Iloprost inhalation solution
What is Iloprost inhalation solution?
ILOPROST (Ventavis®) is used to treat a serious heart and lung disorder called pulmonary arterial hypertension. While iloprost inhalation solution will not cure this disorder, it is designed to improve symptoms and the quality of life. Generic iloprost inhalation solution is not yet available.
What should I tell my health care provider before I take this medicine?
They need to know if you have any of these conditions:
• bleeding problems
• infection
• low blood pressure
• lung or breathing problem such as asthma or chronic obstructive pulmonary disease (COPD)
• an unusual reaction to Iloprost, medicines, foods, dyes, or preservatives
• pregnant or trying to get pregnant
• breast-feeding
How should this medicine be used?
Iloprost inhalation solution is for use in the Prodose® AAD® or I-neb AAD® nebulizer only.
Iloprost inhalation is breathed (inhaled) into your lungs with the help of a special nebulizer. Nebulizers convert a solution of iloprost into an aerosol for inhalation through the mouth and into the lungs. The amount of drug you receive will be determined by your doctor. You will be provided a special device that is to be used with the Prodose® AAD® or I-neb AAD® nebulizer. This device will deliver the correct dose to you. Follow the instructions provided with the product to prepare and inhale the iloprost inhalation solution. Follow the directions that come with the Prodose® AAD® or I-neb AAD® system for proper use of the nebulizer. Take precautions to avoid bacterial contamination of the iloprost inhalation solution dose or nebulizer system.
Take your prescribed doses at regular intervals. Your doctor will tell you how to space out your doses. Do not use more often than directed.
Do not let iloprost solution come into contact with your skin or eyes. If it does, rinse the skin or your eyes right away with water.
Do not allow other people to be exposed to iloprost inhalation while you are breathing it, especially babies and pregnant women.
Contact your pediatrician or health care professional regarding the use of this medicine in children. Special care may be needed.
What if I miss a dose?
If you miss a dose, use it as soon as you can. If it is almost time for your next dose, use only that dose. Do not use double or extra doses.What drug(s) may interact with Iloprost?
• alcohol
• aspirin and aspirin-like medicines
• blood thinners such as warfarin (your prescriber or health care professional, however, is likely to want you to take blood thinners while you are using iloprost; this can be done safely)
• cilostazol
• clopidogrel
• dipyridamole
• ephedrine or pseudoephedrine
• medicines for colds and breathing difficulties
• herbal stimulants or weight loss products, like ephedra, ma huang
• medicines for chest pain or heart disease
• medicines for high blood pressure
• monoamine oxidase inhibitors (Azilect®, Eldepryl®, Emsam®, Marplan®, Nardil®, Parnate®, Zelapar™)
• ticlopidine
• water pills (diuretics)
Tell your prescriber or health care professional: about all other medicines you are taking including non-prescription medicines; if you are a frequent user of drinks with caffeine or alcohol; if you smoke; or if you use illegal drugs. These may effect the way your medicine works. Check before starting or stopping any of your medicines.
What should I watch for while taking Iloprost?
Visit your prescriber or health care professional for checks on your progress. You will need to be seen regularly. Report any unusual or severe side effects promptly.
You may get dizzy. Do not drive or use machinery until you know how iloprost affects you. To reduce the risk of dizzy or fainting spells, do not sit or stand up quickly, especially if you are an older patient. Avoid alcoholic drinks. Alcohol can make you more dizzy and increase flushing of the face.
If you take too much of this medicine, you may get a severe headache, chest pain, reddening of the face, jaw pain, dizziness, nausea, vomiting, and diarrhea. If this happens, stop taking iloprost inhalation and call your health care provider promptly.
Despite receiving iloprost inhalation solution, your condition may worsen and you may need your dose adjusted. Call your prescriber or health care professional if you experience any worsening of your condition.
What side effects may I notice from receiving Iloprost?
Side effects that you should report to your prescriber or health care professional as soon as possible:
• chest pain
• change in the amount of urine passed
• dark yellow or brown urine
• difficulty breathing
• dizziness or faintness
• fever
• pain or difficulty passing urine
• swelling in your arms, legs, hands, or feet
• slow, fast, or irregular heart beat
• unusual tiredness or weakness
Side effects that usually do not require medical attention (report to your prescriber or health care professional if they continue or are bothersome):
• chills or flu-like symptoms
• cough
• diarrhea
• difficulty sleeping
• flushing
• headache
• jaw pain
• muscle ache or pain
• nausea/vomiting
• stomach pain
Where can I keep my medicine?
Ampules of unopened iloprost inhalation solution are good until the date printed on the package when stored between 68 and 77 degrees F (20 and 25 degrees C) and protected from light in the package.
An opened ampule should be used immediately and any solution remaining in the Prodose® AAD® or I-neb AAD® medication chamber should be discarded. Use of the remaining solution will result in unpredictable dosing.
Keep out of the reach of children in a container that small children cannot open.
Ventavis
抑制血小板聚集，血小板粘附及其释放反应。
扩张小动脉与小静脉。
增加毛细血管密度以及降低微循环中存在的炎症介质如5-羟色胺或组胺所导致的血管通透性增加。
促进内源性纤溶活性。
抗炎作用，如抑制内皮损伤后白细胞的粘附以及损伤组织中白细胞的聚集，并减少肿瘤坏死因子的释放。
吸入后可直接扩张肺动脉血管床，可持续降低肺动脉压力与肺血管阻力，增加心输出量，使混合静脉血氧饱和度得到明显改善。对体循环血管阻力以及动脉压力影响很小。
健康志愿者在静脉输注伊洛前列素后，稳态表观分布容积为0.6-0.8升/公斤体重。血浆浓度在30-3000微微克/毫升范围内时，与血浆蛋白的结合呈浓度依赖性，最高结合率大约为60%，其中75%是与白蛋白结合。
伊洛前列素主要通过β-羧基氧化酶进行大量代谢。原形药物不能排泄。其主要代谢产物为四去甲-伊洛前列素，这一代谢产物在尿中以自由和结合的4种非对映异构体形式存在。动物实验表明四去甲-伊洛前列素无药理活性。体外研究表明无论静脉给药或吸入给药，伊洛前列素在肺内的代谢产物均相同。
肾功能与肝功能正常的志愿者静脉输注伊洛前列素后，大多数情况下表现为双相消除的特点，平均半衰期分别为3-5分钟以及15-30分钟。伊洛前列素的总清除率大约为20毫升/公斤体重/分钟，这表明伊洛前列素存在肝外代谢途径。
应用H3-伊洛前列素在健康志愿者进行质量-平衡研究。静脉输注后，总放射性的回收率为81%，尿液与粪便中的回收率分别为68%和12%。代谢产物通过血浆与尿液双相排除，经计算半衰期分别为2-5小时（血浆）和2-18小时（尿液）。
肾功能异常 ：一项静脉输注伊洛前列素的研究表明，终末期肾功能衰竭接受间断血液透析治疗的患者伊洛前列素的清除率（平均CL=5±2毫升/公斤体重/分钟）与肾功能衰竭无需接受间断血液透析治疗的患者（平均CL=18±2毫升/公斤体重/分钟）相比明显降低。
肝功能异常 ：由于伊洛前列素主要通过肝脏进行代谢，肝功能的变化将影响药物的血浆水平。一项对8名肝硬化患者静脉应用伊洛前列素的研究中，伊洛前列素的平均清除率大约为10毫升/公斤体重/分钟。
年龄与性别 ：年龄与性别与伊洛前列素的药代动力学无临床相关性。
啮齿类或非啮齿类动物持续静脉/皮下注射伊洛前列素，剂量超过人体全身治疗量的14-47倍（根据血浆药物浓度计算），疗程26周，未出现任何组织毒性。只出现预期的药理学作用如低血压，皮肤发红，呼吸困难，肠蠕动加快。
在对大鼠和小鼠致癌性研究中，未发现伊洛前列素有潜在致癌性。
在兔以及猴子身上进行的类似胚胎毒性研究中，伊洛前列素达到最大使用剂量并未造成幼兔及幼猴指趾发育异常或其他明显的组织结构异常。
在大鼠研究中发现乳汁中含有极微量的伊洛前列素。
在豚鼠身上进行的皮肤致敏作用（极大化检测）以及抗原性研究中未发现有潜在的致过敏作用。
根据不同患者的需要和耐受性，每天应吸入伊洛前列素6-9次。
根据口含器与雾化器所需的药物剂量，每次吸入时间大约应为5-10分钟。
疗程 ：长期治疗。
液滴的中位空气动力学直径（MMAD）或中位直径（MMD）为 3-4 m ；
口含器输出剂量为 ：每次吸入伊洛前列素2.5或5 ug；
一个剂量为2.5或5 ug伊洛前列素的雾化时间 ：大约为4-10 分钟（为了避免全身性副作用，4分钟内输出的伊洛前列素不得超过5 ug）。
下表列出了几种推荐用于万他维给药的喷雾器 ：
为了尽可能减少意外暴露，吸入伊洛前列素时推荐使用装有过滤器或吸入触发装置的雾化器，并保持房间的良好通风。
将准备好的溶液用适当的设备（雾化器）吸入。继续以往的治疗并作个体化调整（参见[药物相互作用]）。
对伊洛前列素或任何赋形剂过敏。
出血危险性增加的疾病（如活动性消化性溃疡，外伤，颅内出血或者其他出血），由于本药对血小板的作用可能会使出血的危险性增加。
患有心脏病的患者，如 ：严重心律失常、严重冠状动脉性心脏病、不稳定性心绞痛、 发病6个月内的心肌梗塞、未予控制和治疗的或未在严密检测下的非代偿性心力衰竭、先天性或获得性心脏瓣膜疾病伴非肺动脉高压所致的有临床意义的心肌功能异常。
明显的肺水肿伴呼吸困难。
主要由于肺静脉阻塞或者狭窄，而不是动脉阻塞或者狭窄引起的肺动脉高压。
近3个月发生过脑血管事件（如短暂性脑缺血发作、中风）或其他脑供血障碍。
妊娠，哺乳。
应注意监测以避免血压的进一步降低。对于急性肺部感染，慢性阻塞性肺疾病，以及严重哮喘的患者应作密切监测。
对于能够进行外科手术的栓塞性肺动脉高压患者不应首选本药治疗。
有晕厥史的肺动脉高压患者应避免一切额外的负荷和应激，如运动过程中。如果晕厥发生于直立体位时，每天清醒但未下床时吸入首剂药物是有帮助的。如果晕厥的恶化是由基础疾病所造成，应考虑改变治疗方案。
肝功能异常患者，肾功能衰竭需要血液透析的患者，伊洛前列素的清除均是降低的，因此应考虑减低剂量。
新生儿、婴儿不得经空气接触本药。
因为伊洛前列素有抑制血小板功能的作用，因此与抗凝药物（如肝素，香豆素类抗凝药物）或其他抑制血小板聚集的药物（如乙酰水杨酸，非类固醇抗炎药物，磷酸二酯酶抑制剂以及硝基血管扩张药）合用时可增加出血的危险性。
对静脉输注伊洛前列素与地高辛，乙酰水杨酸以及组织型纤溶酶原激活剂（t-PA）的相互作用作了研究。结果表明静脉输注伊洛前列素不影响患者多次口服地高辛后的药代动力学，对同时给予的t-PA的药代动力学也无影响。动物实验发现伊洛前列素可能导致t-PA稳态血药浓度降低。
动物实验表明，预先给予糖皮质激素可减轻伊洛前列素的扩血管作用，但不影响对血小板聚集的抑制作用。这一发现对于本药用于人体的意义尚不清楚。