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使用说明书

 

【产品名称】吸入用伊洛前列素溶液

【商品名/商标】万他维

【规格】

        1ml:20mcg*5支

【主要成份】

        伊洛前列素

【性状】

        为无色或微黄色的澄清液体，3毫升I型无色玻璃安瓿内含2毫升吸入用伊洛前列素溶液。

【适应症】

        治疗中度原发性肺动脉高压。

【用法用量】

        成人：每次吸入应从2.5微克开始(吸入装置中口含器所提供的剂量)。可根据不同患者的需要和耐受性逐渐增加伊洛前列素剂量至5.0微克。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。肾功能或肝功能不全患者：肝功能异常以及肾功能衰竭需要血液透析的患者，伊洛前列素的清除率是降低的，应考虑减少用药剂量（参见[注意事项]以及[药代动力学]）。

        儿童以及青少年（18岁以下）：目前还没有在儿童或青少年中应用的经验。除非有资料支持，否则万他维不能应用于18岁以下的患者（参见[注意事项]）。疗程：长期治疗。雾化器的使用：如果某种雾化器能达到下列标准，则认为它适用于万他维溶液的雾化：液滴的中位空气动力学直径（MMAD）或中位直径（MMD）为3-4m；口含器输出剂量为：每次吸入伊洛前列素2.5或5ug；一个剂量为2.5或5ug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5ug）。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]）。

【不良反应】

        除了由于吸入用药的局部不良反应如咳嗽加重外，吸入伊洛前列素的不良反应主要与前列环素药理学特性有关。临床试验中最常见的不良反应包括血管扩张，头疼以及咳嗽加重。非常常见的不良反应(100位患者中可能有10或者更多的人出现下述情况)：因血管扩张而出现潮热或者面部发红；咳嗽增加；血压降低（低血压）。常见不良反应（100位患者中可能有1-10人出现下述情况）：头痛；颊肌痉挛（口腔开合困难）；晕厥：晕厥是该疾病的一种常见症状，临床试验中伊洛前列素治疗组与对照组晕厥的发生率无明显差异，但是也可能在使用万他维时发生，请参见注意事项部分。其他可能的反应：如果患者服用抗凝剂(抗凝血剂)，也许会发生微量的出血。由于大部分肺动脉高压患者服用抗凝药物，常见出血事件（大部分为血肿）。伊洛前列素组出血事件的发生频率与安慰剂对照组相比无明显差异。

【禁忌】

        以下患者禁用：-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），由于万他维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，哺乳妇女禁用。

【注意事项】

        对于体循环压力较低的患者（收缩压低于85mmHg），不应当开始万他维治疗。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万他维治疗。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。

【药物相互作用】

        伊洛前列素可增强β-受体阻滞剂，钙离子拮抗剂，血管扩张剂以及血管紧张素转换酶抑制剂等药物的抗高血压作用。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。这一发现对于万他维用于人体的意义尚不清楚。

【孕妇及哺乳期妇女用药】

        孕妇及哺乳期妇女禁用.C级:动物研究证明药物对胎儿有危害性（致畸或胚胎死亡等），或尚无设对照的妊娠妇女研究，或尚未对妊娠妇女及动物进行研究。本类药物只有在权衡对孕妇的益处大于对胎儿的危害之后，方可使用。

【老年患者用药】

        对老年人应用此药物无特殊要求。

【贮藏】

        遮光、密闭保存。

【有效期】

        2年。

【生产厂家】

        西班牙BerliMed S.A.

(EYE loe prost)

Iloprost TromethamineProstacyclin PGI2

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Inhalation [preservative free]:

Ventavis: 10 mcg/mL (1 mL); 20 mcg/mL (1 mL) [contains alcohol, usp, tromethamine]

Ventavis ProstacyclinProstaglandinVasodilator

Acutely, iloprost dilates systemic and pulmonary arterial vascular beds. With longer-term use, alters pulmonary vascular resistance and suppresses vascular smooth muscle proliferation. In addition, it is a mild endogenous inhibitor of platelet aggregation when aerosolized (Beghetti, 2002).

Vd: 0.7-0.8 L/kg

Hepatic via beta oxidation of the carboxyl side chain; main metabolite, tetranor-iloprost (inactive in animal studies)

Urine (68% as metabolite); feces (12%)

Serum: Within 5 minutes after inhalation

30-60 minutes

20-30 minutes (effect), 7-9 minutes (elimination)

~60%, primarily to albumin

Inhaled iloprost has not been evaluated in subjects with impaired renal function. In a study with IV infusion of iloprost in patients with ESRD requiring intermittent dialysis treatment, the mean AUC0-4hwas 230 pg•h/mL compared with 54 pg•h/mL in patients with renal failure not requiring intermittent dialysis, and 48 pg•h/mL in healthy patients. The half-life was similar in both groups.

Inhaled iloprost has not been evaluated in subjects with impaired hepatic function. In an IV iloprost study in patients with liver cirrhosis, the mean Cl in Child-Pugh class B subjects was approximately 10 mL/min/kg(half that of healthy patients). Following oral administration, the mean AUC0-8h in Child-Pugh class B patients was 1,725 pg•h/mL compared with 117 pg•h/mL in healthy subjects receiving the same oral iloprost dose. In Child-Pugh class A subjects, the mean AUC0-8h was 639 pg•h/mL. Although exposure increased with hepatic impairment, there was no effect on half-life.

Pulmonary arterial hypertension: Treatment of pulmonary arterial hypertension (World Health Organization [WHO] group I) in patients with New York Heart Association (NYHA) class III or IV symptoms to improve exercise tolerance, symptoms, and diminish clinical deterioration.

There are no contraindications listed in the manufacturer's labeling.

Pulmonary arterial hypertension (PAH): Inhalation: Initial: 2.5 mcg/dose; if tolerated, increase to 5 mcg/dose. Administer 6-9 times daily (dosing at intervals ≥2 hours while awake according to individual need and tolerability). Maintenance dose: 2.5-5 mcg/dose; maximum daily dose: 45 mcg (ie, 5 mcg/dose 9 times daily)

Refer to adult dosing.

Inhaled iloprost has not been studied in renal impairment; however, according to the manufacturer, no adjustment is required in patients with renal impairment who are not on dialysis (the effect of dialysis on iloprost is unknown).

Child-Pugh class B or C: Consider increasing dosing interval (eg, every 3-4 hours) based on response at the end of the dose interval.

Immediate access to medication and a back-up inhalation device is essential to prevent treatment interruptions. Do not mix with other medications. For inhalation only via the I-neb AAD System. Refer to the I-neb AAD System instructions for adding ampul contents to the medication chamber. The 20 mcg/mL concentration is intended for patients who are maintained at the 5 mcg dose and who have repeatedly experienced extended treatment times. After use, discard remainder of the medicine; not for reuse.

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (58°F to 86°F).

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): Prostacyclin Analogues may enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Anticoagulants: Prostacyclin Analogues may enhance the adverse/toxic effect of Anticoagulants. Specifically, the antiplatelet effects of these agents may lead to an increased risk of bleeding with the combination. Monitor therapy

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Blood Pressure Lowering Agents: Prostacyclin Analogues may enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine.Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside.Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine.Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents.Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Thrombolytic Agents: May enhance the adverse/toxic effect of Prostacyclin Analogues. Specifically, the antiplatelet effects of prostacyclin analogues may lead to an increased risk of bleeding when combined with thrombolytic agents. Monitor therapy

>10%:

Cardiovascular: Flushing (27%), hypotension (11%)

Central nervous system: Headache (30%), trismus (12%)

Gastrointestinal: Nausea (13%)

Neuromuscular & skeletal: Jaw pain (12%)

Respiratory: Cough (39%), flu-like symptoms (14%)

1% to 10%:

Cardiovascular: Syncope (8%), palpitations (7%)

Central nervous system: Insomnia (8%)

Endocrine & metabolic: Increased gamma-glutamyl transferase (6%)

Gastrointestinal: Vomiting (7%), glossalgia (4%)

Hepatic: Increased serum alkaline phosphatase (6%)

Neuromuscular & skeletal: Back pain (7%), muscle cramps (6%)

Respiratory: Hemoptysis (5%), pneumonia (4%)

<1% (Limited to important or life-threatening): Bronchospasm, cardiac failure, dyspnea, epistaxis, hypersensitivity reaction, paradoxical reaction (increased post-void residual urine volume), renal failure, supraventricular tachycardia, thrombocytopenia

Concerns related to adverse effects:

• Pulmonary edema: If pulmonary edema occurs during administration, discontinue therapy immediately; may be a sign of pulmonary venous hypertension.

• Rebound pulmonary hypertension: Abrupt withdrawal/large dosage reductions may worsen symptoms of PAH. Immediate access to medication and back-up inhalation device is essential to prevent treatment interruptions.

• Syncope: Hypotension leading to syncope has been observed. Dosage or therapy adjustment may be required if exertional syncope occurs. Use caution with concurrent conditions or medications that may increase risk of syncope.

Disease-related concerns:

• Bleeding disorders: Use with caution in patients with active bleeding or at increased risk of bleeding (eg, concomitant anticoagulation); mild inhibitor of platelet aggregation when administered as an aerosol.

• Hypotension: Do not use in patients with hypotension (systolic BP <85 mm Hg).

• Respiratory disease: Safety and efficacy have not been established in patients with other concurrent pulmonary diseases (eg, COPD, severe asthma, or acute pulmonary infections); may induce bronchospasm in patients with hyper-reactive airways.

Other warnings/precautions:

• Administration: Intended for inhalation administration using only the I-neb AAD System. Solution should not come in contact with skin or eyes. Monitor vital signs during initiation.

With initiation and dosage adjustments, monitor heart rate, blood pressure, and respiratory rate at baseline. Monitor for improvements in pulmonary function, improved exercise tolerance, and NYHA Class improvement.

C

Adverse events were observed in some animal reproduction studies. Information related to the use of iloprost in pregnancy is limited (Horng 2016). Women with pulmonary arterial hypertension (PAH) are encouraged to avoid pregnancy (McLaughlin 2009; Taichman 2014).

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience back pain, mouth pain, cough, headache, jaw tightness, flushing, muscle cramps, nausea, vomiting, insomnia, or flu-like symptoms. Have patient report immediately to prescriber severe dizziness, passing out, bruising, bleeding, angina, tachycardia, difficulty breathing, coughing up blood, urinary retention, change in amount of urine passed, abnormal heartbeat, shortness of breath, excessive weight gain, swelling in arms or legs, or difficulty opening mouth (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.