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5-HT₃-Receptor Antagonists for the Treatment of Nausea and Vomiting: A Reappraisal of Their Side-Effect Profile

^a The Cancer Institute of New Jersey, New Brunswick, New Jersey, USA; ^b UMDNJ/Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA

Correspondence: Susan Goodin, Pharm. D., The Cancer Institute of New Jersey, 195 Albany Street, New Brunswick, New Jersey 08903-2681, USA. Telephone: 732-235-7472; Fax: 732-235-7493; e-mail: goodin{at}umdnj.edu

	LEARNING OBJECTIVES

Top Learning Objectives Abstract Introduction Pharmacotherapy for Nausea and... Safety and Tolerability of... Use of 5-HT3-Receptor... Risk of Drug Interactions... Conclusions General References References

 
After completing this course, the reader will be able to:

1. List the differences in side-effect profiles of the 5-HT₃-receptor antagonists.
   
2. Explain the potential issues of each 5-HT₃-receptor antagonist in patients with cardiovascular disease.
   
3. Understand the potential issues of each 5-HT₃-receptor antagonist in patients with hepatic or renal impairment.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction Pharmacotherapy for Nausea and... Safety and Tolerability of... Use of 5-HT3-Receptor... Risk of Drug Interactions... Conclusions General References References

 
Nausea and vomiting can cause considerable distress and discomfort to patients undergoing chemotherapy, radiotherapy, or surgery. Several classes of antiemetic agents exist to combat these side effects, though the 5-HT₃-receptor antagonists have become the first-line treatment choice for many cancer patients and are considered the "gold standard" in antiemetic therapy. Compared with the older generation antiemetic drugs, 5-HT₃-receptor antagonists are effective, well tolerated, and associated with few side effects. However, emerging differences among these agents suggest that the incidence and/or intensity of adverse events should not be regarded as a class effect.

The side-effect profile of any supportive care therapy is particularly important in certain subgroups of patients, including pediatric patients and the elderly, as well as those suffering comorbid conditions, such as cardiovascular disease and renal or hepatic impairment. Indeed, dolasetron is associated with cardiovascular effects, and thus, should be used with extreme caution in patients who suffer from or may develop prolongation of cardiac conduction intervals. Ondansetron, on the other hand, is associated with a greater incidence of central nervous system side effects than either dolasetron or ondansetron, and pharmacokinetic parameters are affected in patients with hepatic impairment, thereby requiring dose adjustments.

Clinicians are encouraged to evaluate patients on an individual basis when choosing which 5-HT₃-receptor antagonist to prescribe.

Key Words. 5-HT₃-receptor antagonists • Granisetron • Ondansetron • Dolasetron • Side effects • Emesis

	INTRODUCTION

Top Learning Objectives Abstract Introduction Pharmacotherapy for Nausea and... Safety and Tolerability of... Use of 5-HT3-Receptor... Risk of Drug Interactions... Conclusions General References References

 
Antiemetic drugs are often used to treat nausea and vomiting induced by chemotherapeutic agents, radiation therapy, or surgery. Severe nausea and vomiting can result in dehydration, malnutrition, metabolic disturbances, and aspiration pneumonia, which can have substantial effects on quality of life, survival, and health care costs. Treatments used to control nausea and vomiting form a critical part of the supportive care regimen of cancer patients and should not, therefore, add to the patient’s side-effect burden. Thus, the safety and tolerability of antiemetics constitute important considerations in their selection and use.

The side-effect profile of antiemetics used to treat patients undergoing treatment for cancer is of particular importance because such patients may be taking multiple chemotherapeutic agents and other medications and may be unable to tolerate any further reduction in quality of life. Furthermore, many patients are elderly and, therefore, particularly susceptible to adverse events due to renal and/or hepatic impairment, as well as receiving treatment for a range of comorbid conditions, including cardiovascular disease, gastrointestinal disorders, psychological conditions, pain, arthritis and bone disease, immune suppression, pulmonary disease, and diabetes.

Evidence-based guidelines, such as those compiled by the American Society of Health-System Pharmacists, the American Society of Clinical Oncology, and the National Comprehensive Cancer Network, generally describe the 5-HT₃-receptor antagonists as having comparable efficacy and tolerability profiles [1–3]. However, these guidelines underemphasize several issues that affect the outcomes of studies of such drugs. Clinical studies typically use antiemetic agents at limited doses and duration over a single chemotherapy cycle where patients are often not followed up adequately to assess long-term adverse events. Additionally, many clinical studies exclude certain patient groups, such as those with cardiac disease or renal or hepatic dysfunction, conditions that are likely to be prevalent in elderly patients with cancer. It is, therefore, imperative that both the individual patient profile as well as the tolerability profile of the proposed treatment be considered when prescribing antiemetic therapy.

This article provides an overview of the safety and tolerability of the 5-HT₃-receptor antagonists, which have become the first-line antiemetic treatment choice for many cancer patients. Patient subgroups in which the side-effect profile of these agents is of particular relevance are outlined.

	PHARMACOTHERAPY FOR NAUSEA AND VOMITING

Top Learning Objectives Abstract Introduction Pharmacotherapy for Nausea and... Safety and Tolerability of... Use of 5-HT3-Receptor... Risk of Drug Interactions... Conclusions General References References

 
Many antiemetic drugs belonging to a number of classes are available in clinical practice. These classes act on various neurotransmitter systems, including the dopaminergic, histaminic (H₁), cholinergic, muscarinic, and 5-HT₃ receptors, all of which appear to play a role in the mediation of the emetic response. However, the frequency of use of these agents has declined with the introduction of the 5-HT₃-receptor antagonists, though many agents, particularly the corticosteroids, are still employed in the clinical setting.

Investigation of 5-HT₃-receptor antagonists in clinical trials in the mid-1980s, and their subsequent introduction into clinical practice in the early 1990s, have been recognized as important advances in the control of nausea and vomiting associated with cancer treatment [4–6]. Indeed, these agents are now the accepted "gold standard" of antiemetic therapy. Three 5-HT₃-receptor antagonists are licensed in the U.S., namely ondansetron, granisetron, and dolasetron, all of which have been shown to be effective in reducing nausea and vomiting following cancer chemotherapy, and others are available outside the U.S. All provide highly effective and well-tolerated alternatives to older agents [7]. For example, comparative trials with high-dose metoclopramide have shown that granisetron [8], dolasetron [9], and ondansetron [10, 11] were more effective in preventing acute emesis, were better tolerated, and were preferred by more patients. Thus, the 5-HT₃-receptor antagonists have become the agents of choice in preventing acute chemotherapy-induced nausea and vomiting [4]. Moreover, the efficacy of these agents is further enhanced by the addition of a corticosteroid [7, 12–17].

	SAFETY AND TOLERABILITY OF THE 5-HT3-RECEPTOR ANTAGONISTS

Top Learning Objectives Abstract Introduction Pharmacotherapy for Nausea and... Safety and Tolerability of... Use of 5-HT3-Receptor... Risk of Drug Interactions... Conclusions General References References

 
The adverse effects of the principal classes of antiemetics are summarized in Table 1. Each class is associated with a well-recognized and broad side-effect profile that frequently includes sedation (e.g., antihistamines, benzamides, phenothiazines, and benzodiazepines), antimuscarinic effects (e.g., antihistamines and anticholinergics), and extrapyramidal side effects (e.g., benzamides, phenothiazines, and butyrophenones). Compared with these older agents, the 5-HT₃-receptor antagonists are considered to be well tolerated with low patient dropout rates in clinical trials. The most common side effects of 5-HT₃-receptor antagonists include headache, constipation, diarrhea, asthenia, and somnolence [18–20]. Their incidence is affected by the dosing regimen and route of administration, as well as the emetogenicity of the chemotherapy. Nevertheless, emerging differences among these agents suggest that the incidence and/or intensity of many adverse events should not be regarded as a class effect.

Headache as a consequence of 5-HT₃-receptor antagonist therapy is rarely of clinical significance and can usually be easily controlled. In a comparative study of dolasetron, 1.8 mg/kg and 2.4 mg/kg, and ondansetron, 32 mg, reported incidences of headache were 13.6%, 13.2%, and 5.8%, respectively [23]. Similar results were obtained in a comparative study of oral granisetron, 2 mg, and intravenous ondansetron, 32 mg, with headache reported in 21% and 20.6% of patients, respectively (Table 2) [24]. Headache was reported as mild or moderate in the majority of patients. However, in a review of 47 patients who received 269 cycles of chemotherapy, treatment with ondansetron was associated with severe headache leading to discontinuation of the antiemetic regimen (ondansetron plus metoclopramide) in 6.4% of patients [25]. The authors found no correlation with a history of recurrent or severe headache and attributed this effect to the administration of intravenous ondansetron.

In contrast to most other antiemetic drug classes, drowsiness does not appear to be a significant problem with 5-HT₃-receptor antagonists. This is a likely consequence of their relative receptor selectivity and lack of effect on histamine H₁ receptors.

Gastrointestinal Effects
A study comparing a single oral dose of granisetron, 2 mg (n = 542), with intravenous ondansetron, 32 mg (n = 543), in 1,085 patients receiving moderately emetogenic chemotherapy [24] showed the incidences of constipation to be 12.9% and 10.9%, respectively (Table 2). A comparative study of dolasetron, 1.8 and 2.4 mg/kg, with ondansetron, 32 mg, found that diarrhea was the second most common adverse event after headache, with incidences of 13.6%, 13.2%, and 5.8%, respectively [23].

Cardiovascular Effects
Chemotherapy, particularly at high doses, initiates vomiting by releasing large amounts of serotonin (5-HT) that stimulate 5-HT₃ receptors on vagal abdominal afferent fibers in the gastrointestinal tract [27]. The heart, however, also has vagal innervation, and a potential for cardiac interaction may occur when 5-HT₃-receptor antagonists are administered.

Despite excellent overall safety profiles, 5-HT₃-receptor antagonists have been reported to produce small, statistically significant but clinically asymptomatic changes in electrocardiographic parameters [28–33]. However, the propensity for inducing cardiac effects varies among the 5-HT₃-receptor antagonists. Intravenous granisetron has been shown to be associated with fewer effects on the electrocardiogram (ECG) than intravenous ondansetron [30]. Dolasetron has been shown to produce transient asymptomatic ECG changes, including small increases in the PR interval and QRS complex duration accompanied by small increases in heart rate or QT_c [34]. In a comparative study, ondansetron, 32 mg i.v., and dolasetron, 2.4 mg/kg i.v., both significantly increased the QT interval compared with placebo by 6.7 and 4.8 msec, respectively [29]. Dolasetron, 1.2, 1.8, and 2.4 mg/kg i.v., also caused a dose-related increase in the QT_c interval of between 2.7 and 10.4 msec (to 381.7-389.5 msec; p < 0.001), and ondansetron caused an increase in the JT interval by 5.8 msec to 306 msec (p = 0.0048). Prolongation of the QT_c interval was shown to be an independent risk factor for sudden death in a study of 6,693 patients [35]; a relative risk for sudden death of 2.3 was reported for patients without intraventricular conduction defects or cardiac dysfunction with a QT_c of 440 msec or longer. This prolongation is also a risk factor for torsades de pointes, a hard-to-treat arrhythmia that can be fatal. Although the recorded QT_c interval following dolasetron infusion [29] was less than that deemed to pose a risk of sudden death, it is reasonable to assume that coadministration of dolasetron with medications that also prolong this interval would produce additive prolongations of QT_c intervals, increasing the risk to patients.

Comparative drug trials reporting cardiac effects with 5-HT₃-receptor antagonists are summarized in Table 3. In a study of dolasetron (n = 198) versus ondansetron (n = 206) for acute cisplatin-induced emesis, patients were excluded if they had a history of congestive heart failure, antiarrhythmic medication, preexisting complete bundle branch block, cardiomyopathy, or greater than first-degree heart block [23]. Asymptomatic prolongations of the PR, QRS, QT, QT_c, and JT intervals were recorded on ECGs with both agents, but several studies showed that the average changes from baseline in PR, QRS, and QT_c intervals at 1-2 hours were greater with dolasetron than with ondansetron (Table 4).

In a study of patients receiving cisplatin chemotherapy, single doses of ondansetron, 32 mg i.v. (n = 20), or dolasetron, 2.4 mk/kg i.v. (n = 25), resulted in asymptomatic reversible ECG interval prolongations for PR, QRS, QT, and QT_c 2 hours following antiemetic therapy [36]. Increases in the PR (by 14-20 msec), QRS (by 4-7 msec), and QT (by 18-19 msec) intervals after administration of each agent and QT_c interval (by 15 msec) after dolasetron were significant (p < 0.05). In addition, ondansetron significantly slowed heart rate by a mean eight beats/minute (p < 0.05).

A multicenter, randomized, double-blind, double-dummy trial compared dolasetron, 1.8 and 2.4 mg/kg i.v. (n = 324), with granisetron, 3 mg i.v. (n = 150), for emesis induced by high-dose cisplatin [28]. Patients with congestive heart failure, arrhythmias requiring medication, greater than first-degree heart block, cumulative cardiotoxicity secondary to anthracyclines or anthracenediones, and abnormal serum levels of potassium or calcium were excluded. Patients receiving dolasetron had significantly greater increases in QT_c intervals (p = 0.0016) and PR intervals (p = 0.0002) at 1-2 hours following treatment than those receiving granisetron. The ECG changes in any of the treatment groups did not result in clinical symptoms, and there was no evidence of an effect on vital signs.

Thus, clinical trials show dolasetron, in particular, is associated with prolongation of the QT_c interval. In contrast, granisetron and ondansetron do not appear to be as significantly associated with this effect. These differences are reflected in the prescribing information for these agents. The dolasetron (Anzemet^®; Aventis Pharmaceuticals Inc; Kansas City, MO; http://www.aventispharma-us.com) prescribing information [18] states that dolasetron should be administered with caution in patients who either have, or may develop, prolongation of cardiac conduction intervals, particularly the QT_c interval. Such patients include those with hypokalemia or hypomagnesemia, those taking diuretics with potential for inducing electrolyte abnormalities, those with congenital QT syndrome, those taking antiarrhythmics or other drugs that lead to QT prolongation, and patients receiving cumulative high-dose anthracycline therapy. In contrast, the prescribing information for granisetron and ondansetron does not include any such warnings.

Other
Local pain or burning on i.v. administration is listed by the manufacturer as an infrequently reported adverse event associated with dolasetron injection [18]. However, in a study of 54 patients who received dolasetron, 100 mg by "i.v. push" (i.e., administration over 5 seconds), a total of 10 patients (19%) experienced venous irritation [37]. The author hypothesized that this reaction was due to the relative acidity of the dolasetron mesylate injection (pH 3.2-3.8) compared with the pH of human blood (7.36-7.45), coupled with its rapid administration. A slower rate of administration and dilution in normal saline has been found to reduce this risk [37]. In contrast, venous irritation is not commonly reported for either ondansetron hydrochloride injection (pH 3.0-4.0) or granisetron hydrochloride injection (pH 4.7-7.3) [19, 20, 37]. The lower incidence of pain, redness, and burning at the site of injection experienced by patients receiving ondansetron compared with dolasetron, despite its comparably high acidity, may be attributable to its slower rate of administration, as recommended by the manufacturers [37].

	USE OF 5-HT3-RECEPTOR ANTAGONISTS IN SPECIAL PATIENT GROUPS

Top Learning Objectives Abstract Introduction Pharmacotherapy for Nausea and... Safety and Tolerability of... Use of 5-HT3-Receptor... Risk of Drug Interactions... Conclusions General References References

 
Extrapolation of tolerability data from the "controlled" clinical trial setting to clinical practice is hampered by the frequent exclusion from studies of patients with comorbid diseases. For example, a comparative study of three 5-HT₃-receptor antagonists excluded patients with any concomitant severe illness other than cancer [38]. However, estimates suggest that a significant number of patients receive multiple medications [39] and that patients receive on average five or more medications for symptom relief [40]. It has also been estimated that there is a 5% probability of a drug interaction in patients receiving six medications, which rises dramatically (40%) with 15 or more medications [41]. Other comparative studies of 5-HT₃-receptor antagonists excluded patients with clinically significant cardiac, hepatic, or renal disease [14, 42]. Thus, study populations are often not representative of everyday clinical practice, and the effects of drugs in the excluded patient populations also need to be established.

The side-effect profile of any supportive care therapy is particularly important in certain subgroups of patients. Patients with cancer are often elderly with other comorbid diseases for which they frequently receive multiple treatments. Pertinent considerations include the presence of hepatic or renal dysfunction, preexisting cardiovascular disease or diabetes (which increases cardiovascular risk), and whether the patient is receiving any other drugs that have the potential for interaction with 5-HT₃-receptor antagonists. Other patient characteristics, including weight and gender, may also affect the tolerability of treatment. Thus, consideration of a patient’s unique risk-factor profile is appropriate when prescribing antiemetic prophylaxis with all agents, including the 5-HT₃-receptor antagonists.

Patients with Cardiovascular Disease
Cardiac disease in patients with cancer can be a preexisting comorbid condition, can develop during cytotoxic treatment with cardiotoxic regimens, or occasionally, can result from the malignancy itself. It is, therefore, important that the cardiotoxic propensity of agents for supportive care, such as the 5-HT₃-receptor antagonists, is also considered. Furthermore, the greater anxiety that cancer patients face as a result of their condition may have deleterious effects on the cardiovascular system in persons with, or predisposed to have, cardiovascular disease [43].

Comorbidity with Cancer
Many patients with cancer are older and have other comorbid conditions. Cardiovascular disease is a major cause of comorbidity and mortality in older patients with cancer [44]. The aging of the cardiovascular system is reflected by a number of morphologic changes, including thickening of blood vessel walls, atherosclerotic plaque formation, loss of elastin fibers, and increasing fibrosis and cross-linkage of collagen [44]. Impaired calcium handling and decreased energy turnover prolong relaxation of the heart muscle. The reserve blood supply to the heart and the blood oxygen content also tend to decrease with age. Because of these anatomical and functional changes, the older heart is less able to respond adequately to even minor stress. Such changes can result in increased blood pressure, which in turn can cause enlargement of the left ventricle. The thickened heart muscle requires more oxygen and leads to ischemic heart disease, which predisposes to cardiac arrhythmias.

Patients who smoke not only have a higher incidence of certain cancers, but also are more likely to have ischemic heart disease, which is associated with underlying cardiac rhythm abnormalities. These patients are also more likely to be receiving drugs for bronchitis, which may have the potential for interaction with 5-HT₃-receptor antagonists (see later).

Cytotoxic Treatment for Cancer
A number of drugs used in cancer chemotherapy have negative effects on cardiac function. Anthracycline-mediated cardiotoxicity is cumulative and causes cardiomyopathy, pericarditis, myocarditis, arrhythmia, ECG changes, and myocardial ischemia and infarction. In particular, patients who have received cumulative high-dose anthracyclines may be predisposed to the cardiac side effects of drugs. For example, in a study of 469 patients with metastatic breast cancer treated with epirubicin, 34 (7.2%) developed congestive heart failure [45].

Patients receiving mitoxantrone may experience acute and delayed adverse cardiac effects, particularly if they have previously been exposed to anthracyclines or mediastinal irradiation or have underlying cardiovascular disease [46]. The overall incidence of mitoxantrone-associated cardiac effects is estimated to be 3% in adults and 6% in children, with an estimated worst-case incidence of congestive heart failure being 1.3% [47, 48] compared with 2.2% for doxorubicin [47].

The taxane, paclitaxel, also has been reported to cause disturbances in cardiac rhythm, most commonly inducing a transient asymptomatic bradycardia that was noted in 29% of patients in one trial [49]. Whether there is a direct causal relation between paclitaxel and ventricular and atrial tachycardia, or between paclitaxel and ischemic events, is uncertain [50].

Among the other chemotherapeutic agents reported to have negative cardiovascular effects are fluorouracil, high-dose cyclophosphamide, arsenic trioxide, and interleukin-2 (IL-2). Fluorouracil administration has been associated with angina and myocardial ischemia, and ventricular arrhythmias due to coronary spasm occur in up to 1% of all treated patients [51–53]. Cyclophosphamide, at doses greater than 120 mg/kg, can cause fatal hemorrhagic myocardial necrosis [51] and has been associated with a dose-dependent decrease in ECG voltage and an increase in left ventricular mass [54]. Arsenic trioxide, which was recently approved for the treatment of acute promyelocytic leukemia, has been reported to induce various cardiotoxic effects, including prolongation of the QT interval and ventricular arrhythmias [55]. In patients receiving IL-2, 1%-4% experience supraventricular and ventricular arrhythmias, myocarditis, ischemia, and myocardial infarction [56].

Radiotherapy is also associated with cardiotoxic effects caused by damage to pericardial tissues, the myocardium, and coronary arteries and valves during treatment [57]. In particular, radiotherapy given to patients with lymphomas or thoracic tumors, such as esophageal, lung, or breast cancer, may cause damage to the heart [57]. Cardiac rhythm abnormalities following radiotherapy are thought to be due to ischemic fibrosis affecting the conduction system [57].

Patients with Renal Impairment/Electrolyte Disturbances
Most patients receiving cancer chemotherapy are elderly; in the U.S., 61% of people diagnosed with cancer are aged 65 years or older [58]. Furthermore, the incidence of cancer is likely to increase significantly in coming decades with the predicted increase in growth of the aging population. Renal function may be impaired as a result of aging, hypertension, or ischemic heart disease. Many elderly patients also receive diuretics as part of an antihypertensive regimen. Diuretics can alter serum concentrations of electrolytes and may predispose patients to arrhythmias. Low levels of potassium and magnesium increase the risk of prolonging the QT_c interval, consequently increasing the risk of sudden death. Furthermore, abnormal electrolyte levels are not uncommon in patients with cancer. For example, patients with small cell lung cancer may have hypercalcemia and/or hyponatremia. Chemotherapy-induced vomiting may cause electrolyte imbalance, and cisplatin may induce electrolyte disturbances [59]. Cisplatin is often given with fluids and a diuretic (mannitol), which can affect electrolyte levels. Thus, it is important to know whether the clearance, efficacy, or safety of antiemetic agents is affected in patients with renal impairment.

Dolasetron
Following intravenous administration, the apparent clearance of hydrodolasetron is decreased by 47% in patients with severe renal impairment [18]. Similarly, the apparent oral clearance of hydrodolasetron decreased 44% with severe renal impairment [18]. In a study of patients with renal impairment, though some significant differences in pharmacokinetic parameters were observed following intravenous dolasetron administration (including increases in maximum serum concentrations, area under the concentration-time curve, and half-life, and decreases in renal and total apparent clearance of hydrodolasetron), no systematic findings were related to the degree of renal dysfunction [60]. No dose adjustment is considered necessary in patients with renal impairment [18].

Granisetron
Total clearance of granisetron was not affected in patients with severe renal failure (creatinine clearance <30 ml/minute/ 1.73 m²) who received a single injection of granisetron, 40 µg/kg, [20, 61]. No adjustment of dose is therefore needed in this patient population [20].

Ondansetron
In patients with severe renal impairment (creatinine clearance <30 ml/minute), ondansetron plasma clearance was reduced by 41% (95% confidence interval 20%-57%). As this reduction in clearance was variable and was not consistent with an increase in half-life, no reduction in dose or dosing frequency is considered necessary [19].

Patients with Hepatic Impairment
The incidence of hepatic dysfunction also increases with age and in the presence of liver metastases. The clearance, and hence safety, of antiemetic agents metabolized by this route may, therefore, be affected in patients with hepatic impairment.

Dolasetron
Following intravenous administration, the apparent clearance of hydrodolasetron remains unchanged with severe hepatic impairment [18]. Although the apparent oral clearance of hydrodolasetron decreased by 42% in patients with severe hepatic impairment, no dose adjustment is considered necessary.

Granisetron
In patients with hepatic impairment due to neoplastic liver involvement (alkaline phosphatase or -glutamyl transferase levels 1.5 times the upper limit of normal), total clearance was approximately halved following administration of granisetron, 40 µg/kg, compared with patients with normal hepatic function. However, given the wide variability in pharmacokinetic parameters noted in patients and the good tolerance of doses well above the recommended 10 µg/kg dose, dose adjustment in patients with possible hepatic impairment is not necessary [20].

Ondansetron
In patients with mild-to-moderate hepatic impairment, ondansetron clearance was lower by twofold and the mean half-life was greater at 11.6 hours compared with 5.7 hours in normal individuals. In patients with severe hepatic impairment (Child-Pugh score of 10), clearance was lower by two- to threefold and the apparent volume of distribution was greater, with a resultant greater half-life of 20 hours and bioavailability approaching 100%. Dose adjustment is, therefore, necessary, and a total daily dose of 8 mg in such patients should not be exceeded [19, 62].

Elderly Patients
Although elderly patients (usually defined as age >65 years) generally tolerate chemotherapy better than younger patients, they have reduced physiologic functioning and often receive less aggressive treatment. In addition, elderly patients are more likely to be receiving other drugs to treat comorbid conditions and are at a greater risk of CNS effects in general. This population is, therefore, likely to be particularly susceptible to the CNS side effects of any administered therapy.

Elderly patients are also more likely to be receiving diuretics and other antihypertensive and heart failure medications than younger patients. Diuretics can disrupt the electrolyte balance, thus increasing the risk of arrhythmias, particularly in patients receiving dolasetron. Antidepressant drugs, such as imipramine and the newer selective serotonin reuptake inhibitors (SSRIs), and antipsychotic drugs, such as chlorpromazine, are also commonly used in elderly patients with cancer; these drugs can cause QT_c prolongation and should only be used with caution in patients receiving dolasetron. In addition, gastrointestinal medications, anti-arthritics, and bronchitis mediations are more commonly used in the elderly.

Dolasetron
Clearance of hydrodolasetron following oral or intravenous dolasetron administration was not affected by age, and no adjustment in dosing is necessary in elderly patients [18].

Granisetron
The ranges of pharmacokinetic parameters in elderly volunteers (mean age 71 years) given granisetron, 40 µg/kg i.v., were generally similar to those in younger healthy volunteers. Mean values were lower for clearance and longer for half-life in the elderly [20]. No dosing adjustment is necessary in elderly patients.

Ondansetron
Lower clearance and a greater elimination half-life of ondansetron are seen in patients aged over 75 years. In clinical trials with patients with cancer, safety and efficacy were similar in patients aged over 65 years and in younger patients. No dose adjustment is considered necessary in elderly patients [19].

Pediatric Patients
Control of chemotherapy-induced emesis in children is particularly problematic because conventional antiemetics, such as chlorpromazine, metoclopramide, and prochlorperazine, are either ineffective or associated with significant side effects, such as extrapyramidal symptoms, akathisia, and somnolence [63–65]. In comparative trials of antiemetic drugs in children receiving chemotherapy, 5-HT₃-receptor antagonists have shown better efficacy and tolerability than older agents [66]. It has been suggested that the combination of a 5-HT₃-receptor antagonist plus dexamethasone should be the standard antiemetic prophylaxis in all pediatric patients receiving highly or moderately emetogenic chemotherapy [1, 67].

Dolasetron
Four open-label, noncomparative pharmacokinetic studies with dolasetron have been performed in a total of 108 pediatric patients receiving emetogenic chemotherapy or undergoing surgery with general anesthesia [18]. Although mean apparent clearance of orally administered dolasetron is 34% greater and half-life is 21% shorter than in healthy adults given the same dose [18], overall, dolasetron was well tolerated in pediatric patients. Antiemetic efficacy following cancer chemotherapy was similar to that observed in adult patients.

Granisetron
Several studies have shown granisetron to be an effective and well-tolerated antiemetic in children receiving chemotherapy [61, 68–70]. No dose-related toxicity was evident, and no extrapyramidal symptoms were reported. Fever and headache were the most common adverse events [61, 69]. Similarly, granisetron was well tolerated with no evidence of alterations in vital signs or laboratory findings in an open-label study of 40 patients given highly or moderately emetogenic chemotherapy [70].

In a single-blind, randomized study, the antiemetic efficacy of granisetron, 20-60 µg/kg/day i.v., was greater than that of chlorpromazine, 0.3-0.5 mg/kg every 4-6 hours, plus dexamethasone, 2 mg/m² every 8 hours, in 88 children aged 2-16 years [71, 72]. Significantly fewer children had sedation with granisetron (2 versus 19, p < 0.001), and two patients experienced extrapyramidal effects after chlorpromazine and dexamethasone compared with none on granisetron [72].

A pharmacokinetic study in pediatric patients showed that granisetron’s volume of distribution and total clearance were greater with greater patient age. No relationship with age was observed for peak plasma concentration or terminal phase plasma half-life. When volume of distribution and total clearance were adjusted for body weight, the pharmacokinetics of granisetron were similar in pediatric and adult cancer patients [20].

Ondansetron
In a study of 21 pediatric patients aged 3-12 years undergoing surgery, mean weight-normalized clearance and volume of distribution values of ondansetron were similar to those previously reported for young adults. Mean terminal half-life was slightly lower in pediatric patients (range 2.5-3 hours) compared with adults (range 3-3.5 hours) [19].

In a prospective randomized study, ondansetron was shown to provide better antiemetic cover than metoclopramide/diphenhydramine in children treated with antineoplastic chemotherapy [73]. In addition, side effects were noted in nine courses of metoclopramide/diphenhydramine compared with three courses of ondansetron.

Prevention of emesis in 209 pediatric patients in four open-label, noncomparative trials (58% complete response) was similar to that in patients older than 18 years of age and, overall, ondansetron was well tolerated [19].

	RISK OF DRUG INTERACTIONS WITH THE 5-HT3-RECEPTOR ANTAGONISTS

Top Learning Objectives Abstract Introduction Pharmacotherapy for Nausea and... Safety and Tolerability of... Use of 5-HT3-Receptor... Risk of Drug Interactions... Conclusions General References References

 
Combination therapy with several chemotherapeutic agents is common in the treatment of patients with cancer. Furthermore, many of these patients—particularly the elderly—are likely to be receiving other drugs for comorbid conditions. Commonly prescribed drugs in this patient population include cardiovascular and gastrointestinal agents, as well as antidepressants, pain modulators, and medications for arthritis, bronchitis and diabetes. Dolasetron, granisetron, and ondansetron are all metabolized, at least in part, by the cytochrome P450 (CYP) system—a group of enzymes predominantly located in hepatocytes [74]. Approximately 53% of medications are metabolized by the cytochrome monoxygenase enzyme CYP3A4, 25% by CYP2D6 [75], and 10%-15% by CYP1A2 [76]. These three enzyme systems account for almost all hepatic drug interactions. Finally, it should be noted that the risk for drug interaction is substantially greater when patients take 15 or more concomitant medications [41].

Dolasetron
Dolasetron is rapidly converted to hydrodolasetron, which is then metabolized primarily by cytochrome P4502D6 and the 3A subfamily [18, 77]. Concomitant administration of dolasetron with cimetidine (a nonselective inhibitor of cytochrome P450) for 7 days has been found to increase blood levels of hydrodolasetron by 24% [18]. Conversely, blood levels of hydrodolasetron decreased by 28% when dolasetron was coadministered with rifampin (a potent inducer of cytochrome P450) [18]. When dolasetron was administered intravenously concomitantly with atenolol, clearance of hydrodolasetron decreased by 27% [18].

Genetic variants of CYP2D6 exist, with a proportion of the population being either poor metabolizers or ultrarapid metabolizers [40]. Poor metabolizers may experience a prolonged effect of drugs metabolized by CYP2D6 as well as adverse drug reactions when standard doses of such drugs are taken together [40]. The combination of this genetic polymorphism with numerous concomitant medications may lead to potentially life-threatening consequences, and thus, extreme caution must be exercised in patients with known mutations of the CYP2D6 enzyme.

Granisetron
Granisetron is metabolized primarily by the cytochrome P450 3A subfamily, as demonstrated by inhibition of granisetron metabolism by ketoconazole in in vitro liver microsomal studies [20]. The predominant form of this enzyme subfamily is 3A4 [78], and, unlike CYP2D6, polymorphisms of the CYP3A subfamily have not been demonstrated [40]. Granisetron does not induce or inhibit the cytochrome P450 drug-metabolizing system [20]. Although no definitive drug-drug interaction studies have been performed to examine pharmacokinetic or pharmacodynamic interaction with other drugs, intravenous granisetron has been safely administered with drugs including the benzodiazepines, neuroleptics, and antiulcer medications commonly prescribed with antiemetic treatments and with emetogenic cancer chemotherapies [20]. However, inducers or inhibitors of cytochrome P450 3A enzymes may alter the clearance and, hence, the half-life of granisetron.

Ondansetron
Ondansetron is metabolized by several cytochrome P450 enzymes, primarily 1A2, 2D6, and 3A4, but does not induce or inhibit the cytochrome P450 drug-metabolizing system [19, 79]. Because of its relatively extensive cytochrome P450 metabolism, which includes the major pathways mediated by 3A4 and 2D6, inducers or inhibitors of these enzymes may alter the clearance and, hence, the half-life of ondansetron. Indeed, rifampicin has been shown to reduce considerably the plasma concentration of both oral and intravenous ondansetron, an effect that the authors attributed to the induction of CYP3A4-mediated metabolism by rifampin [80]. Additionally, ondansetron has been identified to cause a significant reduction in systemic exposure of both cyclophosphamide [81, 82] and cisplatin [82].

	CONCLUSIONS

Top Learning Objectives Abstract Introduction Pharmacotherapy for Nausea and... Safety and Tolerability of... Use of 5-HT3-Receptor... Risk of Drug Interactions... Conclusions General References References

 
Clinical experience with the 5-HT₃-receptor antagonists has demonstrated their superior efficacy, safety, and tolerability over conventional antiemetics. These drugs, either administered alone or in combination with steroids, are now recommended as the agents of choice in the prophylaxis of nausea and vomiting in many patients receiving cytotoxic therapy [1–3].

The safety profile of any administered therapy is particularly important in cancer patients. Not only are these patients frequently receiving multiple treatments to treat comorbid conditions, they are also less able to tolerate any further reduction in their quality of life and are more susceptible to adverse events. At equipotent doses, the 5-HT₃-receptor antagonists are considered to have comparable efficacy. In addition to cost considerations, treatment choice should depend largely on such factors as the drug’s safety profile, convenience of dosing, and the specific needs of the patient population in which it is to be used. It should also be noted that many emerging considerations related to true clinical experience, for example, comorbid conditions or organ impairment, are not adequately addressed within clinical trials due to exclusion criteria.

Despite their good tolerability, differences exist in the side-effect profiles of the 5-HT₃-receptor antagonists. Dolasetron is associated with more cardiovascular effects than granisetron and ondansetron, and should, therefore, be used with caution, if at all, in patients who have or may develop prolongation of cardiac conduction intervals. Ondansetron appears to be associated with a greater incidence and severity of certain CNS side effects compared with other 5-HT₃-receptor antagonists, and the dose needs to be reduced in patients with hepatic impairment due to altered pharmacokinetic parameters; the potential risk for drug interaction in these patients may be more likely. Such differences should form important considerations when antiemetic prescribing decisions are made. Indeed, superior tolerability leads to enhanced patient compliance with treatment that, in turn, may be expected to result in improved patient outcomes.

	ACKNOWLEDGMENT

Top Learning Objectives Abstract Introduction Pharmacotherapy for Nausea and... Safety and Tolerability of... Use of 5-HT3-Receptor... Risk of Drug Interactions... Conclusions General References References

 
Support of this manuscript was provided by Hoffman-La Roche. S.G. has received honoraria and is a consultant for Roche, and has received honoraria from GlaxoSmithKline. Both S.G. and R.C. have received honoraria from Merck.

	GENERAL REFERENCES

Top Learning Objectives Abstract Introduction Pharmacotherapy for Nausea and... Safety and Tolerability of... Use of 5-HT3-Receptor... Risk of Drug Interactions... Conclusions General References References

 
The following references provide the reader with good background information:

ASHP therapeutic guidelines on the pharmacologic management of nausea and vomiting in adult and pediatric patients receiving chemotherapy or radiation therapy or undergoing surgery. Am J Health Syst Pharm 1999;56:729–764.[Free Full Text]

Blower PR. Differences in anti-emetic predictability amongst 5-HT₃ receptor antagonist drugs. In: Dubois A, King GL, Livengood DR, eds. Radiation and the GI Tract. Boca Raton, FL: CRC Press Inc, 1995:37-49.

Hesketh PJ. Comparative review of 5-HT₃ receptor antagonists in the treatment of acute chemotherapy-induced nausea and vomiting. Cancer Invest 2000;18:163–173.[Medline]

Wei JY. Cardiovascular comorbidity in the older cancer patient. Semin Oncol 1995;22:9–10.

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