Procoralan(中文：伊伐布雷定)部份处方资料

通用名：盐酸依伐布雷定

化学名：7，8-二甲氧基-3-(3-[[(1S)(4，5-二甲氧基苯并环丁烷-1-基)甲基]-甲氨基] 丙基)-1，3，4，5-四氢化-2氢-苯并氮杂卓-2-酮盐酸盐

英文名：Ivabradine hydrochlorid

分子式：C27H36N2O5·HCl

分子量：468.60

类别：盐酸依伐布雷定原料、盐酸伊伐布雷定片均为化药3.1

适应症：用于禁用或不耐受β受体阻断剂、窦性心律正常的慢性稳定型心绞痛患者。

制剂规格：薄膜衣片，5mg、7.5mg。

用法用量：通常推荐起始剂量：5mg/次，2次/日。用药三至四周后，根据治疗效果，增加至7.5mg/次，2次/日。如果在治疗期间，休息时心率减少持续低于50次/分，或病人体验涉及心跳缓慢的症状，如头昏、疲劳或者血压过低，剂量必须向下调整，包括可能剂量2.5mg/次，2次/日。必须每日两次口服，例如早餐和晚餐时服用。如果心率低于50次/分，或心博徐缓症状持续，则应停止用药。
老年患者用药：伊伐布雷定在少数75岁或以上老年病人研究表明，病人应采用较低的起始剂量，根据需要增加剂量。
肾功能不全：肌酐清除率高于15ml/min的肾功能不全患者不需要调整给药剂量，肌酐清除率低于15ml/min的肾功能不全患者，缺乏研究数据，应慎用本品
肝功损害：轻度肝功能损害患者，不需调整给药剂量。中度肝功能损害患者，应慎用本品。严重的肝功能不足患者，尚未进行相关研究，应禁用本品。
儿童、青少年患者：因为缺乏安全性和有效性的数据，本品不推荐应用于儿童和青少年患者。
　　
药理研究：Muldder P应用伊伐布雷定使慢性心力衰竭大鼠模型长期减慢心率，于停药3天后测定左室功能和结构组织的改变参数，根据结果认为，长期应用伊伐布雷定能够有效地改善心衰动物的左室功能和结构。Camm等研究了伊伐布雷定对心脏电生理参数的影响。结果显示，随着心率的下降，QT间期延长，而心率校正后的QT间期没有延长。但是，PR间期、QRS间期不受影响，此外，心房、房室结、希氏-浦肯野系统、心室的传导性和不应期也不受影响。Lucats L等人通过犬试验研究伊伐布雷定对心脏收缩后期室壁增厚的作用。结果显示伊伐布雷定的纯心率减缓作用不会改变这些参数，且保护室壁增厚的组成,促进了心脏泵血。Vilaine JP研究发现，伊伐布雷定能减少离体鼠右心房的自发性搏动频率和家兔窦房结标本动作电位的代谢率。Berdeaux A比较了伊伐布雷定和β受体阻断剂的药理效应，试验发现两者在心率降低相同水平情况下，伊伐布雷定提供的心脏舒张期灌流时间更长。
　　
药动学和药物代谢：伊伐布雷定口服给药后，能迅速和较彻底地吸收，在禁食条件下，一小时后能达到血药峰浓度。在患者体内，伊伐布雷定的血浆蛋白结合率大约为70%，表观分布容积在稳态下接近100 L。在推荐给药每次5 mg，每日两次的长期给药中，最大血浆浓度为22 ng/mL(CV=29%)，稳态下的平均血浆浓度为10 ng/mL(CV=38%)。在肝脏和消化道内，伊伐布雷定仅通过细胞色素P450 3A4发生氧化作用从而被代谢，主要的活性代谢物为N-去甲基化衍生物。伊伐布雷定在血浆中的消除半衰期为2小时(70%～75% of the AUC)，有效半衰期为11小时。总清除率为400 mL/min，肾脏消除率为70 mL/min。通过大便和小便最终排泄代谢物，在尿液中能找到4％的口服原药。
伊伐布雷定的动力学呈线性，口服剂量范围为0.5 mg～24 mg。使用剂量增加到15 mg～20 mg（每日两次），能够增加伊伐布雷定和主要代谢物的血浆浓度，从而使心率的降低呈线性。在高剂量下，心率的降低与伊伐布雷定血浆浓度不再成比例。尽管CYP3A4抑制剂的危险性较低，但伊伐布雷定与强的CYP3A4抑制剂联合使用时，会导致心率过度降低。

【产地英文商品名】PROCORALAN FILM COATED TAB 5mg/tablet 98tablets/box
【原产地英文药品名】IVABRADINE
【中文参考商品译名】
注：以下产品不同的规格和不同的价格，购买时请咨询为准
·PROCORALAN肠溶片 5毫克/片 98片/盒
·PROCORALAN肠溶片 5毫克/片 56片/盒
·PROCORALAN肠溶片 5毫克/片 28片/盒
【中文参考药品译名】伊伐布雷定
【生产厂家中文参考译名】施维雅
【生产厂家英文名】Servier

伊伐布雷定Procoralan（ivabradine）-治疗慢性稳定型心绞痛独特效果
与β-受体阻断剂联用治疗慢性稳定型心绞痛患者-伊伐布雷定(PROCORALAN)新适应症获批。
法国巴黎-09年12月15日-欧洲药品监管局（EMEA）最近批准了Procoralan（伊伐布雷定）的新适应症。伊伐布雷定现在可以用于那些即使接受了最佳剂量的β-受体阻滞剂，但病情仍未得到充分控制，心率高于每分钟60次的慢性稳定型心绞痛患者。
2005年10月欧洲药品监管局批准伊伐布雷定用于临床，治疗那些具有窦性心律，对β-受体阻滞剂不耐受或存在禁忌的稳定型心绞痛的患者。此后大量有关伊伐布雷定临床疗效的新的研究被公布，其中，ASSOCIATE1和BEAUTIFUL2临床试验结果影响了其适应症的改变。
ASSOCIATE试验结果表明，针对889名患者，在阿替洛尔（每天50毫克口服剂量）的基础上，伊伐布雷定在药物浓度低谷期时，对患者的所有运动耐量（ETT）参数都有额外益处。这项试验的结果具有特殊意义，因为为了充分控制患者的心绞痛发作，尽管联合疗法已被广泛用，但临床试验并未获得一致的结果。
加拿大蒙特利尔心脏研究所特里谢塔迪夫博士说，“从研究的规模，对指南建议的依从性，以及研究中不同时间段所有ETT指标有一致的明显改进等方面而言，ASSOCIATE试验可能是迄今为止在所有已发表的抗心绞痛联合疗法研究中最引人注目的一次治疗利益的展示”。
BEAUTIFUL研究是一项针对10917例冠心病伴左心室功能障碍患者（左心室射血分数<42％）的大型研究，研究中的患者接受了最佳的标准治疗，其中86.9％的患者接受了β-受体阻滞剂的治疗。对心绞痛患者的亚组分析表明，患者使用伊伐布雷定后，其心血管事件、因心力衰竭而住院治疗和心血管死亡的发生风险更小（伊伐布雷定组12%，对照组15.5%,；P=0.05）。
伊伐布雷定在这两大临床研究中显示了良好的耐受性。ASSOCIATE和BEAUTIFUL试验结果已经总结在新的产品特性的资料中。
曾参加了伊伐布雷定数个临床试验的英国皇家布朗普顿医院的福克斯教授评论说，“我们已经证明了伊伐布雷定对心绞痛患者的抗心绞痛疗效及可能预防心血管事件的疗效，这次其获准的与β-受体阻滞剂联合应用的新适应症将使我们能够更好地治疗那些大量的已接受β-受体阻滞剂但仍难以控制的稳定性冠心病患者。”
法国领先的独立制药公司施维雅发布。

Procoralan (ivabradine)

How does it work?
Procoralan tablets contain the active ingredient ivabradine, which is a type of medicine called a selective If current inhibitor. It helps to lower the heart rate.

The pain of angina is caused by too little oxygen reaching the heart when the heart rate increases and its workload increases, such as during exercise. This is usually a result of hardening of the arteries (atherosclerosis) that supply blood to the heart. This is also known as coronary heart disease.

Ivabradine reduces the heart rate by a few beats per minute, therefore reducing the heart’s need for oxygen.

Ivabradine works by inhibiting the electrical current produced in the pacemaker of the heart that controls the heart rate. It does this by binding to ‘If-channels’ that are found in the pacemaker. These If-channels are responsible for generating an electrical impulse that spreads through the heart, causing it to contract so that blood can be pumped to the lungs and the rest of the body. By binding to the If-channels, ivabradine slows the rate at which the heart beats.

Slowing the heart rate reduces the heart’s demand for oxygen, especially in situations when the heart rate increases and an angina attack is more likely to happen. Ivabradine therefore helps to control and reduce the number of angina attacks.

This medicine is taken on regular basis, twice a day, with food.

What is it used for?
Treatment of chronic stable angina pectoris in people with a normal heart rhythm.
This medicine is used when medicines called beta-blockers (for example atenolol, bisoprolol and metoprolol) are unsuitable, or cause unacceptable side effects.

Warning!
You should avoid drinking grapefruit juice while taking this medicine. This is because grapefruit juice can affect the metabolism of ivabradine and could increase the amount of the medicine in your blood, thus increasing the risk of side effects.

The most common side effect of this medicine is known as luminous visual phenomena. People experiencing this side effect describe it as a brief moment of increased brightness in a limited area of the visual field. This is usually brought on by sudden changes in light intensity. This temporary visual disturbance may affect your ability to drive and operate machinery, particularly when driving at night. If affected you should not drive or use machines until your vision improves.

If you experience any other problems with your vision while taking this medicine you should consult your doctor.

If your heart rate drops persistently below 50 beats per minute while taking this medicine, or you experience symptoms of a slow heart rate such as dizziness, fatigue or low blood pressure, your doctor may need to decrease your dose of this medicine or stop the treatment completely.

Use with caution in
People over 75 years old.
People with moderately decreased liver function.
People with severely decreased kidney function (creatinine clearance rate below 15ml/min).
Mild heart failure.
Mild to moderate low blood pressure (hypotension).
People with an eye disease called retinitis pigmentosa (overactivity of the pigmented retina cells).

Not to be used in
People with a resting heart rate below 60 beats per minute before treatment is started.
Failure of the heart to maintain adequate circulation of blood (cardiogenic shock).
People having a heart attack (acute myocardial infarction).
Very low blood pressure (below 90/50mmHg).
Severe heart failure.
Severe angina that occurs with or without exertion and is not well controlled by medical treatment (unstable angina).
A problem common in the elderly, related to poor control of the working of the heart (sick sinus syndrome).
People who have an artificial pacemaker.

Failure of the electrical impulse that causes the heart to beat to leave the pacemaker of the heart, resulting in decreased heart function (sino-atrial heart block)

Serious defect in the heart's electrical message pathways resulting in decreased function of the heart (2nd or 3rd degree heart block).

Severely decreased liver function.
Pregnancy.
Breastfeeding.
Rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption (Procoralan tablets contain lactose).

This medicine is not recommended for people with irregular heartbeats (arrhythmias) that interfere with the functioning of the pacemaker, or an irregular heartbeat called atrial fibrillation (AF).

This medicine is not recommended for people taking calcium channel blockers that reduce heart rate, such as verapamil or diltiazem.

This medicine is not recommended for people who have recently had a stroke.

This medicine is not recommended for children and adolescents under 18 years of age because it has not been studied in this age group.

This medicine should not be used if you are allergic to one or any of its ingredients. Please inform your doctor or pharmacist if you have previously experienced such an allergy.

If you feel you have experienced an allergic reaction, stop using this medicine and inform your doctor or pharmacist immediately.

Pregnancy and breastfeeding
Certain medicines should not be used during pregnancy or breastfeeding. However, other medicines may be safely used in pregnancy or breastfeeding providing the benefits to the mother outweigh the risks to the unborn baby. Always inform your doctor if you are pregnant or planning a pregnancy, before using any medicine.

The safety of this medicine for use in pregnancy has not been established. There is a possibility that it could be harmful to a developing baby. For this reason, it should not be used during pregnancy.

This medicine passes into breast milk. The manufacturer states that it should not be taken by women who are breastfeeding. Seek further medical advice from your doctor.

Side effects
Medicines and their possible side effects can affect individual people in different ways. The following are some of the side effects that are known to be associated with this medicine. Just because a side effect is stated here does not mean that all people using this medicine will experience that or any side effect.

Very common (affect more than 1 in 10 people)

Luminous visual phenomena (people experiencing this effect describe it as a brief moment of increased brightness in a limited area of their vision - see warning above).

Common (affect between 1 in 10 and 1 in 100 people)
Blurred vision.
Slow heart rate (bradycardia).
Slowed conduction of electrical messages between the chambers of the heart (1st degree atrioventricular block).
Premature contraction of the lower chambers of the heart (ventricular extrasystoles).
Headache.
Dizziness.
Uncommon (affect between 1 in 100 and 1 in 1000 people)
Awareness of your heartbeat (palpitations).
Difficulty breathing or shortness of breath (dyspnoea).
Sensation of spinning (vertigo).
Disturbances of the gut, such as nausea, constipation, diarrhoea.
Muscle cramps.
Raised levels of white blood cells called eosinophils (eosinophilia).
Elevated levels of creatinine in the blood.
High blood uric acid level (hyperuricaemia).

The side effects listed above may not include all of the side effects reported by the medicine's manufacturer.

For more information about any other possible risks associated with this medicine, please read the information provided with the medicine or consult your doctor or pharmacist.

How can this medicine affect other medicines?
It is important to tell your doctor or pharmacist what medicines you are already taking, including those bought without a prescription and herbal medicines, before you start treatment with this medicine. Similarly, check with your doctor or pharmacist before taking any new medicines while taking this one, to ensure that the combination is safe.

There may be an increased risk of abnormal heart rhythms if this medicine is taken in combination with any of the following medicines, and these are not recommended for use in combination with ivabradine. If you need to take any of these while taking ivabradine your heart function will need to be closely monitored:
medicines for abnormal heat beats (anti-arrhythmics) eg amiodarone, disopyramide, sotalol
certain antipsychotics, eg pimozide, sertindole
certain antimalarials, eg. mefloquine, halofantrine
erythromycin or pentamidine given by injection
cisapride (no longer available in the UK).

The following medicines can increase the amount of ivabradine in your blood and this could increase the risk of its side effects. These medicines should not be taken in combination with ivabradine:
azole antifungals, such as ketoconazole or itraconazole (fluconazole may be used, but your dose of ivabradine may need to be reduced if a multi-dose course of fluconazole is taken)
macrolide antibiotics, such as clarithromycin, erythromycin, telithromycin
nefazodone
protease inhibitors for HIV infection, eg nelfinavir, ritonavir.

Diltiazem and verapamil can also increase the amount of ivabradine in the blood, which can result in the heart rate being reduced too much. For this reason it is recommended that this medicine is not taken in combination with diltiazem or verapamil.

The following medicines can decrease the amount of ivabradine in your blood and so could make it less effective:
barbiturates
phenytoin
rifampicin
the herbal remedy St John's wort (Hypericum perforatum) – it is recommended that you should avoid taking this remedy if you are taking ivabradine.

Other medicines containing the same active ingredient
There are currently no other medicines available in the UK that contain ivabradine as the active ingredient.