地氟烷说明

大扶康®（氟康唑），所述第一合成三唑类抗真菌剂的新的子类的，可作为片剂用于口服给药，作为口服悬浮液的粉末。

氟康唑被化学命名为2,4-二氟-α，α1 -二（1H-1,2,4-三唑-1-基甲基）苄基醇与C 13 H的经验式12 F 2 N 6 O和分子重量为306.3。结构式为：

氟康唑是白色结晶固体，微溶于水和盐水。

Diflucan片剂含有50 mg，100 mg，150 mg或200 mg氟康唑和以下非活性成分：微晶纤维素，无水磷酸氢钙，聚维酮，交联羧甲基纤维素钠，FD＆C Red No. 40铝色淀湖染料和硬脂酸镁。

Diflucan口服混悬剂含有350 mg或1400 mg fluconazole和以下非活性成分：蔗糖，柠檬酸钠二水合物，无水柠檬酸，苯甲酸钠，二氧化钛，胶体二氧化硅，黄原胶和天然橙色香料。用24 mL蒸馏水或纯水（USP）复溶后，每mL复溶的悬浮液均含有10 mg或40 mg氟康唑。

地氟康-临床药理学

药代动力学与代谢

通过静脉内或口服途径给药后，氟康唑的药代动力学性质相似。在正常志愿者中，与静脉内给药相比，口服氟康唑的生物利用度超过90％。当以单次200 mg剂量给药时，在100 mg片剂和两种悬浮液强度之间建立了生物等效性。

禁食的正常志愿者的血浆峰值浓度（C max ）在口服后1至2小时内出现，最终血浆消除半衰期约为30小时（范围：20至50小时）。

在禁食的正常志愿者中，单次口服400 mg的Diflucan（氟康唑）的平均C max为6.72 mcg / mL（范围：4.12至8.08 mcg / mL），单次口服50至400 mg后，氟康唑的血浆浓度与血浆浓度-时间曲线（AUC）下的面积成比例。

来自一项食品效果研究的C max和AUC数据，该研究涉及在空腹情况下和高脂饮食下向健康志愿者服用地氟康（氟康唑）片剂，表明该药物的暴露不受食物的影响。因此，可以不考虑饮食而服用地氟康。 （请参阅剂量和管理。）

每天口服一次50至400毫克，口服后5至10天内达到稳态浓度。负荷剂量（通常是第1天）的两倍（第1天）导致第二天血浆浓度接近稳态。氟康唑的表观分布体积近似于全身水的分布体积。血浆蛋白结合率低（11％至12％）。单次或多次口服给药长达14天后，氟康唑会渗入所有研究的体液中（请参见下表）。在正常志愿者中，氟康唑的唾液浓度等于或略高于血浆浓度，而与剂量，途径或给药时间无关。在支气管扩张患者中，单次口服150 mg氟康唑的痰液浓度等于给药后4小时和24小时的血浆浓度。在患有真菌性脑膜炎的患者中，脑脊髓液（CSF）中的氟康唑浓度约为相应血浆浓度的80％。

给予27位患者的150 mg氟康唑单次口服渗透入阴道组织，在给药后的前48小时内，组织与血浆的比率在0.94至1.14之间。

给予14位患者单次口服150毫克氟康唑的剂量后，其阴道内渗入液中，在给药后的最初72小时内，液与血浆之比在0.36至0.71之间。

在正常志愿者中，氟康唑主要通过肾脏排泄而清除，大约80％的给药剂量以不变的药物形式出现在尿液中。大约11％的剂量作为代谢产物排泄在尿液中。

氟康唑的药代动力学受肾功能降低的显着影响。消除半衰期与肌酐清除率之间存在反比关系。肾功能受损的患者可能需要减少地氟康的剂量。 （请参阅剂量和用法。）3小时的血液透析可使血浆浓度降低约50％。

在正常志愿者中，给予Diflucan（每天一次，剂量从200 mg至400 mg，最多14天）与对睾丸激素浓度，内源性皮质类固醇浓度和促肾上腺皮质激素（ACTH）刺激的皮质醇反应的影响较小且不一致。

儿童药代动力学

在儿童中，已报告以下药代动力学数据{平均值（％cv）}：

在这些研究中，校正的体重清除率不受年龄的影响。据报告，成年人的平均身体清除率为0.23（17％）mL / min / kg。

在早产儿（胎龄为26至29周）中，出生后36个小时内的平均（％cv）清除率为0.180（35％，N = 7）mL / min / kg，随时间增加，平均值为0.218（六天后为31％，N = 9）mL / min / kg，十二天后为0.333（56％，N = 4）mL / min / kg。同样，半衰期为73.6小时，随时间减少，六天后平均为53.2小时，而十二天后平均为46.6小时。

老年人的药代动力学

在22名65岁以上的受试者中进行了药代动力学研究，他们接受了50 mg氟康唑的单次口服剂量。这些患者中有十名同时接受利尿剂治疗。 C max为1.54mcg / mL，并在给药后1.3小时发生。平均AUC为76.4±20.3 mcg∙h / mL，平均终末半衰期为46.2小时。这些药代动力学参数值高于正常年轻男性志愿者报道的类似值。利尿剂的共同给药并没有显着改变AUC或C max 。此外，老年人的肌酐清除率（74 mL / min），尿液中药物回收率不变（0至24小时，22％）和氟康唑肾清除率估计值（0.124 mL / min / kg）通常较低比年轻的志愿者因此，老年人中氟康唑的分布改变似乎与该组肾功能下降有关。根据正常受试者和肾功能不全程度不同的受试者得出的每个受试者的终末消除半衰期相对于肌酐清除率与预测的半衰期-肌酐清除率曲线的关系图表明，22名受试者中有21名处于95％置信区间内预测的半衰期肌酐清除率曲线。这些结果与以下假设相一致：在老年受试者中观察到的药代动力学参数值比正常的年轻男性志愿者更高，是由于预期的老年人肾功能下降。

药物相互作用研究

（请参阅预防措施，药物相互作用）

口服避孕药

在10例健康女性中，口服Diflucan 50 mg之前和之后，每天一次口服避孕药，持续10天。给予50 mg地氟康后，乙炔雌二醇或左炔诺孕酮AUC差异无统计学意义。乙炔雌二醇AUC平均增加6％（范围：–47至108％），左炔诺孕酮AUC增加17％（范围：–33至141％）。

在第二项研究中，有25名正常女性每天接受200毫克地氟康片或安慰剂，为期两天，十天。治疗周期相隔一个月，所有受试者在一个周期内接受Diflucan，在另一个周期内接受安慰剂。研究治疗的顺序是随机的。在两个周期的最后一个治疗日（第10天），服用单剂量的含左炔诺孕酮和炔雌醇的口服避孕药。服用200毫克地氟康后，左炔诺孕酮与安慰剂相比AUC的平均增加百分比为25％（范围：–12至82％），而乙炔雌二醇与安慰剂相比的AUC的平均百分比增加值为38％（范围：–11）至101％）。从统计学上来说，这两种增加均与安慰剂有显着差异。

第三项研究评估了每周一次口服氟康唑300毫克与21名服用含炔雌醇和炔诺酮的口服避孕药的正常女性之间的潜在相互作用。在这项为期三个周期的口服避孕药治疗的安慰剂对照，双盲，随机，双向交叉研究中，与相似的安慰剂给药相比，氟康唑的剂量导致乙炔雌二醇和炔诺酮的平均AUC略有增加。相对于安慰剂，乙炔雌二醇和炔诺酮的平均AUC分别增加了24％（95％CI范围：18至31％）和13％（95％CI范围：8至18％）。与安慰剂给药相比，氟康唑治疗在本研究中未引起任何个体受试者的炔雌醇AUC降低。氟康唑治疗后的21名受试者中有3名炔诺酮的个体AUC值略有下降（<5％）。

西咪替丁

100毫克地氟康单独口服，西咪替丁400毫克单次给药后两个小时，向六名健康男性志愿者给药。服用西咪替丁后，氟康唑AUC和C max明显降低。氟康唑AUC的平均±SD降低了13％±11％（范围：–3.4至–31％），C max降低了19％±14％（范围：–5至–40％）。但是，在四个小时的时间内（单次口服Diflucan 200 mg口服前一小时至口服后3小时），静脉内给予西咪替丁600 mg至900 mg，不会影响24名健康男性志愿者中氟康唑的生物利用度或药代动力学。 。

抗酸剂

抗酸药®（20mL）中，以14名正常男性志愿者的给药之前即刻的大扶康100mg的单剂量对氟康唑吸收或消除没有影响。

氢氯噻嗪

与单独给予地氟康相比，在13名正常志愿者中口服100 mg地氟康和50 mg氢氯噻嗪10天，导致氟康唑AUC和C max显着增加。氟康唑AUC和C max的平均±SD增加分别为45％±31％（范围：19至114％）和43％±31％（范围：19至122％）。这些变化归因于肾脏清除率的平均±SD降低30％±12％（范围：–10至–50％）。

利福平

在8名健康男性志愿者中，以600 mg的利福平每天15天给药后，单次口服200 mg的Diflucan导致氟康唑AUC显着降低和氟康唑的表观口腔清除率显着提高。氟康唑AUC的平均±SD降低为23％±9％（范围：–13至–42％）。氟康唑的表观口腔清除率增加了32％±17％（范围：16至72％）。氟康唑的半衰期从33.4±4.4小时降低至26.8±3.9小时。 （请参阅注意事项。）

华法林

与每天给药相比，每天口服200mg氟苯氟醚14天后，对13位正常男性志愿者单剂量服用华法林（15 mg）后，凝血酶原时间响应（凝血酶原时间曲线下的面积）显着增加。单独服用华法林。凝血酶原时间响应（凝血酶原时间-时间曲线下的面积）的平均值±SD增加为7％±4％（范围：–2至13％）。 （请参阅注意事项。）平均值基于来自12位受试者的数据，因为13位受试者中的一位经历了凝血酶原时间响应2倍的增加。

苯妥英

在10名正常男性中，在服用和不服用氟康唑的情况下（每天200毫克，口服3天，然后静脉注射250毫克，一次剂量），服用苯妥英4天后测定苯妥英AUC（每天200毫克，连续16天口服）志愿者。苯妥英AUC显着增加。苯妥英钠AUC的平均±SD升高为88％±68％（范围：16至247％）。由于苯妥英钠本质上是非线性的，这种相互作用的绝对强度是未知的。 （请参阅注意事项。）

环孢菌素

在接受环孢素治疗至少6个月和稳定环孢素剂量至少6周的8名肾移植患者中，每天给予氟康唑200 mg，连续14天之前和之后测定环孢素AUC和C max 。氟康唑给药后，环孢素AUC，C max和C min （24小时浓度）显着增加，并且表观口腔清除率显着降低。 AUC的平均±SD增加为92％±43％（范围：18至147％）。 C max增加60％±48％（范围：–5至133％）。 C min增加了157％±96％（范围：33至360％）。表观口腔清除率降低了45％±15％（范围：–15至–60％）。 （请参阅注意事项。）

齐多夫定

在13名接受稳定齐多夫定剂量至少两周的AIDS或ARC志愿者中，两次测定血浆齐多夫定浓度（每天氟康唑200 mg之前和之后，持续15天）。氟康唑给药后齐多夫定AUC显着增加。 AUC的平均±SD增加为20％±32％（范围：–27至104％）。氟康唑给药后，代谢产物GZDV与母体药物的比例显着降低，从7.6±3.6降至5.7±2.2。

茶碱

由茶碱的单次静脉内剂量（6 mg / kg）测定茶碱的药代动力学，该试验在16名正常男性志愿者中，每天口服口服氟康唑200 mg，持续14天之前和之后。茶碱AUC，C max和半衰期显着增加，清除率相应降低。平均±SD茶碱AUC增加21％±16％（范围：–5至48％）。 C max增加13％±17％（范围：–13至40％）。茶碱清除率降低了16％±11％（范围：–32至5％）。茶碱的半衰期从6.6±1.7小时增加到7.9±1.5小时。 （请参阅注意事项。）

特非那定

六名健康志愿者接受了15天特非那定60 mg BID。从第9天到第15天每天给药200毫克氟康唑。氟康唑不影响特非那定的血浆浓度。从第8天到第15天，并用氟康唑时，特非那定酸代谢物AUC升高36％±36％（范围：7至102％）。通过动态心电图QTc间隔测量，心脏复极没有改变。另一项以400毫克和800毫克氟康唑的日剂量进行的研究表明，以400毫克/天或更高的剂量服用地氟康时，与之同时服用可显着提高特非那定的血浆水平。 （请参阅禁忌症和预防措施。）

奎尼丁

尽管未进行体外或体内研究，但氟康唑与奎尼丁同时给药可能会抑制奎尼丁的代谢。奎尼丁的使用与QT延长和很少发生的扭转尖端有关。禁止同时使用氟康唑和奎尼丁。 （请参阅禁忌症和预防措施。）

口服降糖药

在正常志愿者中进行的三项安慰剂对照研究中，评估了氟康唑对磺酰脲类口服降糖药甲苯丁胺，格列吡嗪和格列本脲的药代动力学的影响。所有受试者单独接受磺酰脲单剂，并在每日两次给予Diflucan 100 mg，7天后再次接受单剂。在这三项研究中，接受地氟康治疗的患者为22/46（47.8％），接受安慰剂治疗的患者为9/22（40.1％），其症状与低血糖症一致。 （请参阅注意事项。）

甲苯磺丁酰胺

在13名正常男性志愿者中，氟康唑给药后，甲苯磺丁酰胺（单次剂量500 mg）的AUC和C max显着增加。甲苯磺丁酰胺AUC的平均±SD增加为26％±9％（范围：12至39％）。甲苯磺丁酰胺C max增加11％±9％（范围：–6至27％）。 （请参阅注意事项。）

格列吡嗪

13名正常男性志愿者服用氟康唑后，格列吡嗪（2.5 mg单剂量）的AUC和C max显着增加。 AUC的平均值±SD增加了49％±13％（范围：27至73％），C max增加了19％±23％（范围：–11至79％）。 （请参阅注意事项。）

格列本脲

在20名正常男性志愿者中服用氟康唑后，格列本脲（5 mg单剂量）的AUC和C max显着增加。 AUC的平均值±SD增加了44％±29％（范围：–13至115％），C max增加了19％±19％（范围：–23至62％）。氟康唑给药7天后，服用格列本脲后，五名受试者需要口服葡萄糖。 （请参阅注意事项。）

利福布汀

有已发表的报道指出，当氟康唑与利福布汀同时给药时，存在相互作用，导致血清利福布汀水平升高。 （请参阅注意事项。）

他克莫司

有已发表的报道说，氟康唑与他克莫司同时给药时存在相互作用，导致他克莫司的血清水平升高。 （请参阅注意事项。）

西沙必利

安慰剂对照的随机多剂量研究检查了氟康唑与西沙必利的潜在相互作用。两组10名正常受试者每天给予200毫克氟康唑或安慰剂。氟康唑或安慰剂给药7天后开始每日20毫克西沙必利。单剂氟康唑后，西沙必利AUC增加101％，西沙必利C max增加91％。多次服用氟康唑后，西沙必利AUC增加192％，西沙必利C max增加154％。氟康唑显着增加接受西沙必利20 mg每天4次，共5天的受试者的QTc间隔。 （请参阅禁忌症和预防措施。）

咪达唑仑

在一项针对12名志愿者的随机交叉研究中，研究了氟康唑对咪达唑仑的药代动力学和药效学的影响。在研究中，受试者在第1天摄入安慰剂或400 mg氟康唑，然后从第2天到第6天每天摄入200 mg。此外，在第一天口服摄入7.5 mg咪达唑仑，静脉内注射0.05 mg / kg第四天口服，第二天口服7.5毫克。氟康唑将IV咪达唑仑的清除率降低了51％。在给药的第一天，氟康唑分别将咪达唑仑的AUC和C max分别提高了259％和150％。在给药的第六天，氟康唑分别将咪达唑仑的AUC和C max分别提高了259％和74％。口服咪达唑仑后，咪达唑仑的精神运动作用显着增强，但静脉内服用咪达唑仑后，其精神运动作用未明显受影响。

在三个阶段中进行了第二项随机，双模拟，安慰剂对照的交叉研究，以确定氟康唑的给药途径对氟康唑与咪达唑仑之间相互作用的影响。在每个阶段，给受试者口服400毫克氟康唑和静脉注射生理盐水。口服安慰剂和静脉注射氟康唑400 mg;以及口服安慰剂和静脉注射生理盐水。氟康唑/安慰剂后口服7.5 mg咪达唑仑。口服咪达唑仑的AUC和C max明显高于静脉注射氟康唑。口服氟康唑可使咪达唑仑的AUC和Cmax分别增加272％和129％。 IV氟康唑使咪达唑仑的AUC和C max分别增加244％和79％。口服氟康唑和静脉注氟康唑均可提高咪达唑仑的药效学作用。 （请参阅注意事项。）

阿奇霉素

一项针对18位健康受试者的开放标签，随机，三向交叉研究评估了800 mg氟康唑单次口服剂量对1200 mg口服阿奇霉素的药代动力学的影响以及阿奇霉素对药代动力学的影响氟康唑。氟康唑和阿奇霉素之间没有明显的药代动力学相互作用。

伏立康唑

伏立康唑是CYP2C9和CYP3A4同工酶的底物。同时向6名健康男性受试者口服口服伏立康唑（400 mg Q12h 1天，然后200 mg Q12h 2.5天）和口服氟康唑（400 mg在第1天，然后200 mg Q24h 4天）导致C升高伏立康唑的最大和AUCτ平均分别为57％（90％CI：20％至107％）和79％（90％CI：40％至128％）。在一项涉及8位健康男性受试者的后续临床研究中，伏立康唑和氟康唑的剂量减少和/或频率降低并没有消除或减弱这种作用。不建议同时服用伏立康唑和氟康唑。如果在氟康唑后顺序使用伏立康唑，特别是在最后一次氟康唑给药后24小时内，建议密切监测与伏立康唑有关的不良事件。 （请参阅注意事项。 ）

托法替尼

健康受试者中氟康唑（第1天为400 mg，第6天[第2-7天每天200 mg，每天一次）共同给药和托法替尼（第5天为30 mg单剂量）共同导致托法替尼AUC和C max平均值增加约与单独使用托法替尼相比，分别为79％（90％CI：64％至96％）和27％（90％CI：12％至44％）。 （请参阅注意事项。 ）

微生物学

作用机理

氟康唑是真菌细胞色素P450依赖性酶羊毛甾醇14-α-脱甲基酶的高度选择性抑制剂。该酶起到将羊毛甾醇转化为麦角甾醇的作用。正常固醇的后续损失与真菌中14-α-甲基固醇的积累有关，可能与氟康唑的抑菌活性有关。哺乳动物细胞去甲基化对氟康唑的抑制作用不那么敏感。

抵抗性

对氟康唑产生抗药性的潜力是众所周知的。对其他唑类药物敏感性降低的真菌分离物对氟康唑的敏感性也可能降低。对该药物所针对的各种真菌的耐药性发生频率尚不清楚。

氟康唑耐药性可能源于靶酶（羊毛甾醇14-α-脱甲基酶）的质量或数量的改变，药物靶点的获取减少或这些机制的某种组合。

编码目标酶的基因（ ERG11 ）中的点突变导致目标改变，对唑的亲和力降低。 ERG11的过表达导致产生高浓度的目标酶，从而需要更高的细胞内药物浓度来抑制细胞中的所有酶分子。

耐药性的第二个主要机制涉及通过激活两种类型的多药外排转运蛋白，使氟康唑主动外排到细胞外。主要辅助因子（由MDR基因编码）和ATP结合盒超家族的辅助因子（由CDR基因编码）。 MDR基因的上调导致氟康唑耐药，而CDR基因的上调可能导致对多种唑类的耐药。

光滑念珠菌的抗性通常包括CDR基因上调，导致对多种唑类的抗性。对于最低抑菌浓度（MIC）归类为中级（16至32 mcg / mL）的分离株，建议使用最高氟康唑剂量。

克鲁斯假丝酵母应被认为对氟康唑有抗药性。克鲁维酵母的抗药性似乎是由靶酶对试剂抑制的敏感性降低所介导的。

有报告说，白色念珠菌以外的念珠菌属发生了超级感染，而白念珠菌通常固有地不易受地氟康的影响（例如克鲁斯念珠菌）。此类情况可能需要其他抗真菌治疗。

抗菌活性

已显示氟康唑在体外和临床感染中均对下列微生物的大多数分离物具有活性。

白色念珠菌
光滑念珠菌（许多分离株中等敏感）
副念珠菌
热带假丝酵母
新型隐球菌

可获得以下体外数据，但其临床意义尚不清楚。下列真菌中至少有90％的体外MIC小于或等于氟康唑（https://www.fda.gov/STIC）对相似属或机群的分离物的敏感断裂点。但是，氟康唑在治疗由于这些真菌引起的临床感染中的有效性尚未在充分且得到良好控制的临床试验中确定。

假丝酵母
古迪假丝酵母
假丝酵母
黄念珠菌

克鲁斯假丝酵母应被认为对氟康唑有抗药性。克鲁维酵母的抗药性似乎是由靶酶对试剂抑制的敏感性降低所介导的。

有报告说，白色念珠菌以外的念珠菌种发生了超级感染，而白念珠菌通常固有地不易受到地氟烷的影响（例如克鲁斯念珠菌）。此类情况可能需要其他抗真菌治疗。

药敏试验

有关此药物的药敏试验解释标准，相关试验方法和FDA认可的质量控制标准的详细信息，请参阅：https://www.fda.gov/STIC。

地氟康的适应症和用法

地氟康（氟康唑）可用于治疗：

1. 阴道念珠菌病（由于念珠菌引起的阴道酵母菌感染）。
2. 口咽和食管念珠菌病。在针对少数患者的开放式非对比研究中，地氟康还有效治疗念珠菌尿路感染，腹膜炎和全身念珠菌感染，包括念珠菌血症，散发性念珠菌病和肺炎。
3. 隐球菌性脑膜炎。在对患有隐球菌性脑膜炎的AIDS患者开处方Diflucan（氟康唑）之前，请参阅“临床研究”部分。尚未进行在非HIV感染患者中比较双氟醚与两性霉素B的研究。

预防：Diflucan还被表明可以降低接受细胞毒性化学疗法和/或放射疗法的接受骨髓移植的患者中念珠菌病的发生率。

治疗前应获取真菌培养和其他相关实验室研究（血清学，组织病理学）的标本，以分离和鉴定病原体。在了解培养结果和其他实验室研究之前，可以开始治疗；但是，一旦获得这些结果，就应相应调整抗感染治疗。

临床研究

隐球菌性脑膜炎

在一项多中心研究中比较了Diflucan（200 mg / day）和两性霉素B（0.3 mg / kg / day）在艾滋病患者中治疗隐球菌性脑膜炎的情况，多因素分析显示了三种预测治疗过程中死亡的预治疗因素：异常精神状态，脑脊液隐球菌抗原滴度大于1：1024，并且脑脊液白细胞计数小于20个/ mm 3 。两性霉素B和Diflucan患者的高危患者死亡率分别为33％和40％（p = 0.58），其中两组的总死亡率分别为14％（63名受试者中的9名）和18％（131名受试者中的24名）。研究（p = 0.48）。对于急性隐球菌性脑膜炎且治疗失败风险高的患者，最佳剂量和方案尚待确定。 （Saag等人，N Engl J Med 1992； 326：83-9。）

阴道念珠菌病

在美国，使用150毫克片剂进行了两项充分且对照良好的研究。在治疗后一个月的评估中，氟康唑方案的结果在临床和统计学上均与对照方案（阴道内克霉唑或咪康唑阴道内治疗7天）相当。

氟康唑组和阴道用药的治疗治愈率定义为完全解决阴道念珠菌病的症状和体征（临床治愈），KOH检查阴性，念珠菌培养阴性（微生物根除），均为55％。组。

入院患者中约四分之三患有急性阴道炎（<4次发作/ 12个月），口服150毫克Diflucan片剂治疗可达到80％的临床治愈率，67％的真菌学根除率和59％的治疗性治愈率。这些比率与对照产品相当。其余四分之一的患者患有复发性阴道炎（≥4次发作/ 12个月），临床治愈率为57％，根除真菌学率为47％，治疗治愈率为40％。该数字太小，无法在治疗复发性阴道炎的患者中与阴道产品进行有意义的临床或统计学比较。

与阴道用产品组相比，氟康唑组的胃肠道事件要多得多。大多数事件为轻度至中度。因为氟康唑为单剂量，所以没有停药发生。

儿科研究

口咽念珠菌病

进行了一项开放标签的比较研究，研究了在儿童免疫功能低下的口咽念珠菌病中，地氟康（2至3 mg / kg /天）和口服制霉菌素（400,000 IU每天4次）的有效性和安全性。氟康唑治疗的儿童的临床和真菌学应答率较高。

据报道，氟康唑治疗的患者在治疗结束时的临床治愈率为86％，而制霉菌素治疗的患者为46％。在真菌学上，氟康唑治疗的患者中有76％的感染菌已被根除，而制霉菌素治疗的患者中则有11％被消灭。

治疗结束后2周临床复发的患者比例为接受Diflucan的受试者为14％，接受制霉菌素的受试者为16％。在治疗结束后的第4周，具有临床复发率的患者中Diflucan为22％，制霉菌素为23％。

禁忌症

对氟康唑或其任何赋形剂过敏的患者禁用双氟康（氟康唑）。 There is no information regarding cross-hypersensitivity between fluconazole and other azole antifungal agents. Caution should be used in prescribing Diflucan to patients with hypersensitivity to other azoles. Coadministration of terfenadine is contraindicated in patients receiving Diflucan (fluconazole) at multiple doses of 400 mg/day or higher based upon results of a multiple dose interaction study. Coadministration of other drugs known to prolong the QT interval and which are metabolized via the enzyme CYP3A4 such as cisapride, astemizole, erythromycin, pimozide, and quinidine are contraindicated in patients receiving fluconazole. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies and PRECAUTIONS .)

警告事项

(1) Hepatic injury: Diflucan should be administered with caution to patients with liver dysfunction. Diflucan has been associated with rare cases of serious hepatic toxicity, including fatalities primarily in patients with serious underlying medical conditions. In cases of Diflucan-associated hepatotoxicity, no obvious relationship to total daily dose, duration of therapy, sex, or age of the patient has been observed. Diflucan hepatotoxicity has usually, but not always, been reversible on discontinuation of therapy. Patients who develop abnormal liver function tests during Diflucan therapy should be monitored for the development of more severe hepatic injury. Diflucan should be discontinued if clinical signs and symptoms consistent with liver disease develop that may be attributable to Diflucan.

(2) Anaphylaxis: In rare cases, anaphylaxis has been reported.

(3) Dermatologic: Exfoliative skin disorders during treatment with Diflucan have been reported. Fatal outcomes have been reported in patients with serious underlying diseases. Patients with deep seated fungal infections who develop rashes during treatment with Diflucan should be monitored closely and the drug discontinued if lesions progress. Fluconazole should be discontinued in patients treated for superficial fungal infection who develop a rash that may be attributed to fluconazole.

(4) Potential for fetal harm: There are no adequate and well-controlled clinical trials of Diflucan in pregnant women. Case reports describe a pattern of distinct congenital anomalies in infants exposed in utero to high dose maternal fluconazole (400 to 800 mg/day) during most or all of the first trimester. These reported anomalies are similar to those seen in animal studies. If Diflucan is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be informed of the potential hazard to the fetus. Effective contraceptive measures should be considered in women of child-bearing potential who are being treated with Diflucan 400 to 800 mg/day and should continue throughout the treatment period and for approximately 1 week (5 to 6 half-lives) after the final dose. Epidemiological studies suggest a potential risk of spontaneous abortion and congenital abnormalities in infants whose mothers were treated with 150 mg of fluconazole as a single or repeated dose in the first trimester, but these epidemiological studies have limitations and these findings have not been confirmed in controlled clinical trials. (See PRECAUTIONS: Pregnancy . )

预防措施

一般

Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. Fluconazole causes QT prolongation via the inhibition of Rectifier Potassium Channel current (Ikr). The QT prolongation caused by other medicinal products (such as amiodarone) may be amplified via the inhibition of cytochrome P450 (CYP) 3A4. (See PRECAUTIONS: Drug Interactions . ) During post-marketing surveillance, there have been rare cases of QT prolongation and torsade de pointes in patients taking fluconazole. Most of these reports involved seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities, and concomitant medications that may have been contributory. Patients with hypokalemia and advanced cardiac failure are at an increased risk for the occurrence of life-threatening ventricular arrhythmias and torsade de pointes.

Fluconazole should be administered with caution to patients with these potentially proarrhythmic conditions.

Concomitant use of fluconazole and erythromycin has the potential to increase the risk of cardiotoxicity (prolonged QT interval, torsade de pointes) and consequently sudden heart death. This combination should be avoided.

Fluconazole should be administered with caution to patients with renal dysfunction.

Adrenal insufficiency has been reported in patients receiving azoles, including fluconazole. Reversible cases of adrenal insufficiency have been reported in patients receiving fluconazole.

Diflucan Powder for Oral Suspension contains sucrose and should not be used in patients with hereditary fructose, glucose/galactose malabsorption, and sucrase-isomaltase deficiency.

When driving vehicles or operating machines, it should be taken into account that occasionally dizziness or seizures may occur.

Single Dose

The convenience and efficacy of the single dose oral tablet of fluconazole regimen for the treatment of vaginal yeast infections should be weighed against the acceptability of a higher incidence of drug related adverse events with Diflucan (26%) versus intravaginal agents (16%) in US comparative clinical studies. (See ADVERSE REACTIONS and CLINICAL STUDIES .)

药物相互作用

(See CONTRAINDICATIONS .) Fluconazole is a moderate CYP2C9 and CYP3A4 inhibitor. Fluconazole is also a strong inhibitor of CYP2C19. Patients treated with Diflucan, who are also concomitantly treated with drugs with a narrow therapeutic window metabolized through CYP2C9 and CYP3A4, should be monitored for adverse reactions associated with the concomitantly administered drugs. In addition to the observed /documented interactions mentioned below, there is a risk of increased plasma concentration of other compounds metabolized by CYP2C9, CYP2C19, and CYP3A4 coadministered with fluconazole. Therefore, caution should be exercised when using these combinations and the patients should be carefully monitored. The enzyme inhibiting effect of fluconazole persists 4 to 5 days after discontinuation of fluconazole treatment due to the long half-life of fluconazole. Clinically or potentially significant drug interactions between Diflucan and the following agents/classes have been observed and are described in greater detail below:

Alfentanil

A study observed a reduction in clearance and distribution volume as well as prolongation of t ½ of alfentanil following concomitant treatment with fluconazole. A possible mechanism of action is fluconazole's inhibition of CYP3A4. Dosage adjustment of alfentanil may be necessary.

Amiodarone

Concomitant administration of fluconazole with amiodarone may increase QT prolongation. Caution must be exercised if the concomitant use of fluconazole and amiodarone is necessary, notably with high-dose fluconazole (800 mg).

Amitriptyline, nortriptyline

Fluconazole increases the effect of amitriptyline and nortriptyline. 5-Nortriptyline and/or S-amitriptyline may be measured at initiation of the combination therapy and after 1 week. Dosage of amitriptyline/nortriptyline should be adjusted, if necessary.

Amphotericin B

Concurrent administration of fluconazole and amphotericin B in infected normal and immunosuppressed mice showed the following results: a small additive antifungal effect in systemic infection with Candida albicans , no interaction in intracranial infection with Cryptococcus neoformans , and antagonism of the two drugs in systemic infection with A. fumigatus . The clinical significance of results obtained in these studies is unknown.

Astemizole

Concomitant administration of fluconazole with astemizole may decrease the clearance of astemizole. Resulting increased plasma concentrations of astemizole can lead to QT prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and astemizole is contraindicated.

Azithromycin

An open-label, randomized, three-way crossover study in 18 healthy subjects assessed the effect of a single 1200 mg oral dose of azithromycin on the pharmacokinetics of a single 800 mg oral dose of fluconazole as well as the effects of fluconazole on the pharmacokinetics of azithromycin. There was no significant pharmacokinetic interaction between fluconazole and azithromycin.

Calcium channel blockers

Certain calcium channel antagonists (nifedipine, isradipine, amlodipine, verapamil, and felodipine) are metabolized by CYP3A4. Fluconazole has the potential to increase the systemic exposure of the calcium channel antagonists. Frequent monitoring for adverse events is recommended.

Carbamazepine

Fluconazole inhibits the metabolism of carbamazepine and an increase in serum carbamazepine of 30% has been observed. There is a risk of developing carbamazepine toxicity. Dosage adjustment of carbamazepine may be necessary depending on concentration measurements/effect.

Celecoxib

During concomitant treatment with fluconazole (200 mg daily) and celecoxib (200 mg), the celecoxib C max and AUC increased by 68% and 134%, respectively. Half of the celecoxib dose may be necessary when combined with fluconazole.

Cisapride

There have been reports of cardiac events, including torsade de pointes, in patients to whom fluconazole and cisapride were coadministered. A controlled study found that concomitant treatment with fluconazole 200 mg once daily and cisapride 20 mg four times a day yielded a significant increase in cisapride plasma levels and prolongation of QTc interval. The combined use of fluconazole with cisapride is contraindicated. (See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: Drug Interaction Studies .)

Coumarin-type anticoagulants

Prothrombin time may be increased in patients receiving concomitant Diflucan and coumarin-type anticoagulants. In post-marketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena) have been reported in association with increases in prothrombin time in patients receiving fluconazole concurrently with warfarin. Careful monitoring of prothrombin time in patients receiving Diflucan and coumarin-type anticoagulants is recommended. Dose adjustment of warfarin may be necessary. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies . )

Cyclophosphamide

Combination therapy with cyclophosphamide and fluconazole results in an increase in serum bilirubin and serum creatinine. The combination may be used while taking increased consideration to the risk of increased serum bilirubin and serum creatinine.

环孢菌素

Diflucan significantly increases cyclosporine levels in renal transplant patients with or without renal impairment. Careful monitoring of cyclosporine concentrations and serum creatinine is recommended in patients receiving Diflucan and cyclosporine. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies . ) This combination may be used by reducing the dosage of cyclosporine depending on cyclosporine concentration.

Fentanyl

One fatal case of possible fentanyl-fluconazole interaction was reported. The author judged that the patient died from fentanyl intoxication. Furthermore, in a randomized crossover study with 12 healthy volunteers, it was shown that fluconazole delayed the elimination of fentanyl significantly. Elevated fentanyl concentration may lead to respiratory depression.

Halofantrine

Fluconazole can increase halofantrine plasma concentration due to an inhibitory effect on CYP3A4.

HMG-CoA reductase inhibitors

The risk of myopathy and rhabdomyolysis increases when fluconazole is coadministered with HMG-CoA reductase inhibitors metabolized through CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin. If concomitant therapy is necessary, the patient should be observed for symptoms of myopathy and rhabdomyolysis and creatinine kinase should be monitored. HMG-CoA reductase inhibitors should be discontinued if a marked increase in creatinine kinase is observed or myopathy/rhabdomyolysis is diagnosed or suspected.

氢氯噻嗪

In a pharmacokinetic interaction study, coadministration of multiple-dose hydrochlorothiazide to healthy volunteers receiving fluconazole increased plasma concentrations of fluconazole by 40%. An effect of this magnitude should not necessitate a change in the fluconazole dose regimen in subjects receiving concomitant diuretics.

Ibrutinib

Moderate inhibitors of CYP3A4 such as fluconazole may increase plasma ibrutinib concentrations and increase risk of adverse reactions associated with ibrutinib. If ibrutinib and fluconazole are concomitantly administered, reduce the dose of ibrutinib as instructed in ibrutinib prescribing information and the patient should be frequently monitored for any adverse reactions associated with ibrutinib.

Losartan

Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74) which is responsible for most of the angiotensin Il-receptor antagonism which occurs during treatment with losartan. Patients should have their blood pressure monitored continuously.

美沙酮

Fluconazole may enhance the serum concentration of methadone. Dosage adjustment of methadone may be necessary.

Non-steroidal anti-inflammatory drugs

The C max and AUC of flurbiprofen were increased by 23% and 81%, respectively, when coadministered with fluconazole compared to administration of flurbiprofen alone. Similarly, the C max and AUC of the pharmacologically active isomer [S-(+)-ibuprofen] were increased by 15% and 82%, respectively, when fluconazole was coadministered with racemic ibuprofen (400 mg) compared to administration of racemic ibuprofen alone.

Although not specifically studied, fluconazole has the potential to increase the systemic exposure of other non-steroidal anti-inflammatory drugs (NSAIDs) that are metabolized by CYP2C9 (eg, naproxen, lornoxicam, meloxicam, diclofenac). Frequent monitoring for adverse events and toxicity related to NSAIDs is recommended. Adjustment of dosage of NSAIDs may be needed.

Olaparib

Moderate inhibitors of CYP3A4 such as fluconazole increase olaparib plasma concentrations; concomitant use is not recommended. If the combination cannot be avoided, reduce the dose of olaparib as instructed in the LYNPARZA ® (Olaparib) Prescribing Information.

口服避孕药

Two pharmacokinetic studies with a combined oral contraceptive have been performed using multiple doses of fluconazole. There were no relevant effects on hormone level in the 50 mg fluconazole study, while at 200 mg daily, the AUCs of ethinyl estradiol and levonorgestrel were increased 40% and 24%, respectively. Thus, multiple-dose use of fluconazole at these doses is unlikely to have an effect on the efficacy of the combined oral contraceptive.

Oral hypoglycemics

Clinically significant hypoglycemia may be precipitated by the use of Diflucan with oral hypoglycemic agents; one fatality has been reported from hypoglycemia in association with combined Diflucan and glyburide use. Diflucan reduces the metabolism of tolbutamide, glyburide, and glipizide and increases the plasma concentration of these agents. When Diflucan is used concomitantly with these or other sulfonylurea oral hypoglycemic agents, blood glucose concentrations should be carefully monitored and the dose of the sulfonylurea should be adjusted as necessary. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies .)

苯妥英

Diflucan increases the plasma concentrations of phenytoin. Careful monitoring of phenytoin concentrations in patients receiving Diflucan and phenytoin is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies .)

Pimozide

Although not studied in vitro or in vivo , concomitant administration of fluconazole with pimozide may result in inhibition of pimozide metabolism. Increased pimozide plasma concentrations can lead to QT prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and pimozide is contraindicated.

Prednisone

There was a case report that a liver-transplanted patient treated with prednisone developed acute adrenal cortex insufficiency when a 3 month therapy with fluconazole was discontinued. The discontinuation of fluconazole presumably caused an enhanced CYP3A4 activity which led to increased metabolism of prednisone. Patients on long-term treatment with fluconazole and prednisone should be carefully monitored for adrenal cortex insufficiency when fluconazole is discontinued.

Quinidine

Although not studied in vitro or in vivo , concomitant administration of fluconazole with quinidine may result in inhibition of quinidine metabolism. Use of quinidine has been associated with QT prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and quinidine is contraindicated. (See CONTRAINDICATIONS . )

Rifabutin

There have been reports that an interaction exists when fluconazole is administered concomitantly with rifabutin, leading to increased serum levels of rifabutin up to 80%. There have been reports of uveitis in patients to whom fluconazole and rifabutin were coadministered. Patients receiving rifabutin and fluconazole concomitantly should be carefully monitored. （看到