Ondansetron

Abstract

Ondansetron, a selective serotonin (5-hydroxytryptamine; 5-HT) 5-HT₃ receptor antagonist, is an antiemetic agent available for use in adults and children. In children receiving ondansetron (multiple 5 mg/m² or 0.15 mg/kg intravenous and/or oral doses) in addition to chemotherapy in 2 large (n > 100) non-comparative analyses, ≤2 emetic episodes were observed in 33 and 40% of cisplatin recipients, 48 and 68% of ifosfamide recipients, and 70 and 72% of patients receiving other chemotherapeutic regimens. In comparative trials, ondansetron was significantly more effective at reducing nausea and vomiting than metoclopramide or chlorpromazine (both combined with dexamethasone), although the incidence of delayed symptoms were similar between children receiving ondansetron and metoclopramide. In addition, dexamethasone significantly improved the antiemetic efficacy of ondansetron in 1 randomised trial. When used in children undergoing conditioning therapy (including total body irradiation) prior to bone marrow transplantation, ondansetron was significantly better at controlling nausea and vomiting than combined perphenazine and diphenhydramine therapy. In dose-ranging and large placebo-controlled trials, intravenous (0.075 to 0.15 mg/kg) or oral (0.1 mg/kg) ondansetron was significantly more effective than placebo in preventing emesis in children undergoing surgery associated with a high risk of postoperative nausea and vomiting (PONV) including tonsillectomy or strabismus repair. In comparative studies, intravenous administration of ondansetron 0.1 to 0.15 mg/kg was significantly superior to droperidol 0.02 to 0.075 mg/kg or metoclopramide 0.2 to 0.25 mg/kg in preventing emesis in children undergoing various surgical procedures. In comparison with other antiemetics, including prochlorperazine and dimenhydrinate, ondansetron generally showed greater prophylactic antiemetic efficacy. Ondansetron combined with dexamethasone was significantly more effective than ondansetron or dexamethasone alone, as was the combination of ondansetron with a propofol-based anaesthetic compared with either agent alone. Ondansetron is generally well tolerated in children, rarely necessitating treatment withdrawal. The most frequently reported adverse events were mild to moderate headache, constipation and diarrhoea in patients receiving chemotherapy. Wound problems, anxiety, headache, drowsiness and pyrexia were reported most frequently in patients postsurgery. Conclusions: Ondansetron has shown good efficacy in the prevention of acute nausea and vomiting in children receiving moderately or highly emetogenic chemotherapy and/or irradiation, particularly when combined with dexamethasone. In the chemotherapy setting, ondansetron is significantly better than metoclopramide and chlorpromazine and has a more favourable tolerability profile. In children undergoing surgery, ondansetron demonstrated superior prophylactic antiemetic efficacy compared with placebo, droperidol and metoclopramide, and was relatively free of adverse events. Ondansetron is thus an effective first-line antiemetic in children undergoing chemotherapy, radiotherapy and surgery. Ondansetron is a serotonin (5-hydroxytryptamine; 5-HT) 5-HT₃ receptor antagonist used in the management of nausea and vomiting. Although other neurotransmitters are also involved, serotonin appears to have an important role in emetogenic pathways associated with chemotherapy- and radiation-induced nausea and vomiting; likewise, no single neurotransmitter controls postoperative nausea and vomiting (PONV) completely. For cytotoxic drugs in particular, the primary site of emetogenesis during the early or acute phase is thought to be the gut wall, and vagal afferent 5-HT₃ receptors are specifically involved. In vitro, ondansetron has high affinity and specificity for 5-HT₃ receptors and antagonises the effects of serotonin. The affinity of ondansetron for the 5-HT₃ receptor is at least 250 to 500 times that of its affinity for 5-HT_1B, 5-HT_1C, α-adrenergic and opioid μ, receptors. The drug has no activity at dopamine receptors. Ondansetron has demonstrated antiemetic efficacy in animal models, and these data have been validated by clinical trials and extensive use of ondansetron in clinical practice for many years. The pharmacokinetic properties of ondansetron in children are broadly similar to those in adults, although pharmacokinetic data in children are somewhat limited. In adults, oral bioavailability is about 60% and peak plasma concentrations are achieved 1.5 hours after an oral dose. The drug is 70 to 76% bound to plasma proteins in vitro. After oral, intravenous or intramuscular administration, ondansetron has a volume of distribution of about 140L, elimination half-life (t1/2) of 3 to 3.5 hours and undergoes extensive hepatic metabolism by the cytochrome P450 (CYP) enzyme system. Less than 5% of an absorbed dose is eliminated unchanged in the urine. Some data in children ≤12 years of age indicate a somewhat shorter t1/2, faster clearance and larger volume of distribution than in older children or adults, although these differences do not seem to be clinically significant. Despite being a substrate of the CYP enzyme system, ondansetron appears to have a relatively low potential for clinically significant drug interactions. The antiemetic efficacy of ondansetron has been evaluated in children receiving the drug for the prevention of chemotherapy- and radiation-induced nausea and vomiting, and in patients undergoing conditioning therapy prior to bone marrow transplantation. Ondansetron has also been evaluated for the prevention of PONV in children and adolescents. Chemotherapy-Induced Nausea and Vomiting: Studies evaluating the efficacy of ondansetron in preventing chemotherapy-induced nausea and vomiting in children and adolescents (≤18 years of age) included a variety of different chemotherapeutic regimens. Ondansetron was typically administered as an intravenous infusion before chemotherapy (5 mg/m²; maximum dose 8mg or 0.15 mg/kg) and then 2 or 3 times a day during chemotherapy, and for up to 5 days thereafter. Oral and intravenous administration was often combined. In noncomparative trials in children and adolescents (≤18 years of age) receiving emetogenic chemotherapy, 25 to 100% of patients receiving ondansetron experienced ≤2 emetic episodes on their worst day of chemotherapy (24-hour period where the worst vomiting or nausea was experienced). The response rate differed according to the emetogenicity of the chemotherapeutic regimen used: ≤2 emetic episodes were observed in 33 and 40% of those receiving cisplatin-based regimens, 48 and 68% of ifosfamide recipients and 72 and 70% of patients receiving other chemotherapeutic regimens in the 2 largest noncomparative analyses. Similar results were found for measures of nausea in these studies. In 3 comparative studies, ondansetron was significantly more effective at reducing emesis and nausea than metoclopramide or chlorpromazine, even when these latter agents were combined with dexamethasone. In 1 small trial in patients receiving moderately emetogenic chemotherapy (intravenous vincristine, daunorubicin, etoposide and cytarabine), the percentage of patients experiencing a complete or major response (≤2 emetic episodes) was 93% in ondansetron recipients (n = 15) versus 33% in patients receiving metoclopramide and dexamethasone (n = 15) [p < 0.001]. Significantly less nausea and vomiting was also observed in patients receiving ondansetron 5 mg/m² intravenously than in patients receiving chlorpromazine 0.3 mg/kg combined with dexamethasone 2 mg/m² intravenously in a crossover study: 72 vs 31% of patients experienced a complete or major response on their worst day of chemotherapy (p < 0.01). However, the incidence of delayed nausea and vomiting in patients treated with ondansetron was similar to that in patients treated with metoclopramide in these trials. Ondansetron has also shown slightly better efficacy than tropisetron in 2 studies. The combination of ondansetron and dexamethasone resulted in better control of emesis than ondansetron alone in 1 crossover study (n = 33; 25 patients completed 2 cycles). In patients treated with both agents, 61% experienced no emetic episodes compared with 23% of patients receiving ondansetron alone (significance not reported). After crossover, 12 patients responded better to combination therapy and 4 patients responded better during ondansetron monotherapy (p = 0.04); 9 patients responded equally well to both treatments. Appetite was also significantly better with combination therapy. Nausea and Vomiting Associated with Radiation Therapy and Bone Marrow Transplantation: Most patients receiving ondansetron to reduce radiation-induced nausea and vomiting were undergoing total body irradiation as part of a conditioning regimen prior to bone marrow transplantation. The 1 exception was a small study in 10 children who received ondansetron during postoperative local or craniospinal radiotherapy for brain tumours. Of 396 ondansetron treatment days, 54% were free from nausea and vomiting. In patients undergoing bone marrow transplantation, ondansetron was administered during high dose conditioning chemotherapy and/or total body irradiation. In noncomparative trials, complete and major response rates ranged from 57 to 88% on the worst day of total body irradiation and 50 to 80% on the worst day of chemotherapy. Only 2 comparative trials have been conducted in patients undergoing bone marrow transplantation. In 1 randomised study, ondansetron (n = 15) was significantly better than combined perphenazine and diphenhydramine (n = 13) in controlling emesis in children and adolescents receiving conditioning chemotherapy and total body irradiation. Complete or major response (≤2 emetic episodes) was 67 versus 0% (p = 0.044). In another study, ondansetron showed similar antiemetic efficacy to the 5-HT3 receptor antagonist granisetron. In patients aged ≤18 years, the mean number of emetic episodes per day was 0.87 for ondansetron recipients and 0.54 for granisetron recipients (p = 0.08). Postoperative Nausea and Vomiting (PONV): Dose-ranging studies showed that ondansetron 0.075 to 0.15 mg/kg intravenously is superior to placebo in preventing PONV in children after surgical procedures associated with a high risk of PONV (high risk surgery) including tonsillectomy, adenotonsillectomy or strabismus repair. Complete control of emesis within 24 hours of surgery (complete response) was seen in significantly more ondansetron than placebo recipients (70 to 91% vs 17 to 63%, respectively, p < 0.05). In large (n > 200) well controlled trials ondansetron 0.1 mg/kg up to 4mg intravenously, administered immediately before or after induction of general anaesthesia, was significantly more effective than placebo in preventing emesis in children after high risk surgery (60 to 68% vs 38 to 47%, p < 0.05). Oral ondansetron 0.1 mg/kg also proved to be significantly superior to placebo in children undergoing tonsillectomy or adenotonsillectomy (61 vs 46%, p < 0.05). In some smaller placebo-controlled trials a consistent significant superiority of ondansetron versus droperidol or metoclopramide could not be demonstrated based on the small number of patients in these trials; however, in most studies more ondansetron than droperidol or metoclopramide recipients experienced no emesis during the 24-hour postoperative period. Additionally, in some placebo-controlled studies ondansetron 0.1 to 0.15 mg/kg intravenously was significantly superior to intravenous droperidol 0.02 to 0.075 mg/kg (complete response in 67 to 98% vs 48 to 83%, p < 0.05) or metoclopramide 0.2 to 0.25 mg/kg (71 to 78% vs 40 to 62%, p < 0.05) in the prophylaxis of postoperative emesis in children undergoing high risk surgery. Furthermore, in a comparison with all 3 agents (n ≈ 60 per treatment arm) in children undergoing tonsillectomy or adenotonsillectomy, intravenous ondansetron 0.15 mg/kg was significantly superior to both droperidol 0.075 mg/kg and metoclopramide 0.5 mg/kg intravenously (73 vs 38 and 42%, respectively, p < 0.001). However, this outcome was not repeated in a study of children undergoing strabismus repair surgery. In limited comparative studies in children undergoing outpatient surgery, ondansetron 0.06 to 0.15 mg/kg intravenously showed a tendency for greater prophylactic antiemetic efficacy than some phenothiazines (prochlorperazine 0.1 mg/kg intravenously or 0.2 mg/kg intramuscularly) and 5-HT3 antagonists (low dose granisetron 0.01 mg/kg). Efficacy was similar between ondansetron and intravenously administered perphenazine 0.07 mg/kg, granisetron 0.1 mg/kg or dolasetron 0.5 mg/kg. Efficacy was significantly greater with ondansetron 0.1 mg/kg intravenously than with dimenhydrinate 0.5 mg/kg intravenously, yet similar compared with dexamethasone 0.1 mg/kg intravenously. Preliminary results of well controlled trials (abstract reports) have shown improved efficacy with ondansetron in combination with other antiemetics compared with the drug alone. In 2 double-blind randomised studies (1 published in full manuscript form) of children undergoing strabismus repair surgery (n = 331), the combination of low dose intravenous ondansetron 0.05 mg/kg plus dexamethasone 0.15 mg/kg was significantly more effective than either a higher dose of ondansetron 0.15 mg/kg or dexamethasone 0.15 mg/kg alone (91 vs 72 and 79%, respectively, p < 0.05). Furthermore, the same combination was as effective as intravenous perphenazine 0.07 mg/kg plus dexamethasone 0.15 mg/kg in maintaining complete response in children after tonsillectomy (n = 223; 81 vs 79%) or strabismus surgery (n = 153; 86 vs 94%). In children undergoing strabismus repair surgery (n = 300) or tonsillectomy (n = 90), ondansetron 0.15 mg/kg with a halothane-based anaesthetic had similar efficacy compared with a propofol-based anaesthetic alone (73 vs 74%). However, ondansetron 0.1 mg/kg intravenous administration after induction of anaesthesia maintained with propofol further reduced the incidence of emesis compared with propofol-maintained anaesthesia alone (93 vs 78%, p < 0.05). Intravenous ondansetron 0.1 mg/kg was also superior to placebo in treating established PONV in children undergoing predominantly ear, nose, throat or eye surgery; complete response rates within 24 hours of administration of the treatment dose were 53 versus 17% (p < 0.001). Ondansetron is generally well tolerated in paediatric patients and the tolerability profile of the drug in children appears similar to that in adults. In larger clinical trials, the most frequently reported adverse events in children receiving ondansetron for the prevention of nausea and vomiting associated with cancer chemotherapy were headache (2 to 8% of patients), constipation (1 to 3.5%) and diarrhoea (2%). Pooled data from clinical trials in 1486 children receiving the drug for PONV showed a similar incidence of adverse events associated with ondansetron and placebo. In these trials, the most commonly reported adverse events with ondansetron and placebo were as follows: wound problem (11 vs 12%), anxiety/agitation (6 vs 6%), headache (6 vs 6%), drowsiness/sedation (5 vs 8%) and pyrexia (4 vs 6%). Most adverse events reported in children receiving ondansetron have been mild to moderate in severity and rarely necessitated treatment withdrawal. Available comparative tolerability data in children receiving chemotherapy indicate that extrapyramidal effects occurred with metoclopramide-based antiemetic regimens but not with ondansetron, and sedation was less problematic with ondansetron than with chlorpromazine- or perphenazine-based therapy. In children receiving emetogenic chemotherapy or conditioning regimens, ondansetron had a similar tolerability profile to that of tropisetron and granisetron. In a US cost-effectiveness analysis conducted from the perspective of the healthcare payer (e.g. insurance company), intravenous ondansetron was associated with a cost of $US219 per intrathecal cytotoxic treatment with complete protection from nausea and vomiting in children with lymphoblastic leukaemia (1997 costs). Also in the US, a once daily regimen of ondansetron (0.45 mg/kg) plus dexamethasone was associated with a cost reduction of $US258 per additional child with complete protection from nausea and vomiting compared with ondansetron 0.15 mg/kg 3 times daily plus methylprednisolone (year of costing not stated). Willingness-to-pay data from the UK showed that the median amount parents would be willing to pay for a reduction in postoperative emesis was £50, with a 95% confidence interval of £20 to £80 (1996 values). Chemotherapy- and Radiation Therapy-Induced Nausea and Vomiting: For the prevention of chemotherapy-induced nausea and vomiting in paediatric patients 4 to 18 years of age, the recommended intravenous dosage of ondansetron in the US is 0.15 mg/kg given 30 minutes before emetogenic chemotherapy begins, followed by 0.15 mg/kg doses 4 and 8 hours after the first dose of ondansetron. Oral therapy (ondansetron tablets, orally disintegrating tablets or oral solution) can be used in children receiving moderately emetogenic chemotherapy. The recommended oral dosage in the US for patients ≥12 years of age is ondansetron 8mg given twice a day. The first dose should be administered 30 minutes before the start of emetogenic chemotherapy, with a subsequent dose 8 hours after the first dose. Ondansetron 8mg orally every 12 hours should be administered for 1 to 2 days after completion of chemotherapy. For children 4 to 11 years of age the recommended oral dosage is ondansetron 4mg given 3 times a day. The first dose should be administered 30 minutes before the start of emetogenic chemotherapy with subsequent doses 4 and 8 hours after the first dose. Ondansetron 4mg orally every 8 hours should be administered for 1 to 2 days after completion of chemotherapy. In the UK, the recommended regimen for ondansetron in children receiving severely emetogenic chemotherapy is 5 mg/m² intravenously (infused over 15 minutes) immediately before chemotherapy, then 4mg orally every 12 hours for up to 5 days. PONV: For the prevention of PONV in children, ondansetron is administered (undiluted) by slow intravenous injection, although intramuscular administration is also an option. The recommended dosage in the US for patients ≥12 years of age is a single intravenous (or intramuscular) dose of ondansetron 4mg immediately prior to induction of anaesthesia, or postoperatively if the patient experiences nausea or vomiting shortly after surgery. For children 2 to 12 years of age, the recommendation is a single intravenous dose of 0.1 mg/kg for paediatric patients weighing >40kg, or a single 4mg dose for those weighing >40kg. In the UK, for children over 2 years of age, a single dose of ondansetron 0.1 mg/kg (maximum dose 4mg) is administered by slow intravenous injection before, during or after induction of anaesthesia for preventing or treating PONV.