99．枢复宁
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551页（18293字）
【中文释文】：
(昂丹司琼)注射剂和片剂
〔简介〕
枢复宁注射剂：每安瓿含4mg昂丹司琼(氢氯化二水合物形式)于2ml水溶液中作静脉注射用，另一剂型是每安瓿含8mg昂丹司琼(氢氯化二水合物形式)于4ml溶液中作静脉注射用。
枢复宁4mg片剂：黄色椭圆薄膜覆盖的片剂，一面刻有“Glaxo”字样，另一面刻有“4”字样，每片含4mg(氢氯化二水合物形式)。
枢复宁8mg片剂：黄色椭圆薄膜覆盖的片剂，一面刻有“Glaxo”，字样，另一面刻有“8”字样，每片含8mg(氢氯化二水合物形式)。
〔适应证〕
枢复宁适用于处理由细胞毒性药物化疗和放射治疗引起的恶心呕吐，枢复宁亦适用于预防和治疗手术后的恶心呕吐。
〔作用方式〕
昂丹司琼是一种强效的、高度选择性的5-羟色胺5-HT3受体拮抗剂，它控制恶心呕吐的精确作用方式尚未了解清楚。化疗药物和放射治疗可引．起小肠的5-羟色胺释放，通过5-HT3受体引起迷走传入神经兴奋导致呕吐反射。昂丹司琼阻断这个反射的发生。迷走传入神经的兴奋也可引起位于第四脑室底的后支区释放5-HT3，这也可以通过中枢机制触发呕吐。故此，昂丹司琼控制由细胞毒性化疗药和放射治疗引起的恶心呕吐的机理，可能是拮抗外周的和中枢的神经元5-HT3受体。手术后的恶心呕吐作用机制不详，但由细胞毒性引起的恶心呕吐则可能有共通的轨迹可寻。
精神运动性试验证明昂丹司琼不影响行为效率，也没有镇静作用。
昂丹司琼不会改变血浆促乳素浓度。
〔剂量与用法〕
由药物化疗和放射治疗引起的恶心呕吐
成人：癌症引起的催吐严重程度，因化疗和放射治疗的用量和治疗组合而异，以枢复宁治疗癌症病人的恶心呕吐症状时，给药途径和剂量均应视病人情况灵活处理。剂量一般为8～32mg／d，给药方式按照下述情况决定。
引起呕吐的化疗和放射治疗：对于引起呕吐的化疗和放射治疗，应在病人接受该治疗前，缓慢静脉注射枢复宁8mg，或在治疗前1～2h口服8mg，之后每隔12h口服8mg。为避免在24h开始出现的恶心现象，应持续给予病人口服枢复宁两次，每次8mg，连服5d。
高度催吐的化疗：对于接受高度催吐化疗，例如含高成分顺铂化疗的病人，在化疗的首24h内根据以下程序给予病人服用枢复宁，显示同样有效：化疗前缓慢静脉注射8mg。之后用两剂8mg枢复宁，间隔2～4h以缓慢静脉注射输入，或以1mg／h的速度持续输注24h。
将32mg枢复宁于50～100ml盐水或其他可相溶的输注液中(参看“药剂的注意事项”)，在化疗前输注，输注时间为15min。
用药剂量和途径应视化疗及放疗引致的恶心呕吐严重程度而定。
化疗前，如加注一剂20mg地塞米松磷酸钠，以静脉输注输入，可加强枢复宁缓解高度催吐化疗引致病人不适的疗效。
为避免在24h后出现的恶心呕吐现象，应持续给予病人每日口服枢复宁2次，每次8mg，连服5d。
儿童：化疗前静脉注射以5mg的剂量，12h后再口服4mg。化疗后应持续给予病人每天口服2次，每次4mg，连服5d。
年老病人：65岁以上病人用药疗效及对药物的耐受性与普通成年病人一样，没必要调整剂量、用药次数或用药途径。
〔手术后的恶心呕吐〕
成人：对于预防手术后的恶心呕吐，应在麻醉前1h口服一剂8mg枢复宁，之后每隔8h口服8mg枢复宁两次。另一种给药方法是在麻醉的同时静脉输注4mg。
对于手术后恶心呕吐的病人，建议缓慢静脉输注4mg。
儿童：目前尚未有用枢复宁预防和治疗儿童手术后恶心呕吐的经验。
年老病人：用枢复宁预防和治疗老人手术后恶心呕吐的经验有限。
肾衰竭病人：没必要调整剂量、用药次数或用药途径。
肝脏衰竭病人：肝脏功能中度或严重衰竭病人清除枢复宁的能力显着下降，血清半衰期也显着延长，因此用药剂量每天不应超过8mg。
〔禁忌证〕
对制剂中任何成分过敏者不适用。
〔警告〕
怀孕：枢复宁对动物胚胎无致畸作用，但在人类无此经验。
如其他药物一样，枢复宁不应在怀孕期用。尤其是怀孕头3个月内，除非病人用药的好处会大过胎儿可能发生的任何危险。
哺乳：实验显示昂丹司琼由大鼠乳汁中分泌，故此建议母亲服用昂丹司琼时不要用母乳喂养他们的婴儿。
〔副作用〕
头痛、头部和上腹部发热或温暖感，偶有短暂性无症状的转氨酶增加。会出现增加大肠蠕动输送时间而导致某些病人便秘。曾有即时过敏反应的罕见报道。
〔过量〕
对于这方面的资料所知甚少。曾有2名病人分别接受了静脉输入84mg和145mg枢复宁，只出现轻微副作用，不需积极处理。当怀疑用药过量时，应适当地采取对症疗法和支持疗法。
〔药剂的注意事项〕
枢复宁注射剂应避光贮存，不需特别的贮存条件。
枢复宁注射剂不能任与其他药物混于同一注射器中使用或同时输入。
枢复宁注射剂的安瓿不能高压消毒。
与静脉注射液的相容性：枢复宁注射剂只能与推荐的静脉输注液混合使用。
为了保证药物效果良好，作静脉输入的溶液应在使用前配制。不过，在室温(25℃以下)荧光照射下或在冰箱中，枢复宁注射剂与下列静脉输注液混合后仍能保持稳定7d，这些液体是：
0．9%w／v氯化钠静脉输注液BP；
5%w／v葡萄糖静脉输注液BP；
10%w／v甘露醇静脉输注液BP；
林格氏静脉输注液；
0．3%w／v氯化钾与0．9w／v氯化钠静脉输注液BP；
0．3%w／v氯化钾与5%w／v葡萄糖静脉输炷液BP；
此外还对聚氯乙烯输液袋和聚氯乙烯给药装置作过相容性研究。认为用聚乙烯输液袋或用1型玻璃瓶，本药亦有恰当的稳定性。在聚丙二醇酯注射器中，0．9%(w／v)氯化钠或5%(w／v)葡萄糖的枢复宁稀释液显现稳定。故此认为在聚丙二醇酯注射器中，枢复宁注射剂与其他相容性输注液混合也会稳定。
注意：如需延长贮存时间就必须在适当的无菌条件下配制药品。
与其他药物的相容性：可用输液袋或注射泵静脉输注昂丹司琼1mg／h。如果昂丹司琼浓度16～160μl／ml，下列药均可通过枢复宁给药装置的Y位置来给药，顺铂：给药时间可由1～8h不等，浓度不超过0．48mg／ml。
5-氟尿嘧啶：浓度0．8mg／ml以下，给药速度至少20ml／h。
高于这浓度的5-氟尿嘧啶可导致昂丹司琼沉淀。除了其他显示出相容性的赋形剂之外，5-氟尿嘧啶可以含不超过0．045%(w／v)的氯化镁。
卡铂：给药时间为10min～1h，浓度范围在0．18～9．9mg／ml。
依托泊苷：给药时间为30min～1h，浓度范围在0．144～0．25mg／ml。
头孢他啶：按药厂推荐那样，用注射用水BP配制250～2000mg药物(即用2．5ml配 250mg及用10ml配2g头孢他啶)，以约超过5min的时间作大剂推注的静脉注射。
环磷酰胺：按药厂推荐那样，用注射用水BP配制100mg～1g的药物，即用每5ml100mg环磷酰胺，以大约超过5min的时间作大剂推注的静脉注射。
多柔比星：按药厂推荐那样，用注射用水BP配制10～100mg的药物，即用每5ml10mg多柔比星，以大约超过5min的时间作大剂推注的静脉注射。
地塞米松：20mg的地塞米松磷酸钠可用缓慢静脉输注法在2～5min内完成输注。地塞米松磷酸钠可透过正在输注8mg或32mg昂丹司琼的装置的Y-位输入，此昂丹司琼以50～100ml相容的输注液稀释，在15min内完成输注。地塞米松磷酸钠证明为可以与昂丹司琼相容，这2种药可同时间用一个输注装置输注，使浓度达至地塞米松磷酸钠32μg／ml～2．5mg／ml和昂丹司琼8μg／ml～1mg／ml。
〔药代动力学及代谢〕
口服昂丹司琼后，病人吸收快速，在口服8mg后约1．5h达到约30μg／ml的血浆峰值浓度。口服此药的绝对生物有效性大约是60%。口服或静脉输注时，昂丹司琼的体内代谢情况大致相同，药物终末清除的半衰期约3h，稳定分布量约为140L。
血浆蛋白结合率是70%～76%。昂丹司琼主要籍代谢从系统循环清除，剂量中少于5%未经清除由尿中排出。
由健康老人进行的自愿试验显示，口服昂丹司琼的生物利用度有所提高(65%)，清除半衰期亦见延长(5h)。严重肝脏衰竭病人由于系统性代谢减慢，系统清除显着减少，清除半衰期亦延长(15～32h)。口服此药的生物利用度接近100%。
目前尚未能证明昂丹司琼会引发或抑制一般与其同用的其他药物的代谢率，惟迄今的具体试验只限于酒精和替马西泮。
枢复宁为葛兰素集团公司所拥有的商标。
〔生产厂家〕
英国格林福德葛兰素公司
(附本品别名：恩丹西隆、恩丹西酮)
【外文释文】：
Presentation
Zofran Injection：ampoules each containing 4mg or 8mg ondansetron(as hydrochloride dihydrate)in 2ml or 4ml respectively of aqueous solution for intravenous administration．Zofran Tablets 4mg and 8mg：yellow，oval，film coated tablet engraved‘Glaxo’on one face and‘4’or‘8’on the other，according to the strength．Each tablet contains ondansetron 4mg or 8mg(as hydrochloride dihydrate)．
Indications
Zofran preparations are indicated for the management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy．Zofran is also indicated for the prevention and treatment of postoperative nausea and vomiting．
Mode of action
Ondansetron is a potent，highly selective 5HT3 receptor antagonist．Its precise mode of action in the control of nausea and vomiting is not known．Chemotherapeutic agents and radiotherapy may cause release of 5HT3 in the small intestine initiating a vomiting reflex by activating vagal afferents via 5HT3 receptors．Ondansetron blocks the initiation of this reflex．Activation of vagal afferents may also cause a release of 5HT3 in the area postrema，located on the floor of the fourth ventricle，and this may also promote emesis through a central mechanism．Thus，the effect of ondansetron in the management of the nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy is probably due to antagonism of 5HT3 receptors on neurons located both in the peripheral and central nervous system．The mechanisms of action in postoperative nausea and vomiting are not known but there may be common pathways with cytotoxic induced nausea and vomiting．
In psychomotor testing，ondansetron does not impair performance nor cause sedation．Ondansetron does not alter plasma prolactin concentrations．
Dosage and administration
Chemotherapy and radiotherapy induced nausea and vomiting
Adults：the emetogenic potential of cancer treatment varies according to the doses and combinations of chemotherapy and radiotherapy regimens used．The route of administration and dose of Zofran should be flexible in the range of 8-32mg a day and selected as shown below．
Emetogenic chemotherapy and radiotherapy：for most patients receiving emetogenic chemotheapy or radiotherapy，zofran 8mg should be administered as a slow intravenous injection immediately before treatment，or orally 1-2 hours before treatment，followed by 8mg orally twelve-hourly．
To protect against delayed emesis after the first 24 hours，Zofran should be continued orally，8mg twice daily for up to 5 days after a course of treatment．
Highly emetogenic chemotherapy：for patients receiving highly emetogenic chemotherapy，eg．high-dose cisplatin，Zofran has been shown to be equally effective in the following dose schedules over the first 24 hours of chemotherapy：
A single dose of 8mg by slow intravenous injection immediately before chemotherapy．
A dose of 8mg by slow intravenous injection immediately before chemotherapy．Followed by two further intravenous doses of 8mg two to four hours，apart，or by a constant infusion of lmg／hour for up to 24 hours．
A single dose of 32mg diluted in 50-100ml of saline or other compatible infusion fluid(see Pharmaceutical precautions)and infused over 15 minutes immediately before chemotherapy．
The selection of dose regimen should be determined by the severity of the emetogenic challenge．
The efficacy of Zofran in highly emetogenic chemotherapy may be enhanced by the addition of a single intravenous dose of dexamethasone sodium phosphate，20mg administered prior to chemotherapy．
To protect against delayed emesis after the first 24 hours，Zofran should be continued orally，8 mg twice daily for up to 5 days after a course of treatment．
Children：Zofran may be administered as a single intravenous dose of 5mg／m2 immediately before chemotherapy，followed by 4mg orally twelve hours later．4mg Orally twice daily should be continued for up to 5 days after a course of treatment．
Elderly：Zofran is well tolerated by patients over 65 years and no alteration of dosage，dosing frequency or route of administration are required．
Postoperative nausea and vomiting
Adults：for prevention of postoperative nausea and vomiting，Zofran may be administered orally at a dose of 8mg given an hour prior to anaesthesia followed by two further doses of 8mg at eight-hourly intervals．Alternatively，a single dose of 4mg may be given by slow intravenous injection at induction of anaesthesia．
For treatment of established postoperative nausea and vomiting，a single dose of 4 mg given by slow intravenous injection is recommended．
Children：there is no experience in the use of Zofran in the prevention and treatment of postoperative nausea and vomiting in children．
Elderly：there is limited experience in the use of Zofran in the prevention and treatment of postoperative nausea and vomiting in the elderly．
Patients with renal impairment：no alteration of daily dosage or frequency of dosing，or route of administration are required．
Patients with hepatic impairment：clearance of Zofran is significantly reduced and serum half-life significantly prolonged in subjects with moderate or severe impairment of hepatic function．In such patients，a total daily dose of 8mg should not be exceeded．
Contra-indications
Hypersensitivity to any component of the preparation
Precautions
Pregnancy：Zofran preparations are not teratogenic in animals，however there is no experience in humans．
As with other medicines，Zofran preparations should not be used during pregnancy，especially during the first trimester，unless the expected benefit to the patient is thought to outweigh any possible risk to the fetus．
Lactation：tests have shown that ondansetron is excreted in the breast milk of rats．It is therefore recommended that mothers receiving ondansetron should not breast-feed their babies．
Side effects
The following side effects can occur：headache，a sensation of flushing or warmth in the head and epigastrium，and occasional transient，asymptomatic increases in aminotransferases．
Ondansetron is known to increase large bowel transit time and may cause constipation in some patients．
There have also been rare reports of immediate hypersensitivty reactions．
Overdosage
Little is at present known about overdosage with Zofran preparations．However，two patients who received doses of 84 and 145 mg intravenously reported only mild side effects and required no active therapy．
In cases of suspected overdose，symptomatic and supportive therapy should be given as appropriate．
Pharmaceutical precautions
Zofran injection should be protected from light．No other special storage conditions are necessary．
Zofran injection should not be administered in the same syringe or infusion as any othermedication．
Zofran iniection ampoules should not be autoclaved．
Compatibility with intravenous fluids：Zofran injection should only be admixed with those infusion solutions which are recommended．
In keeping with good pharmaceutical practice，intravenous solutions should be prepared at the time of infusion．However，Zofran injection has been shown to be stable for seven days at room temperature(below 25℃)under fluorescent lighting or in a refrigerator with the following intravevous infusion fluids：
Sodium Chloride Intravenous Infusion BP 0．9%w／v
Glucose Intravenous Infusion BP 5%w／v
Mannitol Intravenous Infusion BP 10%w／v
Ringers Intravenous Infusion
Potassium Chloride 0．3%w／v and Sodium Chloride 0．9%w／v Intravenous Infusion BP
Potassium Chloride 0．3%w／v and Glucose 5%w／v Intravenous Infusion BP
Compatibility studies have been undertaken in polyvinyl chloride infusion bags and polyvinyl chloride administration sets．It is considered that adequate stability would also be conferred by the use of polyethylene infusion bags or type 1 glass bottles．
Dilutions of Zofran in sodium chloride 0．9%w／v or in glucose 5%w／v have been demonstrated to be stable in polypropylene syringes．It is considered that Zofran injection diluted with other compatible infusion fluids would be stable in polypropylene syringes．
Note：preparation must be under the appropriate aseptic conditions if extended storage periods are required．
Compatibility with other drugs：Zofran may be administered by intravenous infusion at 1mg／hour，e．g．from an infusion bag or syringe pump．The following drugs may be administered via the Y-site of the Zofran giving set for ondansetron concentrations of 16-160 microgram／ml(e．g．8 mg／500 ml and 8mg／50 ml respectively)；
Cisplatin：concentrations up to 0．48 mg／ml(e．g．240 mg in 500 ml)administered over one to eight hours．
5-Fluorouracil：concentrations up to 0．8mg／ml(e．g．2．4g in 3 litres or 400mg in 500 ml)administered at a rate of at least 20ml per hour(500ml per 24 hours)．Higher concentrations of 5-fluorouracil may cause precipitation of ondansetron．The 5-fluorouracil infusion may contain up to 0．045%w／v magnesium chloride in addition to other excipients shown to be compatible．
Carboplatin：concentrations in the range 0．18mg／ml to 9．9 mg／ml(e．g．72 mg in 500 ml to 990 mg in 100 ml)，administered over ten minutes to one hour．
Etoposide：concentrations in the range 0．144 mg／ml to 0．25mg／ml(e．g．90 mg in 500ml to 250 mg in 1 litre)，administered over thirty minutes to one hour．
Ceftazidime：doses in the range 250 mg to 2000 mg reconstituted with Water for Injections BP，as recommended by the manufacturer(e．g．2．5 ml for 250mg and 10 ml for 2g cefiazidime)and given as an intravenous bolus injection over approximately five minutes．
Cyclophosphamide：doses in the range 100mg to 1 g，reconstituted with Water for Injections BP，5 ml per 100 mg cyclophosphamide，as recommended by the manufacturer and given as an intravenous bolus injection over approximately five minutes．
Doxorubicin：doses in the range 10-100mg reconstituted with Water for Injections BP，5 ml per 10 mg doxorubicin，as recommended by the manufacturer and given as an intravenous bolus injection over approximately five minutes．
Dexamethasone：dexamethasone sodium phosphate 20mg may be administered as a slow intravenous injection over 2-5 minutes via the Y-site of an infusion set delivering 8 or 32 mg of ondansetron diluted in 50-100 ml of a compatible infusion fluid over approximately 15 minutes．Compatibility between dexamethasone sodium phosphate and ondansetron has been demonstrated supporting administration of these drugs through the same giving set resulting in concentrations line of 32 μg-2．5 mg／ml for dexamethasone sodium phosphate and 8 μg1 mg／ml for ondansetron．
Pharmacokinetics and metabolism
Following oral administration of ondansetron，absorption is rapid with maximum plasma concentrations of about 30 ng／ml being attained approximately 1．5 hours after an 8mg dose．The absolute oral bioavailability of the drug is approximately 60%．The disposition of ondansetron following both oral and intravenous dosing is similar with a terminal elimination half-life of about 3 hours and a steady-state volume of distribution of about 140 L．
Plasma protein binding is 70-76%．Ondansetron is cleared from the systemic circulation predominantly by metabolism with less than 5% of a dose excreted unchanged in the urine．
Studies in healthy eldery volunteers have shown a slightly increased oral bioavailability(65%)and prolonged elimination half-life(5 h)for ondansetron．In patients with severe hepatic impairment，systemic clearance is markedly reduced with prolonged elimination halflives(15-32 h)and an oral bioavailability approaching 100%because of reduced presystemic metabolism．
There is no evidence that ondansetron either induces or inhibits the metabolism of other drugs commonly coadministered with it，although specific studies have been limited to alcohol and temazepam to date．
Zofran is a trade mark owned by Glaxo Group of Companies．
Manufacturer
Glaxo Operations UK Ltd．，Greenford，England