部份枢复宁中文处方资料（仅供参考）
药理
本品为一种高度选择性的5-羟色胺3（5-HT3）受体拮抗剂，能抑制由化疗和放疗引起的恶心呕吐，其作用机制目前尚不完全清楚。一般认为，化疗和放疗可引起小肠的嗜铬细胞释放5-HT3，并通过5-HT3受体引起迷走传入神经兴奋从而导致呕吐反射，而昂丹司琼可阻断这一反射发生。
本品不影响行为效率，无镇静作用，且不改变血浆催乳素水平。口服吸收迅速，单剂量8mg，tmax为1.5小时，Cmax为30ng／ml，口服生物利用度约为60％；Vd约为140L，t1/2β约3小时；血浆蛋白结合率为70％～76％。主要自肝脏代谢，代谢产物主要自粪和尿排泄，50％以内的本品以原形自尿排出。老年人由于代谢减慢，服用本品后消除半衰期延长（5小时），同时口服生物利用度提高（65％）；严重肝功能障碍患者系统清除率可显著减少，消除半衰期可延长至15～32小时，同时口服生物利用度可接近100％。
应用
本品适用于治疗由化疗和放疗引起的恶心呕吐，也可用于预防和治疗手术后引起的恶心呕吐。
用法
1.治疗由化疗和放疗引起的恶心呕吐。
（1）成人：给药途经和剂量应视病人情况因人而异。剂量一般为8～32mg；对可引起中度呕吐的化疗和放疗，应在病人接受治疗前，缓慢静脉注射8mg；或在治疗前1～2小时口服8mg，之后问隔12小时口服8mg。对可引起严重呕吐的化疗和放疗，可于治疗前缓慢静注本品8mg，之后间隔2～4小时再缓慢静注8mg，共2次；也可将本品加入50～100ml生理盐水中于化疗前静脉滴注，滴注时间为15分钟。对可能引起严重呕吐的化疗，也可于治疗前将本品与20mg地塞米松磷酸钠合用静脉滴注，以增强本品的疗效。对于上述疗法，为避免治疗后24小时出现恶心呕吐，均应持续让病人服药，每次8mg，每日2次，连服5天。
（2）儿童：化疗前按体表面积计算，每米2静脉注射5mg，12小时后再口服4mg，化疗后应持续给予病儿口服4mg，每日两次，连服5天。
（3）老年人：可依成年人给药法给药，一般不需调整。
2　预防或治疗手术后呕吐
（1）成人：一般可于麻醉诱导同时静脉滴注4mg，或于麻醉前1小时口服8mg，之后每隔8小时口服8mg，共2次。已出现术后恶心呕吐时，可缓慢滴注4mg进行治疗。
（2）肾衰竭病人：不需调整剂量、用药次数或用药途径。
（3）肝脏衰竭病人：由于本品主要自肝脏代谢，对中度或严重肝功能衰竭病人每日用药剂量不应超过8mg。
静脉滴注时，本品在下述溶液中是稳定的（在室温或冰箱中可保持稳定1周）：0.9％氯化钠注射液、5％葡萄糖注射液、复方氯化钠注射液和10％甘露醇注射液，但本品仍应于临用前配制。
注意
本品对动物无致畸作用，但对人类无此经验，故应十分谨慎。怀孕期间（尤其头3个月）除非用药的益处大大超过可能引起的危险，否则不宜使用本品。由于本品可经乳汁分泌，故哺乳妇女服用本品时应停止哺乳。有过敏史或对本品过敏者不得使用。
常见副作用有头痛、头部和上腹部发热感、静坐不能、腹泻、发疹、急性张力障碍性反应、便秘等；部分病人可有短暂性氨基转移酶升高；罕见副作用有支气管痉挛、心动过速、胸痛、低钾血症、心电图改变和癫痫大发作。曾有即时过敏反应的报道。
ZOFRAN - ondansetron hydrochloride injection  
GlaxoSmithKline LLC
DESCRIPTION
The active ingredient in ZOFRAN Injection is ondansetron hydrochloride (HCl), the racemic form of ondansetron and a selective blocking agent of the serotonin 5-HT3 receptor type. Chemically it is (±) 1, 2, 3, 9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one, monohydrochloride, dihydrate. It has the following structural formula:

The empirical formula is C18H19N3O•HCl•2H2O, representing a molecular weight of 365.9.
Ondansetron HCl is a white to off-white powder that is soluble in water and normal saline.
Sterile Injection for Intravenous (I.V.) or Intramuscular (I.M.) Administration
Each 1 mL of aqueous solution in the 2-mL single-dose vial contains 2 mg of ondansetron as the hydrochloride dihydrate; 9.0 mg of sodium chloride, USP; and 0.5 mg of citric acid monohydrate, USP and 0.25 mg of sodium citrate dihydrate, USP as buffers in Water for Injection, USP.
Each 1 mL of aqueous solution in the 20-mL multidose vial contains 2 mg of ondansetron as the hydrochloride dihydrate; 8.3 mg of sodium chloride, USP; 0.5 mg of citric acid monohydrate, USP and 0.25 mg of sodium citrate dihydrate, USP as buffers; and 1.2 mg of methylparaben, NF and 0.15 mg of propylparaben, NF as preservatives in Water for Injection, USP.
ZOFRAN Injection is a clear, colorless, nonpyrogenic, sterile solution. The pH of the injection solution is 3.3 to 4.0.
CLINICAL PHARMACOLOGY
Pharmacodynamics 
Ondansetron is a selective 5-HT3 receptor antagonist. While ondansetron’s mechanism of action has not been fully characterized, it is not a dopamine-receptor antagonist. Serotonin receptors of the 5-HT3 type are present both peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone of the area postrema. It is not certain whether ondansetron's antiemetic action in chemotherapy-induced nausea and vomiting is mediated centrally, peripherally, or in both sites. However, cytotoxic chemotherapy appears to be associated with release of serotonin from the enterochromaffin cells of the small intestine. In humans, urinary 5-HIAA (5-hydroxyindoleacetic acid) excretion increases after cisplatin administration in parallel with the onset of vomiting. The released serotonin may stimulate the vagal afferents through the 5-HT3 receptors and initiate the vomiting reflex.
In animals, the emetic response to cisplatin can be prevented by pretreatment with an inhibitor of serotonin synthesis, bilateral abdominal vagotomy and greater splanchnic nerve section, or pretreatment with a serotonin 5-HT3 receptor antagonist.
In normal volunteers, single I.V. doses of 0.15 mg/kg of ondansetron had no effect on esophageal motility, gastric motility, lower esophageal sphincter pressure, or small intestinal transit time. In another study in six normal male volunteers, a 16-mg dose infused over 5 minutes showed no effect of the drug on cardiac output, heart rate, stroke volume, blood pressure, or electrocardiogram (ECG). Multiday administration of ondansetron has been shown to slow colonic transit in normal volunteers. Ondansetron has no effect on plasma prolactin concentrations.
In a gender-balanced pharmacodynamic study (n = 56), ondansetron 4 mg administered intravenously or intramuscularly was dynamically similar in the prevention of nausea and vomiting using the ipecacuanha model of emesis. 
Ondansetron does not alter the respiratory depressant effects produced by alfentanil or the degree of neuromuscular blockade produced by atracurium. Interactions with general or local anesthetics have not been studied.
Pharmacokinetics 
Ondansetron is extensively metabolized in humans, with approximately 5% of a radiolabeled dose recovered as the parent compound from the urine. The primary metabolic pathway is hydroxylation on the indole ring followed by glucuronide or sulfate conjugation.
Although some nonconjugated metabolites have pharmacologic activity, these are not found in plasma at concentrations likely to significantly contribute to the biological activity of ondansetron.
In vitro metabolism studies have shown that ondansetron is a substrate for human hepatic cytochrome P-450 enzymes, including CYP1A2, CYP2D6, and CYP3A4. In terms of overall ondansetron turnover, CYP3A4 played the predominant role. Because of the multiplicity of metabolic enzymes capable of metabolizing ondansetron, it is likely that inhibition or loss of one enzyme (e.g., CYP2D6 genetic deficiency) will be compensated by others and may result in little change in overall rates of ondansetron elimination. Ondansetron elimination may be affected by cytochrome P-450 inducers. In a pharmacokinetic study of 16 epileptic patients maintained chronically on CYP3A4 inducers, carbamazepine, or phenytoin, reduction in AUC, Cmax, and T½ of ondansetron was observed.1 This resulted in a significant increase in clearance. However, on the basis of available data, no dosage adjustment for ondansetron is recommended (see PRECAUTIONS: Drug Interactions).
In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron.
In normal adult volunteers, the following mean pharmacokinetic data have been determined following a single 0.15-mg/kg I.V. dose.
Table 1. Pharmacokinetics in Normal Adult Volunteers 

the mean elimination half-life was 4.0 hours, and there was no difference in the multidose pharmacokinetics over a 4-day period. In a study of 21 pediatric cancer patients (4 to 18 years of age) who received three I.V. doses of 0.15 mg/kg of ondansetron at 4-hour intervals, patients older than 15 years of age exhibited ondansetron pharmacokinetic parameters similar to those of adults. Patients 4 to 12 years of age generally showed higher clearance and somewhat larger volume of distribution than adults. Most pediatric patients younger than 15 years of age with cancer had a shorter (2.4 hours) ondansetron plasma half-life than patients older than 15 years of age. It is not known whether these differences in ondansetron plasma half-life may result in differences in efficacy between adults and some young pediatric patients (see CLINICAL TRIALS: Pediatric Studies). 
Pharmacokinetic samples were collected from 74 cancer patients 6 to 48 months of age, who received a dose of 0.15 mg/kg of I.V. ondansetron every 4 hours for 3 doses during a safety and efficacy trial. These data were combined with sequential pharmacokinetics data from 41 surgery patients 1 month to 24 months of age, who received a single dose of 0.1 mg/kg of I.V. ondansetron prior to surgery with general anesthesia, and a population pharmacokinetic analysis was performed on the combined data set. The results of this analysis are included in Table 2 and are compared to the pharmacokinetic results in cancer patients 4 to 18 years of age. 
Table 2. Pharmacokinetics in Pediatric Cancer Patients 1 Month to 18 Years of Age

a Population PK (Pharmacokinetic) Patients: 64% cancer patients and 36% surgery patients.
Based on the population pharmacokinetic analysis, cancer patients 6 to 48 months of age who receive a dose of 0.15 mg/kg of I.V. ondansetron every 4 hours for 3 doses would be expected to achieve a systemic exposure (AUC) consistent with the exposure achieved in previous pediatric studies in cancer patients (4 to 18 years of age) at similar doses. 
In a study of 21 pediatric patients (3 to 12 years of age) who were undergoing surgery requiring anesthesia for a duration of 45 minutes to 2 hours, a single I.V. dose of ondansetron, 2 mg (3 to 7 years) or 4 mg (8 to 12 years), was administered immediately prior to anesthesia induction. Mean weight-normalized clearance and volume of distribution values in these pediatric surgical patients were similar to those previously reported for young adults. Mean terminal half-life was slightly reduced in pediatric patients (range, 2.5 to 3 hours) in comparison with adults (range, 3 to 3.5 hours). 
In a study of 51 pediatric patients (1 month to 24 months of age) who were undergoing surgery requiring general anesthesia, a single I.V. dose of ondansetron, 0.1 or 0.2 mg/kg, was administered prior to surgery. As shown in Table 3, the 41 patients with pharmacokinetic data were divided into 2 groups, patients 1 month to 4 months of age and patients 5 to 24 months of age, and are compared to pediatric patients 3 to 12 years of age.
Table 3. Pharmacokinetics in Pediatric Surgery Patients 1 Month to 12 Years of Age

In general, surgical and cancer pediatric patients younger than 18 years tend to have a higher ondansetron clearance compared to adults leading to a shorter half-life in most pediatric patients. In patients 1 month to 4 months of age, a longer half-life was observed due to the higher volume of distribution in this age group.
In normal volunteers (19 to 39 years old, n = 23), the peak plasma concentration was 264 ng/mL following a single 32-mg dose administered as a 15-minute I.V. infusion. The mean elimination half-life was 4.1 hours. Systemic exposure to 32 mg of ondansetron was not proportional to dose as measured by comparing dose-normalized AUC values to an 8-mg dose. This is consistent with a small decrease in systemic clearance with increasing plasma concentrations.
A study was performed in normal volunteers (n = 56) to evaluate the pharmacokinetics of a single 4-mg dose administered as a 5-minute infusion compared to a single intramuscular injection. Systemic exposure as measured by mean AUC was equivalent, with values of 156 [95% CI 136, 180] and 161 [95% CI 137, 190] ng•h/mL for I.V. and I.M. groups, respectively. Mean peak plasma concentrations were 42.9 [95% CI 33.8, 54.4] ng/mL at 10 minutes after I.V. infusion and 31.9 [95% CI 26.3, 38.6] ng/mL at 41 minutes after I.M. injection. The mean elimination half-life was not affected by route of administration.
Plasma protein binding of ondansetron as measured in vitro was 70% to 76%, with binding constant over the pharmacologic concentration range (10 to 500 ng/mL). Circulating drug also distributes into erythrocytes.
A positive lymphoblast transformation test to ondansetron has been reported, which suggests immunologic sensitivity to ondansetron.
CLINICAL TRIALS
Chemotherapy-Induced Nausea and Vomiting 
Adult Studies: In a double-blind study of three different dosing regimens of ZOFRAN Injection, 0.015 mg/kg, 0.15 mg/kg, and 0.30 mg/kg, each given three times during the course of cancer chemotherapy, the 0.15-mg/kg dosing regimen was more effective than the 0.015-mg/kg dosing regimen. The 0.30-mg/kg dosing regimen was not shown to be more effective than the 0.15-mg/kg dosing regimen.
Cisplatin-Based Chemotherapy:In a double-blind study in 28 patients, ZOFRAN Injection (three 0.15-mg/kg doses) was significantly more effective than placebo in preventing nausea and vomiting induced by cisplatin-based chemotherapy. Treatment response was as shown in Table 4.
Table 4. Prevention of Chemotherapy-Induced Nausea and Vomiting in Single-Day Cisplatin Therapy a in Adults

a Chemotherapy was high dose (100 and 120 mg/m2; ZOFRAN Injection n = 6, placebo n = 5) or moderate dose (50 and 80 mg/m2; ZOFRAN Injection n = 8, placebo n = 9). Other chemotherapeutic agents included fluorouracil, doxorubicin, and cyclophosphamide. There was no difference between treatments in the types of chemotherapy that would account for differences in response.
b Efficacy based on "all patients treated" analysis.
c Median undefined since at least 50% of the patients were rescued or had more than five emetic episodes.
d Visual analog scale assessment of nausea: 0 = no nausea, 100 = nausea as bad as it can be.
e Visual analog scale assessment of satisfaction: 0 = not at all satisfied, 100 = totally satisfied.
Ondansetron was compared with metoclopramide in a single-blind trial in 307 patients receiving cisplatin ≥ 100 mg/m2 with or without other chemotherapeutic agents. Patients received the first dose of ondansetron or metoclopramide 30 minutes before cisplatin. Two additional ondansetron doses were administered 4 and 8 hours later, or five additional metoclopramide doses were administered 2, 4, 7, 10, and 13 hours later. Cisplatin was administered over a period of 3 hours or less. Episodes of vomiting and retching were tabulated over the period of 24 hours after cisplatin. The results of this study are summarized in Table 5.
Table 5. Prevention of Vomiting Induced by Cisplatin (≥ 100 mg/m 2) Single-Day Therapy a in Adults

a In addition to cisplatin, 68% of patients received other chemotherapeutic agents, including cyclophosphamide, etoposide, and fluorouracil. There was no difference between treatments in the types of chemotherapy that would account for differences in response.
b Visual analog scale assessment: 0 = not at all satisfied, 100 = totally satisfied.
In a stratified, randomized, double-blind, parallel-group, multicenter study, a single 32-mg dose of ondansetron was compared with three 0.15-mg/kg doses in patients receiving cisplatin doses of either 50 to 70 mg/m2 or ≥ 100 mg/m2. Patients received the first ondansetron dose 30 minutes before cisplatin. Two additional ondansetron doses were administered 4 and 8 hours later to the group receiving three 0.15-mg/kg doses. In both strata, significantly fewer patients on the single 32-mg dose than those receiving the three-dose regimen failed.
Table 6. Prevention of Chemotherapy-Induced Nausea and Vomiting in Single-Dose Therapy in Adults 

a Visual analog scale assessment: 0 = no nausea, 100 = nausea as bad as it can be.
b Median undefined since at least 50% of patients did not have any emetic episodes.
Cyclophosphamide-Based Chemotherapy:  In a double-blind, placebo-controlled study of ZOFRAN Injection (three 0.15-mg/kg doses) in 20 patients receiving cyclophosphamide (500 to 600 mg/m2) chemotherapy, ZOFRAN Injection was significantly more effective than placebo in preventing nausea and vomiting. The results are summarized in Table 7.
Table 7. Prevention of Chemotherapy-Induced Nausea and Vomiting in Single-Day Cyclophosphamide Therapy a in Adults

a Chemotherapy consisted of cyclophosphamide in all patients, plus other agents, including fluorouracil, doxorubicin, methotrexate, and vincristine. There was no difference between treatments in the type of chemotherapy that would account for differences in response.
b Efficacy based on "all patients treated" analysis.
c Median undefined since at least 50% of patients did not have any emetic episodes.
d Visual analog scale assessment of nausea: 0 = no nausea, 100 = nausea as bad as it can be.
e Visual analog scale assessment of satisfaction: 0 = not at all satisfied, 100 = totally satisfied.
Re-treatment: In uncontrolled trials, 127 patients receiving cisplatin (median dose, 100 mg/m2) and ondansetron who had two or fewer emetic episodes were re-treated with ondansetron and chemotherapy, mainly cisplatin, for a total of 269 re-treatment courses (median, 2; range, 1 to 10). No emetic episodes occurred in 160 (59%), and two or fewer emetic episodes occurred in 217 (81%) re-treatment courses.
Pediatric Studies:Four open-label, noncomparative (one US, three foreign) trials have been performed with 209 pediatric cancer patients 4 to 18 years of age given a variety of cisplatin or noncisplatin regimens. In the three foreign trials, the initial ZOFRAN Injection dose ranged from 0.04 to 0.87 mg/kg for a total dose of 2.16 to 12 mg. This was followed by the oral administration of ondansetron ranging from 4 to 24 mg daily for 3 days. In the US trial, ZOFRAN was administered intravenously (only) in three doses of 0.15 mg/kg each for a total daily dose of 7.2 to 39 mg. In these studies, 58% of the 196 evaluable patients had a complete response (no emetic episodes) on day 1. Thus, prevention of vomiting in these pediatric patients was essentially the same as for patients older than 18 years of age. 
An open-label, multicenter, noncomparative trial has been performed in 75 pediatric cancer patients 6 to 48 months of age receiving at least one moderately or highly emetogenic chemotherapeutic agent. Fifty-seven percent (57%) were females; 67% were white, 18% were American Hispanic, and 15% were black patients. ZOFRAN was administered intravenously over 15 minutes in three doses of 0.15 mg/kg. The first dose was administered 30 minutes before the start of chemotherapy, the second and third doses were administered 4 and 8 hours after the first dose, respectively. Eighteen patients (25%) received routine prophylactic dexamethasone (i.e., not given as rescue). Of the 75 evaluable patients, 56% had a complete response (no emetic episodes) on day 1. Thus, prevention of vomiting in these pediatric patients was comparable to the prevention of vomiting in patients 4 years of age and older.
Postoperative Nausea and Vomiting: Prevention of Postoperative Nausea and Vomiting 
Adult Studies:Adult surgical patients who received ondansetron immediately before the induction of general balanced anesthesia (barbiturate: thiopental, methohexital, or thiamylal; opioid: alfentanil or fentanyl; nitrous oxide; neuromuscular blockade: succinylcholine/curare and/or vecuronium or atracurium; and supplemental isoflurane) were evaluated in two double-blind US studies involving 554 patients. ZOFRAN Injection (4 mg) I.V. given over 2 to 5 minutes was significantly more effective than placebo. The results of these studies are summarized in Table 8.
Table 8. Prevention of Postoperative Nausea and Vomiting in Adult Patients 

The study populations in Table 8 consisted mainly of females undergoing laparoscopic procedures.
In a placebo-controlled study conducted in 468 males undergoing outpatient procedures, a single 4-mg I.V. ondansetron dose prevented postoperative vomiting over a 24-hour study period in 79% of males receiving drug compared to 63% of males receiving placebo (P < 0.001). 
Two other placebo-controlled studies were conducted in 2,792 patients undergoing major abdominal or gynecological surgeries to evaluate a single 4-mg or 8-mg I.V. ondansetron dose for prevention of postoperative nausea and vomiting over a 24-hour study period. At the 4-mg dosage, 59% of patients receiving ondansetron versus 45% receiving placebo in the first study (P < 0.001) and 41% of patients receiving ondansetron versus 30% receiving placebo in the second study (P = 0.001) experienced no emetic episodes. No additional benefit was observed in patients who received I.V. ondansetron 8 mg compared to patients who received I.V. ondansetron 4 mg.
Pediatric Studies: Three double-blind, placebo-controlled studies have been performed (one US, two foreign) in 1,049 male and female patients (2 to 12 years of age) undergoing general anesthesia with nitrous oxide. The surgical procedures included tonsillectomy with or without adenoidectomy, strabismus surgery, herniorrhaphy, and orchidopexy. Patients were randomized to either single I.V. doses of ondansetron (0.1 mg/kg for pediatric patients weighing 40 kg or less, 4 mg for pediatric patients weighing more than 40 kg) or placebo. Study drug was administered over at least 30 seconds, immediately prior to or following anesthesia induction. Ondansetron was significantly more effective than placebo in preventing nausea and vomiting. The results of these studies are summarized in Table 9.
Table 9. Prevention of Postoperative Nausea and Vomiting in Pediatric Patients 2 to 12 Years of Age 

a Failure was one or more emetic episodes, rescued, or withdrawn.
b Nausea measured as none, mild, or severe.
A double-blind, multicenter, placebo-controlled study was conducted in 670 pediatric patients 1 month to 24 months of age who were undergoing routine surgery under general anesthesia. Seventy-five percent (75%) were males; 64% were white, 15% were black, 13% were American Hispanic, 2% were Asian, and 6% were “other race” patients. A single 0.1-mg/kg I.V. dose of ondansetron administered within 5 minutes following induction of anesthesia was statistically significantly more effective than placebo in preventing vomiting. In the placebo group, 28% of patients experienced vomiting compared to 11% of subjects who received ondansetron (P ≤ 0.01). Overall, 32 (10%) of placebo patients and 18 (5%) of patients who received ondansetron received antiemetic rescue medication(s) or prematurely withdrew from the study. 
Prevention of Further Postoperative Nausea and Vomiting 
Adult Studies: Adult surgical patients receiving general balanced anesthesia (barbiturate: thiopental, methohexital, or thiamylal; opioid: alfentanil or fentanyl; nitrous oxide; neuromuscular blockade: succinylcholine/curare and/or vecuronium or atracurium; and supplemental isoflurane) who received no prophylactic antiemetics and who experienced nausea and/or vomiting within 2 hours postoperatively were evaluated in two double-blind US studies involving 441 patients. Patients who experienced an episode of postoperative nausea and/or vomiting were given ZOFRAN Injection (4 mg) I.V. over 2 to 5 minutes, and this was significantly more effective than placebo. The results of these studies are summarized in Table 10.
Table 10. Prevention of Further Postoperative Nausea and Vomiting in Adult Patients

a After administration of study drug.
b Nausea measured on a scale of 0-10 with 0 = no nausea, 10 = nausea as bad as it can be.
The study populations in Table 10 consisted mainly of women undergoing laparoscopic procedures.
Repeat Dosing in Adults: In patients who do not achieve adequate control of postoperative nausea and vomiting following a single, prophylactic, preinduction, I.V. dose of ondansetron 4 mg, administration of a second I.V. dose of ondansetron 4 mg postoperatively does not provide additional control of nausea and vomiting.
Pediatric Study: One double-blind, placebo-controlled, US study was performed in 351 male and female outpatients (2 to 12 years of age) who received general anesthesia with nitrous oxide and no prophylactic antiemetics. Surgical procedures were unrestricted. Patients who experienced two or more emetic episodes within 2 hours following discontinuation of nitrous oxide were randomized to either single I.V. doses of ondansetron (0.1 mg/kg for pediatric patients weighing 40 kg or less, 4 mg for pediatric patients weighing more than 40 kg) or placebo administered over at least 30 seconds. Ondansetron was significantly more effective than placebo in preventing further episodes of nausea and vomiting. The results of the study are summarized in Table 11.
Table 11. Prevention of Further Postoperative Nausea and Vomiting in Pediatric Patients 2 to 12 Years of Age 

a Failure was one or more emetic episodes, rescued, or withdrawn.
INDICATIONS AND USAGE
Prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including high-dose cisplatin. Efficacy of the 32-mg single dose beyond 24 hours in these patients has not been established. 
Prevention of postoperative nausea and/or vomiting. As with other antiemetics, routine prophylaxis is not recommended for patients in whom there is little expectation that nausea and/or vomiting will occur postoperatively. In patients where nausea and/or vomiting must be avoided postoperatively, ZOFRAN Injection is recommended even where the incidence of postoperative nausea and/or vomiting is low. For patients who do not receive prophylactic ZOFRAN Injection and experience nausea and/or vomiting postoperatively, ZOFRAN Injection may be given to prevent further episodes (see CLINICAL TRIALS). 
CONTRAINDICATIONS
ZOFRAN Injection is contraindicated for patients known to have hypersensitivity to the drug.
WARNINGS
Hypersensitivity reactions have been reported in patients who have exhibited hypersensitivity to other selective 5-HT3 receptor antagonists.
PRECAUTIONS
General 
Ondansetron is not a drug that stimulates gastric or intestinal peristalsis. It should not be used instead of nasogastric suction. The use of ondansetron in patients following abdominal surgery or in patients with chemotherapy-induced nausea and vomiting may mask a progressive ileus and/or gastric distention.
Rarely and predominantly with intravenous ondansetron, transient ECG changes including QT interval prolongation have been reported.
Drug Interactions 
Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver (see CLINICAL PHARMACOLOGY: Pharmacokinetics). Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. 
Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 
Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 
Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron.
In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate.
Carcinogenesis, Mutagenesis, Impairment of Fertility 
Carcinogenic effects were not seen in 2-year studies in rats and mice with oral ondansetron doses up to 10 and 30 mg/kg per day, respectively. Ondansetron was not mutagenic in standard tests for mutagenicity. Oral administration of ondansetron up to 15 mg/kg per day did not affect fertility or general reproductive performance of male and female rats.
Pregnancy 
Teratogenic Effects:  Pregnancy Category B. Reproduction studies have been performed in pregnant rats and rabbits at I.V. doses up to 4 mg/kg per day and have revealed no evidence of impaired fertility or harm to the fetus due to ondansetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Nursing Mothers 
Ondansetron is excreted in the breast milk of rats. It is not known whether ondansetron is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ondansetron is administered to a nursing woman.
Pediatric Use 
Little information is available about the use of ondansetron in pediatric surgical patients younger than 1 month of age. (See CLINICAL TRIALS section for studies of ondansetron in prevention of postoperative nausea and vomiting in patients 1 month of age and older.) Little information is available about the use of ondansetron in pediatric cancer patients younger than 6 months of age. (See CLINICAL TRIALS section for studies of ondansetron in chemotherapy-induced nausea and vomiting in pediatric patients 6 months of age and older.) (See DOSAGE AND ADMINISTRATION.)
The clearance of ondansetron in pediatric patients 1 month to 4 months of age is slower and the half-life is ~2.5 fold longer than patients who are > 4 to 24 months of age. As a precaution, it is recommended that patients less than 4 months of age receiving this drug be closely monitored. (See CLINICAL PHARMACOLOGY: Pharmacokinetics).
The frequency and type of adverse events reported in pediatric patients receiving ondansetron were similar to those in patients receiving placebo. (See ADVERSE EVENTS.)
Geriatric Use 
Of the total number of subjects enrolled in cancer chemotherapy-induced and postoperative nausea and vomiting in US- and foreign-controlled clinical trials, 862 were 65 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Dosage adjustment is not needed in patients over the age of 65 (see CLINICAL PHARMACOLOGY).
ADVERSE REACTIONS
Chemotherapy-Induced Nausea and Vomiting 
The adverse events in Table 12 have been reported in adults receiving ondansetron at a dosage of three 0.15-mg/kg doses or as a single 32-mg dose in clinical trials. These patients were receiving concomitant chemotherapy, primarily cisplatin, and I.V. fluids. Most were receiving a diuretic.
Table 12. Principal Adverse Events in Comparative Trials in Adults 

a See Neurological.
The following have been reported during controlled clinical trials:
Cardiovascular: Rare cases of angina (chest pain), electrocardiographic alterations, hypotension, and tachycardia have been reported. In many cases, the relationship to ZOFRAN Injection was unclear.
Gastrointestinal: Constipation has been reported in 11% of chemotherapy patients receiving multiday ondansetron.
Hepatic: In comparative trials in cisplatin chemotherapy patients with normal baseline values of aspartate transaminase (AST) and alanine transaminase (ALT), these enzymes have been reported to exceed twice the upper limit of normal in approximately 5% of patients. The increases were transient and did not appear to be related to dose or duration of therapy. On repeat exposure, similar transient elevations in transaminase values occurred in some courses, but symptomatic hepatic disease did not occur.
Integumentary: Rash has occurred in approximately 1% of patients receiving ondansetron.
Neurological: There have been rare reports consistent with, but not diagnostic of, extrapyramidal reactions in patients receiving ZOFRAN Injection, and rare cases of grand mal seizure. The relationship to ZOFRAN was unclear.
Other: Rare cases of hypokalemia have been reported. The relationship to ZOFRAN Injection was unclear.
Postoperative Nausea and Vomiting 
The adverse events in Table 13 have been reported in ≥ 2% of adults receiving ondansetron at a dosage of 4 mg I.V. over 2 to 5 minutes in clinical trials. Rates of these events were not significantly different in the ondansetron and placebo groups. These patients were receiving multiple concomitant perioperative and postoperative medications.
Table 13. Adverse Events in ≥ 2% of Adults Receiving Ondansetron at a Dosage of 4 mg I.V. over 2 to 5 Minutes in Clinical Trials 

a Sites of pain included abdomen, stomach, joints, rib cage, shoulder.
Pediatric Use: The adverse events in Table 14  were the most commonly reported adverse events in pediatric patients receiving ondansetron (a single 0.1-mg/kg dose for pediatric patients weighing 40 kg or less, or 4 mg for pediatric patients weighing more than 40 kg) administered intravenously over at least 30 seconds. Rates of these events were not significantly different in the ondansetron and placebo groups. These patients were receiving multiple concomitant perioperative and postoperative medications.
Table 14. Frequency of Adverse Events From Controlled Studies in Pediatric Patients 2 to 12 Years of Age 

The adverse events in Table 15 were the most commonly reported adverse events in pediatric patients, 1 month to 24 months of age, receiving a single 0.1-mg/kg I.V. dose of ondansetron. The incidence and type of adverse events were similar in both the ondansetron and placebo groups. These patients were receiving multiple concomitant perioperative and postoperative medications.
Table 15. Frequency of Adverse Events (Greater Than or Equal to 2% in Either Treatment Group) in Pediatric Patients 1 Month to 24 Months of Age

Observed During Clinical Practice 
In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of intravenous formulations of ZOFRAN. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to ZOFRAN.
Cardiovascular: Arrhythmias (including ventricular and supraventricular tachycardia, premature ventricular contractions, and atrial fibrillation), bradycardia, electrocardiographic alterations (including second-degree heart block, QT interval prolongation, and ST segment depression), palpitations, and syncope.
General: Flushing. Rare cases of hypersensitivity reactions, sometimes severe (e.g., anaphylaxis/anaphylactoid reactions, angioedema, bronchospasm, cardiopulmonary arrest, hypotension, laryngeal edema, laryngospasm, shock, shortness of breath, stridor) have also been reported.
Hepatobiliary: Liver enzyme abnormalities have been reported. Liver failure and death have been reported in patients with cancer receiving concurrent medications including potentially hepatotoxic cytotoxic chemotherapy and antibiotics. The etiology of the liver failure is unclear. 
Local Reactions: Pain, redness, and burning at site of injection.
Lower Respiratory: Hiccups
Neurological: Oculogyric crisis, appearing alone, as well as with other dystonic reactions. 
Skin: Urticaria
Special Senses: Transient dizziness during or shortly after I.V. infusion.
Eye Disorders:Transient blurred vision, in some cases associated with abnormalities of accommodation. Cases of transient blindness, predominantly during intravenous administration, have been reported. These cases of transient blindness were reported to resolve within a few minutes up to 48 hours.
DRUG ABUSE AND DEPENDENCE
Animal studies have shown that ondansetron is not discriminated as a benzodiazepine nor does it substitute for benzodiazepines in direct addiction studies.
OVERDOSAGE
There is no specific antidote for ondansetron overdose. Patients should be managed with appropriate supportive therapy. Individual doses as large as 150 mg and total daily dosages (three doses) as large as 252 mg have been administered intravenously without significant adverse events. These doses are more than 10 times the recommended daily dose.
In addition to the adverse events listed above, the following events have been described in the setting of ondansetron overdose: “Sudden blindness” (amaurosis) of 2 to 3 minutes’ duration plus severe constipation occurred in one patient that was administered 72 mg of ondansetron intravenously as a single dose. Hypotension (and faintness) occurred in another patient that took 48 mg of oral ondansetron. Following infusion of 32 mg over only a 4-minute period, a vasovagal episode with transient second-degree heart block was observed. In all instances, the events resolved completely.
DOSAGE AND ADMINISTRATION
Prevention of Chemotherapy-Induced Nausea and Vomiting 
Adult Dosing:The recommended I.V. dosage of ZOFRAN for adults is a single 32-mg dose or three 0.15-mg/kg doses. A single 32-mg dose is infused over 15 minutes beginning 30 minutes before the start of emetogenic chemotherapy. The recommended infusion rate should not be exceeded (see OVERDOSAGE). With the three-dose (0.15-mg/kg) regimen, the first dose is infused over 15 minutes beginning 30 minutes before the start of emetogenic chemotherapy. Subsequent doses (0.15 mg/kg) are administered 4 and 8 hours after the first dose of ZOFRAN.
ZOFRAN Injection should not be mixed with solutions for which physical and chemical compatibility have not been established. In particular, this applies to alkaline solutions as a precipitate may form.
Vial: DILUTE BEFORE USE FOR PREVENTION OF CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING. ZOFRAN Injection should be diluted in 50 mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection before administration.
Pediatric Dosing:On the basis of the available information (see CLINICAL TRIALS: Pediatric Studies and CLINICAL PHARMACOLOGY: Pharmacokinetics), the dosage in pediatric cancer patients 6 months to 18 years of age should be three 0.15-mg/kg doses. The first dose is to be administered 30 minutes before the start of moderately to highly emetogenic chemotherapy, subsequent doses (0.15 mg/kg) are administered 4 and 8 hours after the first dose of ZOFRAN. The drug should be infused intravenously over 15 minutes. Little information is available about dosage in pediatric cancer patients younger than 6 months of age.
Vial:DILUTE BEFORE USE FOR PREVENTION OF CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING. ZOFRAN Injection should be diluted in 50 mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection before administration.
Geriatric Dosing: The dosage recommendation is the same as for the general population.
Prevention of Postoperative Nausea and Vomiting 
Adult Dosing: The recommended I.V. dosage of ZOFRAN for adults is 4 mg undiluted administered intravenously in not less than 30 seconds, preferably over 2 to 5 minutes, immediately before induction of anesthesia, or postoperatively if the patient experiences nausea and/or vomiting occurring shortly after surgery. Alternatively, 4 mg undiluted may be administered intramuscularly as a single injection for adults. While recommended as a fixed dose for patients weighing more than 40 kg, few patients above 80 kg have been studied. In patients who do not achieve adequate control of postoperative nausea and vomiting following a single, prophylactic, preinduction, I.V. dose of ondansetron 4 mg, administration of a second I.V. dose of 4 mg ondansetron postoperatively does not provide additional control of nausea and vomiting.
Vial:REQUIRES NO DILUTION FOR ADMINISTRATION FOR POSTOPERATIVE NAUSEA AND VOMITING.
Pediatric Dosing: The recommended I.V. dosage of ZOFRAN for pediatric surgical patients (1 month to 12 years of age) is a single 0.1-mg/kg dose for patients weighing 40 kg or less, or a single 4-mg dose for patients weighing more than 40 kg. The rate of administration should not be less than 30 seconds, preferably over 2 to 5 minutes immediately prior to or following anesthesia induction, or postoperatively if the patient experiences nausea and/or vomiting occurring shortly after surgery. Prevention of further nausea and vomiting was only studied in patients who had not received prophylactic ZOFRAN.
Vial:REQUIRES NO DILUTION FOR ADMINISTRATION FOR POSTOPERATIVE NAUSEA AND VOMITING.
Geriatric Dosing: The dosage recommendation is the same as for the general population.
Dosage Adjustment for Patients With Impaired Renal Function 
The dosage recommendation is the same as for the general population. There is no experience beyond first-day administration of ondansetron.
Dosage Adjustment for Patients With Impaired Hepatic Function 
In patients with severe hepatic impairment (Child-Pugh2 score of 10 or greater), a single maximal daily dose of 8 mg to be infused over 15 minutes beginning 30 minutes before the start of the emetogenic chemotherapy is recommended. There is no experience beyond first-day administration of ondansetron.
Stability 
ZOFRAN Injection is stable at room temperature under normal lighting conditions for 48 hours after dilution with the following I.V. fluids: 0.9% Sodium Chloride Injection, 5% Dextrose Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, 5% Dextrose and 0.45% Sodium Chloride Injection, and 3% Sodium Chloride Injection.
Although ZOFRAN Injection is chemically and physically stable when diluted as recommended, sterile precautions should be observed because diluents generally do not contain preservative. After dilution, do not use beyond 24 hours.
Note: Parenteral drug products should be inspected visually for particulate matter and discoloration before administration whenever solution and container permit.
Precaution: Occasionally, ondansetron precipitates at the stopper/vial interface in vials stored upright. Potency and safety are not affected. If a precipitate is observed, resolubilize by shaking the vial vigorously.
HOW SUPPLIED
ZOFRAN Injection, 2 mg/mL, is supplied as follows:
NDC 0173-0442-02     2-mL single-dose vials (Carton of 5)
NDC 0173-0442-00     20-mL multidose vials (Singles)
Store between 2° and 30°C (36° and 86°F). Protect from light. 
REFERENCES
Britto MR, Hussey EK, Mydlow P, et al. Effect of enzyme inducers on ondansetron (OND) metabolism in humans. Clin Pharmacol Ther. 1997;61:228. 
Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Brit J Surg.  1973;60:646-649. 
Villikka K, Kivisto KT, Neuvonen PJ. The effect of rifampin on the pharmacokinetics of oral and intravenous ondansetron. Clin Pharmacol Ther. 1999;65:377-381. 
De Witte JL, Schoenmaekers B, Sessler DI, et al. Anesth Analg. 2001;92:1319-1321. 
Arcioni R, della Rocca M, Romanò R, et al. Anesth Analg. 2002;94:1553-1557. 
止吐剂Zofran（昂丹司琼）修订心脏风险警示
止吐剂Zofran（昂丹司琼）正在进行的安全性审查和标签更改事宜，告知医护专业人员和患者，昂丹司琼可能延长心电图QT间期，这可能导致一种异常和潜在致命危险的心脏节律，包括尖端扭转型室性心动过速。那些有潜在心脏疾病，如先天性长QT综合征的患者出现尖端扭转型室性心动过速特别危险。
FDA要求生产厂商葛兰素史克进行一项缜密的QT研究，以确定昂丹司琼导致QT间期延长的程度。目前FDA正在对昂丹司琼的标签作修订，包括警告先天性长QT综合征患者避免使用，因为这类患者尖端扭转型室性心动过速风险特别严重。
美国上市的（40mg/20mL注射剂）资料附件：http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d9a71b42-ddfc-49d5-7280-0fc0041dba41
日本上市（2毫克和4毫克）的资料附件http://www.info.pmda.go.jp/go/pack/2391401A1026_1_09/2391401A1026_1_09?view=body#33
---------------------------------------------------------
产地国家: 美国
原产地英文商品名:
Zofran 40mg/20ml/vials
原产地英文药品名:
Ondansetron Hydrochloride Hydrate
中文参考商品译名:
枢复宁注射液 40毫克/20毫升/瓶
中文参考药品译名:
盐酸恩丹西酮水
生产厂家中文参考译名:
葛兰素史克
生产厂家英文名:
GlaxoSmithKline

---------------------------------------------------------
产地国家: 美国
原产地英文商品名:
Zofran 2mg/ml/vials 5vials
原产地英文药品名:
Ondansetron Hydrochloride Hydrate
中文参考商品译名:
枢复宁注射液 2毫克/毫升/瓶 5瓶/盒
中文参考药品译名:
盐酸恩丹西酮
生产厂家中文参考译名:
葛兰素史克
生产厂家英文名:
GlaxoSmithKline
--------------------------------------------------------
产地国家: 美国
原产地英文商品名:
Zofran 20mg/ml/vials
原产地英文药品名:
Ondansetron Hydrochloride Hydrate
中文参考商品译名:
枢复宁注射液 20毫克/毫升/瓶
中文参考药品译名:
盐酸恩丹西酮
生产厂家中文参考译名:
葛兰素史克
生产厂家英文名:
GlaxoSmithKline
------------------------------------------------------
产地国家: 日本
原产地英文商品名:
Zofran Injection(ゾフラン注)2mg/1ml/vials  5vials/box
原产地英文药品名:
Ondansetron Hydrochloride Hydrate
中文参考商品译名:
枢复宁(ゾフラン注)2毫克/1毫升/瓶 5瓶/盒
中文参考药品译名:
盐酸恩丹西酮水合物
生产厂家中文参考译名:
葛兰素史克
生产厂家英文名:
GlaxoSmithKline

    
----------------------------------------------------------
产地国家: 日本
原产地英文商品名:
Zofran Injection(ゾフラン注)4mg/2ml/vials  5vials/box
原产地英文药品名:
Ondansetron Hydrochloride Hydrate
中文参考商品译名:
枢复宁(ゾフラン注)4毫克/2毫升/瓶 5瓶/盒
中文参考药品译名:
盐酸恩丹西酮水合物
生产厂家中文参考译名:
葛兰素史克
生产厂家英文名:
GlaxoSmithKline

1Few patients above 80 kg have been studied.

2Administration of a second intravenous dose of 4 mg ondansetron postoperatively in adult patients who received a 4 mg prophylactic dose does not provide additional control of nausea and vomiting [see ClinicalStudies (14.3)].

3For pediatric patients (1 month to 12 years) prevention of nausea and vomiting was only studied in patients who had not received prophylactic ondansetron.

Population 

Recommended Single Dose 

Administration Instructions 

Timing of Administration 

Adults and pediatric patients older than 
12 years of age 

4 mg1 

May be administered intravenously or intramuscularly: 
•  Intravenously: infuse undiluted syringe 
contents (4 mg) over at least 30 seconds and 
preferably longer (over 2 to 5 minutes).
•  Intramuscularly: inject undiluted syringe contents (4 mg)

Administer immediately before induction of  anesthesia, or 
postoperatively if the patient did not receive 
prophylactic antiemetics and experiences nausea 
and/or vomiting occurring within 2 hours after surgery2,3

Pediatric patients 
1 month to 12 years 
and more than 40 kg

4 mg

Infuse intravenously over at least 
30 seconds and preferably longer 
(over 2 to 5 minutes).

Pediatric patients 
1 month to 12 years 
and 40 kg or less

0.1 mg/kg

Infuse intravenously over at least 
30 seconds and preferably longer 
(over 2 to 5 minutes).

Number of  Adult Patients with Reaction 

Adverse Reaction 

Ondansetron Injection   
0.15 mg/kg x 3 
(n = 419) 

Metoclopramide 
(n = 156) 

Placebo 
(n = 34) 

Diarrhea

16 %

44 %

18 %

Headache

17 %

7 %

15 %

Fever

8 %

5 %

3 %

a Adverse reactions: Rates of these reactions were not significantly different in the ondansetron and placebo groups.

b Patients were receiving multiple concomitant perioperative and postoperative medications.

Adverse Reactiona,b 

Ondansetron Injection 4 mg Intravenous  
(n = 547) 

Placebo 
(n = 547) 

Headache

92 (17 %)

7
 (14 %)

Drowsiness/sedation

44 (8 %)

37 (7 %)

Injection site reaction

21 (4 %)

18 (3%)

Fever

10 (2 %)

6 (1%)

Cold sensation

9 (2 %)

8 (1%)

Pruritus

9 (2 %)

3 (<1%)

Paresthesia

9 (2 %)

2 (<1 %)

Age-group (years) 

n 

Peak Plasma Concentration  
(ng/mL) 

Mean Elimination Half-life  
(h) 

Plasma Clearance 
(L/h/kg) 

19 to 40

11

102

3.5

0.381

61 to 74

12

106

4.7

0.319

(75

11

170

5.5

0.262

a Population PK (Pharmacokinetic) Patients: 64% cancer patients and 36% surgery patients.

Subjects and Age-group 

N 

CL 
(L/h/kg) 

Vdss 
(L/kg) 

t½ 
(h) 

Geometric Mean 

Mean 

Pediatric Cancer Patients
4 to 18 years

N = 21

0.599

1.9

2.8

Population PK Patientsa
1 month to 48 months

N = 115

0.582

3.65

4.9

Subjects and Age-group  

N 

CL 
(L/h/kg) 

Vdss (L/kg) 

t½ 
(h) 

Geometric Mean 

Mean 

Pediatric Surgery Patients 
3 to 12 years

N = 21

0.439

1.65

2.9

Pediatric Surgery Patients 
5 to 24 months 

N = 22

0.581

2.3

2.9

Pediatric Surgery Patients
1 month to 4 months

N = 19

0.401

3.5

6.7

aChemotherapy was high dose (100 and 120 mg/m2; Ondansetron Injection n = 6, placebo n = 5) or moderate dose (50 and 80 mg/m2; Ondansetron Injection n = 8, placebo n = 9). Other chemotherapeutic agents included fluorouracil, doxorubicin, and cyclophosphamide. There was no difference between treatments in the types of chemotherapy that would account for differences in response.

bEfficacy based on “all-patients-treated” analysis.

cMedian undefined since at least 50% of the patients were rescued or had more than five emetic episodes.

dVisual analog scale assessment of nausea: 0 = no nausea, 100 = nausea as bad as it can be.

eVisual analog scale assessment of satisfaction: 0 = not at all satisfied, 100 = totally satisfied.

Ondansetron Injection 
(0.15 mg/kg x 3) 

Placebo 

P Valueb 

Number of patients 

14 

14 

Treatment response

   0 Emetic episodes

2 (14%)

0 (0%)

   1 to 2 Emetic episodes

8 (57%)

0 (0%)

   3 to 5 Emetic episodes

2 (14%)

1 (7%)

   More than 5 emetic episodes/rescued 

2 (14%)

13 (93%)

0.001 

Median number of emetic episodes  

1.5 

Undefinedc 

Median time to first emetic episode (h) 

11.6

2.8

0.001

Median nausea scores (0 to 100)d 

3

59

0.034

Global satisfaction with control 
of nausea and vomiting (0 to 100)e

96

10.5

0.009

a In addition to cisplatin, 68% of patients received other chemotherapeutic agents, including cyclophosphamide, etoposide, and fluorouracil. There was no difference between treatments in the types of chemotherapy that would account for differences in response.

b Visual analog scale assessment: 0 = not at all satisfied, 100 = totally satisfied.

Ondansetron Injection 
(0.15 mg/kg x 3) 

Metoclopramide 
(2 mg/kg x 6) 

P Value 

Number of patients in efficacy population  

136 

138 

Treatment response

   0 Emetic episodes

54 (40%)

41 (30%)

   1 to 2 Emetic episode

34 (25%)

30 (22%)

   3 to 5 Emetic episodes

19 (14%)

18 (13%)

More than 5 emetic episodes/rescued 

29 (21%)

49 (36%)

Comparison of treatments with respect to
   0 Emetic episodes

54/136

41/138

0.083

   More than 5 emetic episodes/rescued

29/136

49/138

0.009

Median number of emetic episodes  

1

2

0.005

Median time to first emetic episode (h) 

20.5

4.3

< 0.001

Global satisfaction with control of nausea 
and vomiting (0 to 100)b 

85

63

0.001

Acute dystonic reactions 

0

8

0.005

Akathisia

0

10

0.002

aChemotherapy consisted of cyclophosphamide in all patients, plus other agents, including fluorouracil, doxorubicin, methotrexate, and vincristine. There was no difference between treatments in the type of chemotherapy that would account for differences in response.

bEfficacy based on “all-patients-treated” analysis.

cMedian undefined since at least 50% of patients did not have any emetic episodes.

d Visual analog scale assessment of nausea: 0 = no nausea, 100 = nausea as bad as it can be.

e Visual analog scale assessment of satisfaction: 0 = not at all satisfied, 100 = totally satisfied.

Ondansetron Injection 
(0.15 mg/kg x 3) 

Placebo 

P Valueb 

Number of patients

10

10

Treatment response

   0 Emetic episodes

7 (70%)

0 (0%)

0.001

   1 to 2 Emetic episodes

0 (0%)

2 (20%)

   3 to 5 Emetic episodes

2 (20%)

4 (40%)

   More than 5 emetic episodes/rescued

1 (10%)

4 (40%)

0.131

Median number of emetic episodes

0

4

0.008

Median time to first emetic episode (h)

Undefinedc

8.79

Median nausea scores (0 to 100) d

0

60

0.001

Global satisfaction with control of nausea 
and vomiting (0 to 100)e

100

52

0.008

Ondansetron 
4 mg Intravenous 

Placebo 

P Value 

Study 1 

Emetic episodes:

Number of patients

136

139

Treatment response over 24-h
postoperative period

   0 Emetic episodes

103 (76%)

64 (46%)

< 0.001

   1 Emetic episode

13 (10%)

17 (12%)

   More than 1 emetic episode/rescued

20 (15%)

58 (42%)

Nausea assessments:

Number of patients

134

136

No nausea over 24-h postoperative period 

56 (42%)

39 (29%)

Study 2 

Emetic episodes:

Number of patients

136

143

Treatment response over 24-h
postoperative period

   0 Emetic episodes

85 (63%)

63 (44%)

0.002

   1 Emetic episode

16 (12%)

29 (20%)

   More than 1 emetic episode/rescued

35 (26%)

51 (36%)

Nausea assessments:

Number of patients

125

133

No nausea over 24-h postoperative period

48 (38%)

42 (32%)

a Failure was one or more emetic episodes, rescued, or withdrawn.

b Nausea measured as none, mild, or severe.

Treatment Response Over 24 Hours 

Ondansetron 
n (%) 

Placebo 
n (%) 

P Value 

Study 1 
Number of patients
0 Emetic episodes
Failurea

205
140 (68%)
65 (32%)

210
82 (39%)
128 (61%)

≤ 0.001

Study 2 
Number of patients
0 Emetic episodes
Failurea

112
68 (61%)
44 (39%)

110
38 (35%)
72 (65%)

≤ 0.001

Study 3 
Number of patients
0 Emetic episodes
Failurea

206
123 (60%)
83 (40%)

206
96 (47%)
110 (53%)

≤ 0.01

Nausea assessmentsb:
Number of patients
None

185
119 (64%)

191
99 (52%)

≤ 0.01

a After administration of study drug.

b Nausea measured on a scale of 0-10 with 0 = no nausea, 10 = nausea as bad as it can be.

Ondansetron  
4 mg Intravenous 

Placebo 

P Value 

Study 1 

Emetic episodes:

Number of patients

104

117

Treatment response 24 h after study drug

   0 Emetic episodes

49 (47%)

19 (16%)

< 0.001

   1 Emetic episode

12 (12%)

9 (8%)

   More than 1 emetic episode/rescued

43 (41%)

89 (76%)

Median time to first emetic episode (min)a

55.0

43.0

Nausea assessments:

Number of patients

98

102

Mean nausea score over 24-h postoperative periodb

1.7

3.1

Study 2 

Emetic episodes:

Number of patients

112

108

Treatment response 24 h after study drug

   0 Emetic episodes

49 (44%)

28 (26%)

0.006

   1 Emetic episode

14 (13%)

3 (3%)

   More than 1 emetic episode/rescued

49 (44%)

77 (71%)

Median time to first emetic episode (min)a

60.5

34.0

Nausea assessments:

Number of patients

105

85

Mean nausea score over 24-h postoperative periodb

1.9

2.9

a Failure was one or more emetic episodes, rescued, or withdrawn.

Treatment Response 
Over 24 Hours 

Ondansetron 
n (%) 

Placebo 
n (%) 

P Value 

Number of patients
0 Emetic episodes
Failurea

180
96 (53%)
84 (47%)

171
29 (17%)
142 (83%)

≤0.001

ONDANSETRON HYDROCHLORIDE ondansetron hydrochloride injection

ONDANSETRON HYDROCHLORIDE ondansetron hydrochloride injection

Labeler - Wockhardt USA LLC. (170508365)

Registrant - Wockhardt Limited (650069115)

Establishment

Name

Address

ID/FEI

Operations

Wockhardt Limited

676257570

ANALYSIS(64679-726, 64679-727), MANUFACTURE(64679-726, 64679-727), LABEL(64679-726, 64679-727), PACK(64679-726, 64679-727)