部分中文维替泊芬处方资料（仅供参考） 通用名：注射用维替泊芬 商品名：维速达尔/Visudyne 英文名：Verteporfin for injection 汉语拼音：Zhusheyong Weitibofen 本品主要成份及其化学名称：维替泊芬，其化学名为9-甲基（I）和13-甲基（II）反式-（±）-18-乙烯-4,4a-二氢-3,4-双（甲酯基）-4a,8,14,19-四甲基-23H,25H-苯卟啉-9,13-二丙酯 分子式：C41H42N4O8 分子量：718.8 性状 本品为深绿色疏松块状物。 药理毒理 治疗年龄相关性黄斑变性、病理性近视和可疑眼组织胞浆菌病综合征等疾病引起的脉络膜新生血管（CNV）维替泊芬治疗分两步，需要注射维替泊芬和非致热红光源.维替泊芬在血浆中主要被脂蛋白转运。在有氧环境下，维替泊芬一旦被光激活就会产生高度活性的、维持时间短暂的单氧和具有活性的氧自由基。被光激活的维替泊芬可以损伤局部新生血管内皮细胞，引起血管闭合。已知，受损的内皮细胞可以通过脂氧化酶（白三烯）和环氧化酶（类花生酸如血栓素）途径释放促凝因子和血管活性因子，引起血小板聚集纤维蛋白凝块形成和血管收缩。维替泊芬主要在新生血管包括脉络膜新生血管积聚，然而动物试验显示维替泊芬也出现于视网膜。因而在光动力学治疗的同时也会出现视网膜的损伤，包括视网膜色素上皮细胞和外核层。在人类，维替泊芬治疗引起脉络膜新生血管（CNV）暂时性闭合的疗效已经被荧光血管造影结果所证实致癌，致畸和对生殖功能的影响目前还没有对维替泊芬致癌性的研究。 有报道，光动力治疗（PDT）可以引起DNA 损伤，包括DNA 链断裂，出现碱基敏感位点，DNA 降解和DNA-蛋白交联，从而引起染色体畸变、姐妹染色单体互换（SCE）和突变。 另外，应用其他光动力学治疗药物后，经过可见光照射的中国仓鼠卵巢（CHO）细胞和经过近紫外光照射的中国仓鼠肺成纤维细胞出现姐妹染色单体互换的几率增加，在小鼠L5178 细胞突变和DNA-蛋白交联增加，在人恶性子宫颈癌细胞DNA 链断裂增加，而在正常细胞无此现象。在最后几个体系中，未对维替泊芬进行评估。PDT 治疗药物对DNA 的损伤作用对人类的潜在危险尚不清楚。在大鼠每天静脉给予维替泊芬10mg/kg，（分别给予雄性和雌性大鼠，根据AUCinf值，人类6mg/m2 暴露量的大约60 和40倍剂量注射），未观察到对雄性或雌性大鼠生殖能力的影响。 药代动力学 静脉输注维替泊芬后，维替泊芬以二指数形式清除，终末消除半衰期大约为5~6小时。 剂量在6~20mg/m2 之间时，暴露量和最大血药浓度均与注射剂量成比例。在一定的剂量范围内，药物的药代动力学参数不受性别影响。维替泊芬经过肝和血浆酯酶代谢终产物苯卟啉衍生双酸。NADPH 依赖的肝酶系统（包括细胞色素P450 同工酶）不参与维替泊芬代谢。药物通过粪便排泄，只有不到0.01%的药物剂量可以在尿液中发现。在一项，轻度肝功能不全患者中（入选时有两项肝功能指标异常）进行的研究中，AUC 和Cmax与对照组相比无明显差异，但是半衰期明显延长，大约增加20%。 适应症 维替泊芬治疗适用于继发于年龄相关性黄斑变性，病理性近视或可疑眼组织胞浆菌病的，以典型性为主型中心凹下脉络膜新生血管形成的患者。对于隐匿性中心凹下脉络膜新生血管为主的患者，尚无充分证据支持维替泊芬治疗。 用法用量 维替泊芬治疗分为两个步骤，同时需要药物和激光。第一步静脉输注维替泊芬，第二步用非热性二极管激光活化维替泊芬。每隔3个月医生需要检查患者，一旦荧光血管造影出现脉络膜新生血管渗漏就应该重复治疗。 病灶大小判定病灶最大线性距离（GLD）通过荧光血管造影和彩色眼底像判定。各种典型和隐匿型CNV，出血和/或荧光遮挡，任何视网膜色素上皮浆液性脱离都应该进行判定。 建议使用2.4~2.6倍的彩色眼底照相机。荧光血管造影片上病灶的GLD必须经过相机放大率矫正，获得病灶在视网膜上的GLD。光斑大小判定治疗光斑大小应该比病灶在视网膜上GLD大1000um，留有500um的边缘，保证完全覆盖病灶。临床研究应用的最大治疗光斑为6400um。治疗光斑的鼻侧缘必须距离视乳头颞侧至少200um，即使这样会在视神经200um范围内出现CNV 光凝不足。 维替泊芬应用 每支维替泊芬用7ml 无菌注射用水配制成7.5ml浓度为2mg/ml的注射液。配制好的溶液必须避光保存，并且在4 小时内使用。建议在注射前观察配制好的溶液是否出现沉淀和变色现象。配制好的溶液是一种深绿色的透明液体。按6mg/m2 体表面积剂量配制维替泊芬，溶解于5%的葡萄糖溶注射液，配成30ml溶液。用合适的注射泵和过滤器，以每分钟3ml的速度在10分钟完全经静脉输注完毕。临床研究中应用的是1.2um 的过滤器。注意防止出现注射局部药液外渗。一旦发生要注意注射局部避光（详见注意事项）。 激光治疗 自输注开始后15分钟，用波长689nm 激光照射患者。维替泊芬的光活化程度由所接受的激光总量决定。治疗脉络膜新生血管形成时，在病灶局部推荐使用激光剂量为50J/cm2，激光强度600mW/cm2。此剂量在83 秒内照射完毕。激光剂量，激光强度，检眼镜的放大率和焦距的设置等都是合理激光治疗，形成理想的激光斑的重要参数。具体的设置和操作见激光系统操作手册。激光系统必须能产生波长在689±3nm，能量恒定的光。激光通过光纤维，裂隙灯和一定放大倍率的检眼镜镜头在视网膜形成单一的圆形光斑。 以下激光系统已被证实与维替泊芬相匹配，能产生波长在689±3nm,能量恒定的光。 由Lumenis Inc, Santa Clara, CA生产的科医人 Opal Photoactivator 激光控制台和改良的科医人LaserLink adapter 适配器,由Carl Zeiss Inc., Thornwood, NY生产的VISULAS 690s激光和VISULINK PDT/U适配器。双眼同时治疗对照研究只允许每位患者治疗一只眼。如果患者双眼病灶都适合治疗，医生应权衡双眼同时治疗的利弊。如果患者以往有维替泊芬单眼治疗史，治疗的安全性已经得到证实，就可以采用一次注射维替泊芬治疗双眼。在注射开始后15分钟，首先治疗病情进展较快的眼。在第一眼光照后立即调整第二眼治疗的激光参数，采用同第一眼相同的激光剂量和强度，在输注开始后不晚于20 分钟开始治疗。 如果患者首次出现双眼可以治疗的病灶，以往无维替泊芬治疗史，最好先治疗病情进展较快的眼。 如果第一只眼治疗后1周，未出现明显的安全性问题，可以采用第一眼的治疗方案，再输注维替泊芬进行第二只眼治疗。大约三个月后检查双眼，如果双眼病灶都出现渗漏，需要重复治疗，可以重新输注维替泊芬进行治疗。 不良反应 维替泊芬治疗报道最多的不良事件为头疼，注射局部反应（包括药液外渗和皮疹）和视力障碍（视物模糊，视敏度下降，视野缺损）。大约10~30%的患者出现这些事件。 以下不良事件按照身体各个系统排列，是维替泊芬治疗最多见的反应，出现率高于安慰剂组，出现于1~10%的患者：眼部： 睑缘炎、白内障、结膜炎/结膜充血、干眼、眼痒、伴或不伴视网膜下或玻璃体出血的严重视力丧失。 全身： 衰弱，背痛（主要在药物输注时）、发热、流感样综合征、光敏反应心血管系统： 房颤、高血压、外周血管异常、静脉曲张皮肤： 湿疹消化系统： 便秘、胃肠癌、恶心血液/淋巴系统：贫血、白细胞计数减少、白细胞计数增加肝脏： 肝功能检验指标异常代谢/营养：蛋白尿、肌酐升高骨骼肌：关节痛、关节病、肌无力神经系统：感觉减退、睡眠障碍、眩晕呼吸系统：咳嗽、咽炎、肺炎特殊感觉：白内障、听力障碍、复视、流泪障碍泌尿系统：前列腺障碍已报告1~5%的患者在治疗后7天内出现严重视力下降，相当于视力下降4行或以上。某些患者视力能部分恢复。光敏反应通常出现在治疗后皮肤暴露于日光下，以皮肤灼伤为表现形式。维替泊芬治疗组背痛的发生率较高，主要出现在输注时。 以下不良事件在临床研究中发生率较低（<1%）或出现在临床应用过程中，来源于自发报道，报道来源的人群样本量不详，不能获得精确的发生率。 这些不良事件的分类是基于一些因素，如其严重程度、报道频率，与维替泊芬治疗可能有关或是以上的总和：眼部： 视网膜脱离（非孔源性），视网膜或脉络膜血管无灌注非眼部事件：输注时出现胸痛或肌肉骨骼疼痛、过敏反应（可以很严重）、晕厥、严重过敏反应伴呼吸困难和潮红以及血管-迷走神经反应。 禁忌 维替泊芬治疗禁用于卟啉症患者及已知对本品制剂中任何成份过敏者。 注意事项 维替泊芬治疗后5天内，避免皮肤或眼部直接暴露于阳光或强的室内光源。一旦在输注过程中出现药液外渗，外渗局部必须完全避光，直到局部肿胀和变色完全消失，否则会出现严重局部灼伤。如果治疗后48小时内需要行急症手术，大多数体内组织应该尽可能避免接受强光照射。如果治疗后一周内视力严重下降4 行或以上的患者不能重复治疗，至少要在视力完全恢复到术前水平以及治疗医生充分考虑重复治疗的利弊后再进行。 应用不匹配激光，不能提供维替泊芬光活化所需的条件，可能会由于维替泊芬不完全活化，引起治疗不完全，或维替泊芬过度活化引起治疗过量或周围正常组织损伤。 一般注意事项：输注维替泊芬时要避免药液外渗，注意事项包括、但不局限于以下几点： ·在维替泊芬开始输注前要先建立静脉通道，并时刻注意通道的通畅性。 ·由于某些老年患者的静脉壁脆性较大，尽量选择手臂最大的静脉比如肘前静脉输注。 ·避免选用手背小静脉。如果出现药液外渗，必须立即停止输注并局部冷敷（见警告）。对有中-重度肝功能损害或胆道阻塞患者要慎用维替泊芬治疗，因为目前尚无治疗这些患者的临床经验。目前尚无在麻醉患者使用维替泊芬治疗的相关临床资料。对镇静或麻醉状态的豚鼠进行10倍以上剂量注射，维替泊芬可以引起严重的血流动力学障碍，包括死亡，可能是补体激活的结果。如果事先进行抗组胺治疗，就可以减轻或消除此现象，而在清醒非镇静状态的豚鼠未见类似表现。体外在人血液中，维替泊芬可以引起浓度依赖的补体活化反应。在浓度为10ug/ml时（大约为患者预期血药浓度的5 倍），出现轻到中度补体活化现象。在浓度为100ug/ml时，出现明显的补体活化。在不足1%的维替泊芬治疗患者出现与补体活化相一致的症状（胸痛，晕厥，呼吸困难和潮红）。因此在维替泊芬输注过程，应密切监测患者。 患者须知 接受维替泊芬治疗的患者，在输注后会出现一过性的光过敏现象。患者应该佩戴袖带，提醒他们在治疗5天内避免阳光直射。在这个阶段，未防护的皮肤、眼或其他器官要避免阳光或强的室内光源直射。强光源包括但不局限于：日光浴，大功率卤素灯光，手术室和牙科诊所的强光。维替泊芬治疗5 天内也要避免某些医学仪器发射的持续光，如脉搏氧饱和度仪。如果患者在治疗后最初5天必须在白天去户外，必须穿保护性衣服，佩戴墨镜以保护全部皮肤和眼睛。紫外线防护剂不能有效防止光敏反应，因为皮肤残留药物可以通过可见光活化。患者也不应完全处于黑暗状态，应该鼓励患者将皮肤暴露于周围的室内光线，这样可以通过光漂白过程使皮肤残留药物失活。 孕妇及哺乳期妇女用药 大鼠胎儿在器官发生期给予维替泊芬≥10mg/kg/天静脉注射（给予雌性大鼠，根据AUCinf值，大约为人6mg/m2暴露量的40倍剂量），显示无眼畸形/小眼畸形的发生率增加。大鼠胎儿给予维替泊芬25mg/kg/天（给予雌性大鼠，根据AUCinf值，大约为人6mg/m2暴露量的125倍剂量），显示畸形肋、无眼畸形/小眼畸形的发生率增加。在妊娠期兔的器官发生期，给予维替泊芬10mg/kg/天静脉注射，出现体重增加的减少和进食减少现象。对母体毒性的不出现副反应剂量水平(NOAEL)为3mg/kg/天（大约是人按照体表面积6mg/m2暴露量的7倍）。在兔以10mg/kg/天剂量注射未出现致畸现象。目前尚无对妊娠妇女的充分、良好对照的研究。只有当用药可能的益处远高于给胎儿带来的风险时，才考虑在妊娠期进行本品治疗。哺乳期妇女目前尚不明确注射维替泊芬是否会进入母乳。由于许多药物会进入母乳，哺乳期妇女进行维替泊芬治疗必须谨慎。 儿童用药 尚无儿童用药的安全性和有效性结果。 老年患者用药 在维替泊芬疗效临床研究中，维替泊芬治疗患者大约90%年龄在65岁以上。随着年龄增加，疗效逐渐减弱。 药物相互作用 目前尚无人体内维替泊芬药物相互作用的研究。维替泊芬主要以原型通过肝脏快速排泄。药物代谢局限于肝和血浆酯酶。细胞色素P450并不参与维替泊芬的代谢。根据维替泊芬的作用机理，许多药物联合使用会影响维替泊芬的疗效。比如：钙通道阻断剂，多粘菌素B 或放疗会增加血管内皮细胞摄取维替泊芬。其他光敏剂（如四环素，磺胺类药物，酚噻嗪，磺脲类降血糖药，噻嗪类利尿药和灰黄霉素）可以增加皮肤光敏反应性。可以消除活性氧类或清除自由基的复合物，如二甲基亚砜，?-胡萝卜素，乙醇，甲酸盐和甘露醇可能会降低维替泊芬的活性。减少凝血、血管收缩和血小板聚集的药物如血栓素A2 抑制剂，也可以降低维替泊芬的疗效。 药物过量 治疗眼药物和/或激光过量可以引起正常视网膜血管无灌注，引起持续严重的视力下降。药物过量可以延长患者对强光过敏的时间。建议一旦发生过量，需根据患者过量的程度成比例的延长避光时间。 规格 15mg（以维替泊芬计） 贮藏 包装产品必须在室温下（25℃以下）避光保存。冻干粉针溶解后应避免光照，并4小时内使用。 有效期 3年 VISUDYNE 15mg, powder for solution for infusion 1. Name of the medicinal product Visudyne® 15 mg powder for solution for infusion 2. Qualitative and quantitative composition Each vial contains 15 mg of verteporfin. After reconstitution, 1 ml contains 2 mg of verteporfin. 7.5 ml of reconstituted solution contains 15 mg of verteporfin. For the full list of excipients see section 6.1. 3. Pharmaceutical form Powder for solution for infusion Dark green to black powder. 4. Clinical particulars 4.1 Therapeutic indications Visudyne is indicated for the treatment of - adults with exudative (wet) age-related macular degeneration (AMD) with predominantly classic subfoveal choroidal neovascularisation (CNV) or - adults with subfoveal choroidal neovascularisation secondary to pathological myopia. 4.2 Posology and method of administration Visudyne should be administered only by ophthalmologists experienced in the management of patients with age-related macular degeneration or with pathological myopia. Posology Adults, including the elderly (≥65 years old) Visudyne photodynamic therapy (PDT) is a two-step process: The first step is a 10-minute intravenous infusion of Visudyne at a dose of 6 mg/m2 body surface area, diluted in 30 ml infusion solution (see section 6.6). The second step is the light activation of Visudyne at 15 minutes after the start of the infusion (see method of administration). Patients should be re-evaluated every 3 months. In the event of recurrent CNV leakage, Visudyne therapy may be given up to 4 times per year. Treatment of the second eye with Visudyne There are no clinical data to support concomitant treatment of the second eye. However, if treatment of the second eye is deemed necessary, light should be applied to the second eye immediately after light application in the first eye but no later than 20 minutes from the start of the infusion. Hepatic impairment Visudyne therapy should be considered carefully in patients with moderate hepatic dysfunction or biliary obstruction. No experience is available in these patients. Since verteporfin is excreted primarily via the biliary (hepatic) route, increased verteporfin exposure is possible. Verteporfin exposure is not significantly increased in patients with mild hepatic impairment (see biotransformation and elimination under section 5.2) and does not require any dose adjustment. Visudyne is contraindicated in patients with severe hepatic impairment (see section 4.3). Renal impairment Visudyne has not been studied in patients with renal impairment. However the pharmacological characteristics do not indicate any need to adjust the dose (see biotransformation and elimination under section 5.2). Paediatric population The safety and efficacy of Visudyne in the paediatric population have not been established. Visudyne is not indicated in this population. Method of administration This medicinal product is intended for intravenous infusion only. For the light activation of Visudyne, a diode laser generating non-thermal red light (wavelength 689 nm ± 3 nm) is used via a slit lamp mounted fibre optic device and a suitable contact lens. At the recommended light intensity of 600 mW/cm2, it takes 83 seconds to deliver the required light dose of 50 J/cm2. The greatest linear dimension of the choroidal neovascular lesion is estimated using fluorescein angiography and fundus photography. Fundus cameras with a magnification within the range of 2.4 - 2.6X are recommended. The treatment spot should cover all neovasculature, blood and/or blocked fluorescence. To ensure treatment of poorly demarcated lesion borders, an additional margin of 500 µm should be added around the visible lesion. The nasal edge of the treatment spot must be at least 200 μm from the temporal edge of the optic disc. The maximum spot size used for the first treatment in the clinical studies was 6,400 μm. For treatment of lesions that are larger than the maximum treatment spot size, apply the light to the greatest possible area of active lesion. It is important to follow the above recommendations to achieve the optimal treatment effect. For instructions on reconstitution of the medicinal product before administration, see section 6.6. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Visudyne is also contraindicated in patients with porphyria and in patients with severe hepatic impairment (see hepatic impairment under section 4.2). 4.4 Special warnings and precautions for use Photosensitivity and exposure to light Patients who receive Visudyne will become photosensitive for 48 hours after the infusion. During that period, patients should avoid exposure of unprotected skin, eyes or other body organs to direct sunlight or bright indoor light such as tanning salons, bright halogen lighting, or high power lighting in surgery operating rooms or dental surgeries. Prolonged exposure to light from light-emitting medical devices such as pulse oximeters should also be avoided for 48 hours following Visudyne administration. If patients have to go outdoors in daylight during the first 48 hours after treatment, they must protect their skin and eyes by wearing protective clothing and dark sunglasses. UV sunscreens are not effective in protecting against photosensitivity reactions. Ambient indoor light is safe. Patients should not stay in the dark and should be encouraged to expose their skin to ambient indoor light, as it will help eliminate the medicinal product quickly through the skin by a process called photobleaching. Use in patients with moderate hepatic impairment or biliary obstruction Visudyne therapy should be considered carefully in patients with moderate hepatic impairment or biliary obstruction since no experience has been gained in these patients. Since verteporfin is excreted primarily via the biliary (hepatic) route, increased verteporfin exposure is possible. Risk of severe decrease of vision Patients who experience a severe decrease of vision (equivalent to 4 lines or more) within one week after treatment should not be re-treated, at least until their vision has completely recovered to pre-treatment level and the potential benefits and risks of subsequent treatment have been carefully considered by the treating physician. Extravasation of the solution for infusion Extravasation of Visudyne, especially if the affected area is exposed to light, can cause severe pain, inflammation, swelling, blistering or discoloration at the injection site. The relief of pain may require analgesic treatment. If extravasation occurs, infusion should be stopped immediately. Protect the affected area thoroughly from bright direct light until swelling and discoloration have disappeared, and put cold compresses on the injection site. To avoid extravasation, a free-flowing intravenous line should be established before starting Visudyne infusion and the line should be monitored. The largest possible arm vein, preferably the antecubital, should be used for the infusion and small veins in the back of the hand should be avoided. Hypersensitivity reactions Chest pain, vasovagal reactions and hypersensitivity reactions, which on rare occasions can be severe, have been reported. Both vasovagal and hypersensitivity reactions are associated with general symptoms such as syncope, sweating, dizziness, rash, dyspnoea, flushing, and changes in blood pressure and heart rate. Patients should be under close medical supervision during the Visudyne infusion. Anaesthesia There are no clinical data on the use of Visudyne in anaesthetised patients. In sedated or anaesthetised pigs, a Visudyne dose significantly higher than the recommended dose in patients given as a bolus injection caused severe haemodynamic effects including death, probably as a result of complement activation. Pre-dosing with diphenhydramine diminished these effects, suggesting that histamine may play a role in this process. This effect was not observed in conscious non-sedated pigs, or in any other species, including man. Verteporfin at more than 5 times the expected maximum plasma concentration in treated patients, caused a low level of complement activation in human blood in vitro. No clinically relevant complement activation was reported in clinical trials but anaphylactic reactions have been reported during post-marketing surveillance. Patients should be under close medical supervision during the Visudyne infusion and caution should be exercised when Visudyne treatment under general anaesthesia is considered. Other Visudyne contains small amounts of butylated hydroxytoluene (E321), which may be irritant to eyes, skin and mucous membranes. Therefore it must be washed off extensively with water in the event of direct contact. 4.5 Interaction with other medicinal products and other forms of interaction No interaction studies have been performed in humans. Other photosensitising agents It is possible that concomitant use of other photosensitising medicinal products (e.g. tetracyclines, sulphonamides, phenothiazines, sulfonylurea, hypoglycaemic medicinal products, thiazide diuretics, and griseofulvin) could increase the potential for photosensitivity reactions. Caution should therefore be exercised when using Visudyne concomitantly with other photosensitising medicinal products (see information on photosensitivity and exposure to light in section 4.4). Agents which increase verteporfin uptake in the vascular endothelium Agents such as calcium channel blockers, polymixin B, and radiation therapy are known to alter the vascular endothelium. Based on theoretical data and despite the lack of clinical evidence these agents might result in enhanced verteporfin tissue-uptake when used concurrently. Free radical scavengers Although there is no clinical evidence, theoretical data suggest that antioxidants (e.g. beta-carotene) or medicinal products which scavenge free radicals (e.g. dimethylsulfoxide (DMSO), formate, mannitol or alcohol) might quench the activated oxygen species generated by verteporfin, resulting in decreased verteporfin activity. Medicinal products which antagonise blood vessel occlusion Since blood vessel occlusion is the major mechanism of verteporfin action, there is a theoretical possibility that agents such as vasodilators and those which diminish clotting and platelet aggregation (e.g. thromboxane A2 inhibitors) can antagonise the action of verteporfin. 4.6 Fertility, pregnancy and lactation Pregnancy No clinical data on exposed pregnancies are available for verteporfin. Studies in animals have shown teratogenic effects in one species (rat) (see section 5.3). The potential risk for humans is unknown. Visudyne should not be used during pregnancy unless clearly necessary (only if the benefit justifies the potential risk to the foetus). Breast-feeding Verteporfin and its diacid metabolic are excreted in human milk in low amounts. It should therefore not be administered to nursing mothers, or breastfeeding should be interrupted for 48 hours after administration. Fertility There are no human fertility data for verteporfin. In non-clinical studies, no impairment of fertility and no genotoxicity have been observed (see section 5.3). The clinical relevance is unknown. Patients of reproductive age should be made aware of the lack of fertility data, and Visudyne should only be given after consideration of individual risks and benefits. 4.7 Effects on ability to drive and use machines Following Visudyne treatment, patients may develop transient visual disturbances such as abnormal vision, vision decrease, or visual field defects that may interfere with their ability to drive or use machines. Patients should not drive or use machines as long as these symptoms persist. 4.8 Undesirable effects Most adverse reactions were mild to moderate and transient in nature. Undesirable effects reported in patients with pathological myopia were similar to those reported in patients with AMD. The most frequently reported adverse reactions to Visudyne (verteporfin for infusion) are injection site reactions (including pain, oedema, inflammation, extravasation, rashes, haemorrhage, discolouration) and visual impairment (including blurred, fuzzy vision, photopsia, reduced visual acuity and visual field defects, including scotoma and black spots). The following adverse reactions were considered potentially related to Visudyne therapy. The adverse reactions are listed by system organ class and frequency using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness Immune system disorders Not known Hypersensitivity1. Metabolism and nutrition disorders Common Hypercholesteraemia. Nervous system disorders Uncommon Hyperesthesia. Not known Vasovagal reactions1. Eye disorders Common Severe reduced visual acuity2, visual impairment such as reduced visual acuity, blurred, fuzzy vision, or photopsia, visual field defect such as scotoma, grey or dark haloes and black spots. Uncommon Retinal detachment (non-rhegmatogenous), subretinal/retinal haemorrhage, vitreous haemorrhage. Rare Retinal or choroidal vessel non-perfusion. Not known Retinal pigment epithelial tear, macular oedema, retinal oedema. Cardiac disorders Not known Myocardial infarction3. Vascular disorders Uncommon Hypertension. Gastrointestinal disorders Common Nausea. Skin and subcutaneous tissue disorders Common Photosensitivity reaction4. General disorders and administration site conditions Common Injection site pain, injection site oedema, injection site inflammation, injection site extravasation, asthenia. Uncommon Injection site hypersensitivity, injection site haemorrhage, injection site discoloration, pyrexia, pain. Not known Injection site blister. Injury, poisoning and procedural complications Common Infusion-related reaction primarily presented as back pain5, 6. Not known Infusion-related chest pain 6. 1 Vasovagal reactions and hypersensitivity reactions, which on rare occasions can be severe, have been reported. General symptoms can include headache, malaise, syncope, hyperhydrosis, dizziness, rash, urticaria, pruritus, dyspnoea, flushing, and changes in blood pressure and heart rate. 2 Severely reduced visual acuity, equivalent to 4 lines or more, within seven days after treatment was reported in 2.1 % of the verteporfin-treated patients in the placebo-controlled ocular Phase III clinical studies and in less than 1 % of patients in uncontrolled clinical studies. The reaction occurred mainly in patients with occult only (4.9 %) or minimally classic CNV lesions in patients with AMD and was not reported for placebo-treated patients. Partial recovery of vision was observed in some patients. 3 Myocardial infarction has been reported, particularly in patients with previous cardiovascular history, sometimes within 48 hours after the infusion. 4 Photosensitivity reactions (in 2.2 % of patients and <1 % of Visudyne courses) occurred in the form of sunburn following exposure to sunlight, usually within 24 hours from Visudyne treatment. Such reactions should be avoided by compliance with the photosensitivity protection instructions given in section 4.4. 5 The higher incidence of back pain during infusion in the Visudyne group was not associated with any evidence of haemolysis or allergic reaction and usually resolved by the end of the infusion. 6 Infusion-related back and chest pain, which may radiate to other areas, including, but not limited to, the pelvis, shoulder girdle or rib cage. 4.9 Overdose Overdose of the medicinal product and/or light in the treated eye may result in non-selective non-perfusion of normal retinal vessels, with the possibility of severe vision decrease. Overdose of the medicinal product may result in the prolongation of the period during which the patient remains photosensitive. In such cases, the patient should prolong skin and eye protection from direct sunlight or bright indoor light for a period proportionate with the overdose given. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Ophthalmologicals, Antineovascularisation agents, ATC code: S01LA01 Verteporfin, also referred to as benzoporphyrin derivative monoacids (BPD-MA) consists of a 1:1 mixture of the equally active regioisomers BPD-MAC and BPD-MAD. It is used as a light-activated medicinal product (photosensitiser). By itself, the clinically recommended dose of verteporfin is not cytotoxic. It produces cytotoxic agents only when activated by light in the presence of oxygen. When energy absorbed by the porphyrin is transferred to oxygen, highly reactive short-lived singlet oxygen is generated. Singlet oxygen causes damage to biological structures within the diffusion range, leading to local vascular occlusion, cell damage and, under certain conditions, cell death. The selectivity of PDT using verteporfin is based, in addition to the localised light exposure, on selective and rapid uptake and retention of verteporfin by rapidly proliferating cells including the endothelium of choroidal neovasculature. Age-related macular degeneration with predominantly classic subfoveal lesions Visudyne has been studied in two randomised, placebo-controlled, double-masked, multicentre studies (BPD OCR 002 A and B or Treatment of Age-related Macular Degeneration with Photodynamic Therapy [TAP]). A total of 609 patients were enrolled (402 Visudyne, 207 placebo). The objective was to demonstrate the long-term efficacy and safety of photodynamic therapy with verteporfin in limiting the decrease in visual acuity in patients with subfoveal choroidal neovascularisation due to age-related macular degeneration. The primary efficacy variable was responder rate, defined as the proportion of patients who lost less than 15 letters (equivalent to 3 lines) of visual acuity (measured with the ETDRS charts) at month 12 relative to baseline. The following inclusion criteria were considered for the treatment: patients older than 50 years of age, presence of CNV secondary to AMD, presence of classic lesion components in the CNV (defined as a well-demarcated area of the fluorescence on angiography), CNV located subfoveally (involved the geometric centre of the foveal avascular zone), area of classic plus occult CNV ≥50 % of the total lesion surface, greatest linear dimension of the entire lesion ≤9 Macular Photocoagulation Study (MPS) disc area, and a best-corrected visual acuity between 34 and 73 letters (i.e. approximately 20/40 and 20/200) in the treated eye. Presence of occult CNV lesions (fluorescence not well demarcated on the angiogram) was allowed. Results indicate that, at 12 months, Visudyne was statistically superior to placebo in terms of the proportion of patients responding to the treatment. The studies showed a difference of 15 % between treatment groups (61 % for Visudyne-treated patients compared to 46 % placebo-treated patients, p<0.001, ITT analysis). This 15 % difference between treatment groups was confirmed at 24 months (53 % Visudyne versus 38 % placebo, p<0.001). The subgroup of patients with predominantly classic CNV lesions (N=243; Visudyne 159, placebo 84) were more likely to exhibit a larger treatment benefit. After 12 months, these patients showed a difference of 28 % between treatment groups (67 % for Visudyne patients compared to 39 % for placebo patients, p<0.001); the benefit was maintained at 24 months (59 % versus 31 %, p<0.001). In relation to TAP extension: In patients followed from month 24 onwards and treated with uncontrolled, open-label Visudyne treatment as needed, long-term extension data suggest that month-24 vision outcomes may be sustained for up to 60 months. In the TAP study in all lesion types, the average number of treatments per year were 3.5 in the first year after diagnosis and 2.4 in the second for the randomised placebo-controlled phase and 1.3 in the third year, 0.4 in the fourth and 0.1 in the fifth year for the open-label extension phase. No additional safety concern was identified. Age-related macular degeneration with occult with no classic lesions The benefit of the product in the AMD patient population who have occult subfoveal CNV with evidence of recent or ongoing disease progression has not been demonstrated consistently. Two randomised, placebo-controlled, double-masked, multicentre, 24-month studies (BPD OCR 003 AMD, or Verteporfin in Photodynamic Therapy-AMD [VIP-AMD], and BPD OCR 013, or Visudyne in Occult Choroidal Neovascularisation [VIO]) were conducted in patients with AMD characterised by occult with no classic subfoveal CNV. The VIO study included patients with occult with no classic subfoveal CNV with a visual acuity score of 73-34 letters (20/40-20/200), and patients with lesions >4 MPS disc areas were to have baseline visual acuity <65 letters (<20/50). 364 patients (244 verteporfin, 120 placebo) were enrolled in this study. The primary efficacy parameter was the same as in TAP (see above), with an additional endpoint of month 24 defined. Another efficacy parameter was also defined: the proportion of patients who lost less than 30 letters (equivalent to 6 lines) of visual acuity at months 12 and 24 relative to baseline. The study did not show statistically significant results on the primary efficacy parameter at month 12 (15-letter responder rate 62.7 % versus 55.0 %, p=0.150; 30-letter responder rate 84.0 % versus 83.3 %, p=0.868) or at month 24 (15-letter responder rate 53.3 % versus 47.5 %, p=0.300; 30-letter responder rate 77.5 % versus 75.0 %, p=0.602). A higher percentage of patients who received Visudyne, compared with those who received placebo, experienced adverse events (88.1 % versus 81.7 %), associated adverse events (23.0 % versus 7.5 %), events leading to discontinuation (11.9 % versus 3.3 %) and events leading to death (n=10 [4.1 %] versus n=1 [0.8 %]). No death was considered to be related to treatment. The VIP-AMD included patients with occult with no classic subfoveal CNV with a visual acuity score of >50 letters (20/100). This study also included patients with classic containing CNV with a visual acuity score >70 letters (20/40). 339 patients (225 verteporfin, 114 placebo) were enrolled in this study. The efficacy parameter was the same as in TAP and VIO (see above). At month 12, the study did not show statistically significant results on the primary efficacy parameter (responder rate 49.3 % versus 45.6 %, p=0.517). At month 24, a statistically significant difference of 12.9 % in favour of Visudyne compared to placebo was observed (46.2 % versus 33.3 %, p=0.023). A group of patients who had occult with no classic lesions (n=258) showed a statistically significant difference of 13.7 % in favour of Visudyne compared to placebo (45.2 % versus 31.5 %, p=0.032). A higher percentage of patients who received Visudyne, compared with those who received placebo, experienced adverse events (89.3 % versus 82.5 %), associated adverse events (42.7 % versus 18.4 %) and events leading to discontinuation (6.2 % versus 0.9 %). A lower percentage of Visudyne patients had events leading to death (n=4 [1.8 %] versus n=3 [2.6 %]); no death was considered to be related to treatment. Pathological myopia One multicentre, double-masked, placebo-controlled, randomised study (BPD OCR 003 PM [VIP-PM]) was conducted in patients with subfoveal choroidal neovascularisation caused by pathological myopia. A total of 120 patients (81 Visudyne, 39 placebo) were enrolled in the study. The posology and retreatments were the same as in the AMD studies. At month 12, there was a benefit of Visudyne for the primary efficacy endpoint (percentage of patients who lost less than 3 lines of visual acuity) – 86 % for Visudyne versus 67 % for placebo, p=0.011. The percentage of patients who lost less than 1.5 lines was 72 % for Visudyne and 44 % for placebo (p=0.003). At month 24, 79 % Visudyne patients versus 72 % placebo patients had lost less than 3 lines of visual acuity (p=0.38). The percentage of patients who lost less than 1.5 lines was 64 % for Visudyne and 49 % for placebo (p=0.106). This indicates that clinical benefit may diminish over time. In relation to VIP-PM extension: In patients followed from month 24 onwards and treated with uncontrolled, open-label Visudyne treatment as needed, long-term extension data suggest that month-24 vision outcomes may be sustained for up to 60 months. In the VIP-PM study in pathological myopia, the average number of treatments per year were 3.5 in the first year after diagnosis and 1.8 in the second for the randomised placebo-controlled phase and 0.4 in the third year, 0.2 in the fourth and 0.1 in the fifth year for the open-label extension phase. No additional safety concern was identified. 5.2 Pharmacokinetic properties The two regioisomers of verteporfin exhibit similar pharmacokinetic properties of distribution and elimination and thus both isomers are considered verteporfin as a whole from the pharmacokinetic perspective. Distribution Cmax after a 10-minute infusion of 6 and 12 mg/m2 body surface area in the target population is approximately 1.5 and 3.5 µg/ml, respectively. The volume of distribution of around 0.60 l/kg at steady state and clearance of around 101 ml/h/kg has been reported following a 10-minute infusion in dose range of 3-14 mg/m2. A maximum 2-fold inter-individual variation in plasma concentrations at Cmax (immediately after end of the infusion) and at the time of light administration was found for each Visudyne dose administered. In whole human blood, 90 % of verteporfin is associated with plasma and 10 % associated with blood cells, of which very little was membrane associated. In human plasma, 90 % of verteporfin is associated with plasma lipoprotein fractions and approximately 6 % are associated with albumin. Biotransformation The ester group of verteporfin is hydrolysed via plasma and hepatic esterases, leading to the formation of benzoporphyrin derivative diacid (BPD-DA). BPD-DA is also a photosensitiser but its systemic exposure is low (5-10 % of the verteporfin exposure, suggesting that most of the active substance is eliminated unchanged). In vitro studies did not show any significant involvement of oxidative metabolism by cytochrome P450 enzymes. Elimination Plasma elimination half-life mean values ranged from approximately 5–6 hours for verteporfin. Combined excretion of verteporfin and BPD-DA in human urine was less than 1 %, suggesting biliary excretion Linearity/non-linearity The extent of exposure and the maximal plasma concentration are proportional to the dose between 6 and 20 mg/m2. Special populations Elderly (65 years age or above) Although mean plasma Cmax and AUC values in elderly patients who received verteporfin are higher than those in young volunteers or patients, these differences are not considered to be clinically significant. Hepatic impairment In a study of patients with mild hepatic impairment (defined as having two abnormal hepatic function tests at enrolment), AUC and Cmax were not significantly different from the control group. Half-life, however, was significantly increased by approximately 20%. Renal impairment No studies on the pharmacokinetics of verteporfin in patients with renal impairment are reported. The renal excretion of verteporfin and its metabolite is minimal (<1% of the verteporfin dose) and thus, clinically significant changes in verteporfin exposure in patients with renal impairment are unlikely. Ethnic groups/races The pharmacokinetics of verteporfin have been reported to be similar in healthy Caucasian and Japanese men after a dose of 6 mg/m2 by a 10-minute infusion. Effects of gender At the intended dose, pharmacokinetic parameters are not significantly affected by gender. 5.3 Preclinical safety data Single and repeated dose toxicity The acute and light-dependent toxicity of verteporfin was characterised by dose dependent localised deep-tissue damage as a consequence of the pharmacological effect of PDT with verteporfin. Toxicity observed following multiple doses of verteporfin without light was associated mainly with effects on the haematopoietic system. The extent and severity of these effects were consistent among all studies and were dependent on drug dose and dosing duration. Ophthalmic toxicity Levels of ocular toxicity in healthy rabbits and monkeys, particularly on the retina/choroid, correlated with medicinal product dose, light dose, and time of light treatment. A retinal toxicity study in healthy dogs with intravenous verteporfin and ambient light on the eye showed no treatment-related ocular toxicity. Reproductive toxicity In pregnant rats, intravenous verteporfin doses of 10 mg/kg/day (approximately 40-fold human exposure at 6 mg/m2 based on AUCinf in female rats) were associated with an increased incidence of anophthalmia/microphthalmia and doses of 25 mg/kg/day (approximately 125-fold the human exposure at 6 mg/m2 based on AUCinf in female rats) were associated with an increased incidence of wavy ribs and anophthalmia/microphthalmia. There were no teratogenic effects observed in rabbits at doses up to 10 mg/kg/day (approximately 20-fold human exposure at 6 mg/m2 based on body surface area). No effect on male or female fertility has been observed in rats following intravenous verteporfin doses of up to 10 mg/kg/day (approximately 60 and 40-fold human exposure at 6 mg/m2 based on AUCinf in male and female rats, respectively). Carcinogenicity No studies have been conducted to evaluate the carcinogenic potential of verteporfin. Mutagenicity Verteporfin was not genotoxic in the absence or presence of light in the usual battery of genotoxic tests. However, photodynamic therapy (PDT) induces the formation of reactive oxygen species and has been reported to result in DNA damage including DNA strand breaks, alkali-labile sites, DNA degradation, and DNA-protein cross links which may result in chromosomal aberrations, sister chromatid exchanges (SCE) and mutations. It is not known how the potential for DNA damage with PDT agents translates into human risk. 6. Pharmaceutical particulars 6.1 List of excipients Lactose monohydrate Egg phosphatidylglycerol Dimyristoyl phosphatidylcholine Ascorbyl palmitate Butylated hydroxytoluene (E321) 6.2 Incompatibilities Visudyne precipitates in sodium chloride solution. Do not use normal sodium chloride solutions or other parenteral solutions. In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6. 6.3 Shelf life Shelf-life in the sealed vial 4 years Shelf-life after reconstitution and dilution Chemical and physical in-use stability has been demonstrated for 4 hours at 25°C. From a microbiological point of view, the medicinal product should be used immediately. If not used immediately, the in-use storage time and conditions prior to use are the responsibility of the user and would normally not last longer than 4 hours below 25°C protected from light. 6.4 Special precautions for storage Do not store above 25°C. Keep the vial in the outer carton in order to protect from light. After reconstitution and dilution: see section 6.3. 6.5 Nature and contents of container 15 mg of powder for solution for infusion in a single-use glass vial (type I), sealed with bromobutyl stopper and aluminium flip-off cap. Pack containing 1 vial. 6.6 Special precautions for disposal and other handling Reconstitute Visudyne in 7.0 ml water for injections to produce 7.5 ml of a 2.0 mg/ml solution. Reconstituted Visudyne is an opaque dark green solution. It is recommended that reconstituted Visudyne be inspected visually for particulate matter and discoloration prior to administration. For a dose of 6 mg/m2 body surface (see section 4.2) dilute the required amount of Visudyne solution in glucose 50 mg/ml (5 %) solution for infusion to a final volume of 30 ml. Do not use sodium chloride solution (see section 6.2). Use of a standard infusion line filter with hydrophilic membranes (such as polyethersulfone) of a pore size of not less than 1.2 μm is recommended. The vial and any unused portion of reconstituted solution should be discarded after single use. If material is spilled, it should be contained and wiped up with a damp cloth. Eye and skin contact should be avoided. Use of rubber gloves and eye protection is recommended. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder Novartis Europharm Limited Frimley Business Park Camberley GU16 7SR United Kingdom 8. Marketing authorisation number(s) EU/1/00/140/001 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 27 July 2000 Date of latest renewal: 27 July 2010 10. Date of revision of the text 10 November 2014 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu ---------------------------------------------------------- 产地国家: 德国 原产地英文商品名: VISUDYNE 15mg/vial 原产地英文药品名: VERTEPORFIN 中文参考商品译名: 维速达尔 15毫克/瓶 中文参考药品译名: 维替泊芬 中文参考化合物名称: 9-甲基（I）和13-甲基（II）反式-（±）-18-乙烯-4,4a-二氢-3,4-双（甲酯基）-4a,8,14,19-四甲基-23H,25H-苯卟啉-9,13-二丙酯 生产厂家中文参考译名: QLT Ophthalmics, Inc 生产厂家英文名: QLT Ophthalmics, Inc ---------------------------------------------------------- 产地国家: 美国 原产地英文商品名: VISUDYNE 15mg/vial 原产地英文药品名: VERTEPORFIN 中文参考商品译名: 维速达尔 15毫克/瓶 中文参考药品译名: 维替泊芬 中文参考化合物名称: 9-甲基（I）和13-甲基（II）反式-（±）-18-乙烯-4,4a-二氢-3,4-双（甲酯基）-4a,8,14,19-四甲基-23H,25H-苯卟啉-9,13-二丙酯 生产厂家英文名: Novartis Europharm Limited