等待内容更新

产品说明书

 

通用名：注射用维替泊芬 
商品名：维速达尔/Visudyne 
文名：Verteporfin for injection 

 

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） 

 

Visudyne

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

Medically reviewed on Jun 1, 2018

 

 

 

 

 

Indications and Usage for Visudyne

Visudyne (verteporfin for injection) therapy is indicated for the treatment of patients with predominantly classic subfoveal choroidal neovascularization due to age-related macular degeneration, pathologic myopia or presumed ocular histoplasmosis.

There is insufficient evidence to indicate Visudyne for the treatment of predominantly occult subfoveal choroidal neovascularization

 

 

 

Visudyne Dosage and Administration

A course of Visudyne (verteporfin for injection) therapy is a two-step process requiring administration of both drug and light.

The first step is the intravenous infusion of Visudyne. The second step is the activation of Visudyne with light from a nonthermal diode laser.

The physician should re-evaluate the patient 3 months after treatment and if choroidal neovascular leakage is detected on fluorescein angiography, therapy may be repeated.

 

 

 

Lesion Size Determination

The greatest linear dimension (GLD) of the lesion should be estimated by fluorescein angiography and color fundus photography. All classic and occult CNV, blood and/or blocked fluorescence, and any serous detachments of the retinal pigment epithelium should be included for this measurement. Fundus cameras with magnification within the range of 2.4-2.6X are recommended. The GLD of the lesion on the fluorescein angiogram must be corrected for the magnification of the fundus camera to obtain the GLD of the lesion on the retina.

Spot Size Determination

The treatment spot size should be 1000 microns larger than the GLD of the lesion on the retina to allow a 500 micron border, ensuring full coverage of the lesion. The maximum spot size used in the clinical trials was 6400 microns.

The nasal edge of the treatment spot must be positioned at least 200 microns from the temporal edge of the optic disc, even if this will result in lack of photoactivation of CNV within 200 microns of the optic nerve.

Visudyne Administration

Reconstitute each vial of Visudyne with 7 mL of Sterile Water for Injection to provide 7.5 mL containing 2 mg/mL of verteporfin. Reconstituted Visudyne must be protected from light and used within 4 hours. It is recommended that reconstituted Visudyne be inspected visually for particulate matter and discoloration prior to administration. Reconstituted Visudyne is an opaque dark green solution. Visudyne may precipitate in saline solutions. Do not use normal saline or other parenteral solutions, except 5% Dextrose for Injection, for dilution of the reconstituted Visudyne. Do not mix Visudyne in the same solution with other drugs.

The volume of reconstituted Visudyne required to achieve the desired dose of 6 mg/m2 body surface area is withdrawn from the vial and diluted with 5% Dextrose for Injection to a total infusion volume of 30 mL. After dilution, protect from light and use within 4 hours. The full infusion volume is administered intravenously over 10 minutes at a rate of 3 mL/minute, using an appropriate syringe pump and in-line filter. The clinical studies were conducted using a

standard infusion line filter of 1.2 microns.

Precautions should be taken to prevent extravasation at the injection site. If extravasation occurs, protect the site from light [see Warnings and Precautions (5.1)].

Light Administration

Initiate 689 nm wavelength laser light delivery to the patient 15 minutes after the start of the 10 minute infusion with Visudyne.

Photoactivation of Visudyne is controlled by the total light dose delivered. In the treatment of choroidal neovascularization, the recommended light dose is 50 J/cm2 of neovascular lesion administered at an intensity of 600 mW/cm2. This dose is administered over 83 seconds.

Light dose, light intensity, ophthalmic lens magnification factor and zoom lens setting are important parameters for the appropriate delivery of light to the predetermined treatment spot. Follow the laser system manuals for procedure set up and operations.

The laser system must deliver a stable power output at a wavelength of 689±3 nm. Light is delivered to the retina as a single circular spot via a fiber optic and a slit lamp, using a suitable ophthalmic magnification lens.

The following laser systems have been tested for compatibility with Visudyne and are approved for delivery of a stable power output at a wavelength of 689±3 nm:

Coherent Opal Photoactivator laser console and modified Coherent LaserLink adapter, manufactured by Lumenis, Inc., 2400 Condensa Street, Santa Clara, CA 95051-0901,

Zeiss VISULAS 690s laser and VISULINK PDT adapter manufactured by Carl Zeiss Meditec Inc., 5160 Hacienda Drive, Dublin, CA 94568,

Ceralas I laser system and Ceralink Slit Lamp Adapter manufactured by Biolitec Inc., 515 Shaker Road, East Longmeadow, MA 01028,

Quantel Activis laser console and the ZSL30 ACT, ZSL120 ACT and HSBMBQ ACT slit lamp adapters distributed by Quantel Medical, 601 Haggerty Lane, Bozeman, MT 59715

Concurrent Bilateral Treatment

The controlled trials only allowed treatment of one eye per patient. In patients who present with eligible lesions in both eyes, physicians should evaluate the potential benefits and risks of treating both eyes concurrently. If the patient has already received previous Visudyne therapy in one eye with an acceptable safety profile, both eyes can be treated concurrently after a single administration of Visudyne. The more aggressive lesion should be treated first, at 15 minutes after the start of infusion. Immediately at the end of light application to the first eye, the laser settings should be adjusted to introduce the treatment parameters for the second eye, with the same light dose and intensity as for the first eye, starting no later than 20 minutes from the start of infusion.

In patients who present for the first time with eligible lesions in both eyes without prior Visudyne therapy, it is prudent to treat only one eye (the most aggressive lesion) at the first course. One week after the first course, if no significant safety issues are identified, the second eye can be treated using the same treatment regimen after a second Visudyne infusion. Approximately 3 months later, both eyes can be evaluated and concurrent treatment following a new Visudyne infusion can be started if both lesions still show evidence of leakage.

Dosage Forms and Strengths

Visudyne (verteporfin for injection) is a reconstituted sterile solution intended for intravenous injection only. Each reconstituted vial provides 7.5 mL solution containing 2 mg/mL of verteporfin.

Contraindications

Visudyne (verteporfin for injection) is contraindicated for patients with porphyria or a known hypersensitivity to any component of this preparation [see Adverse Reactions (6)].

Warnings and PrecautionsLocal Adverse Reactions – Extravasation

Standard precautions should be taken during infusion of Visudyne (verteporfin for injection) to avoid extravasation. Examples of standard precautions include, but are not limited to:

• A free-flowing intravenous (IV) line should be established before starting Visudyne infusion and the line should be carefully monitored.

• Due to the possible fragility of vein walls of some elderly patients, it is strongly recommended that the largest arm vein possible, preferably antecubital, be used for injection.

• Small veins in the back of the hand should be avoided. Extravasation of Visudyne, especially if the affected area is exposed to light, can cause severe pain, inflammation, swelling or discoloration at the injection site.

If extravasation does occur, the infusion should be stopped immediately. The extravasation area must be thoroughly protected from direct light until swelling and discoloration have faded in order to prevent the occurrence of local burn, which could be severe. Cold compresses should be applied to the injection site. Oral medications for pain relief may be administered.

Exposure to Sun or Direct Light

Following injection with Visudyne (verteporfin for injection), care should be taken to avoid exposure of skin or eyes to direct sunlight or bright indoor light for 5 days. In the event of extravasation during infusion, the extravasation area must be thoroughly protected from direct light until the swelling and discoloration have faded in order to prevent the occurrence of a local burn which could be severe. If emergency surgery is necessary within 48 hours after treatment, as much of the internal tissue as possible should be protected from intense light.

Decreased Vision after Treatment

Patients who experience severe decrease of vision of 4 lines or more within 1 week after treatment should not be retreated, at least until their vision completely recovers to pretreatment levels and the potential benefits and risks of subsequent treatment are carefully considered by the treating physician.

Adverse Reactions

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

•

Local Adverse Reactions – Extravasation [see Warnings and Precautions (5.1)]

•

Exposure to Sun or Direct Light [see Warnings and Precautions (5.2)]

•

Decreased Vision after Treatment [see Warnings and Precautions (5.3)]

•

Porphyria and hypersensitivity [see Contraindications (4)]

Clinical Trials Experience

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

Severe chest pain, vaso-vagal and hypersensitivity reactions have been reported. Vaso-vagal and hypersensitivity reactions on rare occasions can be severe. These reactions may include syncope, sweating, dizziness, rash, dyspnea, flushing and changes in blood pressure and heart rate. General symptoms can include headache, malaise, urticaria, and pruritus.

The most frequently reported adverse reactions to Visudyne (verteporfin for injection) are injection site reactions (including pain, edema, inflammation, extravasation, rashes, hemorrhage and discoloration) and visual disturbances (including blurred vision, flashes of light, decreased visual acuity and visual field defects, including scotoma). These events occurred in approximately 10%-30% of patients. The following events, listed by Body System, were reported more frequently with Visudyne therapy than with placebo therapy and occurred in 1%-10% of patients:

Ocular Treatment Site: Blepharitis, cataracts, conjunctivitis/conjunctival injection, dry eyes, ocular itching, severe vision decrease with or without subretinal/retinal or vitreous hemorrhage

Body as a Whole: Asthenia, fever, flu syndrome, infusion related pain primarily presenting as back pain, photosensitivity reactions

Cardiovascular: Atrial fibrillation, hypertension, peripheral vascular disorder, varicose veins

Dermatologic: Eczema

Digestive: Constipation, gastrointestinal cancers, nausea

Hemic and Lymphatic: Anemia, white blood cell count decreased, white blood cell count increased

Hepatic: Elevated liver function tests

Metabolic/Nutritional: Albuminuria, creatinine increased

Musculoskeletal: Arthralgia, arthrosis, myasthenia

Nervous System: Hypesthesia, sleep disorder, vertigo

Respiratory: Cough, pharyngitis, pneumonia

Special Senses: Cataracts, decreased hearing, diplopia, lacrimation disorder

Urogenital: Prostatic disorder

Severe vision decrease, equivalent of >4 lines, within 7 days after treatment has been reported in 1%-5% of patients. Partial recovery of vision was observed in some patients. Photosensitivity reactions usually occurred in the form of skin sunburn following exposure to sunlight. The higher incidence of back pain in the Visudyne group occurred primarily during infusion.

The following adverse events have occurred either at low incidence (<1%) during clinical trials or have been reported during the use of Visudyne in clinical practice where these reactions were reported voluntarily from a population of unknown size and frequency of occurrence cannot be determined precisely. They have been chosen for inclusion based on factors such as seriousness, frequency of reporting, possible causal connection to Visudyne, or a combination

of these factors:

Ocular Treatment Site: Retinal detachment (nonrhegmatogenous), retinal or choroidal vessel nonperfusion, retinal pigment epithelial tear.

Non-ocular Events: Chest pain and other musculoskeletal pain during infusion

Drug Interactions

Drug interaction studies in humans have not been conducted with Visudyne.

Verteporfin is rapidly eliminated by the liver, mainly as unchanged drug. Metabolism is limited and occurs by liver and plasma esterases. Microsomal cytochrome P450 does not appear to play a role in verteporfin metabolism.

Based on the mechanism of action of verteporfin, many drugs used concomitantly could influence the effect of Visudyne therapy. Possible examples include the following:

Calcium channel blockers, polymyxin B or radiation therapy could enhance the rate of Visudyne uptake by the vascular endothelium. Other photosensitizing agents (e.g., tetracyclines, sulfonamides, phenothiazines, sulfonylurea hypoglycemic agents, thiazide diuretics and griseofulvin) could increase the potential for skin photosensitivity reactions. Compounds that quench active oxygen species or scavenge radicals, such as dimethyl sulfoxide, β-carotene, ethanol, formate and mannitol, would be expected to decrease Visudyne activity. Drugs that decrease clotting, vasoconstriction or platelet aggregation, e.g., thromboxane A2 inhibitors, could also decrease the efficacy of Visudyne therapy.

USE IN SPECIFIC POPULATIONSPregnancy

Risk Summary

There are no data with the use of Visudyne in pregnant women to inform a drug-associated risk. Intravenous administration of verteporfin to pregnant rats during the period of organogenesis produced an increase in the incidence of anophthalmia/microphthalmia and wavy ribs at exposures approximately 40-fold the human exposure at the recommended clinical dose.

Verteporfin did not produce adverse fetal effect in rats or rabbits at exposures 6-to 20-fold the human exposure at the recommended clinical dose.

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

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

Rat fetuses of dams administered verteporfin for injection intravenously during organogenesis exhibited an increase in the incidence of anophthalmia/microphthalmia and wavy ribs at doses ≥10 mg/kg/day (approximately 40-fold the human exposure at the recommended dose of 6 mg/m2, based on AUC in female rats). No teratogenic effects were observed in rat fetuses at a dose of 2 mg/kg/day (approximately 6-fold the human exposure at the recommended dose of 6 mg/m2, based on AUC in female rats).

In pregnant rabbits, a decrease in maternal body weight gain and food consumption was observed in animals that received verteporfin for injection intravenously at doses up to 10 mg/kg/day during organogenesis. The no observed adverse effect level (NOAEL) for maternal toxicity was 3 mg/kg/day (approximately 6-fold the recommended human dose of 6 mg/m2,

based on body surface area). No teratogenic effects were observed in rabbit fetuses at doses up to 10 mg/kg/day (approximately 20-fold the recommended human dose of 6 mg/m2, based on body surface area).

Lactation

Risk Summary

Verteporfin and its diacid metabolite have been found in human breast milk following an intravenous infusion at the recommended human dose of 6 mg/m2. Verteporfin was present in breast milk at levels up to 66% of the corresponding plasma levels and declined below the limit of quantification (2 ng/mL) within 24 hours. The diacid metabolite had lower peak concentrations but persisted up to at least 48 hours.

Because of the potential for serious adverse reactions in nursing infants from Visudyne, a decision should be made whether to discontinue nursing or postpone treatment, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Approximately 90% of the patients treated with Visudyne in the clinical efficacy trials were over the age of 65. A reduced treatment effect was seen with increasing age.

Overdosage

Overdose of drug and/or light in the treated eye may result in non-perfusion of normal retinal vessels with the possibility of severe decrease in vision that could be permanent. An overdose of drug will also result in the prolongation of the period during which the patient remains photosensitive to bright light. In such cases, it is recommended to extend the photosensitivity precautions for a time proportional to the overdose.

Visudyne Description

Visudyne (verteporfin for injection) is a light activated drug used in photodynamic therapy. The finished drug product is a lyophilized dark green cake. Verteporfin is a 1:1 mixture of two regioisomers (I and II), represented by the following structures:

 

The chemical names for the verteporfin regioisomers are:

9-methyl (I) and 13-methyl (II) trans-(±)-18-ethenyl-4,4a,-dihydro-3,4-bis(methoxycarbonyl)-4a,8,14,19-tetramethyl-23H, 25H-benzo[b]porphine-9,13-dipropanoate

The molecular formula is C41H42N4O8 with a molecular weight of approximately 718.8. Each mL of reconstituted Visudyne contains:

ACTIVE: Verteporfin, 2 mg

INACTIVES: Ascorbyl palmitate, butylated hydroxytoluene, dimyristoyl phosphatidylcholine, egg phosphatidylglycerol and lactose

Visudyne - Clinical PharmacologyMechanism of Action

Visudyne (verteporfin for injection) therapy is a two-stage process requiring administration of both verteporfin for injection and nonthermal red light.

Verteporfin is transported in the plasma primarily by lipoproteins. Once verteporfin is activated by light in the presence of oxygen, highly reactive, short-lived singlet oxygen and reactive oxygen radicals are generated. Light activation of verteporfin results in local damage to neovascular endothelium, resulting in vessel occlusion. Damaged endothelium is known to release procoagulant and vasoactive factors through the lipoxygenase (leukotriene) and cyclo-oxygenase (eicosanoids such as thromboxane) pathways, resulting in platelet aggregation, fibrin clot formation and vasoconstriction. Verteporfin appears to somewhat preferentially accumulate in neovasculature, including choroidal neovasculature. However, animal models indicate that the drug is also present in the retina. Therefore, there may be collateral damage to retinal structures following photoactivation including the retinal pigmented epithelium and outer nuclear layer of the retina. The temporary occlusion of the choroidal neovascularization (CNV) following Visudyne therapy has been confirmed in humans by fluorescein angiography.

Pharmacokinetics

Following intravenous infusion, verteporfin exhibits a bi-exponential elimination with a terminal elimination half-life of approximately 5-6 hours. The extent of exposure and the maximal plasma concentration are proportional to the dose between 6 and 20 mg/m2. At the intended dose, pharmacokinetic parameters are not significantly affected by gender.

Verteporfin is metabolized to a small extent to its diacid metabolite by liver and plasma esterases. NADPH-dependent liver enzyme systems (including the cytochrome P450 isozymes) do not appear to play a role in the metabolism of verteporfin. Elimination is by the fecal route, with less than 0.01% of the dose recovered in urine.

In a study of patients with mild hepatic insufficiency (defined as having two abnormal hepatic function tests at enrollment), AUC and Cmax were not significantly different from the control group; half-life, however, was significantly increased by approximately 20%.

Nonclinical ToxicologyCarcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

No studies have not been conducted to determine the carcinogenic potential of verteporfin.

Mutagenesis

Photodynamic therapy (PDT) as a class 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. In addition, other photodynamic therapeutic agents have been shown to increase the incidence of SCE in Chinese hamster ovary (CHO) cells irradiated with visible light and in Chinese hamster lung fibroblasts irradiated with near UV light, increase mutations and DNA-protein cross-linking in mouse L5178 cells, and increase DNA-strand breaks in malignant human cervical carcinoma cells, but not in normal cells. Verteporfin was not evaluated in these latter systems. It is not known how the potential for DNA damage with PDT agents translates into human risk.

Impairment of Fertility

No effect on male or female fertility has been observed in rats following intravenous administration of verteporfin for injection up to 10 mg/kg/day (approximately 60- and 40-fold human exposure at 6 mg/m2 based on AUC in male and female rats, respectively).

Animal Toxicology and/or Pharmacology

At a >10-fold higher dose given by bolus injection to sedated or anesthetized pigs, verteporfin caused severe hemodynamic effects, including death, probably as a result of complement activation. These effects were diminished or abolished by pretreatment with antihistamine and they were not seen in conscious nonsedated pigs.

Clinical StudiesAge-Related Macular Degeneration (AMD)

Two adequate and well-controlled, double-masked, placebo-controlled, randomized studies were conducted in patients with classic-containing subfoveal CNV secondary to age-related macular degeneration. A total of 609 patients (Visudyne 402, placebo 207) were enrolled in these two studies. During these studies, retreatment was allowed every 3 months if fluorescein angiograms showed any recurrence or persistence of leakage. The placebo control (sham treatment) consisted of intravenous administration of Dextrose 5% in Water, followed by light application identical to that used for Visudyne therapy.

The difference between treatment groups statistically favored Visudyne at the 1-year and 2-year analyses for visual acuity endpoints.

The subgroup of patients with predominately classic CNV lesions was more likely to exhibit a treatment benefit (N=242; Visudyne 159, placebo 83).

Predominantly classic CNV lesions were defined as those in which the classic component comprised 50% or more of the area of the entire lesion. For the primary efficacy endpoint (percentage of patients who lost less than 3 lines of visual acuity), these patients showed a difference of approximately 28% between treatment groups at both Months 12 and 24 (67% for Visudyne patients compared to 40% for placebo patients, at Month 12; and 59% for Visudyne patients compared to 31% for placebo patients, at Month 24). Severe vision loss (≥6 lines of visual acuity from baseline) was experienced by 12% of Visudyne-treated patients compared to 34% of placebo-treated patients at Month 12, and by 15% of Visudyne-treated patients compared to 36% of placebo-treated patients at Month 24.

Patients with predominantly classic CNV lesions that did not contain occult CNV exhibited the greatest benefit (N=134; Visudyne 90, placebo 44). At 1 year, these patients demonstrated a 49% difference between treatment groups when assessed by the <3 lines-lost definition (77% vs. 27%).

Older patients (≥75 years), patients with dark irides, patients with occult lesions or patients with less than 50% classic CNV were less likely to benefit from Visudyne therapy.

The safety and efficacy of Visudyne beyond 2 years have not been demonstrated.

Based on the Treatment of Age Related Macular Degeneration with Photodynamic Therapy Study (TAP) extension study, the average number of treatments per year were 3.5 in the first year after diagnosis, 2.4 in the second, 1.3 in the third, 0.4 in the fourth and 0.1 in the fifth year.

Pathologic Myopia

One adequate and well-controlled, double-masked, placebo-controlled, randomized study was conducted in patients with subfoveal CNV secondary to pathologic myopia. A total of 120 patients (Visudyne 81, placebo 39) were enrolled in the study. The treatment dosing and retreatments were the same as in the AMD studies. The difference between treatment groups statistically favored Visudyne at the 1-year analysis but not at the 2-year analysis for visual acuity endpoints. For the primary efficacy endpoint (percentage of patients who lost less than 3 lines of visual acuity), patients at the 1-year timepoint showed a difference of approximately 19% between treatment groups (86% for Visudyne patients compared to 67% for placebo patients). However, by the 2-year timepoint, the effect was no longer statically significant (79% for Visudyne patients compared to 72% for placebo patients).

Based on the Verteporfin in Photodynamic Therapy in Pathologic Myopia (VIP-PM) extension study in pathologic myopia, the average number of treatments per year were 3.5 in the first year after diagnosis, 1.8 in the second, 0.4 in the third, 0.2 in the fourth and 0.1 in the fifth.

Presumed Ocular Histoplasmosis

One open-label study was conducted in patients with subfoveal CNV secondary to presumed ocular histoplasmosis. A total of 26 patients were treated with Visudyne in the study. The treatment dosing and retreatments for Visudyne were the same as the AMD studies. Visudyne-treated patients compare favorably with historical control data demonstrating a reduction in the number of episodes of severe visual acuity loss (>6 lines of loss).

Based on the Visudyne Ocular Histoplasmosis extension study in presumed ocular histoplasmosis, the average number of treatments per year was 2.9 in the first year after diagnosis, 1.2 in the second, 0.2 in the third and 0.1 in the fourth.

How Supplied/Storage and Handling

Visudyne (verteporfin for injection) is supplied in a single-use glass vial with a gray bromobutyl stopper and aluminum flip-off cap. It contains a lyophilized dark green cake with 15 mg verteporfin.

NDC 0187-5600-15

Store Visudyne between 20°-25°C (68°-77°F).

Spills and Disposal

Spills of Visudyne should be wiped up with a damp cloth. Skin and eye contact should be avoided due to the potential for photosensitivity reactions upon exposure to light. Use of rubber gloves and eye protection is recommended. All materials should be disposed of properly.

Accidental Exposure

Because of the potential to induce photosensitivity reactions, it is important to avoid contact with the eyes and skin during preparation and administration of Visudyne. Any exposed person must be protected from bright light [see Warnings and Precautions (5.1)].

Patient Counseling Information

Advise patients who receive Visudyne that they will become temporarily photosensitive after the infusion. Patients should be advised to wear a wrist band to remind them to avoid direct sunlight for 5 days. During that period, patients should be advised to avoid exposure of unprotected skin, eyes or other body organs to direct sunlight or bright indoor light. Sources of bright light include, but are not limited to, tanning salons, bright halogen lighting and high power lighting used in surgical operating rooms or dental offices. Prolonged exposure to light from light-emitting medical devices such as pulse oximeters should also be avoided for 5 days following Visudyne administration.

If treated patients must go outdoors in daylight during the first 5 days after treatment, they should be advised to protect all parts of their skin and their eyes by wearing protective clothing and dark sunglasses. UV sunscreens are not effective in protecting against photosensitivity reactions because photoactivation of the residual drug in the skin can be caused by visible light.

Patients should be advised to not stay in the dark and should be encouraged to expose their skin to ambient indoor light, as it will help inactivate the drug in the skin through a process called photobleaching.

Following Visudyne treatment, patients should be advised that they may develop 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 be advised to not drive or use machines as long as these symptoms persist.

Distributed by:
Bausch + Lomb, a division of
Valeant Pharmaceuticals North America LLC
Bridgewater, NJ 08807 USA

Manufactured by:
Par Sterile Products LLC
Rochester, MI 48307

Visudyne is a registered trademark of Novartis AG used under license.
All other product/brand names are trademarks of their respective owners.

©Bausch & Lomb Incorporated

9539900

Rev. 06/2016

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL

Rx only

NDC 0187-5600-15

Visudyne®

(verteporfin
for injection)

15 mg

 

Visudyne verteporfin for injection injection, powder, lyophilized, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0187-5600 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength VERTEPORFIN (VERTEPORFIN) VERTEPORFIN 15 mg

Inactive Ingredients Ingredient Name Strength ASCORBYL PALMITATE   BUTYLATED HYDROXYTOLUENE   LACTOSE, UNSPECIFIED FORM

Packaging # Item Code Package Description   1 NDC:0187-5600-15 1 INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION in 1 CARTON

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021119 04/12/2000

Labeler - Valeant Pharmaceuticals North America LLC (042230623)

Establishment
Name	Address	ID/FEI	Operations
Par Sterile Products LLC		808402890	MANUFACTURE(0187-5600)

 

Valeant Pharmaceuticals North America LLC