1872 Gastrointestinal

Omdom; Omecer-D; Omecid-D; Omecid-RD; Omecip-D; Orne­ Administration. Ondansetron has been successfully used cos-O; Omeezol-D; Omejel-DM; Omelax-D; Omen-D; Ome­ Uses and Administration by continuous subcutaneous infusion to control intractable praz-HP Kit; Omeraze-D; Omeris-D; Omesun-D; Omesym-D; Ondansetron is a 5-HT3 antagonist (5-HT3 -receptor nausea and vomiting.1 Despite concern about the low pH Omevar-D; Omez Insta; Omez-D; Omfact-D; Omibase-D; Ornic­ antagonist) with antiemetic activity. It is used in the of ondansetron injection there was no problem with the O; Omicas-D; Omicool-D; Omidec; Omidip; Omidom; Omiflux; management of nausea and vomiting induced by skin at the infusion site. An oral protocol for chemother­ Omig-DM; Omilee-D; Omitive-D; Omitop-DM; Omitop; Omi­ cytotoxic chemotherapy and radiotherapy. It is also used apy-induced emesis in children has been described;2 effi­ zol-D; Omkair-D; Omlink-D; Omlo-D; Ommac Plus; Omore-D; for the prevention and treatment of postoperative nausea cacy was similar to intravenous use. Omoxitin; Ompli-D; Ompraz-D; Omprest-D; Ornracap-DM; and vomiting. For the management of nausea and vomiting, Omriz-D; Omven-D; Omzee-D; Onazole-DP; Onazole-RD; 1. Mulvenna PM, Regnard CFB. Subcutaneous ondansetron. Lancet 1992; and the important role of 5-HT antagonists, see p. 1811.3. 339: 1059. Oned; Onto-D; Op-Zole D; Opaz-DM; Opel-D; Opera-D; Oraz­ 3 Ondansetron is given by intramuscular or slow 2. Walker PC, et al. Promoting the use of oral ondansetron in children D; Orole-D; Ospicid-D; Ossum-D; OTC HP Kit; OTG-D; Otto-D; 58: intravenous injection or infusion as the hydrochloride, receiving cancer chemotherapy. Am J Health-Syst Pharm 2001; 598- Ozed-D; Ozodom; Ozol-D; Pacidom-0; Malaysia: Pylobact 602. Combi; Mex. : Pridamiral Pack; NZ: Losee Hp7; Philipp.: OAC orally as the hydrochloride or base, or rectally as the base. Hp7t; Rus.: Domstal-0 (,[\oMCTIUI-0); Omez D (0Me3 ,[(); Pylo­ Doses are expressed in terms of the base. Ondansetron bact (IImm6rucr); Ukr.: Limzer (JiiM3ep); Omez-D (0Me3-,[(); hydrochloride 4. 99 mg is equivalent to about 4 mg of Administration in children. Ondansetron is used in chil­ Pylobact Neo (I1rum6aKTHeo ); USA: Omeclamox-Pak; Zegerid. ondansetron base. dren for the management of nausea and vomiting induced Numerous dosing schedules of ondansetron have been by cytotoxic chemotherapy and radiotherapy. It is also used for the prevention and treatment of postoperative Arg.: Dioxaflex Protect; Philipp.: Skelan used; some typical examples are cited below. Used as an adjunct in:. nausea and vomiting. Ondansetron is given by slow intra­ Protect; UK: Axorid. For highly emetogenic chemotherapy the following dose schedules appear to be equally effective in preventing acute venous injection or infusion as the hydrochloride, or oral­ emesis: ly as the hydrochloride or base. Doses are expressed in PharmacopoeialPreparations a single dose of 8 mg by slow intravenous or terms of the base. BP 2014: Gastro-resistant Omeprazole Capsules; Gastro-resistant • In the USA a licensed regimen for chemotherapy­ Omeprazole Tablets; Omeprazole Oral Suspension; intramuscular injection immediately before treatment induced nausea and vomiting in children over 6 months of USP 36: Omeprazole Delayed-Release Capsules; Omeprazole or Oral Suspension. age is ondansetron 150 micrograms/kg by intravenous 8 mg by slow intravenous or intramuscular injection infusion 30 minutes before moderately to highly • immediately before treatment, either followed by a emetogenic chemotherapy, repeated 4 and 8 hours after continuous intravenous infusion of l mg/hour for up to the first dose. Alternatively, for children aged 4 to 11 years, 24 hours, or by a further two doses of 8 mg two to four an oral dose of 4mg may be given 30 minutes before the hours apart start of moderately emetogenic chemotherapy, with subsequent 4-mg doses given 4 and 8 hours thereafter. An or oral dose of 4mg three times daily may be given for 1 to 2 a single dose of 16 mg given by intravenous infusion over days after the end of chemotherapy. • at least 15 minutes immediately before treatment, which In the UK, ondansetron is licensed for use in children can be followed by a further 2 doses of 8 mg by slow aged from 6 months and doses are calculated using body­ intravenous or intramuscular injection four hours apart weight or body-surface; weight-based dosing results in higher daily doses compared with those based on body­ or surface. In a typical regimen based on body-surface, an 150 micrograms/kg (maximum 16 mg) by intravenous intravenous dose of ondansetron 5 mg/m2 (maximum 8 mg) • infusion over 15 minutes, beginning 30 minutes before is infused (over at least 15 minutes) immediately before chemotherapy, followed by a further 2 doses four hours chemotherapy and followed after 12 hours by oral dosing USP 36: (Ondansetron). A white to off-white powder. apart for up to 5 days: children aged from 6 months and less than 0.6 m2 body- Sparingly soluble in water; very soluble in acid solutions. or • Store in airtight containers. Protect from light. surface: 2 mg every 12 hours a 16-mg suppository rectally, given 1 to 2 hours before from 6 months and 0.6 m2 and over: 4mg every 12 hours • • treatment When using body-weight, an intravenous dose of ondan­ Ondansetron Hydrochloride or setron 150 micrograms/kg (maximum 8 mg) is given immediately before chemotherapy and repeated every 4 (BANM. USAN, r!NNM) a single oral dose of 24 mg taken 30 minutes before the • hours for up to 3 doses. This is followed after 12 hours by start of single-day chemotherapy oral dosing for up to 5 days: The efficacy of ondansetron in highly emetogenic chemo­ body-weight lO kg and less: 2 mg every l2 hours • therapy may be enhanced by giving intravenous dexa­ over lO kg: 4 mg every 12 hours • methasone sodium phosphate 20 mg before chemotherapy. The daily dose of ondansetron by any route should not Similar regimens to those given above are used for exceed 32 mg. preventing acute emesis with less emetogenic chemotherapy While ondansetron is not licensed in the UK for and/or radiotherapy and also include: radiotherapy-induced nausea and vomiting in children, 8 mg given orally or by slow intravenous injection up to 2 • the BNFC recommends the same doses as those used for hours before treatment, followed by an oral dose of 8 mg chemotherapy-induced nausea and vomiting (above). given 8 to l2 bours later A protocol for oral ondansetron dosage, with similar To protect against delayed emesis these regimens are efficacy to intravenous use, has also been described, see followed by oral ondansetron 8mg twice daily, or 16mg Administration, above. rectally once daily, for up to 5 days after the end of a course For the prevention and treatment of postoperative of chemotherapy. Pharmacopoeias. In Chin., Bur. (see p. vii), and US. nausea and vomiting in children aged from 1 month, To prevent postoperative nausea and vomiting the 100micrograms/kg may be given by slow intravenous Ph. Eur. 8: (Ondansetron Hydrochloride Dihydrate). following doses may be given: injection, up to a maximum dose of 4mg. white or almost white powder. Sparingly soluble in water 16 mg orally an hour before anaesthesia and in alcohol; slightly soluble in dichloromethane; soluble • in methyl alcohol. Protect from light. or Administration in the elderly. Most licensed product infor­ mation for ondansetron states that dose adjustments for USP 36: (Ondansetron Hydrochloride). A white to off-white 8 mg orally an hour before anaesthesia followed by 2 • patients over 65 years of age are not necessary. However, powder. Sparingly soluble in water and in alcohol; very further doses of 8 mg at 8-hour intervals slightly soluble in acetone, in chloroform, and in ethyl the product information for one preparation (Zofran; GSK, acetate; slightly soluble in dichloromethane and in or UK) recommends that patients over 7 5 years of age are given an initial dose of 8 mg by intravenous infusion over isopropyl alcohol; soluble in methyl alcohol. Store in a single dose of 4 mg by slow intravenous or • 15 minutes for the management of nausea and vomiting airtight containers at a temperature of 25 degrees, intramuscular injection at induction of anaesthesia induced by cytotoxic chemotherapy and radiotherapy; this excursions permitted between 15 degrees and 30 degrees. For the treatment of postoperative nausea and vomiting a may be followed by a further 2 infusions of 8 mg given at Protect from light. single dose of 4 mg by intramuscular or slow intravenous least four hours apart. injection is recommended. For dosing in children, elderly patients, or those with Incompatibility. Ondansetron hydrochloride and dexa­ hepatic impairment, see below. Administration in hepatic impairment. Licensed product methasone sodium phosphate were not compatible when information recommends that the dose of ondansetron high concentrations were combined in polypropylene syr­ Reviews. should not exceed 8 mg daily in patients with moderate or inges.1 Lower concentrations (up to 640 micrograms/mL of 1. Perez EA. A risk-benefit assessment of serotonin 5-HT3 recepto� severe hepatic impairment. When this dose was given ondansetron and 400 micrograms/mL of dexamethasone antagonists in antineoplastic therapy-induced emesis. Drng Safety 1998; intravenously to patients with hepatic impairment, those phosphate) were stable in 50 mL containers of infusion 18: 43-56. with severe impairment showed an increase in the area fluid for 30 days under refrigeration. Compatibility has 2. Gregory RE, Ettinger DS. 5-HT3 receptor antagonists forthe prevention of chemotherapy-induced nausea and vomiting: a comparison of their under the plasma concentration/time curve and in the been reported for 24 hours in plastic syringes at 4 degrees pharmacology and clinical efficacy. Drngs 1998; 55: 173-89. terminal plasma half-life, and a decrease in plasma clear­ or 23 degrees with a variety of other drugs,2 and with sev­ 3. Lindley C, Blower P. Oral serotonin type 3-receptor antagonists for ance.1 The authors of this study, some of whom worked eral antineoplastics ( cytarabine, dacarbazine, doxorubicin, prevention of chemotherapy-induced emesis. Am J Health-Syst Pharm for the manufacturers (Glaxo), considered that ondan­ etoposide, or methotrexate) in PVC infusion bags for 48 2000; 57: 1685-97. 4. Culy CR. et a!. Ondansetron: a review of its use as an antiemetic in setron should be restricted to once daily dosage in severe hours at room temperature. 3 children. Paediatr Drngs2001; 3: 441-79. hepatic impairment. 1. Hagan RL, et a!. Stability of ondansetron hydrochloride and 5. Gridelli C. 5-HTrreceptor antagonists in the control of delayed-onset 1. Blake JC. et at. The pharmacokinetics of intravenous ondansetron in dexamethasone sodium phosphate in infusion bags and syringes for 32 emesis. Anticancer Res 2003; 23: 2773-82. patients with hepatic impairment. Br J Clin Pharmacol l993; 35: 441-3. days. Am J Health-Syst Pharm 1996; 53: 1431-5. 6. Constenla M. 5-HT3 receptor antagonists for prevention of late acute­ 2. Stewart JT, et al. Stability of ondansetron hydrochloride and l2 onset emesis. Ann Phannacother2004; 38: 1683-91. Am J Health-Syst Pharm 55: medications in plastic syringes. 1998; 2630-4. 7. Aapro M. 5-HT3-receptor antagonists in the management ofnausea and Bulimia nervosa. A combination of counselling, support, 3. Stewart JT, et al. Stability of ondansetron hydrochloride and five vomiting in cancer and cancer treatment. Oncology 2005; 69: 97�109. antineoplastic medications. Am J Health-Syst Pharm 1996; 53: 1297- 8. Anonymous. 5HT,-receptor antagonists as antiemetics in cancer. Drng psychotherapy, and antidepressants is the usual treatment 1300. Ther Bull 2005; 43: 57-62. of bulimia nervosa. Preliminary reports have indicated

All cross-references refer to entries in Volume A Ondansetron 1873

that ondansetron may be of benefit in the treatment of 3. Schumann R. Hudcova J. Cholestasis of pregnancy, pruritus and 5- disorders, including extrapyramidal reactions such as Acta Obstet Gynecol Scand this disorder.1•2 hydroxytryptamine 3 receptor antagonists. dystonia, dyskinesia, and oculogyric crisis have been 2004; 83: 861-2. I. Faris PL, et a!. Effect of decreasing afferent vagal activity with 4. MOller C, et al. Treatment of pruritus in chronic liver disease with the 5- reported. Rashes and urticaria have also occurred. Injection ondansetron on symptoms of bulimia nervosa: a randomised, double­ hydroxytryptamine receptor type 3 antagonist ondansetron: a site reactions may develop, and local burning sensations are 355: blind trial. Lancet 2000; 792-7. randomized. placebo-controlled, double-blind cross-over trial. Bur J common after insertion of suppositories. 2. Fung SM, Ferrill MJ. Treatment of bulimia nervosa with ondansetron. Gastroenterol Hepatol 1998; 10: 865-70. 35: 5-HT antagonists should generally not be used in Ann Pharmacother 2001; 1270-3. 5. O'Donohue JW, et al. A controlled trial of ondansetron in the pruritus of 3 cholestasis. Aliment Pharmacol Ther 2005; 21: 1041-5. patients who have had a hypersensitivity reaction to a 6. et at. Fatigue. Preliminary results indicated that treatment with Jones EA, Ondansetron and pruritus in chronic liver disease: a member of this drug class. They should be used with care in controlled study. Hepatogastroenterology 2007; 54: 1196--9. patients with signs of subacute intestinal obstruction or 5-HT antagonists such as ondansetron and tropisetron 7. 3 Balaskas EV, et al. Histamine and serotonin in uremic pruritus: effect of may be of benefit in patients with chronic fatigue.1 Oral ondansetron in CAPD-pruritic patients. Nephron !998; 78: 395-402. ileus. Ondansetron should be given in reduced doses to ondansetron 4mg twice daily was reported2 to resolve fati­ B. Murphy M. et al. A randomized, placebo-controlled, double-blind trial of patients with moderate to severe hepatic impairment. Br J Dermato/ 2003; 148: 314-7. gue in a woman with chronic hepatitis C. In a randomised ondansetron in renal itch. 9. Weisshaar E, et at. Antipruritic effects of two different 5-HT3 receptor study in 36 patients with chronic hepatitis C, this dose of antagonists and an antihistamine in haemodialysis patients. Exp Effects on carbohydrate metabolism. Hypoglycaemia ondansetron given for I month significantly improved fati­ Dermatol 2004; 13: 298-304. associated with dystonia and seizures developed in a four­ gue scores at day 15 and day 60 (beyond the treatment 10. Borgeat A, Stirnemann H-R. Ondansetron is effective to treat spinal or epidural morphine-induced pruritus. Anesthesiology 1999; 90: 432-6. year-old child after ondansetron treatment for vomiting.1 period) when compared with placebo. 3 The authors noted AM II. Korhonen , et al. Ondansetron does not prevent pruritus induced by Blood glucose concentrations returned to normal with that patient awareness that constipation was a possible 47: low-dose intrathecal fentanyl. Acta Anaesthesiol Scand 2003; 1292-7. intravenous glucose. Indirect inhibition of stress-induced effect of active treatment may have potentially unblinded 12. Wells J, et al. Intrathecal fentanyl-induced pruritus during labour: the corticotropin and cortisol secretion via the effects of the study. Further confirmation by larger studies is effect of prophylactic ondansetron. lnt J Obstet Anesth 2004; 13: 35-9. et al. ondansetron on serotonergic pathways was suggested as a needed. I3. Waxler B, Prophylactic ondansetron does not reduce the incidence of itching induced by intrathecal sufentanil. Can J Anesth 2004; 51: 685- possible cause for the hypoglycaemia. For more reports of l. Spdth M, et al. Treatment of chronic fatigue syndrome with 5-HT3 9. extrapyramidal effects and seizures, see Effects on the Ner­ receptor antagonists-preliminary results. Scand J Rheumatol 2000; 113 14. Iatrou CA, et al. Prophylactic intravenous ondansetron and dolasetron in vous System, p. 1874. 1. (suppl): 72-7. intrathecal morphine-induced pruritus: a randomized, double-blinded, 2. Jones EA. Relief from profound fatigue associated with chronic liver placebo-controlled study. Anesth Analg 2005; 101: 1516-20. l. Patel A, et al. Ondansetron-induced dystonia, hypoglycemia. and disease by long-term ondansetron therapy. Lancet 1999; 354: 397. 15. Siddik-Sayyid SM, et al. Does ondansetron or granisetron prevent seizures in a child. Ann Phannacother 2011; 45: e7. 3. Piche T, et al. Effect of ondansetron, a 5-HT3 receptor antagonist, on subarachnoid morphine-induced pruritus after cesarean delivery? fatigue in chronic hepatitis C: a randomised, double blind, placebo Anesth Anal_q 2007; 104: 421-4. controlled study. Gut 2005; 54: 1169-73. 16. Zenker S, et al. Behandlung von Pruritus als Symptom von Effects on the cardiovascular system. In 1992 chest pain Hauterkrankungen mit dem Serotonin-Rezeptorantagonisten Ondan­ and/or cardiac arrhythmias that might have been asso­ setron. 1 Dtsch Dennatol Ges 2003; 1: 705-10. Gastroenteritis. Antiemetics such as ondansetron have ciated with ondansetron were reported1 in 4 patients, 2 of been tried to reduce vomiting during acute gastroenteritis whom died. In 3 subsequent patients who developed Ondansetron has been tried experi­ in children. Reviews1-3 have found that ondansetron Psychiatric disorders. mentally in several psychiatric disorders including schizo­ severe chest or anginal pain, treatment with ondansetron (given orally or intravenously) reduces the risk of persis­ phrenia,1-3 and psychosis in patients with parkinsonism,4 was stopped. tent vomiting, the need for intravenous fluids, and hospi­ and may be of value in moderating tardive dyskinesia.5 A The manufacturers (Glaxo) had at that time no evidence tal admissions; an increased incidence of diarrhoea was reduction in tic severity in Tourette's Syndrome (see Tics, of a causal relationship between ondansetron and episodes seen, but further research was considered necessary to 2 p. 1030.1) has been reported, 6 and preliminary results of chest pain and cardiac abnormalities. Giving ondan­ determine its clinical significance.2 Metoclopramide was have suggested benefit in obsessive-compulsive disorder, 7 setron or granisetron intravenously produced no clinically also effective in reducing the number of vomiting episodes and bulimia nervosa (see p. 1872.3). It is also reported to important cardiovascular changes in a study in 12 healthy and hospital admissions, although it was less often used be under investigation in the management of panic attacks subjects.3 Since then, however, hypotension, coronary because of its potentially serious adverse effects. 3 (p. 1029.1). For the more conventional management of vasospasm, and atrial fibrillation have been reported with l. DeCamp LR, et a!. Use of antiemetic agents in acute gastroenteritis: a ondansetron, 4 and myocardial ischaemia has been reported systematic review and meta-analysis. Arch Pediatr Adolesc Med 2008; 162: schizophrenia, parkinsonism, and obsessive-.compulsive 858-65. disorder see p. 1031.3, p. 889.1, and p. 1028.2, respec­ with both ondansetron5 and dolasetron;6 in the latter case 2. Phillips B. Towards evidence based medicine for paediatricians. Arch Dis tively. this led to an acute myocardial infarction. Supraventricular Child 2010; 95: 945-7. tachycardia reported with dolasetron was attributed to an l. White A, et al. Ondansetron in the treatment of schizophrenia. Lancet 3. Fedorowicz Z, et al. Antiemetics for reducing vomiting related to acute 1991; 337: ll73. interaction with sevoflurane.7 Dolasetron-induced torsade gastroenteritis in children and adolescents. Available in The Cochrane 2. Adler LE, el al. Improved P50 auditory gating with ondansetron in de pointes has also occurred, 8 and overdose of dolasetron Database of Systematic Reviews; Issue 9. Chichester: John Wiley; 2011 medicated schizophrenia patients. Am J Psychiatry 2005; 162: 386-8. (accessed 05/10fll). has produced prolongation of the QT, interval and 3. Levkovitz Y, et al. The effect of ondansetron on memory in schizophrenic patients. Brain Res Bull 2005; 65: 291-5. hypotension.' Another study in healthy subjects found Pain. Preliminary results from a small crossover study1 4. Zoldan J, etal. Psychosis in advanced Parkinson's disease: treatment with that dolasetron mainly altered ECG parameters indicative of ondansetron. a 5-HT 3 receptor antagonist. Neurology I995; 45: I305-8. ventricular depolarisation, whereas ondansetron affected indicated that oral ondansetron was more effective than 5. Sirota P. et al. Use of the selective serotonin 3 receptor antagonist mainly ventricular repolarisation. 10 However, ECG changes paracetamol in relieving the pain of fibromyalgia, a ondansetron in the treatment of neuroleptic-induced tardive dyskinesia. chronic disorder that responds poorly to conventional Am J Psychiatry 2000; 157: 287-9. were transient and asymptomatic. Studies of high-dose analgesics. A single bolus of ondansetron given to patients 6. Toren P, et at. Ondansetron treatment in Tourette's disorder: a 3-week. intravenous granisetron11-13 found no significant adverse Clin Psychiatry with chronic neuropathic pain significantly reduced pain randomized, double-blind, placebo-controlled study. 1 effects on pulse, blood pressure, or ECG measurements. A 2005; 66: 499-503. review14 of the electrocardiographic and cardiovascular scores 2 hours after injection in a placebo-controlled 7. Pallanti S, et al. Ondansetron augmentation in treatment-resistant study;2 this effect may be due to an action on 5-HT recep­ obsessive-compulsive disorder: a preliminary, single-blind, prospective effects of the 5-HT antagonists concluded that although this 3 3 tors in the spinal cord. study. CNS Drugs 2009; 23: 1047-55. class of drugs may cause small, transient ECG changes, the Other 5-HT antagonists such as granisetron3-5 and clinical benefits of the drugs outweighed the small 3 tropisetron6-8 have also been investigated in various painful Substance dependence. Ondansetron is being studied in theoretical risk of any clinically significant cardiovascular syndromes. the management of alcohol dependence (p. 1734.1). How­ events. Nonetheless, the use of dolasetron in children has I. Hrycaj P, et al. Pathogenetic aspects of responsiveness to ondansetron (5- ever, in one study1 a significant reduction in alcohol con­ been contra-indicated in some countries (see Administra­ hydroxytryptamine type 3 receptor antagonist) in patients with primary sumption was found only in lighter drinkers after sub­ tion in Children, p. 1837.3). 1 Rheumatol 1996; 23: fibromyalgia syndrome-a preliminary study. group analysis. Another study2 found a reduction in I. Ballard HS, etal. Ondansetron and chest pain. Lancet 1992; 340:. 1107. I4I8-23. alcohol consumption by patients with early-onset alcohol­ 2. Palmer JBD, Greenstreet YL. Ondansetron and chest pain. Lancet 1992; 2. et al. McCleane GJ, Does a single intravenous injection of the 5HT3 340: 1410. receptor antagonist ondansetron have an analgesic effect in neuropathic ism (onset before age 25) who took ondansetron com­ 3. Boike SC, et al. Cardiovascular effects of i.v. granisetron at two pain? A double-blinded, placebo-controlled cross-over study. Anesth pared with placebo. No such effect was seen, however, in administration rates and of ondansetron in healthy adults. Am J Health­ Analg 2003; 97: 1474-8. patients with late-onset alcoholism. Further study found Syst Pharm 1997; 54: 1172-6. 3. Voog et al. Immediate effects of the serotonin antagonist granisetron 0, that ondansetron also effectively ameliorated mood distur­ 4. Havrilla PL, et al. Coronary vasospasm and atrial fibrillation associated on temporomandibular joint pain in patients with systemic inflamm­ with ondansetron therapy. Ann Pharmacother 2009; 43: 532-6. atory disorders. Life Sd 2000; 68: 591-602 bances including symptoms of depression, anxiety, and 5. Bosek V, et al. Acute myocardial ischemia after administration of 4. Dubey PK, Prasad SS. Pain on injection of propofol: the effect of hostility, in early-onset alcoholics -' Self-reported alcohol ondansetron hydrochloride. Anesthesiology 2000; 92: 885-7. granisetron pretreatment. Clin 1 Pain 2003; 19: 121-4. consumption also reduced in adolescents (between ages 6. Arole A, et al. Coronary vasospasm leading to an acute myocardial 5. Emberg M, et al. Effects on muscle pain by intramuscular injection of 14 and 20) with alcohol dependence who were given infarction after the administration of dolasetron. J Clin Anesth 2005; 17: Pain 2003; 101: 275-82. granisetron in patients with fibromyalgia. 72-4. 6. Farber L, et al. Short-term treatment of primary fibromyalgiawith the 5- ondansetron in an open study.4 7. Higgins DJ, Bunker NJ. Dolasetron and peri-operative cardiac HT3-receptor antagonist tropisetron: results of a randomized, double­ I. Sellers EM, et al. Clinical efficacy of the 5-HT3 antagonist ondansetron in arrhythmia. Anaesthesia 2005; 60: 936�7. blind, placebo-controlled multicenter trial in 418 patients. lnt J Clin alcohol abuse and dependence. Alcohol Clin Exp Res 1994; 18: 879�85. 8. Turner S, et al. Dolasetron-induced torsades de pointes. J Clin Anesth Pharmacol Res 2001; 21: 1-13. 2. Johnson BA, et al. Ondansetron for reduction of drinking among 2007; 19: 622-5. 7. Stratz T, etal. Local treatment of tendinopathies: a comparison between biologically predisposed alcoholic patients. lAMA 2000; 284: 963-71. 9. Rochford M, et al. Dolasetron overdose resulting in prolonged QTc tropisetron and depot corticosteroids combined with local anesthetics. 3. Johnson BA, et al. Ondansetron reduces mood disturbance among interval and severe hypotension: a case report and literature review. Scand J Rheumatol 2002; 31: 366-70. biologically predisposed, alcohol-dependent individuals. Alcohol Clin Exp Emerg Med .J 2007; 24: 515-7. 8. Spath M, et al. Efficacy and tolerability of intravenous tropisetron in the Res 2003; 27: 1773-9. I 0. Benedict CR, et al. Single-blind study of the effects of intravenous treatment of fibromyalgia. Scand 1 Rheumatol 2004; 33: 267-70. 4. Dawes MA et a!. A prospective, open-label trial of ondansetron in , dolasetron mesylate versus ondansetron on electrocardiographic adolescents with alcohol dependence. Addict Behav 2005; 30: I 077-85. parameters in normal volunteers. J Cardiovasc Pharmacol l 996; 28: 5 3-9. Pruritus. There are several case reportsl.2 of cholestatic 11. Carmichael J, Harris AL High-dose i.v. granisctron for the prevention of pruritus (p. 1687.3) responding to intravenous or oral chemotherapy-induced emesis: cardiac safety and tolerability. Anticancer Adverse Effects and Precautions Drugs 2003; 14: 739-44. ondansetron, including one in pregnancy. 3 However, Ondansetron and other 5-HT antagonists may cause 12. Carmichael J, Harris AL. The cardiovascular safety of high-dose results from controlled studies4-6 have been mixed. It is 3 headache, a sensation of flushing or warmth, hiccups, and intravenous granisetron in cancer patients receiving highly emetogenic similarly unclear if ondansetron is of benefit in pruritus chemotherapy. Cancer Chemother Pharmacot 2004; 53: 123-8. constipation. A transient rise in liver enzymes has due to renal failure,?-9 and results have been conflicting 13. Aapro M, Bourke JP. Rapid intravenous administration of granisetron occasionally occurred. There have been rare reports of from controlled studies evaluating its use in opioid­ prior to chemotherapy is not arythmogenic [sic]: results of a pilot study. immediate hypersensitivity reactions, including anaphy­ Bur J Cancer 2003; 39: 927-3 1. induced pruritus.10-15 There are reports of ondansetron laxis. Chest pain, arrhythmias, hypotension, tachycardia, 14. Navari RM, Koeller JM. Electrocardiographic and cardiovascular effects ameliorating the pruritus associated with some skin disor­ Ann Pharmacother and bradycardia have been reported rarely. Dizziness and of the 5-hydroxytryptamine3 receptor antagonists. ders.16 Other 5-HT antagonists such as tropisetron9 and 2003; 37: 1276-86. 3 transient visual disturbances such as blurred vision (or very dolasetron 14 have also been investigated. rarely, transient blindness) have been reported during rapid l. Schw6rer H. Ramadori G. Improvement of cholestatic pruritus by intravenous injection. Transient ECG changes including QT Effects on theeyes. Blurring followed by transient loss of ondansetron. Lancet 1993; 341: 1277. 2. Raderer M, et a!. Ondansetron for pruritus due to cholestasis. N Eng! J interval prolongation have occurred very rarely, mainly vision has been reported after rapid intravenous injection Med 1994; 330: 1540. with intravenous ondansetron. Seizures and movement of ondansetron.1 Oculogyric crisis may occur as part of

The symbol t denotes a preparation no longer actively marketed 1874 Gastrointestinal

extrapyramidal reactions seen with ondansetron, see 6. Kanny G, et at. IgE-mediated allergy to granisetron and safe use of i ondansetron. 1 Allergy Clin Immunol 200l; 108: 1059-60. P.r.�P.?r?t Effects on the Nervous System, below. ?n.�...... ProprietaryPreparations (details are given in Volume B) L Cherian A, Maguire M. Transient blindness following intravenous ondansetron. Anaesthesia 2005; 60: 938-9. Porphyria. The Drug Database for Acute Porphyria, com­ piled by the Norwegian Porphyria Centre (NAPOS) and Single-ingredient Preparations. Arg.: Cetron; Dantenk; Dismo­ lan; Espasevit; Finaber; Finoxit; Tiosalis; Zofran; Austral.: Effectson the liver. Although disturbances in liver enzyme the Porphyria Centre Sweden, classifies ondansetron as Ondaz; Onsetron; Zofran; Austria: Ondensan; Zofran; Zotrixt; probably not porphyrinogenic; it may be used as a drug of values have been reported in patients given ondansetron, 1 Belg.: Avessat; Avessaron; Zofran; Braz.: Ansentron; Injectrax; first choice and no precautions are needed.1 more severe symptoms of liver disorder appear to be very Modifical; Nausedron; Ondantril; Ontrax; Vonau; Zofran; rare; however, there is a report of severe jaundice asso­ l. The Drug Database for Acute Porphyria. Available at: http:/fwww. Canad. : Zofran; Chile: Arnilene; Gardoton; Izofran; Levrox; ciated with ondansetron as an antiemetic for chemother­ drugs-porphyria.org (accessed 07/10/ll) Odanext; Oncoemett; Trorixt; China: An Si Xin ('!i'W!IiX); apy. 2 Symptoms did not recur when the patient received Aoyimai (JJ:!-�);Di Li Xin (Ji!l}Ji!IT); En Fu De (!8!'1!1:11i!l); En granisetron. Interactions Nuo Ping (}e/.Ul-'f);Fu Mi Ting C i*H); Kang Da Li Te (J*it:lz: l. Lewandowski MJ, Chapman SA. Ondansetron-induced aminotransfer­ Lu Wei Sen (lli\�it�);Ou Bei (IlXY!);Shi Tai (ll'f-�); Wei Ze ase level elevation: case report and review of the literature. Ondansetron does not appear to induce or inhibit the Yi Feng ('!i2$); Yi Shu Ning (.fui.:ll''T);Zofran (./1Rl1!:'i"'): 28: Pharmacotherapy 2008; 1542-6. cytochrome P450 isoenzyme system, but it is itself Zudan (tE:ft); Cz. : Danemett; Emeset; Novetron; Ondemet; 2. Verrill M, Judson Jaundice with ondansenon. Lancet 1994; 344: 190-1. L metabolised by multiple hepatic isoenzymes, including Setronont; Zofran; Denm.: Setofilm; Setrogen; Zofran; Zotrixt; CYP3A4, CYP2D6, and CYPlA2. US licensed product Fin.: Zofran; Fr.: Setofilm; Zophren; Ger.: Axisetron; cellondan; Gr.: Effects on the nervous system. Tonic-clonic movements information states that inducers or inhibitors of these Zofran; Biosetron; Cruzafen; Dentron; Fedral; Jodol; Nofail; Odasen; Odnatron; Onda; Ondameton; Ondaren; Ondaseprol; and frothing at the mouth occurred in a patient 90 min� isoenzymes may change the clearance and half-life of Ondeton; Otredil; Setrodan; Trondamet; Vefron; Zetron; Zoda� utes after an infusion of ondansetron;1 the patient ondansetron, but that on the basis of available data, no dose responded to diazepam intravenously. The manufacturers tron; Zofron; Zophralen; Hong Kong: Zofran; Hung.: Antivom; adjustments are recommended. UK licensed product Emetron; Ondagen; Zofran; India: Adom�O; Afon MD; Anse� had seen 10 patients who developed seizures during initial information states that enzyme inhibition of one isoenzyme care; set; Back2Norm; C-Tron; Dan set; Dasin; Dentron; clinical studies, but considered that, unlike this case, all Ail is usually compensated for by other enzymes and should Doin; Domi-Up; Donset; Donsetron; Doran�O; Dotson; Dutron; these patients had predisposing factors. Hypotension and result in little or no significant change in overall E�On; Eldon; Emeran; Emeset; Emestal�O; Emestop; Emigo; generalised tonic-clonic seizures were reported in a patient ondansetron clearance or dose requirement. Potent Emitino; Emitus; Emnil; Emsetron; Emstal; Emtron; Flatron; with metastatic breast cancer given ondansetron as an inducers of CYP3A4, such as phenytoin, carbamazepine, Flexi; Fodino; Gendem-MD; Glendan; Glotron; K�Tron; Kanset; intravenous bolus.2 Although seizures might have been and rifampicin, have been reported to increase ondansetron Keron; Lupisetron; Monda; Myset; Mytic; Naucet; Naucid; Neo� due to brain metastases, the authors concluded that clearance and reduce ondansetron plasma concentrations. mit; Nitron; Nosirid; Novatron; Nuset; O�Set; Odanse; Olex Tab; ondansetron had been the likely cause, since the patient Because of the reports of transient ECG changes in some Ominil; Omit; Onbit; Oncare; Oncoden; Oncon; Ond; Ondace; had no further problems when antiemetic therapy was Ondai; Ondansetran; Ondanz; Ondar; Ondarom; Ondas; Onda­ patients taking 5-m3 antagonists (see p. 1873.3), there is a changed to metoclopramide. A seizure associated with theoretical need for caution if given with drugs that prolong vom; Ondax; Ondem; Ondemet-MD; Ondet; Ondigo; Onditron; palonosetron therapy has also been reported -' Extrapyra­ QT�interval or cardiotoxic drugs such as anthracyclines; Ondocil; Ondocos; Ondorise; Ondosia; Ondosym; Ondot; Ondrea; Ondron; Ondrovit; Onest; Ongone; Oniz; Onkam; midal reactions in patients given ondansetron as part of a however, clinical evidence of a significant interaction seems Onlex; Ono; Onriz; Onsat; Onset; Onsett; Onstal; Onstar; chemotherapy regimen4•5 and for postoperative nausea to be mostly lacking. and vomiting6�8 have also been reported. In one case, 8 Ontek; Ontic; Ontil; Ontiz; Ontome; Onv; Onvin; Onzy; Oralis; Indon.: transient multifocal encephalopathy developed. Clinical Orio�DT; Oset; Osetron; Otron; Periset; Vomiof; Cedan� tron; Ceteron; Dantroxal; Entron; Frazon; Invomit; Kliran; manifestations such as clonus, oculogyric crisis, and oro� Analgesics. For evidence of reduced analgesic efficacy of Lametic; Narfoz; Odanostin; Ondavell; Onetic; Trovensis; Vom� mandibular and limb dystonia resembled those of structur­ tramadol in patients also given 5�HT3�receptor antagonists, such as ondansetron, see p. 140.3. ceran; Vometraz; Vometron; Zantron; Zofran; Irl. : Emitalt; al brain injury, and response to diphenhydramine was Emizof; Ondatab; Ondran; Setofilm; Zofran; Israel: Zofran; poor; despite this, the patient made a full neurological Ital.: Zofran; Malaysia: Osetron; Setronax; Zofran; Mex. : Danae; recovery over the course of 12 hours. For reference to sei � Antibacterials. Rifampicin pretreatment reduced the area Dosatron; Modifical; Nalisen; Nodantont; Onancen; Ondal; Pre� zures and dystonia associated with hypoglycaemia in an under the plasma concentration�time curve of oral ondan­ cirux; Vosrym; Zofran; Neth.: Setofilm; Zofran; Norw.: Zofran; ondansetron-treated child see Effects on Carbohydrate setron by 65% and of intravenous ondansetron by 48% in NZ: Ondanaccord; Onsetront; Zofran; Philipp.: Emistop; Emo­ Metabolism, p. 1873.3. Ondansetron and related drugs can healthy subjects.1 Use of rifampicin, or other potent indu� dan; Nozuca; Onset; Vometron; Zofran; Pol.: Atossa; Emetron; induce headache; it has sometimes been confused with cers of cytochrome P450 isoenzyme CYP3A4, with ondan­ Ondagen; OndaLEK; Setronon; Zofran; Port. : Emetron; Morpar; post-dural puncture headache 9 setron may reduce antiemetic efficacy. Nausiendt; Olmar; Otobrol; Zofran; Rus.: Domegan (,lJ;oMeraH); Emeset (3MeceT); Emetron (3MeTpoH); Latran (naTpaH); Ondasol 1. Sargent AI, et al. Seizure associated with ondansetron. Clin Pharm 1993; l. Villikka K, et al. The effect of rifampin on the pharmacokinetics of oral 12: (OHJmcoJI); Osetron (OceTpoH); Setronon (CeTpOHOH); Zofran 613-1 5. and inLravenous ondansetron. Clin Pharmacal Ther 1999; 65: 377�8 1. 2. Sharma A, Raina V. Generalised seizures following ondansetron. Ann (3o¢paH); S.Afr. : Alepet; Danset; Dantron; Nausetron; Vomiz; Oncol 2001; 12: 131-2. Zofer; Zofran; Singapore: Osetron; Setronax; Zofran; Spain: 3. Zambelli A. et al. Seizure associated with palonosetron. Support Care Antineoplastics. For mention of retrospective studies sug­ Carvyxt; Setofilm; Yatrox; Zofran; Swed. : Zofran; Zotrixt; Cancer 2009; 17: 217. Switz.: Zofran; Thai.: Dantron; Emeset; Emistop; Ondavell; 4. Krstenansky PM, et al. Extrapyramidal reaction caused by ondansetron. gesting a change of pharmacokinetic parameters of high­ Ann Pharmacother 1994; 28: 280. dose cyclophosphamide and cisplatin when given with an Onsia; Zetron; Zofran; Turk.: Zofer; Zofran; Zoltem; Zontron; 5. Mathews HG, Tancil CG. Extrapyramidal reaction caused by ondan­ ondansetron�containing antiemetic regimen, see Gastroin­ Zophralen; UK: Ondemet; Setofilm; Zofran; Ukr. : Emetron setron. Ann Pharmacother 1996; 30: 196. testinal Drugs, p. 773.3. (3MeipoH); Osetron (OceTpoH); Setronon (CeTpoHoH); Zofran 6. Stonell C. An extrapyramidal reaction to ondansetron. Br 1 Anaesth (3o¢paH); Zoltem (30JneM); USA: Zofran; Zuplenz; Venez.: Dis­ 1998; 81: 658. molan; Emeset; Tructum; Zofran. 7. Tolan MM, et al. Perioperative extrapyramidal reactions associated with ondansetron. Anesthesiology l 999; 90: 340-1. Pharmacokinetics 8. Ritter MJ,et al. Ondansetron-induced multifocal encephalopathy. Mayo India: Acidom-0; Alcirid�O; Alo� Peak plasma concentrations of ondansetron occur about 1.5 Multi-ingredient Preparations. Clin Proc 2003; 78: 1150-2. tac; Doran-0; Lupisetron Plus; Ond-R. 9. Sharma R, Panda A. Ondansetron-induced headache in a parturient hours after an oral dose of 8 mg, and about 6 hours after a mimicking postdural puncture headache. Can 1 Anaesth 2010; 57: 187-8. rectal dose. The absolute bioavailability is about 60%, mainly because of hepatic first-pass metabolism. In elderly Pharmacopoeial Preparations BP 2014: Ondansetron Injection; Ondansetron Tablets; subjects, bioavailability may be somewhat higher (65%) Hypersensitivity. Anaphylactoid reactions have been USP 36: Ondansetron Hydrochloride Oral Suspension; Ondan� reported in patients given ondansetron injections. The and clearance lower, presumably due to reduced hepatic setron Injection; Ondansetron Oral Solution; Ondansetron FDA stated in October 1993 that it had received 24 reports first-pass metabolism. Orally Disintegrating Tablets; Ondansetron Tablets. of such reactions, 1 mostly occurring after the first ondan­ Ondansetron is extensively distributed in the body; setron dose of the second or third chemotherapy cycle, about 70 to 75% of the drug in plasma is protein bound. It is and characterised by urticaria, angioedema, hypotension, metabolised in the liver through multiple enzymatic bronchospasm, and dyspnoea. Similar effects have been pathways; ondansetron is a substrate for cytochrome P450 reported in a patient with no prior exposure to ondan­ isoenzymes, primarily CYP3A4, but also CYPIA2 and setron.2 A protocol for skin testing has been documented.3 CYP2D6. Less than 5% of a dose is excreted unchanged in the urine. Cross-sensitivity between 5-HT3 antagonists has been reported;4 2 patients who had had a mild hypersensitivity The terminal elimination half-life is about 3 hours after oral or parenteral doses, and about 6 hours after rectal use. reaction to one 5�HT3 antagonist developed a more severe reaction after exposure to another. In the first case severe The terminal elimination half-life is prolonged to about 5 acute asthma, cyanosis, and loss of consciousness developed hours in the elderly and in those with renal impairment. after ondansetron in a patient who had previously had an These differences are not considered sufficient to warrant asthmatic reaction after tropisetron. The second patient had dosage adjustment. However, in patients with severe developed pruritus after a tropisetron injection and urticaria hepatic impairment, bioavailability may approach 100% NOTE. Distinguish from Ciclonium Bromide, p. after ondansetron, and subsequently developed anaphylac­ and clearance is markedly reduced, with elimination half­ unrelated antispasmodic. tic shock 5 minutes after a further dose of tropisetron. It was lives of 15 to 32 hours; dosage restriction is advisable (see Pharmacopoeias. In Jp n. Administration in Hepatic Impairment, p. 1872.3). In recommended that another 5-m3 antagonist should not be given as a replacement to patients who developed a general, children have a higher clearance than adults, hypersensitivity reaction to a drug of this class. However, although age-related reductions in clearance have also been there are reports of the successful use of granisetron in reported, with younger children having lower clearances. patients sensitive to ondansetron5 and vice versa.6 Use of weight-based doses compensates for these changes Oxapium iodide is an antimuscarinic that has been used as l. Chen M, et al. Anaphylactoid-anaphylactic reactions associated with and normalises exposure in paediatric patients. an antispasmodic in the treatment of gastrointestinal ondansetron. Ann Intern Med 1993; 119: 862. disorders and renal calculi. 2. Weiss KS. Anaphylactic reaction to ondansetron. Arch Intern Med 2001; References. 161: 2263. I. Roila F, Del Favero A. Ondansetron clinical pharmacokinetics. Clin 3. Fernando SL. Broadfoot AJ. Ondansetron anaphylaxis: a case report and Pharmacokinet 1995; 29: 95-109. 102: P. i protocol for skin testing. Br J Anaesth 2009; 285-6. 2. Figg WD, et al. Pharmacokinetics of ondansctron in patients with hepatic r.�P.?r?t ?n.S...... KM Clin Pharmacol l996; 36: 4. Kataja V, de Bruijn . Hypersensitivity reactions associated with 5- insufficiency. 1 206-15. ProprietaryPreparations (details are given in Volume B) hydroxytryptaminerrecentor antagonists: a class effect? Lancet 1996; 3. Van Den Berg CM, et al. Pharmacokinetics of three formulations of 347: 584-5. ondansetron hydrochloride in healthy volunteers: 24-mg oral tablet, 5. Bousquet PJ, et al. Isolated urticaria to ondansetron and successful rectal suppository, and iv infusion. Am J Health-Syst Pharm 2000; 57: Single-ingredient Preparations. Jpn: Esperan. treatment with granisetron. Allergy 2005; 60: 543-4. 1046-50.

All cross�references refer to entries in Volume A