Vardenafil ODT的适应症和用法

盐酸伐地那非口服崩解片适用于勃起功能障碍的治疗。

Vardenafil ODT剂量和给药

一般

盐酸伐地那非口服崩解片有10 mg口腔崩解片。盐酸伐地那非口服崩解片不能与伐地那非10毫克薄膜衣片（LEVITRA）互换。与伐地那非10 mg薄膜衣片（LEVITRA）相比，盐酸伐地那非口服崩解片具有更高的全身暴露[参见临床药理学（12.3）]。

盐酸伐地那非口服崩解片应根据需要在性活动前约60分钟口服。最高给药频率为每天服用1片盐酸伐地那非口服崩解片。对治疗的反应需要性刺激。

盐酸伐地那非口服崩解片应放在会崩解的舌头上。平板电脑应不带液体服用。从水泡中取出后应立即服用。

那些需要较低或较高剂量的伐地那非剂量的患者需要处方伐地那非薄膜衣片[见患者咨询信息（17）] 。

与食物一起使用

盐酸伐地那非口服崩解片可以带或不带食物服用。

在特殊人群中使用

肝功能不全：对于中度（Child-Pugh B）或重度（Child-Pugh C）肝功能不全的患者，请勿使用盐酸伐地那非口服崩解片[请参阅警告和注意事项（5.8）和临床药理学（12.3）] 。

肾功能不全：在进行肾透析的患者中，请勿使用盐酸伐地那非口服崩解片[请参阅警告和注意事项（5.9）和临床药理学（12.3）]。

伴随药物

硝酸盐：禁止与任何形式的硝酸盐同时使用[见禁忌症（4.1）] 。

鸟苷酸环化酶（GC）刺激剂，例如riociguat ：禁忌同时使用[请参阅禁忌症（4.2）]。

CYP3A4抑制剂：请勿将含有盐酸伐地那非的口服崩解片与有效或中度的CYP3A4抑制剂（例如酮康唑，伊曲康唑，利托那韦，茚地那韦，沙奎那韦，阿扎那韦，克拉霉素和红霉素）一起使用[见警告和注意事项（5.2）。注意事项和注意事项（5.2） 。

α受体阻滞剂：对于那些对α受体阻滞剂稳定的患者，应以推荐的最低起始剂量开始使用PDE5抑制剂。服用包括伐地那非的磷酸二酯酶（PDE5）抑制剂的患者，α-受体阻滞剂剂量的逐步增加可能与血压的进一步降低有关。在服用α-受体阻滞剂的患者中，请勿使用盐酸伐地那非口服崩解片开始伐地那非治疗。这些患者应使用较低剂量的伐地那非薄膜衣片作为初始治疗[见剂量和给药方法（2.4）] 。以前曾使用伐地那非薄膜衣片的服用α-受体阻滞剂的患者可在其医疗保健提供者的建议下改用盐酸伐地那非口服崩解片[见警告和注意事项（5.6）和药物相互作用（7.1）]。

当盐酸伐地那非口服崩解片与α-受体阻滞剂同时给药时，应考虑给药间隔时间[见临床药理学（12.2）]。

剂型和优势

盐酸伐地那非口腔崩解片有10毫克白色至灰白色，圆形，双凸形，凹陷有“ 477”字样。

禁忌症

硝酸盐

禁止将盐酸伐地那非口服崩解片与硝酸盐（定期和/或间歇地）和一氧化氮供体一起使用[见临床药理学（12.2）] 。与PDE5对一氧化氮/环状鸟苷一磷酸途径的抑制作用一致，包括盐酸伐地那非口服崩解片在内的PDE5抑制剂可能会增强硝酸盐的降压作用。尚未确定盐酸伐地那非口服崩解片给药后为安全施用硝酸盐或一氧化氮供体的合适时间间隔。

鸟苷酸环化酶（GC）刺激物

对于正在使用GC刺激剂的患者（如riociguat），请勿使用盐酸伐地那非口服崩解片。 PDE5抑制剂，包括盐酸伐地那非口服崩解片，可能会增强GC刺激剂的降压作用。

警告和注意事项

勃起功能障碍的评估应包括医学评估，确定潜在的潜在原因以及确定适当的治疗方法。

在开具盐酸伐地那非口服崩解片的处方前，务必注意以下几点：

心血管作用

一般

医生应考虑患者的心血管状况，因为与性活动有关的心脏风险存在一定程度。因此，对于那些由于其潜在的心血管状态而不建议进行性活动的男性，不应使用包括盐酸伐地那非口服崩解片在内的勃起功能障碍治疗。

没有关于伐地那非在下列患者中的安全性或有效性的可控临床数据；因此，在获得更多信息之前，不建议使用它。低血压（收缩压<90 mmHg）；不受控制的高血压（> 170/110 mmHg）;最近的中风，危及生命的心律失常或心肌梗塞史（最近6个月内）；严重的心力衰竭。

左心室流出道梗阻

左心室流出道梗阻（例如，主动脉瓣狭窄和特发性肥厚性主动脉瓣下狭窄）的患者可能对包括PDE5抑制剂在内的血管扩张药的作用敏感。

血压影响

伐地那非具有全身性血管舒张特性，可导致健康志愿者的仰卧位血压暂时降低（平均收缩压最大降低7 mmHg，舒张压最大降低8 mmHg） [请参见临床药理学（12.2）] 。尽管通常认为这对大多数患者几乎没有影响，但在开具盐酸伐地那非口服崩解片处方之前，医生应仔细考虑其潜在心血管疾病患者是否会受到这种血管舒张作用的不利影响。

与强效或中度CYP3A4抑制剂发生药物相互作用的潜力

与强效CYP3A4抑制剂（如ritonavir，indinavir，ketoconazole）或中度CYP3A4抑制剂（如红霉素）同时给药会增加伐地那非的血浆浓度。服用强效或中度CYP3A4抑制剂的患者不要使用盐酸伐地那非口服崩解片[见剂量和给药方法（2.4），药物相互作用（7.2）和患者咨询信息（17）。]

暴乱的风险

很少有报道称此类化合物（包括伐地那非）的勃起时间超过4小时，并且阴茎勃勃（疼痛勃起时间超过6小时）。如果勃起持续超过4小时，则患者应立即寻求医疗帮助。如果不立即治疗阴茎异常勃勃，可能会导致阴茎组织损伤和永久性丧失效能。

阴茎解剖变形（例如成角度，海绵体纤维化或佩罗尼氏病）的患者或有可能易患阴茎异常勃起症（例如镰状细胞性贫血，骨髓瘤或白血病）。

对眼睛的影响

医生应建议患者停止使用所有5型磷酸二酯酶（PDE5）抑制剂，包括盐酸伐地那非口服崩解片，并在一只或两只眼睛突然失明的情况下寻求医疗救助。此类事件可能是非动脉性前部缺血性视神经病变（NAION）的征兆，这是一种罕见的疾病，并且是视力下降（包括永久性视力下降）的原因，据报道，与所有PDE5抑制剂的使用在时间上相关的上市时间很少。根据已发表的文献，在50岁以上的男性中，NAION的年发病率为每100,000例2.5至11.8例。
一项观察性病例交叉研究评估了与之前一段时间内使用PDE5抑制剂相比，当将PDE5抑制剂作为一类使用发生在NAION发作之前（5个半衰期内）时发生NAION的风险。结果表明，NAION的风险大约增加了2倍，风险估计为2.15（95％CI 1.06，4.34）。一项类似的研究报告了一致的结果，风险估计为2.27（95％CI 0.99，5.2）。在这些研究中，NAION的其他危险因素，例如“拥挤的”视盘的存在，也可能导致了NAION的发生。

无论是罕有的售后报道，还是观察性研究中PDE5抑制剂的使用与NAION的关联都不能证实PDE5抑制剂的使用与NAION之间的因果关系[见不良反应（6.2）]。

医生应考虑使用潜在的NAION危险因素的患者是否会因使用PDE5抑制剂而受到不利影响。已经经历过NAION的个体发生NAION复发的风险增加。因此，这些患者应谨慎使用PDE5抑制剂，包括盐酸伐地那非口服崩解片，并且仅在预期获益大于风险的情况下才应谨慎使用。与一般人群相比，“拥挤”视盘的人群也被认为患NAION的风险更高，但是，对于这种罕见病，证据不足以支持对PDE5抑制剂（包括盐酸伐地那非口服崩解片）的潜在使用者的筛查。

盐酸伐地那非口服崩解片尚未在患有已知的遗传性退行性视网膜疾病（包括色素性视网膜炎）的患者中进行评估，因此不建议使用该药物，除非这些患者可获得更多信息。

突发性听力损失

医生应建议患者停止服用所有PDE5抑制剂，包括盐酸伐地那非口服崩解片，并在突然减少或听力丧失的情况下寻求及时的医疗护理。这些事件可能伴有耳鸣和头晕，据报道与Pard5抑制剂（包括伐地那非）的摄入有关。无法确定这些事件是否与PDE5抑制剂的使用或其他因素直接相关[参见不良反应（6.2）]。

阿尔法阻滞剂

在服用α-受体阻滞剂的患者中，请勿使用盐酸伐地那非口服崩解片开始伐地那非治疗。以前曾使用过伐地那非薄膜衣片的接受过α-受体阻滞剂治疗的患者可在其医疗保健提供者的建议下改用盐酸伐地那非口服崩解片。建议将PDE5抑制剂与α受体阻滞剂同时使用时要小心。 PDE5抑制剂（包括盐酸伐地那非口服崩解片）和α-肾上腺素阻断剂都是具有降血压作用的血管扩张药。当将血管扩张剂组合使用时，可以预期会对血压产生累加作用。在某些患者中，同时使用这两种药物可以显着降低血压[参见药物相互作用（7.1）和临床药理学（12.2）]，导致症状性低血压（例如昏厥）。应考虑以下内容：

·在开始PDE5抑制剂治疗之前，患者应稳定接受α受体阻滞剂治疗。仅通过α-受体阻滞剂治疗就表现出血液动力学不稳定的患者出现症状性低血压的风险增加，同时使用PDE5抑制剂。

·对于那些对α受体阻滞剂稳定的患者，应以推荐的最低起始剂量开始使用PDE5抑制剂。在服用α-受体阻滞剂的患者中，请勿使用盐酸伐地那非口服崩解片开始伐地那非治疗。这些患者应使用较低剂量的伐地那非薄膜衣片作为初始治疗[见剂量和给药方法（2.4）] 。

·对于已经服用最佳剂量PDE5抑制剂的患者，应以最低剂量开始α受体阻滞剂治疗。逐步增加α受体阻滞剂的剂量可能与服用PDE5抑制剂的患者的血压进一步降低有关。

PDE5抑制剂和α受体阻滞剂并用的安全性可能会受到其他变量的影响，包括血管内容量减少和其他抗高血压药物。

先天性或获得性QT延长

在一项关于伐地那非对59例健康男性的QT间期影响的研究中[参见临床药理学（12.2）] ，治疗性剂量（10毫克薄膜衣片）和治疗上剂量的伐地那非（80毫克）和活性对照莫西沙星（400毫克） ）在QTc间隔中产生了类似的增长。一项上市后研究评估了伐地那非与另一种具有类似QT效果的药物合用的效果，与单独使用任一药物相比，其QT效果相加[见临床药理学（12.2）] 。在将伐地那非处方给已知QT延长病史的患者或正在服用已知延长QT间隔药物的患者时，应在临床决策中考虑这些观察结果。

服用1A类（例如奎尼丁，普鲁卡因酰胺）或III类（例如胺碘酮，索他洛尔）抗心律不齐药物或先天性QT延长的患者，应避免使用盐酸伐地那非口服崩解片。

肝功能不全

对于中度（Child-Pugh B）或重度（Child-Pugh C）肝功能不全的患者，请勿使用盐酸伐地那非口服崩解片[请参阅剂量和给药方法（2.3）临床药理学（12.3）]和在特定人群中使用（8.6） ] 。

肾功能不全

肾透析患者不要使用盐酸伐地那非口服崩解片，因为尚未对该人群进行伐地那非评估[见剂量和给药方法（2.3）和在特定人群中的使用（8.7）]。

与其他勃起功能障碍疗法的组合

尚未研究盐酸伐地那非口服崩解片与其他治疗勃起功能障碍的药物联合使用的安全性和有效性。因此，不建议使用此类组合。

对出血的影响

在人体中，单独使用伐地那非薄膜衣片的剂量最高可达20 mg，不会延长出血时间。没有临床证据表明伐地那非与阿司匹林联用时出血时间的任何累加延长。盐酸伐地那非口服崩解片尚未用于出血性疾病或严重的主动消化性溃疡患者。因此，应在仔细评估获益风险后，对这些患者使用盐酸伐地那非口服崩解片。

苯酮尿酸

盐酸伐地那非口服崩解片含有阿斯巴甜，阿斯巴甜是苯丙氨酸的来源，对苯丙酮尿症患者可能有害。苯酮尿症：每片盐酸伐地那非口服崩解片每片含1.403毫克苯丙氨酸。

性病

使用盐酸伐地那非口服崩解片不能预防性传播疾病。应考虑就有关预防性传播疾病（包括人类免疫缺陷病毒（HIV））的必要保护措施向患者提供咨询。

不良反应

标签上其他地方讨论了使用盐酸伐地那非口腔崩解片引起的以下严重不良反应：

·心血管效应[见禁忌症（4.1）和警告和注意事项（5.1）]

·独裁[请参阅警告和注意事项（5.3）]

·QT延长[请参阅警告和注意事项（5.7）]

·对眼睛的影响[请参阅警告和注意事项（5.4）]

·突发性听力损失[请参阅警告和注意事项（5.5）]

临床研究经验

由于临床试验是在广泛不同的条件下进行的，因此无法将在某种药物的临床试验中观察到的不良反应率直接与另一种药物在临床试验中观察到的不良反应率进行比较，并且可能无法反映实际中观察到的不良反应率。

盐酸伐地那非口服崩解片：在两项相同的多国，随机，双盲，安慰剂对照试验中评估了盐酸伐地那非口服崩解片的安全性。在两项关键性研究中，入组都是分层的，因此约50％的患者年龄≥65岁。大约8％（n = 29）≥75岁。两项研究的综合分析包括总共355名接受盐酸伐地那非口服崩解片的受试者，而340名接受安慰剂的受试者（平均年龄为61.7，范围为21至88；白人为68％，黑人为5％，亚裔为6％，亚洲裔为11岁） ％西班牙裔和11％其他）。盐酸伐地那非口服崩解片由于不良反应引起的停药率为1.4％，而安慰剂为0.6％。下表1详细列出了最常报告的不良反应。

表1：在对照试验中，接受盐酸伐地那非口服崩解片治疗的患者中≥2％发生了药物不良反应，并且与安慰剂相比使用药物的频率更高

盐酸伐地那非口服崩解片安慰剂对照试验中报告的不良药物反应与早期伐地那非膜衣片剂安慰剂对照试验中报告的药物不良反应相当。

所有Vardenafil研究：已向17,000多名男性（平均年龄54.5，年龄18至89岁；男性70％，白人，5％黑人，13％亚洲裔，4％西班牙裔和8名男性）服用了Vardenafil薄膜衣片和盐酸伐地那非口服崩解片％（其他）。接受治疗6个月或更长时间的患者人数为3357，其中1350例患者接受了至少1年的治疗。

在伐地那非薄膜衣片和盐酸伐地那非口服崩解片的安慰剂对照临床试验中，伐地那非因不良事件引起的停药率为1.9％，而安慰剂为0.8％。

安慰剂对照试验表明，剂量超过5 mg，10 mg和20 mg伐地那非薄膜衣片的某些不良反应（例如头晕，头痛，潮红，消化不良，恶心，鼻塞）的剂量影响。

下一节确定了在临床上开发的伐地那非薄膜衣片和盐酸伐地那非口服崩解片的其他不良反应（<2％）。从该列表中排除的是那些不常见和轻微的不良反应，在没有药物治疗的情况下通常可以观察到的那些事件以及与该药物没有合理关联的那些事件：

整个身体：过敏性水肿和血管性水肿，不适，过敏反应，胸痛

听觉：耳鸣，眩晕

心血管疾病：心lp，心动过速，心绞痛，心肌梗塞，室速性心律失常，低血压

消化系统：恶心，胃肠道和腹痛，口干，腹泻，胃食管反流病，胃炎，呕吐，转氨酶升高

肌肉骨骼：肌酸磷酸激酶（CPK）增加，肌肉张力和痉挛增加，肌痛

神经：感觉异常和感觉异常，嗜睡，睡眠障碍，晕厥，健忘症，癫痫发作

呼吸道：呼吸困难，鼻窦充血

皮肤和附件：红斑，皮疹

眼科：视觉障碍，眼充血，视觉色彩失真，眼痛和眼部不适，畏光，眼压升高，结膜炎

泌尿生殖器：勃起增加，阴茎异常勃勃

上市后经验

在将伐地那非用于薄膜包衣片剂制剂的批准后使用期间，已确认出现以下不良反应。由于这些反应是从不确定大小的人群中自愿报告的，因此并非总是能够估计其发生频率或建立与药物暴露的因果关系。

眼科：非动脉性前部缺血性视神经病变（NAION）是导致视力下降（包括永久性视力下降）的原因，很少有人报道上市后与使用伐地那非的PDE5抑制剂在时间上的关联。这些患者中的大多数（但不是全部）具有导致NAION发育的潜在解剖或血管危险因素，包括但不限于：杯盘比低（“拥挤的盘”），50岁以上，糖尿病，高血压，冠状动脉疾病，高脂血症和吸烟[请参阅警告和注意事项（5.4）和患者咨询信息（17）] 。

在售后的经验中也很少报道包括视力丧失（暂时或永久性）在内的视力障碍，例如视野缺损，视网膜静脉阻塞和视力下降。无法确定这些事件是否与伐地那非的使用直接相关。

神经性：据报道上市后与伐地那非相关的癫痫发作，癫痫发作复发和短暂性整体性失忆。

耳科：据报道上市后与PDE5抑制剂（包括伐地那非）的使用有关，听力突然下降或丧失。在某些情况下，据报道医学状况和其他因素也可能在耳科不良事件中起作用。在许多情况下，医疗随访信息有限。无法确定这些报告的事件是否与伐地那非的使用，患者听力下降的潜在危险因素，这些因素的组合或其他因素直接相关[参见患者咨询信息（17）] 。

药物相互作用

以下描述的药物相互作用研究是使用伐地那非薄膜衣片剂进行的。

与盐酸伐地那非口服崩解片的药效相互作用的潜力

硝酸盐：禁忌同时使用盐酸伐地那非口腔崩解片和硝酸盐。伐地那非1和4小时后服用舌下硝酸盐（0.4 mg）的降血压作用和伐地那非1、4和8小时后服用伐地那非20 mg剂量可增强健康中年受试者的心率。在硝酸甘油（NTG）前24小时服用伐地那非20 mg时未观察到这些作用。尚未评估硝酸盐对缺血性心脏病患者的降压作用的增强作用，禁忌同时使用盐酸伐地那非口服崩解片和硝酸盐[见禁忌证（4.1）和临床药理学（12.2）] 。

阿尔法阻滞剂：服用阿尔法阻滞剂的患者不应使用盐酸伐地那非口服崩解片来启动伐地那非治疗。先前曾使用过伐地那非薄膜衣片的接受过α-受体阻滞剂治疗的患者可以在其医疗保健提供者的建议下改用盐酸伐地那非口服崩解片。建议将PDE5抑制剂与α受体阻滞剂同时使用时要小心。 PDE5抑制剂，包括盐酸伐地那非口服崩解片和α-肾上腺素阻断剂，都是具有降血压作用的血管扩张药。当将血管扩张剂组合使用时，可以预期会对血压产生累加作用。伐地那非与阿夫唑嗪，特拉唑嗪或坦索罗辛的共同给药已经进行了临床药理学研究[参见剂量和给药方法（2.4），警告和注意事项（5.6）和临床药理学（12.2）。]

降压药：盐酸伐地那非口服崩解片可能会增加降压药的降压作用。在一项针对勃起功能障碍患者的临床药理研究中，单剂量20 mg伐地那非可导致仰卧位血压平均最大降低7毫米汞柱收缩压和舒张期8毫米汞柱舒张压（与安慰剂相比），并伴有平均心率最大升高。每分钟4次。给药后1至4小时内血压出现最大下降。连续服药31天后，在第31天观察到与第1天相似的血压反应。

酒精：在健康志愿者中，服用酒精（0.5 g / kg体重：70公斤体重的人约40毫升无水酒精）后，在4小时观察期内，伐地那非20毫克不能增强酒精的降压作用。同时给药时，酒精和伐地那非的血浆水平没有改变。

其他药物对伐地那非的影响

体外研究

对人肝微粒体的研究表明，伐地那非主要通过细胞色素P450（CYP）亚型3A4 / 5代谢，而在较小程度上被CYP2C9代谢。因此，预期这些酶的抑制剂会降低伐地那非的清除率[参见剂量和用法（2.4）和警告和注意事项（5.2）] 。

体内研究

请勿将盐酸伐地那非口服崩解片与中度和强效CYP3A4抑制剂（例如红霉素，葡萄柚汁，克拉霉素，酮康唑，伊曲康唑，茚地那韦，沙奎那韦，阿扎那韦，利托那韦）一起使用，因为在它们存在时，伐地那非的全身浓度会升高，并应予预防。 （5）和剂量与用法（2.4）] 。

高效CYP3A4抑制剂

酮康唑（200 mg每天一次）与伐地那非5 mg在健康志愿者中共同给药时，曲线下伐地那非面积（AUC）增加10倍，最大浓度（C max ）增加4倍[请参阅剂量和剂量管理（2.4）和警告和注意事项（5）。]

茚地那韦（800 mg tid）与伐地那非10 mg共同给药导致伐地那非AUC增长16倍，伐地那非C max增长7倍和伐地那非半衰期增加2倍[参见剂量和给药方法（ 2.4）以及警告和注意事项（5）。]

利多那韦（600 mg bid）与伐地那非5 mg共同给药，导致伐地那非AUC升高49倍，伐地那非C max升高13倍。相互作用是由于利托那韦，一种HIV蛋白酶抑制剂和一种高效的CYP3A4抑制剂阻断了伐地那非的肝代谢，后者也抑制了CYP2C9 [参见剂量和给药方法（2.4）和警告和注意事项（5.2）。]

中度CYP3A4抑制剂

在健康志愿者中与伐地那非5 mg并用时，红霉素（500 mg tid）使伐地那非AUC升高4倍，伐地那非C max升高3倍[见剂量和给药方法（2）和警告和注意事项（5 ）]。

其他药物相互作用

在伐地那非与以下药物之间未观察到药代动力学相互作用：格列本脲，华法林，地高辛，基于氢氧化铝的抗酸剂和雷尼替丁。在华法林研究中，伐地那非对凝血酶原时间或其他药效学参数没有影响。

在健康志愿者中，西咪替丁（400 mg bid）对伐地那非的AUC和C max无影响。

伐地那非对其他药物的影响

体外研究

伐地那非及其代谢产物对CYP1A2、2A6和2E1（Ki> 100微摩尔）无影响。发现对其他同工型（CYP2C8、2C9、2C19、2D6、3A4）的抑制作用较弱，但Ki值超过服药后达到的血浆浓度。观察到伐地那非代谢物M1的抑制作用最强，对CYP3A4的Ki为1.4微摩尔，比伐地那非80毫克剂量后的M1 C max值高约20倍。

体内研究

硝苯地平：伐地那非20 mg（薄膜衣片）与缓释硝苯地平30 mg或60 mg每天一次并用时，不会影响硝苯地平（通过CYP3A4代谢的药物）的相对AUC或C max 。联合使用时，硝苯地平不会改变伐地那非的血浆水平。在盐酸硝苯地平控制的患者中，盐酸伐地那非口服崩解片与缓释硝苯地平30 mg或60 mg每天一次联合给药时，可使仰卧位收缩压/舒张压平均降低3/4 mmHg（65岁年龄组）至69岁）和5/5 mmHg（年龄在70至80岁之间）与安慰剂相比。

利托那韦和茚地那韦： 5 mg伐地那非与600 mg利托那韦联用时，利托那韦的C max和AUC降低约20％。给予10 mg伐地那非（薄膜衣片）和800毫克tid茚地那韦后，茚地那韦的C max和AUC分别降低40％和30％。

阿司匹林：伐地那非10 mg和20 mg不能增强阿司匹林引起的出血时间增加（两片81 mg片剂）。

其他相互作用：伐地那非对格列本脲（葡萄糖和胰岛素浓度）和华法林（凝血酶原时间或其他药效参数）的药效学没有影响。

在特定人群中的使用

怀孕

风险摘要

盐酸伐地那非口服崩解片未用于女性。

尚无孕妇使用盐酸伐地那非口服崩解片告知任何与药物相关的风险的数据。在对怀孕大鼠和兔子进行的动物生殖研究中，未受限制的伐地那非及其主要代谢物的暴露量分别为最大推荐人剂量（MRHD）的100倍和29倍，在器官发生期间口服伐地那非并没有观察到不利的发育结果。基于AUC的20 mg （见数据） 。

数据

动物资料

在器官发生期间，接受伐地那非剂量高达18 mg / kg / day的大鼠和兔子，未观察到有致畸性，胚胎毒性或胎儿毒性的特定潜在证据。给定最大推荐人剂量（MRHD）为20 mg，该剂量比未结合的伐地那非及其主要代谢产物的AUC值高约100倍（大鼠）和29倍（兔）。

在大鼠产前和产后发育研究中，母体毒性的NOAEL（未观察到不利影响水平）为8 mg / kg /天。在母体接触1和8 mg / kg的母体后，观察到幼仔在没有母体效应的情况下发育迟缓，可能是由于血管扩张和/或药物分泌到牛奶中。出生前和出生后暴露的大鼠所生幼崽的数量减少了60 mg / kg / day。根据产前和产后研究的结果，发育性NOAEL低于1 mg / kg /天。根据大鼠发育毒性研究中的血浆暴露，估计在怀孕大鼠中1 mg / kg /天，产生未结合的伐地那非及其主要代谢物的总AUC值与MRHD为20 mg时的人AUC相当。

哺乳期

风险摘要

Vardenafil hydrochloride orally disintegrating tablets are not indicated for use in females.

There is no information on the presence of vardenafil and its major metabolite in human milk, the effects on the breastfed infant, or the effects on milk production. Vardenafil is present in rat milk of lactating rats (see Data) .

数据

Vardenafil was secreted into the milk of lactating rats at concentrations approximately 10-fold greater than found in the plasma. Following a single oral dose of 3 mg/kg, 3.3% of the administered dose was excreted into the milk within 24 hours.

儿科用

Vardenafil hydrochloride orally disintegrating tablets are not indicated for use in pediatric patients. Safety and efficacy in children has not been established.

老人用

Vardenafil AUC and C max in elderly males 65 years or older taking vardenafil hydrochloride orally disintegrating tablets were increased by 39% and 21%, respectively, in comparison to patients aged 45 years and below. No overall differences in safety or effectiveness were observed between patients ≥65 years old and those < 65 years old in placebo-controlled clinical trials [see Clinical Pharmacology (12.3)].

肝功能不全

Do not use vardenafil hydrochloride orally disintegrating tablets in patients with moderate or severe hepatic impairment.

In volunteers with mild hepatic impairment (Child-Pugh A), the C max and AUC following a 10 mg vardenafil (film-coated tablets) dose were increased by 22% and 17%, respectively, compared to healthy control subjects. Vardenafil hydrochloride orally disintegrating tablets can be used in patients with mild hepatic impairment. In volunteers with moderate hepatic impairment (Child-Pugh B), the C max and AUC following a 10 mg vardenafil (film-coated tablets) dose were increased by 130% and 160%, respectively, compared to healthy control subjects. Vardenafil has not been evaluated in patients with severe (Child-Pugh C) hepatic impairment. Do not use vardenafil hydrochloride orally disintegrating tablets in patients with moderate to severe hepatic impairment [see Warnings and Precautions (5.8) and Dosage and Administration (2).]

肾功能不全

Do not use vardenafil hydrochloride orally disintegrating tablets in patients on renal dialysis.

In volunteers with mild renal impairment (CLcr = 50 to 80 mL/min), the pharmacokinetics of vardenafil 20 mg film-coated tablets were similar to those observed in a control group with normal renal function. In the moderate (CLcr = 30 to 50 mL/min) or severe (CLcr <30 mL/min) renal impairment groups, the AUC of vardenafil was 20 to 30% higher compared to that observed in a control group with normal renal function (CLcr >80 mL/min). Vardenafil hydrochloride orally disintegrating tablets can be used in patients with mild, moderate or severe renal impairment. Do not use vardenafil hydrochloride orally disintegrating tablets in patients on renal dialysis as vardenafil has not been evaluated in such patients [see Dosage and Administration (2.3) and Warnings and Precautions (5.9)].

过量

The maximum dose of vardenafil for which human data are available is a single 120 mg dose of the film–coated tablets administered to healthy male volunteers. The majority of these subjects experienced reversible back pain/myalgia and/or “abnormal vision.” Single doses up to 80 mg vardenafil and multiple doses up to 40 mg vardenafil administered once daily over 4 weeks were tolerated without producing serious adverse side effects.

When 40 mg of vardenafil was administered twice daily, cases of severe back pain were observed. No muscle or neurological toxicity was identified.

In cases of overdose, standard supportive measures should be taken as required. Renal dialysis is not expected to accelerate clearance because vardenafil is highly bound to plasma proteins and is not significantly eliminated in the urine.

Vardenafil ODT Description

Vardenafil hydrochloride orally disintegrating tablets are an oral therapy for the treatment of erectile dysfunction. This monohydrochloride salt of vardenafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific PDE5.

Vardenafil HCl, USP is designated chemically as piperazine, 1-[[3-(1,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxyphenyl]sulfonyl]-4-ethyl-, monohydrochloride and has the following structural formula:

Vardenafil HCl, USP is a white or slightly brown or yellow powder with a molecular weight of 579.1. It is slightly soluble in water, freely soluble in anhydrous Ethanol. Practically insoluble in heptane.

Vardenafil hydrochloride orally disintegrating tablets are formulated as white to off white, round, orally disintegrating tablets. Each tablet contains 11.85 mg vardenafil hydrochloride USP (in trihydrate form), which is equivalent to 10 mg vardenafil and the following inactive ingredients: lactose monohydrate, silicified microcrystalline cellulose, crospovidone, colloidal silicon dioxide, aspartame, citric acid monohydrate, NAT Peppermint FL WONF SD #491, sodium stearyl fumarate and magnesium stearate.

Vardenafil ODT - Clinical Pharmacology

作用机理

Penile erection is a hemodynamic process initiated by the relaxation of smooth muscle in the corpus cavernosum and its associated arterioles. During sexual stimulation, nitric oxide is released from nerve endings and endothelial cells in the corpus cavernosum. Nitric oxide activates the enzyme guanylate cyclase resulting in increased synthesis of cyclic guanosine monophosphate (cGMP) in the smooth muscle cells of the corpus cavernosum. The cGMP in turn triggers smooth muscle relaxation, allowing increased blood flow into the penis, resulting in erection. The tissue concentration of cGMP is regulated by both the rates of synthesis and degradation via phosphodiesterases (PDEs). The most abundant PDE in the human corpus cavernosum is the cGMP-specific PDE5; therefore, the inhibition of PDE5 enhances erectile function by increasing the amount of cGMP. Because sexual stimulation is required to initiate the local release of nitric oxide, the inhibition of PDE5 has no effect in the absence of sexual stimulation.

In vitro studies have shown that vardenafil is a selective inhibitor of PDE5. The inhibitory effect of vardenafil is more selective on PDE5 than for other known phosphodiesterases (>15-fold relative to PDE6, >130-fold relative to PDE1, >300-fold relative to PDE11, and >1,000-fold relative to PDE2, 3, 4, 7, 8, 9, and 10).

药效学

The pharmacodynamic studies described below were conducted using vardenafil film-coated tablets.

Effects on Blood Pressure

In a clinical pharmacology study of patients with erectile dysfunction, single doses of vardenafil 20 mg film-coated tablets caused a mean maximum decrease in supine blood pressure of 7 mmHg systolic and 8 mmHg diastolic (compared to placebo), accompanied by a mean maximum increase of heart rate of 4 beats per minute. The maximum decrease in blood pressure occurred between 1 and 4 hours after dosing. Following multiple dosing for 31 days, similar blood pressure responses were observed on Day 31 as on Day 1. Vardenafil may add to the blood pressure lowering effects of antihypertensive agents [see Drug Interactions (7)] .

Effects on Blood Pressure and Heart Rate when Vardenafil is Combined with Nitrates

A study was conducted in which the blood pressure and heart rate response to 0.4 mg nitroglycerin (NTG) sublingually was evaluated in 18 healthy subjects following pretreatment with vardenafil 20 mg film-coated tablets at various times before NTG administration. Vardenafil 20 mg caused an additional time-related reduction in blood pressure and increase in heart rate in association with NTG administration. The blood pressure effects were observed when vardenafil 20 mg was dosed 1 or 4 hours before NTG and the heart rate effects were observed when 20 mg was dosed 1, 4, or 8 hours before NTG. Additional blood pressure and heart rate changes were not detected when vardenafil 20 mg film-coated tablet was dosed 24 hours before NTG (see Figure 1).

Figure 1: Placebo-subtracted point estimates (with 90% CI) of mean maximal blood pressure and heart rate effects of pre-dosing with vardenafil 20 mg at 24, 8, 4, and 1 hour before 0.4 mg NTG sublingually

Because the disease state of patients requiring nitrate therapy is anticipated to increase the likelihood of hypotension, the use of vardenafil by patients on nitrate therapy or on nitric oxide donors is contraindicated [see Contraindications (4.1)] .

Blood Pressure Effects in Patients on Stable Alpha-Blocker Treatment

Three clinical pharmacology studies were conducted in patients with benign prostatic hyperplasia (BPH) on stable-dose alpha-blocker treatment , consisting of alfuzosin, tamsulosin or terazosin.

Study 1: This study was designed to evaluate the effect of 5 mg vardenafil film-coated tablets compared to placebo when administered to BPH patients on chronic alpha-blocker therapy in two separate cohorts: tamsulosin 0.4 mg daily (cohort 1, n=21) and terazosin 5 or 10 mg daily (cohort 2, n=21). The design was a randomized, double blind, cross-over study with four treatments: vardenafil 5 mg or placebo administered simultaneously with the alpha-blocker and vardenafil 5 mg or placebo administered 6 hours after the alpha-blocker. Blood pressure and pulse were evaluated over the 6-hour interval after vardenafil dosing. For blood pressure (BP) results, see Table 2 . One patient, after simultaneous treatment with 5 mg vardenafil and 10 mg terazosin, exhibited symptomatic hypotension with standing blood pressure of 80/60 mmHg occurring one hour after administration and subsequent mild dizziness and moderate lightheadedness lasting for 6 hours. For vardenafil and placebo, five and two patients, respectively, experienced a decrease in standing systolic blood pressure (SBP) of >30 mmHg following simultaneous administration of terazosin. Hypotension was not observed when vardenafil 5 mg and terazosin were administered 6 hours apart. Following simultaneous administration of vardenafil 5 mg and tamsulosin, two patients had a standing SBP of <85 mmHg. A decrease in standing SBP of >30 mmHg was observed in two patients on tamsulosin receiving simultaneous vardenafil and in one patient receiving simultaneous placebo treatment. When tamsulosin and vardenafil 5 mg were separated by 6 hours, two patients had a standing SBP <85 mmHg and one patient had a decrease in SBP of >30 mmHg. There were no severe adverse events related to hypotension reported during the study. There were no cases of syncope.

Table 2: Mean (95% CI) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 5 mg in BPH patients on stable alpha-blocker therapy (study 1)

Blood pressure effects (standing SBP) in normotensive men on stable dose tamsulosin 0.4 mg following simultaneous administration of vardenafil 5 mg or placebo, or following administration of vardenafil 5 mg or placebo separated by 6 hours are shown in Figure 2 . Blood pressure effects (standing SBP) in normotensive men on stable dose terazosin (5 or 10 mg) following simultaneous administration of vardenafil 5 mg or placebo, or following administration of vardenafil 5 mg or placebo separated by 6 hours, are shown in Figure 3 .

Figure 2: Mean change from baseline in standing systolic blood pressure (mmHg) over 6 hour interval following simultaneous or 6 hr separation administration of vardenafil 5 mg or placebo with stable dose tamsulosin 0.4 mg in normotensive BPH patients (study 1)

Figure 3: Mean change from baseline in standing systolic blood pressure (mmHg) over 6 hour interval following simultaneous or 6 hr separation administration of vardenafil 5 mg or placebo with stable dose terazosin (5 or 10 mg) in normotensive BPH patients (study 1)

Study 2: This study was designed to evaluate the effect of 10 mg vardenafil (film-coated tablets) (stage 1) and 20 mg vardenafil (film-coated tablets) (stage 2) compared to placebo, when administered to a single cohort of BPH patients (n=23) on stable therapy with tamsulosin 0.4 mg or 0.8 mg daily for at least four weeks. The design was a randomized, double blind, two-period, cross-over study. Vardenafil or placebo was given simultaneously with tamsulosin. Blood pressure and pulse were evaluated over the 6-hour interval after vardenafil dosing. For BP results see Table 3 . One patient experienced a decrease from baseline in standing SBP of >30 mmHg following vardenafil 10 mg. There were no other instances of outlier blood pressure values (standing SBP <85 mmHg or decrease from baseline in standing SBP of >30 mmHg). Three patients reported dizziness following vardenafil 20 mg. There were no cases of syncope.

Table 3: Mean (95% CI) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg (film-coated tablets) in BPH patients on stable alpha-blocker therapy with tamsulosin 0.4 or 0.8 mg daily (study 2)

Blood pressure effects (standing SBP) in normotensive men on stable dose of tamsulosin 0.4 mg following simultaneous administration of vardenafil 10 mg, vardenafil 20 mg or placebo are shown in Figure 4 .

Figure 4: Mean change from baseline in standing systolic blood pressure (mmHg) over 6 hour interval following simultaneous administration of vardenafil 10 mg film-coated tablet (stage 1), vardenafil 20 mg film-coated tablet (Stage 2), or placebo with stable dose tamsulosin 0.4 mg in normotensive BPH patients (study 2)

Study 3 : This study was designed to evaluate the effect of single doses of 5 mg vardenafil (stage 1) and 10 mg vardenafil (stage 2) compared to placebo, when administered to a single cohort of BPH patients (n=24) on stable therapy with alfuzosin 10 mg daily for at least four weeks. The design was a randomized, double blind, 3period cross-over study. Vardenafil or placebo was administered 4 hours after the administration of alfuzosin. Blood pressure and pulse were evaluated over a 10-hour interval after dosing of vardenafil or placebo. For BP results see Table 4.

Table 4: Mean (95% CI) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 5 and 10 mg in BPH patients on stable alpha-blocker therapy with alfuzosin 10 mg daily (Study 3)

One patient experienced decreases from baseline in standing systolic blood pressure >30 mm Hg after administration of vardenafil 5 mg film-coated tablets and vardenafil 10 mg film-coated tablets. No instances of standing systolic blood pressure <85 mm Hg were observed during this study. Four patients, one dosed with placebo, two dosed with vardenafil 5 mg film-coated tablets and one dosed with vardenafil 10 mg film-coated tablets, reported dizziness. Blood pressure effects (standing SBP) in normotensive men on a stable dose of alfuzosin 10 mg following administration of vardenafil 5 mg, vardenafil 10 mg, or placebo separated by 4 hours, are shown in Figure 5.

Figure 5: Mean change from baseline in standing systolic blood pressure (mmHg) over 6 hour interval following 4 hr separation administration of vardenafil 5 mg (stage 1), vardenafil 10 mg (stage 2) or placebo with stable dose alfuzosin 10 mg in BPH patients (Study 3)

Blood Pressure Effects in Normotensive Men After Forced Titration with Alpha-Blockers

Two randomized, double blind, placebo-controlled clinical pharmacology studies with healthy normotensive volunteers (age range, 45 to 74 years) were performed after forced titration of the alpha-blocker terazosin to 10 mg daily over 14 days (n=29), and after initiation of tamsulosin 0.4 mg daily for five days (n=24). There were no severe adverse events related to hypotension in either study. Symptoms of hypotension were a cause for withdrawal in 2 subjects receiving terazosin and in 4 subjects receiving tamsulosin. Instances of outlier blood pressure values (defined as standing SBP <85 mmHg and/or a decrease from baseline of standing SBP >30 mmHg) were observed in 9/24 subjects receiving tamsulosin and 19/29 receiving terazosin.

The incidence of subjects with standing SBP <85 mmHg given vardenafil and terazosin to achieve simultaneously the amount of time at the maximum concentration in serum (T max ) led to early termination of that arm of the study. In most (7/8) of these subjects, instances of standing SBP <85 mmHg were not associated with symptoms. Among subjects treated with terazosin, outlier values were observed more frequently when vardenafil and terazosin were given to achieve simultaneous T max than when dosing was administered to separate T max by 6 hours. There were 3 cases of dizziness observed with concomitant administration of terazosin and vardenafil. Seven subjects experienced dizziness mainly occurring with simultaneous T max administration of tamsulosin. There were no cases of syncope.

Table 5: Mean (95% CI) maximal change in baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg (film-coated tablets) in healthy volunteers on daily alpha-blocker therapy