60．诺果宁
出处：按学科分类—医药、卫生 军事医学科学出版社《临床常用进口药物手册》第331页（13054字）
【中文释文】：
(喹高利特)
多巴胺受体激动剂、催乳素分泌抑制剂
〔成分〕
活性成分：盐酸喹高利特啉*
非活性成分：二氧化硅(无水胶态)、乳糖、硬脂酸镁、甲基羟丙基纤维素、玉米淀粉、纤维素(微结晶)、氧化铁红(用于25μg片剂)以及色淀靛蓝(用于50μg片剂)。
规格：每片分别含盐酸喹高利特(八氢苄喹啉)25μg、50μg、75μg或150μg(0．025mg、0．050mg、0．075mg或0．15mg)。所提供的25μg和50μg片剂的包装，通常用于初始治疗(“初始给药包装”)；所提供的75μg和150μg片剂的包装，可用于维持量治疗。
·国际非专利药名记载
〔特性〕
喹高利特是诺果宁的活性成分，为一种选择性的多巴胺D2受体激动剂，它不属于麦角或麦角灵衍生物的化学类别。由于本品的多巴胺能作用，故能明显抑制垂体前叶激素(催乳素)的分泌，但并不降低其它垂体激素的正常水平。在某些病人中，催乳素分泌减少可能伴血浆生长激素短时间地持续小量升高，其临床意义尚不明。
作为一种特殊的催乳素分泌抑制剂，诺果宁作用持续时间较长。现已证实：对那些具高催乳素血症并有乳溢、月经过少、闭经、不孕和性欲减退等临床表现的病人，每天口服一次是有效和适宜的。
长期应用本品可使分泌催乳素的垂体腺瘤缩小或使其生长受到抑制。
〔药代动力学〕
口服放射性标记的本品后，可发现喹高利特能被迅速而完全地吸收。用非选择性放射免疫法所测得的血浆浓度是喹高利特及一些代谢物的血药浓度，它们都接近可测定量的极限，并不提供可信的信息。单次口服放射性标记的喹高利特后可见其表观分布容积约为100L，半衰期为11．5h。连续服药至血药水平稳定后，半衰期为17h。
喹高利特在首过效应时可被广泛地代谢，以3H标记的喹高利特研究显示95%以上的药物经代谢后排出(同样量的总放射活性发现存在于粪便和尿中)。在血中主要的代谢物为N-去乙基和N，N-二去乙基的类似物，它们都具有和喹高利特相似的生物活性，在尿液和粪便中的主要代谢物为喹高利特的葡萄糖醛酸和硫酸结合物，喹高利特可非特异地与蛋白结合，其结合率约为90%。药代动力学研究显示口服推荐剂量后2h内，本品可发挥明显的临床降催乳素作用。4～6h内达到最大效应，作用可维持约24h。本品的作用时间存在着明显的剂量-效应关系，但和降催乳素作用的大小不相关。在单次给予本品50μg后，其降催乳素作用接近达最大强度，提高剂量仅可延长其作用时间，但不提高其作用强度。
〔适应证〕
高催乳素血症(特发性的或由催乳素分泌垂体微腺瘤或大腺瘤所引起的)。
〔剂量及用法〕
由于多巴胺能受体兴奋可能导致体位性低血压，故病人于开始治疗时应采用“初始给药包装”，且仅在睡前服用。
〔成人〕
不同病人的理想用量应根据药物的降催乳素作用以及个人的耐受性予以调整。可采用“初始给药包装”；即治疗最初3d的剂量为25μg／d，第2个3d的剂量为50μg／d，从第7d起为75μg／d，以后若需要的话，可逐步提高用量，直至取得满意的疗效，维持量一般为75～150μg／d。
少于30%的病人可能需要300μg／d或更高的剂量，这些病例在间隔时间达4周以上时，可递增剂量75～150μg，直至获得满意的疗效或因病人不能耐受而需中止治疗。
〔老年〕
尚无诺果宁用于老年的经验。
〔儿童〕
尚无诺果宁用于儿童的经验。
〔给药方法〕
本品应于睡前与一些食物同服，每天一次。
〔禁忌证〕
对本品过敏及肝肾功能不全者禁用。孕妇用药请参阅“妊娠和哺乳妇女用药”。
〔注意事项〕
诺果宁治疗可能会恢复生育力，不愿生育的育龄妇女，服药期间须采取可靠的避孕措施。由于少数病人可发生低血压的警觉性降低，因此，特别在治疗的最初几天，驾驶车辆及操作机械宜小心。由于体位性低血压可能引起晕厥，在治疗的最初几天和剂量加大期间，应作卧、立位的血压检查。在极个别病人中，包括有精神病史的病人，曾见用药后发生急性精神病，但通常可于停药后恢复正常。故既往有精神病史的病人，应用本品时应特别小心。
至今，尚无肝肾功能不全病人使用诺果宁的资料(见“禁忌证”)。
本品应置于儿童接触不到的地方。
〔妊娠和哺乳妇女用药〕
1．妊娠妇女 动物资料显示：诺果宁无任何胚胎毒性或致畸的潜在危险。但用于孕妇的经验仍有限。一旦证实怀孕，除非有医疗上的理由需继续治疗外，应停止使用本品。此时停药并不增加流产率。垂体腺瘤病人怀孕且停用本品时，应在妊娠期对病人病情作严密的监察。
2．哺乳妇女 由于诺果宁抑制乳汁分泌，故通常患妇不可能哺乳。在治疗期间，即使病人仍有乳汁分泌，仍不宜哺乳，因为尚不知喹高利特是否进入人体的乳汁。
3．相互作用 至今未见诺果宁与其它药物相互作用的报告。不过，在理论上，当本品与某些强效多巴胺受体拮抗剂(如精神安定剂)合用时，预期其抑制催乳素分泌的作用会减弱。
由于诺果宁对5-HT1和5-HT2受体的作用较其对多巴胺D2受体的作用弱约100倍，故诺果宁与5-HT受体发生相互作用的可能极小，不过，当这些药物合用时，仍应小心。
乙醇可降低人体对本品的耐受性。
〔副作用〕
服用诺果宁后可能引起的副作用是采用多巴胺受体激动剂疗法时典型性的表现，一般不会严重到需中断治疗且继续治疗时副作用趋于逐渐消失。最常见(＞10%)的副作用为恶心、呕吐、头痛、头晕和乏力。它们主要发生在治疗的最初几天或者极短暂地发生于提高剂量以后。若需要的话，可于用药前几天，至少于用药前1h，给予外周多巴受体拮抗剂如多潘立酮来预防恶心和呕吐。较少发生(1%～10%)的副作用包括食欲不振、腹痛、便秘和腹泻、失眠、水肿、面部潮红、鼻充血以及低血压。体位性低血压偶可导致晕厥(处理见“注意事项”)。曾见极个别病人发生急性精神病，于停药后均恢复正常。
〔过量处理〕
尚无急性过量的报告。预期急性过量可能会引起严重的恶心、呕吐、头痛、头晕、倦睡、低血压，甚至虚脱，也可能产生幻觉。
应该对症治疗。
〔其他说明〕
贮于儿童不能触及处。
贮于30℃以下。
〔生产厂家〕
瑞士巴塞尔山道士制药公司
【外文释文】：
Dopamine-receptor agonist，inhibitor of prolactin secretion
Composition
Active ingredient：Quinagolide*(as the hydrochloride)
Tablets containing 25 μg，50 μg，75 μg or 150 μg
Excipients：tabletting excipients
rec，INN
Pharmaceutical form：tablets containing 25 μg，50 μg，75 μg or 150 μg(0．025，0．050，0．075 or 0．150mg)quinagolide as the hydrochloride．
Tablets of 25 μg and 50 μg are provided in a package intended for initiating therapy(‘starter pack’)；tablets of 75 μg or 1 50 μg are provided in packages intended for maintenance therapy．
Properties／Actions
Quinagolide，the active ingredient of Norprolac，is a selective D2-receptor agonist．Unlike other dopamine agonists currently available it is not an ergot alkaloid or ergoline derivative．As a result of its dopaminergic action，quinagolide exerts a potent inhibitory effect on prolactin secretion but does not affect levels of other pituitary hormones．
As a specific inhibitor of prolactin secretion with a good tolerability profile and prolonged duration of action，Norprolac is an effective once-a-day treatment for hyperprolactinaemia and its clinical manifestations，including in patients who have not responded adequacy to treatment with other dopamine agonists．
Long-term treatment with Norprolac has been found to reduce the size or restrict the growth of prolactin-secreting pituitary macroadenomas．
Pharmacokinetics
Quinagolide was rapidly and readily absorbed following oraI administration of tritium-labelled Norprolac，but plasma concentration values obtained by nonselective RIA(measuring quinagolide and certain metabolites)were close to the limit of detection and therefore not reliable．
The apparent volume of distribution of guinagolide following a single oral dose of tritium-labelled drug was approx．100 litres．The terminal half-life of the parent compound was 11．5 hours after a single dose and 17 hours at steady state．
The compound is extensively metabolized during first pass and studies with tritium-labelled quinagolide have shown that more than 95% of the dose is excreted in the form of metabolites．Approximately equal amounts of radioactivity were found in the urine and feces
Approx．90% of guinagolide is bound to proteins；binding is non-specific．
The main metabolites found in the blood are N-desethyl and N，N-bidesethyl analogues；the biological activity of both is qualitatively similar to that of the parent compound．In the urine the main metabolites are the glucuronide and sulphate conjugates of quinagolide and its analogues．
The most meaningful information on the pharmacokinetic behaviour of quinagolide and its active metabolites can be derived from pharmacodynamic studies investigating the reduction in the plasma level of prolactin，which is a reliable marker of the drug’s activity．The resuits show that at the recommended therapeutic dosage a clinically significant prolactin lowering effect is achieved within 2 hours of ingestion，reaches a peak within 4-6 hours and is maintained for approx．24 hours．
A definite dose-response relation has been established for the duration but not the magnitude，of the prolactin-lowering effect．This was virtually maximal following a single oral dose of 50μg higher doses producing no increase in potency of effect but only in its duration．
Indications／Uses
Substantiated uses
Hyperprolactinaemia(idiopathic or due to a prolactinsecreting micro-or macroadenoma)and its clinical manifestations(galactorrhoea，oligomenorrhoea，amenorrhoea，infertility，reduced libido)．
Dosage and Administration
Norprolac tablets should be taken once daily at bedtime with some food．The optimum dose should be determined individually on the basis of the prolactin-lowering effect and tolerability．
With the starter pack treatment begins with 25 μg／day for the first three days，followed by 50 μg／day for the further three days，The recommended dose from day 7 onwards is 75 μg／day．If necessary，the daily dose may be increased stepwise at intervals of not less than one week until the optimum individual response is achieved．
The usual maintenance dose is 75-150 μg／day．Daily doses of 300 μg or more are re quired in less than one third of patients；in such cases dosage may be increased in steps of 75-150 μg at intervals of not less than 4 weeks．
Patients receiving Parlodel(bromocriptine)
Such patients should be switched directly from Parlodel to Norprolac using the starter pack，with subsequent dose increases as described above．
Patients with kidney or liver failure
No data is available for these patients．See‘Contraindications’．
Use in the elderly
There is no evidence to suggest that elderly patients tolerate Norprolac less well or require a different dosage．
Paediatric use
There is no experience with the use of Norprolac in children．
Restrictions on Use
1．Contraindications
Hypersensitivity to the drug．
Severe kidney or liver failure．
2．Precautions
Since there is currently no data on the use of Norprolac in patients with kidney or liver failure the drug should not be given to such patients．
Infertility may be reversed by treatment with Norprolac and women of childbearing age who do not wish to become pregnant are therefore advised to use a reliable method of contraception．
Caution is required when giving Norprolac to patients with a history of psychotic disorders．
Patients may experience hypotensive reactions leading to reduced alertness，particularly during the first few days of treatment．They should therefore exercise particular caution when driving vehicles or operating machinery．
Since postural hypotension may，very occasionally，result in syncope，blood pressure should be monitored during the first few days of treatment．
For use during pregnancy see section‘Pregnancy and lactation’．
3．Pregnancy and lactation
Animal data provide no evidence that Norprolac has any embryotoxic or teratogenic potential but experience with the drug in pregnant women is limited．Women wishing to have a child should be told to stop taking Norprolac as soon as pregnancy is confirmed unless there is a medical reason for continuing to take it．The incidence of absortion following withdrawal under these conditions is not increased．
Women with a pituitary adenoma who become pregnant and discontinue Norprolac must be closely monitored throughout the pregnancy and treatment resumed，or surgery considered，if evidence of pronounced tumour enlargement(e．g．headache or visual field deterioration)is found．
Owing to its inhibitory effect on prolactin secretion，Norprolac suppresses lactation．Women receiving the drug are therefore unable to breastfeed．
Adverse Reactions
The adverse reactions reported with Norprolac are characteristic of dopamine agonists．They occur primarily during the first few days of treatment，are not normally sufficiently severe to necessitate withdrawal，and tend to disappear spontaneously，as treatment is continued．
The most frequently reported adverse reactions(＞10%)are：nausea，vomiting，headache，dizziness and fatigue．
If necessary，initial nausea and vomiting may be prevented by prescribing a peripheral dopamine antagonist(e．g．domperidone)to be taken at least one hour before ingestion of Norprolac．
Less frequent adverse reactions(1-10%)include loss of appetite，abdominal pain，constipation or diarrhoea，insomnia，nasal congestion and hypotension．
Norprolac has been associated with the occurrence of acute psychotic episodes in a few instances，though this effect was reversible on withdrawal of treatment．
Overdosage
There have been no reports of acute overdosage with Norprolac．The most likely symptoms would be nausea，vomiting，headache，dizziness，drowsiness，hypotension，and possible syncope．Hallucinations could also occur．
Management would be symptomatic．Metoclopramide could be given for vomiting or hallucinations．
Interactions
No interactions between Norprolac and other drugs have so far been reported．In theory，however，concomitant administration of drugs with pronounced antidopaminergic activity(e．g．neuroleptic agents)could diminish the prolactin-lowering effect of Norprolac．There is no evidence of an interaction with erythromycin．
The tolerability of Norprolac may be reduced by alcohol．
Other Information
Norprolac should be kept out of reach of children．
Norprolac should be stored at a temperature below 30℃．
Manufacturer
Sandoz Pharma，Ltd．，Basle，Switzerland