457 AUGMENTIN Syrup 457 mg/5ml
安滅菌糖漿用粉劑 457 毫克/5 毫升 AUGMENTIN Syrup 457 mg/5ml Amoxicillin trihydrate - Potassium clavulanate 衛署藥輸字 022447 號 定性與定量組成 AUGMENTIN Syrup 457 mg/5 mL 每 5 毫升中含 400 毫克 Amoxicillin(以 Amoxicillin trihydrate 型態存在)以及 57 毫克 clavulanic acid (以 potassium clavulanate 型態存在)。 劑型 本品為乾粉製劑，調劑時，加水配製成口服無糖糖漿。 臨床特性 【適應症】 葡萄球菌，鏈球菌，肺炎雙球菌，腻膜炎球菌及其他具有感受性細菌引起之感染 症。 【說明】 AUGMENTIN Syrup(457 mg/5mL)每日口服投予兩次(b.i.d)，適用於當懷疑病原菌 可能是會產生 β 內醯胺酵素(β-lactamase)而對 Amoxicillin 具抗藥性的菌株時，短 期治療下列部位的病菌感染症；在其它的情況下，則應考慮使用單方 Amoxicillin。 —上呼吸道感染症(包括耳鼻喉)﹔如復發的扁桃腺炎、鼻竇炎、中耳炎。 —下呼吸道感染症﹔如急性與慢性支氣管炎(特別是嚴重者)、肺葉肺炎及支氣管 肺炎。 —泌尿道感染症﹔如膀胱炎(特別是復發或有併發症者，但前列腺炎除外)。 —皮膚與軟組織感染症﹔如蜂窩組織炎、動物叮咬。 —牙科感染症﹔如併有擴散性蜂窩組織炎的嚴重牙齒膿腫。 —對本品具感受性之病菌詳列於„藥效學‟中。 對 Amoxicillin 具感受性之病菌與對 AUGMENTIN 具感受性之可產生 β 內醯胺酵 素的病菌所共同造成的混合感染症，可以 AUGMENTIN Syrup(457 mg/5mL)治療 之，這類感染症應該不須再加上另一個對抗 β 內醯胺酵素的抗生素。 【劑量及用法】 本藥須由醫師處方使用 一般建議的每日劑量為: 治療輕至中度感染症(上呼吸道感染症，如復發性扁桃腺炎；下呼吸道感染 症；及皮膚與軟組織感染症)：25/3.6 mg/kg/day。 治療較嚴重的感染症(上呼吸道感染症，如中耳炎及鼻竇炎；下呼吸道感染 症，如支氣管肺炎；及泌尿道感染症)：45/6.4 mg/kg/day。 下表為兒童給藥指南： 1 兩歲以上之兒童 25/3.6 mg/kg/day 45/6.4 mg/kg/day 2-6 歲 (13 - 21 公斤) 7 - 12 歲 (22 - 40 公斤) 2-6 歲 (13 - 21 公斤) 7 - 12 歲 2.5 毫升 AUGMENTIN Syrup 457 mg/5 mL，一天兩次。 5.0 毫升 AUGMENTIN Syrup 457 mg/5 mL，一天兩次。 5.0 毫升 AUGMENTIN Syrup 457 mg/5 mL，一天兩次。 10.0 毫升 AUGMENTIN Syrup 457 mg/5 mL，一天兩次。 兩個月大至兩歲之兒童 兩歲以下之兒童應根據體重調整劑量 AUGMENTIN Syrup 457 mg/5 mL 體重 25/3.6 45/6.4 (公斤) mg/kg/day mg/kg/day (ml/一天兩次*) (ml/一天兩次*) 2 0.3 0.6 3 0.5 0.8 4 0.6 1.1 5 0.8 1.4 6 0.9 1.7 7 1.1 2.0 8 1.3 2.3 9 1.4 2.5 10 1.6 2.8 11 1.7 3.1 12 1.9 3.4 13 2.0 3.7 14 2.2 3.9 15 2.3 4.2 AUGMENTIN Syrup 457 mg/5 mL 35 毫升和 70 毫升包裝附有一計量杯，見“使用 及操作說明”。 AUGMENTIN Syrup 457 mg/5 mL 於兩個月大以下兒童之使用經驗尚不足以提供 劑量建議。 腎功能未成熟之兒童： AUGMENTIN Syrup 457 mg/5 mL 不建議使用於腎功能未成熟之兒童。 腎功能損害： 對腎絲球體過濾速率(CFR)大於 30 ml/min 之兒童，毋須調整劑量，AUGMENTIN Syrup 457 mg/5 mL 不建議使用於腎絲球體過濾速率(CFR)低於 30 ml/min 之兒 童。 肝功能損害： 小心用藥；定期監測肝功能，目前尚無足夠的證據可據以提供劑量建議。 投予： 為使潛在的胃腸不耐藥性減至最低，應於開始進食時服用。則可使 AUGMENTIN 2 吸收達較佳狀況，治療時間之長短應視適應症之需要適切訂定，且不應超過 14 天而未加以檢查評估。可先以注射方式開始治療，之後再改用口服劑型繼續治療。 【禁忌症】 對 β-lactams(penicillins, cephalosporins)有過敏病史之病人。 出現過與 AUGMENTIN 或 penicillin 有關的黃疸/肝功能失常的病史。 【警語及注意事項】 - 在開始 AUGMENTIN 治療之前，應仔細詢問是否曾經發生 penicillins、 cephalosporins 以及其他過敏原相關之過敏反應。 - 以 penicillins 治療的病患曾有嚴重且偶爾會致死之過敏性(類過敏性)反應的 報告。這些反應較易發生於有 penicillins 過敏病史的患者(見“禁忌症”)。 - 疑似有感染性單核白血球增多症時，應避免使用 AUGMENTIN，因為在這 個狀況下使用 Amoxicillin 可能出現麻疹樣疹。 - 延長使用偶而可能會造成非感受性微生物的過度生長。 - 曾有罕見的報告顯示病人在接受 AUGMENTIN 及口服抗凝血治療後會出現 異常的凝血時間延長(INR 上升)情形。對於同時正在接受抗凝血療法的病 人，應小心監測。必要時應調整口服抗凝血製劑以維持適當的抗凝血功能。 - 某些接受 AUGMENTIN 治療的病人中，曾發現肝功能詴驗結果產生變化的 例子。這些變化的臨床意義尚不清楚，但肝功能不正常的病人在使用 AUGMENTIN 時應特別小心。 - 極少數報告會有膽汁鬱滯性黃疸的出現，可能會很嚴重但為可逆。在停止給 藥後六週內，其徵候及症狀可能漸不明顯。 - 對於患有腎功能損傷的病人，AUGMENTIN 的劑量應依照劑量及用法一節 所建議的內容作適當調整。 - 在排尿量減少的病人，曾經發生結晶尿，但非常罕見，大多數發生在接受注 射治療的病人。高劑量 Amoxicillin 給藥期間，建議維持適當的水份攝取和排 尿，以減少發生結晶尿的可能性(見“過量”)。 - AUGMENTIN Syrup 457 mg/5 mL(草莓口味)每 5 毫升的劑量中含有 16.64 毫克的天冬胺酸衍生物(aspartame)，因此，使用於苯酮尿症(phenylketonuria) 患者，時應加小心。 【藥物交互作用】 不建議同時使用 probenecid，因其會減少腎小管對 AUGMENTIN 的排除作用。 AUGMENTIN 與 probenecid 併用，可能會提高並延長 Amoxicillin 的血中濃度， 不過不影響 clavulanate。 Amoxicillin 與 allopurinol 併用會增加皮膚過敏反應的可能性；至於 AUGMENTIN 與 allopurinol 併用，目前無相關數據。 和其他抗生素相同，AUGMENTIN 可能會影響腸內菌株，造成雌激素再吸收降 低並使得口服避孕藥效果下降。 曾有罕見的案例見於文獻報告中，關於持續使用 acenocoumarol 或 warfarin 且 併用 Amoxicillin 的病患出現 INR (International normalized ratio)上升的情形。 3 如需併用此類藥物，應小心監測凝血時間或 International normalized ratio 且適 時增加或停用 AUGMENTIN。 【懷孕與授乳】 利用小老鼠及大白鼠所進行的動物詴驗中，在經口及注射的方式投予 AUGMENTIN 後顯示此藥並不會有畸胎的情形發生。一針對孕婦早產和胚胎膜 早熟破裂(premature rupture of the foetal membrane, pPROM)進行之單盲詴驗 指出，AUGMENTIN 之預防療法可能與新生兒壞死性腸炎的危險性增加有關。 如同所有其他藥品一樣，若非醫師認為有必要，在懷孕期間應避免使用，尤其是 在懷孕的前三個月。 在授乳的期間仍可使用 AUGMENTIN，本藥用於母體時，對於嬰兒並不會有所 傷害，唯一的例外是當微量的藥物隨著母乳進入嬰兒體內時，可能會有造成過敏 的危險。 【對駕駛及機械操作能力的影響】 目前未發現有相關副作用。 【不良反應】 根據大型臨床詴驗的數據，將副作用的發生率歸類為極常見(very common)、常 見(common)、不常見(uncommon)或罕見(rare)。至於歸類為極罕見(very rare) 的副作用，則是使用上市後的數據，因此其較接近通報率而非實際的發生率。 極常見(very common)：＞1/10 常見(common)： ＞1/100，＜1/10 不常見(uncommon)： ＞1/1000，＜1/100 罕見(rare)： ＞1/10000，＜1/1000 極罕見(very rare)： ＜1/10000 感染及寄生蟲 常 見： 皮膚黏膜念珠菌症。 血液及淋巴系統疾患 罕 見： 可逆性白血球減少症(含中性球減少)及血小板減少。 極罕見： 可逆性顆粒性白血球減少、溶血性貧血。流血時間及凝血時間延長。 免疫系統疾患 極罕見： 血管神經性水腫、過敏反應、血清病變樣症候群、過敏性血管炎。 神經系統疾患 不常見： 頭昏、頭痛。 極罕見： 可逆性亢奮與痙攣。痙攣可能發生在腎功能不全或使用高劑量的病 人。 腸胃道疾患 成人： 極常見： 腹瀉。 常 見： 噁心、嘔吐。 兒童： 4 常 見： 腹瀉、噁心、嘔吐。 所有族群： 噁心常與較高的口服劑量相關。倘若腸胃之反應明顯，可於開始進 食時服用以減輕腸胃不適。 不常見： 消化不良。 極罕見： 與抗生素相關之結腸炎(包括偽膜性結腸炎及出血性結腸炎)。 黑色毛樣舌。 於兒童曾有極罕見牙齒表面變色發生的報告。良好的口腔衛生習慣 可以幫助預防牙齒變色的發生且此情形通常可以刷牙移除。 肝膽疾患 不常見： 曾在使用 β-lactams 類抗生素的病人，發現中度 AST 及(或)ALT 上升的現象，然目前其重要性不明。 極罕見： 肝炎及膽汁鬱滯性黃膽。其他 penicillins、cephalosporins 亦有相同 之報告。 肝臟反應主要發生於男性及高齡患者，並可能與治療時間延長有關。在孩童則極 罕見。 徵候及症候可通常在治療期間或治療後不久即出現，但也有些病例是在治療結束 數週後才發生。這些反應通常是可逆轉的。至於肝臟方面的反應但可能會很嚴 重，也曾報告有極罕見的死亡病例。這些大部分發生在帶有嚴重疾病的病人或同 時服用已知會造成肝損害的藥物。 皮膚及皮下組織疾患 不常見： 皮疹、搔癢、蕁麻疹。 罕 見： 多形性紅斑。 極罕見： Stevens-Johnson 症候群、毒性表皮壞死、水泡剝離性皮膚炎、急性 全身性膿疹。 若發生其中任何一種過敏性皮膚炎反應，均應停止治療。 腎及泌尿道疾患 極罕見： 間質性腎炎、結晶尿 (見“過量”)。 【過量】 可能有明顯的腸胃道症狀、體液與電解質的失衡。採取症狀療法，並注意水與電 解質的帄衡，可緩解症狀。 曾經發現 Amoxicillin 結晶尿在某些情況下引起腎衰竭(見警語及注意事項)。 可以血液透析移除循環中的 AUGMENTIN。 藥理學特性 【藥效學】 細菌的抗藥性來自於細菌產生的酵素，使抗生素作用在病原體前就已被破壞。 AUGMENTIN 中的 clavulanate 就是針對此一防衛機制抑制 β-lactamase，增加微 生物對抗生素的感受度，使 Amoxicillin 在一般血中濃度時就能對微生物形成快 速的殺菌效果。Clavulanate 本身略具抗菌效果，但與 Amoxicillin 配方成 AUGMENTIN 後，則形成一廣效性抗生素，可廣泛使用於醫院與診所。 格蘭氏陽性菌 5 需氧菌：炭疽桿菌(Bacillus anthracis)，棒狀桿菌(Corynebacterium species)， Enterococcus faecalis，Enterococcus faecium，單核細胞增多性李斯特氏桿菌 (Listeria monocytogenes)，肺炎鏈球菌(Streptococcus pneumoniae)，釀膿鏈球菌 (Streptococcus pyogenes)，草綠色鏈球菌(Streptococcus viridans)，Streptococcus agalactiae，Streptococcus species，*金黃色葡萄球菌(Staphylococcus aureus)，*凝 固酶陰性葡萄球菌，包括表皮葡萄球菌(Coagulase negative staphylococci <including Staphylococcus epidermidis>)。 厭氧菌：梭菌屬細菌(Clostridium species)，球菌(Peptococcus species)，鏈球菌 (Peptostreptococcus)。 格蘭氏陰性菌 需氧菌：百日咳桿菌(Bordetella pertussis)，布氏桿菌(Brucella species)，*大腸桿 菌(Escherichia coli)，Gardnerella vaginalis，*流行性感冒桿菌(Hemophilus influenzae)，Helicobacter pylori，*克雷白桿菌(Klebsiella species)，Legionella species，*卡它莫拉克氏菌(Moraxella catarrhalis)，*淋病奈瑟菌(Neisseria gonorrhoeae)，腻膜炎奈瑟氏菌(Neisseria meningitides)，雞霍亂桿菌(Pasteurella multocida)，*奇異變形菌(Proteus mirabilis)，*普通變形菌(Proteus vulgaris)，*沙 門桿菌(Salmonella species)，*志賀桿菌(Shigella species)，霍亂弧菌(Vibrio cholerae)，*Yersinia enterocolitica。 厭氧菌：包括脆弱類桿菌(B.fragilis)在內的*類細菌屬(Bacteroides spp.)。 *具有能製造 β-lactamase 的變種，能對 ampicillin 及 Amoxicillin 產生抗藥性。 【藥物動力學】 【吸收】 AUGMENTIN Syrup 457 mg/5 mL 中的兩種成分，Amoxicillin 與 clavulanate，在 生理酸鹼值的水溶液中均可完全游離。口服投予後，兩種成分均可快速充分地吸 收。當於開始進食時服用 AUGMENTIN，其吸收極佳。 在成人中，一天兩次投予 AUGMENTIN 875/125 mg 錠劑，或一天三次投予 AUGMENTIN 500/125 mg 錠劑，其 Amoxicillin 的帄均濃度曲線下面積(AUC)事 實上是相同的。投予不同劑量的 Amoxicillin，待常態化之後，比較 Amoxicillin 的半衰期(T1/2)與血中最高濃度(Cmax)，結果發現一天兩次 875 mg 與 500 mg 一 天三次這兩種療法之間未見任何差異。同樣地，在劑量適當地常態化之後，兩種 療法間的 clavulanate 之半衰期、血中最高濃度、或濃度曲線下面積亦未見任何差 異。 在成人中，投予 AUGMENTIN 與開始進食的相對時間，對 Amoxicillin 的藥物動 力學並無任何明顯的影響。在一項對 AUGMENTIN 875/125 mg 錠劑的研究中顯 示，投藥與食物消化的相對時間，對 clavulanate 的藥物動力學有明顯的影響。相 較於空腹狀態、或開始進食 30 分鐘後、或開始進食 150 分鐘後投藥，於開始進 食時投予 AUGMENTIN 可達到最高的 clavulanate 濃度曲線下面積及血中最高濃 度，且個體間的差異也最小。 下表為於開始進食時投予單一劑量的 875/125 mg 之 Amoxicillin/clavulanate 之 後，Amoxicillin 與 clavulanate 之帄均血中最高濃度(Cmax)、半衰期(T1/2)與濃度 曲線下面積(AUC) 帄均藥物動力學參數 6 投予之藥物 劑量 血中最高濃度 達到最高濃度 濃度曲線下 半衰期 (mg) (Cmax) 所需之時間 面積 (AUC) (T1/2) (mg/L) (Tmax)* (mg.h/L) (hours) (hours) AUGMENTIN 1 g Amoxicillin 875 mg 12.4 1.5 29.9 1.36 Clavulanate 125 mg 3.3 1.3 6.88 0.92 *中位數值(Median values) 口服投予劑量相當之單方 Amoxicillin 與 AUGMENTIN 所達到之 Amoxicillin 血 中濃度相近。 【分佈】 AUGMENTIN 中之兩種成份的藥物動力學極為相符。 Clavulanate 與 Amoxicillin 兩者血漿蛋白結合率都很低；在血漿中均維持 70%的 游離態。 AUGMENTIN 的劑量加倍後，其所達到的血中濃度也約增為兩倍。 【臨床前安全性資料】 無進一步相關資料。 藥劑學特性 【賦形劑】 Crospovidone, silicon dioxide (anhydrous), carmellose sodium, xanthan gum, colloidal anhydrous silica, magnesium stearate, sodium benzoate, aspartame, strawberry flavour 【不相容性】 未知。 【有效期限】 藥品有效期限標示於包裝上。 【貯存注意事項】 乾粉製劑應貯存於密封容器中，置於 25℃以下之乾燥處。 配製後的懸浮液應貯存於冰箱(2-8℃)，並在七天內使用。 本品應置於兒童不及之處。 【容器之性質與內容物】 澄清玻璃瓶裝，上附鋁製螺旋蓋，內含白色之乾粉製劑。AUGMENTIN Syrup 457 mg/5 mL 35 毫升和 70 毫升包裝附有一計量杯。 或單劑量袋裝(僅限 AUGMENTIN Syrup 457 mg/5 mL)。 配製後形成灰白色懸浮液。 【使用及操作說明】 玻璃瓶裝： 7 調劑時，應將乾粉製劑配製成口服用懸浮液，詳述如下： AUGMENTIN Syrup 457 mg/5 mL – 草莓口味 填重量 配製時應加入水量 配製後口服懸浮液的 最終容積 5.3 克 32 毫升 35.4 毫升 10.6 克 64 毫升 70.8 毫升 21.0 克 127 毫升 140.5 毫升 或者，也可以將水加至標籤上之充填線(箭頭指示)的三分之二處；蓋上瓶蓋，搖 動瓶身，直到所有粉末均懸浮其中為止；接著加入更多的水，直到液面到達充填 線；然後再次搖動瓶身。首次配製後，靜置 5 分鐘，以確定分散完全。 AUGMENTIN Syrup 457 mg/5 mL 35 毫升和 70 毫升包裝附有一計量杯。 袋裝： 單劑量袋裝，內含 2.5 毫升劑量之 AUGMENTIN Syrup 457 mg/5 mL 粉劑。 使用指示：使用前應檢視包裝是否完整無損。 1. 沿虛線剪開包裝，將內容物完全倒入玻璃杯中。 2. 將水注入袋中至半滿。 3. 倒入杯中，攪拌混合。 4. 配製後立刻喝掉。 如果一次須服用二或四包，可在同一杯中混合使用。 版本編號：GDS018/IPI05 版本日期：27 April 2009 製造廠：SmithKline Beecham Plc 廠 址：(O) SB House, Brentford, Middlesex TW8 9BD, U.K. (P) Clarendon Road, Worthing, West Sussex BN14 8QH, U.K. 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六十六號二十四樓 8 CONFIDENTIAL AUGMENTINTM SUSPENSION 457 mg/5 ml - Strawberry flavour Amoxicillin trihydrate - Potassium clavulanate QUALITATIVE AND QUANTITATIVE COMPOSITION AUGMENTIN suspension 457 mg/5 ml contains 400 mg Amoxicillin (as Amoxicillin trihydrate) and 57 mg clavulanic acid (as potassium clavulanate) per 5 ml. PHARMACEUTICAL FORM Dry powder for reconstitution in water, at time of dispensing, to form an oral sugar free suspension. CLINICAL PARTICULARS Indications AUGMENTIN suspension 457mg/5 ml, for twice daily oral dosing, is indicated for short term treatment of bacterial infections at the following sites when Amoxicillin resistant beta-lactamase producing strains are suspected as the cause. In other situations, Amoxicillin alone should be considered. Upper respiratory tract infections (including ENT) e.g. recurrent tonsillitis, sinusitis, otitis media. Lower respiratory tract infections e.g. acute exacerbations of chronic bronchitis lobar and bronchopneumonia. Urinary tract infections e.g. cystitis urethritis, pyelonephritis Skin and soft tissue infections e.g. cellulitis, animal bites. Dental infections e.g. severe dental abscess with spreading cellulitis. A comprehensive list of susceptible organisms is provided in the Pharmacodynamics section. Mixed infections caused by Amoxicillin-susceptible organisms in conjunction with AUGMENTIN susceptible beta-lactamase-producing organisms may be treated with AUGMENTIN suspension 457mg/5 ml. These infections should not require the addition of another antibiotic resistant to beta-lactamases. Dosage and Administration The usual recommended daily dosage is: 25/3.6 mg/kg/day in mild to moderate infections (upper respiratory tract infections e.g. recurrent tonsillitis, lower respiratory infections and skin and soft tissue infections) 45/6.4 mg/kg/day for the treatment of more serious infections (upper respiratory tract infections e.g. otitis media and sinusitis, lower respiratory tract infections e.g. bronchopneumonia and urinary tract infections) The tables below give guidance for children. CONFIDENTIAL Children over 2 years 25/3.6 mg/kg/day 45/6.4 mg/kg/day 2 - 6 years (13 - 21 kg) 2.5 ml AUGMENTIN suspension 457 mg/5 ml twice daily 7 - 12 years (22 - 40 kg) 5.0 ml AUGMENTIN suspension 457 mg/5 ml twice daily 2 - 6 years (13 - 21 kg) 5.0 ml AUGMENTIN suspension 457 mg/5 ml twice daily 7 - 12 years 10.0 ml AUGMENTIN suspension 457 mg/5 ml twice daily Children aged 2 months to 2 years Children under 2 years should be dosed according to body weight. AUGMENTIN suspension 457 mg/5 ml Weight (kg) 25/3.6 mg/kg/day 45/6.4 mg/kg/day (ml/ twice daily*) (ml/ twice daily*) 2 0.3 0.6 3 0.5 0.8 4 0.6 1.1 5 0.8 1.4 6 0.9 1.7 7 1.1 2.0 8 1.3 2.3 9 1.4 2.5 10 1.6 2.8 11 1.7 3.1 12 1.9 3.4 13 2.0 3.7 14 2.2 3.9 15 2.3 4.2 CONFIDENTIAL The AUGMENTIN suspension 457 mg/5 ml 35 ml and 70 ml presentations may be supplied with a cup dosing device - See Instructions for use/handling. There is insufficient experience with AUGMENTIN suspension 457 mg/5 ml to make dosage recommendations for children under 2 months old. Infants with immature kidney function For infants with immature renal function AUGMENTIN suspension 457 mg/5 ml is not recommended. Renal Impairment For children with a GFR of >30 ml/min no adjustment in dosage is required. For children with a GFR of <30 ml/min AUGMENTIN suspension 457 mg/5 ml is not recommended. Hepatic Impairment Dose with caution; monitor hepatic function at regular intervals. There is, as yet, insufficient evidence on which to base a dosage recommendation. Administration To minimise potential gastrointestinal intolerance, administer at the start of a meal. The absorption of AUGMENTIN is optimised when taken at the start of a meal. Duration of therapy should be appropriate to the indication and should not exceed 14 days without review. Therapy can be started parenterally and continued with an oral preparation. Contraindications AUGMENTIN is contraindicated in patients with a history of hypersensitivity to betalactams, e.g. penicillins and cephalosporins. AUGMENTIN is contraindicated in patients with a previous history of AUGMENTINassociated jaundice/hepatic dysfunction. Warnings and Precautions Before initiating therapy with AUGMENTIN, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or other allergens. Serious and occasionally fatal hypersensitivity (anaphylactoid) reactions have been reported in patients on penicillin therapy. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity (see Contraindications). AUGMENTIN should be avoided if infectious mononucleosis is suspected since the occurrence of a morbilliform rash has been associated with this condition following the use of Amoxicillin. Prolonged use may also occasionally result in overgrowth of non-susceptible organisms. Abnormal prolongation of prothrombin time (increased INR) has been reported rarely in patients receiving AUGMENTIN and oral anticoagulants. Appropriate monitoring CONFIDENTIAL should be undertaken when anticoagulants are prescribed concurrently. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation. Changes in liver function tests have been observed in some patients receiving AUGMENTIN. The clinical significance of these changes is uncertain but AUGMENTIN should be used with caution in patients with evidence of hepatic dysfunction. Cholestatic jaundice, which may be severe, but is usually reversible, has been reported rarely. Signs and symptoms may not become apparent for up to six weeks after treatment has ceased. In patients with renal impairment AUGMENTIN suspension 457 mg/5 ml is not recommended. In patients with reduced urine output, crystalluria has been observed very rarely, predominantly with parenteral therapy. During the administration of high doses of Amoxicillin, it is advisable to maintain adequate fluid intake and urinary output in order to reduce the possibility of Amoxicillin crystalluria (see Overdose). AUGMENTIN 457 mg/5ml suspension (Strawberry flavour) contains 16.64 mg aspartame per 5 ml dose and therefore care should be taken in patients with phenylketonuria. Interactions Concomitant use of probenecid is not recommended. Probenecid decreases the renal tubular secretion of Amoxicillin. Concomitant use with AUGMENTIN may result in increased and prolonged blood levels of Amoxicillin but not of clavulanate. Concomitant use of allopurinol during treatment with Amoxicillin can increase the likelihood of allergic skin reactions. There are no data on the concomitant use of AUGMENTIN and allopurinol. In common with other antibiotics, AUGMENTIN may affect the gut flora, leading to lower oestrogen reabsorption and reduced efficacy of combined oral contraceptives. In the literature there are rare cases of increased international normalised ratio in patients maintained on acenocoumarol or warfarin and prescribed a course of Amoxicillin. If co-administration is necessary, the prothrombin time or international normalised ratio should be carefully monitored with the addition or withdrawal of AUGMENTIN. Pregnancy and Lactation Reproduction studies in animals (mice and rats) with orally and parenterally administered AUGMENTIN have shown no teratogenic effects. In a single study in women with preterm, premature rupture of the foetal membrane (pPROM), it was reported that prophylactic treatment with AUGMENTIN may be associated with an increased risk of necrotising enterocolitis in neonates. As with all medicines, use should be avoided in pregnancy, especially during the first trimester, unless considered essential by the physician. AUGMENTIN may be administered during the period of lactation. With the exception of CONFIDENTIAL the risk of sensitisation, associated with the excretion of trace quantities in breast milk, there are no detrimental effects for the infant. Effects on Ability to Drive and Use Machines Adverse effects on the ability to drive or operate machinery have not been observed. Adverse Reactions Data from large clinical trials were used to determine the frequency of very common to rare undesirable effects. The frequencies assigned to all other undesirable effects (i.e., those occurring at <1/10,000) were mainly determined using post-marketing data and refer to a reporting rate rather than a true frequency. The following convention has been used for the classification of frequency: very common >1/10 common >1/100 and <1/10 uncommon >1/1000 and <1/100 rare >1/10,000 and <1/1000 very rare <1/10,000. Infections and infestations Common Mucocutaneous candidiasis Blood and lymphatic system disorders Rare Reversible leucopenia (including neutropenia) and thrombocytopenia Very rare Reversible agranulocytosis and haemolytic anaemia. Prolongation of bleeding time and prothrombin time Immune system disorders Very Rare Angioneurotic oedema, anaphylaxis, serum sickness-like syndrome, hypersensitivity vasculitis Nervous system disorders Uncommon Dizziness, headache Very rare Reversible hyperactivity and convulsions. Convulsions may occur in patients with impaired renal function or in those receiving high doses. Gastrointestinal disorders Adults: CONFIDENTIAL Very common Diarrhoea Common Nausea, vomiting Children: Common Diarrhoea, nausea, vomiting All populations: Nausea is more often associated with higher oral dosages. If gastrointestinal reactions are evident, they may be reduced by taking AUGMENTIN at the start of a meal. Uncommon Indigestion Very rare Antibiotic-associated colitis (including pseudomembranous colitis and haemorrhagic colitis). Black hairy tongue Superficial tooth discolouration has been reported very rarely in children. Good oral hygiene may help to prevent tooth discolouration as it can usually be removed by brushing. Hepatobiliary disorders Uncommon A moderate rise in AST and/or ALT has been noted in patients treated with beta-lactam class antibiotics, but the significance of these findings is unknown. Very rare Hepatitis and cholestatic jaundice. These events have been noted with other penicillins and cephalosporins. Hepatic events have been reported predominantly in males and elderly patients and may be associated with prolonged treatment. These events have been very rarely reported in children. Signs and symptoms usually occur during or shortly after treatment but in some cases may not become apparent until several weeks after treatment has ceased. These are usually reversible. Hepatic events may be severe and in extremely rare circumstances, deaths have been reported. These have almost always occurred in patients with serious underlying disease or taking concomitant medications known to have the potential for hepatic effects. Skin and subcutaneous tissue disorders Uncommon Skin rash, pruritus, urticaria Rare Erythema multiforme Very Rare Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous exfoliative-dermatitis, acute generalised exanthemous pustulosis (AGEP) If any hypersensitivity dermatitis reaction occurs, treatment should be discontinued. CONFIDENTIAL Renal and urinary disorders Very rare Interstitial nephritis, crystalluria (see Overdose) Overdose Gastrointestinal symptoms and disturbance of the fluid and electrolyte balances may be evident. Gastrointestinal symptoms may be treated symptomatically with attention to the water electrolyte balance. Amoxicillin crystalluria, in some cases leading to renal failure, has been observed (see Warnings and Precautions). AUGMENTIN can be removed from the circulation by haemodialysis. PHARMACOLOGICAL PROPERTIES Pharmacodynamics Resistance to many antibiotics is caused by bacterial enzymes which destroy the antibiotic before it can act on the pathogen. The clavulanate in AUGMENTIN suspension anticipates this defence mechanism by blocking the -lactamase enzymes, thus rendering the organisms sensitive to Amoxicillin's rapid bactericidal effect at concentrations readily attainable in the body. Clavulanate by itself has little antibacterial activity; however, in association with Amoxicillin as AUGMENTIN it produces an antibiotic agent of broad spectrum with wide application in hospital and general practice. AUGMENTIN is bactericidal to a wide range of organisms including: Gram-positive Aerobes: Bacillus anthracis*, Corynebacterium species, Enterococcus faecalis*, Enterococcus faecium*, Listeria monocytogenes, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus viridans, Streptococcus agalactiae, Streptococcus species, Staphylococcus aureus*, coagulase negative staphylococci* (including Staphylococcus epidermidis). Anaerobes: Clostridium species, Peptococcus species, Peptostreptococcus. Gram-negative Aerobes: Bordetella pertussis, Brucella species, Escherichia coli*, Gardnerella vaginalis, Haemophilus influenzae*, Helicobacter pylori, Klebsiella species*, Legionella species, Moraxella catarrhalis* Neisseria gonorrhoeae*, Neisseria meningitidis*, Pasteurella multocida, Proteus mirabilis*, Proteus vulgaris*, Salmonella species*, Shigella species*, Vibrio cholerae, Yersinia enterocolitica*. Anaerobes: Bacteroides species* including Bacteroides species*(including Bacteroides fragilis), Fusobacterium species*. Some members of these species of bacteria produce -lactamase, rendering them insensitive to Amoxicillin alone. CONFIDENTIAL Infections caused by Amoxicillin-susceptible organisms are amenable to AUGMENTIN treatment due to its Amoxicillin content. Mixed infections caused by Amoxicillin susceptible organisms in conjunction with AUGMENTIN -susceptible -lactamase producing organisms may therefore be treated with AUGMENTIN. Pharmacokinetics Absorption: The two components of AUGMENTIN suspension 457 mg/5 ml, Amoxicillin and clavulanate, are each fully dissociated in aqueous solution at physiological pH. Both components are rapidly and well absorbed by the oral route of administration. Absorption of AUGMENTIN is optimised when taken at the start of a meal. The mean AUC values for Amoxicillin are essentially the same following twice a day dosing with the AUGMENTIN 875/125 mg tablet or three times a day dosing with the AUGMENTIN 500/125 mg tablet, in adults. No differences between the 875 mg twice daily and 500 mg three times daily dosing regimes are seen when comparing the Amoxicillin T1/2, or Cmax after normalisation for the different doses of Amoxicillin administered. Similarly, no differences are seen for the clavulanate T1/2, Cmax or AUC values after appropriate dose normalisation. The time of dosing of AUGMENTIN relative to the start of a meal has no marked effects on the pharmacokinetics of Amoxicillin in adults. In a study of the AUGMENTIN 875/125 mg tablet, the time of dosing relative to ingestion of a meal had a marked effect on the pharmacokinetics of clavulanate. For clavulanate AUC and Cmax, the highest mean values and smallest inter-subject variabilities were achieved by administering AUGMENTIN at the start of a meal, compared to the fasting state or 30 or 150 minutes after the start of a meal. The mean Cmax, Tmax, T1/2 and AUC values for Amoxicillin and clavulanate are given below for an 875 mg/125 mg dose of Amoxicillin /clavulanic acid administered at the start of a meal. Mean Pharmacokinetic Parameters Drug Administration Dose (mg) Cmax (mg/L) Tmax* (hours) AUC (mg.h/L) T1/2 (hours) Amoxicillin 875 mg 12.4 1.5 29.9 1.36 Clavulanate 125 mg 3.3 1.3 6.88 0.92 AUGMENTIN 1g *Median values Amoxicillin serum concentrations achieved with AUGMENTIN are similar to those produced by the oral administration of equivalent doses of Amoxicillin alone. Distribution: CONFIDENTIAL The pharmacokinetics of the two components of AUGMENTIN are closely matched. Both clavulanate and Amoxicillin have low levels of serum binding; about 70% remains free in the serum. Doubling the dosage of AUGMENTIN approximately doubles the serum levels achieved. Pre-clinical Safety Data No further information of relevance. PHARMACEUTICAL PARTICULARS List of Excipients Crospovidone, silicon dioxide (anhydrous), carmellose sodium, xanthan gum, colloidal anhydrous silica, magnesium stearate, sodium benzoate, aspartame, strawberry flavour Incompatibilities None known. Shelf Life The expiry date is indicated on the packaging. Special Precautions for Storage The dry powder should be stored in unopened containers in a dry place at below 25C. Reconstituted suspensions should be stored in a refrigerator (2-8°C) and used within seven days. Nature and Contents of Container Clear, glass bottles with aluminium screw caps, containing an off-white dry powder. The AUGMENTIN suspension 457 mg/5 ml 35 ml and 70 ml presentations may be supplied with a cup dosing device. or Single-dose sachets When reconstituted, an off-white suspension is formed. Instructions for Use/Handling GLASS BOTTLES: At time of dispensing, the dry powder should be reconstituted to form an oral suspension, as detailed below: AUGMENTIN suspension 457 mg/5 ml - Strawberry flavour CONFIDENTIAL Nominal Fill Weight Volume of water to be added to reconstitute Final volume of reconstituted oral suspension 5.3 g 32 ml 35.4 ml 10.6 g 64 ml 70.8 ml 21.0 g 127 ml 140.5 ml Alternatively, water can be added to 2/3 of the fill line on the label (shown by an arrow and line). Replace the cap, and shake the bottle until all of the powder is suspended. Add more water until the level of the fill line is attained, and shake again. When first reconstituted, allow to stand for 5 minutes to ensure full dispersion. The AUGMENTIN suspension 457 mg/5 ml 35 ml and 70 ml presentations may be provided with a cup dosing device. SACHETS: Single-dose sachets contain powder for a 2.5 ml dose of AUGMENTIN suspension 457 mg/5 ml. Directions for use: Check that the sachet is intact before use 1. Cut sachet along dotted line. 2. Empty contents into a glass 2. Half fill sachet with water 3 Pour into a glass, stir to mix 4. Drink immediately upon reconstitution If two or four sachets have to be taken at once then they can be mixed in the same glass. Not all presentations are available in every country. Version number: GDS18/IPI05 Date of issue: 27 April 2009 AUGMENTIN is a trademark of the GlaxoSmithKline group of companies
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