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【通用名称】 注射用替加环素

【英文名称】 Tigecycline for Injection

 

 

警示语：

·在Ⅲ、Ⅳ期临床试验中观察到，使用替加环素治疗的患者比对照组患者的全因死亡率增加。增加的原因尚未明确，但在治疗选择时应考虑全因死亡率的增加。
·已有替加环素的过敏反应/类过敏反应的报告，并且可能威胁生命。对四环素过敏的患者使用时应慎用。
·已有使用替加环素后出现肝功能絮乱和肝衰竭的报告。
·呼吸机相关性肺炎的患者使用替加环素后观察到较低治愈率和更高死亡率。
·已有使用替加环素后出现胰腺炎，包括死亡的报告。如果使用替加环素后怀疑引起胰腺炎，应考虑停止给予替加环素。
·给予怀孕妇女替加环素可能会导致胎儿受损。
·在牙齿发育阶段，替加环素的使用可能导致永久性牙齿变色。
·艰难梭菌相关性腹泻：当出现腹泻应进行评估。

成份：

本品主要成份为替加环素。
化学名称：（4S,4aS,5aR,12aS）-9-（2-叔丁基氨基乙酰氨基）-4,7-双二甲氨基-1,4,4a,5,5a,6,11,12a-八氢-3,10,12,12a-四羟基-1,11-二氧代-2-并四苯甲酰胺
化学结构式：
分子式：C29H39N5O8
分子量：585.65
辅 料：乳糖、盐酸

 

性状：

本品为橙色疏松块状物或粉末。

适应症：

本品适用于18岁以上患者在下列情况下由特定细菌的敏感菌株所致感染的治疗：
复杂性腹腔内感染：由弗劳地枸橼酸杆菌、阴沟肠杆菌、大肠埃希菌、产酸克雷伯菌、肺炎克雷伯菌、粪肠球菌（仅限于万古霉素敏感菌株）、金黄色葡萄球菌（甲氧西林敏感菌株和甲氧西林耐药菌株）、咽峡炎链球菌族（包括咽峡炎链球菌、中间链球菌和星座链球菌）、脆弱拟杆菌、多形拟杆菌、单形拟杆菌、普通拟杆菌、产气荚膜梭菌和微小消化链球菌所致者。
复杂皮肤及软组织感染：由大肠埃希菌、肠球菌（万古霉素敏感株）、金黄色葡萄球菌（甲氧西林敏感和耐药株）、无乳链球菌、咽峡炎链球菌属（包括咽峡炎链球菌、中间链球菌和星座链球菌），化脓性链球菌、阴沟肠杆菌、肺炎杆菌和脆弱拟杆菌所致者。
社区获得性肺炎：由肺炎链球菌（青霉素敏感株），流感嗜血杆菌（β-内酰胺酶阴性株）和嗜肺性军团病杆菌等所致，包括并发菌血症。
为了分离、鉴定病原菌并明确其对替加环素的敏感性，应该留取合适标本进行细菌学检测。在尚未获知这些试验结果之前，可采用本品作为经验性单药治疗。
为了减少耐药细菌的出现并维持本品及其他抗菌药物的有效性，本品应该仅用于治疗确诊或高度怀疑细菌所致的感染。一旦获知培养及药敏试验结果，应该据之选择或调整抗菌药物治疗。缺乏此类资料时，可根据当地流行病学和敏感性模式选用经验性治疗药物。
仅在已知和怀疑不宜使用其他抗菌药物治疗时才使用本品治疗。

规格：

50mg

用法用量：

剂量和用法：
1、常规剂量
静脉滴注，推荐的给药方案为首剂100mg（2瓶），然后，每12小时50mg（1瓶）。替加环素的静脉滴注时间应该每12小时给药一次，每次约30~60min。
替加环素用于治疗复杂性腹腔内感染的推荐疗程为5~14天。治疗疗程应该根据感染的严重程度及部位、患者的临床和细菌学进展情况而定。
2、肝功能不全患者
轻至中度肝功能损害（Child Pugh 分级A 和B级）患者无需调整剂量。根据重度肝功能损害患者（Child Pugh 分级C级）的药代动力学特征，替加环素的剂量应调整为100mg（2瓶），然后每12小时25mg（半瓶）。重度肝功能损害患者（Child Pugh 分级C级）应谨慎用药并监测治疗反应。
3、肾功能不全患者或接受血液透析的患者
肾功能不全或接受血液透析的患者无需进行剂量调整。
4、本品在18岁以上患者中无需根据年龄、性别或种族调整剂量。
药物配制与处理：
本品每瓶应该以5.3ml 0.9%氯化钠注射液、5%葡萄糖注射液或者乳酸林格氏注射液进行溶解，配制的替加环素溶液浓度为10 mg/ml（注：每瓶超量6%，因此5 ml的配制溶液相当于50mg药物。）。轻晃药瓶直至药物溶解。从药瓶中抽取5 ml溶液加入含100 ml液体的静脉输液袋中或其他合适的输液容器（如玻璃瓶）中（100mg剂量配制2瓶，50mg剂量配制1瓶）。静脉输液袋或其他合适的输液容器（如玻璃瓶）中药物的最高浓度应为1 mg/ml。配制的溶液颜色应呈黄色至橙色。如果不是，则不应使用，应将此溶液丢弃。
在给药之前应该对药物制剂进行肉眼可见的颗粒和变色（如绿色或黑色）检查。注射用替加环素复溶后形成的溶液可在室温下贮藏达24小时（包括在本品小瓶包装中贮藏达6小时后在静脉输液袋袋中贮藏可达18小时）。此外，以0.9%氯化钠注射液或5%葡萄糖注射液复溶后应立即转移至静脉输液袋或其他合适的输液容器（如玻璃瓶），在2~8℃冷藏条件下可贮藏48小时。
本品可通过专用输液管或Y型管静脉给药。如果同一输液管连续用于输注多种药物，应该在输注本品前后应用0.9%氯化钠注射液或5%葡萄糖注射液（USP）冲洗管线。经共用管线给药应该使用与替加环素及其它任何药物相容的注射溶液。
相容性：
相容的静脉输注溶液包括0.9%氯化钠注射液、5%葡萄糖注射液和乳酸林格氏注射液（USP）。
当使用0.9%氯化钠注射液或5%葡萄糖注射液通过Y型管给药时，本品与下列药物或稀释液相容：阿米卡星、多巴酚丁胺、盐酸多巴胺、庆大霉素、氟哌啶醇、乳酸林格氏溶液、盐酸利多卡因、甲氧氯普胺、吗啡、去甲肾上腺素、哌拉西林/三唑巴坦（EDTA制剂）、氯化钾、异丙酚、盐酸雷尼替丁、茶碱和妥布霉素。
不相容性：
下列药物不应通过同一Y型管与替加环素同时给药：两性霉素B、两性霉素B脂质体复合物、地西泮、艾美拉唑和奥美拉唑。

不良反应：

文献资料介绍的注射用替加环素的不良反应如下：
1、临床试验经验
由于临床研究是在各种条件下进行的，一种药物临床研究所观察到的不良反应发生率不能直接与另一种药物临床研究所观察到的不良反应发生率进行比较，而且也不能反映实际的不良反应发生率。
在多个临床研究中，共有2514例患者接受了替加环素治疗，其中7%患者因治疗中出现不良反应而中止替加环素治疗，而所有对照组患者中6%因治疗中出现不良反应而中止治疗。
下表所列为到疗效检验访视为止，治疗中出现的发生率≥2%的不良反应的发生率。
到疗效检验访视为止，临床研究接受治疗的患者中不良反应的发生率（%）（≥2%）

对全部13个设有对照组的III期和IV期临床研究进行分析，接受替加环素治疗的患者死亡率为4.0%（150/3788），接受对照抗生素的死亡率为3.0%（110/3646）。在对这些研究的汇总分析中，基于按研究权重分层的随机效应模型，替加环素和对照药物之间校正后的全因死亡率风险差异为0.6%（95% CI 0.1,1.2）（见下表）。导致这种不平衡的原因未明，一般而言，死亡是感染或基础疾病的恶化或并发症的结果。
各种感染类型下结果为死亡的患者人数

注：临床试验包括300、305、900（cSSSI），301、306、315、316、400（cIAI ），308和313（CAP），311（HAP），307[在甲氧西林耐药金黄色葡萄球菌（MRSA）或万古霉素耐药肠球菌（VRE）感染患者中进行的革兰氏阳性耐药菌试验]和319（伴或不伴骨髓炎的糖尿病足感染）。
在对照临床研究中，替加环素治疗组患者感染相关严重不良事件的发生率较对照组高，分别为7%和6%。替加环素治疗组脓毒血症/感染性休克严重不良事件的发生率较对照组高，分别为2%和1%。因为治疗组间此亚组患者存在基线差异，所以结果与治疗的关系不能明确。
治疗中出现的最常见不良反应为恶心、呕吐，通常发生于治疗的第1~2天。大多数与替加环素和对照药物相关的恶心及呕吐的严重程度为轻至中度。替加环素治疗组患者恶心的发生率为26%（轻度占17%，中度占8%，重度占1%），呕吐的发生率为18%（轻度占11%，中度占6%，重度占1%）。
复杂性皮肤和皮肤软组织感染（cSSSI）患者中，替加环素治疗组和万古霉素/氨曲南治疗组恶心的发生率分别为35%和9%，呕吐的发生率分别为20%和4%。复杂性腹腔内感染（cIAI）患者中，替加环素治疗组和亚胺培南/西司他丁治疗组恶心的发生率分别为25%和21%，呕吐的发生率分别为20%和15%。社区获得性细菌性肺炎（CABP）患者中，替加环素治疗组和左氧氟沙星治疗组恶心的发生率分别为24%和8%，呕吐的发生率分别为16%和6%。
替加环素治疗组与中止治疗相关的最常见原因为恶心（1%）和呕吐（1%）。对照组与中止治疗相关的最常见不良事件为恶心（＜1%）。
下列不良反应在接受替加环素治疗的临床试验患者中并不常见（＜2%）：
全身性不良事件：注射部位炎症，注射部位疼痛，注射部位反应，感染性休克，过敏反应，寒战，注射部位水肿，注射部位静脉炎。
心血管系统：血栓性静脉炎。
消化系统：食欲减退，黄疸，排便异常。
代谢/营养系统：肌酐水平升高，低钙血症，低血糖症，低钠血症，血清AST和ALT升高。
神经系统：嗜睡。
特殊感觉：味觉倒错。
血液淋巴系统：部分凝血活酶时间（aPTT）延长，凝血酶原时间（PT）延长，嗜酸性粒细胞增多，国际标准化比率（INR）升高，血小板减少。
皮肤及其附属结构：瘙痒。
泌尿生殖系统：阴道念珠菌病，阴道炎，白带。
2、上市后经验
下述为替加环素上市后使用过程中出现的不良反应，由于这些不良反应属于自发性报告，而且人群数量难以确定，所以不太可能可靠地评估它们的发生率，或者建立与药物暴露的因果关系。
·过敏反应/类过敏反应
·急性胰腺炎
·肝脏胆汁瘀积和黄疸

禁忌：

禁用于已知对本品任何成分过敏的患者。

注意事项：

1.警告
全因死亡率
III期和IV期临床研究发现，与对照药组相比，替加环素组患者全因死亡率升高。在全部13个设有对照组的III期和IV期临床研究中，接受替加环素治疗的患者死亡率为4.0%（150/3788），对照组的死亡率为3.0%（110/3646）。在对这些研究的汇合分析中，基于按研究权重分层的随机效应模型，替加环素和对照药物之间校正后的全因死亡率风险差异为 0.6%（95% CI 0.1，1.2）。导致这种升高的原因不明。选择治疗药物时应考虑到这种全因死亡率的升高（见注意事项及不良反应）。
过敏反应/类过敏反应
几乎所有的抗菌药物（包括替加环素）都曾报道有过敏反应/类过敏反应，并且可危及生命。替加环素在结构上与四环素类抗生素相似，因此，四环素类抗生素过敏的患者应慎用替加环素。
肝脏效应
在接受替加环素治疗的患者中，可观察到总胆红素浓度、凝血酶原时间及转氨酶类升高的情况。有发生严重的肝功能不全和肝功能衰竭的个案报道。其中的一些患者同时服用了多种药物。应监测接受替加环素治疗的肝功能检查异常的患者，防止肝功能继续恶化并评价替加环素治疗的风险和利益。这些不良事件可能在停药后发生。
治疗呼吸机相关性肺炎时出现死亡率不平衡及低治愈率
一项医院获得性肺炎患者的研究未能证明替加环素的有效性。该研究中，患者被随机分配进入替加环素组（首剂100mg，然后每12小时50mg）或对照药组。此外，患者被允许接受特定的辅助疗法。接受替加环素治疗的呼吸机相关性肺炎患者亚组与对照药组相比，治愈率较低（临床可评价人群47.9%比70.1%）而死亡率较高（25/131[19.1%]比15/122[12.3%]）。特别是呼吸机相关肺炎及基线有菌血症的患者接受替加环素治疗后死亡率高于对照组，分别为9/18（50.0%）及1/13（7.7%）。
胰腺炎
已有与替加环素给药相关的急性胰腺炎，包括致死性病例的报道。对服用替加环素并出现提示急性胰腺炎的临床症状、指征或试验室检测指标异常的患者需考虑诊断为急性胰腺炎。在无已知胰腺炎危险因素的患者中已有相关病例报导。患者通常在停用替加环素后症状改善。对怀疑出现胰腺炎的患者应考虑停止替加环素治疗。
怀孕期使用
妊娠妇女应用本品时可导致胎儿受到伤害。如果患者在应用替加环素期间妊娠，应该告知患者其对胎儿的潜在危害。动物研究结果提示，替加环素可透过胎盘在胎儿组织中被发现。替加环素可致胎鼠和胎兔体重减轻（合并相应的骨化延迟）、家兔死胎。
牙齿发育
在牙齿发育期间（妊娠后半期、婴儿期以及8岁以下儿童期）使用本品可导致牙齿永久性变色（黄色-灰色-棕色）。大鼠研究结果显示替加环素可致骨骼变色。因此，在牙齿发育期间，除非其它药物无效或禁忌使用，否则不应使用本品。
艰难梭菌相关性腹泻
几乎所有的抗生素使用中均有发生艰难梭菌相关性腹泻（CDAD）的报道，包括替加环素。严重程度从轻度腹泻到危及生命的结肠炎。抗生素治疗会改变肠道正常菌群，导致艰难梭菌的过度繁殖。
艰难梭菌产生毒素A和B，这些毒素导致了CDAD的发生发展。艰难梭菌高产毒菌株导致发病率和病死率的升高，用抗生素治疗这些感染常常难以治愈，故可能需要接受结肠切除术。在接受抗生素治疗后发生腹泻的患者，应该考虑有CDAD的可能。因有报道CDAD发生在抗生素使用后两个多月，故应仔细了解病史。
如果怀疑或确证是CDAD，正在使用的但不能直接抑制艰难梭菌的抗生素要停用。根据临床指征，适当地补充液体、电解质和蛋白质，使用抗生素治疗艰难梭菌并且进行外科评估。
2.一般注意事项
肠穿孔
当考虑单用本品治疗临床明显可见的肠穿孔继发的复杂性腹腔内感染（cIAI）时，应该谨慎。在cIAI临床研究中（n=1642），6名接受替加环素治疗的患者和2名接受亚胺培南/西司他丁治疗的患者出现肠穿孔，并发生脓毒血症/感染性休克。6名接受替加环素的患者APACHEⅡ评分（中位数=13）较2名接受亚胺培南/西司他丁的患者（APACHEⅡ评分为4和6）高。由于两治疗组间基线APACHEⅡ评分存在差异，且总体病例数少，此结果与治疗的关系尚未确证。
四环素类药物效应
替加环素在结构上与四环素类抗生素相似，可能存在相似的不良反应。此类不良反应包括：光敏感性、假性脑瘤、胰腺炎以及抑制蛋白合成作用（后者导致BUN升高、氮质血症、酸中毒和高磷酸盐血症）。和四环素类药物一样，替加环素使用中报道有胰腺炎的发生。
二重感染
与其他抗生素类制剂相似，本品的使用可导致不敏感微生物的过度生长，包括真菌。治疗期间应该密切监测患者病情变化。如果出现二重感染，则应该采取适当措施。
耐药菌的发展
在未确诊或高度怀疑细菌感染情况下，处方本品不仅不会使患者获益，还会增加耐药菌出现的危险性。
3.患者须知
应该告知患者，包括本品在内的抗菌药物应该仅用于治疗细菌感染。不能用于治疗病毒感染（如普通感冒）。当采用本品治疗细菌感染时，应该告知患者，尽管疗程早期通常可感觉病情好转，但药物应该继续使用。遗漏给药或未完成全部治疗过程可导致：（1）降低及时治疗的有效性；（2）增加细菌出现耐药的可能性，使得将来不能应用本品或其他抗菌药物治疗。
腹泻是由抗生素引起的常见问题，通常在停用抗生素后中止。有时在开始接受抗生素治疗后，甚至在最后一剂抗生素后的两个月或数月，患者会有水样便和血便（有或没有胃痛和发热）。如果发生，患者应该尽快告知医生。
4.替加环素在有严重基础疾病的感染患者中的治疗经验有限。
5.本品在临床使用时请参考国外临床试验数据。

孕妇及哺乳期妇女用药：

妊娠期妇女
致畸效应
妊娠妇女服用替加环素可能引起胎儿毒性。替加环素对大鼠或家兔无致畸作用。临床前安全性研究发现，14C标记的替加环素能通过胎盘进入胎儿组织，包括胎儿骨骼结构。以AUC计算，大鼠和家兔的替加环素暴露量分别处于5倍和1倍于人每日剂量与胎鼠或胎兔体重的轻度减轻以及未成年动物骨骼异常（骨化延迟）相关。家兔暴露于等同于人类剂量的母体毒性剂量时，死胎的发生率增加。
尚未有在妊娠妇女中进行关于替加环素的、足够的、对照良好的研究。本品只有在对胎儿的潜在利益超过潜在风险时才可考虑在妊娠期间使用。
哺乳期妇女
应用14C标记的替加环素进行动物研究，结果提示替加环素易于经泌乳大鼠的乳汁分泌。替加环素口服生物利用度有限，与此一致的是，哺乳小狗经母乳喂养获得的替加环素全身暴露量微乎其微。
尚不清楚本品是否经人乳分泌。因为许多药物经人乳分泌，所以本品应用于乳母时应谨慎。

儿童用药：

18岁以下患者的疗效及安全性尚不明确。因此，不推荐用于18岁以下患者。
牙齿发育阶段（怀孕后半期、婴儿期和8岁前儿童期）使用治疗可能造成永久性的牙齿变色（棕黄色）。因此，不推荐8岁以下儿童使用本品。

老年用药：

在III期临床试验共2514名接受本品治疗的患者中，65岁及以上共664名，75岁及以上共288名。这些老年患者在总体安全性或疗效上与年轻患者相比无意料之外的差异，但不能除外一些老年患者更容易出现不良事件。
健康老年受试者和年轻受试者给予单剂量100mg的替加环素后，试验结果显示替加环素暴露量没有显著性差异。

药物相互作用：

只对成年人进行了药物相互作用研究。
在药物相互作用研究中，同时给予健康受试者本品（首剂100mg，然后每12小时50mg）和地高辛（首剂0.5mg继之0.25mg口服，每24小时一次），替加环素能使地高辛的Cmax 轻度降低13%，但对地高辛的AUC或清除率并无影响。以ECG间期改变作为衡量标准，Cmax的轻度改变并未影响地高辛的稳态药效学效应。另外，地高辛不影响替加环素的药代动力学特性。因此，本品与地高辛合用时两者均无需调整剂量。
健康受试者同时应用本品（首剂100mg，然后每12小时50mg）和华法令（单剂量25mg）可导致R-华法令和S-华法令的清除率分别减少40%和23%，Cmax 分别升高38%和43%，AUC分别增加68%和29%。替加环素未显著改变华法令对INR的影响。另外，华法令未对替加环素的药代动力学特性造成影响。然而，替加环素与华法令合并用药应该监测凝血酶原时间或其他合适的抗凝试验。
人肝微粒体体外研究结果提示，替加环素不抑制下列6种细胞色素P450（CYP）亚型所介导的代谢过程：1A2、2C8、2C9、2C19、2D6和3A4。因此预期替加环素不会改变需经上述代谢酶代谢的药物的代谢过程。另外，因为替加环素的代谢并不广泛，预期那些抑制或诱导这些CYP450亚型活性的药物不会影响本品的清除率。
抗生素与口服避孕药同时使用可导致口服避孕药作用降低。

药物过量：

替加环素过量尚无特殊治疗措施。
单剂量静脉给予健康志愿者替加环素300mg（60min以上）可导致恶心和呕吐的发生率增加。
在小鼠中进行的单剂量静脉给药毒性研究结果显示，雄性小鼠的估计半数致死量（LD50）为124mg/kg，雌性小鼠的LD50为98mg/kg。两种性别大鼠的LD50均为106mg/kg。
血液透析不能显著清除替加环素。

药理毒理：

药理作用：
替加环素为甘氨酰环素类抗菌药，其通过与核糖体30S亚单位结合、阻止氨酰化tRNA分子进入核糖体A位而抑制细菌蛋白质合成。这阻止了肽链因合并氨基酸残基而延长。替加环素含有一个甘氨酰氨基，取代于米诺环素的9位。此取代形式未见于任何天然或半合成四环素类化合物，从而赋予替加环素独特的微生物学特性。替加环素不受四环素类两大耐药机制（核糖体保护和外排机制）的影响。相应地，体外和体内试验证实替加环素具有广谱抗菌活性。尚未发现替加环素与其他抗生素存在交叉耐药。替加环素不受β内酰胺酶（包括超广谱β内酰胺酶）、靶位修饰，大环内酯类外排泵或酶靶位改变（如旋转酶/拓扑异构酶）等耐药机制的影响。体外研究未证实替加环素与其他常用抗菌药物存在拮抗作用。总体上说，替加环素为抑菌剂。
无论体外试验或[适应症]所描述的临床感染研究均显示替加环素对下列细菌的大多数菌株具有抗菌活性：
需氧及兼性需氧革兰阳性菌
粪肠球菌（仅限万古霉素敏感菌株）/金黄色葡萄球菌（甲氧西林敏感及耐药菌株）/无乳链球菌/咽峡炎链球菌族（包括咽峡炎链球菌、中间链球菌和星座链球菌）/化脓性链球菌
需氧及兼性需氧革兰阴性菌
弗劳地枸橼酸杆菌/阴沟肠杆菌/大肠埃希菌/产酸克雷伯菌/肺炎克雷伯菌
厌氧菌
脆弱拟杆菌/多形拟杆菌/单形拟杆菌/普通拟杆菌/产气荚膜梭菌/微小消化链球菌
体外研究资料证实替加环素对下列细菌具有抗菌活性，但其临床意义尚不清楚。这些细菌中至少90%菌株的体外最低抑菌浓度（MICS）低于或等于替加环素的敏感临界浓度。然而替加环素治疗这些细菌所致临床感染的安全性和有效性尚未被足够的对照良好的临床试验所证实。
需氧和兼性需氧革兰阳性菌
鸟肠球菌/酪黄肠球菌/粪肠球菌（万古霉素耐药菌株）/屎肠球菌（万古霉素敏感和耐药菌株）/鸡鹑肠球菌/产单核细胞李斯特菌/表皮葡萄球菌（甲氧西林敏感及耐药菌株）/溶血葡萄球菌
需氧和兼性需氧革兰阴性菌
鲍曼不动杆菌/嗜水气单胞菌/克氏柠檬酸杆菌/产气肠杆菌/多杀巴斯德菌/粘质沙雷菌/嗜麦芽窄食单胞菌
厌氧菌
吉氏拟杆菌/卵形拟杆菌/消化链球菌属/紫单胞菌属/普雷沃菌属
其他细菌
脓肿分枝杆菌/龟分枝杆菌/偶发分枝杆菌
药敏试验方法
在可能时，临床微生物学实验室应该为临床医生提供关于医院获得性及社区获得性病原菌的药敏概况的定期报告，此报告应当是当地医院及执业地区所用抗菌药物体外药敏试验结果的总结。这些报告有助于临床医生选择最有效的抗菌药物。
稀释法
抗菌药物最低抑菌浓度（MICS）的测定采用定量法。这些MICS可用于估计细菌对于抗菌药物的敏感性。MICS应采用基于稀释法（肉汤稀释法、琼脂稀释法或微量稀释法）的标准化操作或等量采用标准化接种物及替加环素浓度来确定。对于使用肉汤稀释法监测需氧菌，MICS须在新鲜配制（12小时内）的测试介质中进行。MICS值应该根据表4所提供的标准进行判读。
扩散法
需要测量抑菌圈直径的定量法也可用于重复估计细菌对抗菌药物的敏感性。其标准操作需要采用标准化接种物浓度。此操作使用15μg替加环素浸渍纸片以检测微生物对替加环素的敏感性。结果判读包括纸片扩散法所测直径与替加环素MIC结果之间的相互关系。实验室提供的关于使用15μg替加环素纸片进行的标准单纸片敏感试验结果应该根据表4进行判读。
厌氧技术
由于肉汤稀释法的质控参数尚未确立，替加环素厌氧药敏试验应该采用琼脂稀释法进行。
表4.替加环素药敏试验结果判读标准

a 近期未分离到耐药菌株，所以预先排除了 “敏感”之外的其他任何结果定义。 MIC结果提示 “不敏感”的菌株应该提请参考实验室进行进一步检测。
b替加环素对摩根菌属、变形杆菌属和普鲁威登菌属的体外抗菌活性降低。
c 琼脂稀释法 
报告为“敏感”则提示，如果抗菌化合物达到通常可以达到的浓度，那么病原菌很可能被抑制。报告为“中间”则提示结果可疑，如果微生物对替代药物、临床可得药物不够敏感，那么应该重复检测。此分类意味着在药物生理性浓集的身体部位或在可以高剂量使用药物的情况下，此类药物具有临床适用性。此分类也提供了一个缓冲地带，以免因细小的未能控制的技术因素导致判读时出现大的偏差。报告为“耐药”则提示，即使抗菌化合物达到通常可以达到的浓度也不足以抑制病原菌，此时应该选用其他治疗药物。
质量控制
与其他药敏试验技术相似，为了控制实验室标准化操作的技术层次，需要采用实验室对照菌株。标准替加环素粉末应能提供表5所示的MIC值。采用15μg替加环素纸片的扩散技术应该达到表5所示的标准。
表5. 药敏试验所能接受的质量控制范围

ATCC = 美国标准菌库
a 琼脂稀释法
毒理研究：
重复给药毒性：
在2周研究中，以AUC计算，分别给予大鼠和狗8倍和10倍于人每日剂量的替加环素暴露量时，可出现与骨髓抑制相关的红细胞、网状细胞、白细胞、血小板减少。在2周的给药之后，这些改变呈可逆性。
给予大鼠替加环素之后未观察到光敏感性证据。
遗传毒性：
在一组测试（包括中国仓鼠卵巢（CHO）细胞体外染色体畸变检测、 CHO细胞（HGRPT基因座）体外正向突变检测、小鼠淋巴瘤细胞体外正向突变检测以及体内小鼠微核检测）中，均未发现替加环素具有致突变作用。
生殖毒性：
按照AUC计算，替加环素的暴露剂量即便达到人类每日剂量的5倍也不影响大鼠的交配或生育力，对雌性大鼠的卵巢或动情周期也无药物相关性影响。
致癌性：
未进行动物终生研究以评价替加环素的致癌性。
其他：
在临床前研究中发现大量静脉内给予替加环素与组胺反应有关。

药代动力学：

根据临床药理学研究汇总资料，替加环素单剂量和多剂量静脉给药后的平均药代动力学参数总结见下表。替加环素静脉输注时间大约30~60分钟。
替加环素的平均药代动力学参数及其变异度（CV%）

1. 分布
根据临床研究（0.1~1.0μg/mL）观察，替加环素的体外血浆蛋白结合率范围大约为71%~89%。替加环素的稳态分布容积平均500~700L（7~9L/kg），提示替加环素组织分布广泛，其分布超过其血浆容积。
33位健康志愿者接受替加环素首剂100 mg继之50 mg q12h给药之后，肺泡细胞中替加环素的AUC0-12h（134μg·h/mL）比血清AUC0-12h高约78倍，上皮细胞衬液中替加环素的AUC0-12h（2.28μg· h/mL）比血清AUC0-12h约高32%。10位健康受试者的皮肤水疱液中替加环素的AUC0-12h（1.61μg· h/mL）较血清AUC0-12h约低26%。
在单剂量研究中，在接受切除组织的择期手术或医疗操作之前给予受试者替加环素100mg。与血清药物浓度相比，替加环素给药4h后胆囊（38倍，n=6）、肺（3.7倍，n=5）、结肠（2.3倍，n=6）的药物浓度较高，而滑液（0.58倍，n=5）和骨骼（0.35倍，n=6）的药物浓度较低。多剂量给药后这些组织的替加环素浓度尚未进行研究。
2. 代谢
替加环素的代谢并不广泛。应用人肝微粒体、肝脏切片和肝细胞进行替加环素体外研究，结果仅产生痕量代谢产物。在接受14C-替加环素的男性健康志愿者中，替加环素是尿液和粪便中发现的主要14C标记物质，但也可见葡萄糖醛酸苷、N-乙酰代谢产物和替加环素异构体（每种成份均未超过给药剂量的10%）。
3. 排泄
14C-替加环素给药后粪便和尿液中放射活性的总回收率结果提示，替加环素给药剂量的59%通过胆道/粪便排泄消除，33%经尿液排泄。总剂量的22%以替加环素原型经尿液排泄。总之，替加环素排泄的主要途径为替加环素原型及其代谢产物的胆汁分泌。葡萄苷酸化和替加环素原型的肾脏排泄为次要途径。
4.特殊人群
肝功能不全患者：
一项研究对10位轻度肝功能损害患者（Child Pugh 分级A级）、10位中度肝功能损害患者（Child Pugh 分级B级）、5位重度肝功能损害患者（Child Pugh 分级C级）与23位年龄和体重相匹配的健康对照受试者进行比较，结果发现轻度肝功能损害患者中替加环素的单剂量药代动力学分布并未发生改变。然而，中度肝功能损害患者（Child Pugh分级 B级）中替加环素的系统清除率减少25%，其半衰期延长23%。重度肝功能损害患者（Child Pugh 分级C级）中替加环素的系统清除率减少55%，其半衰期延长43%。
肾功能不全患者：
一项对6名重度肾功能损害患者（肌酐清除率＜30ml/min）、4名在血液透析前2h应用替加环素的终末期肾病（ESRD）患者、4名在血液透析后1h应用替加环素的终末期肾病（ESRD）患者和6名健康对照受试者的单剂量研究进行了比较，结果发现任何肾功能损害患者组替加环素的药代动力学特性均未见显著改变，替加环素也不能经过透析清除。所以肾功能损害或接受血液透析治疗患者无需调整本品的剂量。
儿童患者：
18岁以下患者中替加环素的药代动力学尚不明确。
老年患者：
健康老年受试者（年龄65~75岁，n=15；年龄＞75岁，n=13）和年轻受试者（n=18）单剂量给予本品100mg 之后的药代动力学特性并无显著差异，因此无需根据年龄调整剂量。
性别：
在参加临床药理学研究的38位女性和298位男性受试者的汇总分析中，女性受试者中替加环素的平均（±SD）清除率（20.7±6.5 L/h）与男性受试者无显著差异（22.8±8.7 L/h）。因此无需根据性别调整替加环素的剂量。
种族：
在参加临床药理学研究的73位亚裔受试者、53位黑人受试者、15位西班牙裔受试者、190位白人受试者和3位分类为“其他”的受试者的汇总分析中，亚裔受试者（28.8±8.8 L/h）、黑人受试者（23.0±7.8 L/h）、西班牙裔受试者（24.3±6.5 L/h）、白人受试者（22.1±8.9 L/h）和“其他”受试者（25.0±4.8 L/h）之间替加环素的平均（±SD）清除率无显著差异。因此无需根据种族调整替加环素的剂量。

贮藏：

在25℃以下保存。

包装：

管制注射剂瓶装，10瓶/盒。

有效期：

18个月

Tygacil

Generic Name: tigecycline
Dosage Form: injection, powder, lyophilized, for solution

Medically reviewed on May 1, 2018

 

WARNING: ALL-CAUSE MORTALITY

An increase in all-cause mortality has been observed in a meta-analysis of Phase 3 and 4 clinical trials in Tygacil-treated patients versus comparator. The cause of this mortality risk difference of 0.6% (95% CI 0.1, 1.2) has not been established. Tygacil should be reserved for use in situations when alternative treatments are not suitable [see Indications and Usage (1.4), Warnings and Precautions (5.1, 5.2) and Adverse Reactions (6.1)].

 

 

 

Indications and Usage for Tygacil

‡Starting from price of $28,599 available on all new 2018 Santa Fe Sport 2.4L FWD models. Price excludes Delivery and Destination charges of $1,905, fees, levies and all applicable charges (excluding HST, GST/PST). Price also excludes registration, insurance, PPSA, license fees and dealer admin. fees of up to $499. Offer not available in Quebec. Fees may vary by dealer. ♦Price of model shown: 2018 Santa Fe 2.0T Limited AWD Nightfall Blue/2018 Santa Fe 2.0T Limited AWD Serrano Red/ 2018 Santa Fe Sport 2.0T Ultimate AWD Frost White Pearl is $43,437/$43,587/$46,887. Price includes Delivery and Destination charges of $1,905, fees, levies, and all applicable charges (excluding HST; GST/PST). Prices exclude registration, insurance, PPSA, license fees and dealer admin. fees of up to $499. Fees may vary by dealer. ♦‡Offers available for a limited time and subject to change or cancellation without notice. Delivery and Destination charge includes freight, P.D.I. and a full tank of gas. Dealer may sell for less. Inventory is limited, dealer order may be required. Visit www.hyundaicanada.com or see dealer for complete details. *Never rely completely on Blind Spot Detection (BSD) and be sure to use proper lane changing procedures. BSD will not detect every object or vehicle and will not prevent accidents. Always look over your shoulder and use your mirrors to confirm clearance. See Owner’s Manual for further details and limitations. ™/®The Hyundai name, logos, product names, feature names, images and slogans are trademarks owned or licensed by Hyundai Auto Canada Corp. All other trademarks are the property of their respective owners. Optional equipment shown throughout.

 

 

 

 

 

Complicated Skin and Skin Structure Infections

Tigecycline for injection is indicated in patients 18 years of age and older for the treatment of complicated skin and skin structure infections caused by susceptible isolates ofEscherichia coli, Enterococcus faecalis (vancomycin-susceptible isolates),Staphylococcus aureus (methicillin-susceptible and -resistant isolates),Streptococcus agalactiae, Streptococcus anginosus grp. (includesS. anginosus, S. intermedius, andS. constellatus),Streptococcus pyogenes, Enterobacter cloacae, Klebsiella pneumoniae, andBacteroides fragilis.

Complicated Intra-abdominal Infections

Tigecycline for injection is indicated in patients 18 years of age and older for the treatment of complicated intra-abdominal infections caused by susceptible isolates ofCitrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Enterococcus faecalis (vancomycin-susceptible isolates),Staphylococcus aureus (methicillin-susceptible and -resistant isolates),Streptococcus anginosus grp. (includesS. anginosus, S. intermedius, andS. constellatus),Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens, andPeptostreptococcus micros.

Community-Acquired Bacterial Pneumonia

Tigecycline for injection is indicated in patients 18 years of age and older for the treatment of community-acquired bacterial pneumonia caused by susceptible isolates ofStreptococcus pneumoniae (penicillin-susceptible isolates), including cases with concurrent bacteremia,Haemophilus influenzae, andLegionella pneumophila.

Limitations of Use

Tygacil is not indicated for the treatment of diabetic foot infections. A clinical trial failed to demonstrate non-inferiority of Tygacil for treatment of diabetic foot infections.

Tygacil is not indicated for the treatment of hospital-acquired or ventilator-associated pneumonia. In a comparative clinical trial, greater mortality and decreased efficacy were reported in Tygacil-treated patients[seeWarnings and Precautions (5.2)].

Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Tygacil and other antibacterial drugs, Tygacil should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Appropriate specimens for bacteriological examination should be obtained in order to isolate and identify the causative organisms and to determine their susceptibility to tigecycline. Tygacil may be initiated as empiric monotherapy before results of these tests are known.

 

Tygacil Dosage and Administration

 

Recommended Adult Dosage

The recommended dosage regimen for Tygacil is an initial dose of 100 mg, followed by 50 mg every 12 hours. Intravenous infusions of Tygacil should be administered over approximately 30 to 60 minutes every 12 hours.

The recommended duration of treatment with Tygacil for complicated skin and skin structure infections or for complicated intra-abdominal infections is 5 to 14 days. The recommended duration of treatment with Tygacil for community-acquired bacterial pneumonia is 7 to 14 days. The duration of therapy should be guided by the severity and site of the infection and the patient's clinical and bacteriological progress.

Dosage in Patients With Hepatic Impairment

No dosage adjustment is warranted in patients with mild to moderate hepatic impairment (Child Pugh A and Child Pugh B). In patients with severe hepatic impairment (Child Pugh C), the initial dose of Tygacil should be 100 mg followed by a reduced maintenance dose of 25 mg every 12 hours. Patients with severe hepatic impairment (Child Pugh C) should be treated with caution and monitored for treatment response[seeClinical Pharmacology (12.3) andUse in Specific Populations (8.6)].

Dosage in Pediatric Patients

The safety and efficacy of the proposed pediatric dosing regimens have not been evaluated due to the observed increase in mortality associated with Tygacil in adult patients. Avoid use of Tygacil in pediatric patients unless no alternative antibacterial drugs are available. Under these circumstances, the following doses are suggested:

• Pediatric patients aged 8 to 11 years should receive 1.2 mg/kg of Tygacil every 12 hours intravenously to a maximum dose of 50 mg of Tygacil every 12 hours.

• Pediatric patients aged 12 to 17 years should receive 50 mg of Tygacil every 12 hours.

The proposed pediatric doses of Tygacil were chosen based on exposures observed in pharmacokinetic trials, which included small numbers of pediatric patients[seeUse in Specific Populations (8.4) andClinical Pharmacology (12.3)].

There are no data to provide dosing recommendations in pediatric patients with hepatic impairment.

Preparation and Administration

Each vial of Tygacil should be reconstituted with 5.3 mL of 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP, or Lactated Ringer's Injection, USP to achieve a concentration of 10 mg/mL of tigecycline. (Note: Each vial contains a 6% overage. Thus, 5 mL of reconstituted solution is equivalent to 50 mg of the drug.) The vial should be gently swirled until the drug dissolves. Reconstituted solution must be transferred and further diluted for intravenous infusion. Withdraw 5 mL of the reconstituted solution from the vial and add to a 100 mL intravenous bag for infusion (for a 100 mg dose, reconstitute two vials; for a 50 mg dose, reconstitute one vial). The maximum concentration in the intravenous bag should be 1 mg/mL. The reconstituted solution should be yellow to orange in color; if not, the solution should be discarded. Parenteral drug products should be inspected visually for particulate matter and discoloration (e.g., green or black) prior to administration. Once reconstituted, Tygacil may be stored at room temperature (not to exceed 25ºC/77ºF) for up to 24 hours (up to 6 hours in the vial and the remaining time in the intravenous bag). If the storage conditions exceed 25ºC (77ºF) after reconstitution, tigecycline should be used immediately. Alternatively, Tygacil mixed with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP may be stored refrigerated at 2° to 8°C (36° to 46°F) for up to 48 hours following immediate transfer of the reconstituted solution into the intravenous bag.

 

 

 

Tygacil may be administered intravenously through a dedicated line or through a Y-site. If the same intravenous line is used for sequential infusion of several drugs, the line should be flushed before and after infusion of Tygacil with 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP or Lactated Ringer's Injection, USP. Injection should be made with an infusion solution compatible with tigecycline and with any other drug(s) administered via this common line.

Drug Compatibilities

Compatible intravenous solutions include 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP, and Lactated Ringer's Injection, USP. When administered through a Y-site, Tygacil is compatible with the following drugs or diluents when used with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP: amikacin, dobutamine, dopamine HCl, gentamicin, haloperidol, Lactated Ringer's, lidocaine HCl, metoclopramide, morphine, norepinephrine, piperacillin/tazobactam (EDTA formulation), potassium chloride, propofol, ranitidine HCl, theophylline, and tobramycin.

Drug Incompatibilities

The following drugs should not be administered simultaneously through the same Y-site as Tygacil: amphotericin B, amphotericin B lipid complex, diazepam, esomeprazole and omeprazole.

Dosage Forms and Strengths

For Injection: Each single-dose 5 mL glass vial and 10 mL glass vial contain 50 mg of tigecycline as an orange lyophilized powder for reconstitution.

Contraindications

Tygacil is contraindicated for use in patients who have known hypersensitivity to tigecycline. Reactions have included anaphylactic reactions[seeWarnings and Precautions (5.3) andAdverse Reactions (6.2)].

Warnings and Precautions

All-Cause Mortality

An increase in all-cause mortality has been observed in a meta-analysis of Phase 3 and 4 clinical trials in Tygacil-treated patients versus comparator-treated patients. In all 13 Phase 3 and 4 trials that included a comparator, death occurred in 4.0% (150/3788) of patients receiving Tygacil and 3.0% (110/3646) of patients receiving comparator drugs. In a pooled analysis of these trials, based on a random effects model by trial weight, the adjusted risk difference of all-cause mortality was 0.6% (95% CI 0.1, 1.2) between Tygacil and comparator-treated patients. An analysis of mortality in all trials conducted for approved indications (cSSSI, cIAI, and CABP), including post-market trials showed an adjusted mortality rate of 2.5% (66/2640) for tigecycline and 1.8% (48/2628) for comparator, respectively. The adjusted risk difference for mortality stratified by trial weight was 0.6% (95% CI 0.0, 1.2).

The cause of this mortality difference has not been established. Generally, deaths were the result of worsening infection, complications of infection or underlying co-morbidities. Tygacil should be reserved for use in situations when alternative treatments are not suitable[seeBoxed Warning,Indications and Usage (1.4),Warnings and Precautions (5.2) andAdverse Reactions (6.1)].

Mortality Imbalance and Lower Cure Rates in Hospital-Acquired Pneumonia

A trial of patients with hospital acquired, including ventilator-associated, pneumonia failed to demonstrate the efficacy of Tygacil. In this trial, patients were randomized to receive Tygacil (100 mg initially, then 50 mg every 12 hours) or a comparator. In addition, patients were allowed to receive specified adjunctive therapies. The sub-group of patients with ventilator-associated pneumonia who received Tygacil had lower cure rates (47.9% versus 70.1% for the clinically evaluable population).

In this trial, greater mortality was seen in patients with ventilator-associated pneumonia who received Tygacil (25/131 [19.1%] versus 15/122 [12.3%] in comparator-treated patients)[seeAdverse Reactions (6.1)]. Particularly high mortality was seen among Tygacil-treated patients with ventilator-associated pneumonia and bacteremia at baseline (9/18 [50.0%] versus 1/13 [7.7%] in comparator-treated patients).

Anaphylactic Reactions

Anaphylactic reactions have been reported with nearly all antibacterial agents, including Tygacil, and may be life-threatening. Tygacil is structurally similar to tetracycline-class antibiotics and should be avoided in patients with known hypersensitivity to tetracycline-class antibiotics.

 

‡Starting from price of $28,599 available on all new 2018 Santa Fe Sport 2.4L FWD models. Price excludes Delivery and Destination charges of $1,905, fees, levies and all applicable charges (excluding HST, GST/PST). Price also excludes registration, insurance, PPSA, license fees and dealer admin. fees of up to $499. Offer not available in Quebec. Fees may vary by dealer. ♦Price of model shown: 2018 Santa Fe 2.0T Limited AWD Nightfall Blue/2018 Santa Fe 2.0T Limited AWD Serrano Red/ 2018 Santa Fe Sport 2.0T Ultimate AWD Frost White Pearl is $43,437/$43,587/$46,887. Price includes Delivery and Destination charges of $1,905, fees, levies, and all applicable charges (excluding HST; GST/PST). Prices exclude registration, insurance, PPSA, license fees and dealer admin. fees of up to $499. Fees may vary by dealer. ♦‡Offers available for a limited time and subject to change or cancellation without notice. Delivery and Destination charge includes freight, P.D.I. and a full tank of gas. Dealer may sell for less. Inventory is limited, dealer order may be required. Visit www.hyundaicanada.com or see dealer for complete details. *Never rely completely on Blind Spot Detection (BSD) and be sure to use proper lane changing procedures. BSD will not detect every object or vehicle and will not prevent accidents. Always look over your shoulder and use your mirrors to confirm clearance. See Owner’s Manual for further details and limitations. ™/®The Hyundai name, logos, product names, feature names, images and slogans are trademarks owned or licensed by Hyundai Auto Canada Corp. All other trademarks are the property of their respective owners. Optional equipment shown throughout.

 

 

 

 

Hepatic Adverse Effects

Increases in total bilirubin concentration, prothrombin time and transaminases have been seen in patients treated with tigecycline. Isolated cases of significant hepatic dysfunction and hepatic failure have been reported in patients being treated with tigecycline. Some of these patients were receiving multiple concomitant medications. Patients who develop abnormal liver function tests during tigecycline therapy should be monitored for evidence of worsening hepatic function and evaluated for risk/benefit of continuing tigecycline therapy. Hepatic dysfunction may occur after the drug has been discontinued.

Pancreatitis

Acute pancreatitis, including fatal cases, has occurred in association with tigecycline treatment. The diagnosis of acute pancreatitis should be considered in patients taking tigecycline who develop clinical symptoms, signs, or laboratory abnormalities suggestive of acute pancreatitis. Cases have been reported in patients without known risk factors for pancreatitis. Patients usually improve after tigecycline discontinuation. Consideration should be given to the cessation of the treatment with tigecycline in cases suspected of having developed pancreatitis[seeAdverse Reactions (6.2)].

Fetal Harm

Tygacil may cause fetal harm when administered to a pregnant woman. If the patient becomes pregnant while taking tigecycline, the patient should be apprised of the potential hazard to the fetus. Results of animal studies indicate that tigecycline crosses the placenta and is found in fetal tissues. Decreased fetal weights in rats and rabbits (with associated delays in ossification) and fetal loss in rabbits have been observed with tigecycline[seeUse in Specific Populations (8.1)].

Tooth Discoloration

The use of Tygacil during tooth development (last half of pregnancy, infancy, and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). Results of studies in rats with Tygacil have shown bone discoloration. Tygacil should not be used during tooth development unless other drugs are not likely to be effective or are contraindicated.

Clostridium difficile Associated Diarrhea

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Tygacil, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth ofC. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains ofC. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed againstC. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment ofC. difficile, and surgical evaluation should be instituted as clinically indicated.

Sepsis/Septic Shock in Patients With Intestinal Perforation

Monotherapy with tigecycline should be avoided in patients with complicated intra-abdominal infections (cIAI) secondary to clinically apparent intestinal perforation. In cIAI studies (n=1642), 6 patients treated with Tygacil and 2 patients treated with imipenem/cilastatin presented with intestinal perforations and developed sepsis/septic shock. The 6 patients treated with Tygacil had higher APACHE II scores (median = 13) versus the 2 patients treated with imipenem/cilastatin (APACHE II scores = 4 and 6). Due to differences in baseline APACHE II scores between treatment groups and small overall numbers, the relationship of this outcome to treatment cannot be established.

Tetracycline-Class Adverse Effects

Tygacil is structurally similar to tetracycline-class antibacterial drugs and may have similar adverse effects. Such effects may include: photosensitivity, pseudotumor cerebri, and anti-anabolic action (which has led to increased BUN, azotemia, acidosis, and hyperphosphatemia).

Development of Drug-Resistant Bacteria

Prescribing Tygacil in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

 

‡Starting from price of $28,599 available on all new 2018 Santa Fe Sport 2.4L FWD models. Price excludes Delivery and Destination charges of $1,905, fees, levies and all applicable charges (excluding HST, GST/PST). Price also excludes registration, insurance, PPSA, license fees and dealer admin. fees of up to $499. Offer not available in Quebec. Fees may vary by dealer. ♦Price of model shown: 2018 Santa Fe 2.0T Limited AWD Nightfall Blue/2018 Santa Fe 2.0T Limited AWD Serrano Red/ 2018 Santa Fe Sport 2.0T Ultimate AWD Frost White Pearl is $43,437/$43,587/$46,887. Price includes Delivery and Destination charges of $1,905, fees, levies, and all applicable charges (excluding HST; GST/PST). Prices exclude registration, insurance, PPSA, license fees and dealer admin. fees of up to $499. Fees may vary by dealer. ♦‡Offers available for a limited time and subject to change or cancellation without notice. Delivery and Destination charge includes freight, P.D.I. and a full tank of gas. Dealer may sell for less. Inventory is limited, dealer order may be required. Visit www.hyundaicanada.com or see dealer for complete details. *Never rely completely on Blind Spot Detection (BSD) and be sure to use proper lane changing procedures. BSD will not detect every object or vehicle and will not prevent accidents. Always look over your shoulder and use your mirrors to confirm clearance. See Owner’s Manual for further details and limitations. ™/®The Hyundai name, logos, product names, feature names, images and slogans are trademarks owned or licensed by Hyundai Auto Canada Corp. All other trademarks are the property of their respective owners. Optional equipment shown throughout.

 

 

 

 

Adverse Reactions

The following serious adverse reactions are described elsewhere in the labeling:

• All-Cause Mortality[seeBoxed Warning andWarnings and Precautions (5.1)]

• Mortality Imbalance and Lower Cure Rates in Hospital-Acquired Pneumonia[seeWarnings and Precautions (5.2)]

• Anaphylaxis[Warning and Precautions (5.3)]

• Hepatic Adverse Effects[Warnings and Precautions (5.4)]

• Pancreatitis[Warnings and Precautions (5.5)]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical trials, 2514 patients were treated with Tygacil. Tygacil was discontinued due to adverse reactions in 7% of patients compared to 6% for all comparators. Table 1 shows the incidence of adverse reactions through test of cure reported in ≥2% of patients in these trials.

Table 1. Incidence (%) of Adverse Reactions Through Test of Cure Reported in ≥ 2% of Patients Treated in Clinical Studies

Body System   Adverse Reactions	Tygacil (N=2514)	Comparators* (N=2307)
Body as a Whole
Abdominal pain	6	4
Abscess	2	2
Asthenia	3	2
Headache	6	7
Infection	7	5
Cardiovascular System
Phlebitis	3	4
Digestive System
Diarrhea	12	11
Dyspepsia	2	2
Nausea	26	13
Vomiting	18	9
Hemic and Lymphatic System
Anemia	5	6
Metabolic and Nutritional
Alkaline Phosphatase Increased	3	3
Amylase Increased	3	2
Bilirubinemia	2	1
BUN Increased	3	1
Healing Abnormal	3	2
Hyponatremia	2	1
Hypoproteinemia	5	3
SGOT Increased†	4	5
SGPT Increased†	5	5
Respiratory System
Pneumonia	2	2
Nervous System
Dizziness	3	3
Skin and Appendages
Rash	3	4

 

‡Starting from price of $28,599 available on all new 2018 Santa Fe Sport 2.4L FWD models. Price excludes Delivery and Destination charges of $1,905, fees, levies and all applicable charges (excluding HST, GST/PST). Price also excludes registration, insurance, PPSA, license fees and dealer admin. fees of up to $499. Offer not available in Quebec. Fees may vary by dealer. ♦Price of model shown: 2018 Santa Fe 2.0T Limited AWD Nightfall Blue/2018 Santa Fe 2.0T Limited AWD Serrano Red/ 2018 Santa Fe Sport 2.0T Ultimate AWD Frost White Pearl is $43,437/$43,587/$46,887. Price includes Delivery and Destination charges of $1,905, fees, levies, and all applicable charges (excluding HST; GST/PST). Prices exclude registration, insurance, PPSA, license fees and dealer admin. fees of up to $499. Fees may vary by dealer. ♦‡Offers available for a limited time and subject to change or cancellation without notice. Delivery and Destination charge includes freight, P.D.I. and a full tank of gas. Dealer may sell for less. Inventory is limited, dealer order may be required. Visit www.hyundaicanada.com or see dealer for complete details. *Never rely completely on Blind Spot Detection (BSD) and be sure to use proper lane changing procedures. BSD will not detect every object or vehicle and will not prevent accidents. Always look over your shoulder and use your mirrors to confirm clearance. See Owner’s Manual for further details and limitations. ™/®The Hyundai name, logos, product names, feature names, images and slogans are trademarks owned or licensed by Hyundai Auto Canada Corp. All other trademarks are the property of their respective owners. Optional equipment shown throughout.

 

 

 

 

In all 13 Phase 3 and 4 trials that included a comparator, death occurred in 4.0% (150/3788) of patients receiving Tygacil and 3.0% (110/3646) of patients receiving comparator drugs. In a pooled analysis of these trials, based on a random effects model by trial weight, an adjusted risk difference of all-cause mortality was 0.6% (95% CI 0.1, 1.2) between Tygacil and comparator-treated patients (see Table 2). The cause of the imbalance has not been established. Generally, deaths were the result of worsening infection, complications of infection or underlying co-morbidities.

Table 2. Patients with Outcome of Death by Infection Type

	Tygacil		Comparator		Risk Difference*
Infection Type	n/N	%	n/N	%	% (95% CI)
cSSSI	12/834	1.4	6/813	0.7	0.7 (-0.3, 1.7)
cIAI	42/1382	3.0	31/1393	2.2	0.8 (-0.4, 2.0)
CAP	12/424	2.8	11/422	2.6	0.2 (-2.0, 2.4)
HAP	66/467	14.1	57/467	12.2	1.9 (-2.4, 6.3)
Non-VAP†	41/336	12.2	42/345	12.2	0.0 (-4.9, 4.9)
VAP†	25/131	19.1	15/122	12.3	6.8 (-2.1, 15.7)
RP	11/128	8.6	2/43	4.7	3.9 (-4.0, 11.9)
DFI	7/553	1.3	3/508	0.6	0.7 (-0.5, 1.8)
Overall Adjusted	150/3788	4.0	110/3646	3.0	0.6 (0.1, 1.2)‡

An analysis of mortality in all trials conducted for approved indications - cSSSI, cIAI, and CABP, including post-market trials (one in cSSSI and two in cIAI) - showed an adjusted mortality rate of 2.5% (66/2640) for tigecycline and 1.8% (48/2628) for comparator, respectively. The adjusted risk difference for mortality stratified by trial weight was 0.6% (95% CI 0.0, 1.2).

In comparative clinical studies, infection-related serious adverse reactions were more frequently reported for subjects treated with Tygacil (7%) versus comparators (6%). Serious adverse reactions of sepsis/septic shock were more frequently reported for subjects treated with Tygacil (2%) versus comparators (1%). Due to baseline differences between treatment groups in this subset of patients, the relationship of this outcome to treatment cannot be established[seeWarnings and Precautions (5.9)].

The most common adverse reactions were nausea and vomiting which generally occurred during the first 1 – 2 days of therapy. The majority of cases of nausea and vomiting associated with Tygacil and comparators were either mild or moderate in severity. In patients treated with Tygacil, nausea incidence was 26% (17% mild, 8% moderate, 1% severe) and vomiting incidence was 18% (11% mild, 6% moderate, 1% severe).

In patients treated for complicated skin and skin structure infections (cSSSI), nausea incidence was 35% for Tygacil and 9% for vancomycin/aztreonam; vomiting incidence was 20% for Tygacil and 4% for vancomycin/aztreonam. In patients treated for complicated intra-abdominal infections (cIAI), nausea incidence was 25% for Tygacil and 21% for imipenem/cilastatin; vomiting incidence was 20% for Tygacil and 15% for imipenem/cilastatin. In patients treated for community-acquired bacterial pneumonia (CABP), nausea incidence was 24% for Tygacil and 8% for levofloxacin; vomiting incidence was 16% for Tygacil and 6% for levofloxacin.

Discontinuation from Tygacil was most frequently associated with nausea (1%) and vomiting (1%). For comparators, discontinuation was most frequently associated with nausea (<1%).

The following adverse reactions were reported (<2%) in patients receiving Tygacil in clinical studies:

Body as a Whole: injection site inflammation, injection site pain, injection site reaction, septic shock, allergic reaction, chills, injection site edema, injection site phlebitis

Cardiovascular System: thrombophlebitis

Digestive System: anorexia, jaundice, abnormal stools

Metabolic/Nutritional System: increased creatinine, hypocalcemia, hypoglycemia

 

‡Starting from price of $28,599 available on all new 2018 Santa Fe Sport 2.4L FWD models. Price excludes Delivery and Destination charges of $1,905, fees, levies and all applicable charges (excluding HST, GST/PST). Price also excludes registration, insurance, PPSA, license fees and dealer admin. fees of up to $499. Offer not available in Quebec. Fees may vary by dealer. ♦Price of model shown: 2018 Santa Fe 2.0T Limited AWD Nightfall Blue/2018 Santa Fe 2.0T Limited AWD Serrano Red/ 2018 Santa Fe Sport 2.0T Ultimate AWD Frost White Pearl is $43,437/$43,587/$46,887. Price includes Delivery and Destination charges of $1,905, fees, levies, and all applicable charges (excluding HST; GST/PST). Prices exclude registration, insurance, PPSA, license fees and dealer admin. fees of up to $499. Fees may vary by dealer. ♦‡Offers available for a limited time and subject to change or cancellation without notice. Delivery and Destination charge includes freight, P.D.I. and a full tank of gas. Dealer may sell for less. Inventory is limited, dealer order may be required. Visit www.hyundaicanada.com or see dealer for complete details. *Never rely completely on Blind Spot Detection (BSD) and be sure to use proper lane changing procedures. BSD will not detect every object or vehicle and will not prevent accidents. Always look over your shoulder and use your mirrors to confirm clearance. See Owner’s Manual for further details and limitations. ™/®The Hyundai name, logos, product names, feature names, images and slogans are trademarks owned or licensed by Hyundai Auto Canada Corp. All other trademarks are the property of their respective owners. Optional equipment shown throughout.

 

 

 

 

Special Senses: taste perversion

Hemic and Lymphatic System: prolonged activated partial thromboplastin time (aPTT), prolonged prothrombin time (PT), eosinophilia, increased international normalized ratio (INR), thrombocytopenia

Skin and Appendages: pruritus

Urogenital System: vaginal moniliasis, vaginitis, leukorrhea

Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of Tygacil. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.

• anaphylactic reactions

• acute pancreatitis

• hepatic cholestasis, and jaundice

• severe skin reactions, including Stevens-Johnson Syndrome

• symptomatic hypoglycemia in patients with and without diabetes mellitus

Drug Interactions

Warfarin

Prothrombin time or other suitable anticoagulation test should be monitored if Tygacil is administered with warfarin[seeClinical Pharmacology (12.3)].

Oral Contraceptives

Concurrent use of antibacterial drugs with oral contraceptives may render oral contraceptives less effective.

USE IN SPECIFIC POPULATIONS

Pregnancy

Teratogenic Effects—Pregnancy Category D[seeWarnings and Precautions (5.6)]

Tigecycline was not teratogenic in the rat or rabbit. In preclinical safety studies, 14C-labeled tigecycline crossed the placenta and was found in fetal tissues, including fetal bony structures. The administration of tigecycline was associated with reductions in fetal weights and an increased incidence of skeletal anomalies (delays in bone ossification) at exposures of 5 times and 1 times the human daily dose based on AUC in rats and rabbits, respectively (28 mcg∙hr/mL and 6 mcg∙hr/mL at 12 and 4 mg/kg/day). An increased incidence of fetal loss was observed at maternotoxic doses in the rabbits with exposure equivalent to human dose.

There are no adequate and well-controlled studies of tigecycline in pregnant women. Tygacil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Results from animal studies using 14C-labeled tigecycline indicate that tigecycline is excreted readily via the milk of lactating rats. Consistent with the limited oral bioavailability of tigecycline, there is little or no systemic exposure to tigecycline in nursing pups as a result of exposure via maternal milk.

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Tygacil is administered to a nursing woman[seeWarnings and Precautions (5.7)].

Pediatric Use

Use in patients under 18 years of age is not recommended. Safety and effectiveness in pediatric patients below the age of 18 years have not been established. Because of the increased mortality observed in Tygacil-treated adult patients in clinical trials, pediatric trials of Tygacil to evaluate the safety and efficacy of Tygacil were not conducted.

In situations where there are no other alternative antibacterial drugs, dosing has been proposed for pediatric patients 8 to 17 years of age based on data from pediatric pharmacokinetic studies[seeDosage and Administration (2.3) andClinical Pharmacology (12.3)].

Because of effects on tooth development, use in patients under 8 years of age is not recommended[seeWarnings and Precautions (5.7)].

Geriatric Use

Of the total number of subjects who received Tygacil in Phase 3 clinical studies (n=2514), 664 were 65 and over, while 288 were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity to adverse events of some older individuals cannot be ruled out.

 

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‡Starting from price of $28,599 available on all new 2018 Santa Fe Sport 2.4L FWD models. Price excludes Delivery and Destination charges of $1,905, fees, levies and all applicable charges (excluding HST, GST/PST). Price also excludes registration, insurance, PPSA, license fees and dealer admin. fees of up to $499. Offer not available in Quebec. Fees may vary by dealer. ♦Price of model shown: 2018 Santa Fe 2.0T Limited AWD Nightfall Blue/2018 Santa Fe 2.0T Limited AWD Serrano Red/ 2018 Santa Fe Sport 2.0T Ultimate AWD Frost White Pearl is $43,437/$43,587/$46,887. Price includes Delivery and Destination charges of $1,905, fees, levies, and all applicable charges (excluding HST; GST/PST). Prices exclude registration, insurance, PPSA, license fees and dealer admin. fees of up to $499. Fees may vary by dealer. ♦‡Offers available for a limited time and subject to change or cancellation without notice. Delivery and Destination charge includes freight, P.D.I. and a full tank of gas. Dealer may sell for less. Inventory is limited, dealer order may be required. Visit www.hyundaicanada.com or see dealer for complete details. *Never rely completely on Blind Spot Detection (BSD) and be sure to use proper lane changing procedures. BSD will not detect every object or vehicle and will not prevent accidents. Always look over your shoulder and use your mirrors to confirm clearance. See Owner’s Manual for further details and limitations. ™/®The Hyundai name, logos, product names, feature names, images and slogans are trademarks owned or licensed by Hyundai Auto Canada Corp. All other trademarks are the property of their respective owners. Optional equipment shown throughout.

 

 

 

 

No significant difference in tigecycline exposure was observed between healthy elderly subjects and younger subjects following a single 100 mg dose of tigecycline[seeClinical Pharmacology (12.3)].

Hepatic Impairment

No dosage adjustment is warranted in patients with mild to moderate hepatic impairment (Child Pugh A and Child Pugh B). In patients with severe hepatic impairment (Child Pugh C), the initial dose of tigecycline should be 100 mg followed by a reduced maintenance dose of 25 mg every 12 hours. Patients with severe hepatic impairment (Child Pugh C) should be treated with caution and monitored for treatment response[seeClinical Pharmacology (12.3) andDosage and Administration (2.2)].

Overdosage

No specific information is available on the treatment of overdosage with tigecycline. Intravenous administration of Tygacil at a single dose of 300 mg over 60 minutes in healthy volunteers resulted in an increased incidence of nausea and vomiting. Tigecycline is not removed in significant quantities by hemodialysis.

Tygacil Description

Tygacil (tigecycline) is a tetracycline class antibacterial for intravenous infusion. The chemical name of tigecycline is (4S,4aS,5aR,12aS)-9-[2-(tert-butylamino)acetamido]-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide. The empirical formula is C29H39N5O8 and the molecular weight is 585.65.

The following represents the chemical structure of tigecycline:

Figure 1: Structure of Tigecycline

Tygacil is an orange lyophilized powder or cake. Each Tygacil single-dose 5 mL or 10 mL vial contains 50 mg tigecycline lyophilized powder for reconstitution for intravenous infusion and 100 mg of lactose monohydrate. The pH is adjusted with hydrochloric acid, and if necessary sodium hydroxide. The product does not contain preservatives.

Tygacil - Clinical Pharmacology

Mechanism of Action

Tigecycline is a tetracycline class antibacterial[seeMicrobiology (12.4)].

Pharmacodynamics

Cardiac Electrophysiology

No significant effect of a single intravenous dose of Tygacil 50 mg or 200 mg on QTc interval was detected in a randomized, placebo- and active-controlled four-arm crossover thorough QTc study of 46 healthy subjects.

 

 

Pharmacokinetics

The mean pharmacokinetic parameters of tigecycline after single and multiple intravenous doses based on pooled data from clinical pharmacology studies are summarized in Table 3. Intravenous infusions of tigecycline were administered over approximately 30 to 60 minutes.

Table 3. Mean (CV%) Pharmacokinetic Parameters of Tigecycline

	Single Dose 100 mg (N=224)	Multiple Dose* 50 mg every 12h (N=103)
Cmax (mcg/mL)†	1.45 (22%)	0.87 (27%)
Cmax (mcg/mL)‡	0.90 (30%)	0.63 (15%)
AUC (mcg∙h/mL)	5.19 (36%)	- -
AUC0–24h (mcg∙h/mL)	- -	4.70 (36%)
Cmin (mcg/mL)	- -	0.13 (59%)
t½ (h)	27.1 (53%)	42.4 (83%)
CL (L/h)	21.8 (40%)	23.8 (33%)
CLr (mL/min)	38.0 (82%)	51.0 (58%)
Vss (L)	568 (43%)	639 (48%)

 

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‡Starting from price of $28,599 available on all new 2018 Santa Fe Sport 2.4L FWD models. Price excludes Delivery and Destination charges of $1,905, fees, levies and all applicable charges (excluding HST, GST/PST). Price also excludes registration, insurance, PPSA, license fees and dealer admin. fees of up to $499. Offer not available in Quebec. Fees may vary by dealer. ♦Price of model shown: 2018 Santa Fe 2.0T Limited AWD Nightfall Blue/2018 Santa Fe 2.0T Limited AWD Serrano Red/ 2018 Santa Fe Sport 2.0T Ultimate AWD Frost White Pearl is $43,437/$43,587/$46,887. Price includes Delivery and Destination charges of $1,905, fees, levies, and all applicable charges (excluding HST; GST/PST). Prices exclude registration, insurance, PPSA, license fees and dealer admin. fees of up to $499. Fees may vary by dealer. ♦‡Offers available for a limited time and subject to change or cancellation without notice. Delivery and Destination charge includes freight, P.D.I. and a full tank of gas. Dealer may sell for less. Inventory is limited, dealer order may be required. Visit www.hyundaicanada.com or see dealer for complete details. *Never rely completely on Blind Spot Detection (BSD) and be sure to use proper lane changing procedures. BSD will not detect every object or vehicle and will not prevent accidents. Always look over your shoulder and use your mirrors to confirm clearance. See Owner’s Manual for further details and limitations. ™/®The Hyundai name, logos, product names, feature names, images and slogans are trademarks owned or licensed by Hyundai Auto Canada Corp. All other trademarks are the property of their respective owners. Optional equipment shown throughout.

 

 

 

 

Distribution

Thein vitro plasma protein binding of tigecycline ranges from approximately 71% to 89% at concentrations observed in clinical studies (0.1 to 1.0 mcg/mL). The steady-state volume of distribution of tigecycline averaged 500 to 700 L (7 to 9 L/kg), indicating tigecycline is extensively distributed beyond the plasma volume and into the tissues.

Following the administration of tigecycline 100 mg followed by 50 mg every 12 hours to 33 healthy volunteers, the tigecycline AUC0–12h (134 mcg∙h/mL) in alveolar cells was approximately 78-fold higher than the AUC0–12h in the serum, and the AUC0–12h (2.28 mcg∙h/mL) in epithelial lining fluid was approximately 32% higher than the AUC0–12h in serum. The AUC0–12h (1.61 mcg∙h/mL) of tigecycline in skin blister fluid was approximately 26% lower than the AUC0–12h in the serum of 10 healthy subjects.

In a single-dose study, tigecycline 100 mg was administered to subjects prior to undergoing elective surgery or medical procedure for tissue extraction. Concentrations at 4 hours after tigecycline administration were higher in gallbladder (38-fold, n=6), lung (3.7-fold, n=5), and colon (2.3-fold, n=6), and lower in synovial fluid (0.58-fold, n=5), and bone (0.35-fold, n=6) relative to serum. The concentration of tigecycline in these tissues after multiple doses has not been studied.

Elimination

Metabolism

Tigecycline is not extensively metabolized.In vitro studies with tigecycline using human liver microsomes, liver slices, and hepatocytes led to the formation of only trace amounts of metabolites. In healthy male volunteers receiving 14C-tigecycline, tigecycline was the primary 14C-labeled material recovered in urine and feces, but a glucuronide, an N-acetyl metabolite, and a tigecycline epimer (each at no more than 10% of the administered dose) were also present.

Tigecycline is a substrate of P-glycoprotein (P-gp) based on anin vitro study using a cell line overexpressing P-gp. The potential contribution of P-gp-mediated transport to the in vivo disposition of tigecycline is not known.

Excretion

The recovery of total radioactivity in feces and urine following administration of 14C-tigecycline indicates that 59% of the dose is eliminated by biliary/fecal excretion, and 33% is excreted in urine. Approximately 22% of the total dose is excreted as unchanged tigecycline in urine. Overall, the primary route of elimination for tigecycline is biliary excretion of unchanged tigecycline and its metabolites. Glucuronidation and renal excretion of unchanged tigecycline are secondary routes.

Specific Populations

Hepatic Impairment

In a study comparing 10 patients with mild hepatic impairment (Child Pugh A), 10 patients with moderate hepatic impairment (Child Pugh B), and 5 patients with severe hepatic impairment (Child Pugh C) to 23 age and weight matched healthy control subjects, the single-dose pharmacokinetic disposition of tigecycline was not altered in patients with mild hepatic impairment. However, systemic clearance of tigecycline was reduced by 25% and the half-life of tigecycline was prolonged by 23% in patients with moderate hepatic impairment (Child Pugh B). Systemic clearance of tigecycline was reduced by 55%, and the half-life of tigecycline was prolonged by 43% in patients with severe hepatic impairment (Child Pugh C). Dosage adjustment is necessary in patients with severe hepatic impairment (Child Pugh C)[seeUse in Specific Populations (8.6) andDosage and Administration (2.2)].

Renal Impairment

A single dose study compared 6 subjects with severe renal impairment (creatinine clearance <30 mL/min), 4 end stage renal disease (ESRD) patients receiving tigecycline 2 hours before hemodialysis, 4 ESRD patients receiving tigecycline 1 hour after hemodialysis, and 6 healthy control subjects. The pharmacokinetic profile of tigecycline was not significantly altered in any of the renally impaired patient groups, nor was tigecycline removed by hemodialysis. No dosage adjustment of Tygacil is necessary in patients with renal impairment or in patients undergoing hemodialysis.

Geriatric Patients

No significant differences in pharmacokinetics were observed between healthy elderly subjects (n=15, age 65–75; n=13, age >75) and younger subjects (n=18) receiving a single 100-mg dose of Tygacil. Therefore, no dosage adjustment is necessary based on age[seeUse in Specific Populations (8.5)].

Pediatric Patients

A single-dose safety, tolerability, and pharmacokinetic study of tigecycline in pediatric patients aged 8–16 years who recently recovered from infections was conducted. The doses administered were 0.5, 1, or 2 mg/kg. The study showed that for children aged 12–16 years (n = 16) a dosage of 50 mg twice daily would likely result in exposures comparable to those observed in adults with the approved dosing regimen. Large variability observed in children aged 8 to 11 years of age (n = 8) required additional study to determine the appropriate dosage.

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A subsequent tigecycline dose-finding study was conducted in 8–11 year old patients with cIAI, cSSSI, or CABP. The doses of tigecycline studied were 0.75 mg/kg (n = 17), 1 mg/kg (n = 21), and 1.25 mg/kg (n=20). This study showed that for children aged 8–11 years, a 1.2 mg/kg dose would likely result in exposures comparable to those observed in adults resulting with the approved dosing regimen[seeDosage and Administration (2.3)].

Gender

In a pooled analysis of 38 women and 298 men participating in clinical pharmacology studies, there was no significant difference in the mean (±SD) tigecycline clearance between women (20.7±6.5 L/h) and men (22.8±8.7 L/h). Therefore, no dosage adjustment is necessary based on gender.

Race

In a pooled analysis of 73 Asian subjects, 53 Black subjects, 15 Hispanic subjects, 190 White subjects, and 3 subjects classified as "other" participating in clinical pharmacology studies, there was no significant difference in the mean (±SD) tigecycline clearance among the Asian subjects (28.8±8.8 L/h), Black subjects (23.0±7.8 L/h), Hispanic subjects (24.3±6.5 L/h), White subjects (22.1±8.9 L/h), and "other" subjects (25.0±4.8 L/h). Therefore, no dosage adjustment is necessary based on race.

Drug Interaction Studies

Digoxin

Tygacil (100 mg followed by 50 mg every 12 hours) and digoxin (0.5 mg followed by 0.25 mg, orally, every 24 hours) were co-administered to healthy subjects in a drug interaction study. Tigecycline slightly decreased the Cmax of digoxin by 13%, but did not affect the AUC or clearance of digoxin. This small change in Cmax did not affect the steady-state pharmacodynamic effects of digoxin as measured by changes in ECG intervals. In addition, digoxin did not affect the pharmacokinetic profile of tigecycline. Therefore, no dosage adjustment of either drug is necessary when Tygacil is administered with digoxin.

Warfarin

Concomitant administration of Tygacil (100 mg followed by 50 mg every 12 hours) and warfarin (25 mg single-dose) to healthy subjects resulted in a decrease in clearance of R-warfarin and S-warfarin by 40% and 23%, an increase in Cmax by 38% and 43% and an increase in AUC by 68% and 29%, respectively. Tigecycline did not significantly alter the effects of warfarin on INR. In addition, warfarin did not affect the pharmacokinetic profile of tigecycline. However, prothrombin time or other suitable anticoagulation test should be monitored if tigecycline is administered with warfarin.

In vitro studies in human liver microsomes indicate that tigecycline does not inhibit metabolism mediated by any of the following 6 cytochrome P450 (CYP) isoforms: 1A2, 2C8, 2C9, 2C19, 2D6, and 3A4. Therefore, Tygacil is not expected to alter the metabolism of drugs metabolized by these enzymes. In addition, because tigecycline is not extensively metabolized, clearance of tigecycline is not expected to be affected by drugs that inhibit or induce the activity of these CYP450 isoforms.

In vitro studies using Caco-2 cells indicate that tigecycline does not inhibit digoxin flux, suggesting that tigecycline is not a P-glycoprotein (P-gp) inhibitor. Thisin vitro information is consistent with the lack of effect of tigecycline on digoxin clearance noted in the in vivo drug interaction study described above.

Tigecycline is a substrate of P-gp based on anin vitro study using a cell line overexpressing P-gp. The potential contribution of P-gp-mediated transport to the in vivo disposition of tigecycline is not known. Coadministration of P-gp inhibitors (e.g., ketoconazole or cyclosporine) or P-gp inducers (e.g., rifampicin) could affect the pharmacokinetics of tigecycline.

Microbiology

Mechanism of Action

Tigecycline inhibits protein translation in bacteria by binding to the 30S ribosomal subunit and blocking entry of amino-acyl tRNA molecules into the A site of the ribosome. This prevents incorporation of amino acid residues into elongating peptide chains. In general, tigecycline is considered bacteriostatic; however, Tygacil has demonstrated bactericidal activity against isolates ofS. pneumoniae andL. pneumophila.

Resistance

To date there has been no cross-resistance observed between tigecycline and other antibacterials. Tigecycline is less affected by the two major tetracycline-resistance mechanisms, ribosomal protection and efflux. Additionally, tigecycline is not affected by resistance mechanisms such as beta-lactamases (including extended spectrum beta-lactamases), target-site modifications, macrolide efflux pumps or enzyme target changes (e.g. gyrase/topoisomerases). However, some ESBL-producing isolates may confer resistance to tigecycline via other resistance mechanisms. Tigecycline resistance in some bacteria (e.g.Acinetobacter calcoaceticus-Acinetobacter baumannii complex) is associated with multi-drug resistant (MDR) efflux pumps.

Interaction with Other Antimicrobials

In vitro studies have not demonstrated antagonism between tigecycline and other commonly used antibacterials.

 

Antimicrobial Activity

Tigecycline has been shown to be active against most of the following microorganisms, bothin vitro and in clinical infections[seeIndications and Usage (1)].

Gram-positive bacteria

Enterococcus faecalis (vancomycin-susceptible isolates)

Staphylococcus aureus (methicillin-susceptible and -resistant isolates)

Streptococcus agalactiae

Streptococcus anginosus group (includesS. anginosus, S. intermedius, andS. constellatus)

Streptococcus pneumoniae (penicillin-susceptible isolates)

Streptococcus pyogenes

Gram-negative bacteria

Citrobacter freundii
Enterobacter cloacae
Escherichia coli
Haemophilus influenzae
Klebsiella oxytoca
Klebsiella pneumoniae
Legionella pneumophila

Anaerobic bacteria

Bacteroides fragilis
Bacteroides thetaiotaomicron
Bacteroides uniformis
Bacteroides vulgatus
Clostridium perfringens
Peptostreptococcus micros

The followingin vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit anin vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for tigecycline against isolates of similar genus or organism group. However, the efficacy of tigecycline in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials.

Gram-positive bacteria

Enterococcus avium
Enterococcus casseliflavus
Enterococcus faecalis (vancomycin-resistant isolates)

Enterococcus faecium (vancomycin-susceptible and -resistant isolates)

Enterococcus gallinarum
Listeria monocytogenes
Staphylococcus epidermidis (methicillin-susceptible and -resistant isolates)

Staphylococcus haemolyticus

Gram-negative bacteria

Acinetobacter baumannii1
Aeromonas hydrophila
Citrobacter koseri
Enterobacter aerogenes
Haemophilus influenzae (ampicillin-resistant)

Haemophilus parainfluenzae
Pasteurella multocida
Serratia marcescens
Stenotrophomonas maltophilia

Anaerobic bacteria

Bacteroides distasonis
Bacteroides ovatus
Peptostreptococcus spp.

Porphyromonas spp.

Prevotella spp.

Other bacteria

Mycobacterium abscessus
Mycobacterium fortuitum

1

There have been reports of the development of tigecycline resistance inAcinetobacter infections seen during the course of standard treatment. Such resistance appears to be attributable to an MDR efflux pump mechanism. While monitoring for relapse of infection is important for all infected patients, more frequent monitoring in this case is suggested. If relapse is suspected, blood and other specimens should be obtained and cultured for the presence of bacteria. All bacterial isolates should be identified and tested for susceptibility to tigecycline and other appropriate antimicrobials.

Susceptibility Testing

 

For specific information regarding susceptibility test interpretive criteria, and associated test methods and quality control standards recognized by FDA for this drug, please see https://www.fda.gov/STIC.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Lifetime studies in animals have not been performed to evaluate the carcinogenic potential of tigecycline. No mutagenic or clastogenic potential was found in a battery of tests, includingin vitro chromosome aberration assay in Chinese hamster ovary (CHO) cells,in vitro forward mutation assay in CHO cells (HGRPT locus),in vitro forward mutation assays in mouse lymphoma cells, andin vivo mouse micronucleus assay. Tigecycline did not affect mating or fertility in rats at exposures up to 5 times the human daily dose based on AUC (28 mcg∙hr/mL at 12 mg/kg/day). In female rats, there were no compound-related effects on ovaries or estrous cycles at exposures up to 5 times the human daily dose based on AUC.

Animal Toxicology and/or Pharmacology

In two week studies, decreased erythrocytes, reticulocytes, leukocytes, and platelets, in association with bone marrow hypocellularity, have been seen with tigecycline at exposures of 8 times and 10 times the human daily dose based on AUC in rats and dogs, (AUC of approximately 50 and 60 mcg∙hr/mL at doses of 30 and 12 mg/kg/day) respectively. These alterations were shown to be reversible after two weeks of dosing.

Clinical Studies

Complicated Skin and Skin Structure Infections

Tygacil was evaluated in adults for the treatment of complicated skin and skin structure infections (cSSSI) in two randomized, double-blind, active-controlled, multinational, multicenter studies (Studies 1 and 2). These studies compared Tygacil (100 mg intravenous initial dose followed by 50 mg every 12 hours) with vancomycin (1 g intravenous every 12 hours)/aztreonam (2 g intravenous every 12 hours) for 5 to 14 days. Patients with complicated deep soft tissue infections including wound infections and cellulitis (≥10 cm, requiring surgery/drainage or with complicated underlying disease), major abscesses, infected ulcers, and burns were enrolled in the studies. The primary efficacy endpoint was the clinical response at the test of cure (TOC) visit in the co-primary populations of the clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) patients. See Table 4. Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients are presented in Table 5.

Table 4. Clinical Cure Rates from Two Studies in Complicated Skin and Skin Structure Infections after 5 to 14 Days of Therapy

	Tygacil* n/N (%)	Vancomycin/Aztreonam† n/N (%)
Study 1
CE	165/199 (82.9)	163/198 (82.3)
c-mITT	209/277 (75.5)	200/260 (76.9)
Study 2
CE	200/223 (89.7)	201/213 (94.4)
c-mITT	220/261 (84.3)	225/259 (86.9)

Table 5. Clinical Cure Rates By Infecting Pathogen in Microbiologically Evaluable Patients with Complicated Skin and Skin Structure Infections*

Pathogen	Tygacil n/N (%)	Vancomycin/Aztreonam n/N (%)
Escherichia coli	29/36 (80.6)	26/30 (86.7)
Enterobacter cloacae	10/12 (83.3)	15/15 (100)
Enterococcus faecalis (vancomycin-susceptible only)	15/21 (71.4)	19/24 (79.2)
Klebsiella pneumoniae	12/14 (85.7)	15/16 (93.8)
Methicillin-susceptible Staphylococcus aureus (MSSA)	124/137 (90.5)	113/120 (94.2)
Methicillin-resistant Staphylococcus aureus (MRSA)	79/95 (83.2)	46/57 (80.7)
Streptococcus agalactiae	8/8 (100)	11/14 (78.6)
Streptococcus anginosus grp.†	17/21 (81.0)	9/10 (90.0)
Streptococcus pyogenes	31/32 (96.9)	24/27 (88.9)
Bacteroides fragilis	7/9 (77.8)	4/5 (80.0)

•  







 

 

Complicated Intra-abdominal Infections

Tygacil was evaluated in adults for the treatment of complicated intra-abdominal infections (cIAI) in two randomized, double-blind, active-controlled, multinational, multicenter studies (Studies 1 and 2). These studies compared Tygacil (100 mg intravenous initial dose followed by 50 mg every 12 hours) with imipenem/cilastatin (500 mg intravenous every 6 hours) for 5 to 14 days. Patients with complicated diagnoses including appendicitis, cholecystitis, diverticulitis, gastric/duodenal perforation, intra-abdominal abscess, perforation of intestine, and peritonitis were enrolled in the studies. The primary efficacy endpoint was the clinical response at the TOC visit for the co-primary populations of the microbiologically evaluable (ME) and the microbiologic modified intent-to-treat (m-mITT) patients. See Table 6. Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients are presented in Table 7.

Table 6. Clinical Cure Rates from Two Studies in Complicated Intra-abdominal Infections after 5 to 14 Days of Therapy

	Tygacil* n/N (%)	Imipenem/Cilastatin† n/N (%)
Study 1
ME	199/247 (80.6)	210/255 (82.4)
m-mITT	227/309 (73.5)	244/312 (78.2)
Study 2
ME	242/265 (91.3)	232/258 (89.9)
m-mITT	279/322 (86.6)	270/319 (84.6)

Table 7. Clinical Cure Rates By Infecting Pathogen in Microbiologically Evaluable Patients with Complicated Intra-abdominal Infections*

Pathogen	Tygacil n/N (%)	Imipenem/Cilastatin n/N (%)
Citrobacter freundii	12/16 (75.0)	3/4 (75.0)
Enterobacter cloacae	15/17 (88.2)	16/17 (94.1)
Escherichia coli	284/336 (84.5)	297/342 (86.8)
Klebsiella oxytoca	19/20 (95.0)	17/19 (89.5)
Klebsiella pneumoniae	42/47 (89.4)	46/53 (86.8)
Enterococcus faecalis	29/38 (76.3)	35/47 (74.5)
Methicillin-susceptible Staphylococcus aureus (MSSA)	26/28 (92.9)	22/24 (91.7)
Methicillin-resistant Staphylococcus aureus (MRSA)	16/18 (88.9)	1/3 (33.3)
Streptococcus anginosus grp.†	101/119 (84.9)	60/79 (75.9)
Bacteroides fragilis	68/88 (77.3)	59/73 (80.8)
Bacteroides thetaiotaomicron	36/41 (87.8)	31/36 (86.1)
Bacteroides uniformis	12/17 (70.6)	14/16 (87.5)
Bacteroides vulgatus	14/16 (87.5)	4/6 (66.7)
Clostridium perfringens	18/19 (94.7)	20/22 (90.9)
Peptostreptococcus micros	13/17 (76.5)	8/11 (72.7)

Community-Acquired Bacterial Pneumonia

Tygacil was evaluated in adults for the treatment of community-acquired bacterial pneumonia (CABP) in two randomized, double-blind, active-controlled, multinational, multicenter studies (Studies 1 and 2). These studies compared Tygacil (100 mg intravenous initial dose followed by 50 mg every 12 hours) with levofloxacin (500 mg intravenous every 12 or 24 hours). In Study 1, after at least 3 days of intravenous therapy, a switch to oral levofloxacin (500 mg daily) was permitted for both treatment arms. Total therapy was 7 to 14 days. Patients with community-acquired bacterial pneumonia who required hospitalization and intravenous therapy were enrolled in the studies. The primary efficacy endpoint was the clinical response at the test of cure (TOC) visit in the co-primary populations of the clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) patients. See Table 8. Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients are presented in Table 9.

 

Table 8. Clinical Cure Rates from Two Studies in Community-Acquired Bacterial Pneumonia after 7 to 14 Days of Total Therapy

	Tygacil* n/N (%)	Levofloxacin† n/N (%)	95% CI‡
Study 1§
CE	125/138 (90.6)	136/156 (87.2)	(-4.4, 11.2)
c-mITT	149/191 (78)	158/203 (77.8)	(-8.5, 8.9)
Study 2
CE	128/144 (88.9)	116/136 (85.3)	(-5.0, 12.2)
c-mITT	170/203 (83.7)	163/200 (81.5)	(-5.6, 10.1)

Table 9. Clinical Cure Rates By Infecting Pathogen in Microbiologically Evaluable Patients with Community-Acquired Bacterial Pneumonia*

Pathogen	Tygacil n/N (%)	Levofloxacin n/N (%)
Haemophilus influenzae	14/17 (82.4)	13/16 (81.3)
Legionella pneumophila	10/10 (100.0)	6/6 (100.0)
Streptococcus pneumoniae (penicillin-susceptible only)†	44/46 (95.7)	39/44 (88.6)

To further evaluate the treatment effect of tigecycline, a post-hoc analysis was conducted in CABP patients with a higher risk of mortality, for whom the treatment effect of antibiotics is supported by historical evidence. The higher-risk group included CABP patients from the two studies with any of the following factors:

• Age ≥50 years

• PSI score ≥3

• Streptococcus pneumoniae bacteremia

The results of this analysis are shown in Table 10. Age ≥50 was the most common risk factor in the higher-risk group.

Table 10. Post-hoc Analysis of Clinical Cure Rates in Patients with Community-Acquired Bacterial Pneumonia Based on Risk of Mortality*

	Tygacil n/N (%)	Levofloxacin n/N (%)	95% CI†
Study 1‡
CE
Higher risk
Yes	93/103 (90.3)	84/102 (82.4)	(-2.3, 18.2)
No	32/35 (91.4)	52/54 (96.3)	(-20.8, 7.1)
c-mITT
Higher risk
Yes	111/142 (78.2)	100/134 (74.6)	(-6.9, 14)
No	38/49 (77.6)	58/69 (84.1)	(-22.8, 8.7)
Study 2
CE
Higher risk
Yes	95/107 (88.8)	68/85 (80)	(-2.2, 20.3)
No	33/37 (89.2)	48/51 (94.1)	(-21.1, 8.6)
c-mITT
Higher risk
Yes	112/134 (83.6)	93/120 (77.5)	(-4.2, 16.4)
No	58/69 (84.1)	70/80 (87.5)	(-16.2, 8.8)

 

How Supplied/Storage and Handling

Tygacil (tigecycline) for injection is supplied in a single-dose 5 mL glass vial or 10 mL glass vial, each containing 50 mg tigecycline lyophilized powder for reconstitution.

Supplied:

5 mL - 10 vials/box. NDC 0008-4994-02

10 mL - 10 vials/box. NDC 0008-4994-20

Prior to reconstitution, Tygacil should be stored at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature.] The reconstituted solution of Tygacil may be stored at room temperature (not to exceed 25°C/77°F) for up to 24 hours (up to 6 hours in the vial and the remaining time in the intravenous bag)[seeDosage and Administration (2.1)].

Patient Counseling Information

• Advise patients, their families, or caregivers that diarrhea is a common problem caused by antibacterial drugs. Sometimes, frequent watery or bloody diarrhea may occur and may be a sign of a more serious intestinal infection. If severe watery or bloody diarrhea develops, tell them to contact his or her healthcare provider[seeWarnings and Precautions (5.8)].

• Patients should be counseled that antibacterial drugs including Tygacil should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Tygacil is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Tygacil or other antibacterial drugs in the future.

This product's label may have been updated. For current full prescribing information, please visit www.pfizer.com.

Distributed by

Wyeth Pharmaceuticals LLC

A subsidiary of Pfizer Inc

Philadelphia, PA 19101

 

PREMIERProRx® is a registered trademark of Premier Healthcare Alliance, L.P., used under license.

LAB-0794-3.0

PRINCIPAL DISPLAY PANEL - 50 mg Vial Label

NDC 0008-4994-19

Single Use Vial

Tygacil®

(tigecycline)

for injection

50 mg

tigecycline per vial

For I.V. Infusion Only

 

PRINCIPAL DISPLAY PANEL - 50 mg Vial Carton

10 Single Use Vials

NDC 0008-4994-20

Contains 10 of NDC 0008-4994-19

Rx only

Tygacil®

(tigecycline)

for injection

 

50 mg

tigecycline per vial

PREMIERProRx®

RECONSTITUTED SOLUTION
MUST BE FURTHER DILUTED
FOR I.V. INFUSION

 

Tygacil  tigecycline injection, powder, lyophilized, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0008-4994 Route of Administration INTRAVENOUS DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength TIGECYCLINE (TIGECYCLINE) TIGECYCLINE 50 mg  in 5 mL Inactive Ingredients Ingredient Name Strength HYDROCHLORIC ACID   SODIUM HYDROXIDE   LACTOSE MONOHYDRATE 100 mg  in 5 mL

Packaging # Item Code Package Description 1 NDC:0008-4994-02 10 VIAL, SINGLE-USE in 1 CARTON 1 NDC:0008-4994-01 50 mL in 1 VIAL, SINGLE-USE 2 NDC:0008-4994-20 10 VIAL, SINGLE-USE in 1 CARTON 2 NDC:0008-4994-19 50 mL in 1 VIAL, SINGLE-USE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021821 02/08/2017

 

Labeler - Wyeth Pharmaceuticals LLC, a subsidiary of Pfizer Inc. (113008515)
Establishment
Name	Address	ID/FEI	Operations
Patheon Italia S.p.A.		338336589	ANALYSIS(0008-4994), MANUFACTURE(0008-4994)
Establishment
Name	Address	ID/FEI	Operations
Pfizer Ireland Pharmaceuticals		985586408	ANALYSIS(0008-4994)
Establishment
Name	Address	ID/FEI	Operations
Wyeth Lederle S.R.L.		542812040	ANALYSIS(0008-4994), LABEL(0008-4994), MANUFACTURE(0008-4994), PACK(0008-4994)
Establishment
Name	Address	ID/FEI	Operations
Pfizer Ireland Pharmaceuticals		896090987	ANALYSIS(0008-4994), API MANUFACTURE(0008-4994)
Establishment
Name	Address	ID/FEI	Operations
Prime European Therapeuticals SpA		430253557	API MANUFACTURE(0008-4994)
Establishment
Name	Address	ID/FEI	Operations
Pharmacia and Upjohn Company LLC		618054084	LABEL(0008-4994), PACK(0008-4994)

 

Wyeth Pharmaceuticals LLC, a subsidiary of Pfizer Inc.