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Granisetron

An Update of its Therapeutic Use in Nausea and Vomiting Induced by Antineoplastic Therapy

Drugs volume 48, pages 761–793 (1994)Cite this article

Abstract

Synopsis

Granisetron is a selective serotonin3 (5-hydroxytryptamine3, 5-HT3) receptor antagonist which has significant antiemetic activity against chemotherapy-induced nausea and vomiting. A single prophylactic intravenous dose is sufficient to control acute nausea and vomiting in approximately 60 to 70% of patients. In comparative studies, the acute antiemetic efficacy of granisetron is equivalent or superior to that of traditional antiemetic regimens even in patients receiving highly emetogenic cisplatin-containing chemotherapy. However, limited data have suggested that granisetron therapy offers no advantages over traditional antiemetics in terms of the control of delayed emesis. Recently, a number of large randomised studies have directly compared the efficacy and tolerability of granisetron, ondansetron and tropisetron and reported no significant differences between the 3 drugs in controlling acute nausea and vomiting, although 1 study reported a modest statistical advantage for granisetron over ondansetron but not tropisetron in the complete control of vomiting. In crossover studies, significantly more patients preferred granisetron to either ondansetron or tropisetron.

The efficacy of granisetron appears to be maintained with repeated doses over several cycles of chemotherapy, although the influence of various prognostic factors affecting antiemetic response has not been adequately analysed. Concomitant administration of dexamethasone significantly improves the acute antiemetic efficacy of granisetron, increasing response rates by approximately 15%.

Granisetron is an effective antiemetic in children undergoing highly emetogenic chemotherapy, and effectively controls radiotherapy-induced and postoperative nausea and vomiting. Trials using an oral formulation are scarce at present, but preliminary results suggest a similar efficacy and tolerability profile to that of the intravenous formulation.

Granisetron has been well tolerated in clinical trials. The most frequently reported adverse event has been headache (14%). Extrapyramidal effects, which can limit the use of traditional antiemetics such as metoclopramide, have not been reported with granisetron.

Thus, recent data confirm that granisetron is an effective and well tolerated agent for the prophylactic treatment of chemotherapy-induced acute nausea and vomiting, with efficacy equivalent or superior to that of other currently available agents. It has a promising role to play in paediatric oncology, and is an effective agent in controlling radiotherapy-induced acute emesis. Granisetron offers comparable or superior efficacy in controlling acute nausea and vomiting with a much simpler dosage regimen than that of traditional antiemetic regimens.

Pharmacological Properties

Granisetron is an antiemetic and antinauseant agent which exerts its activity via selective antagonism of serotonin3 (5-hydroxytryptamine3, 5-HT3) receptors, both peripherally and centrally. It has no significant affinity for 5-HT1A-D, 5-HT2, 5-HT4, dopamine D1 or D2, histamine H1, benzodiazepine, picrotoxin, or α1-, α2-or β-adrenergic receptor binding sites. Antiemetic studies in animals, primarily in the ferret, have shown that prophylactic parenteral or oral administration of granisetron reduced, or completely abolished, nausea and vomiting induced by highly or moderately emetogenic antineoplastic therapy, including regimens containing high-dose cisplatin. Granisetron probably exerts its effects on acute emesis (i.e. episodes occurring within 24 hours of cytotoxic therapy) by acting at both peripheral and central sites. Peripherally it probably blocks serotonin-evoked stimulation of vagal afferent nerves from the gastrointestinal tract; centrally it probably blocks stimulation of 5-HT3 receptors in the chemoreceptor trigger zone and the nucleus of the tractus solitarius of the brain stem, both of which activate the vomiting reflex.

There have been reports that the pharmacodynamic profile of granisetron differs from that of ondansetron and tropisetron, with superior selectivity of granisetron for 5-HT3 receptors and a greater affinity of 5-HT3 receptors for granisetron in in vitro studies. However, data are conflicting and the clinical relevance of these differences is debatable.

The pharmacokinetic profile of granisetron has been determined in healthy volunteers for intravenous doses between 20 and 300 μg/kg. Granisetron has a large volume of distribution, approximately 200L in healthy human volunteers. Peak plasma concentrations and the area under the plasma concentration-time curve (AUC) increase proportionately with dose, whereas plasma elimination half-life (t1/2β) and total plasma clearance remain essentially unchanged, indicating linear kinetics over this dose range. In healthy volunteers, t1/2β is approximately 3 to 4 hours, and the total clearance rate is between 33 and 51 L/h (for a 70kg person). Clearance of granisetron occurs primarily by hepatic metabolism; less than 20% of the dose is excreted unchanged in urine. Preliminary data on an oral formulation of granisetron have suggested a similar pharmacokinetic profile. There are several notable differences in the pharmacokinetics of intravenous granisetron in cancer patients, the reasons for which are unclear. The elimination half-life is prolonged, to between 9 and 12 hours, and total body clearance is reduced by approximately half, resulting in an increase in AUC relative to that in healthy volunteers.

Therapeutic Use

The majority of clinical trials with intravenous granisetron have assessed the efficacy of a single prophylactic dose of 40 μg/kg infused over 5 or 30 minutes in controlling acute nausea and vomiting induced by cancer chemotherapy. This dose had previously been shown to be the optimal antiemetic dose to control acute symptoms, with complete response rates (no vomiting and no more than mild nausea) in the region of 60 to 70%. However, a recent randomised, double-blind study in patients receiving highly or moderately emetogenic chemotherapy has shown that efficacy is not significantly reduced at a dose of 10 μg/kg.

Comparative studies with traditional antiemetic regimens have shown that granisetron had acute antiemetic efficacy equivalent or superior to combinations of dexamethasone plus either high-dose metoclopramide (with or without diphenhydramine), chlorpromazine, prochlorperazine, or alizapride, or high-dose methylprednisolone monotherapy. Complete response rates for granisetron were approximately 70 and 50% in patients receiving standard and fractionated chemotherapy regimens, respectively. In studies where nausea and vomiting were measured over 5 or 7 days after chemotherapy, there was no difference in delayed emesis between patients receiving granisetron and those receiving combination therapy with traditional antiemetic agents.

Several large randomised, comparative studies have compared granisetron (3mg single dose, equivalent to 40 μg/kg in a 75kg person) with 2 other 5-HT3 antagonists, ondansetron (8 or 32mg single dose, or 8mg prophylactically then 8mg every 8 hours) and tropisetron (5mg single dose). No significant differences were reported between the 3 agents in the control of acute nausea and vomiting, except in the complete control of acute vomiting in 1 study, where granisetron had a modest statistical advantage over ondansetron but not tropisetron. However, in crossover studies, significantly more patients preferred granisetron to either ondansetron or tropisetron.

The efficacy of granisetron does not appear to be reduced by repeated use in patients receiving multiple cycles of highly or moderately emetogenic chemotherapy. In nonblind, noncomparative trials, response rates were maintained for between 4 and 8 cycles, although analysis of prognostic factors influencing the response to antiemetic therapy was limited.

Several randomised studies have compared the acute antiemetic efficacy of granisetron alone and in combination with dexamethasone. In all studies the concomitant administration of dexamethasone significantly increased the complete response rate, by approximately 15%.

In children, doses of granisetron similar to those used in adults are effective in controlling acute nausea and vomiting induced by moderately or highly emetogenic chemotherapy, and granisetron was more effective than dexamethasone plus either chlorpromazine or metoclopramide, eliciting response rates approximately double those achieved with combinations of the traditional agents.

Clinical data on an oral formulation of granisetron are limited at present. However, preliminary dose-finding studies have suggested that the optimal antiemetic oral dose of granisetron was 2mg, given either as a single dose or as 2 equal doses. Limited noncomparative data have rated oral granisetron 2 mg/day as ‘effective’ or better in approximately 86% of patients receiving highly or moderately emetogenic chemotherapy, and oral granisetron was significantly more effective than placebo in controlling both acute and delayed nausea and vomiting.

Data are scarce regarding the use of granisetron in patients receiving radiotherapy, but results to date are similar to those reported for chemotherapy-induced emesis, and in agreement with results using other 5-HT3 antagonists. Furthermore, data from randomised, placebo-controlled studies have shown that granisetron was significantly superior to placebo and to metoclopramide in controlling postoperative nausea and vomiting.

Tolerability

Granisetron appears to be well tolerated in clinical trials. Headache is the most frequently reported adverse event, occurring in about 14% of patients. Other less common adverse events associated with granisetron administration include constipation, diarrhoea, asthenia and somnolence. However, compared with traditional antiemetic combinations, only headache was reported more frequently with granisetron therapy. There have been no reports to date of extrapyramidal symptoms associated with granisetron therapy.

The use of granisetron in children does not appear to affect its tolerability profile, nor does the use of repeated doses of granisetron over up to 8 cycles of chemotherapy. Oral administration of granisetron does not appear to affect the pattern of adverse events experienced. Comparisons between granisetron, ondansetron and tropisetron have suggested that these drugs have similar tolerability profiles.

Dosage and Administration

Until recently, dose-finding studies had suggested that the optimal antiemetic dose of granisetron was a single prophylactic intravenous infusion of 40 μg/kg or 3mg. This has been the most commonly used dose in clinical trials, infused over 5 or 30 minutes and completed 5 minutes before administration of chemotherapy. Indeed, the manufacturer’s recommended dose is 3mg or 40 μg/kg in most markets. However, recent data have indicated that antiemetic efficacy is not significantly reduced at a dose of 10 μg/kg, and this is currently the manufacturer’s recommended dose in certain markets, infused over 5 minutes and administered within 30 minutes of the commencement of chemotherapy. No dosage adjustments are recommended by the manufacturer for use in children, the elderly or patients with renal or hepatic impairment.

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  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand

    Yvonne E. Yarker & Donna McTavish

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  1. Yvonne E. Yarker
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Various sections of the manuscript reviewed by: M.S. Aapro, FMH Oncologie-Hématologie, Clinique de Genolier SA, Genologie, Switzerland; G.H. Blijham, Department of Internal Medicine, University Hospital, Utrecht, The Netherlands; B. Costall, The School of Pharmacy, University of Bradford, Bradford, England; A. Del Favero, Istituto Medicina Interna e Scienze Oncologiche, Policlinico Monteluce, Perugia, Italy; J.D. Hainsworth, The Sarah Cannon Cancer Center, Nashville, Tennessee, USA; C.R. Lewis, Department of Medical Oncology, Prince of Wales Hospital, Randwick, New South Wales, Australia; I.N. Oliver, Department of Medical Oncology, Royal Adelaide Hospital, Adelaide, South Australia, Australia; H.G. Prentice, Department of Haematology, Royal Free Hospital, London, England; F. Roila, Istituto Medicina Interna e Scienze Oncologiche, Policlinico Monteluce, Perugia, Italy; D. Warr, Department of Medicine, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada.

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Yarker, Y.E., McTavish, D. Granisetron. Drugs 48, 761–793 (1994). https://doi.org/10.2165/00003495-199448050-00008

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Keywords

  • Adis International Limited
  • Ondansetron
  • Granisetron
  • Complete Response Rate
  • Tropisetron