Microsoft Word - Protos DOH version-Chinese.doc

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1 補骨挺疏 2 公克 PROTOS 2g 衛署藥輸字第 號 組成 每小包 (sachet) 含 strontium ranelate gm 賦形劑 : 含有 20 mg aspartame (E951) 全部的賦形劑請參考 藥品性質 劑型 顆粒劑 適應症 停經後婦女骨質疏鬆症之治療, 以降低脊椎骨折與髖骨骨折的風險 用法 用量 本藥須由醫師處方使用 建議劑量為每日一次, 每次服用一包 Protos 2g, 加水成懸液劑後口服使用 strontium ranelate 之吸收會受食物 牛奶及其衍生產物影響而降低, 所以 Protos 應該於兩餐之間服用 基於其緩慢吸收之特性,Protos 應該在睡前服用, 最好是在用餐後至少兩小時後服用 ( 請參考 藥物交互作用及其他形式之交互作用, 及 藥物動力學性質 ) 小包內之顆粒劑必須在加入一杯水中形成懸液劑後口服使用 雖然在已中止的研究中已經證實 strontium ranelate 在製成懸液劑後 24 小時內仍然是穩定的, 但是懸液劑應在製備後立即服用 使用 Protos 需每日補充 1500mg 鈣 ( 含飲食及鈣片 ) 及維生素 D (400IU ~ 800IU) 同時服用 strontium ranelate 與鈣或食物, 會降低 strontium 的生體可用率約 60% ~ 70% 因此服用 Protos 前後應避免用餐或攝取含鈣食物 口服維生素 D 補充劑對 strontium 濃度並無影響 老年人 strontium ranelate 之療效與安全性已經在廣泛年齡層 ( 在收案時最高年齡為 100 歲 ) 之患有骨質疏鬆症的停經後婦女中確立, 因此毋需依據年齡調整劑量 腎功能不全之患者 對於輕度到中度腎功能不全的患者 (creatinine 廓清率為 30~70 毫升 / 分 ), 毋需調整劑量 ( 請參考 藥物動力學性質 ) strontium ranelate 不建議使用於嚴重腎功能不全的患者 (creatinine 廓清率低於 30 毫升 / 分 ) ( 請參考 特別警語及注意事項 及 藥物動力學性質 ) 肝功能不全之患者 因為 strontium ranelate 不會被代謝, 所以對肝功能不全之患者毋需調整劑量 兒童及青少年 strontium ranelate 對兒童及青少年的療效與安全性資料尚未被確立, 因此不建議使用 禁忌 對有效成分或本藥任一賦形劑過敏者禁用 特別警語及注意事項 由於尚無嚴重腎功能不全患者使用 strontium ranelate 之骨安全性資料,Protos 不建議使用於 creatinine 廓清率低於 30 毫升 / 分的患者 ( 請參考 藥物動力學性質 ) 依據優良醫療規範, 建議對慢性腎功能不全的患者定期評估腎功能 對於進展成嚴重腎功能不全的患者, Protos 的持續治療, 應視個別情況加以考量 在第三期安慰劑對照性臨床試驗中, 發現 strontium ranelate 治療組與靜脈血栓性栓塞 (VTE) 包括肺栓塞的年發生率增加有關 ( 請參考 不良反應 ), 其原因仍然未知 因此 Protos 應避免使用於 VTE 之高危險群病人, 包括有 VTE 病史的患者 於治療有風險或有進展為 VTE 風險的患者時, 對於 VTE 可能的癥候與症狀應給予特別的注意, 並採取適當的預防措施 strontium 會干擾測定血鈣與尿鈣濃度的色量計法, 因此於實際醫療中, 應使用感應耦合電漿原子發射光譜法 (inductively coupled plasma atomic emission spectrometry) 或原子吸收光譜法 (atomic absorption spectrometry) 來測定, 以確保血鈣及尿鈣濃度值之正確測量 Protos 含有 phenylalanine 之來源, 而 phenylalanine 可能對患有苯酮尿症 (phenylketonuria) 的患者有害 如果發生任何過敏反應特別是皮膚方面的症狀, 應停止使用 Protos, 並儘速回診 使用 Protos 曾報告過有嚴重過敏症候群的病例, 尤其是嗜伊紅血球增多性藥疹與全身症狀 (DRESS), 有時會致命 ( 請參考 不良反應 ) DRESS 症候群的特徵是皮疹 發燒 嗜伊紅血球增多以及全身症狀 ( 如 : 腺病 肝炎 間質性腎病 間質性肺病 ) 發作時間通常在用藥 3 至 6 週之間, 皮疹常是最先開始的症狀, 其原因仍然未知 Protos 應謹慎使用於有過敏病史的患者, 若曾有對 Protos 過敏之患者, 應避免使用本藥品 如果發生皮膚過敏反應如皮疹, 應立即停止使用 Protos, 並儘速回診 藥物交互作用及其他形式之交互作用 食物 牛奶及其衍生產物以及含鈣藥物可能會降低 strontium ranelate 的生體可用率約 60~70% 因此服用 Potos 與前述產品的時間應間隔至少 2 小時 ( 請參考 藥物動力學性質 ) 於一體內臨床交互作用試驗顯示, 在 2 小時前或是同時與 strontium ranelate 併服氫氧化鋁及氫氧化鎂, 會些微的降低對 strontium ranelate 的吸收 (AUC 降低 20~25%), 而當服用 strontium ranelate 兩小時後再服用制酸劑,strontium ranelate 之吸收幾乎不會受到影響 因此最好在服用 Protos 至少兩小時後再服用制酸劑 ; 然而由於 Protos 被建議在睡前服用, 當這樣處方 ( 在服用 Protos 至少兩小時後再服用制酸劑 ) 1

2 不可行時, 一併服用是可以被接受的 因為雙價陽離子會與口服 tetracycline 與 quinolone 抗生素在胃腸道形成複合物而降低其吸收, 因此不建議 strontium ranelate 與此類藥物併服 為預防起見, 在口服 tetracycline 或 quinolone 抗生素治療期間,Protos 之治療應暫停 本藥與口服維生素 D 補充劑並未發現有交互作用 在臨床試驗期間, 於研究的標的族群中, 預期常與 Protos 併用的藥物中, 並未發現臨床交互作用之證據或與藥物相關的血中 strontium 濃度增加的情形 這些常用併用藥物包括 : 非類固醇抗發炎藥 (NSAIDs) ( 包括乙醯水楊酸 ) anilides ( 如 paracetamol) H 2 - 阻斷劑 (H 2 -blocker) 及質子幫浦抑制劑 (proton pump inhibitors) 利尿劑 (diuretics) 毛地黃素 (digoxin) 及強心配醣體 (cardiac glycosides) 有機硝酸鹽 (organic nitrates) 及其他治療心血管疾病之血管擴張劑 (vasodilators) 鈣離子通道阻斷劑 (calcium channel blockers) β- 阻斷劑 (β-blockers) 血管收縮素轉化酶抑制劑 (ACE inhibitors) Angiotensin II 拮抗劑 (Angiotensin II antagonists) 選擇性 β-2 腎上腺素接受體作用劑 (selective β-2 adrenoceptor agonists) 口服抗凝血劑 (oral anticoagulants) 血小板凝結抑制劑 (platelet aggregation inhibitors) statins 類 fibrates 類 及 benzodiazepine 衍生物等 懷孕與授乳 本藥僅用於停經後婦女 尚無 strontium ranelate 用於懷孕婦女之臨床資料 於動物實驗中顯示, 對懷孕期中的大鼠與兔投與高劑量, 對其子代的骨骼有可逆性影響 ( 請參考 臨床前安全性資料 ) 若在懷孕期間不慎使用 Protos, 必須停止使用 strontium 會被分泌到乳汁中, 因此 strontium ranelate 不應投予授乳婦女 對於駕駛與機器操作能力之影響 strontium ranelate 對於駕駛與機器操作之能力並無影響, 或 其影響極輕微而可忽略 不良反應 Protos 已經在涵括將近 8,000 位受試者的臨床試驗中進行研究 在第三期臨床試驗中, 針對患有骨質疏鬆症的停經後婦女, 每日以 strontium ranelate 2g (n=3352) 或安慰劑 (n=3317) 治療, 最高長達 56 個月的長期安全性已經進行過評估 在收案時受試者平均年齡為 75 歲, 而收入的受試者中 23% 的年齡是 80~100 歲 以 strontium ranelate 治療之不良反應總發生率與安慰劑組並無不同, 而且所發生的不良反應通常是輕微而短暫的 最常見的不良反應為噁心與下痢, 通常報告於治療初期, 之後在兩組間並無明顯差異 治療中止通常是因為噁心 ( 在安慰劑組與 strontium ranelate 組的發生率分別為 1.3% 與 2.2%) 不良反應之定義為在第三期臨床試驗中所發生至少可能與 strontium ranelate 治療相關之不良事件, 使用以下慣例 ( 相較於安慰劑組之發生頻率 ) 列出如下 : 易見 (>1/10); 常見 (>1/100, <1/10); 少見 (>1/1,000, <1/100); 罕見 (>1/10,000, <1/1,000); 極罕見 (<1/10,000) 非特異性神經系統疾病 2 常見 : 頭痛 (3.3% vs. 2.7%) 胃腸道疾病常見 : 噁心 (7.1% vs. 4.6%) 下痢 (7.0% vs. 5.0%) 軟便 (1.0% vs. 0.2%) 皮膚與皮下組織疾病常見 : 皮膚炎 (2.3% vs. 2.0%) 濕疹 (1.8% vs. 1.4%) 無論患者在納入臨床試驗時是低於或高於 80 歲, 兩組之間不良事件的種類沒有差異 心臟血管疾病於第三期臨床試驗中經過五年觀察, 相較於安慰劑組, 以 strontium ranelate 治療的患者之靜脈血栓性栓塞 (VTE) 年發生率約為 0.7%, 其相對危險性為 1.4 (95% 信賴區間 :[1.0; 2.0]) ( 請參考 特別警語及注意事項 ) 中樞神經系統疾病於第三期臨床試驗中經過五年觀察, 相較於安慰劑組, 以 strontium ranelate 治療患者較常報告之神經系統疾病 : 意識不清 (2.6% vs. 2.1%) 記憶喪失 (2.5% vs. 2.0%) 及癲癇 (seizures) (0.4% vs. 0.1%) 實驗室檢測數據於 strontium ranelate 組及安慰劑組分別有 1.4% 及 0.6% 報告 creatine kinase (CK) 活性 ( 肌肉 - 骨骼部分 ) 短暫而急遽升高 ( 大於 3 倍正常值上限 ) 大部份的病例中, 不需改變治療而這些數值會自動回覆至正常 以下事件曾報告於上市後經驗 : 胃腸道疾病發生頻率未知 : 嘔吐 上腹痛 口腔黏膜刺激性包括口腔炎及 / 或口腔潰瘍 皮膚與皮下組織疾病發生頻率未知 : 皮膚過敏反應包括皮疹 搔癢 蕁麻疹 血管性水腫 (angioedema) Steven-Johnson 症候群 Protos 可能引起更罕見的 藥物疹合併嗜伊紅性白血球症及全身症狀 (Drug Rash with Eosinophilia and Systemic Symptoms; DRESS) 在 57 萬人年的使用經驗中共發生 16 位案例 通常在使用後三至六週開始發生症狀, 主要特徵為發燒, 皮膚炎及內部器官之侵犯, 嚴重可致死 因此使用本藥品有任何皮膚過敏者, 應立即停止使用本藥品, 並儘速回診 ( 請參考 特別警語及注意事項 ) 肌肉骨骼與結締組織的疾病發生頻率未知 : 肌肉骨骼疼痛包括肌肉痙攣 肌肉痛 骨疼痛 關節痛 以及四肢痛 藥物過量 於健康停經婦女的臨床試驗中, 每日給予 strontium ranelate 4g 連續 25 日, 顯示有良好的耐受性 於健康年輕男性自願者, 給予單一劑量最高 11g, 並未導致任何特別症狀 在臨床試驗中追蹤藥物過量事件 ( 最高每日 4g 長達 147 日 ), 未發現臨床相關事件 服用牛奶或制酸劑可能有助於降低有效成分的吸收 於實際藥物過量事件中, 可以考慮催吐以移除未吸收的有效成分 藥理性質 藥效性質藥理分類 : 骨骼疾病治療劑 其他影響骨骼結構與礦質化的藥物

3 ATC code:m05bx03 於體外試驗中,strontium ranelate: 在骨組織培養中增加骨質形成 並且在骨細胞培養中, 增加造骨細胞先驅物 (osteoblast precusor) 複製及膠質合成 降低破骨細胞 (osteoclast) 分化及再吸收之活性 在不同的非臨床試驗模式中已對 strontium ranelate 之活性進行過研究 特別是在完整的大鼠中,strontium ranelate 會增加骨小梁 (trabecular) 骨質量 骨小梁 (trabeculae) 數量及厚度 ; 而改善骨骼強度 在接受治療的動物與人的骨組織中,strontium 主要被吸附到磷灰石結晶表面, 而且有些取代新形成骨質中磷灰石結晶內的鈣 在使用三年後, 骨組織中每 100 個鈣約含有 1 個 strontium, 在動物實驗 ( 猴子 ) 中最多每 10 個鈣便有一個被 strontium 取代 但並不會因此改變骨結晶性質 於第三期臨床試驗中, 每日以 strontium ranelate 2g 治療長達 60 個月後所取得的骼嵴 (iliac crest) 骨切片中, 未發現到對骨品質或礦質化有害的影響 strontium 在骨中的分佈 ( 請參考 藥物動力學性質 ) 及其高於鈣的 X 光吸收之性質, 使得以骨密度測量儀 (DXA) 測得之骨質密度值 (BMD) 比實際值高出約 40% 因此使用 Protos 治療期間,BMD 的增加應根據上述因素加以校正 在第三期臨床試驗中已說明 Protos 抗骨折的療效, 以 Protos 治療, 所測得的平均 BMD 值比基準點 (baseline) 增加, 在腰椎每年增加將近 4%, 在股骨頸 (femoral neck) 每年增加約 2%, 在不同臨床試驗中在 3 年後分別達到 13~15% 及 5~6% 於第三期臨床試驗中, 相較於安慰劑組,strontium ranelate 組從第 3 個月到最長 3 年, 其骨質形成的生化標記 ( 骨特異性的 alkaline phosphatase 及第一型 procollagen C 端 propeptide) 增加, 而骨質再吸收的生化標記 ( 血清 C-telopeptide 及尿液 N-telopeptide 交互連結 ) 降低 經過 strontium ranelate 的藥理作用之後, 會觀察到血鈣濃度及血中副甲狀腺 (PTH) 濃度降低, 血中磷濃度及 alkaline phosphatase 活性增加, 並沒有觀察到臨床症狀 臨床療效 骨質疏鬆症定義為脊椎骨或髖骨的 BMD 值比正常年輕族群平均值低 2.5 倍標準差或更低 有許多危險因子和停經後骨質疏鬆症有相關, 包括低骨量 低骨密度 (BMD) 提早停經 抽菸史或骨質疏鬆症家族史 骨質疏鬆症臨床上的後續結果是骨折 骨折的風險會隨著危險因子數增加而增加 停經後骨質疏鬆症之治療 : Protos 抗骨折研究計畫是由兩個安慰劑對照的第三期臨床試驗組成 :SOTI 試驗及 TROPOS 試驗 SOTI 涵括 1,649 位確定患有骨質疏鬆症 ( 腰椎的 BMD 值低且曾有脊椎骨折 ) 的停經婦女, 其平均年齡為 70 歲 TROPOS 涵括 5,091 位患有骨質疏鬆症的停經婦女 ( 股骨頸 (femoral neck) BMD 值低且一半以上有一般性骨折 ), 其平均年齡為 77 歲 SOTI 和 TROPOS 在收案時總共收入 1,556 位超過 80 歲的患者 ( 占總受試者人數的 23.1%) 在這兩個臨床試驗中除了試驗藥物之外 ( 每日 strontium ranelate 2g 或安慰劑 ), 受試者並接受適當的鈣與維生素 D 補充 於 SOTI 試驗中, 經過 3 年後,Protos 會使新脊椎骨折相對危險性降低達 41% ( 表一 ) 此效果從第一年已達顯著 3 性 對於在基準點已患有多重骨折的婦女, 也顯示出類似的效果 關於臨床上的脊椎骨折 ( 定義為與背痛相關之骨折以及 / 或身高減少至少 1 公分者 ), 其相對危險性降低約 38% 相較於安慰劑組,Protos 也使身高減少至少 1 公分的受試者數目減少 相較於安慰劑組, 以 QUALIOST 特定尺度所作的生活品質評估以及 SF-36 一般尺度的總體健康認知分數都指出 Protos 的益處 於 TROPOS 試驗中確認了 Protos 降低新脊椎骨折危險性的療效, 包括在基準點時沒有脆弱骨折的骨質疏鬆症患者 表一 : 受試者脊椎骨折發生率及相對危險性之降低 安慰劑組 Protos 組 SOTI 試驗 N=723 N=719 相較於安慰劑組, 相對危險性之降低 (95% 信賴區間 ),p 值 3 年後新脊椎骨折 32.8% 20.9% 41% (27~52), p< 年後新脊椎骨折 11.8% 6.1% 49% (26~64), p< 年後新臨床上的脊椎骨折 TROPOS 試驗 N=1,823 N=1, % 11.3% 38% (17~53), p< 年後新脊椎骨折 20.0% 12.5% 39% (27~49), p<0.001 對於在收案時年齡超過 80 歲的患者, SOTI 和 TROPOS 試驗的共同分析結果顯示, 經過 3 年治療,Protos 會降低新脊椎骨折相對危險性約 32% (strontium ranelate 組發生率為 19.1% vs. 安慰劑組發生率為 26.5%) 混合 SOTI 及 TROPOS 試驗的患者, 對於在基準點時腰椎 (lumbar spine) 及 / 或股骨頸 (femoral neck) BMD 值在骨質缺乏範圍, 且沒有一般性骨折但有至少一項骨折的危險因子者 (N=176), 進行試驗後分析 (a-posteriori 分析 ), 發現經過 3 年 Protos 可以降低第一次脊椎骨折的危險性約 72% (strontium ranelate 組之脊椎骨折發生率為 3.6% vs. 安慰劑組之脊椎骨折發生率為 12.0%) 依此 Meta-analysis 研究顯示 ( 此種研究會有其他干擾因素 ), 使用 Protos 患者 3 年, 股骨頸 (proximal femur) BMD 的增加與脊椎 (vertebral) BMD 值雖有改變, 其對降低新的脊椎骨折發生率無統計學之相關性 於次群體 TROPOS 試驗中, 對有特別醫學興趣及高骨折危險的次族群患者 [ 定義為其股骨頸 (femoral neck) BMD T-score 3SD ( 製造廠商設定範圍, 對應於使用 NHANES III 之 2.4SD), 且年齡 74 歲者 (n=1,977, 佔 TROPOS 試驗人數的 40%)] 進行試驗後分析 (a-posteriori 分析 ) 在此次群體中, 經過 3 年治療, 相較於安慰劑組,Protos 可降低髖骨骨折危險性約 36% ( 表 2) 表 2: 於 BMD 2.4SD (NHANS III) 且年齡 74 歲的患者中, 髖骨骨折發生率及相對危險性之降低安慰劑組 Protos 組相較於安慰劑組, 相對危險性之降低 (95% 信賴區間 ),p 值 TROPOS 試驗 N=995 N=982 3 年後髖骨骨折 6.4% 4.3% 36% (0~59), p=0.046 藥物動力學性質 strontium ranelate 是由兩個穩定的鍶原子及一個 ranelic acid 分子組合而成 strontium 和 ranelic acid 的藥物動力學性質已經在健康年輕男性及健康停經後婦女進行過評估, 同時

4 也在停經後骨質疏鬆的婦女, 包括年長婦女的長期治療中進行過評估 由於 ranelic acid 的高極性, 其吸收 分佈 及血漿蛋白質結合率低 在動物與人體中無 ranelic acid 蓄積, 亦無證據顯示有代謝 被吸收的 ranelic acid 會很快地經由腎臟以原型排出 吸收於口服 strontium ranelate 2g 後,strontium 的絕對生體可得率約 25% ( 範圍 19~27%) 在投與單一劑量 2g 後 3~5 小時達到最高血漿濃度 於開始治療後兩週可達穩定狀態 與餐後 3 小時後服用 strontium ranelate 相較, 同時服用 strontium ranelate 與鈣或食物, 會降低 strontium 的生體可用率約 60~70% 由於 strontium 的吸收相當緩慢, 於服用 Protos 前或後應避免用餐或攝取含鈣食物 口服維生素 D 補充劑對 strontium 濃度並無影響 分佈 strontium 分佈體積約 1 L/Kg strontium 與人體血漿蛋白質結合率低 (25%), 且 strontium 對骨組織有高親和性 於每日以 strontium ranelate 2g 治療長達 60 個月的患者中所取得的骼嵴 (iliac crest) 骨切片, 測量其中 strontium 濃度, 發現治療約 3 年後, 骨中 strontium 濃度會達到穩定 尚未有患者資料說明停止用藥後 strontium 由骨中排除的動力學 及牙齒發生異常, 主要包含自發性骨折及延緩礦質化作用 這些反應是在骨中 strontium 濃度比長期臨床上骨中 strontium 濃度高 2~3 倍時所報告, 且在停止投與之後為可逆性 以大鼠與兔所進行的發育毒性試驗, 導致其子代骨骼與牙齒發生異常 ( 例如彎曲的長骨及波浪狀肋骨 ) 於大鼠身上, 這些影響在停止投予藥物後 8 週可回復 藥品性質 1. 賦形劑 :Aspartame, Maltodextrin, Mannitol 2. 不相容性 : 無 3. 有效期間 :3 年 4. 儲存條件 :25 以下 包裝 每盒含 2 ~500 小包 生物轉換性因為 strontium 是雙價陽離子, 它不會被代謝 strontium ranelate 並不會抑制 cytochrome P450 酵素 排除 strontium 的排除與時間及劑量無關 其有效的半衰期約 60 小時 strontium 經由腎及胃腸道排除 其血漿廓清率約 12 毫升 / 分 (CV 22%), 而其腎廓清率約 7 毫升 / 分 (CV 28%) 特殊族群的藥物動力學性質 老年人群體藥物動力學 (Population pharmacokinetics) 資料顯示, 於治療之標的族群中, 年齡與 strontium 的表面廓清率 (apparent clearance) 無關 腎功能不全之患者於患有輕度至中度腎功能不全的患者中 (creatinine 廓清率為 30~70 毫升 / 分 ),strontium 廓清率會隨著 creatinine 廓清率降低 ( 在 creatinine 廓清率 30~70 毫升 / 分範圍內約降低 30%) 而降低, 因而導致血漿中 strontium 濃度增加 於第三期臨床試驗中, 在收案時 85% 患者之 creatinine 廓清率在 30~70 毫升 / 分之間, 而 6% 患者是低於 30 毫升 / 分, 其平均 creatinine 廓清率約為 50 毫升 / 分 因此對於輕度至中度腎功能不全的患者毋需調整劑量 對於嚴重腎功能不全的患者 (creatinine 廓清率低於 30 毫升 / 分 ), 並無藥物動力學資料 肝功能不全之患者對於肝功能不全之患者, 並無藥物動力學資料 由於 strontium 的藥物動力學性質, 預期並無影響 藥商 : 新加坡商施維雅股份有限公司台灣分公司地址 : 台北市松江路 168 號 3 樓 製造廠及廠址 : Les Laboratoires Servier 22 rue Garnier Neuilly sur Seine - France Manufacturer: Les Laboratoires Servier Industrie 905 route de Saran Gidy - France 臨床前安全性資料 依據安全性藥理學 生殖毒性 致癌性等傳統的試驗, 臨床前資料顯示對人體並無特殊的傷害 對大鼠長期經口投與高劑量 strontium ranelate 會導致骨骼 4

5 1. NAME OF THE MEDICINAL PRODUCT PROTELOS 2 g granules for oral suspension 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each sachet contains 2 g of strontium ranelate. Excipient: also contains 20 mg of aspartame (E951). For a full list of excipients, see section PHARMACEUTICAL FORM Granules for oral suspension Yellow granules 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Treatment of postmenopausal osteoporosis to reduce the risk of vertebral and hip fractures (see section 5.1). 4.2 Posology and method of administration The recommended daily dose is one 2 g sachet once daily by oral administration. Due to the nature of the treated disease, strontium ranelate is intended for long-term use. The absorption of strontium ranelate is reduced by food, milk and derivative products and therefore, PROTELOS should be administered in-between meals. Given the slow absorption, PROTELOS should be taken at bedtime, preferably at least two hours after eating (see sections 4.5 and 5.2). The granules in the sachets must be taken as a suspension in a glass of water. Although in-use studies have demonstrated that strontium ranelate is stable in suspension for 24 hours after preparation, the suspension should be drunk immediately after being prepared. Patients treated with strontium ranelate should receive vitamin D and calcium supplements if dietary intake is inadequate. Use in the elderly The efficacy and safety of strontium ranelate have been established in a broad age range (up to 100 years at inclusion) of postmenopausal women with osteoporosis. No dosage adjustment is required in relation to age. Use in renal impairment No dosage adjustment is required in patients with mild-to-moderate renal impairment (30-70 ml/min creatinine clearance) (see section 5.2). Strontium ranelate is not recommended for patients with severe renal impairment (creatinine clearance below 30 ml/min) (see sections 4.4 and 5.2). Use in hepatic impairment 1

6 As strontium ranelate is not metabolised, no dosage adjustment is required in patients with hepatic impairment. Use in children and adolescents PROTELOS is not recommended for use in children and adolescents due to a lack of data on safety and efficacy. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients. 4.4 Special warnings and precautions for use In the absence of bone safety data in patients with severe renal impairment treated with strontium ranelate, PROTELOS is not recommended in patients with a creatinine clearance below 30 ml/min (see section 5.2). In accordance with good medical practice, periodic assessment of renal function is recommended in patients with chronic renal impairment. Continuation of treatment with PROTELOS in patients developing severe renal impairment should be considered on an individual basis. In phase III placebo-controlled studies, strontium ranelate treatment was associated with an increase in the annual incidence of venous thromboembolism (VTE), including pulmonary embolism (see section 4.8). The cause of this finding is unknown. PROTELOS should be used with caution in patients at increased risk of VTE, including patients with a past history of VTE. When treating patients at risk, or developing risk of VTE, particular attention should be given to possible signs and symptoms of VTE and adequate preventive measures taken. Strontium interferes with colorimetric methods for the determination of blood and urinary calcium concentrations. Therefore, in medical practice, inductively coupled plasma atomic emission spectrometry or atomic absorption spectrometry methods should be used to ensure an accurate assessment of blood and urinary calcium concentrations. PROTELOS contains a source of phenylalanine, which may be harmful for people with phenylketonuria. Treatment with PROTELOS should be discontinued in case of serious allergic reaction. Cases of severe hypersensitivity syndromes, including, in particular, drug rash with eosinophilia and systemic symptoms (DRESS), sometimes fatal, have been reported with the use of PROTELOS (see section 4.8). The DRESS syndrome is characterised by rash, fever, eosinophilia and systemic involvement (e.g. adenopathy, hepatitis, interstitial nephropathy, interstitial lung disease). Time to onset was usually around 3-6 weeks and the outcome in most cases favourable upon discontinuation of PROTELOS and after initiation of corticosteroid therapy. Recovery could be slow and recurrences of the syndrome have been reported in some cases after discontinuation of corticosteroid therapy. Patients should be informed to stop PROTELOS immediately and permanently when a rash occurs and to seek medical advice. Patients who have stopped treatment due to hypersensitivity reactions should not re-start therapy with PROTELOS. 4.5 Interaction with other medicinal products and other forms of interaction Food, milk and derivative products, and medicinal products containing calcium may reduce the bioavailability of strontium ranelate by approximately 60-70%. Therefore, administration of PROTELOS and such products should be separated by at least two hours (see section 5.2). An in vivo clinical interaction study showed that the administration of aluminium and magnesium hydroxides either two hours before or together with strontium ranelate caused a slight decrease in the absorption of strontium ranelate (20-25% AUC decrease), while absorption was almost unaffected 2

7 when the antacid was given two hours after strontium ranelate. It is therefore preferable to take antacids at least two hours after PROTELOS. However, when this dosing regimen is impractical due to the recommended administration of PROTELOS at bedtime, concomitant intake remains acceptable. As divalent cations can form complexes with oral tetracycline and quinolone antibiotics at the gastrointestinal level and thereby reduce their absorption, simultaneous administration of strontium ranelate with these medicinal products is not recommended. As a precautionary measure, PROTELOS treatment should be suspended during treatment with oral tetracycline or quinolone antibiotics. No interaction was observed with oral supplementation of vitamin D. No evidence of clinical interactions or relevant increase of blood strontium levels with medicinal products expected to be commonly prescribed concomitantly with PROTELOS in the target population were found during clinical trials. These included: nonsteroidal anti-inflammatory agents (including acetylsalicylic acid), anilides (such as paracetamol), H 2 blockers and proton pump inhibitors, diuretics, digoxin and cardiac glycosides, organic nitrates and other vasodilators for cardiac diseases, calcium channel blockers, beta blockers, ACE inhibitors, angiotensin II antagonists, selective beta-2 adrenoceptor agonists, oral anticoagulants, platelet aggregation inhibitors, statins, fibrates and benzodiazepine derivatives. 4.6 Pregnancy and lactation PROTELOS is only intended for use in postmenopausal women. No clinical data on exposed pregnancies are available for strontium ranelate. At high doses, animal studies have shown reversible bone effects in the offspring of rats and rabbits treated during pregnancy (see section 5.3). If PROTELOS is used inadvertently during pregnancy, treatment must be stopped. Strontium is excreted in milk. Strontium ranelate should not be given to nursing women. 4.7 Effects on ability to drive and use machines Strontium ranelate has no or negligible influence on the ability to drive and use machines. 4.8 Undesirable effects PROTELOS has been studied in clinical trials involving nearly 8,000 participants. Long-term safety has been evaluated in postmenopausal women with osteoporosis treated for up to 60 months with strontium ranelate 2 g/day (n=3,352) or placebo (n=3,317) in phase III studies. Mean age was 75 years at inclusion and 23% of the patients enrolled were 80 to 100 years of age. Overall incidence rates for adverse events with strontium ranelate did not differ from placebo and adverse events were usually mild and transient. The most common adverse events consisted of nausea and diarrhoea, which were generally reported at the beginning of treatment with no noticeable difference between groups afterwards. Discontinuation of therapy was mainly due to nausea (1.3% and 2.2% in the placebo and strontium ranelate groups respectively). Adverse reactions, defined as adverse events considered at least possibly attributable to strontium ranelate treatment in phase III studies are listed below using the following convention (frequencies versus placebo): 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). Nervous system disorders Common: headache (3.3% vs. 2.7%) Gastrointestinal disorders Common: nausea (7.1% vs. 4.6%), diarrhoea (7.0% vs. 5.0%), loose stools (1.0% vs. 0.2%) 3

8 Skin and subcutaneous tissue disorders Common: dermatitis (2.3% vs. 2.0%), eczema (1.8% vs. 1.4%) There were no differences in the nature of adverse events between treatment groups regardless of whether patients were aged below or above 80 at inclusion. In phase III studies, the annual incidence of venous thromboembolism (VTE) observed over5 years was approximately 0.7%, with a relative risk of 1.4 (95% CI = [1.0 ; 2.0]) in strontium ranelate treated patients as compared to placebo (see section 4.4). In phase III studies, over 5 years, nervous system disorders were reported with higher frequency in patients treated with strontium ranelate, compared with placebo: disturbances in consciousness (2.6% vs. 2.1%), memory loss (2.5% vs. 2.0%) and seizures (0.4% vs. 0.1%). Laboratory test findings Transient emergent increases (> 3 times the upper limit of the normal range) in creatine kinase (CK) activity (musculo-skeletal fraction) were reported in 1.4% and 0.6% of the strontium ranelate and placebo groups respectively. In most cases, these values spontaneously reverted to normal without change in treatment. The following events have been reported in post-marketing experience: Gastrointestinal disorders Frequency unknown: vomiting, abdominal pain, oral mucosal irritation including stomatitis and/or mouth ulceration Skin and subcutaneous tissue disorders Frequency unknown: hypersensitivity skin reactions including rash, pruritus, urticaria, angioedema, Stevens-Johnson syndrome.cases of severe hypersensitivity syndromes including drug rash with eosinophilia and systemic symptoms (DRESS) (see section 4.4). Musculoskeletal and connective tissue disorders Frequency unknown: musculoskeletal pain including muscle spasm, myalgia, bone pain, arthralgia and pain in extremity. 4.9 Overdose Good tolerance was shown in a clinical study investigating the repeated administration of 4 g strontium ranelate per day over 25 days in healthy postmenopausal women. Single administration of doses up to 11 g in healthy young male volunteers did not cause any particular symptoms. Following episodes of overdoses during clinical trials (up to 4 g/day for a maximal duration of 147 days), no clinically relevant events were observed. Administration of milk or antacids may be helpful to reduce the absorption of the active substance. In the event of substantial overdose, vomiting may be considered to remove unabsorbed active substance. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Drugs for the treatment of bone diseases - Other drugs affecting bone structure and mineralisation ATC code: M05BX03 In vitro, strontium ranelate: - increases bone formation in bone tissue culture as well as osteoblast precursor replication and collagen synthesis in bone cell culture; - reduces bone resorption by decreasing osteoclast differentiation and resorbing activity. 4

9 This results in a rebalance of bone turnover in favour of bone formation. The activity of strontium ranelate was studied in various non-clinical models. In particular, in intact rats, strontium ranelate increases trabecular bone mass, trabeculae number and thickness; this results in an improvement of bone strength. In bone tissue of treated animals and humans, strontium is mainly adsorbed onto the crystal surface and only slightly substitutes for calcium in the apatite crystal of newly formed bone. Strontium ranelate does not modify the bone crystal characteristics. In iliac crest bone biopsies obtained after up to 60 months of treatment with strontium ranelate 2 g/day in phase III trials, no deleterious effects on bone quality or mineralisation were observed. The combined effects of strontium distribution in bone (see section 5.2) and increased X-ray absorption of strontium as compared to calcium, leads to an amplification of bone mineral density (BMD) measurement by dual-photon X-ray absorptiometry (DXA). Available data indicate that these factors account for approximately 50% of the measured change in BMD over 3 years of treatment with PROTELOS 2 g/day. This should be taken into account when interpreting BMD changes during treatment with PROTELOS. In phase III studies, which demonstrated the anti-fracture efficacy of PROTELOS treatment, measured mean BMD increased from baseline with PROTELOS by approximately 4% per year at the lumbar spine and 2% per year at the femoral neck, reaching 13% to 15% and 5% to 6% respectively after 3 years, depending on the study. In phase III studies, as compared to placebo, biochemical markers of bone formation (bone-specific alkaline phosphatase and C-terminal propeptide of type I procollagen) increased and those of bone resorption (serum C-telopeptide and urinary N-telopeptide cross links) decreased from the third month of treatment up to 3 years. Secondary to the pharmacological effects of strontium ranelate, slight decreases in calcium and parathyroid hormone (PTH) serum concentrations, increases in blood phosphorus concentrations and in total alkaline phosphatase activity were observed, with no observed clinical consequences. Clinical efficacy Osteoporosis is defined as BMD of the spine or hip 2.5 SD or more below the mean value of a normal young population. A number of risk factors are associated with postmenopausal osteoporosis including low bone mass, low bone mineral density, early menopause, a history of smoking and a family history of osteoporosis. The clinical consequence of osteoporosis is fractures. The risk of fractures is increased with the number of risk factors. Treatment of postmenopausal osteoporosis: The anti-fracture studies program of PROTELOS was made up of two placebo-controlled phase III studies: SOTI study and TROPOS study. SOTI involved 1,649 postmenopausal women with established osteoporosis (low lumbar BMD and prevalent vertebral fracture) and a mean age of 70 years. TROPOS involved 5,091 postmenopausal women with osteoporosis (low femoral neck BMD and prevalent fracture in more than half of them) and a mean age of 77 years. Together, SOTI and TROPOS enrolled 1,556 patients over 80 years at inclusion (23.1% of the study population). In addition to their treatment (2 g/day strontium ranelate or placebo), the patients received adapted calcium and vitamin D supplements throughout both studies. PROTELOS reduced the relative risk of new vertebral fracture by 41% over 3 years in the SOTI study (table 1). The effect was significant from the first year. Similar benefits were demonstrated in women with multiple fractures at baseline. With respect to clinical vertebral fractures (defined as fractures associated with back pain and/or a body height loss of at least 1 cm), the relative risk was reduced by 38%. PROTELOS also decreased the number of patients with a body height loss of at least 1 cm as compared to placebo. Quality of life assessment on the QUALIOST specific scale as well as the General Health perception score of the SF-36 general scale indicated benefit of PROTELOS, compared with placebo. 5

10 Efficacy of PROTELOS to reduce the risk of new vertebral fracture was confirmed in the TROPOS study, including for osteoporotic patients without fragility fracture at baseline. Table 1: Incidence of patients with vertebral fracture and relative risk reduction Placebo PROTELOS Relative Risk Reduction vs. placebo (95%CI), p value SOTI N=723 N=719 New vertebral fracture over 3 years New vertebral fracture over the 1 st year New clinical vertebral fracture over 3 years 32.8% 20.9% 41% (27-52), p< % 6.1% 49% (26-64), p< % 11.3% 38% (17-53), p<0.001 TROPOS N=1823 N=1817 New vertebral fracture over 3 years 20.0% 12.5% 39% (27-49), p<0.001 In patients over 80 years of age at inclusion, a pooled analysis of SOTI and TROPOS studies showed that PROTELOS reduced the relative risk of experiencing new vertebral fractures by 32% over 3 years (incidence of 19.1% with strontium ranelate vs. 26.5% with placebo). In an a-posteriori analysis of patients from the pooled SOTI and TROPOS studies with baseline lumbar spine and / or femoral neck BMD in the osteopenic range and without prevalent fracture but with at least one additional risk factor for fracture (N=176), PROTELOS reduced the risk of a first vertebral fracture by 72% over 3 years (incidence of vertebral fracture 3.6% with strontium ranelate vs. 12.0% with placebo). An a-posteriori analysis was performed on a subgroup of patients from the TROPOS study of particular medical interest and at high-risk of fracture [defined by a femoral neck BMD T-score - 3 SD (manufacturer s range corresponding to -2.4 SD using NHANES III) and an age 74 years (n=1,977, i.e. 40% of the TROPOS study population)]. In this group, over 3 years of treatment, PROTELOS reduced the risk of hip fracture by 36% relative to the placebo group (table 2). Table 2: Incidence of patients with hip fracture and relative risk reduction in patients with BMD -2.4 SD (NHANES III) and age 74 years Placebo PROTELOS Relative Risk Reduction vs. placebo (95%CI), p value TROPOS N=995 N=982 Hip fracture over 3 years 6.4% 4.3% 36% (0-59), p= Pharmacokinetic properties Strontium ranelate is made up of 2 atoms of stable strontium and 1 molecule of ranelic acid, the organic part permitting the best compromise in terms of molecular weight, pharmacokinetics and acceptability of the medicinal product. The pharmacokinetics of strontium and ranelic acid have been assessed in healthy young men and healthy postmenopausal women, as well as during long-term exposure in postmenopausal osteoporotic women including elderly women. Due to its high polarity, the absorption, distribution and binding to plasma proteins of ranelic acid are low. There is no accumulation of ranelic acid and no evidence of metabolism in animals and humans. Absorbed ranelic acid is rapidly eliminated unchanged via the kidneys. Absorption 6

11 The absolute bioavailability of strontium is about 25% (range 19-27%) after an oral dose of 2 g strontium ranelate. Maximum plasma concentrations are reached 3-5 hours after a single dose of 2 g. Steady state is reached after 2 weeks of treatment. Intake of strontium ranelate with calcium or food reduces the bioavailability of strontium by approximately 60-70%, compared with administration 3 hours after a meal. Due to the relatively slow absorption of strontium, food and calcium intake should be avoided both before and after administration of PROTELOS. Oral supplementation with vitamin D has no effect on strontium exposure. Distribution Strontium has a volume of distribution of about 1 l/kg. The binding of strontium to human plasma proteins is low (25%) and strontium has a high affinity for bone tissue. Measurement of strontium concentration in iliac crest bone biopsies from patients treated for up to 60 months with strontium ranelate 2 g/day indicate that bone strontium concentrations may reach a plateau after about 3 years of treatment. There are no data in patients to demonstrate elimination kinetics of strontium from bone off-therapy. Biotransformation As a divalent cation, strontium is not metabolised. Strontium ranelate does not inhibit cytochrome P450 enzymes. Elimination The elimination of strontium is time and dose independent. The effective half-life of strontium is about 60 hours. Strontium excretion occurs via the kidneys and the gastrointestinal tract. Its plasma clearance is about 12 ml/min (CV 22%) and its renal clearance about 7 ml/min (CV 28%). Pharmacokinetics in special clinical situations Elderly Population pharmacokinetic data showed no relationship between age and apparent clearance of strontium in the target population. Patients with renal impairment In patients with mild-to-moderate renal impairment (30-70 ml/min creatinine clearance), strontium clearance decreases as creatinine clearance decreases (approximately 30% decrease over the creatinine clearance range 30 to 70 ml/min) and thereby induces an increase in strontium plasma levels. In phase III studies, 85% of the patients had a creatinine clearance between 30 and 70 ml/min and 6% below 30 ml/min at inclusion, and the mean creatinine clearance was about 50 ml/min. No dosage adjustment is therefore required in patients with mild-to-moderate renal impairment. There is no pharmacokinetic data in patients with severe renal impairment (creatinine clearance below 30 ml/min). Patients with hepatic impairment There is no pharmacokinetic data in patients with hepatic impairment. Due to the pharmacokinetic properties of strontium, no effect is expected. 5.3 Preclinical safety data Non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and carcinogenic potential. Chronic oral administration of strontium ranelate at high doses in rodents induced bone and tooth abnormalities, mainly consisting of spontaneous fractures and delayed mineralisation. These effects were reported at bone strontium levels 2-3 times higher than long-term clinical bone strontium levels and were reversible after cessation of treatment. 7

12 Developmental toxicity studies in rats and rabbits resulted in bone and tooth abnormalities (e.g. bent long bones and wavy ribs) in the offspring. In rats, these effects were reversible 8 weeks after cessation of treatment. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Aspartame (E951) Maltodextrin Mannitol (E421) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years. 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container Paper/polyethylene/aluminium/polyethylene sachets. Pack sizes Boxes containing 7, 14, 28, 56, 84 or 100 sachets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal No special requirements. 7. MARKETING AUTHORISATION HOLDER LES LABORATOIRES SERVIER 22, rue Garnier Neuilly-sur-Seine France 8. MARKETING AUTHORISATION NUMBER(S) EU/1/04/287/001 EU/1/04/287/002 EU/1/04/287/003 EU/1/04/287/004 EU/1/04/287/005 EU/1/04/287/006 8

13 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 21/09/ DATE OF REVISION OF THE TEXT December 2007 Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) 9