Drugs 43 (Supp\. 3): 11-22, 1992 0012-6667/92/0300-0011/$6.00/0 © Adis International Limited. All rights reserved. DRSUP3392
Tropisetron
A Review of the Clinical Experience
Karel M. de Bruijn Department of Clinical Research, Sandoz Pharma Ltd, Basel, Switzerland
Summary
This review describes clinical experience with tropisetron, a new 5-hydroxytryptamine type 3 (serotoninjj-receptor antagonist, which was found to possess antiemetic properties in animal studies and pilot studies in chemotherapy-treated patients. Tropisetron 5mg once daily is an effective and well tolerated antiemetic treatment for chemotherapy-induced emesis. Tropisetron can be administered without special precautions to all patients who undergo aggressive chemotherapy, and remains effective during multiple chemotherapy courses. The efficacy oftropisetron compares well with that of the best available complicated antiemetic cocktails, but tropisetron is better tolerated. The simple dosage schedule of either I injection or I capsule per day makes tropisetron ideal for both inpatient and outpatient treatment.
A new chemical entity must undergo thorough investigation before being accepted as a drug by regulatory authorities and the medical community. This applies all the more to a representative of a new class of drugs. The present review focuses on the clinical development of tropisetron, a new 5-hydroxytryptamine type 3 (serotoninj) [5-HT3]receptor antagonist, which was found to possess antiemetic properties in animal studies and pilot studies in chemotherapy-treated patients.
1. Pharmacological Profile of Tropisetron Tropisetron (Navoban'P, Novaban'P; Sandoz Pharma Ltd) is a highly potent and selective antagonist of 5-HT3 receptors. At therapeutic dosages, tropisetron has virtually no affinity for other receptors, such as histamine (HI and H2), nicotine, muscarine, substance P and dopamine receptors, and a\-, a2-, {31- or {32- adrenergic binding sites.
1.1 Rationale for the Use of Tropisetron as an Antiemetic Drug
Rational therapy of emesis aims at interrupting the vomiting reflex. Vomiting is the last step in a chain reaction involving 5-HT3 receptors at several stages (Andrews et al. 1988). As a selective 5-HT 3-receptor antagonist, tropisetron could interrupt anyone or a combination of steps in the vomiting reflex: 1) Activation of peripheral 5-HT3 receptors in the upper gastrointestinal tract by 5-HT released from enterochromaffin cells after stimulation by chemotherapeutic drugs or radiotherapy; 2) Transfer of afferent information from intestinal receptors to the brain stem via the vagus nerve, which contains 5-HT3 receptors that are highly sensitive to tropisetron; 3) Activation of brain-stem receptors, either in the area postrema, a chemoreceptor site with a high density of 5-HT3 receptors, or in the vomiting centre, which integrates stimuli from the vagus, area postrema and else-
Drugs 43 (Suppl. 3) 1992
12
where in the central nervous system and coordinates the actual vomiting process; 4) Transfer of efferent information via the vagus nerve from the vomiting centre to the target organs (gastrointestinal and respiratory tracts, as well as abdominal and thoracic muscles). Tropisetron probably influences the afferent and integrating parts of the vomiting reflex, i.e. it exerts its action on peripheral and brain-stem 5-HTJ receptors.
2. Clinical Pharmacology The metabolism and pharmacokinetic parameters of tropisetron in the dose range 5 to 100mg were investigated in healthy volunteers. Studies were performed with [14C]-labelled tropisetron, and with single and multiple oral and intravenous administrations of tropisetron. The pharmacokinetic parameters in special risk populations and interactions with other drugs were also studied. 2.1 Pharmacokinetic Properties in Healthy Volunteers The structure of tropisetron is shown in figure 1. After oral administration, the absorption of tropisetron is rapid and almost complete (more than 95% of a 100mg dose within 2.2 hours). The drug has a large volume of distribution, reflecting its lipophilic properties. Tropisetron is poorly metabolised during its first pass through the liver. Metabolism occurs mainly by oxidation at the 5, 6 or 7 positions of its indole ring; the hydroxy metabolites are further metabolised to glucuronides and
sulphates. Demethylation of the drug is negligible. Between 8 and 9% of a 20mg dose of tropisetron is excreted into the urine unchanged and approximately 70% as metabolites; 15% is excreted in the faeces, almost entirely as metabolites. In humans, tropisetron metabolism is linked to the cytochrome P-450IID6 enzyme system, which determines the polymorphism of debrisoquine/ sparteine metabolism. Consequently, there are phenotypical populations of extensive and poor metabolisers; in Western populations the ratio between extensive and poor metabolisers is approximately 12: 1. The pharmacokinetic parameters of tropisetron in poor and extensive metabolisers are summarised in table I. In extensive metabolisers, the plasma clearance of tropisetron after single intravenous doses of 5 to 80mg was dose independent, whereas multiple intravenous administration of tropisetron at doses of 20 and 80mg daily led to a dosedependent decrease in total clearance. This can be explained by a decrease in renal clearance, which accounts for only 10% of the total clearance, after exposure to single doses of tropisetron, and a dosedependent decrease in nonrenal clearance, which accounts for 90% of the total clearance in extensive metabolisers, after exposure to multiple administration. In extensive metabolisers, oral doses greater than 45mg led to a more than proportional increase in AVC and maximum plasma concentration (Cmax) values and to a reduction in renal and nonrenal clearances. Dose-dependent first-pass metabolism resulted in a measured absolute bioavailability of> 60% for 5 to 15mg doses, increasing to 100% at doses of 45mg and over. 2.2 Drug Interactions
Fig. 1. Structure of tropisetron.
The protein binding of tropisetron is moderate (59 to 71%); therefore, no drug-drug interactions due to displacement of the drug from its binding site are to be expected. Tropisetron showed no inductive or inhibitory effects on cytochrome P450dependent enzymes that are not linked to the II D6 polymorphism and inhibition of these enzymes had only a minor influence on the pharmacokin-
Clinical Experience with Tropisetron
13
Table I. Pharmacokinetic parameters of tropisetron in poor and extensive metabolisers, normalised for a 10mg dose
Parameter
IV (n t max (h)
Cmax (I'g/L) AUC (I'g/L. h) t'l2~ (h)
(L) CL (L/min) CLR (L/min) CLNR (L/min)
V~
F(%)
Poor metabolisers
Extensive metabolisers
= 18)
NA 84 239 7.3 554 0.964 0.081 0.883 100
oral
IV
oral
(n = 43)
(n = 36)
(n = 12)
2 21.7 230 8.6
NA 82 1192 30.3 463 0.197 0.087 0.116 100
3.6 29.9 1576 41.9
60-100a
60-100a
a
Dose dependent. = intravenous; t max = time to maximum plasma concentration; NA = not applicable; Cmax = maximum plasma concentration; AUC = area under plasma concentration-time curve; t'l~ = terminal phase elimination half-life; Vp = volume of distribution during terminal elimination phase; CL = total plasma clearance of parent drug; CLR = renal clearance of parent drug; CLNR = nonrenal clearance of parent drug; F = bioavailability.
Abbreviations: IV
etics of tropisetron. In contrast, induction of the cytochrome P450 system reduces Ave values, shortens the elimination half-life and increases the metabolic clearance oftropisetron. Thus, when tropisetron is administered to extensive metabolisers in combinations with enzyme-inducing drugs such as phenytoin, the dose needs to be increased in order to achieve the same exposure as in subjects not receiving enzyme-inducing agents. Drugs that probably share the same excretory pathway as tropisetron at the renal tubules, such as cimetidine, may increase the plasma concentrations of tropisetron, but not at the 5mg dose level. 2.3 Pharmacokinetic Properties in Special Populations The pharmacokinetic parameters of tropisetron in elderly volunteers did not differ from those in young subjects. Patients with liver cirrhosis, but not with hepatitis or fatty liver, had a metabolic clearance of tropisetron 50% lower than that of volunteers who were extensive metabolisers. In patients with moderately or severely impaired renal function, nonrenal clearance of tropisetron was 50% lower than in healthy volunteers who were exten-
sive metabolisers; however, the kinetic parameters in the former group were highly variable. Not all groups that may be exposed to tropisetron in clinical practice have been included in pharmacokinetic studies. However, from the available data it appears that total exposure to tropisetron during the recommended 6 days of treatment at a dose of 5mg once daily is very similar to that after a single 25mg dose. Therefore, if tropisetron were administered for 6 days to patients with 50% impaired renal function and a 25% loss of metabolic liver capacity, the exposure to tropisetron would be much lower than after single doses of 100mg or multiple doses of 25mg, which were well tolerated by healthy volunteers. Thus, although tropisetron exhibits nonlinear pharmacokinetics at doses greater than 15mg, there is no risk of accumulation at the recommended dose of 5mg per day, even in patients with impaired liver and kidney function. 2.4 Tolerability in Volunteer Studies In volunteer studies, no toxic effects were noted during administration of tropisetron 5mg daily (the dose recommended for the prevention of chemotherapy-induced emesis).
Drugs 43 (Suppl. 3) 1992
14
Tropisetron was well tolerated by volunteers when given as single oral doses of up to 150mg or single intravenous doses of up to lOOmg. Headache, constipation and nonspecific tiredness were the most common adverse events at these dose levels, but occurred at similar frequencies during placebo treatment. Single oral doses of tropisetron 200mg given to 6 volunteers were associated with I severe migraine attack and I attack of severe abdominal pain with vomiting and postural hypotension. No single intravenous doses greater than IOOmg were tested. Multiple oral doses oftropisetron of up to 50mg once daily for 14 days were tolerated well by volunteers. Seven-day treatment with tropisetron 50mg twice daily was associated with headache and constipation. All of 3 subjects treated with IOOmg twice daily had severe adverse events, necessitating early discontinuation of treatment; they experienced hallucinations, severe headache and constipation. Multiple intravenous doses of tropisetron were well tolerated at levels of up to lOOmg per day for 14 days. On day 9 of treatment with tropisetron IOOmg daily, 1 subject with a history of brain damage and a previous post-traumatic seizure suffered another seizure.
3. Clinical Studies 3.1 Methodology
3.1.1 Defining the Target Patient Population The crucial need to prevent nausea and vomiting in patients treated with anticancer chemotherapy significantly limits the freedom of trial design in the development of antiemetic drugs. One obstacle is the difficulty in carrying out placebocontrolled studies. These can be performed only in patients receiving mildly emetogenic chemotherapy for whom treatment with placebo is considered ethically acceptable; however, low emetogenicity renders it difficult to demonstrate antiemetic protection and, consequently, very large clinical studies would be required to establish the efficacy of any antiemetic treatment. Moreover, such studies do not address the most distressing symptoms as-
sociated with highly emetogenic chemotherapeutic agents. Without antiemetic treatment, nearly all patients receiving highly emetogenic chemotherapy would suffer nausea and vomiting; therefore, the number of patients not suffering nausea and vomiting during antiemetic treatment represents the efficacy of such treatment. The tropisetron anti emesis programme was based on this reasoning. High dose cisplatin was chosen as standard chemotherapy for the dose-finding and comparative-treatment studies, thus precluding the inclusion of a placebo control group in these studies. However, the choice of high dose cisplatin did not preclude the evaluation of other chemotherapeutic agents. Co-treatment with other, often also highly emetogenic, chemotherapeutic agents was always permitted and in one of the comparative studies highly emetogenic noncisplatin regimens were given.
3.1.2 Choice of Comparative Treatment The choice of comparative antiemetic treatment was not straightforward. Although at the start of the comparative studies no universally accepted guidelines for antiemetic therapy existed, patients receiving highly emetogenic chemotherapy were often treated with combinations of antiemetic agents. These so-called antiemetic cocktails can produce impressive efficacy results, but at the expense of inducing extrapyramidal side effects, especially in young patients (Kris et al. 1983). As a rule, tropisetron was compared with antiemetic cocktails consisting of high dose metoclopramide, high dose corticosteroids and benzodiazepines. In order to compare tropisetron with metoclopramide monotherapy, one study included a less emetogenic, noncisplatin-containing chemotherapeutic regimen. 3.1.3 Defining the Criteria for the Evaluation ofAntiemetic Treatment Until recently, the efficacy of antiemetic treatment was usually assessed as the number of vomits in the 24-hour period after the start of chemotherapy. It became almost universally accepted to express efficacy as 'total control' if no .vomiting
Clinical Experience with Tropisetron
15
Table II. Definitions of control of emesis
many leave hospital the day after their chemotherapy. Therefore, information recorded in diaries kept by the patients during the entire observation period formed the basis for the efficacy analysis. The diaries also provided information on unintended treatment effects as perceived by the patients.
Control
Vomits Nausea8 a
total
partial
o o
1-4 1-4
none
Hours of nausea per 24 hours.
3.2 Efficacy Assessment occurred and 'partial control' if 1 to 5 vomits occurred. Sometimes partial control was further divided into major (l or 2 vomits) and minor (3 or 4 vomits). The improvement in control of vomiting with the introduction of high dose metoclopramide regimens in the early 1980s increased awareness that nausea can be as distressing a side effect of chemotherapy as vomiting. Therefore, the efficacy of tropisetron as an antinauseant drug was also investigated. Since no widely accepted criteria for the quantification of nausea existed, criteria were defined at the start of the programme. The duration, rather than the severity, of nausea was chosen as the efficacyend-point in order to eliminate as much as possible the subjective interpretation of nausea by patients or observers and to allow a simple quantification for the statistical analysis. Ultimately, it is possible to combine the quantitative scores for nausea and vomiting into a single outcome parameter. This has been done for the evaluation of efficacy in the compassionate-need programme reported elsewhere in these proceedings (Bleiberg et al. 1992). The criteria for efficacy evaluation in the tropisetron development programme are presented in table II. A further shortcoming of current methods of evaluating antiemetic treatment is that they are often limited to the first 24 hours after the start of cancer chemotherapy. In recognition of the importance of delayed nausea and vomiting, i.e. nausea and vomiting that occur more than 24 hours after the start of chemotherapy, these parameters were assessed on days 2 to 7 after chemotherapy. Following up patients for more than 1 day after chemotherapy posed a practical problem, since
3.2.1 Pilot Studies The first clinical experience with tropisetron in chemotherapy-induced emesis was obtained in pilot studies (Leibundgut & Lancranjan 1987; Seinen et al. 1989; Tyson et al. 1989). These pilot studies indicated that tropisetron is effective over a wide dose range in the prevention of chemotherapyinduced vomiting and nausea, and that a single dose was effective for up to 24 hours. Tropisetron was generally well tolerated. However, the exploratory nature of the pilot studies makes it difficult to draw general conclusions about dose response and adverse events. 3.2.2 Dose-Finding Studies In 2 dose-finding studies, tropisetron was shown to completely prevent nausea and/or vomiting in up to two-thirds of patients receiving high dose cisplatin treatment (table III); in the majority of patients a single dose of tropisetron was effective for at least 24 hours after chemotherapy. A 5mg dose proved as effective as 10, 20 or 40mg (Van Belle et al., unpublished data), and somewhat more effective than a 2mg dose (Stamatakis et al., unpublished data). Therefore, 5mg is the optimal daily dose for preventing the nausea and vomiting associated with the administration of highly emetogenic chemotherapy. In one study (Van Belleet al., unpublished data), patients were followed up for 96 hours after a single dose of tropisetron. Since delayed nausea and vomiting occurred in more than one-third of the patients in this study, antiemetic treatment was given for 4 to 7 days after chemotherapy in the comparative-treatment studies, in order to reduce delayed nausea and vomiting and to prevent an-
Drugs 43 (Suppl. 3) 1992
16
Table III. Control of vomiting (% patients treated) on day 1 of chemotherapy course 1 in dose-finding studies, by tropisetron dose
Total control Partial control No control
2mg8 (n = 37)
5mg8 (n = 37)
5mg b (n = 35)
10mgb (n = 35)
20mgb (n = 36)
40mgb (n = 36)
59 9 32
70 16 14*
71 20 9
51 26 23
61 20 19
58 23 19
a Unpublished data, Stamatakis et al. b Unpublished data, Van Belle et al. * p = 0.055 vs 2mg dose.
ticipatory nausea and vomiting in subsequent treatment courses. 3.2.3 Comparative-Treatment Studies This review focuses on 4 studies, coordinated by the Clinical Research Department of Sandoz Pharma Ltd, for which all documentation is available at Sandoz. Tropisetron was compared with metoclopramide (either as monotherapy or in combination with benzodiazepines) in 1 study in which noncisplatin chemotherapy was used, and with an antiemetic cocktail in 3 studies in which cisplatin-based chemotherapy was used (table IV). These studies included a total of 582 patients, of whom 309 received tropisetron, 51 received metoclopramide with or without benzodiazepines and 222 received an antiemetic cocktail based on high dose metoclopramide combined with dexamethasone and lorazepam or diphenhydramine. All patients suffered from a proven malignancy and were treated de novo with highly emetogenic cancer chemotherapy, often based on high doses of cisplatin. Patients were followed up for 1 to 3 chemotherapy courses of 1 to 7 days each. Control of vomiting and nausea (as defined in table II) was evaluated on each follow-up day. The results of these studies indicate that tropisetron at a dose of 5mg once a day is an effective and well tolerated single-agent antiemetic treatment that can be given without special precautions to all patients treated with aggressive chemotherapy. Compared with metoclopramide (with or without lorazepam), tropisetron was more effective
in preventing acute nausea and vomiting (fig. 2). Compared with the antiemetic cocktails, tropisetron was equally effective in preventing acute vomiting and somewhat less effective in preventing acute nausea (fig. 3). Tropisetron was as effective as metoclopramide and somewhat less effective than the antiemetic cocktails in preventing delayed nausea and vomiting. However, when patients were followed up for more than 1 treatment course, antiemetic cocktails were no longer superior to tropisetron treatment and produced more adverse events, especially extrapyramidal reactions (see below). 3.3 Miscellaneous Efficacy Studies The efficacy of tropisetron has been evaluated in 4 studies that did not form part of the centrally coordinated clinical development programme. Three of these studies are presented elsewhere in these proceedings (Dogliotti et al. 1992); the fourth compared tropisetron with alizapride and also investigated the combination of tropisetron with haloperidol (Bregni et al. 1991). In these studies, tropisetron was highly effective in preventing nausea and vomiting induced by high doses of cisplatin (Dogliotti et al. 1992) and high doses of cyclophosphamide or melphalan (Bregni et al. 1991). The addition of haloperidol enhanced the efficacy of tropisetron (Bregni et al. 1991), whereas there were no differences in efficacy between tropisetron doses of 5 and 10mg when given as monotherapy (Dogliotti et al. 1992).
Clinical Experience with Tropisetron
3.4 Tolerability Assessment An integrated safety summary has been prepared, including the patients in the dose-finding studies and the comparative-treatment studies listed in table IV. 3.4.1 Tropisetron Tropisetron was well tolerated at the recommended dose of 5mg daily for 6 days. Headache, constipation and diarrhoea with abdominal pain, fatigue and dizziness were reported most frequently (table V). Headache, and constipation with abdominal pain were the only adverse events that recurred in the same patients during repeated courses of tropisetron treatment and, therefore, must be considered to be side effects oftropisetron. Other adverse events could be attributed to the underlying cancer and/or aggressive cytostatic treatment. Adverse events were generally tolerated without symptomatic treatment. Discontinuation of tropisetron administration because of adverse events was exceptional; only 1 of 417 patients receiving tropisetron 5mg daily in the dose-finding
17
and comparative-treatment studies discontinued treatment, because of headache. The headache associated with tropisetron was generally mild, requiring no symptomatic therapy. Constipation reflects in part the patients' reported difficulty in passing stool during days of cancer chemotherapy when normal lifestyle is interrupted. Extrapyramidal adverse events were virtually absent after tropisetron treatment: 2 patients had ataxia during the third treatment course after receiving high doses of vindesine, I patient reported recurrence of a tremor and 1 patient involuntary muscle contractions (cramps). The adverse event profile of tropisetron did not change during repeated administration over 2 or 3 courses. There was no evidence that tropisetron at the recommended dose caused ECG or laboratory abnormalities. Especially, there was no evidence that tropisetron induced liver enzyme abnormalities. Furthermore, no evidence emerged that tropisetron contributes to or exacerbates cisplatin nephrotoxicity or neurotoxicity. At dosages higher than the recommended 5mg per day, hypertensive episodes occasionally occurred, especially in patients
Table IV. Treatments used in comparative studies of tropisetron Chemotherapy
No. of panentss
Antiemetic therapy on day 1
Carboplatin 150-400 mg/m 2 + cyclophosphamide and/or ifosfamide ± doxorubicin, etoposide or mitomycin C (n = 95) or doxorublcin monotherapy (n = 7)
51 51
T 5mg
Cisplatin 50-120 mg/m 2 monotherapy (77%) or combination therapy (23%)
58 53
T 5mg
Study III
Cisplatin 50-120 mg/m 2 monotherapy (28%) or combination therapy (78%)
39 38
T 5mg M 4 mg/kg + Ox + L or Op
Study IVb
Cisplatin 50-120 mg/m 2 monotherapy (56%) or combination therapy (44%)
131 128
Study 1
Study II
M 1.5-4 mg/kg ± L
M 7 mg/kg + Ox
T 5mg M4mg/kg+Ox+L
a Patients evaluable for efficacy. b Unpublished data, Sorbe & Frankendal. Abbreviations: T = tropisetron; M = metoclopramide; L = lorazepam; Ox = dexamethasone; Dp = diphenhydramine.
Drugs 43 (Suppl. 3) / 992
18
90
o
a
•
Partial control Total control
80 ~
70
o- 0E
60
+ .", -~ co o a. _
50
f- 0
co
0
ECij
40 30
~ E oo
20
f-
Cij
o
10 Tropisetron Metoclopramide
l
III
C Q) .~
a..
b
90 80
70
60 50 40
with pre-existing and inadequately controlled hypertension who received 20 to 80mg of tropisetron. In conclusion, treatment with 5mg of tropisetron once dail y for the prevention of chemotherap y-induced emesis does not present any undue risk to the pat ient.
3.4.2 Tropisetron vs Comparative Treatm ents The side effect profile of tropisetron compares favourabl y with that of the antiemetic cocktail (table V). The incidence of adverse events attributed to trop isetron was much lower than that attributed to the cocktail and similar to that attributed to metoclopramide monotherapy, in which the dose of metoclopramide was approximately half of that used in the antiemetic cocktails. .Tropisetron treatment was associated with a greater incidence of headache and constipation, whereas the ant iemetic cockta il treatm ent was associated with a greater incidence of diarrhoea, fatigue and , notably, extrap yramidal reactions. General symptoms such as fatigue and asthenia were seen more often in association with the antiemetic cocktail treatment than with tropisetron. Furthermore, 8 of 222 patients in the antiemetic cocktail group compared with onl y I of 417 patients in the tropisetron group needed to discont inue ant iemetic treatment because of adverse events directl y attributed to that treatment, mainly extrap yramidal side effects.
30
20 10 Tropisetron Metoclopramide (n = 51)
(n = 51)
Fig. 2. Patients with total control (no episodes) or part ial control (1-4 episodes ) of vo miting (a) or nausea (b) on da y I of a course of noncisplatin chemotherapy. after treatment with tropisetron 5mg or metoclopr am ide 1.5 to 4 mg/kg (Stud y I) . Shaded band s represent ranges for rates of total control (0 ) and total plus major control [0 to 2 episodes) or total plus part ial control [0 to 5 episodes) (Ia) of vomiting reponed elsewhere for metoclopram ide monotherapy (Gralla et al. 1981; Hom esley et al. 1982; Kris et al. 1985a; Mart y et al. 1990; Strum et al. 1982); equi valent ranges for control of nau sea are not available.
3.4.3 Tolerability of Tropisetron in Studi es Involving Other Indi cations Tropisetron was given at doses of 0.5 to 50mg per day for up to 3 months in studies for indications other than chemotherapy-induced emesis, usually gastric emptying and prevention of migraine heada che. In these studies , const ipation and headache were the most common adverse events. In addition , 4 patients receiving doses of 25 and 50mg daily developed skin reactions (pruritus, rash, exanthema and urticaria ); I patient receiving 25mg developed a swelling of the upper lip; I patient with carcinoid syndrome, who was receiving 20mg of tropisetron per day, developed lymphadenopathy, fever, rash, joint aches and mild hypotension, which disappeared within 48 hours of drug withdrawal
Clinical Experience with Tropisetron
100
19
o Partial control • Total control
a
90
80
Total + major control
70 -,..__._I-.....,~
60 50
40
ec oo
iii
'E
a
30
20 10
o ~
£.~
~
100
b
Ul
~
0;
a.
90
80 70
60 50
40 30
20 10 T
(n
=58)
C (n = 53)
Study II
T
C
T
C
(n = 39) (n = 38)
(n = 131)(n = 128)
Study III
Study IV
Fig. 3. Patients with total control (no episodes) or partial control (I to 4 episodes) of vomiting (a) or nausea (b) on day I
of a course of noncisplatin chemotherapy, after treatment with tropisetron (T) 5mg or an antiemetic cocktail (C) including high dose metoclopramide (Studies II-IV). The shaded bands represent ranges for rates of total control (II) and total plus major control [0 to 2 episodes) (0) of vomiting reported for rnetoclopramide-based cocktails (Kris et al. 1985b, 1987; Meyer et al. 1987); equivalent ranges for control of nausea are not available.
20
Drugs 43 (Suppl. 3) 1992
Table V. Summary of adverse events, by antiemetic therapy
No. of patients No. (%) of patients discontinuing antiemetic therapy because of adverse events Total no. of adverse events Percentage of adverse events attributed to antiemetic therapy Incidence (% of all adverse events) Headaches Constipations Diarrhoeas FatigueS Extrapyramidal reactions s.b a b
Tropisetron
Metoclopramide monotherapy
Antiemetic cocktail
417
51
222
1 (0.2)
o
8 (3.6)
761 3
67
484
4
16
22
19
13
11 5
7
4
6
12 15
3
9
6 0.3
Relationship to antiemetic treatment uncertain or absent. Ataxia, agitation, dystonia, involuntary muscle contraction, teeth grinding, tremor oculogyric crisis.
and recurred when the tropisetron treatment was reinstated 2 months later; another patient with carcinoid syndrome developed mild arthralgia and myalgia when treated with tropisetron 15mg daily for I week. 3.5 Ongoing Studies Following the submission of the registration dossier in various countries, a number of studies have been initiated. Some of these are small, whereas others may include several hundreds of patients. The aims of these studies are to further tailor the use of tropisetron to clinical oncology practice, e.g. by looking at special types of cancer and chemotherapy, by increasing the number of treatment cycles per patient and by comparing tropisetron with specific antiemetic treatments in local use. In other words, these studies allow clinicians to build their own experience with tropisetron without the restrictions, especially in terms of patient inclusion criteria, imposed by rigidly controlled clinical trials. However, a number of studies are being coordinated centrally by the Clinical Research Department of Sandoz in order to make further, general recommendations for the use of tro-
pisetron in clinical oncology. These studies are briefly outlined in the following paragraphs. In one study, tropisetron is currently being tested in patients with treatment failures on previous antiemetic therapy. The preliminary results of this study, presented elsewhere in these proceedings (Bruntsch et al. 1992), are promising. In addition, strategies are being explored for the treatment of patients who receive highly emetogenic chemotherapy and who are not completely free of all nausea and vomiting during monotherapy with tropisetron. The general strategy is to combine tropisetron with other antiemetic agents, especially dexamethasone, rather than increasing the dose since, in the dose-finding studies, results with a 40mg dose were no better than with a 5mg dose. Tropisetron is available for patients with treatment failure on conventional antiemetic treatment and those (young) patients for whom the risk of extrapyramidal side effects with high dose metoclopramide is considered unacceptable by the treating physician. A prospective analysis of more than 500 of these so-called compassionate-need patients is reported elsewhere in these proceedings (Bleiberg et al. 1992). The first results of this study are remarkable: two-thirds of the patients did not experience any further nausea and vomiting.
Clinical Experience with Tropisetron
The efficacy of tropisetron as an antiemetic treatment for children receiving chemotherapy is currently being explored and the first results are promising (Lemerle et aI., unpublished data). Finally, the use of tropisetron for preventing nausea and vomiting in patients undergoing radiotherapy is currently being investigated, and results from 1 such study are presented in these proceedings (Sorbe et al. 1992). Although the prophylactic administration of tropisetron for 6 to 7 weeks did not prevent all nausea and vomiting, radiotherapy could be given without interruption and the patients suffered only minimal weight loss of approximately lkg during the entire radiotherapy treatment. 3.6 Place of Tropisetron in Oncology Practice From comparative-treatment studies, tropisetron emerged as a highly efficacious antiemetic drug with a favourable adverse event profile. These features alone would justify its use as a first-line antiemetic treatment, but both patients and medical staff have recognised additional properties that make tropisetron of special value to them.
3.6.1 Advantages for Patients Tropisetron may help patients to resume or even maintain their normal lifestyle. Patients will be able to take tropisetron as outpatient treatment and thus not be excluded from their home environment. Patients treated with tropisetron will not suffer the sedative effects of some other antiemetic agents, which, although useful for some distressed patients, are a genuine nuisance for most. Patients treated with tropisetron will not have to fear severe extrapyramidal side effects, which constitute a frightening experience, even if they occur in only a small proportion of patients who receive high dose metoclopramide or other dopamine antagonists. 3.6.2 Advantages for Medical Staff Tropisetron will allow clinicians to choose and optimise cancer chemotherapy on the basis of its appropriateness for the cancer type, rather than for its tolerability. With tropisetron there are no in-
21
teractions or contraindications, which sometimes restrict the use of conventional antiemetics. Because tropisetron does not cause sedation, the risk of aspiration after inadvertent vomiting is remote. The prevention of emesis in most patients frees the nursing staff from extra work and strain, allowing more time to offer support and counselling to the patients. Moreover, tropisetron helps to create a psychologically supportive environment, owing to the virtual absence of the alarming extrapyramidal side effects of metoclopramide, which can disrupt an entire ward.
3.6.3 Advantages for Pharmacists Tropisetron is easier to prepare than antiemetic cocktails, especially when cocktails are given as continuous infusions. Tropisetron can even be injected directly into a running infusion without having to make up intravenous administration sets. Thus, especially in a busy outpatient setting, time will be freed for the preparation of the various chemotherapies. 3.6.4 Advantages for Hospital Administrators Tropisetron may help to increase the availability of hospital beds by enabling cancer patients to receive their chemotherapy on an outpatient basis.
4. Conclusion Tropisetron 5mg per day is an effective and well tolerated antiemetic treatment. It can be administered without special precautions to all patients who undergo aggressive chemotherapy. Tropisetron is effective in preventing nausea and vomiting induced by cytostatic treatment during multiple chemotherapy courses. The efficacy of tropisetron compares well with even the best currently available, but complicated, antiemetic cocktails and tropisetron is much better tolerated. The simple dosing schedule of either 1 injection or 1 capsule per day makes tropisetron ideal for both inpatient and outpatient treatment.
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Correspondence and reprints: Dr K.M. de Bruijn, Department of Clinical Research, Sandoz Pharma, CH-4002, Basel, Switzerland.