic effects were observed in an in vitro study in human lymphocytes and in vivo oral repeat dose micronucleus studies in rats and mice. An in vivo cytogenetic study in rats did not show chromosomal damage. A study of the peripheral blood lymphocytes of eleven AIDS patients showed a higher chromosome breakage frequency in those who had received RETROVIR than in those who had not. A pilot study has demonstrated that zidovudine is incorporated into leukocyte nuclear DNA of adults, including pregnant women, taking RETROVIR as treatment for HIV-1 infection, or for the prevention of mother to child viral transmission. Zidovudine was also incorporated into DNA from cord blood leukocytes of infants from zidovudine-treated mothers. The clinical significance of these findings is unknown. In oral carcinogenicity studies with zidovudine in mice and rats, late appearing vaginal epithelial tumours were observed. There were no other zidovudine-related tumours observed in either sex of either species. A subsequent intravaginal carcinogenicity study confirmed the hypothesis that the vaginal tumours were the result of long term local exposure of the rodent vaginal epithelium to high concentrations of unmetabolised zidovudine in urine. The predictive value of rodent carcinogenicity studies for humans is uncertain and thus the clinical significance of these findings is unclear. In addition two transplacental carcinogenicity studies have been conducted in mice. One study, by the US National Cancer Institute, administered zidovudine at maximum tolerated doses to pregnant mice from day 12 to 18 of gestation. One year post-natally, there was an increase in the incidence of tumours in the lung, liver and female reproductive tract of offspring exposed to the highest dose level (420mg/kg/term body weight). In a second study, mice were administered zidovudine at doses up to 40 mg/kg for 24 months, with exposure beginning prenatally on gestation day 10. Treatment related findings were limited to late-occurring vaginal epithelial tumours, which were seen with a similar incidence and time of onset as in the standard oral carcinogenicity study. The second study thus provided no evidence that zidovudine acts as a transplacental carcinogen. CONFIDENTIAL

It is concluded that the transplacental carcinogenicity data from the first study represents a hypothetical risk, whereas the reduction in risk of maternal transfection of HIV to the uninfected child by the use of zidovudine in pregnancy has been well proven.  Reproductive toxicology Studies in pregnant rats and rabbits with zidovudine have shown increased incidences of early embryo deaths. A separate study in rats found that dosages very near the oral median lethal dose caused an increase in the incidence of foetal malformations. No evidence of teratogenicity has been observed at lower dosages tested. Zidovudine did not impair male or female fertility in studies in rats. PHARMACEUTICAL PARTICULARS List of Excipients RETROVIR Capsule shell: titanium dioxide, gelatin, indigo carmine, polysorbate 80, opacode S-1-8100 HV Black. RETROVIR Capsule contents: starches, microcrystalline cellulose, sodium starch glycollate, magnesium stearate RETROVIR oral solution/syrup: sodium benzoate, strawberry flavour, purified water, glycerol, sucrose (sugar refined), citric acid anhydrous, artificial candied sugar flavour. Incompatibilities None known. Shelf Life The expiry date is indicated on the packaging. Special Precautions for Storage RETROVIR Capsule: Do not store above 30°C. Keep RETROVIR capsules (100 mg and 250 mg) dry and protect from light. RETROVIR oral solution/syrup: Do not store above 25°C. Nature and Contents of Container As registerd locally. Instructions for Use/Handling No special instructions are required.

Not all presentations are available in every country. CONFIDENTIAL

Version number: VGDS26/IPI03 Date of issue: 15 June 2007 RETROVIR is a trademark of the GlaxoSmithKline group of companies [GlaxoSmithKline logo]