Frederick Schnell Central Georgia Hematology Oncology Associates Macon, GA, USA

1. Kytril: a once-daily 5HT3 receptor antagonist for control of chemotherapy-induced nausea and vomiting (CINV) Frederick Schnell Central Georgia Hematology Oncology AssociatesMacon, GA, USA

2. Nausea and vomiting significantly impact on patients’ quality of life1 • Following chemotherapy†, nausea/vomiting scored by patients (n=80) using 5-day diary and 6-day Functional Living Index • Doctors and nurses (n=9) estimated frequency of acute and delayed nausea/vomiting †First-cycle moderately emetogenic chemotherapy 1. Grunberg. Proc Am Soc Clin Oncol 2002;21:250a (Abstract 996)

3. Nausea and vomiting are rated as major side-effects of cancer therapy • Following the introduction of 5HT3 receptor antagonists, the rating of vomiting as a side-effect of chemotherapy has declined2,3 1. Coates et al. Eur J Cancer Clin Oncol 1983;19:203–8 2. de Boer-Dennert et al. Br J Cancer 1997;76:1055–61 3. Griffin et al. Ann Oncol 1996;7:189–95

4. Pharmacologic control of vomiting • Pharmacologic prevention of vomiting is directed at blocking vomiting pathways before the administration of chemotherapy or radiotherapy treatments • Antiemetics may act via the:1 • vomiting center • chemoreceptor trigger zone • peripheral receptors (e.g. vagal afferent nerves) 1. Lindley, Blower. Am J Health-Syst Pharm 2000;57:1685–97

5. Which antiemetic? • Commonly used agents include: • dopamine-receptor antagonists • corticosteroids • benzodiazepines • antihistamines • 5HT3-receptor antagonists • 5HT3-receptor antagonists are currently the ‘gold-standard’ antiemetic1–4 1. Gralla et al. J Clin Oncol 1999;17:2971–94 2. ASHP. Am J Health-Syst Pharm 1999;56:729–64 3. MASCC. Ann Oncol 1998;9:811–194. Koeller et al. Support Care Cancer 2002;10:514–22

6. Optimizing antiemetic treatment • Awareness must be increased for: • current guidelines • evidence supporting guideline recommendations • incidence of and risk factors for nausea and vomiting • Antiemetic treatment must be individualized based on patients’ cytotoxic treatment and patient-specific factors

7. Antiemetic guidelines • Differences exist in antiemetic guidelines • ASCO (American Society of Clinical Oncology) • MASCC (Multinational Association of Supportive Care in Cancer) • ASHP (American Society of Health-Systems Pharmacists) • Need easy-to-follow, comprehensive consensus guidelines • Need guidelines from radiation experts that address needs of radiation therapy patients

8. Patients need less complicated, effective antiemetic therapy • The majority of cancer patients receiving radiotherapy are elderly out-patients • require fast-acting, long-duration oral antiemetics • Convenient once-daily oral dosing should: •  patient compliance •  control of nausea and vomiting •  patient quality of life

9. Who is the ‘average’ cancer patient? • Cancer incidence and mortality greatest in elderly patients1 • ‘average’ patient >65 years2 • increased incidence of co-morbidities with aging (>3.6 in patients aged >65 years)3 • increased use of concomitant medications in patients >65 years (average medications=4.3 per person)4 1. Yancik, Ries. Hematol Oncol Clin North Am 2000;14:17–23 2. Yancik et al. J Clin Oncol 2001;19:1147–51 3. Yancik. Cancer 1997;80:1273–834. Jorgensen et al. Ann Pharmacother 2001;35:1004–9

10. Chemotherapy- and radiation-induced emesis in the elderly • Elderly are more likely to suffer from chemotherapy and radiotherapy-induced toxicity1 • may have declining organ function • co-morbidities • concomitant medications2,3 • Consequences of nausea and vomiting can be exacerbated in elderly, mainly in patients with co-morbidities • dehydration in patients taking diuretics • exacerbation of cognitive problems • falls due to extra-pyramidal effects 1. Extermann et al. Hematol Oncol Clin North Am 2000;14:63–77 2. Jorgensen et al. Ann Pharmacother 2001;35:1004–9 3. Hanlon et al. Drugs Aging 2001

11. Suboptimal antiemetic treatment in the elderly • Older patients may receive suboptimal antiemetic treatment because of: • gastrointestinal changes1 – decreased drug absorption • contraindications to corticosteroids (e.g. with hypertension, diabetes)2 • swallowing problems1,3 • noncompliance to oral therapies4 • possible cognitive impairment/confusion5 • Patients need a single drug intake per day 1. Orr, Chen. Am J Physiol Gastrointest Liver Physiol 2002;283:G1226–31 2. http://www.geriatricsyllabus.com/syllabus/main.jsp?cid=SCC-DER-4-2 3. Wilkinson, de Picciotto. S Afr J Commun Disord 1999;46:55–644. Lebovits et al. Cancer 1990;65:17–22; 5. Schroder et al. J Neural Transm Suppl 1998;54:51–9

12. Which 5-HT3-receptor antagonist? • Kytril (granisetron) and ondansetron are currently indicated for CINV and radiotherapy-induced nausea and vomiting (RINV) • Differences exist between Kytril and ondansetron • underlying pharmacology • duration of efficacy • hepatic metabolism • dose adjustments in hepatically impaired patients • dosing regimens

13. Drug-drug interactions • Kytril • not shown to induce or inhibit hepatic metabolism1 • only 5-HT3-receptor antagonist not linked to CYP2D6 genetic polymorphism1 • Ondansetron • known interactions • chemotherapeutic agents2 • antidepressants3 • antibiotics4,5 • analgesics6 1. Blower. Cancer J 2002;8:405–14; 2.Cagnoni et al. BMT 1999;24:1–4 3. Stanford, Stanford. J Psychopharmacol 1999;13:313–74. www.hivmedicationguide.com/Asp_bin/drug%20interactions.asp 5. www.anaesthetist.com/physiol/basics/metabol/cyp/o.htm 6. DeWitte et al. Anesth Analg 2001;92:1319–21

14. Hepatic metabolism route • Kytril has not been shown to induce or inhibit hepatic metabolism1 *Minor 1. Bower. Cancer J 2002;8:405–14

15. CYP2D6 polymorphism • Genetic polymorphism shown to affect cancer patients’ response to ondansetron and tropisetron therapy1 • Kytril not at risk for genetic polymorphism • genetic testing required to determine true risk Ultra-rapid metabolizers (enzyme induction)  Metabolism  Efficacy Poor metabolizers (enzyme inhibition)  Metabolism  Risk of AEs AE = adverse event 1. Kaiser et al. J Clin Oncol 2002;20:2805–11

16. Cardiovascular warnings 1. Kytril (granisetron hydrochloride) Prescribing Information 2. Zofran (ondansetron hydrochloride) Prescribing Information 3. Anzemet (dolasetron mesylate) Prescribing information 4. Navoban (tropisetron) Prescribing Information

17. Cardiotoxic effects of 5-HT3-receptor antagonists in healthy adults *p<0.05; **p<0.001 1. Boike et al. Am J Health-Syst Pharm 1997;54:1172–6 2. Benedict et al. J Cardiovasc Pharmacol 1996;28:53–9 3. Gray et al. Aviat Space Environ Med 1996;67:759–61 4. Hunt et al. J Clin Pharmacol 1995;35:705–12

18. Dosing regimen: Kytril vs ondansetron • Ondansetron dosed 2–3 times daily • associated with swallowing problems when patients are nauseated • Once-daily Kytril dosing •  patient compliance •  patient quality of life

19. Antiemetic therapy decisions • Therapy should depend on the unique needs of each patient: • age/health • co-morbidities • concomitant medications • Physicians need to be aware that differences exist between the available 5HT3-receptor antagonists

20. Co-morbidity assessment Polypharmacy Drug–drug interactions Antiemetic selection that limits complications Reduced risk of toxicity Increased possibility of clinical efficacy A rational choice in the elderly

21. Kytril vs ‘conventional’/older antiemetics • Double-blind, placebo-controlled trial • 30 patients undergoing single-fraction total body irradiation (7.5 Gy) received i.v.: • Kytril, 3 mg‡ • metoclopramide (20 mg), dexamethasone (6 mg/m2), lorazepam (2 mg), 1 hour prior to radiotherapy *No vomiting, no more than mild nausea and no rescue medication ‡Off-label dose in the USA 1. Prentice et al. Bone Marrow Transplant 1995;15:445–8

22. Kytril is effective in patients refractory to ‘conventional’ antiemetics • Patients (n=15) refractory to treatment with dopamine-receptor antagonists were scheduled to receive Kytril, 1 mg/day p.o.,‡ 1–2 hours prior to further radiotherapy* • Results of Kytril therapy • complete remission of symptoms was observed in all patients on days 1–3 • immediate remission of nausea and vomiting was apparent in 33% of patients *Pelvic, lumboaortic ± iliac/splenic regions or mediastinum radiotherapy ‡Off-label dose 1. Krengli et al. Minerva Med 1996;87:605–8

23. 100 Kytril p<0.002 tropisetron 88 80 p<0.05 82 74 60 Patients (%) 56 40 20 0 Vomiting Nausea Kytril vs tropisetron inpediatric cancer patients Aksoylar et al. Pediatr Hematol Oncol 2001;18:397–406

24. Kytril is well tolerated – adverse events classed as mild and transient • Most frequently reported adverse events in clinical trials with Kytril 12 mg p.o. q.d. (n=1450); 2Metochlopramide/dexamethasone; phenothiazines/ dexamethasone; dexamethasone alone; prochlorperazine (n=599); 3(n=185) Kytril Prescribing Information, chemotherapy data

25. RINV – a significant clinical problem • Over 80% of patients undergoing radiation of the upper torso will experience nausea and vomiting1 • Fractionated radiotherapy may involve up to 40 fractions over 6–8 weeks, resulting in prolonged symptoms of emesis2 • Uncontrolled nausea and vomiting may lead patients to delay or refuse future radiotherapy3 1. Danioux et al. Clin Radiol 1979;30:581–4 2. Feyer et al. Support Care Cancer 1998;6:253–60 3. Laszlo. In: Antiemetics and Cancer Chemotherapy, 1983:1–5

26. p=0.003 50 Previouschemotherapy 45.6% 40 p=0.028 No chemotherapy 33.1% 30 Patients (%) 22.1% 20 15.1% 10 0 Vomiting Nausea Incidence of nausea and vomiting • Overall, 38.7% of patients experienced RINV • Previous chemotherapy increased risk of symptoms IGARR. Int J Radiat Oncol Biol Phys 1999;44:619–25

27. 60 Upper hemibody (n=88) 50 Lower hemibody (n=101) 40 Patients experiencing nausea and vomiting (%) 30 20 10 0 0 60 90 120 150 180 210 240 270 300 330 360 Duration of symptoms (min) Duration of nausea and vomiting following radiotherapy • The symptoms of RINV can last several hours after therapy1 1. Danioux et al. Clin Radiol 1979;30:581–4

28. Cisplatin Cyclophosphamide Carboplatin Kytril has a 24-hour duration of action • Kytril has ‘insurmountable’ 5HT3 receptor binding Kytril Ondansetron 9 hours 4 hours First-day early-onset emesis 2 1 0 First-day late-onset emesis Episodes/hour 0 4 8 12 16 20 24 Time after chemotherapy administration (hours)

29. Addition of NK1 receptor antagonists improves efficacy of standard antiemetic regimen 1. Poli-Bigelli et al. Cancer 2003;97:3090–8 2. Hesketh et al. J Clin Oncol 2003;21:4112–9

30. Kytril effective in combination with steroids and NK1 receptor antagonists • Combination of 5HT3 receptor antagonist and dexamethasone improves emetic control but delayed emesis still problematic • Addition of neurokinin 1 (NK1) receptor antagonists to 5HT3/dexamethasone extends emetic control • triple combination is now standard of care International anti-emetic guidelines† † Adapted from Multinational Association for Symptom Control in Cancer

31. Conclusions • The 5-HT3-receptor antagonists are effective for the treatment of RINV • Kytril (granisetron) • effective in refractory patients • more effective than ‘conventional’ antiemetics • at least as effective as ondansetron • well tolerated • once-daily dosing • low risk for drug-drug interactions • no cardiovascular warning