Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Ondansetron

Literature data pertaining to the physicochemical, pharmaceutical, and pharmacokinetic properties of ondansetron hydrochloride dihydrate are reviewed to arrive at a decision on whether a marketing authorization of an immediate release (IR) solid oral dosage form can be approved based on a Biopharmaceutics Classification System (BCS)-based biowaiver. Ondansetron, a 5HT₃ receptor antagonist, is used at doses ranging from 4 mg to 24 mg in the management of nausea and vomiting associated with chemotherapy, radiotherapy, and postoperative treatment. It is a weak base and thus exhibits pH-dependent solubility. However, it is able to meet the criteria of “high solubility” as well as “high permeability” and can therefore be classified as a BCS class I drug. Furthermore, ondansetron hydrochloride 8 mg IR tablets (Zofran^® 8 mg) and multiples thereof (16 mg = Zofran^® 8 mg × 2 tablets and 24 mg = Zofran^® 8 mg × 3 tablets) meet the criteria of “rapidly dissolving” in dissolution testing. Ondansetron hydrochloride has a wide therapeutic window and is well-tolerated after oral administration. Based on its favorable physicochemical properties, pharmacokinetic data and the minimal risks associated with an incorrect bioequivalence decision, the BCS-based biowaiver procedure can be recommended for ondansetron hydrochloride dihydrate IR tablets.     

格拉司琼与恩丹西酮防治食管癌术后化疗所致恶心呕吐的疗效对比

目的：比较格拉司琼与恩丹西酮防治食管癌术后患者化疗引起恶心、呕吐的作用及毒副反应。方法：回顾性研究439例食管癌术后化疗患者的临床资料，比较格拉司琼和恩丹西酮的治疗效果及毒副反应。结果：吻合VI位于颈部患者比位于胸内患者易发生恶心、呕吐。格拉司琼对化疗后急性（1d）恶心、呕吐有效率为81．6％，延迟性恶心呕吐（2—5d）的有效率分别为75．0％、64．2％、60．8％、56．1％。恩丹西酮对化疗后急性恶心、呕吐有效率为71．4％，延迟性恶心、呕吐的有效率分别为68．7％、57．7％、52．0％、47．1％，两组差异显著（P〈0．05），格拉司琼治疗效果优于恩丹西酮。两者不良反应基本相似。结论：格拉司琼对于防治食管癌术后患者化疗所致恶心、呕吐效果较好。     

A randomized,placebo-controlled,double-blind trial of ondansetron in renal itch

BACKGROUND: Renal itch is a relatively common and distressing problem for patients with chronic renal failure. Ondansetron, a serotonin type 3 receptor antagonist was developed for relief of chemotherapy induced nausea. Recently, anecdotal reports describe relief of renal itch with ondansetron. OBJECTIVES: We performed a double-blind randomized placebo-controlled trial to objectively assess the effectiveness of ondansetron in renal itch. PATIENTS AND METHODS: With approval from the local ethical committee, 24 patients on haemodialysis were enrolled in the trial. On a random basis 14 patients were blindly allocated to the ondansetron-placebo sequence and 10 to the placebo-ondansetron sequence. Baseline values for itch were obtained for 7 days before the treatment period and there was a 7-day washout between the treatment periods. During the treatment patients received either 8 mg of ondansetron three times a day or a placebo tablet three times a day for 2 weeks. Patients were asked to record the severity of their pruritus on a visual analogue scale (VAS) twice a day. At the end of the study patients were asked blindly which treatment they had preferred. RESULTS: Seventeen patients completed the trial. Pruritus decreased by 16% (95% CI: 0.5-32%) during active treatment and by 25% (95% CI: 9-41%) during treatment with placebo. The change in VAS scores during treatment with ondansetron (P = 0.04) and placebo (P = 0.01) were both significant. Eleven patients expressed a preference, seven for placebo and four for ondansetron. CONCLUSIONS: Our results show that ondansetron is no better than placebo in controlling renal itch.     

Comparison of cyclizine and ondansetron for the prevention of postoperative nausea and vomiting in laparoscopic day-case gynaecological surgery

Seventy-four patients undergoing laparoscopic gynaecological surgery were randomly allocated to two groups receiving cyclizine 50 mg or ondansetron 4 mg at induction of anaesthesia. Anaesthetic and postoperative analgesia regimens were standardised. Approximately half of the patients in each group experienced some degree of postoperative nausea and vomiting (cyclizine, 56%; ondansetron, 54%). There was no difference between groups in respect of pre- and postdischarge incidence. Mean (SD) time to eye opening was significantly prolonged in the cyclizine group [10 (4) min vs. 8 (2) min; p < 0.001], but this had no influence on discharge times. Cyclizine and ondansetron appear equally effective in preventing postoperative nausea and vomiting but the 10-fold price differential favours cyclizine.     

Oral ondansetron,tropisetron or metoclopramide to prevent postoperative nausea and vomiting: a comparison in high-risk patients undergoing thyroid or parathyroid surgery

BACKGROUND: Oral antiemetic prophylaxis may be a practical alternative to intravenous administration. Intravenous ondansetron and tropisetron prevent postoperative nausea and vomiting (PONV) at least as efficiently as traditional antiemetics, droperidol and metoclopramide. We tested the hypothesis that the incidence of PONV after oral ondansetron or tropisetron prophylaxis is lower compared with metoclopramide among high-risk patients. METHODS: In a prospective, double-blind study we studied 179 high-risk patients who received either ondansetron 16 mg, tropisetron 5 mg, or metoclopramide 10 mg orally 1 h before the operation. A standard general anesthetic technique and postoperative analgesia were used. The incidence of PONV and the need for rescue antiemetic medication was recorded for 24 h. RESULTS: In the postanesthesia care unit, the incidence of PONV was lower after premedication with tropisetron compared with ondansetron and metoclopramide (15%, 32% and 39%, respectively). The incidence of PONV during 0-24 h was the same in each group (68%, 58% and 75% in the ondansetron, tropisetron and metoclopramide group, respectively), but the incidence of vomiting was significantly lower after ondansetron (34%) and tropisetron (22%) prophylaxis compared with metoclopramide (53%). The need for additional antiemetics was significantly lower after tropisetron prophylaxis compared with metoclopramide. Patient satisfaction was significantly higher after tropisetron than after metoclopramide. CONCLUSIONS: In the initial period, the incidence of PONV was lower after premedication with oral tropisetron than after ondansetron or metoclopramide. Considering the entire 24-h postoperative period, the incidence of PONV was the same after all three premedications, but the incidence of vomiting was lower after oral ondansetron and tropisetron than after metoclopramide.     

恩丹西酮不同给药模式预防妇科术后PCIA恶心呕吐的效果

目的 比较恩丹西酮不同给药模式对预防妇科术后芬太尼PCIA恶心呕吐的效果. 方法 随机选择120例择期妇科手术病人(ASAI-Ⅲ级),选择术后芬太尼PCIA镇痛.随机分四组且每组各30例:A组,用芬太尼复合咪唑安定加生理盐水至100ml于泵中,A组为对照组;B组,在A组基础上将8 mg恩丹西酮加入泵中;C组,在开启PCLA(A组配方)前10min缓慢静脉注入8 mg恩丹西酮;D组,在开启PCIA(A组配方)前10 min缓慢静脉注入4 mg恩丹西酮,并将4 mg恩丹西酮加入泵中.观察并记录各组在启动PCIA镇痛4,8,12,24,42 h各时点恶心呕吐评蕉、疼痛视觉评分、镇静评分. 结果 四组病人恶心呕吐不同时间之间比较有统计学差异(P<0.05).在使用PCIA后相同时点,A组病人恶心呕吐率最高,D组病人恶心呕吐率最低.A、B、C、D各组疼痛视觉评分、镇静评分差异无统计学意义(P>0.05). 结论 恩丹西酮负荷量给药,同时在镇痛泵中加入恩丹西酮可以有效地减少术后PCIA恶心呕吐.     

Economic evaluation of ondansetron vs dimenhydrinate for prevention of postoperative vomiting in children undergoing strabismus surgery

BACKGROUND: Although rarely life-threatening, postoperative vomiting (POV) is a distressing complication. The incidence of POV ranges from 34 to 90% in children undergoing strabismus surgery when antiemetics are not administered prophylactically. METHODS: In this study, a cost-consequence analysis (CCA) is used to estimate the economic benefit of ondansetron and dimenhydrinate as antiemetics administered prophylactically in children undergoing strabismus surgery. This retrospective study was conducted at The Hospital for Sick Children based on a review of 70 charts. RESULTS: Ondansetron was more effective with 45.3 POV-free patients (PFP) in an adjusted cohort of 100, while dimenhydrinate resulted in 38.2 PFP in an adjusted cohort of 100. The costs were significantly different between the two groups, CAD dollars 185.90 (+/-26.37, 95% CI, CAD dollars 173,89; CAD dollars 197.90) and CAD dollars 232.90 (+/-CAD dollars 66.84, 95% CI, CAD dollars 198.53; CAD dollars 267.27) per patient for ondansetron and dimenhydrinate, respectively. The length of stay in the postanesthetic care unit (PACU) represented over 97% of total costs, and the mean lengths of stay in the PACU for ondansetron and dimenhydrinate were significantly different, 3.43 and 4.41 h, respectively. CONCLUSION: This study should serve as a pilot for a large-scale investigation on the correlation between the length of stay in the PACU and the antiemetic agent used.     

A comparison of cyclizine,ondansetron and placebo as prophylaxis against postoperative nausea and vomiting in children

Nausea and vomiting is a relevant and common problem with unfavourable sequelae in children undergoing some plastic surgery procedures. There is a lack of anti-emetic trials performed in children, with only a few investigating the roles of the older anti-emetic agents such as cyclizine compared with newer ones such as ondansetron. This randomised, controlled, double-blind study examined the effectiveness of a single dose of ondansetron (0.1 mg x kg-1), cyclizine (20 mg) and placebo (normal saline) in the prevention of postoperative nausea and vomiting in 150 children (mean age 3.6 years) undergoing plastic genitourinary procedures. Rates of previous postoperative nausea and vomiting and motion sickness were comparable across the groups. Postoperative vomiting was significantly reduced with ondansetron prophylaxis (p = 0.006) but there was no detectable anti-emetic effect with cyclizine. Furthermore, cyclizine caused pain on injection (p < 0.001).     

A randomized controlled trial of the antiemetic effect of three doses of ondansetron after strabismus surgery in children

METHODS: One hundred and thirty-one healthy children, aged 31-152 months, undergoing strabismus surgery under general anaesthesia, were randomly allocated to one of four groups: group A received 0.04 mg.kg-1 ( identical with 1 mg.m-2) of ondansetron, group B 0.1 mg.kg-1 ( identical with 2.5 mg.m-2), group C 0.2 mg.kg-1 ( identical with 5 mg.m-2) and group D placebo, given intravenously following induction of anaesthesia. Morphine 0.15 mg.kg-1 was given intravenously, intraoperatively, to provide postoperative analgesia. Hourly records of emetic episodes were made for 24 h. RESULTS: A considerably higher proportion of children suffered emesis in the placebo group compared to the active treatment groups taken together, during the first 8 h of postoperative care (76% vs. 45%, P=0.002). During the first 8 h, only 25% of those in treatment group C suffered emesis, the number-needed-to-treat was 3. There was a statistically significant decrease in the chance of vomiting with increasing dose of ondansetron (P=0.03). By 24 h, the difference in the rate of emesis was less marked but still statistically significant (90% vs. 69%, P=0.03). CONCLUSION: Overall, children given ondansetron had less than one-half the risk of vomiting compared to those given placebo (hazard ratio 0.46, 95% confidence interval 0.29-0.74). The mean number of emetic episodes declined from 2.73 in the placebo group to 1.92 in treatment group C. There was no difference in the incidence of side-effects between groups.     

针药结合治疗术后恶心呕吐疗效观察

[目的]比较单纯应用西药恩丹西酮和结合针刺内关穴治疗术后恶心呕吐(PONV)的效果.[方法]选择2006年3月-12月所有美国麻醉师学会评级(ASA Ⅰ～Ⅱ)级择期行盆腹腔非胃肠道手术病例,于麻醉后手术前静注恩丹西酮4 mg,选取其中术后6 h内主诉恶心呕吐的患者85例,随机分为两组,Ⅰ组(n=42)给予静脉注射恩丹西酮4 mg同时针刺非穴位点,Ⅱ组(n=43)给予静脉注射恩丹西酮4 mg同时针刺双侧内关穴位点,观察两组的疗效.[结果]两组再次发作恶心呕吐的差异无统计学意义,但症状的分级差异有统计学意义,Ⅱ组低于Ⅰ组(P＜0.05).[结论]恩丹西酮结合针刺治疗手术后恶心呕吐效果好于单纯应用恩丹西酮静脉注射,值得推广.