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Kytril: a once-daily 5HT 3 receptor antagonist for control of chemotherapy-induced nausea and vomiting (CINV). Frederick Schnell Central Georgia Hematology Oncology Associates Macon, GA, USA. Nausea and vomiting significantly impact on patients’ quality of life 1. - PowerPoint PPT Presentation
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Kytril: a once-daily 5HT3 receptor antagonist for control of
chemotherapy-induced nausea and vomiting (CINV)
Frederick SchnellCentral Georgia Hematology Oncology Associates
Macon, GA, USA
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
Physicians/nurses (estimate)
Patients(actual)
Acute (%)
69 53no nausea
no vomiting 83 72
Delayed (%)
no nausea 76 43
no vomiting 91 59
1. Grunberg. Proc Am Soc Clin Oncol 2002;21:250a (Abstract 996)
†First-cycle moderately emetogenic chemotherapy
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
Rank 19831 19952
1 Vomiting Nausea
2 Nausea Alopecia
3 Alopecia Vomiting
1. Coates et al. Eur J Cancer Clin Oncol 1983;19:203–82. de Boer-Dennert et al. Br J Cancer 1997;76:1055–61
3. Griffin et al. Ann Oncol 1996;7:189–95
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
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;17:2971–942. 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
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
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
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
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;14:17–232. 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
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;14:63–772. Jorgensen et al. Ann Pharmacother 2001;35:1004–9
3. Hanlon et al. Drugs Aging 2001
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 day1. Orr, Chen. Am J Physiol Gastrointest Liver Physiol 2002;283:G1226–312. 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
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
Drug-drug interactionsKytril
– 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;24:1–43. Stanford, Stanford. J Psychopharmacol 1999;13:313–7
4. www.hivmedicationguide.com/Asp_bin/drug%20interactions.asp5. www.anaesthetist.com/physiol/basics/metabol/cyp/o.htm
6. DeWitte et al. Anesth Analg 2001;92:1319–21
Hepatic metabolism route
Kytril has not been shown to induce or inhibit hepatic metabolism1
CYP1A1 CYP1A2 CYP2D6 CYP3A3/4/5
Granisetron
Ondansetron *
Dolasetron
Tropisetron *
*Minor
1. Bower. Cancer J 2002;8:405–14
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
AE = adverse event
Ultra-rapid metabolizers (enzyme induction)
Metabolism
Efficacy
Poor metabolizers(enzyme inhibition)
Metabolism
Risk of AEs
1. Kaiser et al. J Clin Oncol 2002;20:2805–11
Cardiovascular warning (prescribing information)
Kytril1
Ondansetron2
Dolasetron3
Tropisetron4
Cardiovascular warnings
1. Kytril (granisetron hydrochloride) Prescribing Information2. Zofran (ondansetron hydrochloride) Prescribing Information
3. Anzemet (dolasetron mesylate) Prescribing information 4. Navoban (tropisetron) Prescribing Information
Cardiotoxic effects of 5-HT3-receptor antagonists in healthy adults
Agent Dose ECG changes Clinical effects
Kytril1 10 µg/kg, i.v. (5 min) No differences Not clinically significant
Ondansetron1 10 µg/kg, i.v. (30 s)
32 mg, i.v. (15 min)
mean post-dose QTc interval*
Dolasetron2 1.2, 1.8, 2.4 mg/kg, i.v. PR, QTc, QRS intervals**
Dose-related in heart rate
Ondansetron2 32 mg, i.v. QTc* & JT** intervals in heart rate
Kytril3 2 mg, p.o. Isolated ventricular & supraventricular ectopic activity
No sustained arrhythmias
Dolasetron4 0.6–5.0 mg/kg, i.v. PR interval & QRS duration
heart rate at
3 mg/kg or over*p<0.05; **p<0.001
1. Boike et al. Am J Health-Syst Pharm 1997;54:1172–62. Benedict et al. J Cardiovasc Pharmacol 1996;28:53–93. Gray et al. Aviat Space Environ Med 1996;67:759–61
4. Hunt et al. J Clin Pharmacol 1995;35:705–12
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
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
A rational choice in the elderly
Co-morbidity assessmentPolypharmacy
Drug–drug interactions
Antiemetic selection that limits complications
Reduced risk of toxicityIncreased possibility of clinical efficacy
Kytril vs ‘conventional’/older antiemeticsDouble-blind, placebo-controlled trial30 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
Kytril Comparator p value
Complete response* rate 53% 13% 0.02
No vomiting rate(24 hours)
60% 13% 0.008
*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
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
Kytril vs tropisetron inpediatric cancer patients
0
20
40
60
80
100
Vomiting Nausea
Kytril
tropisetron
Pa
tie
nts
(%
)
8882
74
56
p<0.05p<0.002
Aksoylar et al. Pediatr Hematol Oncol 2001;18:397–406
Kytril is well tolerated – adverse events classed as mild and transient
Most frequently reported adverse events in clinical trials with Kytril
Occurrence
Event Kytril1 comparator2 placebo3
Headache 20% 13% 12%
Asthenia 18% 10% 4%
Constipation 14% 16% 8%
Diarrhea 9% 10% 4%
Dyspepsia 6% 5% 4%
Abdominal pain 4% 6% 3%
Kytril Prescribing Information, chemotherapy data
12 mg p.o. q.d. (n=1450); 2Metochlopramide/dexamethasone; phenothiazines/ dexamethasone; dexamethasone alone; prochlorperazine (n=599); 3(n=185)
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;30:581–42. Feyer et al. Support Care Cancer 1998;6:253–60
3. Laszlo. In: Antiemetics and Cancer Chemotherapy, 1983:1–5
Incidence of nausea and vomiting
Overall, 38.7% of patients experienced RINV Previous chemotherapy increased risk of symptoms
0
10
20
30
40
50
Vomiting Nausea
Previouschemotherapy
No chemotherapy
Pa
tie
nts
(%
)
22.1%
45.6%
15.1%
33.1%p=0.028
p=0.003
IGARR. Int J Radiat Oncol Biol Phys 1999;44:619–25
Duration of nausea and vomiting following radiotherapy
The symptoms of RINV can last several hours after therapy1
0
10
20
30
40
50
60
0 60 90 120 150 180 210 240 270 300 330 360
Duration of symptoms (min)
Pat
ien
ts e
xper
ien
cin
g n
ause
a an
d v
om
itin
g (
%)
Upper hemibody (n=88)
Lower hemibody (n=101)
1. Danioux et al. Clin Radiol 1979;30:581–4
Kytril has a 24-hour duration of action
Kytril has ‘insurmountable’ 5HT3 receptor binding
2
1
0
Ep
iso
des
/ho
ur
0 4 8 12 16 20 24
Time after chemotherapy administration (hours)
First-day early-onset emesis
First-day late-onset emesis
CisplatinCyclophosphamideCarboplatin
Kytril
Ondansetron
9 hours
4 hours
Addition of NK1 receptor antagonists improves efficacy of standard antiemetic regimen
Standard 5HT3/dex
combinationTriple
combination p value
Poli-Bigelli et al. (n=523)1
Day 1 complete response rate (%)
68.4 82.8 <0.001
Overall 5-dayresponse rate (%)
43.3 62.7 <0.001
Hesketh et al. (n=521)2
Overall 5-dayresponse rate (%)
52.3 72.7 <0.001
1. Poli-Bigelli et al. Cancer 2003;97:3090–82. Hesketh et al. J Clin Oncol 2003;21:4112–9
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
Emetic potential of therapy Acute emesis Delayed emesis
High 5HT3 + Dex + NK1Dex + NK1
Moderate 5HT3 + Dex Dex
Low Dex + metoclopramide –
International anti-emetic guidelines†
† Adapted from Multinational Association for Symptom Control in Cancer
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
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