, Volume 5, Issue 2, pp 123-136
Date: 09 Aug 2012

Metopimazine

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Summary

Abstract

Metopimazine (Vogalene®) is a dopamine D2receptor antagonist that has been used in France for many years for the prevention and treatment of nausea and vomiting. Guidelines suggest a role for dopamine receptor antagonists in the prevention of delayed chemotherapy-induced nausea and vomiting (CINV) following moderately emetogenic chemotherapy and as add-on therapy in refractory cases; recent data on sublingual metopimazine suggest it may have a role as an alternative to ondansetron in the prevention of delayed CINV in patients receiving moderately to highly emetogenic non-cisplatin-based chemotherapy. Trials comparing metopimazine with other drugs used in the prevention of delayed CINV would be of interest. Data also support the use of metopimazine as add-on therapy in the treatment of acute emesis in patients receiving moderately emetogenic chemotherapy who are refractory to initial therapy or unable to take corticosteroids, roles which are also suggested for dopamine receptor antagonists in guidelines, as is their potential use in rescue therapy for patients with breakthrough symptoms.

Pharmacologic Properties

Metopimazine is a phenothiazine derivative with anti-dopaminergic activity. It has a high affinity for dopamine D2receptors (and also α1-adrenoceptors and histamine H1receptors) but no affinity for serotonin 5-HT3receptors. It exerts its antiemetic effects via the chemoreceptor trigger zone. Although metopimazine itself can cross the blood-brain barrier, its acid metabolite, which is the predominant circulating form of the drug, crosses to a very limited extent, and extrapyramidal effects and effects on prolactin are uncommon. Metopimazine can occasionally be associated with orthostatic hypotension, which probably relates to its affinity for the α1-adrenoceptor.

Peak serum concentrations are reached within 60 minutes after fasting oral administration (≈20 minutes for sublingual tablets). The bioavailability of oral metopimazine is 19–34%. Oral absorption is reduced by food. Metopimazine is rapidly metabolized to its active acid metabolite, which constitutes approximately 78–89% of the circulating drug. Approximately 30% of a dose is recovered in the urine (mostly as the acid form), and the elimination half-life of the parent drug is approximately 4.5 hours.

Therapeutic Efficacy

Metopimazine has been evaluated for the prevention of acute or delayed CINV in adults in several randomized, controlled trials, some of which were performed a number of years ago and used treatment regimens that differ from current recommendations. In the earliest studies (performed in the 1970s and using different endpoints to later trials), the overall (and possibly acute) efficacy of oral metopimazine in the reduction of severity of CINV was superior to that of placebo in patients receiving low to highly emetogenic non-cisplatin-based chemotherapy, and similar to that of prochlorperazine in patients receiving fluorouracil.

Results from trials performed since 1997 (which each evaluated similar endpoints) indicated that the addition of intravenous metopimazine to ondansetron plus methylprednisolone significantly increased antiemetic efficacy in the acute phase compared to ondansetron plus methylprednisolone in patients receiving cisplatin who were refractory to the dual therapy (87% vs 75% of patients experienced no acute emesis); also that intravenous metopimazine plus ondansetron was significantly more effective than ondansetron alone at preventing acute emesis in patients receiving highly emetogenic (cisplatin-based) chemotherapy. Oral metopimazine combined with prednisolone was significantly less effective than intravenous granisetron in the acute setting (comparison of all response categories), but more effective than granisetron (both in terms of overall response categories and complete response rate) in the prevention of delayed CINV in patients receiving moderately emetogenic chemotherapy.

Based on two recent studies specifically designed to evaluate efficacy in the prevention of delayed emesis, sublingual metopimazine was as effective as ondansetron when administered as monotherapy, and at least as effective when both drugs were coadministered with methylprednisolone, in patients receiving moderately to highly emetogenic (generally non-cisplatin-based) chemotherapy. The percentages of patients who experienced no delayed emesis (and ≤1 episode of nausea) when treated with metopimazine or metopimazine plus methylprednisolone were 53% and 74% compared with 50% and 58% for recipients of ondansetron or ondansetron plus methylprednisolone. Additional supportive data for the effectiveness of metopimazine in combination with other antiemetic agents (particularly ondansetron) for the prevention of delayed nausea and vomiting are available from studies that were not specifically designed to examine delayed emesis.

Tolerability

Metopimazine is generally well tolerated. In CINV trials, the overall incidence of adverse events with metopimazine monotherapy was similar to that seen with placebo and with ondansetron; however, metopimazine was associated with significantly fewer gastrointestinal adverse events than ondansetron.

The most common adverse events reported with sublingual metopimazine monotherapy in a large clinical trial in CINV included constipation, diarrhea, abdominal pain, headache, and asthenia (and also alopecia and mucositis, which were most probably related to the chemotherapy patients had received).

Based on a summary of periodic safety update reports, the adverse events most frequently reported with metopimazine (all formulations; cancer and non-cancer indications) include somnolence, heartburn, dry mouth, diarrhea, constipation, vertigo, tachycardia, dysuria, headache, and pruritus. Metopimazine can be associated with orthostatic hypotension at high dosages. Extrapyramidal symptoms, including dyskinesias, are very uncommon.

Various sections of the manuscript reviewed by: E. Ballatori, Department of Internal Medicine and Public Health, University of L’Aquila, L’Aquila, Italy; M. Di Palma, Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France; L. Dupuis, Department of Pharmacy, The Hospital for Sick Children, Toronto, Ontario, Canada; J. Herrstedt, Department of Oncology, Copenhagen University Hospital Herlev, Herlev, Denmark; K. Jordan, Klinik füur Innere Medizin IV, Universitätsklinik Halle/Wittenberg, Halle, Germany; J.-E. Kurtz, Département d’Hématologie et d’Oncologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; H. Link, Medizinische Klinik I, Westpfalz-Klinikum, Kaiserslautern, Germany; I. Olver, Department of Cancer Care, University of Adelaide, Adelaide, South Australia, Australia; P.J. Souquet, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Benite Cedex, France; G. Tonini, Oncology Department, Campus Bio-Medico University, Rome, Italy; S. Van Belle, Department of Medical Oncology, University Hospital Ghent, Ghent, Belgium.

Data Selection

Sources: Medical literature published in any language since 1980 on ‘metopimazine’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: MEDLINE search terms were ‘metopimazine’ and (‘chemotherapy-induced’ or ‘nausea’ or ‘vomiting’ or ‘antiemetics’). EMBASE search terms were ‘metopimazine’ and (‘chemotherapy-induced’ or ‘nausea’ or ‘vomiting’ or ‘antiemetic’). AdisBase search terms were ‘metopimazine’ and (‘chemotherapy-induced’ or ‘nausea’ or ‘vomiting’ or ‘antiemetics’ or ‘antiemesis’). Searches were last updated 27 March 2006.
Selection: Studies in patients treated with emetogenic cancer chemotherapy who received metopimazine. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: Metopimazine, chemotherapy-induced nausea and vomiting, dopamine receptor antagonist, pharmacodynamics, pharmacokinetics, phenothiazines, therapeutic use.