Reviews/Evaluations 5-Hydroxytryptamine3 (5-HT3) Receptor Antagonists Generic Name Brand Name Manufacturer Dolasetron Anzemet Aventis Granisetron Kytril Roche Ondansetron Zofran GlaxoSmithKline I. FDA Indications (1-3) Treatment PONV Prevention PONV Prevention CINV (highly emetogenic) Dolasetron oral X X Prevention CINV RINV (moderately emetogenic) parenteral X X X X Granisetron oral X X X parenteral X X X X Ondansetron oral X X X X parenteral X X X PONV=postoperative nausea and vomiting CINV=chemotherapy induced nausea and vomiting RINV=radiation therapy induced nausea and vomiting II. Pharmacology The 5-HT3 are selective serotonin inhibitors, competitively inhibit the binding of serotonin to 5-HT3 receptors. Their antiemetic effects are postulated to stem from blockade of 5-HT3 receptors located on the nerve terminals of the vagus in the periphery and centrally in the chemoreceptor trigger zone of the area postrema. These drugs have little or no affinity for other serotonin receptors; for alpha or beta-adrenergic; for dopaminergic; or for histamine receptors.(1-3) III. Pharmacokinetics These agents are well absorbed from the gastrointestinal tract and undergo some first-pass metabolism.(1-3) The extent and rate of ondansetron's absorption is greater in women than men. A reduction in clearance of ondansetron is found in women and the elderly. However, no dosage adjustment is recommended per manufacturer.(3) IV. Clinical Efficacy A. Postoperative Nausea and Vomiting Many factors can influence the risk and severity of postoperative nausea and vomiting. The risk is higher in adults than children, in women (especially premenopausal women) than in men, in obese patients, in patients who have a high level of preoperative anxiety, and in patients with a previous history of
motion sickness or postoperative nausea and vomiting. Gastric emptying disorder or gastric hypomotility, certain types and length of operative procedure, or preanesthetic medications can all influence the risk of postoperative nausea and vomiting.(4) Not all surgical patients require prophylactic medications for nausea and vomiting. Approximately 30% of patients will have symptoms for the first 24 hours after surgery. The decision to provide prophylactic therapy should be based on the presence of risk factors for nausea and vomiting and the potential for serious sequalae from vomiting.(4) 1. Dolasetron Clinical trials showed single oral dolasetron doses of 25-200 mg or intravenous doses of 12.5-100 mg provided better efficacy than placebo in prevention of PONV in women undergoing gynecological surgery.(5-10) No increase in efficacy was seen with higher doses. 2. Ondansetron Two studies reported that single oral ondansetron dose (16 mg) was significantly more efficacious than placebo in prevention of PONV in women undergoing inpatient surgical procedures.(11,12) Single parenteral doses of ondansetron were studied for prevention of PONV in outpatient and inpatient procedures. Both 4 mg and 8 mg dose had significantly better response rate than placebo; however, no additional benefit was observed in patients who received the 8 mg compared to patients who received the 4 mg dose.(13-15) 3. Granisetron Single parenteral doses of granisetron were found to be more efficacious in prevention of PONV than placebo. However, the 3 mg dose did not provide additional benefit compared to the 1 mg dose.(16) B. Treatment of Postoperative Nausea and Vomiting Single parenteral doses of dolasetron (12.5-100mg) and granisetron (0.1-3mg) were significantly better in providing complete response (no vomiting, no rescue medication) than placebo. No significant increase in efficacy was seen with higher doses for both agents.(2,17,18) C. Acute Chemotherapy-Induced Nausea and Vomiting (CINV) 1. Highly Emetogenic Chemotherapy A direct comparison study between parenteral doses of dolasetron and ondansetron showed that a single 1.8 mg/kg dose of dolasetron injection was equivalent to a single 32 mg dose of ondansetron injection in complete response rate.(19) In another study, a single intravenous 1.8 mg/kg dose of dolasetron showed similar results in prevention of CINV compared to a single 3 mg intravenous dose of granisetron.(20) The response rates of oral granisetron were found to be comparable to those obtained with parenteral ondansetron.(21) Overall, no significant difference were seen between the three agents.(4,22,23) 2. Moderately Emetogenic Chemotherapy Both single and multiple oral dose of granisetron were found to be significantly
better than prochlorperazine historical control in providing complete response rate.(2) Single oral dolasetron dose (100 mg) provided similar effects than multiple dose oral ondansetron (8 mg tid).(24) Oral twice-daily dosing of ondansetron (8 mg bid) has shown to be as efficacious as three times daily dosing (8 mg tid) in patients receiving cyclophosphamide-based therapies.(25) D. Radiation Therapy-Induced Nausea and Vomiting (RINV) Many patients receiving radiation therapy will not require prophylactic medication for RINV. Nausea and vomiting associated with radiation are less predictable and severe than chemotherapy-induced nausea and vomiting. The site of radiation is a primary factor in assessing the risk, onset, peak and duration of nausea and vomiting with radiation therapy. Other radiation-related risk factors include the dose, dose rate, and field size. Chemotherapy given immediately before or concurrently with radiation therapy also increases the risk of nausea and vomiting. Generally, patients receiving total or hemibody irradiation (with or without concomitant chemotherapy) or single-exposure, high-dose radiation therapy to the upper abdomen should receive prophylactic therapy in preventing RINV with each day of therapy.(4) Only granisetron and ondansetron have the FDA approved indication for prevention of RINV. Oral administration is the recommended route. Both agents showed superior efficacy in complete response rates than non-5ht3 antagonists historical antiemetic controls (e.g. metoclopramide, prochlorperazine).(4,26) V. Adverse Effects Generally, these drugs are safe and well tolerated. Their adverse effect profiles are similar. All three drugs have demonstrated cardiac effects of asymptomatic EKG changes in clinical trials. Dolasetron may cause prolongation of the QTc interval while granisetron and ondansetron may cause arrhythmia such as sinus bradycardia. Common adverse effects are headache, dizziness, diarrhea, abdominal pain and transient AST elevation.(1-3) VI. Drug-Drug Interactions Although these drugs are metabolized through the cytochrome P-450 enzyme system, they do not induce or inhibit the P-450 enzymes. Inhibitor or inducer of the P-450 enzyme system may change the clearance of these drugs. There have been no major drug-drug interactions reported in post-marketing period.(1-3) VII. Dosing (Adults)(1-3) Dosing Adults table (pdf file) VIII. Dosing (Pediatrics)(1-3) Dosing Pediatrics table (pdf file) IX. Product Comparison / Summary Ondansetron and granisetron are available in oral solution. Ondansetron orally disintegrating tablets do not provide additive efficacy or improvement in safety versus regular ondansetron tablets. Ondansetron, granisetron and dolasetron have essentially equivalent anti-emetic activity and safety profile based on several large, randomized,
controlled trials. There is no evidence for any difference between oral or parenteral route; thus both dosage forms can be used interchangeably. Single dose 5-HT3 antagonist regimens are as effective as multiple-dose schedules. Using 5-HT3 antagonists beyond the first 24 hour for prevention of delayed emesis is still controversial. X. Antiemetics Clinical Guidelines(4,26) American Society of Health System Pharmacists American Society of Clinical Oncology Chemotherapy-induced N/V Emetogenic* level 1 Not required Not required level 2 Corticosteroids alone or Corticosteroids alone prochlorperazine level 3-5 Treatment of Breakthrough CINV(a) Delayed CINV Radiation induced N/V(b) Treatment of Radiation induced N/V Postoperative N/V Treatment of Postoperative N/V Corticosteroids + 5-HT3 Lorazepam, corticosteroids, prochlorperazine, metoclopramide, haloperidol Corticosteroids + metoclopramide or a 5-HT3 receptor antagonist 5-HT3 receptor antagonists Prochlorperazine, metoclopramide or 5-HT3 receptor antagonists Droperidol or 5-HT3 Droperidol or 5-HT3 Corticosteroids + 5-HT3 Not addressed Corticosteroids + metoclopramide or a 5-HT3 receptor antagonist 5-HT3 ± Corticosteroids (high risk) Prochlorperazine or 5-HT3 (low risk) 5-HT3 ± Corticosteroids (high risk) Prochlorperazine or 5-HT3 (low risk) Not addressed Not addressed Anticipatory Emesis None None (a) ASHP: 5-HT3 are effective, but are not better than the less expensive agents (b) ASHP: There is no evidence to support the use of 5-HT3 24 hours beyond the last dose of radiation * Emetogenicity: Level 1 (<10% frequency); Level 2 (10-30% frequency); Level 3 (30-60% frequency); Level 4 (60-90% frequency); Level 5 (>90% frequency) N/V=nausea and vomiting; CINV=chemotherapy-induced nausea and vomiting Guidelines for use: Review of available clinical evidences showed that the 5-HT3 receptor
antagonists are a cost-effective choice for adults and children receiving moderately to highly emetogenic chemotherapy agents for up to 3 days per course. Clinical studies and guidelines support the use of 5-HT3 receptor antagonists for prevention of radiation therapy-induced nausea and vomiting during the course of radiation. There is no evidence to support the use of 5-HT3 24 hours beyond the last dose of radiation. For delayed chemotherapy-induced emesis, clinical guidelines recommended corticosteroids plus metoclopramide or 5-HT3 receptor antagonists. These drugs have shown to be similar in efficacy and safety at equivalent doses. Clinical guidelines by ASHP and ASCO recommended using oral dosage form, unless clinically inappropriate. These drugs are effective in the treatment of breakthrough nausea and vomiting, but their superiority over more traditional, less expensive agents has not been determined. The decision to provide prophylactic therapy for PONV should be based on the presence of risk factors for nausea and vomiting and the potential for serious sequalae from vomiting. Traditional antiemetics (i.e. droperidol, metoclopramide, prochlorperazine) are commonly considered as first line agents. If side effect profile is of concern, then oral ondansetron and dolasetron, or intravenous granisetron may be considered as alternatives. References 1. Dolasetron (Anzemet) Product Information. Aventis. February 2002 2. Granisetron (Kytril) Product Information. Roche. August 2002 3. Ondansetron (Zofran) Product Information. GlaxoSmithKline May 2001 4. American Society of Health-System Pharmacists. ASHP therapeutic guidelines on the pharmacologic management of nausea and vomiting in adult and pediatric patients receiving chemotherapy or radiation therapy or undergoing surgery. 5. Diemunsch P, Nave S, Meyerson LJ. Evaluation of the antiemetic properties of dolasetron mesylate in gynecological surgery. Br J Anesth 1994;72(Suppl 1):82. 6. Graczyk SG, Mckenzie R, Kallar S et al. Intravenous dolasetron for the prevention of postoperative nausea and vomiting after outpatient laparoscopic gynecologic surgery. Anesth Analg 1997;84:325-330. 7. Diemunsch P, Leeser J, Helmers JH et al. Oral dolasetron mesylate for prevention of postoperative nausea and vomiting (PONV). Anesthesiology 1996;85:3A. 8. Warriner B, Knox D, Belo S et al. Prophylactic oral dolasetron mesylate reduces postoperative nausea and vomiting following abnormal hysterectomy. Anesthesiology 1995;83(3A):A312. 9. Diemunsch P, Kortilla K, Lesser J et al. Oral dolasetron mesylate for prevention of postoperative nausea and vomiting: A multicenter, doubleblind, placebo-controlled study. J Clin Anesth 1998;10:145-152. 10. Diemunsch P, D'Hollander A, Paxton L, Schoeffler P, Wessel P, Nave S et al. Intravenous dolasetron mesilate in the prevention of postoperative nausea and vomiting in females undergoing gynecological surgery. J Clin Anesth 1997;9:365-373. 11. Rust M, Cohen LA. Single oral dose ondansetron in the prevention of
postoperative nausea and emesis. Anaesthesia 1994;49(Suppl):16-23. 12. Scuderi P, Pearman M, Kovac A et al. Single-dose oral ondansetron prevents nausea and vomiting after inpatient surgery. J Appl Res 2001;1(1):49-56. 13. McKenzie R, Kovac A, O'Connor T et al. Comparison of ondansetron versus placebo to prevent postoperative nausea and vomiting in women undergoing ambulatory gynecologic surgery. Anesthesiology 1993;78(1):21-28. 14. Pearman MH. Single dose intravenous ondansetron in the prevention of postoperative nausea and vomiting. Anesthesia 1994;49(Suppl):11-15. 15. Khalil SN, Kataria B, Pearson K et al. Ondansetron prevents postoperative nausea and vomiting in women outpatients. Anesth Analg 1994;79:845-851. 16. Wilson AJ, Diemunsch P, Lindeque BG et al. Single-dose i.v. granisetron in the prevention of postoperative nausea and vomiting: A dose ranging study. Br J Anaesthesia 1992;68:466-70. 17. Diemunsch P, Leeser J, Feiss P et al. Intravenous dolasetron mesylate ameliorates postoperative nausea and vomiting. Can J Anaesthesiol 1997;44(2):173-181. 18. Kovac A, Melson T, Graczyk S et al. Treatment of postoperative nausea and vomiting with single doses of iv dolasetron: A multicenter trial. Anesthesiology 1995;83(3A):A6. 19. Hesketh P, Navari R, Grote T et al. Double-blind, randomized comparison of the antiemetic efficacy of intravenous dolasetron mesylate and intravenous ondansetron in the prevention of acute cisplatin-induced emesis in patients with cancer. J Clin Oncol 1996;14(8):2242-2249. 20. Audhuy B, Cappelaere P, Martin M, Cervantes A, Fabbro M, Riviere A et al. A double-blind, randomized comparison of the antiemetic efficacy of two intravenous doses of dolasetron mesilate and granisetron in patients receiving high dose cisplatin chemotherapy. Eur J Cancer 1996;32A(5):807-813. 21. Gralla RJ Navari RM, Hesketh PJ et al. Single-dose oral granisetron has equivalent antiemetic efficacy to intravenous ondansetron for highly emetogenic cisplatin-based chemotherapy. J Cin Oncol 1998;16:1568-1573. 22. Gebbia V, Cannata G, Testa A et al. Ondansetron versus granisetron in the prevention of chemotherapy-induced nausea and vomiting. Cancer 1994;74(7):1945-1952. 23. Gralla RJ, Popovic W, Strupp J et al. Can an oral antiemetic regimen be as effective as intravenous treatment against cisplatin: Results of a 1054 patient randomized study of oral granisetron versus IV ondansetron. Proc Am Soc Clin Oncol 1997;15:52a (abstract). 24. Fauser AA, Duclos B, Chemaissani A et al. Therapeutic equivalence of single oral doses of dolasetron mesylate and multiple doses of ondansetron for the prevention of emesis after moderately emetogenic chemotherapy. Eur J Cancer 1996;32A(9):1523-1529. 25. Beck TM, York M, Chang A et al. Oral ondansetron 8 mg twice daily is as effective as 8 mg three times daily in the prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy. Cancer Investigation 1997;15(4):297-303. 26. Gralla RJ, Osoba D, Kris MG, Kirkbride P, Hesketh PJ, Chinnery LW et al. Recommendations for the use of antiemetics: evidence-based, clinical practice guidelines. J Clin Oncol 1999;17(9):2971-2994.
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